Anzahl der Treffer: 21 Studien
Kurztitel 42756493BLC1003
EudraCT-Nr 2021-004144-22
Titel Phase-1-Prüfung zum intravesikalen Erdafitinib-Verabreichungssystem (TAR-210) bei Patienten mit nicht-muskelinvasivem oder muskelinvasivem Blasenkrebs und ausgewählten FGFR-Mutationen oder -Fusionen
Studiendesign Interventionsstudie , nicht randomisiert , Phase I
Strategie 1st line
Einschlusskriterien
Each potential participant must satisfy all of the following criteria to be enrolled in the study:

AGE

1. = 18 years (or the legal age of consent in the jurisdiction in which the study is taking place) at the time of informed consent.

TYPE OF PARTICIPANT AND DISEASE CHARACTERISTICS

2. Criterion modified per Amendment 2

2.1. Recurrent, non-muscle-invasive or muscle-invasive urothelial carcinoma of the bladder.

a. Mixed histology tumors are allowed if urothelial differentiation is predominant (ie, < 20 % variant histology). However, the presence of micropapillary, signet ring cell, plasmacytoid, neuroendocrine, or sarcomatoid features are exclusionary.

b. High-risk papillary disease (Cohorts 1 [Parts 1 and 2] and 2 [Part 2 only]), defined as histologically confirmed high-grade Ta/T1 lesion. Concurrent CIS is not allowed. All visible tumor must be completely resected prior to the start of study treatment and documented on screening cystoscopy.

c. Intermediate-risk papillary disease (Cohort 3, Parts 1 and 2) defined as all previous tumors being low grade, Ta or T1, and no previous CIS. Cystoscopic documentation of recurrence is sufficient. Negative urine cytology for high grade urothelial carcinoma is required. Visible disease must be present at the time of first TAR-210 insertion.

d. Muscle-invasive disease (Cohort 4, Part 2 only) cT2-T3a, N0. Participants must have a total tumor size = 3 cm after TURBT at cystoscopic assessment within 8 weeks prior to the start of study treatment or must have a second debulking TURBT to reduce the tumor(s) to = 3 cm in order to be eligible.

3. Activating tumor FGFR mutation or fusion, as determined by local* or central testing, approved by the sponsor prior to the start of study treatment:
* Local tissue-based results (if already existing) from next-generation sequencing (NGS) or polymerase chain reaction (PCR) tests performed in CLIA-certified or equivalent laboratories, or results from commercially available PCR or NGS tests.

4. Criterion modified per Amendment 2

4.1. Cohorts 1 and 2: BCG experienced, or participants with no BCG experience because BCG was not available as a treatment option in the participant’s location within the previous 2 years and is currently unavailable. Participants who received an abbreviated course of BCG due to toxicity are still eligible. BCG experienced is defined as:

- Recurrent high-grade Ta/T1 disease within 18 months of completion of prior BCG therapy

- Prior BCG (minimum treatment requirements):
1) At least 5 of 6 full doses of an initial induction course. Full dose BCG defined as 1 full vial containing a minimum of 1 x 10^8 colony forming units.

Note: Cohort 3 has no predefined prior BCG or intravesical chemotherapy requirement.

5. Cohort 1 only: Refuses or is not eligible for RC

6. Cohorts 2 and 4: Willing and eligible for RC

7. Cohort 4: Refuses (and understands the risks and benefits of doing so) cisplatin-based combination chemotherapy or is deemed ineligible for cisplatin-based chemotherapy by meeting at least one of the following criteria:

- Creatinine clearance (CrCl) < 60 mL/min

- NCI-CTCAE v.5.0 Grade = 2 audiometric hearing loss

- NCI-CTCAE v.5.0 Grade = 2 peripheral neuropathy

8. Eastern Cooperative Oncology Group (ECOG) performance status score of = 2 (Cohorts 1 and 3) or = 1 (Cohorts 2 and 4) (see Section 10.9 for ECOG scoring)

9. Adequate bone marrow, liver, and renal function:

a. Bone marrow function (without the support of growth factors or transfusions in preceding 2 weeks):

- Absolute neutrophil count (ANC) = 1,000/mm^3

- Platelet count = 75,000/mm^3

- Hemoglobin = 8.0 g/dL

b. Liver function:

- Total bilirubin = 1.5 x the upper limit of normal (ULN) OR direct bilirubin = 1.5 x ULN for participants with Gilbert’s syndrome who have total bilirubin levels > 1.5 x ULN

- Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) = 2.5 x ULN

c. Renal function:

- Estimated glomerular filtration rate > 30 mL/min calculated using the Modified Diet in Renal Disease (MDRD) formula (see Appendix 11)

SEX AND CONTRACEPTIVE/BARRIER REQUIREMENTS

10. A female participant of childbearing potential must have a negative serum test at screening and a negative urine test (or serum test if required by local regulations) within 72 hours of the first dose (ie, first insertion) of study treatment, and must agree to further serum or urine pregnancy tests during the study.

11. A female participant must be (as defined in Appendix 4: Contraceptive and Barrier Guidance) either of the following:

a. Not of childbearing potential

b. Of childbearing potential and
- practicing true abstinence;
- or have a sole partner who is vasectomized;
- or practicing at least 1 highly effective method of contraception (see Appendix 4: Contraceptive and Barrier Guidance).
Participant must agree to continue the above throughout the study and for 90 days after the last dose of study treatment (ie, 90 days after removal of the last TAR-210 system).

Note: If a woman becomes of childbearing potential after start of the study the woman must comply with point (b.) as described above.

A female participant must also:

- agree to not donate eggs (ova, oocytes) for the purposes of assisted reproduction during the study and for at least 90 days after removal of the last TAR-210 system.

- not be breastfeeding and not planning to become pregnant during the study and for at least 90 days after removal of the last TAR-210 system.

12. A male participant must wear a condom (with or without spermicidal foam/gel/film/cream/suppository) when engaging in any activity that allows for passage of ejaculate to another person during the study and for a minimum of 90 days after removal of the last TAR-210 system. His female partner, if of childbearing potential, must also be practicing a highly effective method of contraception (see Appendix 4: Contraceptive and Barrier Guidance).

A male participant must also agree:

- not to donate sperm for the purpose of reproduction during the study and for a minimum of 90 days after removal of the last TAR-210 system.

- not plan to father a child while enrolled in this study or within 90 days after removal of the last TAR-210 system.

INFORMED CONSENT

13. Must sign an informed consent form (ICF) indicating that the participant understands the purpose of, and procedures required for, the study and is willing to participate in the study.

14. Willing and able to adhere to the lifestyle restrictions specified in this protocol.
Ausschlusskriterien
Any potential participant who meets any of the following criteria will be excluded from participating in the study:

MEDICAL CONDITIONS

1. Concurrent extra-vesical (ie, urethra, ureter, renal pelvis) transitional cell carcinoma of the urothelium.

2. Prior treatment with an FGFR inhibitor.

3. Known hypersensitivity to any study component including:

- Erdafitinib (or other drug excipients) or chemically related drugs,

- TAR-210 device constituent materials,

- UPC materials.

Refer to the TAR-210 IB for complete information on excipients, device constituent materials, and UPC materials.

4. Received pelvic radiotherapy =6 months prior to the planned start of study treatment. If received pelvic radiotherapy > 6 months prior to the start of study treatment, there must be no cystoscopic evidence of radiation cystitis.

5. Presence of any bladder or urethral anatomic feature that in the opinion of the investigator may prevent the safe placement, indwelling use, or removal of TAR-210.

6. Indwelling urinary catheter. Intermittent catheterization is acceptable.

7. Cystoscopic evidence of bladder perforation unless such perforation has resolved prior to dosing.

8. Bladder post-void residual volume (PVR) > 350 mL after second voided urine.

9. History of clinically significant polyuria with recorded 24-hour urine volumes > 4,000 mL.

10 Subjects with active bladder stones or history of bladder stones < 6 months prior to the start of study treatment.

11. Active malignancies (ie, progressing or requiring treatment change in the last 24 months) other than the disease being treated under study. Potential allowed exceptions include the following (othersmay be allowedwith sponsor approval):

a. skin cancer (non-melanoma or melanoma)that is considered completelycured.

b. non-invasive cervical cancer that is considered completely cured.

c. adequatelytreated lobular carcinoma in situ (LCIS) and ductalCIS

d. history of localized breast cancer and receiving antihormonal agents

e. history of localized prostate cancer (N0M0) and receiving androgen deprivationtherapy

f. Localized prostate cancer (N0M0):

- with a Gleasonscore of 6, treatedwithin the last24 months or untreated andundersurveillance,

- with a Gleason score of 3+4 that has been treated more than 6 months prior to full study Screening and considered to have a very low risk of recurrence,

- or history of localized prostate cancer and receiving androgen deprivation therapy and considered to have a very low risk of recurrence.

12. Current central serous retinopathy or retinal pigment epithelial detachment of any grade.

13. History of uncontrolled cardiovascular disease including:

- Any of the following within 3 months prior to the start of study treatment: unstable angina, myocardial infarction, ventricular arrhythmias or clinically significant atrial arrythmias (eg, atrial fibrillation with uncontrolled rate), cardiac arrest, or known congestive New York Heart Association Class III-IV heart failure (Appendix 10), cerebrovascular accident, or transient ischemic attack.

- Pulmonary embolism or other venous thromboembolism within 1 month prior to the planned start of study treatment.

14. Active or chronic hepatitis B or C infection according to the following criteria:

- Seropositive for hepatitis B: defined by a positive test for hepatitis B surface antigen [HBsAg]. Participants with resolved infection (ie, participants who are HbsAg negative with antibodies to total hepatitis B core antigen [anti-HBc] with or without the presence of hepatitis B surface antibody [anti-HBs]) must be screened using real-time polymerase chain reaction (RT-PCR) measurement of hepatitis B virus (HBV) DNA levels. Those who are RT-PCR positive will be excluded. Participants with anti-HBs positivity as the only serologic marker AND a known history of prior HBV vaccination do not need to be tested for HBV DNA by RT-PCR.

- Hepatitis C infection defined by a positive hepatitis C antibody (anti-HCV) test.
Participants who test positive for anti-HCV are eligible if RNA viral load is undetectable (spontaneous recovery or after completing treatment for hepatitis C virus infection).

15. Major surgery within 4 weeks before Day 1 (TURBT is not considered major surgery)

16. Active bacterial, viral, fungal infection, including urinary tract infection*, requiring oral or systemic therapy within 7 days prior to Day 1.

*Urinary tract infection is defined as a symptomatic infection with a positive urine culture with a bacterial count of = 10^5 colony forming units (CFU)/mL in urine voided from women, or > 10^4 CFU/mL in urine voided from men, or in straight-catheter urine from women. Symptoms may include dysuria, urgency, frequency, and/or systemic symptoms such as fever, chills, elevated white blood cell, and/or abdominal/flank pain.
Participants free from symptoms for 7 days with no culture evidence of > 10^5 CFUs may be eligible.

17. Toxicity from prior anticancer therapy has not resolved to baseline levels or to Grade = 1 (except alopecia, vitiligo, peripheral neuropathy, or endocrinopathies that are stable on hormone replacement, which may be Grade 2).

18. Known human immunodeficiency virus (HIV)-positive participants with 1 or more of the following:

- Not receiving highly active antiretroviral therapy (ART)

- Had a change in ART within 6 months of the start of screening

- Receiving ART that may interfere with study treatment (consult the sponsor for review of medication prior to the start of study treatment)

- CD4+ count < 350 at screening

- Acquired immunodeficiency syndrome (AIDS)-defining opportunistic infection within 6 months of start of screening

- Not agreeing to start ART and be on ART > 4 weeks prior to the start of study treatment. Only participants who have HIV viral load < 400 copies/mL at the end of the 4-week period and agree to continue on ART, would be eligible (to ensure ART is tolerated and HIV controlled).

PRIOT/CONCURRENT CLINICAL STUDY EXPERIENCE

19. Received an investigational intervention (including investigational vaccines) or used an invasive investigational medical device within 28 days before the planned start of study treatment or is currently enrolled in an investigational study.

20. Prior anticancer therapy within 4 weeks before the planned start of study treatment.
Exception: a single intravesical chemotherapy treatment immediately after TURBT is allowed.

21. Any condition for which, in the opinion of the investigator, participation would not be in the best interest of the participant (eg, compromise the well-being) or that could prevent, limit, or confound the protocol-specified assessments.

NOTE: Investigators should ensure that all study enrollment criteria have been met at screening.
If a participant’s clinical status changes (including any available laboratory results or receipt of additional medical records) after screening but before the first dose of study treatment is given such that the participant no longer meets all eligibility criteria, then the participant should be excluded from participation in the study. Section 5.4, Screen Failures, describes options for retesting. The required source documentation to support meeting the enrollment criteria are noted in Appendix 3: Regulatory, Ethical, and Study Oversight Considerations.
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Ansprechpartner Email: ectu.cooperation@uniklinik-ulm.de , Tel. 0731 500 56070
Klinik ECTU (Early Clinical Trials Unit)
Kurztitel 75276617ALE1002
EudraCT-Nr 2021-003999-14
Titel Eine Phase-1b-Prüfung zu JNJ-75276617 in Kombination mit Therapien zur Behandlung der akuten myeloischen Leukämie (AML) bei Patienten mit AML mit KMT2A- oder NPM1 VeränderungenEine Phase-1b-Prüfung zu JNJ-75276617 in Kombination mit Therapien zur Behandlung der akuten myeloischen Leukämie
Studiendesign Interventionsstudie , nicht randomisiert , Phase I
Strategie 2nd line , 3rd line
Einschlusskriterien
Each potential participant must satisfy all of the following criteria (except as indicated for specific cohort[s])to be enrolled in the study:

1. = 18 years of age.

2. Criterion modified per Amendment 1

2.1 Criterion modified per Amendment 2

2.2 Diagnosis of acute myeloid leukemia (AML) according to World Health Organization criteria:
- De novo or secondary AML
- Relapsed /refractory (Arm A only) or newly diagnosed AML
- Participants may receive emergency leukapheresis and/or 1 dose of 1-2 g/m^2 cytarabine as cytoreductive therapy according to local practice guidelines prior to first dose of study treatment to control hyperleukocytosis (see Section 6.8.1). If possible, these treatments should not be given until after the screening bone marrow assessment; however, these treatments must be discontinued = 24 hours prior to start of study treatment).
- Harboring KMT2A or NPM1 alterations

3. Updated per Amendment 1

3.1 COHORT B1 ONLY: Must be newly diagnosed and INELIGIBLE for intensive chemotherapy based on the following criteria:
- = 75 years of age or
- = 18 to < 75 years of age with =1 of the following comorbidities:
- Eastern Cooperative Oncology Group (ECOG) performance status of 2 (see Appendix 11.13)
- Cardiac comorbidity NYHA Class I or II
- Severe pulmonary comorbidity (baseline pulmonary disease), defined as documented pulmonary disease with lung diffusing capacity for carbon monoxide = 65 % of expected or forced expiratory volume in 1 second = 65 % of expected Comorbidity that, in the investigator’s opinion, makes the participant unsuitable for intensive chemotherapy, which must be documented and approved by the sponsor before enrollment

4. COHORT C1 ONLY: Must be = 18 to < 75 years of age, newly diagnosed and ELIGIBLE for intensive chemotherapy

5. Criterion modified per Amendment 2

5.1 Pretreatment clinical laboratory values meeting the following criteria -listed below:

HEMATOLOGY
- White blood cell (WBC) count: = 25 x 10^9/L (hydroxyurea may be used to lower WBC count at screening and during study; cytoreductive therapy may be considered with sponsor approval; see Criterion 2.2 and Section 6.8.1)

Chemistry
- Aspartate aminotransferase (AST) and alanine aminotransferase (ALT): = 2.5 x upper limit of normal (ULN)
- Total bilirubin < 1.5 x ULN (participants with elevated bilirubinemia, such as Gilbert’s syndrome, may enroll if conjugated bilirubin is within clinically acceptable range and total bilirubin = 3 x ULN).
- Renal function: Estimated or measured glomerular filtration rate = 40 mL/min/1.73m^2 per MDRD formula (Levey 2006; see Section 11.14)

6. Criterion modified per Amendment 2/EEA-1

6.1 ECOG performance status grade of 0, 1 or 2 (See Appendix 13; Oken 1982). See Appendix 11.18.1 for ECOG requirements for participants in France.

7. A woman of childbearing potential must have a negative highly sensitive serum Beta-human chorionic gonadotropin at screening and within 48 hours prior to the first dose of study
treatment.

8. Criterion modified per Amendment 1

8.1 Criterion modified per Amendment 2

8.2 A woman of childbearing potential must agree to all the following during the study and for 6 months after the last dose of study treatment (see Appendix 5: Contraceptive and
Barrier Guidance):
- Use a barrier method of contraception
- Use a highly effective preferably user-independent method of contraception
- Not to donate eggs (ova, oocytes) or freeze for future use for the purposes of assisted reproduction
- Not plan to become pregnant
- Not to breast-feed

9. Criterion modified per Amendment 2

9.1 A male must agree to all the following during the study and for 3 months after the last dose of study treatment or for 6 months following the last dose of daunorubicin:
- Wear a condom when engaging in any activity that allows for passage of ejaculate to another person.
- Not to donate sperm or freeze for future use for the purpose of reproduction.
- In addition, the participant should be advised of the benefit for a female partner to use a highly effective method of contraception as condom may break or leak.

10. Must sign an informed consent form (ICF) indicating participant understands the purpose of the study and procedures required for the study and is willing to participate in the study. Consent is to be obtained prior to the initiation of any study-related tests or procedures that are not part of standard of care for the participant’s disease.

11. Willing and able to adhere to the prohibitions and restrictions specified in this protocol.
Ausschlusskriterien
Any potential participant who meets any of the following criteria will be excluded from participating in the study:

1. Acute promyelocytic leukemia according to WHO 2016 criteria (Arber 2016).

2. Leukemic involvement of the central nervous system

3. Recipient of solid organ transplant

4. Criterion modified per Amendment 2

4.1 Any prior treatment with a menin-KMT2A inhibitor (exception: participants with prior menin-KMT2A inhibitor exposure may be considered for enrollment with sponsor approval)

5. Criterion modified per Amendment 2

5.1 Cardiovascular disease that is uncontrolled, increases risk for Torsades de Pointes or that was diagnosed within 6 months prior to the first dose of study treatment including, but not limited to:
a. Myocardial infarction
b. Severe or unstable angina
c. Clinically significant cardiac arrhythmias, including bradycardia (< 50 beats per minute)
d. Currently uncontrolled (persistent) hypertension: systolic blood pressure = 140 mm Hg; diastolic blood pressure > 90 mm Hg
e. Acute neurologic events such as stroke or transient ischemic attack, intracranial or subarachnoid hemorrhage, intracranial trauma
f. Venous thromboembolic events (eg, pulmonary embolism) within 1 month prior to the first dose of study treatment (uncomplicated Grade = 2 deep vein thrombosis is not considered exclusionary)
g. Congestive heart failure (NYHA class III to IV) (AHA 1994)
h. Pericarditis or clinically significant pericardial effusion
i. Myocarditis
j. Endocarditis
k. Clinically significant hypokalemia, hypomagnesemia, hypocalcemia (corrected for hypoalbuminemia)
l. COHORT C1 ONLY:
- Reached cumulative dose of any combination of anthracyclines or anthracenediones of 550 g/m^2
- LVEF < 50 %
6. QTc according to Fridericia’s formula (QTcF) for males = 450 msec or for females = 470 msec. Participants with a family history of Long QT syndrome are excluded.
NOTE: For participants with documented wide QRS interval (eg, due to a bundle branch block), alternate methods of calculating a corrected QT interval may be appropriate for eligibility determination if recommended by a consulting cardiologist and approved by the sponsor, provided there is no evidence or history of a repolarization abnormality.

7. Any toxicity (except for alopecia, stable peripheral neuropathy, thrombocytopenia, neutropenia, anemia) from previous anticancer therapy that has not resolved to baseline or to Grade 1 or less.

8. Pulmonary compromise that requires the need for supplemental oxygen use to maintain adequate oxygenation.

9. Reported temperature > 100.4 Grad F/38 Grad C within 48 hours prior to the first dose of study treatment.

10. Known allergies, hypersensitivity, or intolerance to any assigned study treatment (combination agent or JNJ-75276617), or its excipients.

11. Exclusion criteria related to stem cell transplant:
- Received prior treatment with allogenic bone marrow or stem cell transplant = 3 months before the first dose of study treatment
- Has evidence of graft versus host disease
- Received donor lymphocyte infusion =1 month before the first dose of study treatment
- Requires immunosuppressant therapy (exception: daily doses = 10 mg prednisone or equivalent are allowed for adrenal replacement)

NOTE: Participants must discontinue all immunosuppressive therapy, including calcineurin inhibitors, at least 4 weeks before the first dose of study treatment and remain clinically stable.

12. Criterion modified per Amendment 2

12.1 Chemotherapy, targeted therapy, immunotherapy, or radiotherapy within 2 weeks or 5 half-lives (whichever is longer) before the planned first dose of study treatment (EXCEPT when used as cytoreductive therapy to control hyperleukocytosis as detailed in inclusion criterion 2 above).

13. Administration of:
- live-attenuated vaccine within 4 weeks before the first dose of study treatment or planned during the course of study treatment; or
- investigational vaccine within 2 weeks before the first dose of study treatment.

NOTE: Approved non-live vaccines (eg, influenza) or non-live vaccines authorized for emergency use (eg, SARS-CoV-2 [COVID-19]) by local health authorities are allowed.

14. Received investigational treatment or used an invasive investigational medical device within 2 weeks before the planned first dose of study treatment or is currently receiving active treatment on an investigational study.

15. Major surgery (eg, requiring general anesthesia) within 2 weeks prior to first dose of study treatment or has not recovered from surgery. Must not have major surgery planned during the time the participant is receiving study treatment. Participants with recent or planned surgical procedures utilizing only local anesthesia may participate.

16. Requires a prohibited medication that cannot be discontinued or substituted, or temporally interrupted during the study.

17. Known to be positive or tests positive at screening for human immunodeficiency virus (HIV).

18. Active or chronic hepatitis B virus (HBV) or hepatitis C virus (HCV) infection (as defined below) or clinically active infectious liver disease:
a. Positive hepatitis B (hepatitis B virus [HBV]) surface antigen (HbsAg).

NOTE: Participants with a prior history of HBV demonstrated by positive hepatitis B core antibody are eligible if they have at screening
1) a negative HbsAg and
2) a HBV DNA (viral load) below the lower limit of quantification, per local testing.
Participants with a positive HbsAg due to recent vaccination are eligible if HBV DNA (viral load) is below the lower limit of quantification, per local testing.

b. Positive hepatitis C antibody (anti-hepatitis C virus [HCV]).

NOTE: Participants with a prior history of HCV, who have completed antiviral treatment and have subsequently documented HCV RNA below the lower limit of quantification per local testing are eligible.

19. Any serious underlying medical or psychiatric conditions, such as seizure disorder or psychiatric conditions (eg, alcohol or drug abuse), dementia, or altered mental status.

20. Evidence within 7 days prior to the first dose of study treatment of any active or uncontrolled infection.

21. Inability to take an orally administered drug, or medical disorder or prior surgical resection that may affect the absorption of an oral agent. Such conditions include, but are not limited to, malabsorption syndrome, symptomatic inflammatory bowel disease, partial or complete bowel obstruction, or resection of the stomach or small bowel. If any of these conditions exist, the investigator should discuss with the sponsor to determine participant eligibility.

22. Any condition for which, in the opinion of the investigator, participation would not be in the best interest of the participant (eg, compromise the well-being) or that could prevent, limit, or confound the protocol-specified assessments.

23. Received strong cytochrome P450 3A (CYP3A) inducers or inhibitors within 7 days prior to initiation of study treatment.

24. Active malignancies (defined as those progressing or requiring treatment change in the last 24 months) other than the disease being treated under study.
Note: participants with non-melanoma skin cancers treated within the last 24 months that are considered cured are allowed.

NOTE: Investigators must ensure that all study enrollment (inclusion/exclusion) criteria have been met at screening, and prior to the first dose of study treatment. If a participant’s clinical status
changes (including any available laboratory results or receipt of additional medical records) after screening but before the first dose of study treatment is given such that the participant no longer meets all eligibility criteria, then the participant must be excluded from participation in the study and the sponsor notified. Section 5.4, Screen Failures, describes options for retesting. The required source documentation to support meeting the enrollment criteria are noted in Appendix 3:
Regulatory, Ethical, and Study Oversight Considerations.
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Ansprechpartner Email: ectu.cooperation@uniklinik-ulm.de , Tel. 0731 500 56070
Klinik ECTU (Early Clinical Trials Unit)
Kurztitel Amgen 20180257
EudraCT-Nr 2019-004 780-52
Titel Eine offene Phase-1b-Studie zur Untersuchung der Sicherheit und Pharmakokinetik der Verabreichung von subkutanem Blinatumomab zur Behandlung von Erwachsenen mit rezidivierter oder refraktärer B-Zell-Vorläufer akuter lymphoblastischer Leukämie (R/R B-ALL)
Studiendesign Interventionsstudie , nicht randomisiert , Phase I
Strategie 1st line
Einschlusskriterien
1. Subject has provided informed consent prior to initiation of any study specific activities/procedures and/or the subject’s legally acceptable representative has provided informed consent prior to any study-specific activities/procedures being initiated when the subject has any kind of condition that, in the opinion of the Investigator, may compromise the ability of the subject to give written informed consent.
2. Age >= 18 years at time of informed consent
3. Subjects with B-ALL with any of the following:
- Relapsed or Refractory after at least two cycles of chemotherapy (induction and consolidation).
- Relapse is defined as reappearance of disease after CR for >= 28 days.
- Refractory disease is defined as not having achieved CR after at least 2 cycles of chemotherapy (induction and consolidation).
4. Relapsed or Refractory at any time after first salvage therapy or refractory relapse
5. Relapse at any time after hematopoietic stem cell transplant (HSCT).
6. Greater than 5 % blasts in the BM.
7. Eastern Cooperative Oncology Group (ECOG) Performance Status <= 2.
8. Subjects with relapse or refractory B Cell ALL Ph+ disease and that are intolerant or refractory to prior tyrosine kinase inhibitors (TKIs) are eligible.
9. Negative pregnancy test in women of childbearing potential.
Ausschlusskriterien
Exclusion Criteria
Subjects are excluded from the study if any of the following criteria apply:

Disease Related
1. Active ALL in the CNS. Presence of > 5 white blood cells (WBC) per cubic millimeter in cerebrospinal fluid (CSF) with lymphoblasts present (confirmed by CSF analysis) and or clinical signs of CNS leukemia. If CSF leukemia is present subjects will have to receive intrathecal therapy and have documented negative CSF prior to enrolling.

Other Medical Conditions
2. History or presence of clinically relevant CNS pathology such as epilepsy, childhood or adult seizure, paresis, aphasia, stroke, severe brain injuries, dementia, Parkinson’s disease, cerebellar disease, organic brain syndrome or psychosis.
3. Isolated extramedullary disease.
4. Current autoimmune disease or history of autoimmune disease with potential CNS involvement.
5. Active acute or chronic graft versus host disease requiring systemic treatment with immunosuppressive medication.
6. Known hypersensitivity to blinatumomab or to any component of the product formulation.
7. Known infection with human immunodeficiency virus (HIV) or chronic infection with hepatitis B virus or hepatitis C virus.
8. Subject with uncontrolled active infection(s).
9. Testicular leukemia.
10. History of malignancy other than ALL within 3 years prior to start of protocol-specified therapy except for:
- Malignancy treated with curative intent and with no known active disease present for 3 years before enrollment and felt to be at low risk for recurrence by the treating physician.
- Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease.
- Adequately treated cervical carcinoma in situ without evidence of disease.
- Adequately treated breast ductal carcinoma in situ without evidence of disease.
- Prostatic intraepithelial neoplasia without evidence of prostate cancer.

Prior/Concomitant Therapy
11. Allogeneic HSCT within 12 weeks before the start of protocol-specified therapy
12. Cancer chemotherapy within 2 weeks before the start of protocol-specified therapy. With the exception of intrathecal chemotherapy or pre-phase chemotherapy and/or dexamethasone as outlined in Section 6.1.2.1 and Section 6.1.2.2, respectively.
13. Immunotherapy (eg, rituximab, alemtuzumab) within 4 weeks before start of protocol-specified therapy. Prior failed CD19 directed therapy such as prior blinatumomab or CD19 CAR T cells will be allowed (with demonstrated continued CD19+ expression), if reatment ended > 4 weeks prior to start of protocol therapy.

Prior/Concurrent Clinical Study Experience
14 Currently receiving treatment in another investigational device or drug study, or less than 30 days since ending treatment on another investigational device or drug study(ies). Other investigational studies are not permitted while participating in this study.

Diagnostic Assessments
15. Abnormal screening laboratory values as defined below:
- Total bilirubin >= 1.5 x upper limit of normal (ULN) (unless related to Gilbert’s or Meulengracht disease), AST(SGOT) and/or ALT(SGPT) and/or ALP >= 5 x ULN
- Creatinine >= 1.5 ULN or Creatinine clearance < 60 ml/min (calculated)

Other Exclusions
16. Female subject is pregnant or breastfeeding or planning to become pregnant or breastfeed during treatment and for an additional 96 hours after the last dose of protocol-specified therapy.
17. Female subjects of childbearing potential unwilling to use 1 highly effective method of contraception during treatment and for an additional 96 hours after the last dose of protocol-specified therapy. Refer to Section 11.5 for additional contraceptive information.
18. Female subjects of childbearing potential with a positive pregnancy test assessed during Screening by a serum pregnancy test and/or urine pregnancy test.
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Ansprechpartner Email: ectu.cooperation@uniklinik-ulm.de , Tel. 0731 500 56070
Klinik Innere Medizin III
Kurztitel AVC-201-01
EudraCT-Nr 2022-501797-19-00
Titel Multizentrische, offene Phase-1-Studie mit Allo-RevCAR01-T-CD123 bestehend aus gentechnisch veränderten T-Zellen, die Reverse Chimeric Antigen-Rezeptoren (Allo-RevCAR01-T) in Kombination mit CD123 Zielmodul (R-TM123) für die Behandlung von Patienten mit ausgewählten Hämatologischen Malignomen, die positiv für CD123 sind
Studiendesign Interventionsstudie , nicht randomisiert , Phase I
Weitere Info ClinicalTrials.gov  
Ansprechpartner Email: ectu.cooperation@uniklinik-ulm.de , Tel. 0731 500 56070
Klinik ECTU (Early Clinical Trials Unit)
Kurztitel BGB-11417-101
EudraCT-Nr 2020-004641-37
Titel Eine Open-Label-Dosiseskalations- und Expansionsstudie der Phase 1a/1b des Bcl-2-Inhibitors BGB-11417 bei Patienten mit reifen B-Zell-MalignomenStudie des Bcl-2-Inhibitors BGB-11417 bei Teilnehmern mit reifen B-Zell-Malignomen
Studiendesign Interventionsstudie , nicht randomisiert , Phase I
Strategie 2nd line
Einschlusskriterien
Each patient eligible to participate in this study must meet all applicable criteria:

1. Provision of signed and dated written informed consent prior to any study specific procedures, sampling, or analyses

2. Age 18 years or older

3. Confirmed diagnosis (per World Health Organization [WHO] guidelines, unless otherwise noted) of one of the following:
Note: For R/R cohorts, patients who have only received 1 line of therapy must be otherwise ineligible for, or intolerant to, available standard-of-care options.

NHL Cohorts:

a. MZL
i. R/R extranodal, splenic, or nodal MZL defined as disease that relapsed after, or was refractory to, at least 1 prior therapy
ii. Active disease requiring treatment

b. FL
i. R/R FL (Grade 1, 2 or 3a based on the WHO 2008 classification of tumors of hematopoietic and lymphoid tissue) and defined as disease that relapsed after, or was refractory to, at least 1 prior systemic therapy
ii. Active disease requiring treatment

c. DLBCL
i. R/R DLBCL (including all subtypes of DLBCL) defined as disease that relapsed after, or was refractory to, at least 1 prior systemic therapy and has either progressed following or is not a candidate for autologous stem cell transplant (due to comorbidities or non-responsiveness to salvage chemotherapy)
ii. Active disease requiring treatment

d. Transformed indolent B-cell NHL
i. Any lymphoma otherwise eligible for Part 1 that has transformed into a more aggressive lymphoma. Patients with transformation from CLL or SLL (Richter’s transformation) are not eligible for Part 1.
ii. Active disease requiring treatment

MCL Cohorts:

e. WHO-defined MCL
i. R/R MCL defined as disease that relapsed after, or was refractory to, at least 1 prior systemic therapy
ii. Requiring treatment in the opinion of the investigator

CLL/SLL Cohorts:

f. CLL/SLL diagnosis that meets the International Workshop on Chronic Lymphocytic Leukemia (IWCLL) criteria (Hallek et al 2008)
i. Meeting the following prior treatment criteria:
(1) For R/R cohorts (Cohorts 1B, 1C, 2C, 2D, 2E, 3A, and 4A) disease that relapsed after, or was refractory to, at least 1 prior therapy.
- For the venetoclax-treated cohort (Cohort 2E): prior therapy history must include progression after a therapy containing = 2 months of venetoclax treatment (monotherapy or combination).
(2) For the treatment-naive (TN) cohorts (Cohorts 3C and 4B), patients should have no prior treatment for CLL/SLL (other than 1 aborted regimen < 2 weeks in duration and > 4 weeks before enrollment).
Note: TN CLL/SLL patients will only be enrolled at investigational siteswhere this is allowed by regulatory authorities/local ethics. In Germany, patients will not be enrolled in Cohorts 3C and 4B.
ii. Requiring treatment as defined by history of at least one of the following criteria:
(1) Evidence of progressive marrow failure as manifested by the development of, or worsening of, anemia and/or thrombocytopenia
(2) Massive (ie, = 6.0 cm below left costal margin), or progressive, or symptomatic splenomegaly
(3) Massive nodes (ie, = 10.0 cm in longest diameter), or progressive, or symptomatic lymphadenopathy
(4) Progressive lymphocytosis with an increase of = 50 % over a 2-month period or lymphocyte doubling time of < 6 months. Lymphocyte doubling time may be obtained by linear regression extrapolation of absolute lymphocyte counts obtained at intervals of 2 weeks over an observation period of 2 to 3 months. In patients with initial blood lymphocyte counts of < 30 x 10^9/L (30,000/µL), lymphocyte doubling time should not be used as a single parameter to define treatment indication. In addition, factors contributing to lymphocytosis or
lymphadenopathy other than CLL/SLL (eg, infection, steroid administration, BTK treatment) should be excluded
(5) Constitutional symptoms, defined as any one or more of the following disease-related symptoms or signs
a. Unintentional weight loss of = 10 % within the previous 6 months
b. Significant fatigue (ie, inability to work or perform usual activities)
c. Fevers = 100.5 Grad F or 38 Grad C for = 2 weeks without other evidence of infection
d. Night sweats for = 1 month without evidence of infection
(6) Autoimmune anemia and/or thrombocytopenia that is poorly responsive to corticosteroids or other standard therapy

WM Cohorts:

g. WHO-defined WM (clinical and definitive histologic diagnosis)
i. R/R disease defined as disease that relapsed after, or was refractory to, at least 1 prior therapy
ii. Meeting at least 1 criterion for treatment according to consensus panel criteria from the Seventh International Workshop on Waldenström’s Macroglobulinemia (Dimopoulos et al 2014)

Clinical indications for initiation of therapy
(1) Recurrent fever, night sweats, weight loss, fatigue
(2) Hyperviscosity
(3) Lymphadenopathy which is either symptomatic or bulky (= 5 cm in maximum diameter)
(4) Symptomatic hepatomegaly and/or splenomegaly
(5) Symptomatic organomegaly and/or organ or tissue infiltration
(6) Peripheral neuropathy due to WM
(7) Laboratory indications for initiation of therapy
(8) Symptomatic cryoglobulinemia
(9) Cold agglutinin anemia
(10) Immune hemolytic anemia and/or thrombocytopenia nephropathy related to WM
(11) Amyloidosis related to WM
(12) Hemoglobin = 10 g/dL
(13) Platelet count < 100 x 10^9/L

4. Measurable disease by computed tomography (CT)/magnetic resonance imaging (MRI), defined as:

a. CLL: at least 1 lymph node > 1.5 cm in longest diameter and measurable in 2 perpendicular dimensions or clonal lymphocytes measured by flow cytometry

b. DLBCL, FL, MZL, MCL, or SLL: at least 1 lymph node > 1.5 cm in longest diameter OR 1 extranodal lesion > 1.0 cm in the longest diameter, measurable in 2 perpendicular dimensions. For MZL, isolated splenomegaly is considered measurable for this study. For MCL, clonal lymphocytes measured by flow cytometry is considered measurable.

c. WM: serum IgM level > 0.5 g/dL

5. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2

6. Adequate organ function defined as:

a. Absolute neutrophil count (ANC) = 1.0 x 10^9/L = 7 days before first dose of study drug (without growth factor support). There is an exception for patients with bone marrow involvement, in which case ANC must be = 0.75 x 10^9/L

b. Platelets > 40 x 10^9/L (> 40,000/mm^3) = 7 days before first dose of study drug (without growth factor support or transfusion).

c. Hemoglobin > 75 g/L = 7 days before first dose of study drug (with or without growth factor support or transfusion).

d. Adequate kidney function defined as:
Creatinine clearance or glomerular filtration rate (GFR) = 50 mL/min (for United States: = 60 mL/min) as estimated by one of the following:
i. Cockcroft-Gault equation (see Appendix 14)
ii. Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation (see Appendix 14)
iii. 24-hour urine collection

e. Adequate liver function indicated by:
i. Aspartate aminotransferase (AST)/serum glutamic-oxaloacetic transaminase = 2 x upper limit of normal (ULN)
ii. Alanine aminotransferase (ALT)/serum glutamic-pyruvic transaminase = 2 x ULN
iii. Total bilirubin level = 1.5 x ULN (unless documented Gilbert’s syndrome).
For patients with documented Gilbert’s syndrome, total bilirubin may exceed this value but direct bilirubin must be = 1.0 x ULN.

7. Adequate pancreatic function indicated by:

a. Serum amylase = 1.5 x ULN

b. Serum lipase = 1.5 x ULN

8. Women of childbearing potential must have a negative serum pregnancy test = 7 days before the first dose of study drug. In addition, they must use a highly effective method of birth control initiated before the first dose of study drug, for the duration of the study treatment period, and for = 180 days after the last dose of study drug. See Appendix 11 for highly effective methods of birth control and the definition of childbearing potential.

9. Nonsterile men must use a highly effective method of birth control along with barrier contraception for the duration of the study treatment period and for = 180 days after the last dose of study drug. During this same period, they must not donate sperm. Sterile men must use barrier contraception. See Appendix 11 for highly effective methods of birth control and the definition of sterile.

10. Life expectancy of > 6 months

11. Able to comply with the requirements of the study
Ausschlusskriterien
Each patient eligible to participate in this study must NOT meet any of the following exclusion criteria:

1. Prior malignancy (other than the disease under study) within the past 2 years, except for curatively treated basal or squamous skin cancer, superficial bladder cancer, carcinoma in situ of the cervix or breast, or localized Gleason score = 6 prostate cancer

2. Underlying medical conditions that, in the investigator’s opinion, will render the administration of study drug hazardous or obscure the interpretation of safety or efficacy
results

3. Known central nervous system involvement by lymphoma/leukemia

4. Known plasma cell neoplasm, prolymphocytic leukemia, history of or currently suspected Richter’s syndrome

5. Prior autologous stem cell transplant unless = 3 months after transplant; or prior chimeric antigen receptor T-cell (CAR-T) therapy unless = 3 months after cell infusion

6. Prior allogeneic stem cell transplant with active graft-versus-host disease (GVHD), or requiring immunosuppressive drugs for treatment of GVHD, or have taken calcineurin inhibitors within 4 weeks prior to consent.

7. Use of the following substances prior to the first dose of study drug:

a. = 28 days before the first dose of study drug:
- Any biologic and/or immunologic-based therapy(ies) including experimental therapy(ies) for leukemia, lymphoma, or myeloma (including, but not limited to, monoclonal antibody therapy, eg, rituximab, and/or cancer vaccine therapy)

b. = 14 days before the first dose of study drug:
- Systemic chemotherapy or radiation therapy

c. = 7 days before the first dose of study drug:
- Corticosteroid given with antineoplastic intent other than control of BTK inhibitor withdrawal flare

d. = 5 half-lives before the first dose of study drug:
- BTK inhibitor, tyrosine kinase inhibitor, or other targeted small molecule given with antineoplastic intent.

8. Active fungal, bacterial, and/or viral infection requiring systemic therapy
Note: oral antibiotics for minor bacterial infections are allowed.

9. Prior therapy = 2 months with or progression on a Bcl-2 inhibitor (eg, venetoclax/ABT-199).

NOTE: This criterion does not apply to patients entering into any cohorts that include venetoclax-treated patients (ie, Cohort 2E).

10. Major surgery = 4 weeks before the first dose of study treatment

11. Toxicity from prior anticancer therapy that has not recovered to Grade = 1 (except for alopecia, ANC, and platelet count; for ANC and platelet count, see inclusion criterion 6)

12. Clinically significant cardiovascular disease including the following:

a. Myocardial infarction = 6 months before screening

b. Unstable angina = 3 months before screening

c. New York Heart Association class III or IV congestive heart failure (see Appendix 3)

d. History of clinically significant arrhythmias (eg, sustained ventricular tachycardia, ventricular fibrillation, torsades de pointes)

e. Heart rate-corrected QT interval > 480 milliseconds based on Fridericia’s formula

f. History of Mobitz II second-degree or third-degree heart block without a permanent pacemaker in place

g. Uncontrolled hypertension as indicated by a minimum of 2 consecutive blood pressure measurements, at screening, showing systolic blood pressure > 170 mmHg and diastolic blood pressure > 105 mmHg

13. Known infection with human immunodeficiency virus (HIV) or serologic status reflecting active viral hepatitis B (HBV) or viral hepatitis C (HCV) infection as follows:

a. Presence of viral hepatitis B surface antigen (HBsAg) or viral hepatitis B core antibody (HBcAb)
Note: Patients with presence of HBcAb, but absence of HBsAg, are eligible if HBV DNA is undetectable and if they are willing to undergo monitoring for HBV reactivation (see Section 6.12.6).

b. Presence of HCV antibody
Note: Patients with presence of HCV antibody are eligible if HCV RNA is undetectable and if they are willing to undergo monitoring for HCV reactivation (see Section 6.12.6).

14. Pregnant or lactating women

15. Unable to swallow capsules or disease significantly affecting gastrointestinal function such as malabsorption syndrome, resection of the stomach or small bowel, bariatric surgery procedure, symptomatic inflammatory bowel disease, or partial or complete bowel obstruction

16. Inability to comply with study procedures

17. Receiving any treatment with a moderate CYP3A4 inhibitor or strong CYP3A4 inhibitor or inducer = 14 days (or 5 half-lives, whichever is longer) before first dose of BGB-11417 OR requiring long-term use of strong CYP3A4 inhibitors or inducers. See Appendix 4 for guidance on CYP3A inhibitors and inducers. See Section 8.3.2 for guidance on dose modification of zanubrutinib in patients taking CYP3A4 inhibitors or inducers.

18. History of stroke or intracranial hemorrhage = 6 months before the first dose of study drug

19. History of interstitial lung disease, noninfectious pneumonitis, or uncontrolled lung diseases, including but not limited to pulmonary fibrosis and acute lung diseases

20. Concurrent treatment for the disease under study outside this clinical study (including the screening period) unless otherwise allowed by exclusion criterion 7.

21. Autoimmune anemia and/or thrombocytopenia that is poorly controlled by corticosteroids or other standard therapy

22. Ongoing, drug-induced liver injury, alcoholic liver disease, nonalcoholic steatohepatitis, primary biliary cirrhosis, ongoing extrahepatic obstruction caused by cholelithiasis, cirrhosis of the liver, or portal hypertension.

23. History of hypersensitivity to excipient(s) of the BGB-11417 tablet or, for Parts 3 and 4, the zanubrutinib capsule

24. Requires treatment with warfarin or other vitamin K antagonists

25. History of a severe bleeding disorder such as hemophilia A, hemophilia B, von Willebrand disease, or history of spontaneous bleeding requiring blood transfusion or other medical intervention

26. Receiving drugs known to prolong the QT/QTc interval (see Appendix 10)

27. Vaccination with a live vaccine = 35 days before first dose of study drug
Note: Seasonal vaccines for influenza are generally inactivated vaccines and are allowed.
Intranasal vaccines are live vaccines and are not allowed.

28. [Combination cohorts only] Progressive disease while taking a BTK inhibitor
Weitere Info ClinicalTrials.gov   ICH GCP NETWORK  
Ansprechpartner Email: ectu.cooperation@uniklinik-ulm.de , Tel. 0731 500 56070
Klinik ECTU (Early Clinical Trials Unit)
Kurztitel BGB-16673-101
EudraCT-Nr 2022-502157-33-00
Titel Eine offene Studie der Phase 1/2 zur Dosiseskalation und Dosisexpansion des Bruton Tyrosine Kinase Targeted Protein Degrader BGB-16673 bei Patienten mit B-Zell-Malignomen
Studiendesign Interventionsstudie , nicht randomisiert , Phase I
Strategie 2nd line , 3rd line
Einschlusskriterien
Each patient who is eligible to participate in this study must meet all the following criteria:

1. Provision of signed and dated written informed consent prior to any study-specific procedures, sampling, or data collection

2. Age = 18 years

3. Confirmed diagnosis (per World Health Organization [WHO] guidelines, unless otherwise noted) of one of the following:

a. Patients with MZL (Parts 1a, 1b, and 1c only) and all of the following:

i. Extranodal, splenic, or nodal MZL

ii. R/R MZL is defined as disease that relapsed after, or was refractory to, = 2 prior lines of therapy (a line of therapy is considered = 2 consecutive cycles of a systemic anticancer regimen)

(1) For patients enrolling at US sites ONLY: patients must have been treated with a covalently-binding BTK inhibitor and an anti-CD20 monoclonal antibody in any line of therapy to be eligible for the study.

(2) For patients enrolling at EU sites ONLY: patients must have been treated with an anti-CD20 monoclonal antibody in any line of therapy to be eligible for the study.

iii. Active disease requiring treatment


b. Patients with FL (Parts 1a and 1c only) and all of the following:

i. Grade 1, 2, or 3a based on the WHO 2008 classification of tumors of hematopoietic and lymphoid tissue

ii. R/R FL is defined as disease that relapsed after, or was refractory to, = 2 prior lines of therapy (a line of therapy is considered = 2 consecutive cycles of a systemic anticancer regimen)
Note: prior therapy must include = 1 line of therapy containing an anti-CD20 monoclonal antibody

iii. Active disease requiring treatment

c. Patients with R/R MCL (Parts 1a, 1b, and 2 only) and all of the following:

i. Blastoid or nonblastoid-variant R/R MCL

ii. R/R MCL is defined as disease that relapsed after, or was refractory to, = 2 prior lines of systemic therapy (a line of therapy is considered = 2 consecutive cycles of a systemic anticancer regimen).

(1) For patients enrolling at US and EU sites ONLY, for Part 1a, Part 1b and Part 2: patients must have been treated with a covalently-binding BTK inhibitor and anti CD20 monoclonal antibody in any line of therapy to be eligible for the study.

iii. Part 2 (all ex-US patients): patients must have been treated with a covalently binding BTK inhibitor (eg, ibrutinib, acalabrutinib, or zanubrutinib; as monotherapy or in combination with other anticancer agents) in any line of therapy

iv. Requiring treatment in the opinion of the investigator

d. Patients with R/R CLL/SLL (Parts 1a, 1b, and 2) and all of the following:

i. R/R CLL/SLL diagnosis that meets the International Workshop on Chronic Lymphocytic Leukemia (iwCLL) criteria (Hallek et al 2018)

ii. R/R CLL/SLL is defined as disease that relapsed after, or was refractory to, = 2 prior lines of therapy (a line of therapy is considered = 2 consecutive cycles of a systemic anticancer regimen)

iii. In Part 1a and 1b, patients enrolling at the US, EU, and Australian sites ONLY must have been treated with a covalently-binding BTK inhibitor (eg, ibrutinib, acalabrutinib, or zanubrutinib; as monotherapy or in combination with other anticancer agents) in any line of therapy. In Part 2, all patients must have been treated with a covalently-binding BTK inhibitor (eg, ibrutinib, acalabrutinib, or zanubrutinib; as monotherapy or in combination with other anticancer agents) in any line of therapy.

iv. Requiring treatment as defined by history of = 1 of the following criteria:

(1) Requires treatment in the opinion of the investigator or meets criteria for initiation of a subsequent line of therapy per the 2018 iwCLL criteria, including substantial persistent disease burden following a prior line of therapy or the lack of resolution of the indication for a prior line of therapy

(2) Evidence of progressive marrow failure as manifested by the development or worsening of anemia and/or thrombocytopenia

(3) Massive (ie, = 6.0 cm below left costal margin), progressive, or symptomatic splenomegaly

(4) Massive (ie, = 10.0 cm in longest diameter), progressive, or symptomatic lymphadenopathy

(5) Progressive lymphocytosis with an increase of = 50 % over a 2-month period or a lymphocyte doubling time (LDT) of < 6 months. The LDT may be determined by linear regression extrapolation of absolute lymphocyte counts obtained at intervals of 2 weeks over an observation period of 2 to 3 months; patients with initial blood lymphocyte counts < 30 x 10^9 /L (30,000/MikroL) may require a longer observation period to determine the LDT. Factors contributing to lymphocytosis or lymphadenopathy other than R/R CLL/SLL (eg, infection, steroid administration, BTK inhibitor treatment) should be excluded

(6) Autoimmune complications, including anemia or thrombocytopenia that respond poorly to steroids or other systemic therapies

(7) Symptomatic or functional extranodal involvement (eg, skin, kidney, lung, spine)

(8) Disease-related symptoms defined as any of the following:

a. Unintentional weight loss = 10% within the previous 6 months

b. Significant fatigue (ie, Eastern Cooperative Oncology Group [ECOG] Performance Status 2 or worse; cannot work or unable to perform usual activities)

c. Fevers = 100.5 ^Grad F or 38 ^Grad C for = 2 weeks without evidence of infection

d. Night sweats for = 1 month without evidence of infection

e. Patients with WM (Part 1a, 1b, and 1c only) and all of the following:

i. Clinical and definitive histological diagnosis

ii. R/R WM is defined as disease that relapsed after, or was refractory to, = 2 prior lines of therapy (a line of therapy is considered = 2 consecutive cycles of a systemic anticancer regimen)

iii. = 1 line of therapy containing an anti-CD20 monoclonal antibody

(1) For patients enrolling at US and EU sites ONLY: patients must also have been treated with a covalently-binding BTK inhibitor in any line of therapy to be eligible for the study.

iv. Meeting = 1 criterion for treatment according to consensus panel criteria from the Seventh International Workshop on Waldenström Macroglobulinemia (Dimopoulos
et al 2014):

(1) Recurrent fever, night sweats, weight loss, fatigue

(2) Hyperviscosity

(3) Lymphadenopathy that is either symptomatic or bulky (= 5 cm in maximum diameter)

(4) Symptomatic hepatomegaly and/or splenomegaly

(5) Symptomatic organomegaly and/or organ or tissue infiltration

(6) Peripheral neuropathy due to WM

(7) Laboratory indications for initiation of therapy

(a) Symptomatic cryoglobulinemia

(b) Cold agglutinin anemia

(c) Immune hemolytic anemia and/or thrombocytopenia or nephropathy related to WM

(d) Amyloidosis related to WM

(e) Hemoglobin = 10 g/dL

(f) Platelet count < 100 x 10^9/L

f. Patients with DLBCL (Part 1a and 1c only) and all of the following:

i. Non-Germinal Center B-cell DLBCL Not Otherwise Specified (Non-GCB-DLBCL NOS), as defined by IHC per the Hans algorithm (Hans et al 2004). A previously locally performed gene-expression profiling assay designed to identify the lymphoma cell-of-origin, such as the NanoString Lymphoma Subtyping Test (Seattle, WA, USA), may be substituted to determine non-GCB pathology.

ii. Relapsed after, or was refractory to, = 2 prior lines of systemic therapy (a line of therapy is considered = 2 consecutive cycles of a systemic anticancer regimen)

(1) Patients must have been treated with an anthracycline based regimen and an anti CD20-based regimen
(2) Patients who are not candidates for or refuse intensive chemotherapy, hematopoietic stem cell transplant, and CAR-T based regimens are eligible for this study
(3) Patients who have previously received allogenic or autologous stem cell transplantation or CAR-T based regimens are eligible for this study
(4) Patients must not require concurrent CNS directed therapy or prophylaxis with systemic or intrathecal chemotherapy or radiotherapy
(5) Systemic chemotherapy followed by autologous or allogeneic SCT will be considered as 1 line of systemic therapy

g. Patients with Richter’s transformation to DLBCL (Parts 1a and 1c only) and all of the following:

i. History of R/R CLL/SLL diagnosis that meets the International Workshop on Chronic Lymphocytic Leukemia (iwCLL) criteria (Hallek et al 2018).

(1) Patients enrolling at US, EU and Australian sites ONLY must have been treated with a covalently-binding BTK inhibitor (eg, ibrutinib, acalabrutinib, or zanubrutinib; as monotherapy or in combination with other anticancer agents) in any line of therapy for prior R/R CLL/SLL diagnosis or for RT diagnosis

ii. Confirmed histopathological diagnosis of RT to DLBCL

iii. R/R RT is defined as disease that relapsed after, or was refractory to, = 1 prior line of therapy (a line of therapy is considered = 2 consecutive cycles of a systemic anticancer regimen) administered for RT

4. For patients who have previously received a BTK inhibitor:

a. Parts 1a, 1b, and 1c only: Patients who have experienced disease progression during or after = 1 regimen containing a covalently-binding BTK inhibitor are eligible for the dose-finding cohorts

b. Parts 1a, 1b, 1c and 2: Patients may (but do not have to) have been treated with non covalently binding BTK inhibitor(s) to be eligible

c. Parts 1a, 1b, 1c and 2: Received treatment with a BTK inhibitor as monotherapy or in combination with other anticancer agents for = 8 consecutive weeks (Note – patients who discontinued BTK inhibitor for intolerance are NOT required to have received previous BTK inhibitor therapy for = 8 consecutive weeks)

d. Parts 1a, 1b, 1c and 2: Discontinued the previous BTK inhibitor due to disease progression, toxicity, or intolerance OR experienced progression after completing treatment with the BTK inhibitor

e. Part 2 only: Received only 1 regimen containing a covalently-binding BTK inhibitor
(Note: Patients may have received treatment with 2 different covalently-binding BTK inhibitors if the initial covalently-binding BTK inhibitor was discontinued secondary to an event other than disease progression.)

5. All patients in Parts 1a, 1b, 1c and 2 must have measurable disease defined as follows:

a. R/R CLL/SLL: = 1 lymph node > 1.5 cm in longest diameter and measurable in 2 perpendicular dimensions (assessed by computed tomography [CT]/magnetic resonance imaging [MRI]). NOTE: The presence of measurable disease is NOT
required for patients with CLL in Part 1a and Part 1b only

b. NHL: = 1 lymph node > 1.5 cm in longest diameter OR 1 extranodal lesion > 1.0 cm in the longest diameter, measurable in 2 perpendicular dimensions (assessed by CT/MRI)
i. For patients with MZL, isolated splenomegaly is considered measurable disease for the purposes of eligibility for this study (assessed by CT/MRI)
ii. For patients with R/R MCL in Part 1a and 1b, isolated splenomegaly is considered measurable disease for the purposes of eligibility for this study (assessed by CT/MRI)

c. WM: serum or plasma IgM level > 0.5 g/dL

6. ECOG Performance Status of 0 to 2 (For EU only: ECOG Performance Status of 0 to 1).

7. Adequate organ function defined as follows (based on the results during the screening period):

a. Absolute neutrophil count (ANC) = 1.0 x 10^9/L. There is an exception for patients with bone marrow involvement, in which case ANC must be = 0.75 x 10^9/L. Patients in either scenario must be free from growth factor support as evidenced by an ANC dated = 10 days following the most recent administration of peg-filgrastim (or other pegylated myeloid growth factors) and = 4 days following the most recent administration of filgrastim or other myeloid growth factors.

b. Platelets = 50 x 10^9/L (= 50,000/mm^3); patients with platelet count < 50 x 10^9/L (< 50,000/mm^3) secondary to bone marrow infiltration by the underlying malignancy are
eligible for the study if their platelet count is = 25 x 10^9/L (= 25,000/mm^3). Patients must be free from growth factor support for = 7 days and/or transfusion for = 3 days.

c. Hemoglobin = 80 g/L (independent of growth factor support or transfusion, defined as no growth factor support for = 7 days and/or transfusion for = 3 days); patients may have hemoglobin < 80 g/L without growth factor or transfusion as above if the reduced hemoglobin is secondary to bone marrow infiltration by the underlying malignancy

d. Coagulation meeting all of the following:
International normalized ratio (INR) = 1.5 (patients on therapeutic anticoagulation may have an INR that is > 1.5 as long as it is within the therapeutic range for the medication that they are receiving. Note: Use of warfarin or other vitamin K antagonists is NOT permitted for patients in this study; see exclusion criterion 24.)

Activated partial thromboplastin time (aPTT) = 1.5 x upper limit of normal (ULN) (patients on therapeutic anticoagulation may have aPTT > 1.5 x ULN as long as it is within the therapeutic range for the medication that they are receiving).

EU Only: patients on anticoagulation must be on a stable dose for 7 days or longer prior to start of study medication for Parts 1a and 1b.

Note: Patients with factor inhibitors that prolong prothrombin time/activated partial thromboplastin time without increasing the bleeding risk or those with lupus anticoagulant or acquired von Willebrand’s syndrome due to WM may be enrolled after discussion with the medical monitor or designee.

e. Glomerular filtration rate (GFR) or creatinine clearance (CrCl) = 60 mL/min as estimated by one of the following:

i. Cockcroft-Gault equation:
(1) (140 - age) x mass (kg)/72 x creatinine (mg/dL); multiply by 0.85 if female
(2) (140 - age) x mass (kg) x 1.23 if male (or 1.04 if female)/creatinine (Mikromol/L)

ii. Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation (2021):

(1) eGFR =142*min(standardized Scr/K, 1)^alpha *max(standardized Scr/K, 1)-1.200 *0.9938Age *1.012 [if female]
(a) Scr (serum creatinine) = mg/dL; kappa = 0.7 (females) or 0.9 (males)
(b) alpha = -0.241 (females) or -0.302 (males)
(c) min = indicates the minimum of Scr/kappa or 1, and
(d) max = indicates the maximum of Scr/kappa or 1

iii. CKD-EPI Creatinine-Cystatin Equation (2021)

(1) eGFRcr-cys = 135 x min(Scr/kappa, 1)^alpha x max(Scr/kappa, 1)-0.544 x min(Scys/0.8, 1)-0.323 x max(Scys/0.8, 1)-0.778 x 0.9961Age x 0.963 [if female]
(a) kappa = 0.7 (females) or 0.9 (males)
(b) alpha = -0.219 (female) or -0.144 (male)
(c) min(Scr/kappa, 1) is the minimum of Scr/kappa or 1.0
(d) max(Scr/kappa, 1) is the maximum of Scr/kappa or 1.0
(e) Scys = standardized serum cystatin C in mg/L

iii. Nuclear medicine scan

iv. 24-hour urine collection

f. Adequate pancreatic function
i. Serum or plasma amylase = 1.5 x ULN
ii. Serum or plasma lipase = 1.5 x ULN

g. Adequate liver function indicated by the following:
i. Aspartate aminotransferase (AST)/serum or plasma glutamic-oxaloacetic transaminase = 2 x ULN
ii. Alanine aminotransferase (ALT)/serum or plasma glutamic-pyruvic transaminase = 2 x ULN
iii. Total bilirubin level = 1.5 x ULN (unless documented Gilbert’s syndrome) and direct bilirubin level = 1.0 x ULN for patients with documented Gilbert’s syndrome

8. Women of childbearing potential must have 2 negative pregnancy tests: a serum or plasma test within 10 to 14 days before the first dose of BGB-16673 and a serum, plasma or urine pregnancy test within 24 hours prior to the first dose of BGB-16673. In addition, they must use a highly effective method of birth control initiated before the first dose of the study drug, for the duration of the study treatment period, and for = 90 days after the last dose of the study drug. See Appendix 16 for highly effective methods of birth control and the definition of childbearing potential.

9. Nonsterile men must use a highly effective method of birth control for the duration of the study treatment period and for = 90 days after the last dose of the study drug. During this same period, they must not donate sperm. See Appendix 16 for highly effective methods of birth control and the definition of sterile.

10. Life expectancy of > 6 months

11. Ability to provide written informed consent and to understand and comply with the requirements of the study. Patients with psychiatric conditions or cognitive dysfunction that would preclude providing independent informed consent are NOT eligible for the study.
Ausschlusskriterien
Each patient who is eligible to participate in this study must NOT meet any of the following exclusion criteria:

1. Prior malignancy (other than the disease under study) within the past 2 years, except for curatively treated basal or squamous skin cancer, lentigo maligna melanoma, superficial bladder cancer, carcinoma in situ of the cervix or breast, localized Gleason score = 6 prostate cancer.

2. Requires ongoing systemic treatment for any other malignancy

3. Any life-threatening illness, medical condition, organ system dysfunction, need for profound anticoagulation, or bleeding disorder, which, in the investigator’s opinion, could compromise the patient’s safety or confound the interpretation of safety or efficacy data

4. Requires ongoing systemic (defined as = 10 mg/day of prednisone or equivalent) corticosteroid treatment. Systemic corticosteroids must be discontinued = 7 days before the first day of study drug treatment unless a short course (= 7 days prior to start of study drug treatment) is needed to control lymphoma-related symptoms and it is tapered off within 5 days after initiation of study treatment. (Note: Use of inhaled corticosteroids for primary pulmonary disorders and topical or ophthalmic corticosteroids are not considered systemic treatments and DO NOT meet protocol exclusion criteria)

5. Current or history of central nervous system involvement including the brain, spinal cord, leptomeninges, and cerebrospinal fluid (as documented by imaging, cytology, or biopsy) by B-cell malignancy, regardless of whether patient had received treatment for central nervous system disease

6. Known active plasma cell neoplasm, prolymphocytic leukemia, T-cell lymphoma (including T-cell/histiocyte-rich large B-cell lymphoma), Burkitt lymphoma, acquired immunodeficiency syndrome (AIDS)-related B-cell lymphoma, Castleman disease, post transplant lymphoproliferative disorders, hairy cell leukemia, GCB DLBCL, EBV+ DLBCL NOS, primary DLBCL of the central nervous system (CNS), primary cutaneous DLBCL – leg type, DLBCL associated with chronic inflammation, primary mediastinal (thymic) large B-cell lymphoma, intravascular large B-cell lymphoma, ALK+ large B cell lymphoma, primary effusion lymphoma, high-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements, high-grade B-cell lymphoma – NOS, B-cell lymphoma unclassifiable with features intermediate between DLBCL and classical Hodgkin lymphoma, or history of or currently suspected transformation of an indolent lymphoma to an aggressive histology (only patients with Richter Transformation to DLBCL are eligible for Part 1a).

7. Prior autologous stem cell transplant unless = 3 months after transplant

8. Prior CAR-T unless = 6 months after cell infusion

9. Prior allogeneic stem cell transplant = 6 months before the first dose of the study drug
(Note: patients who have previously received allogeneic stem cell transplant must have no signs or symptoms of graft versus host disease and must not be receiving immunosuppressive therapy.)

10. Use of the following substances prior to the first dose of the study drug:

a. = 28 days (or 5 half-lives, whichever is shorter) before the first dose of the study drug:

i. Any biologic and/or immunologic-based anticancer therapy(ies) including experimental therapy(ies) (including, but not limited to, monoclonal antibody therapy such as rituximab and/or cancer vaccine therapy)

b. = 14 days (or 5 half-lives, whichever is shorter) before the first dose of the study drug:
i. Systemic chemotherapy or radiation therapy

c. = 7 days before the first dose of the study drug:
i. Corticosteroid given with antineoplastic intent (symptom control will not be considered as antineoplastic intent)

d. = 7 days (or 5 half-lives, whichever is shorter) before the first dose of the study drug:
i. BTK inhibitor, tyrosine kinase inhibitor, or other targeted small molecules given with antineoplastic intent

11. Receiving treatment with a strong CYP3A inhibitor (< 7 days or 5 half-lives, whichever is longer) or strong CYP3A inducer (= 14 days or 5 half-lives, whichever is longer) before the first dose of BGB-16673 OR requiring long-term use of strong CYP3A inhibitors or inducers. For a list of selected strong CYP3A inhibitors or inducers, see Appendix 9.

12. Receiving treatment with proton-pump inhibitors = 5 days before the first dose of BGB-16673. Patients receiving proton-pump inhibitors who switch to H2-receptor antagonists or antacids are eligible for enrollment in this study; refer to Section 8.3 for detailed instructions. If proton-pump inhibitors cannot safely be discontinued, patients may enroll in the study after discussion with the medical monitor

13. Active fungal, bacterial, and/or viral infection requiring systemic therapy. Note: Patients with infections that are managed by oral antibiotics who are otherwise clinically stable are not excluded from study participation

14. Coadministration of herbal or homeopathic medication administered with antineoplastic intent is not permitted while on study treatment. Patients must discontinue all herbal or homeopathic medications being administered with antineoplastic intent = 28 days prior to initiating study treatment

15. Major surgery = 4 weeks before the first dose of study treatment

16. Toxicity from prior anticancer therapy that has not recovered to = Grade 1 (except for alopecia, absolute neutrophil count, absolute lymphocyte count, hemoglobin, and platelet count; for guidance regarding absolute neutrophil count, absolute lymphocyte count, hemoglobin, and platelet count, see inclusion criteria above)

17. Clinically significant cardiovascular disease including the following:

a. Myocardial infarction = 6 months before screening

b. Unstable angina = 3 months before screening

c. History of or active clinically significant arrhythmias (eg, sustained ventricular tachycardia, ventricular fibrillation, Torsades de Pointes)

d. New York Heart Association class III or IV congestive heart failure (see Appendix 8)

e. Heart rate-corrected QT interval based on Fridericia’s formula (QTcF) > 450 milliseconds. Patients with bundle branch block can be allowed after discussion with the medical monitor.

f. History of or active Mobitz II second- or third-degree heart block without a permanent pacemaker in place

g. Uncontrolled hypertension as indicated by = 2 consecutive blood pressure measurements, at screening, showing systolic blood pressure > 170 mmHg and diastolic blood pressure > 105 mmHg. For Parts 1a and 1b, EU only: uncontrolled Grade 3 hypertension is defined as systolic blood pressure = 160 mmHg and diastolic blood pressure = 100 mmHg, or lower grade hypertension where dose of anti hypertensives, if administered, is not stable for at least 14 days.

18. Known infection with human immunodeficiency virus (HIV) or serologic status reflecting active hepatitis A virus (HAV), hepatitis B virus (HBV), or hepatitis C virus (HCV) infection as follows:

a. Presence of viral hepatitis B surface antigen (HBsAg) or viral hepatitis B core antibody (HBcAb)
Note: Patients with the presence of HBcAb, but the absence of HBsAg, are eligible if HBV DNA is undetectable (the limit of detection for HBV DNA must have a sensitivity of < 20 IU/mL), and patients must be willing to undergo monitoring for HBV reactivation (see Section 6.12.6). Patients who are positive for HBsAb secondary to a history of vaccination against HBV are eligible.

b. Presence of HCV antibody
Note: Patients with the presence of HCV antibody are eligible if HCV RNA is undetectable (the limit of detection for HCV RNA testing must have a sensitivity of < 15 IU/mL), and patients must be willing to undergo monthly monitoring for HCV reactivation (see Section 6.12.6).

c. Presence of HAV IgM antibody (patients with a history of HAV infection that has resolved are eligible for the study)

19. Pregnant or lactating women

20. Unable to swallow capsules or disease significantly affecting gastrointestinal function such as malabsorption syndrome, resection of the stomach or small bowel, bariatric surgery procedure, symptomatic inflammatory bowel disease, or partial or complete bowel obstruction

21. Inability to comply with study procedures

22. History of stroke or intracranial hemorrhage = 6 months before the first dose of the study drug

23. Concurrent treatment for the disease under study outside this clinical study

24. Requires treatment with warfarin or other vitamin K antagonists

25. Ongoing drug-induced liver injury, alcoholic liver disease, nonalcoholic steatohepatitis, primary biliary cirrhosis, ongoing extrahepatic obstruction caused by cholelithiasis, cirrhosis of the liver, or portal hypertension

26. History of a severe bleeding disorder such as hemophilia A, hemophilia B, von Willebrand disease (see inclusion criterion 7d, regarding patients with acquired von Willebrand’s syndrome due to WM), or history of spontaneous bleeding requiring blood transfusion or other medical intervention

27. Receiving drugs known to prolong the QT/QTc interval (see Appendix 15)

28. Vaccination with a live vaccine = 35 days before the first dose of the study drug
Note: Seasonal vaccines for influenza are generally inactivated vaccines and are allowed. Intranasal vaccines are live vaccines and are not allowed.

29. Prior treatment with BGB-16673 or any other compound where the mechanism of action involves increased degradation of BTK

30. Known hypersensitivity to any component or excipient of BGB-16673

31. Concurrent participation in another therapeutic clinical trial (for any indication
Weitere Info ClinicalTrials.gov  
Ansprechpartner Email: ectu.cooperation@uniklinik-ulm.de , Tel. 0731 500 56070
Klinik ECTU (Early Clinical Trials Unit)
Kurztitel BI 1403-0002
EudraCT-Nr 2019-001173-84
Titel Eine offene Phase-Ia/Ib-Dosis-Eskalationsstudie zur Kombination von BI 907828 mit BI 754091 (Ezabenlimab), gefolgt von Erweiterungskohorten, bei Patienten mit fortgeschrittenen soliden Tumoren
Studiendesign Interventionsstudie , nicht randomisiert , Phase I
Strategie 2nd line , 3rd line
Einschlusskriterien
All cohorts:

1. Provision of signed and dated, written informed consent form ICF in accordance with ICH-GCP and local legislation prior to any trial-specific procedures, sampling, or analyses.

2. Male or female >= 18 years old at the time of signature of the ICF.

3. ECOG performance status of 0 or 1.

4. Life expectancy of at least 12 weeks after the start of the treatment according to the Investigator’s judgement.

5. Patients with radiologically documented disease progression or relapse during or after all standard of care treatments. Patients who are not eligible to receive standard of care treatments, and for whom no proven treatments exist, are eligible.

6. Previous treatment with an anti-PD-1/PD-L1 mAb is allowed as long as the last administration of the anti-PD-1/PD-L1 mAb on the previous treatment occurred a minimum of 28 days prior to the first administration of study treatment.

7. Patient must be willing to participate in the blood sampling for the PK, PD, and tumor mutation analysis

8. Adequate organ function defined as all of the following (all screening labs should be performed locally within 10 days of treatment initiation): Table 3.3.2: 1 Screening reference laboratory values

SYSTEM: Laboratory Value

HEMATOLOGICAL

Absolute neutrophil count: >= 1.5 x 10^9 /L (or >= 1.5 x 10^3 /µL or >= 1500/mm^3 )

Platelets: >= 100 x 10^9 /L (or >= 100 x 10^3 /µL or >= 100 x 10^3 /mm^3 )

Hemoglobin: >= 8.5 g/dL or >= 5.3 mmol/L (red blood cell transfusion allowed to meet eligibility criteria) or >= 85 g/L

HEPATIC

Total bilirubin <= 1.5 times the upper limit of normal (ULN), (patients with Gilbert’s syndrome, total bilirubin must be <= 3 x ULN)

AST and ALT: <= 2.5 x ULN OR <= 5 x ULN for patients with liver metastases

RENAL

Creatinine*: <= 1.5 x ULN Patients may enter if creatinine is > 1.5 x ULN and estimated glomerular filtration rate (eGFR) > 50 mL/min (assessed by Chronic Kidney Disease Epidemiology [CKD EPI] Collaboration equation); confirmation of eGFR is only required when creatinine is > 1.5 x ULN

COAGULATION

International Normalised Ratio (INR) or Prothrombin Time (PT). Activated Partial Thromboplastin Time (aPTT): <= 1.5 x institutional ULN. Patients taking low dose warfarin must have their INR followed closely and according to institutional guidelines.

*Creatinine can be assessed by any of these methods: CREE (enzymatic serum creatinine assay), CREJIDMS (IDMS standardized Jaffe), or CREJ (non IDMS standardized Jaffe).

9. Women of childbearing potential (WOCBP1 ), and men able to father a child must be ready and able to use two medically acceptable methods of birth control per ICH M3 (R2) that result in a low failure rate of less than 1 % per year when used consistently and correctly beginning at screening, during trial participation and until certain time has passed after the last administration of trial medication (details in Section 4.2.2.3):

- Women: 6 months and 12 days after end of BI 907828; 6 months after end of ezabenlimab.

- Men: 102 days after end of BI 907828; 6 months after end of ezabenlimab. A list of contraception methods meeting these criteria is provided in the patient information.

^1 A woman is considered of childbearing potential (WOCBP), i.e. fertile, following menarche and until becoming post-menopausal unless permanently sterile.
Permanent sterilisation methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy. Tubal ligation is NOT a method of permanent sterilization.
A postmenopausal state is defined as no menses for 12 months without an alternative medical cause

Conditions specific to respective part of the trial:

Phase Ia (dose escalation part):

10. Patients with a confirmed diagnosis of unresectable, advanced and/or metastatic solid tumors (any type) irrespective of the TP53 mutation status.

11. Patients with either evaluable or non-evaluable disease.

12. Availability and willingness to provide a sample of archival FFPE tumor tissue material. Phase Ia (Expansion Cohort)

13. Patients with MDM2 amplified tumors and TP53 wild type status confirmed on tumor tissue

14. At least one target lesion that can be accurately measured per RECIST 1.1. In patients who only have one target lesion, the baseline imaging must be performed at least two weeks after any biopsy of the target lesion. Phase Ib (dose expansion part):

15. At least one target lesion that can be accurately measured per RECIST 1.1. In patients who only have one target lesion, the baseline imaging must be performed at least two weeks after any biopsy of the target lesion.

16. Patients with TP53 wild-type status confirmed on tumor tissue.

17. Provision of fresh tissue biopsy at screening (may be omitted if patient has archival tissue within 12 months prior to enrolment) and willingness to provide fresh tissue biopsy on study, if safe and feasible on either occasion.

18. Patients with the following tumor types:

- COHORT 1: Patients with unresectable, advanced and/or metastatic TP53 wt selected subtypes of soft tissue sarcomas as listed below, who received at least one line of systemic medical treatment in the advanced and/or metastatic setting:

- Liposarcoma excluding dedifferentiated liposarcoma
- Undifferentiated pleomorphic sarcoma
- Myxofibrosarcoma
- Synovial sarcoma
- Leiomyosarcoma

- COHORT 2: Patients with unresectable, advanced and/or metastatic TP53 wt MDM2-amplified tumors as listed below, who received at least one line of systemic medical treatment in the advanced and/or metastatic setting:

- NSCLC (patients with NSCLC harboring genomic aberrations for which approved targeted therapy is approved and available, must have received such prior treatment)
- Gastric adenocarcinoma
- Urothelial carcinoma
- Biliary tract carcinoma (including cholangiocarcinoma, intra-and extrahepatic biliary tree, gall bladder and ampulla of vater)
Ausschlusskriterien
Patients must not enter the trial if any of the following exclusion criteria are fulfilled:

1. Previous administration of BI 907828 or any other MDM2-p53 or MDMX (MDM4)-p53 antagonist.

2. In Phase Ib (expansion phase) and Phase Ia expansion cohort only: a documented aminoacid altering mutation in TP53 occurring in the patient’s tumor.

3. Symptomatic brain metastases. Note: Patients with previously treated brain metastases may participate but treated lesions should not be used as target lesions. 4. Exclusion criterion

4 is not applicable for patients enrolled after protocol version 4 is approved.

5. Patients with history of bleeding diathesis.

6. Major surgery (major according to the Investigator’s assessment) performed within 12 weeks prior to start of study treatment or planned within 12 months after screening (e.g. hip replacement).

7. Any other documented active or suspected malignancy or history of malignancy within 3 years prior to screening, except appropriately treated basal cell carcinoma of the skin or in situ carcinoma of uterine cervix, or other local tumors considered cured by local treatment.

8. Patients who must or wish to continue the intake of restricted medications (see Section 4.2.2.1) or any drug considered likely to interfere with the safe conduct of the trial.

9. Currently enrolled in another investigational device or drug trial, or less than 4 weeks since receiving other investigational treatments. Patients who are in follow-up/observation for another clinical trial are eligible.

10. Exclusion criterion 10 is not applicable for patients enrolled after protocol version 4 is approved.

11. Patients who have not recovered from all clinically significant adverse events from their most recent therapy or intervention prior to study enrolment.

12. Known history of human immunodeficiency virus (HIV) infection.

13. Any of the following known laboratory evidence of hepatitis virus infection:

- Positive results of hepatitis B surface (HBs) antigen
- Presence of HBc antibody together with HBV-DNA
- Presence of hepatitis C RNA

14. Known hypersensitivity to the trial drugs or their excipients.

15. Serious concomitant disease or medical condition affecting compliance with trial requirements or which are considered relevant for the evaluation of the efficacy or safety of the trial drug, such as neurologic, psychiatric, infectious disease or active ulcers (gastro-intestinal tract, skin) or laboratory abnormality that may increase the risk associated with trial participation or trial drug administration, and in the judgment of the Investigator, would make the patient inappropriate for entry into the trial.

16. Chronic alcohol or drug abuse or any condition that, in the Investigator’s opinion, makes them an unreliable trial patient or unlikely to complete the trial.

17. Women who are pregnant, nursing, or who plan to become pregnant while in the trial; female patients who do not agree to the interruption of breast feeding from the start of study treatment until 6 months and 12 days after last dose of study treatment.

18. History of (including current) interstitial lung disease or pneumonitis within the last 5 years.

19. History of severe hypersensitivity reactions to other monoclonal antibodies

20. Immunosuppressive corticosteroid doses (> 10 mg prednisone daily or equivalent) within 4 weeks prior to the first dose of study treatment.

21. Active autoimmune disease or a documented history of autoimmune disease, that requires systemic treatment, i.e. corticosteroids or immunosuppressive drugs, except vitiligo or resolved childhood asthma/atopy, alopecia, or any chronic skin condition that does not require systemic therapy; patients with autoimmune-related hypothyroidism on a stable dose of thyroid replacement hormone and/or controlled Type 1 diabetes mellitus on a stable insulin regimen are eligible.

22. Active infection requiring systemic treatment (antibacterial, antiviral, or antifungal therapy) at start of treatment in this trial.

23. Any of the following cardiac criteria:

- Mean resting corrected QT interval (QTc) > 470 msec
- Any clinically important abnormalities (as assessed by the Investigator) in rhythm, conduction, or morphology of resting ECGs, e.g., complete left bundle branch block, third degree heart block
- Any factor that increases the risk of QTc prolongation or risk of arrhythmic events such as heart failure, hypokalaemia, congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under 40 years-of-age, or any concomitant medication known to prolong the QT interval
- Patients with an ejection fraction (EF) < 50 % or the lower limit of normal of the institutional standard will be excluded. Only in cases where the Investigator (or the treating physician or both) suspects cardiac disease with negative effect on the EF, will the EF be measured during screening using an appropriate method according to local standards to confirm eligibility (e.g., echocardiogram, multi-gated acquisition scan). A historic measurement of EF no older than 6 month prior to first administation of study drug can be accepted provided that there is clinical evidence that the EF value has not worsened since this measurement in the opinion of the Investigator or of the treating physician or both.
Weitere Info Kompetenznetz Leukämie - Deutsches Leukämie Studienregister - DLSR   ClinicalTrials.gov   ICH GCP NETWORK  
Ansprechpartner Email: ectu.cooperation@uniklinik-ulm.de , Tel. 0731 500 56070
Klinik ECTU (Early Clinical Trials Unit)
Kurztitel BO43243
EudraCT-Nr 2021-000846-16
Titel Eine offene, multizentrische Phase-Ib-Studie zur Beurteilung der Sicherheit, Wirksamkeit und Pharmakokinetik von Mosunetuzumab bei Patienten mit rezidivierter oder refraktärer chronischer lymphatischer Leukämie
Studiendesign Interventionsstudie , nicht randomisiert , Phase I
Strategie 3rd line
Einschlusskriterien
Participants are eligible to be included in the study only if all of the following criteria apply:

- Capable of giving signed informed consent as described in Appendix 1, which includes compliance with the requirements and restrictions listed in the Informed Consent Form and in this protocol

- Age >= 18 years at the time of signing the Informed Consent Form

- Ability to comply with the study protocol and procedures and required hospitalizations, in the investigator’s judgement

- Have a diagnosis of CLL requiring treatment according to the iwCLL criteria (Hallek et al. 2018)

- Participants must meet the following criteria for R/R CLL per iwCLL 2018 criteria
- Relapse is defined as evidence of disease progression in a patient who has previously achieved a complete response (CR) or partial response (PR) for >= 6 months.
- Refractory disease is defined as treatment or as progression within 6 months from the last dose of therapy.
- Previously treated with at least two lines of therapy, including at least one prior BTKi and/or venetoclax-based regimen

- Screening flow cytometry or immunohistochemistry (IHC) evidence of CD20 positive disease as per local review (dim expression of CD20 is acceptable)

- Eastern Cooperative Oncology Group (ECOG) performance score (PS) of <= 2

- Adequate BM function independent of growth factor or transfusion support, within 2 weeks of screening, at screening as follows unless cytopenia is clearly due to marrow involvement of CLL:
- Platelet count >= 75,000/mm^3; in cases of thrombocytopenia clearly due to marrow involvement of CLL (per the discretion of the investigator), platelet count should be >= 30,000/mm^3
- ANC >= 1000/mm^3 unless neutropenia is clearly due to marrow involvement of CLL (per the discretion of the investigator)
- Total hemoglobin >= 9 g/dL unless anemia is due to marrow involvement of CLL (per the discretion of the investigator)

- Adequate liver function as indicated by a total bilirubin, AST, and ALT <= 2 times the institutional ULN value, unless directly attributable to the patient’s CLL

- Measured or estimated creatinine clearance >= 45 mL/min by institutional standard method

- Life expectancy > 6 months

- For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive methods that result in a failure rate of < 1 % per year, and agreement to refrain from donating eggs, during the treatment period and for at least 3 months after the last dose of mosunetuzumab and 3 months after the last dose of tocilizumab (if applicable)

A woman is considered to be of childbearing potential if she is postmenarchal, has not reached a postmenopausal state (>= 12 continuous months of amenorrhea with no identified cause other than menopause), and is not permanently infertile due to surgery (i.e., removal of ovaries, fallopian tubes, and/or uterus) or another cause as determined by the investigator (e.g., Müllerian agenesis). The definition of childbearing potential may be adapted for alignment with local guidelines or regulations.

Examples of contraceptive methods with a failure rate of < 1 % per year include bilateral tubal ligation, male sterilization, hormonal contraceptives that inhibit ovulation, hormone-releasing intrauterine devices, and copper intrauterine devices.

The reliability of sexual abstinence should be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the individual.
Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not adequate methods of contraception.
If required per local guidelines or regulations, locally recognized adequate methods of contraception and information about the reliability of abstinence will be described in the local Informed Consent Form.

- For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use a condom, and agreement to refrain from donating sperm, as defined below:

With a female partner of childbearing potential or pregnant female partner, men must remain abstinent or use a condom during the treatment period and for 2 months after the final dose of tocilizumab (if applicable), to avoid exposing the embryo. Men must refrain from donating sperm during this same period.

The reliability of sexual abstinence should be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the individual.
Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not adequate methods of preventing drug exposure. If required per local guidelines or regulations, information about the reliability of abstinence will be described in the local Informed Consent Form.
Ausschlusskriterien
Participants are excluded from the study if any of the following criteria apply:

- Pregnant or breastfeeding, or intending to become pregnant during the study or within 3 months after the final dose of mosunetuzumab and tocilizumab (if applicable)

Women of childbearing potential must have a negative serum pregnancy test result within 14 days prior to initiation of study treatment. If a serum pregnancy test has not been performed within 14 days prior to receiving first study treatment, a negative urine pregnancy test result (performed within 7 days prior to study treatment) must be available.

- Participants who have received any of the following treatments prior to study entry:
- Treatment with mosunetuzumab or other CD20/CD3-directed bispecific antibodies
- Allogeneic stem cell transplant

- Participants who have received any of the following treatments, whether investigational or approved, within the respective time periods prior to initiation of study treatment:
- Radiotherapy within 2 weeks prior to the first dose of study treatment
- Autologous stem cell transplant within 100 days prior to first study treatment
- CAR T-cell therapy within 30 days before first study treatment
- Use of monoclonal antibodies or antibody-drug conjugates within 4 weeks prior to
first study treatment
- Systemic immunosuppressive medications (including, but not limited to, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor necrosis factor agents) within 2 weeks prior to first dose of study treatment
Systemic corticosteroid treatment<= 20 mg/day prednisone or equivalent and inhaled corticosteroids are permitted.
Administration of acute, low-dose, systemic immunosuppressant medications (e.g., single dose of dexamethasone for nausea orB-symptoms) is permitted.
The use of mineralocorticoids for management of orthostatic hypotension and corticosteroids for management of adrenal insufficiency is permitted.

- Any other anti-cancer therapy, whether investigational or approved, including but not limited to chemotherapy, within 4 weeks or 5 half-lives of the drug, whichever is shorter, prior to initiation of study treatment.
- Prior cancer immunotherapy not explicitly described in this protocol should be discussed with the Medical Monitor to determine eligibility

- Received a live, attenuated vaccine within 4 weeks before first dose of study treatment, or in whom it is anticipated that such a live attenuated vaccine will be required during the study period or within 5 months after the final dose of study treatment

- Transformation of CLL to aggressive NHL (e.g., Richter’s transformation, prolymphocytic leukemia, or diffuse large B cell lymphoma [DLBCL]) or CNS involvement by CLL

- History of severe allergic or anaphylactic reactions to humanized or murine monoclonal antibody therapy (or recombinant antibody-related fusion proteins)

- Contraindication to tocilizumab

- History of prior malignancy, except for conditions as listed below if patients have recovered from the acute side effects incurred as a result of previous therapy:
- Malignancies treated with curative intent and with no known active disease present for >= 2 years before enrollment
- Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease
- Adequately treated cervical carcinoma in situ without evidence of disease
- Surgically/adequately treated low grade, early stage, localized prostate cancer without evidence of disease

- Participants with infections requiring IV treatment with antibiotics or hospitalization (Grade 3 or 4) within the last 4 weeks prior to enrollment or known active bacterial, viral (including SARS-CoV-2), fungal, mycobacterial, parasitic, or other infection (excluding fungal infections of nail beds) at study enrollment

- Evidence of any significant, concomitant disease that could affect compliance with the protocol or interpretation of results, including, but not limited to:
- significant cardiovascular disease (e.g., New York Heart Association Class III or IV cardiac disease, myocardial infarction within the previous 6 months, unstable arrhythmia, or unstable angina)
- significant pulmonary disease (such as obstructive pulmonary disease or history of bronchospasm)
- clinically significant history of liver disease, including viral or other hepatitis, or cirrhosis
- current or past history of CNS disease, such as stroke, epilepsy, CNS vasculitis, or neurodegenerative disease
Participants with a history of stroke who have not experienced a stroke or transient ischemic attack in the past 1 year and have no residual neurologic deficits as judged by the investigator are allowed.
.Participants with a history of epilepsy who have had no seizures in the past 2 years with or without anti-epileptic medications can be eligible only for the expansion cohort

- History of confirmed progressive multifocal leukoencephalopathy (PML)

- Positive serologic HIV test at screening

- Positive test results for chronic hepatitis B infection (defined as positive hepatitis B surface antigen [HBsAg] serology)
Participants with occult or prior hepatitis B infection (defined as positive total hepatitis B core antibody and negative HBsAg) may be included if hepatitis B virus (HBV) DNA is undetectable at the time of screening.
These participants must be willing to undergo monthly DNA testing and appropriate prophylactic antiviral therapy as indicated.

- Acute or chronic hepatitis C virus (HCV) infection
Participants who are positive for HCV antibody must be negative for HCV by polymerase chain reaction (PCR) to be eligible for study participation.

- Known or suspected history of HLH

- History of autoimmune disease, including, but not limited to, myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis associated with antiphospholipid syndrome, Wegener granulomatosis, Sjögren syndrome, Guillain-Barre syndrome, multiple sclerosis, vasculitis, or glomerulonephritis (see Appendix 6)
Participants with a history of autoimmune-related hypothyroidism on a stable dose of thyroid replacement hormone may be eligible.
Participants with controlled Type 1 diabetes mellitus who are on an insulin regimen are eligible for the study.
Participants with a history of disease-related immune thrombocytopenic purpura or autoimmune hemolytic anemia may be eligible
Participants with a remote history of, or well-controlled autoimmune disease, with a treatment-free interval from immunosuppressive therapy for 12 months may be eligible after review and discussion with the Medical Monitor.

- Evidence of other clinically significant uncontrolled condition(s) including but not limited to active or uncontrolled systemic infection (e.g., viral, bacterial, or fungal)

- Recent major surgery within 4 weeks prior to first study treatment administration, with the exception of protocol-mandated procedures (e.g., tumor biopsies and bone
marrow biopsies)

- Participants who are in dependence to the Sponsor or an investigator

- Any serious medical condition or abnormality in clinical laboratory tests that, in the investigator's judgment, precludes an individual's safe participation in and completion of the study.
Weitere Info ICH GCP NETWORK   ClinicalTrials.gov  
Ansprechpartner Email: ectu.cooperation@uniklinik-ulm.de , Tel. 0731 500 56070
Klinik ECTU (Early Clinical Trials Unit)
Kurztitel CA052-002
EudraCT-Nr 2021-001188-26
Titel Eine Phase-1/2-Studie mit BMS-986340 als Monotherapie und in Kombination mit Nivolumab oder Docetaxel bei Teilnehmern mit fortgeschrittenen soliden TumorenEine Studie zu BMS-986340 als Monotherapie und in Kombination mit Nivolumab oder Docetaxel bei Teilnehmern mit fortgeschrittenen soliden Tumoren
Studiendesign Interventionsstudie , nicht randomisiert , Phase I/II
Strategie 2nd line , 3rd line
Weitere Info ClinicalTrials.gov   ICH GCP NETWORK   EU Clinical Trials Register  
Ansprechpartner Email: ectu.cooperation@uniklinik-ulm.de , Tel. 0731 500 56070
Klinik ECTU (Early Clinical Trials Unit)
Kurztitel CORIST
EudraCT-Nr 2019-003779-20
Titel Eine offene prospektive klinische Phase-II-Studie zur Untersuchung der Sicherheit, Verträglichkeit, der maximalen verträglichen Dosis und Antitumorwirkung von SC0-101 in Kombination mit FOLFIRI als sichere und wirksame Behandlungsmethode bei Patienten mit metastasiertem oder fortgeschrittenem kolorektalem Karzinom (mCRC) mit erworbener FOLFIRI-resistenter Krebserkrankung. - CORIST
Studiendesign Interventionsstudie , nicht randomisiert , Phase II
Strategie 2nd line
Einschlusskriterien
Subjects are required to meet all of the following criteria for enrollment into the applicable stage (stage 1, stage 2, stage 3 or stage 4) of the study:

1. Ability to understand and willingness to provide written informed consent before any trialrelated activities.

2. Age 18 years or older.

3. Histologically verified colorectal adenocarcinoma.

4. Non-resectable mCRC in patients.
A. Stage 1: with or without BRAF, RAS or known repair enzyme mutations ***
B. Stage 2: without known BRAF, RAS or repair enzyme mutations***
C. Stage 3 and stage 4: with or without BRAF, RAS or repair enzyme mutations, actual status to be confirmed prior to enrollment****

5. Previous treatment and documented progressive disease with irinotecan and 5-FU (including 5-FU based analogs, e.g. capecitabine) based chemotherapy regimens (with or without antiangiogenetic and EGFR inhibitory biological treatment) (Fussnote).

6. Maximum reduction of 33 % in prior dose of FOLFIRI.

7. Previous treatment with an oxaliplatin-containing treatment regimen and no indication for re challenge with oxaliplatin. The patient can have received oxaliplatin treatment before and/or after treatment with FOLFIRI.

8. A. Stage 1 and 3 only: Evaluable disease by CT scan or MRI.
B. Stage 2 and stage 4 only: Measurable disease by CT scan or MRI, according to RECIST.
1.1.

9. Performance status of ECOG <= 1.

10. Recovered to Grade 1 or less from prior surgery or acute toxicities of prior radiotherapy or treatment with cytotoxic or biologic agents*****.

11. >= 2 weeks must have elapsed since any prior surgery.

12. Adequate conditions as evidenced by the following clinical laboratory values:
- Absolute neutrophils count (ANC) >= 1.5 x 10^9 /L
- Hemoglobin >= 6.0 mmol/L
- Platelets >= 100 x 10^9 /L
- Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) <= 2.5 x ULN*
- Total serum bilirubin <= 1.0 ULN**
- Alkaline phosphatase <= 2.5 x ULN*
- Normal kidney function defined as either creatinine (<= 1.5 ULN) or calculated creatinine clearance or eGFR within normal limits determined according to local standards
- Adequate blood clotting function as defined by the International Normalized Ratio (INR) <= 1.5;

13. Life expectancy equal to or longer than 3 months.

14. Sexually active males and females of child-producing potential must use highly effective contraception (intrauterine devices, hormonal contraceptives (contraceptive pills, implants, transdermal patches, hormonal vaginal devices or injections with prolonged release)) for the study duration and at least 6 months after the last dose of study drug.

15. Signed informed consent.
16. Patients are only eligible for inclusion if no further on label treatment alternatives are available, i.e:
a. They have progressed on all available standard treatments, and/or
b. are intolerant to all remaining standard treatments, and/or
c. decline treatment with all other standard treatments, and/or
d. if the patient according to the treating physicians cannot be offered further standard treatment for their cancer disease.

*AST is not mandatory. In case of known liver metastases with ALT and AST <= 5 x ULN and/or alkaline phosphatase <= 5 x ULN:
Patients who do not conform to the transaminase and/or alkaline phosphatase inclusion criteria, but who by the PI are considered in good PS and otherwise eligible for inclusion, and where the transaminase and/or alkaline phosphatase levels are considered elevated due to other reasons than deteriorated lever capacity, may be considered for inclusion based on conferred agreement between PI and sponsor.

**Unconjugated bilirubin may be measured as the difference between total bilirubin and conjugated bilirubin.

*** BRAF- and RAS mutation status and repair enzyme status in the category MSI, dMSS and pMSS can be collected from the patient’s journal.

**** RAS status must be confirmed prior to enrollment using local standard procedures. Patients with previously confirmed RAS mutation can also be enrolled based on historical confirmation of RAS mutation available up to 24 months prior to study enrollment. Patients with unknown RAS status are not eligible for inclusion.

***** A minimum of 3 weeks must have elapsed since the last administration of previous anti-cancer treatment before planned first administration of SCO-101.

Fussnote: Evidence of progression within 8 weeks of last anti-cancer treatment.
Ausschlusskriterien
Subjects meeting any of the following criteria will be excluded from enrollment:

1. Concurrent chemotherapy, radiotherapy, or other investigational drugs during study period.

2. Malabsorption syndrome or previous surgeries with resection of the stomach or small intestine, whereby absorption of SCO-101 may be affected. This includes patients with ileostomy.

3. Difficulty in swallowing tablets.

4. Clinical symptoms of CNS metastases requiring steroids.

5. Any active infection requiring parenteral or oral antibiotic treatment.

6. Known HIV positivity.

7. Known active hepatitis B or C.

8. Clinical significant (i.e. active) cardiovascular disease:
- Stroke within <= 6 months prior to day 1
- Transient ischemic attach (TIA) within <= 6 months prior to day 1
- Myocardial infarction within <= 6 months prior to day 1
- Unstable angina
- New York Heart Association (NYHA) Grade II or greater congestive heart failure (CHF)
- Serious cardiac arrhythmia requiring medication

9. Mental status is not fit for clinical study or CNS disease including symptomatic epilepsy.

10. Other medications or conditions that in the Investigator’s opinion would contraindicate study participation of safety reasons or interfere with the interpretation of study results. Other severe medical conditions, including serious heart disease, unstable diabetes, uncontrolled hypercalcemia, clinically active infections or previous organ transplants.
Participation in another clinical trial with experimental medication within 30 days prior to registration.

11. Known hypersensitivity to SCO-101, irinotecan, 5-FU or structurally similar drugs (e.g. capecitabine), leucovorin and G-CSF.

12. Pregnant women or women who are breastfeeding.

13. Patients with known Dihydropyrimidine dehydrogenase (DPD) deficiency.
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Ansprechpartner Email: ectu.cooperation@uniklinik-ulm.de , Tel. 0731 500 56070
Klinik Innere Medizin I
Kurztitel CPDR001X2X01B
EudraCT-Nr 2019-000508-14
Titel Ein offenes multizentrisches Rollover-Protokoll zur weiteren Charakterisierung von Sicherheit und Verträglichkeit bei Patienten, die an einer von Novartis gesponserten Studie mit Spartalizumab als Einzelsubstanz oder in Kombination mit einer anderen Studienbehandlung teilgenommen haben
Studiendesign Interventionsstudie , nicht randomisiert , Phase I
Strategie 2nd line
Einschlusskriterien
Subjects eligible for inclusion in this study must meet all of the following criteria:
1. Signed informed consent must be obtained prior to participation in the study.
2. Subject is currently enrolled in a pre-defined Novartis-sponsored study and is receiving spartalizumab as single agent or in combination with other study treatment.
3. Subject is currently deriving clinical benefit from the study treatment, as determined by the investigator.
4. Subject has demonstrated compliance, as assessed by the investigator, with the parent protocol requirements.
5. Subject is willing and able to comply with the scheduled visits and treatment plans.
Ausschlusskriterien
Subjects meeting any of the following criteria are not eligible for inclusion in this study.
- Subject has been permanently discontinued from spartalizumab in the parent protocol for any reason other than enrollment in the CPDR001X2X01B study.
- Subject does not meet the criteria specified in the parent protocol criteria for continued study treatment.
- Subject not willing to comply with the contraception requirements outlined in the exclusion criteria of the parent protocol.
Weitere Info ClinicalTrials.gov  
Ansprechpartner Email: ectu.cooperation@uniklinik-ulm.de , Tel. 0731 500 56070
Klinik ECTU (Early Clinical Trials Unit)
Kurztitel GMALL-BLIVEN
EudraCT-Nr 2021-001384-25
Titel Eine offene Phase-I/II-Studie mit Venetoclax als Ergänzung zur Blinatumomab Immuntherapie bei erwachsenen Patienten mit rezidivierter/refraktärer akuter B-Zell-Vorläufer akuter lymphoblastischer Leukämie (BCP-ALL)Eine offene, forschungsinitiierte Phase I/II – Studie mit Venetoclax in Kombination mit Blinatumomab Immuntherapie bei erwachsenen Patienten mit rezidivierter/refraktärer ALLVenetoclax bei rezidivierter/refraktärer BCP-ALL in Kombination mit Blinatumomab - GMALL-BLIVEN
Studiendesign Interventionsstudie , nicht randomisiert , Phase I/II
Strategie 1st line , 2nd line , 3rd line
Einschlusskriterien
Patients must meet all of the following inclusion criteria to be eligible to enroll in this study:

1. Written informed consent in accordance with federal, local, and institutional guidelines. The patient must provide informed consent prior to the first screening procedure

2. Age >= 18 years

3. Eastern Cooperative Oncology Group (ECOG) performance status of <= 2

4. Availability of patient-specific molecular MRD markers of immunoglobulin/T-cell receptor gene rearrangements as assessed with a sensitivity of at least 10E-04

5. Diagnosis of Ph-negative, CD19-positive B-precursor acute lymphoblastic leukemia according to WHO classification:

- Refractory BCP-ALL to primary induction therapy, including at least three cycles of standard chemotherapy
- Untreated first relapse of BCP-ALL with first remission duration < 12 months or
- Second or greater relapse of BCP-ALL or refractory relapse or
- Relapse of BCP-ALL any time after allogeneic HSCT or

6. Positivity of MRD marker of immunoglobulin/T-cell receptor gene rearrangements of greater than 0.01 % if in first or second remission of BCP-ALL

7. Negative pregnancy test < 7 days before first study drug in women of childbearing potential, defined as all women physiologically capable of becoming pregnant, unless they fulfil at least one of the following criteria:

- Post-menopausal (i.e. 12 months of natural amenorrhea or 6 months of amenorrhea with Serum FSH > 40 U/ml
- Post-operative after bilateral ovariectomy with or without hysterectomy
- Continuous and correct application of a contraception method with a Pearl index of < 1 % (e.g. implants, depots, oral contraceptives, intrauterine device) from initial study drug administration until at least 3 months after the last dose of study drug. A hormonal contraception method must always be combined with a barrier method (e.g. condom)
- Sexual abstinence
- Vasectomy of the sexual partner

8. Ability to understand and willingness to sign a written informed consent

9. Willingness to participate in the registry of the German Multicenter Study Group for Adult ALL (GMALL)
Ausschlusskriterien
Patients meeting any of the following exclusion criteria are not eligible to enroll in this study:

1. Patients with diagnosis of Philadelphia positive BCP-ALL according to WHO classification

2. Patients with diagnosis of Burkitt´s Leukemia according to WHO classification

3. Patients with extramedullary relapse; non-bulky lymph node (< 7.5 cm diameter) involvement will be accepted

4. Patients with CNS involvement at relapse (as determined by CSF analysis)

5. Patients with suspected or histologically confirmed testicular involvement at relapse

6. Current autoimmune disease of any kind or history of autoimmune disease with potential CNS involvement

7. Patients with Philadelphia-positive BCP-ALL still receiving TKI

8. Prior or concomitant therapy with BH3 mimetics

9. Prior therapy with anti CD19 therapy, unless administered in MRD-positive setting (i.e. with bone marrow blasts <= 5 %)

10. Treatment with any of the following within 7 days prior to the first dose of study drug: strong cytochrome P450 3A (CYP3A) inhibitors, moderate or strong CYP3A inducers

11. Intake of any of the following within 3 days prior to the first dose of study drug: grapefruit, grapefruit products, Seville oranges or star fruit

12. Presence of Graft-versus-Host Disease (GvHD) and/or on immunosuppressant medication
within 2 weeks before start of protocol-specified therapy

13. Radiation, chemotherapy (with the exception of prephase therapy), or immunotherapy or any other anticancer therapy <= 2 weeks prior to Cycle 1 Day 1 or radio-immunotherapy 4 weeks prior to Cycle 1 Day 1.

14. Major surgery within 2 weeks of first dose of study drug

15. Patients who are pregnant or lactating

16. Any life-threatening illness, medical condition or organ system dysfunction which, in the investigator's opinion, could compromise the patient’s safety

17. Unstable cardiovascular function:

- Symptomatic ischemia, or
- Uncontrolled clinically significant conduction abnormalities (1st degree AV block or asymptomatic LAFB/RBBB will not be excluded), or
- Congestive heart failure (CHF) of NYHA Class >= 3, or
- Myocardial infarction (MI) within 3 months

18. Evidence of clinically significant uncontrolled condition(s) including, but not limited to:
Uncontrolled and/or active systemic infection (viral, bacterial or fungal), chronic hepatitis B virus (HBV) or hepatitis C virus (HCV) requiring treatment. Note: subjects with serologic evidence of prior vaccination to HBV (i.e. hepatitis B surface (HBs) antigen negative-, anti HBs antibody (anti-HBs) positive and anti-hepatitis B core (HBc) antibody negative) or positive anti-HBc antibody from intravenous immunoglobulins (IVIG) or blood transfusions may participate.

19. Known human immunodeficiency virus (HIV) infection (HIV testing is not required)

20. Patients unable to swallow tablets, patients with malabsorption syndrome, or any other GI disease or GI dysfunction that could interfere with absorption of study treatment

21. Adequate hepatic function per local laboratory reference range as follows: Aspartate transaminase (AST) and alanine transaminase (ALT) < 3.0 x ULN, Bilirubin <= 1.5 x ULN (unless bilirubin rise is due to Gilbert’s syndrome or of non-hepatic origin)

22. Severe renal dysfunction: estimated creatinine clearance of < 20 mL/min, measured in 24 hour urine or calculated using the formula of Cockroft and Gault

23. History or presence of clinically relevant CNS pathology such as epilepsy, childhood or adult seizure, paresis, aphasia, stroke, severe brain injuries, dementia, Parkinson’s disease, cerebellar disease, organic brain syndrome, or psychosis. History of CNS leukemia that is controlled at relapse may be enrolled in this study.

24. History of malignancy other than ALL within 5 years prior to start of protocol-specified therapy with the exception of:

- Malignancy treated with curative intent and with no known active disease present for 2 years before enrollment and felt to be at low risk for recurrence by the treating physician including

- Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease

- Adequately treated cervical carcinoma in situ without evidence of disease

- Adequately treated breast ductal carcinoma in situ without evidence of disease

- Prostatic intraepithelial neoplasia without evidence of prostate cancer.

25. Current autoimmune disease or history of autoimmune disease with potential CNS involvement

26. Live vaccination within 2 weeks before the start of study treatment

27. Known hypersensitivity to immunoglobulins or to any other component of the study drug formulation

28. Subject has known sensitivity to immunoglobulins or any of the products or components to be administered during dosing.

29. Currently receiving treatment in another investigational device or drug study or less than 30 days since ending treatment on another investigational device or drug study(s). Thirty days is calculated from day 1 of protocol-specified therapy

30. Subject likely to not be available to complete all protocol-required study visits or procedures, including follow-up visits, and/or to comply with all required study procedures to the best of the subject’s and Investigator’s knowledge.

31. History or evidence of any other clinically significant disorder, condition or disease (with the exception of those outlined above) that, in the opinion of the investigator would pose a risk to subject safety or interfere with the study evaluation, procedures or completion.

32. Woman of childbearing potential, defined as all women physiologically capable of becoming pregnant, unless they fulfil at least one of the following criteria:

- Post-menopausal (i.e. 12 months of natural amenorrhea or 6 months of amenorrhea with Serum FSH > 40 U/ml
- Post-operative after bilateral ovariectomy with or without hysterectomy
- Continuous and correct application of a contraception method with a Pearl index of < 1 % (e.g. implants, depots, oral contraceptives, intrauterine device) from initial study drug administration
until at least 3 months after the last dose of study drug. A hormonal contraception method must always be combined with a barrier method (e.g. condom)
- Sexual abstinence
- Vasectomy of the sexual partner

33. Male who has a female partner of childbearing potential, and is not willing to use 2 highly effective forms of contraception while receiving protocol-specified therapy and for at least an additional 3 months after the last dose of protocol-specified therapy
Weitere Info EU Clinical Trials Register   ClinicalTrials.gov   Kompetenznetz Leukämie - Deutsches Leukämie Studienregister - DLSR  
Ansprechpartner Email: ectu.cooperation@uniklinik-ulm.de , Tel. 0731 500 56070
Klinik ECTU (Early Clinical Trials Unit)
Kurztitel IMA401-101
EudraCT-Nr 2021-004326-30
Titel Klinische Studie der Phase Ia/Ib mit Erstanwendung am Menschen zur Bewertung der Sicherheit, Verträglichkeit und ersten Anti-Tumor-Aktivität von IMA401, einem bispezifischen TCER-Molekül, bei Patienten mit rezidivierenden und/oder refraktären soliden Tumoren
Studiendesign Interventionsstudie , nicht randomisiert , Phase I
Strategie 2nd line
Einschlusskriterien
Inclusion Criteria;

HLA (S1), and Tumor Target Screening (S2) and Treatment Eligibility Assessment (VA)

1. Patients must have voluntarily signed a written ICF, be able to understand and comply with clinical trial procedures. S1: ICF1, VA: ICF2

2. Patients >= 18 years old. S1
3. Patients must have pathologically confirmed and documented advanced and/or metastatic solid tumor.

Among the range of solid tumor indications, sarcoma (e.g., synovial, myxoid liposarcoma or angiosarcoma), squamous non small-cell lung cancer (sqNSCLC), small-cell lung cancer (SCLC), head & neck squamous cell carcinoma (HNSCC), bladder urothelial carcinoma, uterine carcinosarcoma, esophageal carcinoma, testicular germ cell tumor, triple-negative breast cancer (TNBC), ovarian serous cystadenocarcinoma, cervical squamous cell carcinoma and adenocarcinoma, and cutaneous melanoma should be screened primarily. Other solid tumor indications may be considered after consultation with the sponsor.

NOTE: There is no limitation on type and number of prior anti-tumor treatments. S1: x

4. Patients must have a lesion considered accessible for a biopsy unless adequate tissue was obtained during a medically indicated procedure conducted at any time during the tumor disease (e.g., resection, debulking surgery, etc.), and obtained tissue was stored under appropriate storage conditions. S2: x

5. Patients must have measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST 1.1). VA: x^2

6. HLA genotype: HLA-A*02:01 positive and at the same time not positive for another HLA-A*02:XX sub allele (repeat assessment allowed).

NOTES: Suitable HLA genotype has to be assessed by an SBT and/or NGS-based assay. The NGS result will be used as decisive result.

For any patient previously HLA typed for participation in other Immatics-sponsored clinical trials or an Immatics-supported IIT using a central laboratory selected by Immatics for HLA-genotyping and confirmed as being HLA-A*02:01 positive via an SBT based assay, the additional NGS-based HLA typing assay must be performed to confirm the appropriate HLA-A genotype.

In case the patient is known to be HLA-A*02:01 positive as tested routinely or as a trial-specific procedure by a local hospital laboratory or central laboratory with appropriate accreditation (e.g., CLIA, CAP, EFI, ASHI, DakkS) using a PCR-based or sequencing-based method, S1 and S2 visit assessments may be conducted on the same day. For these patients, HLA genotyping by NGS must be repeated at Immatics designated CLIA/CAP-certified laboratory. The NGS result will be used as decisive result. S1: x (SBT/NGS), VA: x (NGS)

7. Patients’ tumor must express MAG-003 based on the following:

a. assessment by IMADetect RT-qPCR using a fresh tumor biopsy specimen either from this clinical trial, another Immatics-sponsored clinical trial, or an Immatics-supported IIT

OR

b. assessment by IMADetect RT-qPCR based on fresh tumor material stored in RNAlater/RNAprotect or (for fresh frozen tissues, after consultation with sponsor) RNALater ICE from any medically indicated procedure collected at any time during the tumor disease.

NOTE: If acquired tissue was inadequate to determine the presence of MAG-003 antigen, patients may undergo a repeat biopsy at the discretion of the investigator. S2: x

8. Life expectancy > 2 months. VA: x

9. ECOG Performance Status of 0 to 2. S1: x, S2: x, VA: x^1

10. Absolute neutrophil count (ANC) >= 1.0 x 10^9/L (without granulocyte colony-stimulating factor [G CSF] support); platelets >= 75,000/MikroL; hemoglobin >= 8 g/dL; absolute lymphocyte count (ALC) >= 0.5 x 10^9/L (repeat assessment allowed). S2:x, VA: x^1

11. Adequate hepatic function, as defined by a total bilirubin level <= 1.5 x upper limit of normal unless the patient is a hepatocellular carcinoma patient or has known Gilbert’s syndrome (total bilirubin level of <= 2.5 x ULN), and alanine aminotransferase (ALT)/aspartate aminotransferase (AST) <= 2.5 x ULN or <= 5 x ULN for patients with liver metastases (repeat assessment allowed). S2: x, VA: x^1

12 Adequate renal function defined by serum creatinine within 1.5 x normal range OR estimated glomerular filtration rate (eGFR) >= 50 mL/min/1.73m^2 (as estimated by Cockcroft Gault) (repeat assessment allowed). S2: x, VA: x^1

13. Acceptable coagulation status defined by an international normalized ratio (INR) of prothrombin time (PT) of blood coagulation <= 2.0 x ULN and partial thromboplastin time (PTT) <= 2.0 x ULN (repeat assessment allowed) unless patient is on stable dose of anticoagulants, the interruption of which for the purpose of obtaining the biopsy is medically feasible. S2: x, VA: x^1

14. Patients must have recurrent and/or refractory solid tumors and must have received or not be eligible for all available indicated standard-of-care treatments (e.g., radiation, surgery, chemotherapy, immunotherapy or targeted therapy). There is no limitation on type and number of prior anti-tumor treatments patients may have received. VA: x

15. The patient must have recovered from any side effects of prior therapy to Grade 1 or lower (except for non-clinically significant toxicities; e.g., alopecia, vitiligo) prior to treatment start. As determined by the investigator, the patient may still be eligible if not fully recovered from Grade >= 2 toxicities, in case these toxicities are not anticipated to further improve (e.g., chronic peripheral neuropathy) and such toxicities are not anticipated to worsen with the IMA401 therapy. VA: x

16. Male patients must agree to use highly effective contraception or be abstinent while on treatment and for 1 month after the last infusion of IMA401. VA: x

17. Female patients of childbearing potential must use highly effective contraception or be abstinent during screening, while on treatment and until 1 month after the last infusion of IMA401. S1: x, S2: x, VA: x

^1 Assessment to be performed 7 days prior to start of IMA401 treatment
^2 Imaging to be performed within 3 weeks prior to start of IMA401 treatment
Ausschlusskriterien
Exclusion Criteria;

HLA (S1), and Tumor Target Screening (S2) and Treatment Eligibility Assessment (VA)

1. Other active malignancies that require treatment or that might interfere with the trial endpoints (ongoing adjuvant anti-hormonal treatment is allowed). S1: x, VA: x

2. The patient is pregnant (confirmed by serum or urine pregnancy test) or is breastfeeding. S1: x^1, S2: x, VA: x

3. History of hypersensitivity to components of IMA401 or rescue medications, if no alternative treatment option is available. S1: x, VA: x

4. Patients with prior allogeneic stem cell transplantation or organ transplantation. S1: x, VA: x

5. Patients with autoimmune diseases needing disease-directed treatment such as serious inflammatory bowel disease (including Crohn’s disease and ulcerative colitis), rheumatoid arthritis, multiple sclerosis, systemic progressive sclerosis (scleroderma), systemic lupus erythematosus, vasculitis, hepatitis, nephritis, dermatitis. S1: x, VA: x

6. The patient is known to have any of the following clinically relevant cardiac conditions: uncontrolled hypertension despite optimal therapy, uncontrolled angina, clinically relevant ventricular arrhythmias, congestive heart disease (New York Heart Association Class II or above), baseline left ventricular ejection fraction <= 50 %, prior or current clinically relevant cardiomyopathy, uncontrolled atrial fibrillation, unstable ischemic heart disease (myocardial infarction within 6 months prior to biopsy or angina requiring use of nitrates), coronary heart disease with coronary intervention in the last 6 months or known clinically relevant stenosis upon coronary angiography/CT, or an implanted cardiac pacemaker. S1: x^1, S2: x, VA: x

7. Clinically significant pulmonary dysfunction, that, in the investigator’s judgement, would compromise the patient’s ability to tolerate protocol therapy or significantly increase the risk for complications. VA: x

8. The patient has concurrent severe and/or uncontrolled medical disease that could compromise participation in the trial (e.g., uncontrolled diabetes, severe malnutrition). S1: x, VA: x

9. History of, or current, immunodeficiency disease or prior treatment relevantly compromising immune function, at the discretion of the investigator. S1: x, VA: x

10. Any other condition that would, in the investigator’s judgement, contraindicate the patient’s participation in the clinical trial because of safety concerns (e.g., potential intolerance to IMA401) or compliance with clinical trial procedures (e.g., psychiatric disorders or substance dependence, neurological impairment). S1: x, VA: x

11. Human immunodeficiency virus (HIV) infection, active hepatitis B virus (HBV) infection, active hepatitis C virus (HCV) infection, ongoing active anti-HCV treatment or detectable HBV or HCV viral load at the most recent laboratory report. Patients with both HBV and HCV infections will be excluded from screening and trial participation.

a) Patients with a history of HCV infection and with an undetectable viral load (quantitative RNA assay) per the most recent laboratory report and/or completed anti-HCV treatment but are HCV Ab positive are permitted.

b) History of treated HBV infection is permitted, if the viral load is undetectable per the most recent laboratory report.

NOTE: Patients with controlled HBV infection, as defined by resolved (anti-hepatitis B surface [HBs] antigen [HBsAg] negative, anti-hepatitis B core [HBc] antigen positive) or chronic stable (anti HBsAg positive) HBV infection will be eligible for screening. Patients with active HBV infection who are not on anti-HBV treatment will be excluded. S1: x^1, S2: x, VA: x

12. Patients with any clinically relevant, active viral infection (e.g., COVID-19, influenza, Severe Acute Respiratory Syndrome [SARS], Middle East Respiratory Syndrome [MERS]). S1: x^2, S2: x^2, VA: x^3

13. The patient has received prior to start of IMA401 therapy systemic corticosteroids (>= 10 mg/day prednisone or equivalent), major surgery, any vaccines, therapeutic radiotherapy, cytotoxic agents, or small molecule treatments within 2 weeks, monoclonal antibodies within 3 weeks or 5 half-lives, or cell therapies within 3 months. No wash-out period is required for hormonal therapy.

NOTE: Use of inhaled or topical steroids is permitted. VA: x

14. Concurrent participation in an interventional part of another clinical trial after signature of ICF2. VA: x

15. Patients with active brain metastases.

NOTE: Patients with a history of brain metastases are eligible if imaging studies performed >=4 weeks following treatment indicate stable disease of brain metastasis, the patient is asymptomatic, and steroid therapy has been discontinued for >= 2 weeks. VA: x

^1 Based on medical history
^2 Screening may start or continue 2 weeks after recovery of viral infections and/or a negative test in case of a SARS-CoV-2 infection.
^3 IMA401 infusion may start at the earliest 2 weeks after recovery and a negative SARS-CoV-2 test.
Weitere Info ClinicalTrials.gov   ICH GCP NETWORK  
Ansprechpartner Email: ectu.cooperation@uniklinik-ulm.de , Tel. 0731 500 56070
Klinik ECTU (Early Clinical Trials Unit)
Kurztitel IMGN632-0802
EudraCT-Nr 2019-002477-56
Titel Eine Studie der Phase 1b/2 zur Beurteilung von IMGN632 als Monotherapie oder in Kombination mit Venetoclax und/oder Azacitidin für Patienten mit CD123-positiver akuter myeloischer Leukämie
Studiendesign Interventionsstudie , nicht randomisiert , Phase I/II
Strategie 2nd line
Einschlusskriterien
The inclusion and exclusion criteria will be assessed during screening (within 28 days before the first dose of any study drug on Cycle 1 Day 1, or as otherwise specified). A patient is considered enrolled when administered the first dose of any study drug.
Procedures for completion of enrollment information, and requirements to communicate with the sponsor about enrollment, are detailed in the Study Manual.

1. Patient must be >= 18 years of age.
2. Patients must have confirmed diagnosis of AML (excluding acute promyelocytic leukemia) based on World Health Organization classification (Arber 2016).
3. Disease characteristics and allowable prior therapy:
a. Patients must be evaluated for any available standard of care therapies (including induction, consolidation chemotherapy and/or transplant) and, in the opinion of the treating physician, be deemed appropriate for this experimental therapy.
b. Treatment-naive (untreated) patients will be allowed in the Expansion Phase for Regimens A (IMGN632 + azacitidine) and C (Triplet) (IMGN632 + azacitidine + venetoclax) in separate cohorts. No prior treatments with hypomethylating agents (HMAs) for MDS are allowed.
Note: Patients who are MRD+ are eligible for the Regimen D Cohorts D1 and D2 (Expansion Phase).
c. Patients must have CD123-positive AML as confirmed by local flow cytometry (or immunohistochemistry [IHC]).
d. Patients may have received prior CD123-targeted therapies, except IMGN632, as long as CD123 remains detectable during screening.
e. Relapsed or refractory CD123-positive AML patients will be allowed to enroll in the Escalation Phase of Regimens A, B, and C (Triplet) (IMGN632 + azacitidine, venetoclax, or azacitidine + venetoclax, respectively) and relapsed CD123-positive AML patients will be allowed to enroll the Expansion Phase of Regimens A-C. Note: Patients may also have received up to 2 prior lines of therapy, eg, frontline treatment (induction, consolidation [including transplant], and maintenance) and 1 salvage regimen.
f. Patients enrolling in Regimen D must be in CR (CR/CRh/CRp/CRi) and be MRD+ at the time of screening, confirmed by central laboratory testing. Patients may have no more than 2 prior lines of therapy (which may include stem cell transplant), ie, frontline or first salvage.
Note: Fit patients who received intensive treatment (eg 3+7, HiDAC, etc.) are eligible for Regimen D Cohort D1. Unfit patients who received non-intensive treatment (eg, HMA, low dose cytarabine, etc.) are eligible for Regimen D Cohort D2.
4. Eastern Cooperative Oncology Group performance status <= 1. If nonambulatory due to a chronic disability, must be Karnofsky performance status >= 70.
5. Previous treatment-related toxicities must have resolved to Grade 1 or baseline (excluding alopecia).
6. Total white blood cell count must be less than 25 x 10^9 cells/L. Hydroxyurea may be used to control blood counts before Cycle 1 Day 1, at the discretion of the treating physician, according to institutional practice. During the Escalation Phase in Regimens A-C, hydroxyurea may also be used during Cycle 1.
7. Liver enzymes (AST and ALT) <= 3 x the upper limit of normal (ULN).
8. Total bilirubin <= 1.5 x the ULN.
9. An estimated glomerular filtration rate (eGFR) of > 30 mL/min/1.73 m^2 or creatinine clearance of > 30 mL/min.
10. Left ventricular ejection fraction (LVEF) >= 45 % based on locally available assessment, eg, echocardiogram or other modality.
11. Patients with prior autologous or allogeneic bone marrow transplant are eligible. Patients with an allogeneic transplant must meet the following conditions: The transplant must have been performed more than 120 days before the date of dosing on this study, the patient must not have active >= Grade 2 graft versus host disease (GvHD), or extensive chronic GvHD of any severity, and must be off all immunosuppression for at least 2 weeks prior to first dose of IMGN632.
12. Voluntary written informed consent before performance of any study-related procedure not part of normal medical care.
13. Women of childbearing potential (WCBP), defined as sexually mature women who have not undergone surgical sterilization or who have not been naturally postmenopausal for at least 12 consecutive months (ie, who have had menses any time in the preceding 12 consecutive months), must agree to use acceptable contraceptive methods (see Section 5.2.7) while on study drug and for at least 7 months after the last dose of IMGN632.
14. WCBP must have a negative pregnancy test within 3 days before the first dose of study drug.
15. Male patients who are able to father children must agree to use acceptable methods of contraception (see Section 5.2.7) throughout the study and for at least 4 months after the last dose of IMGN632.
16. Patients with prior malignancy are eligible; however, the patient must be in remission from the prior malignancy and have completed all chemotherapy and radiotherapy for the
prior malignancy at least 6 months before enrollment, and all treatment-related toxicities must have resolved to Grade 1 or less.
Note: patients with prostate cancer or breast cancer on adjuvant hormonal therapy are eligible.
Ausschlusskriterien
1. Patients who have received any anticancer therapy, including investigational agents, within 14 days (or within 28 days for checkpoint inhibitors) before drug administration on this study (hydroxyurea is allowed before beginning study treatment). Patients must have recovered to baseline from all acute toxicity from this prior therapy.
2. Patients who have been previously treated with IMGN632.
3. Patients with myeloproliferative neoplasm–related secondary AML are excluded from the Dose Expansion Phase of the study.
4. Patients with active central nervous system (CNS) AML will be excluded. A lumbar puncture does not need to be performed unless there is clinical suspicion of CNS involvement per investigator judgement. Concurrent therapy for CNS prophylaxis or continuation of therapy for controlled CNS AML is allowed with the approval of the sponsor.
5. Patients with a history of sinusoidal obstruction syndrome/venous occlusive disease of the liver.
6. Myocardial infarction within 6 months before enrollment or New York Heart Association Class III or IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities before study entry.
7. Clinically relevant active infection including known active hepatitis B or C, HIV infection, or cytomegalovirus or any other known concurrent infectious disease that, in the judgment of the investigator, would make a patient inappropriate for enrollment into this study (testing not required).
8. Patients who have undergone a major surgery within 4 weeks (or longer if not fully recovered) before study enrollment.
9. Serious or poorly controlled medical conditions that could be exacerbated by treatment or that would seriously compromise safety assessment or compliance with the protocol, in the judgment of the investigator.
10. Women who are pregnant or breastfeeding
11. Prior known hypersensitivity reactions to monoclonal antibodies (>= Grade 3).
12. Prior known hypersensitivity reactions to study drugs and/or any of their excipients.
Weitere Info ClinicalTrials.gov   EU Clinical Trials Register  
Ansprechpartner Email: ectu.cooperation@uniklinik-ulm.de , Tel. 0731 500 56070
Klinik Innere Medizin III
Kurztitel INSIGHT 003
EudraCT-Nr 2016-002309-20
Titel Eine explorative, offene Phase I Studie zur Durchführbarkeit und Sicherheit von Eftilagimod alpha (IMP321, ein LAG-3Ig Fusionsprotein mit Wirkung als LAG-3-Agonist) in Kombination mit Immuntherapeutika, zielgerichteten Agentien oder Chemotherapeutika oder verabreicht mittels neuer Applikationswege bei forgeschittenen soliden TumorenPhase I Studie zu IMP321 bei verschiedenen fortgeschrittenen soliden Tumoren - INSIGHT
Studiendesign Interventionsstudie , nicht randomisiert , Phase I
Strategie 1st line , 2nd line
Einschlusskriterien
1. Histologically confirmed locally advanced (not manageable with curative intent) or metastatic solid tumor

Specification for Stratum C: Only patients with NSCLC adenocarcinomas, (squamous or adenosquamous not permitted) who are scheduled to receive platin + pembrolizumab + pemetrexed standard treatment (only for Stratum C)

Specification for Stratum E: Including only metastatic or irresectable locally advanced urothelial carcinomas – also refer to IC 15 below (only for Stratum E)

2. Tumor is accessible for repeated injections and biopsies (only for Stratum A)

3. Peritoneal carcinomatosis (only for Stratum B)

4. Patient failed standard therapy or refused standard therapy or is intolerable towards standard therapy (Strata A, B, and D) or who receives Standard-of-Care first line treatment comprising platin + pembrolizumab + pemetrexed (only for Stratum C)

5. Patient has not received more than 4 prior lines of therapy.
Neoadjuvant/adjuvant treatment is not counted unless progression occurs < 6 months after completion of the treatment. In these cases, neoadjuvant/adjuvant treatment is counted as one prior line (only for Stratum D).

Specification for Stratum C: Only patients receiving first line Standard-of-Care therapy (platin + pembrolizumab + pemetrexed; only for Stratum C)

Specification for Stratum E: Refer to IC 15 below with regards to previous lines of therapy; only for Stratum E)

Note exclusion criterion 7 on exclusion of defined previous cancer immunotherapy (only for Strata D and E)

6. Patients >= 18 years. Patients in reproductive age must be willing to use highly effective contraception during the study and 4 months after the end of the study (appropriate contraception is defined as combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation, progestogen-only hormonal contraception associated with inhibition of ovulation, intrauterine device (IUD), intrauterine hormone-releasing system (IUS), vasectomized partner, bilateral tubal occlusion, sexual abstinence. If an oral contraception is used, a barrier method of contraception (e.g. male condom, female condom, cervical cap, diaphragm, contraceptive sponge) has to be applied additionally.). Female patients with childbearing potential need to have a negative pregnancy test within 7 days before study start.

7. ECOG 0 or 1

8. Adequate hematological, hepatic and renal function parameters:
- ANC (absolute neutrophil count) >= 1.500/MikroL
- Leukocytes >= 3.000/MikroL
- Platelets >= 75.000/MikroL (for Stratum D: >= 100.000/MikroL)
- Serum creatinine <= 1.5 x upper limit of normal, or GFR >= 50 ml/min
- Bilirubin <= 1.5 - 3 x upper limit of normal (for Stratum D: <= 1.5 x ULN)
- AST and ALT <= 3 x upper limit of normal (<= 5 x if liver metastases are present) (for Stratum D: AST and ALT <= 2.5 x ULN; <= 5 x if liver metastases are present)
- Alkaline phosphatase <= 6 x upper limit of normal
- Hemoglobin >= 9g/dL

9. Adequate coagulation functions as defined by International Normalized Ratio (INR) <= 1.5, and a partial thromboplastin time (PTT) <= 5 seconds above the ULN (unless receiving anticoagulation therapy). Patients receiving warfarin/phenprocoumon must be switched to low molecular weight heparin and have achieved stable coagulation profile.

10. Patient able and willing to provide written informed consent and to comply with the study protocol and with the planned surgical procedures

11. Evidence of measurable disease as defined by RECIST v1.1 (only for Strata C, D and E) or assessable disease as defined by RECIST v1.1 (only for Stratum C)

12. Expected survival > 3 months

13. Resolution of toxicity associated with prior or current therapy to grade < 2 (except for alopecia and transaminases in case of liver metastases)

14. Patient is eligible if one of the following settings applies (only for Stratum E):
- did not receive any prior systemic therapy for metastatic disease AND would be eligible for platinum-based therapy AND has a PD-L1 CPS >= 10
or
- did not receive any prior systemic therapy for metastatic disease AND is not eligible for platinum-based therapy, independent from PD-L1 CPS status or
- did suffer disease progression during/directly after a platinum-based chemotherapy for metastatic disease AND did not receive avelumab maintenance therapy after platinum-based chemotherapy, independent from PD-L1 CPS status
Ausschlusskriterien
1. Inability to understand the aims of the study and/or protocol procedures

2. Bleeding ulcerative tumors or tumors requiring intratumoral injections of study drug into parenchymatous organs such as, but limited to liver, spleen or pancreas (only for Stratum A)

3. Patients with contraindication versus a laparoscopy or refusing a laparoscopy (only for Stratum B)

4. Hypersensitivity towards eftilagimod alpha, avelumab (only for Strata D and E) or any ingredient of the injection/infusion solutions

5. History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins

6. Currently receiving any other antineoplastic treatment including irradiation, or targeted small molecule therapy, or biological cancer therapy, or less than 4 weeks since completion of these therapies and first dose of study treatment (only Strata A, B, D and E)

7. Prior PD-1/PD-L1 targeted therapy (only for Strata D and E). NOTE: For stratum E only, patients can be enrolled if they received prior PD-1/PD-L1 targeted therapy during neoadjuvant treatment. HOWEVER, enrollment is allowed only after a disease free interval of at least 12 months after neoadjuvant PD-1/PD-L1 addressed- therapy.

8. Cirrhosis of the liver (Child > Grade A), pronounced alcohol abuse with anticipated detoxification, severe pulmonary infection with considerable reduction of pulmonary function

9. Clinically significant active coronary heart disease, cardiomyopathy or congestive heart failure, NYHA III-IV (for Stratum D: >= NYHA II) within 6 months prior to first dose of study treatment including: myocardial infarction, severe/unstable angina, ongoing cardiac dysrhythmias of current NCI CTCAE version Grade > 2, atrial fibrillation of any grade, coronary/peripheral artery
bypass graft, symptomatic congestive heart failure, cerebrovascular accident including transient ischemic attack, ventricular arrhythmias requiring medication or symptomatic pulmonary embolism

10. Cerebral or leptomeningeal metastases
Note: Subjects with previously treated brain metastases may participate if they meet the following criteria: 1) are stable for at least 28 days prior to the first dose of study treatment and if all neurologic symptoms returned to baseline; 2) have no evidence of new or enlarging brain metastases; and 3) have not been using steroids for at least 7 days prior to first dose of study treatment. This exception does not include carcinomatous meningitis which is excluded regardless of clinical stability.

11. Chronic inflammatory bowel disease

12. Active infection requiring systemic therapy at the start of study treatment or chronic infection or serious intercurrent infection within 4 weeks prior to first dose of study treatment

13. QTcF > 480 ms, family or personal history of long or short QT syndrome, Brugada syndrome or known history of QTc prolongation, or Torsade de Pointes (TdP)

14. Uncontrolled electrolyte disorders that can worsen the effects of a QTc prolonging drug (e.g., hypocalcaemia, hypokalaemia, hypomagnesemia)

15. Positive test for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome. Testing is not required in the absence of history.

Participants with known human immunodeficiency virus (HIV) infections are eligible if the following criteria are met:
a. If clinically indicated participants must be stable on antiretroviral therapy (ART) for at least 4 weeks and agree to adhere to ART. If not clinically indicated, consult Principal Investigator (LKP).
b. Participants with HIV infection should have no evidence of documented multidrug resistance that would prevent effective ART.
c. Have an HIV viral load of < 400 copies/mL at Screening.
d. If prophylactic antimicrobial drugs are indicated, patient may still be considered eligible upon agreement with the Principal Investigator (LKP)

16. Active hepatitis B (defined as having a positive hepatitis B surface antigen [HBsAg] test) or hepatitis C Note: Patients with past hepatitis B virus (HBV) infection or resolved HBV infection (defined as having a negative HBsAg test and a positive antibody to hepatitis B core antigen antibody test) are eligible.

Note: Patients positive for hepatitis C virus (HCV) antibody are eligible only if polymerase chain reaction testing is negative for HCV ribonucleic acid (RNA).
Testing is not required in the absence of history.

17. History or evidence of interstitial lung disease, active non-infectious pneumonitis or active tuberculosis

18. Active or prior autoimmune disease requiring immunosuppressive therapy that might deteriorate when receiving an immunostimulatory agent. Patients with diabetes type I, vitiligo, psoriasis, or hypo- or hyperthyroid disease not requiring immunosuppressive treatment are eligible.

19. Known history of immune-mediated colitis, pneumonitis, pulmonary fibrosis (only for Strata D and E).

20. Administration of a live, attenuated vaccine (including Covid-19 vaccination with live, attenuated vaccine) within four weeks prior to start of treatment or anticipation that such a live attenuated vaccine will be required during the remainder of the study.

21. Any condition requiring continuous systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 4 weeks prior to first dose of study treatment. Intranasal, inhaled or topical steroids, eye drops or local steroid injection (eg, intra-articular injection), steroids as premedication for hypersensitivity reactions (eg, computed tomography [CT] scan premedication) and physiological replacement doses of up to 10 mg daily prednisone equivalent are permitted in the absence of active autoimmune disease.

22. Treatment with systemic immunostimulatory agents (including but not limited to interferons or interleukin-2) within four weeks or five half-lives of the drug,
whichever is shorter, prior to start of study treatment

23. Any previous venous thromboembolism > National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 within the last 6 months

24. Past history of severe allergic episodes and/ or Quincke’s oedema

25. Prior organ transplantation or stem cell transplantation

26. On-treatment participation in another clinical study in the period 30 days prior to start of study treatment and during the study

27. Patients in a closed institution according to an authority or court decision (AMG § 40, Abs. 1 No. 4)

28. Pregnancy or lactation

29. Planned intratumoral injections in parenchymatous organs (e.g. liver, spleen, adrenal gland, pancreas)

30. Life-threatening illness unrelated to cancer

31. History of irAEs of CTCAE Grade 4 requiring steroid treatment (only for Strata C, D and E)

32. Persisting toxicity related to prior therapy (NCI CTCAE current version Grade > 1); however, alopecia, sensory neuropathy Grade <= 2, or other Grade <= 2 AEs not constituting a safety risk based on investigator's judgment are acceptable (only for Strata D and E)

33. Other severe acute or chronic medical conditions, psychiatric conditions including recent (within the past year) or active suicidal ideation or behavior; or laboratory abnormalities that may increase the risk associated with study participation or study treatment administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the patient inappropriate for entry into this study.
Weitere Info ClinicalTrials.gov   Kompetenznetz Leukämie - Deutsches Leukämie Studienregister - DLSR  
Ansprechpartner Email: ectu.cooperation@uniklinik-ulm.de , Tel. 0731 500 56070
Klinik ECTU (Early Clinical Trials Unit)
Kurztitel LIMBER
EudraCT-Nr 2022-502514-86-00
Titel Eine offene, multizentrische Phase-1-Studie zu INCA033989, verabreicht als Monotherapie oder in Kombination mit Ruxolitinib bei Teilnehmern mit myeloproliferativen NeoplasienEine Studie zur Bewertung von INCA033989, verabreicht als Monotherapie oder in Kombination mit Ruxolitinib bei Teilnehmern mit myeloproliferativen Neoplasien - LIMBER
Studiendesign Interventionsstudie , nicht randomisiert , Phase I
Strategie 2nd line
Weitere Info ICH GCP NETWORK   ClinicalTrials.gov  
Ansprechpartner Email: ectu.cooperation@uniklinik-ulm.de , Tel. 0731 500 56070
Klinik ECTU (Early Clinical Trials Unit)
Kurztitel M22-132
EudraCT-Nr 2021-005725-24
Titel Eine Studie zur Bewertung von Nebenwirkungen und Veränderungen der Krankheitsaktivität von subkutanem (SC) Epcoritamab in Kombination mit oralen und intravenösen antineoplastischen Mitteln bei erwachsenen Teilnehmern mit Non-Hodgkin-LymphomOffene Studie der Phase Ib/II zur Beurteilung der Sicherheit und Verträglichkeit von Epcoritamab in Kombination mit antineoplastischen Wirkstoffen bei Patienten mit Non Hodgkin-Lymphom
Studiendesign Interventionsstudie , nicht randomisiert , Phase I/II
Strategie 1st line , 2nd line
Einschlusskriterien
ELIGIBILITY CRITERIA
Subjects must meet all of the following criteria in order to be included in the study. Anything other than a positive response to the questions below will result in exclusion from study participation.

CONSENT
1. Subjects or their legally authorized representative, if permitted, must voluntarily sign and date an informed consent, approved by an independent ethics committee (IEC)/institutional
review board (IRB), prior to the initiation of any screening or study-specific procedures.

DEMOGRAPHIC AND LABORATORY ASSESSMENTS
2. Adult male or female, at least 18 years old.

3. Laboratory values meeting the following criteria within the screening period prior to the first dose of study drug:
- Absolute neutrophil count (ANC) = 1.5 x 10^9/L (growth factor use is allowed if evidence of bone marrow involvement, but subject must not have received growth factor within 14 days prior to screening labs)
- Hemoglobin = 8.0 g/dL (red blood cell transfusions permitted, but subject must not have received blood transfusions within 7 days prior to screening labs)
- Platelet count = 75 x 10^9/L, or = 50 x 10^9/L if bone marrow infiltration or hypersplenism (platelet transfusions permitted, but subject must not have received blood transfusions
within 7 days prior to screening labs)
- Serum aspartate transaminase (AST) AND alanine transaminase (ALT) level = 3 x upper limit of normal (ULN)
- Direct bilirubin must be = 2 x ULN
- Estimated Creatinine Clearance (CrCl) = 50 mL/min (as calculated by Cockcroft-Gault Formula, modified as needed for factors such as body weight)
- Prothrombin time/International normalized ratio (INR)/Activated partial thromboplastin time = 1.5 x ULN, unless receiving anticoagulation (although INR should not be > 4.0)
4. Subject is willing and able to comply with procedures required in this protocol.
5. Subject must be able to tolerate subcutaneous injections.
6. Subject must have available adequate fresh or paraffin-embedded tissue at Screening.

DISEASE/CONDITION ACTIVITY
7. Diagnosis of:
- (Arms 1, 2, 3, and 4) DLBCL (de novo or histologically transformed from follicular lymphoma or nodal marginal zone lymphoma) with histologically confirmed CD20+ disease, Inclusive of the following according to WHO 2016 classification and documented in pathology report:
- DLBCL, NOS
- High-grade B cell lymphoma with MYC and BCL-2 and/or BCL-6 translocations per WHO 2016 ("double-hit" or "triple-hit")
Note: High-grade B-cell lymphomas NOS or other double-/triple-hit lymphomas (with histologies not consistent with DLBCL) are not eligible
- Follicular lymphoma Grade 3B
Or
- (Arm 5) FL with histologically confirmed CD20+ Grade 1 to 3a FL and no evidence of histologic transformation to an aggressive lymphoma at most recent representative tumor
biopsy according to WHO 2016 classification
Or
- (Arms 6 and 7) MCL with histologically confirmed CD20+ disease at most recent representative tumor biopsy according to the WHO 2016 classification with evidence of
overexpression of cyclin D1 in association with relevant markers by IHC or evidence of t(11;14) assessed by flow cytometry, FISH, or PCR
- A report from the local laboratory is acceptable if available, however, a tumor block or slides must be sent to the central pathology laboratory for confirmation
8. Subject must have no prior treatment with epcoritamab or any other bispecific antibody targeting CD3 and CD20
9. Subject must have 1 or more measurable disease sites:
- A PET-CT scan demonstrating PET-positive lesion(s)
AND
- At least 1 measurable nodal lesion (long axis > 1.5 cm) or = 1 measurable extra-nodal lesion (long axis > 1.0 cm) on CT scan or MRI
10. Subject must be eligible to receive and have a need for treatment initiation based on symptoms and/or disease burden as per investigator assessment.
11. Subject must have ECOG performance status 0 - 2, except for Arms 6 and 7 where ECOG performance status must be 0-1.

SUBJECT HISTORY
12. Subject has no toxicities from prior anticancer therapy that have not resolved to Common Terminology Criteria for Adverse Events (CTCAE, v 5.0), Grade 2 or below, with the exception of alopecia. Other eligibility criteria (e.g., laboratory, cardiac criteria) must also be met.
13. Subject has no current evidence of primary central nervous system (CNS) tumor or known CNS involvement, including leptomeningeal disease, at screening.
14. Subject has no history of severe allergic or anaphylactic reactions to anti-CD20 mAb therapy or known significant allergy or intolerance to any component or excipient of epcoritamab or components of study drug combination agents (e.g., lenalidomide, rituximab, etc.)
15. Subject must not have had autologous stem cell transplantation (ASCT) within 3 months prior to screening, and no previous allogeneic hematopoietic stem cell transplant.
16. Subject must not have had any chemotherapy or non-investigational anti-neoplastic agents (except CD20 mAbs) within 4 weeks or 5 half-lives (whichever is shorter) prior to the first dose of epcoritamab (except for Arms 6 and 7, where bridging therapy for MCL is allowed, see Section 5.4)
17. Subject has no clinically significant cardiovascular disease, including:
- Myocardial infarction or stroke within 6 months prior to enrollment,
OR
- The following conditions within 6 months prior to enrollment: unstable or uncontrolled disease/condition related to or affecting cardiac function (e.g., unstable angina, congestive
heart failure, New York Heart Association Class III-IV), uncontrolled cardiac arrhythmia, and uncontrolled hypertension)
OR
- Other clinically significant ECG abnormalities within 6 months prior to enrollment unless deemed stable and appropriately treated.
OR
- Left ventricular ejection fraction < 45 %
In case of any history of cardiovascular disease, a cardiology consult is required within 60 days of enrollment.
18. Subject has no clinically significant liver disease, including hepatitis, current alcohol abuse, or cirrhosis.
19. Subject does not have active Hepatitis B Virus or Hepatitis C Virus infection. Subjects who are positive for hepatitis B core antibody, hepatitis B surface antigen, or hepatitis C antibody must have a negative polymerase chain reaction (PCR) result before enrollment. Those who are PCR positive will be excluded.
20. Subject has no known history of Human Immunodeficiency Virus infection. Note: Human immunodeficiency virus testing does not need to be conducted at screening unless it is required per local guidelines or institutional standards.
21. Subject has no known active bacterial, viral, fungal, mycobacterial, parasitic, or other infection (excluding fungal infections of the nail beds) requiring intravenous (IV) therapy within 2 weeks prior to enrollment.
22. Subject has no evidence of significant, uncontrolled concomitant diseases that could affect compliance with the protocol or interpretation of results.
23. Subject has no history of other prior malignancies, except for the following:
- Malignancy treated with curative intent and with no known active disease present for = 3 years before the first dose of study drug and felt to be at low risk for recurrence by the
treating physician
- Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease
- Adequately treated carcinoma in situ without evidence of disease
- Localized prostate cancer, post-radical prostatectomy with non-rising prostate-specific antigen levels < 0.1 ng/mL
24. Subject has not had radiation therapy to target lesion if only 1 target lesion is involved and no other target lesions that have not received radiation therapy can be followed.
25. Subject has no Grade > 1 neuropathy.
Subject must not have active tuberculosis (TB) or history of completed treatment for active TB within the past 12 months.
Note: Interferon gamma release assay (IGRA) testing does not need to be performed at screening unless active or latent TB is suspected. For subjects with positive IGRA, active
pulmonary TB must be excluded with clinical evaluation and radiologic imaging. Subjects with positive IGRA and no evidence of active disease may be enrolled after treatment for latent tuberculosis infection (recommendation isoniazid monotherapy for total of 6 months) has been initiated.
26. Subject does not have active (symptomatic) cytomegalovirus (CMV) disease.
27. Subject has no current autoimmune disease requiring immunosuppressive therapy except for up to 20 mg prednisone daily (or equivalent).
28. Subject has no life-threatening illness, medical condition, or organ system dysfunction that, in the Investigator's opinion, could compromise the subject's safety or put the study outcomes at undue risk.
29. Subject has no current seizure disorder requiring therapy.
30. Subject has no known active severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. If a subject has signs/symptoms suggestive of SARS-CoV-2 infection or have recent known exposure to someone with SARS-CoV infection, they should undergo molecular (e.g., PCR) or 2 negative antigen test results at least 24 hours apart to rule out SARS-CoV-2 infection.
Note: SARS-CoV-2 diagnostic tests should be applied following local requirements/regulations.
31. Subjects who do not meet SARS-CoV-2 infection eligibility criteria must be screen failed and may only rescreen after they meet the following SARS-CoV-2 infection viral clearance criteria:
- At least 10 days since first positive test result have passed in asymptomatic subjects or at least 10 days since recovery, defined as resolution of fever without use of antipyretics and improvement in symptoms.
32. Subject must not have had major surgery within 4 weeks of the first dose of study drug.
33. Subject has a life expectancy of > 3 months from standard of care treatment from time of enrollment
34. Subject has no known history of Progressive Multifocal Leukoencephalopathy (PML).

CONTRACEPTION
35. For all females of child-bearing potential; a negative serum pregnancy test (beta human chorionic gonadotropin [hCG]) at the Screening Visit and a negative urine pregnancy test at baseline prior to the first dose of study drug
36. Female subjects of childbearing potential must practice at least 1 protocol-specified method of birth control that is effective from 30 days prior to enrollment through at least 12 months after the last dose of study drug. Female subjects of non-childbearing potential do not need to use birth control.
37. Female subject who is not pregnant, breastfeeding, donating eggs (ova, oocytes), or considering becoming pregnant during the study or for 12 months after the last dose of study
drug.
38. If male, and subject is sexually active with female partner(s) of childbearing potential, he must agree, from 30 days prior to enrollment through 12 months after the last dose of study drug, to practice the protocol-specified contraception.
39. Male subject who is not considering fathering a child or donating sperm during the study or for 12 months after the last dose of study drug.

CONCOMITANT MEDICATIONS
40. Subject has no active medication use known to decrease T-cell numbers or activity or other concurrent immunosuppressive medication except for up to 20 mg prednisone daily or
equivalent, or for disease control during screening.
41. Subject must not have been treated with any investigational drug within 30 days or 5 half lives of the drug (whichever is longer) prior to the first dose of study drug or is currently enrolled in another interventional clinical study or was previously enrolled in this study (agents that have been approved under emergency authorization, e.g., anti-SARS-CoV-2 mAbs, are allowed)
42. Subject has not received vaccination with live-attenuated vaccines within 28 days prior to screening or is expected to need any live-attenuated vaccination during study participation including at least 3 months following the last dose of study treatment. Coronavirus mRNA and adenovirus-based vaccines, which are not live-attenuated vaccines, are permitted.

ADDITIONAL ELIGIBILITY CRITERIA SPECIFIC TO ARM 1
43. Subject must have R/R DLBCL
Note: Relapsed disease is defined as disease that previously responded to therapy but progressed = 6 months after completion of therapy. Refractory disease is defined as disease that either progressed during therapy, failed to achieve an objective response to prior therapy, or progressed within 6 months after completion of therapy (including maintenance therapy).
44. Subject must have R/R disease to at least one prior systemic anti-lymphoma therapy (radiotherapy is not considered a systemic therapy) which contains an anti-CD20 monoclonal antibody. Subject who received only prior anti-CD20 monoclonal antibody monotherapy is not eligible.
45. Subject must not be refractory (defined as best response of stable disease [SD] or progressive disease [PD]) to prior CAR-T therapy. Subject should not have received any
treatment with CAR-T therapy within 90 days prior to enrollment; any CAR-T related toxicity should have been resolved for at least 30 days.
46. Subjects must have either failed prior ASCT, not be considered eligible for ASCT due to age, performance status, comorbidities and/or insufficient response, or have refused ASCT.
47. Subject must not have documented refractoriness to lenalidomide and must be suitable for treatment with lenalidomide in the opinion of the investigator.
Note: Refractoriness is defined as:
- Best response to prior regimen(s) of SD or PD, OR
- Progressive disease within 6 months of completion of prior regimen(s)
48. Subject must be willing to take aspirin prophylaxis or prophylactic anticoagulation for thromboembolic event (or per local guidelines for lenalidomide administration).
49. Female subjects of childbearing potential must practice at least 2 protocol-specified methods of birth control that are effective from 30 days prior to enrollment through at least
12 months after the last dose of study drug. Female subjects of non-childbearing potential do not need to use birth control.
50. Subject is willing to adhere to the pregnancy risk minimization plan associated with lenalidomide treatment.
51. Subject must not have had lenalidomide exposure within 12 months prior to screening.
52. Subject must be able to swallow capsules and must not have any disease significantly affecting gastrointestinal function (e.g., resection of the stomach or small bowel, symptomatic inflammatory bowel disease, or partial or complete bowel obstruction).
53. Subjects must agree not to donate blood while receiving, during dose interruptions, and for at least 28 days following the last dose of lenalidomide.

ADDITIONAL ELIGIBILITY CRITERIA SPECIFIC TO ARM 2
54. Subject must have R/R (as defined in Criterion 43) DLBCL.
55. Subject must have received at least 1 prior treatment for which must include an anti-CD20 monoclonal antibody in combination with another systemic therapy (radiotherapy is not
considered a systemic therapy).
56. Subject must have received prior CAR-T cell therapy, but for those who achieved a response to prior CAR-T, not less than 90 days prior to first dose of epcoritamab, or for those who were refractory to CAR-T, not less than 30 days prior to first dose of epcoritamab.
Note: Refractoriness is defined as:
- Best response to prior regimen(s) of SD or PD, OR
- Progressive disease within 6 months of completion of prior regimen(s)
57. Subjects must have either failed prior ASCT, not be considered eligible for ASCT due to age, performance status, comorbidities and/or insufficient response, or have refused ASCT.
58. Subject must not have documented refractoriness to lenalidomide and must be suitable for treatment with lenalidomide in the opinion of the investigator.
59. Subject must not have had prior treatment with ibrutinib and must be suitable for treatment with ibrutinib in the opinion of the investigator.
60. Subject must not have had lenalidomide exposure within 12 months prior to screening.
61. Subject must not have known bleeding diathesis (e.g., von Willebrand's disease) or hemophilia.
62. Subject must not require treatment with a strong cytochrome P450 (CYP) 3A inhibitor.
63. Subject must not have consumed grapefruit, grapefruit products, Seville oranges (including marmalade containing Seville oranges), or starfruit for at least 3 days prior to Cycle 1 Day 1.
64. Subject must be willing to take aspirin prophylaxis or prophylactic anticoagulation for thromboembolic event (or per local guidelines for lenalidomide administration).
65. Female subjects of childbearing potential must practice at least 2 protocol-specified methods of birth control that are effective from 30 days prior to enrollment through at least
12 months after the last dose of study drug. Female subjects of non-childbearing potential do not need to use birth control:
66. Subject is willing to adhere to the pregnancy risk minimization plan associated with lenalidomide treatment.
67. Subject must be able to swallow capsules and must not have any disease significantly affecting gastrointestinal function (e.g., resection of the stomach or small bowel, symptomatic inflammatory bowel disease, or partial or complete bowel obstruction).
68. Subjects must agree not to donate blood while receiving, during dose interruptions, and for at least 28 days following the last dose of ibrutinib or lenalidomide.

ADDITIONAL ELIGIBILITY CRITERIA SPECIFIC TO ARM 3
69. Subject must have newly diagnosed, treatment-naive (not including prior treatments for indolent lymphoma that has transformed) DLBCL..
70: Subject must be suitable for treatment with polatuzumab, rituximab, cyclophosphamide, doxorubicin, and prednisone in the opinion of the investigator.
71. Subject must have International Prognostic Index score of 2 - 5.

ADDITIONAL ELIGIBILITY CRITERIA SPECIFIC TO ARM 4
72. Subject must have R/R (as defined in Criterion 43) DLBCL.
73. Subject must have R/R disease to at least one prior systemic anti-lymphoma therapy (radiotherapy is not considered a systemic therapy) which contains an anti-CD20 monoclonal antibody. Subject who received only prior anti-CD20 monoclonal antibody monotherapy is not eligible.
74. Subject must not be refractory (defined as best response of stable disease [SD] or progressive disease [PD]) to prior CAR-T therapy. Subject should not have received any
treatment with CAR-T therapy within 90 days prior to enrollment; any CAR-T related toxicity should have been resolved for at least 30 days.
75. Subjects must have either failed prior ASCT, not be considered eligible for ASCT due to age, performance status, comorbidities and/or insufficient response, or have refused ASCT.
76. Female subjects of childbearing potential must practice at least 2 protocol-specified methods of birth control (at least one highly effective method and one effective method) at the
same time from 30 days prior to enrollment through at least 12 months after the last dose of epcoritamab.
77. Subject must be willing to adhere to the pregnancy risk minimization plan associated with CC-99282 treatment.
78. Subject must be able to swallow capsules and must not have any disease significantly affecting gastrointestinal function (e.g., resection of the stomach or small bowel, symptomatic inflammatory bowel disease, or partial or complete bowel obstruction).
79. Subject must not have received prior treatment with CC-99282 or CC-220 (iberdomide).
80. Subjects must agree not to donate blood while receiving CC-99282, during dose interruptions and for at least 28 days following the last dose of CC-99282.

ADDITIONAL ELIGIBILITY CRITERIA SPECIFIC TO ARM 5
81. Subject must have R/R (as defined in Criterion 43) FL.
82. Subject must have Stage II-IV disease.
83. Subject must have a need for treatment initiation per investigator determination based on symptoms and/or disease burden.
84. Subject must have R/R disease to at least one prior systemic anti-lymphoma therapy (radiotherapy is not considered a systemic therapy) which contains an anti-CD20 monoclonal antibody. Subjects who received only prior anti-CD20 monoclonal antibody monotherapy arenot eligible.
85. Subject must not be refractory (defined as best response of stable disease [SD] or progressive disease [PD]) to prior CAR-T therapy. Subject should not have received any
treatment with CAR-T therapy within 90 days prior to enrollment; any CAR-T related toxicity should have been resolved for at least 30 days.
86. Female subjects of childbearing potential must practice at least 2 protocol-specified methods of birth control (at least one highly effective method and one effective method) at the
same time from 30 days prior to enrollment through at least 12 months after the last dose of epcoritamab.
87. Subject must be willing to adhere to the pregnancy risk minimization plan associated with CC-99282 treatment.
88. Subject must be able to swallow capsules and must not have any disease significantly affecting gastrointestinal function (e.g., resection of the stomach or small bowel, symptomatic inflammatory bowel disease, or partial or complete bowel obstruction).
89. Subject must not have received prior treatment with CC-99282 or CC-220 (iberdomide).
90. Subjects must agree not to donate blood while receiving CC-99282, during dose interruptions and for at least 28 days following the last dose of CC-99282.

ADDITIONAL ELIGIBILITY CRITERIA SPECIFIC TO ARM 6A
91. Subject must have R/R (as defined in Criterion 43) MCL.
92. Subject must have an absolute lymphocyte count < 50 x 10^9/L during screening and < 10 x 10^9/L by Cycle 1 Day 1 (bridging therapy may be needed and is allowed).
93. Subject must have received at least 1 prior treatment for MCL which must include an anti CD20 monoclonal antibody in combination with another systemic therapy (radiotherapy is not considered a systemic therapy).
94. Subject must not be refractory (defined as best response of stable disease [SD] or progressive disease [PD]) to prior CAR-T therapy. Subject should not have received any
treatment with CAR-T therapy within 90 days prior to enrollment; any CAR-T related toxicity should have been resolved for at least 30 days.
95. Subject must be suitable for treatment with ibrutinib in the opinion of the investigator.
96. Subject must not have received prior BTKi therapy.
97. Subject must not have known bleeding diathesis (e.g., von Willebrand's disease) or hemophilia.
98. Subject must not require treatment with a strong cytochrome P450 (CYP) 3A inhibitor.
99. Subject must not have consumed grapefruit, grapefruit products, Seville oranges (including marmalade containing Seville oranges), or starfruit for at least 3 days prior to Cycle 1 Day 1.
100. Subject must be able to swallow capsules and must not have any disease significantly affecting gastrointestinal function (e.g., resection of the stomach or small bowel, symptomatic inflammatory bowel disease, or partial or complete bowel obstruction).

ADDITIONAL ELIGIBILITY CRITERIA SPECIFIC TO ARM 6B
101. Subject must have R/R (as defined in Criterion 43 35) MCL:
102. Subject must have an absolute lymphocyte count < 50 x 10^9/L during screening and < 10 x 10^9/L by Cycle 1 Day 1 (bridging therapy may be needed and is allowed).
103. Subject must have received at least 1 prior treatment for MCL which must include an anti CD20 monoclonal antibody in combination with another systemic therapy (radiotherapy is not considered a systemic therapy).
104. Subject must not be refractory (defined as best response of stable disease [SD] or progressive disease [PD]) to prior CAR-T therapy. Subject should not have received any
treatment with CAR-T therapy within 90 days prior to enrollment; any CAR-T related toxicity should have been resolved for at least 30 days.
105. Subject must be suitable for treatment with ibrutinib and venetoclax in the opinion of the investigator.
106. Subject must not have received prior BTKi therapy.
107. Subject must not have known bleeding diathesis (e.g., von Willebrand's disease) or hemophilia.
108. Subject must not require treatment with a strong cytochrome P450 (CYP) 3A inhibitor and must not have received a strong CYP3A inhibitor for at least 7 days prior to Cycle 1 Day 1.
109. Subject must not have consumed grapefruit, grapefruit products, Seville oranges (including marmalade containing Seville oranges), or starfruit for at least 3 days prior to Cycle 1 Day 1.
110. Subject must not have received prior BCL-2 inhibitor therapy.
111. Subject must be able to swallow capsules and must not have any disease significantly affecting gastrointestinal function (e.g., resection of the stomach or small bowel, symptomatic inflammatory bowel disease, or partial or complete bowel obstruction).

ADDITIONAL ELIGIBILITY CRITERIA SPECIFIC TO ARM 7
112. Subject must have treatment-naive MCL disease
113. Subject must have an absolute lymphocyte count < 50 x 10^9/L during screening and < 10 x 10^9/L by Cycle 1 Day 1 (bridging therapy may be needed and is allowed).
114. Subject must have refused ASCT, not be Transplant for ASCT (due to age, performance status, comorbidities), OR have high-risk disease characteristics (e.g., TP53 alterations
[deletion/mutation], Ki-67 > 30%, blastoid/pleomorphic variant).
115. Subject must be suitable for treatment with ibrutinib and venetoclax in the opinion of the investigator.
116. Subject must not have known bleeding diathesis (e.g., von Willebrand's disease) or hemophilia.
117. Subject must not require treatment with a strong cytochrome P450 (CYP) 3A inhibitor.
118. Subject must not have consumed grapefruit, grapefruit products, Seville oranges (including marmalade containing Seville oranges), or starfruit for at least 3 days prior to Cycle 1 Day 1.
119. Subject must be able to swallow capsules and must not have any disease significantly affecting gastrointestinal function (e.g., resection of the stomach or small bowel, symptomatic inflammatory bowel disease, or partial or complete bowel obstruction).
Weitere Info ClinicalTrials.gov   ICH GCP NETWORK   EU Clinical Trials Register  
Ansprechpartner Email: ectu.cooperation@uniklinik-ulm.de , Tel. 0731 500 56070
Klinik ECTU (Early Clinical Trials Unit)
Kurztitel MTAP
EudraCT-Nr 2021-004764-10
Titel Eine Phase-1/1b/2-Studie zur Bewertung der Sicherheit, Verträglichkeit, Pharmakokinetik, Pharmakodynamik und Wirksamkeit von AMG 193 allein und in Kombination mit Docetaxel bei Patienten mit fortgeschrittenen soliden MTAP-null-TumorenEine Phase-1/1b/2-Studie zu AMG 193 allein und in Kombination mit Docetaxel bei Patienten mit fortgeschrittenen solilden MTAP-Null-Tumoren - MTAP
Studiendesign Interventionsstudie , randomisiert , Phase I/II
Strategie 2nd line
Einschlusskriterien
Subjects are eligible to be included in the study only if all of the following criteria apply:

101 Subject has provided informed consent/assent before initiation of any studyspecific activities/procedures.

102 Age >= 18 years.

103 Evidence of homozygous loss of CDKN2A (null) and/or MTAP (null) or lost MTAP expression in the tumor tissue.

104 Histologically confirmed metastatic or locally advanced solid tumor not amenable to curative treatment with surgery and/or radiation.
- Parts 1a and 1b: MTAP-null and/or CDKN2A-null or lost MTAP expression solid tumor for which no standard therapy exists; or standard therapy has failed or not available/tolerated; or in the investigator’s opinion, standard therapy does not result in meaningful clinical benefit.
- Part 1c: MTAP-null or lost MTAP expression squamous NSCLC, treated with 1 to 2 prior lines of systemic therapy for metastatic/locally advanced disease, must include PD1 or programmed death-ligand 1 (PD-L1) inhibitor and platinum-based chemotherapy.
- Part 1d: MTAP-null or lost MTAP expression adenocarcinoma NSCLC, treated with 1 to 2 prior lines of systemic therapy for metastatic/locally advanced disease, must include PD1 or PD-L1 inhibitors and platinum-based chemotherapy, and/or targeted therapy and chemotherapy (with or without PD1/PD-L1 inhibitors) if actionable oncogenic driver mutations were identified (ie, EGFR, ALK, MET, RET, ROS1, KRASG12C).
- Part 1e: MTAP-null or lost MTAP expression cholangiocarcinoma, treated with 1 to 2 prior lines of systemic therapy for metastatic/locally advanced disease, to include platinum-based chemotherapy and targeted therapy if fibroblast growth factor receptor fusion/rearrangement was identified.
- Part 1f: MTAP-null or lost MTAP expression HNSCC, treated with 1 to 2 prior lines of systemic therapy for metastatic/locally advanced disease, to include platinum-based chemotherapy and PD-1 or PD-L1 inhibitor.
- Part 1g: MTAP-null or lost MTAP expression pancreatic adenocarcinoma, treated with 1 to 2 prior lines of systemic therapy, including standard chemotherapy regimen such as mFOLFIRINOX, gemcitabine/abraxane.
- Part 1h: MTAP-null or lost MTAP expression solid tumors (other than squamous or adenocarcinoma NSCLC cholangiocarcinoma, HNSCC, pancreatic adenocarcinoma, lymphoma, or primary brain tumor), for which no standard therapy exists; or standard therapy has failed or not available/tolerated; or in the investigator’s opinion, standard therapy does not result in meaningful clinical benefit.
- Parts 2a and 2b: MTAP-null or lost MTAP expression NSCLC, treated with 1 to 2 prior lines of systemic therapy for locally advanced/metastatic disease, must include PD1 or PD-L1 inhibitors and platinum-based chemotherapy.

105 Able to swallow and retain PO administered study treatment and willing to record daily adherence to investigational product.

106 Disease measurable as defined by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1).

107 Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1.

108 Adequate hematopoietic function per local laboratory, defined as:
- absolute neutrophil count >= 1.5 x 10^9/L without growth factor support within 7 days (granulocyte colony stimulating factor [G-CSF]) or 14 days (pegylated G-CSF) from screening assessment;
- platelet count >= 100 x 10^9/L without platelet transfusion within 7 days from screening assessment;
- hemoglobin > 9 g/dL without RBC transfusion within 7 days from screening assessment.

109 Adequate renal function per local laboratory, defined as:
- creatine clearance >= 60 mL/min based on the Cockcroft-Gault glomerular filtration rate estimation or Modification of Diet in Renal Disease formula.

110 Adequate glucose control per local laboratory (Part 1 only), defined as:
- fasting blood glucose <= 160 mg/dL.

111 Adequate liver function per local laboratory, defined as:
- Part 1: aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < 3 x upper limit of normal (ULN) (or < 5 x ULN for subjects with liver metastases);
- Part 1: total bilirubin < 1.5 x ULN (or < 2.0 x ULN for subjects with liver metastases, documented Gilbert’s syndrome).
- Part 2: AST and ALT <= 1.5 x ULN with alkaline phosphatase <= 2.5 x ULN
- Part 2: total bilirubin <= ULN (or < 1.5 x ULN for subjects with liver metastases, documented Gilbert’s syndrome).

112 Adequate coagulation parameters, defined as:
- prothrombin time or activated partial thromboplastin time < 1.5 x ULN, and International normalized ratio (INR) < 1.5 x ULN or without target range if on prophylactic anticoagulation therapy.

113 Adequate pulmonary function, defined as:
- no clinically significant pleural effusion (s/p indwelling catheter allowed for NSCLC and malignant pleural mesothelioma)
- baseline oxygen saturation > 90 % on room air.

114 Adequate cardiac function, defined as:
- cardiac ejection fraction >= 50 % as determined by an echocardiogram or multiple-gated acquisition scan
- no evidence of clinically significant pericardial effusion
- 350 msec < baseline QTc <= 470 msec (based on average of screening triplicates, confirmed by central cardiology read).

115 Minimum life expectancy of 12 weeks as per investigator judgement.

116 Archived tumor tissue must be available. Subjects without archived tumor tissue available may be allowed to enroll by undergoing tumor biopsy before AMG 193 dosing, if medically feasible. Subjects without archived tissue available and with no medical feasibility for a new tumor biopsy may be allowed to enroll upon agreement between the investigator and the Amgen Medical Monitor.

117 For Part 1f (MTAP-null or lost MTAP expression HNSCC): Must be willing to undergo tumor biopsy, if medically feasible, before start of treatment (archival sample acceptable if obtained with 6 months of enrollment and subject has not received any other treatment since sample was obtained) and again approximately 4 weeks after starting treatment. Subjects without archived tissue available and with no medical feasibility for a new tumor biopsy may be allowed to enroll upon agreement between the investigator and the Amgen Medical Monitor.
Ausschlusskriterien
Subjects are excluded from the study if any of the following criteria apply:

DISEASE RELATED

201 Spinal cord compression or active brain metastases or leptomeningeal disease from non-brain tumors. Subjects who have had brain metastases resected or have received radiation therapy ending at least 4 weeks before study day 1 are eligible if they meet all of the following criteria: a) residual neurological symptoms grade <= 2; b) on stable doses of dexamethasone, if applicable; and c) follow-up magnetic resonance imaging (MRI) within 30 days of day 1 shows no new lesions appearing.

202 Presence of primary brain cancer.

203 Presence of hematological malignancy or lymphoma.

OTHER MEDICAL CONDITIONS

204 History of other malignancy within the past 2 years, with the following exceptions:
- Malignancy treated with curative intent and with no known active disease present for >= 2 years before enrollment and felt to be at low risk for recurrence by the treating physician.
- Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease.
- Adequately treated cervical carcinoma in situ without evidence of disease.
- Adequately treated breast ductal carcinoma in situ without evidence of disease.
- Prostatic intraepithelial neoplasia without evidence of prostate cancer.
- Adequately treated urothelial papillary noninvasive carcinoma or carcinoma in situ.

205 Any evidence of current interstitial lung disease or pneumonitis or a prior history of interstitial lung disease or non-infectious pneumonitis.

206 Active infection requiring systemic therapy.

207 Evidence of active SARS-COV2 infection. If known or suspected recent SARS-COV2 infection, a minimum of 10 days after symptom onset, if any, must have elapsed.

208 History of arterial thrombosis (eg, stroke or transient ischemic attack) within 6 months of first dose of AMG 193.

209 Myocardial infarction and/or symptomatic congestive heart failure (New York Heart Association > class II), unstable angina, or cardiac arrhythmia requiring medication within 12 months of first dose of AMG 193.

210 Gastrointestinal tract disease causing the inability to take PO medication, malabsorption syndrome, requirement for IV alimentation, gastric/jejunal tube feeds, uncontrolled inflammatory gastrointestinal disease (eg, Crohn’s disease, ulcerative colitis).

211 History of bowel obstruction, abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 6 months of study entry unless approved by the principal investigator and the Amgen Medical Monitor or history of gastrointestinal procedure(s) that result in malabsorption.

212 History of solid organ transplant.

213 Diagnosis of Congenital Short QT Syndrome.

PRIOR/CONCOMITANT THERAPY

214 Major surgery within 28 days of first dose of AMG 193.

215 Anti-tumor therapy (chemotherapy, antibody therapy, molecular targeted therapy, hormonal therapy, or investigational agent) within 28 days of study day 1, unless anti-tumor therapy is a therapy with 5 times the half-life being shorter than 28 days (in this case, enrollment may be allowed with washout from prior therapy of < 28 days, in consultation with the Amgen Medical Monitor).

216 Prior treatment with an MAT2A inhibitor or a PRMT5 inhibitor.

217 Prior treatment with docetaxel (Part 2 only).

218 Prior irradiation to > 25 % of the bone marrow.

219 Therapeutic or palliative radiation therapy within 2 weeks of study day 1.
Subjects must have recovered from all radiotherapy related toxicity.

220 Live vaccine therapy within 4 weeks before study drug administration.

221 Use of therapeutic anti-coagulation for treatment of active thromboembolic events.

222 Use of prescription medications that are known strong inducers (including rifampin, mitotane, avasimibe, rifapentine, apalutamide, ivosidenib, phenytoin, carbamazepine, enzalutamide, St John's wort extract, lumacaftor and phenobarbital) or inhibitors (including VIEKIRA PAK , indinavir/ritonavir, tipranavir/ritonavir, ritonavir, cobicistat, ketoconazole, troleandomycin, telaprevir, danoprevir/ritonavir, elvitegravir/ritonavir, saquinavir/ritonavir, lopinavir/ritonavir, itraconazole, indinavir, voriconazole, mifepristone, mibefradil, LCL161, clarithromycin, josamycin, lonafarnib, posaconazole, telithromycin, grapefruit juice, conivaptan, tucatinib, nefazodone, ceritinib, nelfinavir, saquinavir, ribociclib, idelalisib, and boceprevir) of CYP3A4 within 14 days or 5 half-lives (whichever is longer) before study day 1 that was not reviewed and approved by the principal investigator and the Amgen Medical Monitor.

223 Unresolved toxicity from prior anti-cancer therapy, defined as not having resolved to Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 grade 0 or 1, or to levels dictated in the eligibility criteria, with the exception of alopecia.
Grade 2 or 3 toxicities from prior anti-cancer therapy that are considered irreversible (defined as having been present and stable for >= 5 months), such as endocrinopathies controlled with hormone replacement therapy may be allowed if they are not otherwise described in the exclusion criteria and there is agreement to allow by both the investigator and the sponsor.

PRIOR/CONCURRENT CLINICAL STUDY EXPERIENCE

224 Currently receiving treatment in another investigational device or drug study, or less than 28 days since ending treatment on another investigational device or drug study(ies). Other investigational procedures while participating in this study are excluded.

DIAGNOSTIC ASSESSMENTS

225 Known positive test for Human Immunodeficiency Virus.

226 Evidence of hepatitis B or C infection, based on 1 or more of the following results and/or criteria:
- positive hepatitis B surface antigen (HepBsAg)
- negative HepBsAg with positive hepatitis B core antibody (HepBcAb) and detectable hepatitis B virus (HBV) DNA by polymerase chain reaction (PCR) (note that negative HepBsAg with positive HepBcAb triggers requirement of HBV DNA by PCR)
- positive hepatitis C virus RNA by PCR

OTHER EXCLUSIONS

227 Female subjects of childbearing potential unwilling to use protocol specified method of contraception see Appendix 5 (Section 11.5) during treatment and for an additional 21 days after the last dose of AMG 193 and 6 months after the last dose of protocol-specified chemotherapeutic agents.

228 Female subjects who are breastfeeding or who plan to breastfeed while on study through 21 days after the last dose of AMG 193 and 6 months after the last dose of protocol-specified chemotherapeutic agents.

229 Female subjects planning to become pregnant while on study through 21 days after the last dose of AMG 193 and 6 months after the last dose of protocol-specified chemotherapeutic agents.

230 Female subjects of childbearing potential with a positive pregnancy test assessed at screening and on day 1 by a highly sensitive urine or serum pregnancy test.

231 Male subjects with a female partner of childbearing potential who are unwilling to practice sexual abstinence (refrain from heterosexual intercourse) or use contraception during treatment and for an additional 21 days after the last dose of AMG 193 and 6 months after the last dose of protocol-specified chemotherapeutic agents. Refer to Appendix 5 (Section 11.5) for additional contraceptive information.

232 Male subjects with a pregnant partner who are unwilling to practice abstinence or use a condom during treatment and for an additional 21 days after the last dose of AMG 193 and 6 months after the last dose of protocol-specified chemotherapeutic agents.

233 Male subjects unwilling to abstain from donating sperm during treatment and for an additional 21 days after the last dose of AMG 193 and 6 months after the last dose of protocol-specified chemotherapeutic agents.

234 Subject has known sensitivity to any of the products to be administered during dosing. For Part 2, hypersensitivity to docetaxel or polysorbate 80.

235 For Part 1c to 1h and Part 2, subject unable to receive both iodinated contrast for computed tomography (CT) scans and gadolinium contrast for MRI scans.

236 Subject likely to not be available to complete all protocol-required study visits or procedures, and/or to comply with all required study procedures (eg, Clinical Outcome Assessments) to the best of the subject and investigator’s knowledge.

237 History or evidence of any other clinically significant disorder, condition or disease (with the exception of those outlined above) that, in the opinion of the investigator or Amgen physician, if consulted, would pose a risk to subject safety or interfere with the study evaluation, procedures or completion.
Weitere Info ClinicalTrials.gov  
Ansprechpartner Email: ectu.cooperation@uniklinik-ulm.de , Tel. 0731 500 56070
Klinik ECTU (Early Clinical Trials Unit)
Kurztitel NOA-26 - IT-PD1
EudraCT-Nr 2021-001795-42
Titel Intrathekale Anwendung von PD1-Antikörpern bei metastasierten soliden Tumoren mit leptomeningealer Erkrankung
Studiendesign Interventionsstudie , nicht randomisiert , Phase I
Einschlusskriterien
Subjects meeting all of the following criteria will be considered for admission to the trial:

1. Must be >= 18 years at the time of signing the informed consent.

2. Understand and voluntarily sign an informed consent document prior to any study related assessments/procedures.

3. Patients with a “good risk status as defined by the NCCN guidelines (version 1.2021)

4. Tumor board protocol confirming:

- a clinical recommendation for intrathecal therapy and evaluation of trial enrollment

- a statement on the potential necessity of additional systemic treatment of metastatic tumor outside the CNS

5. Able to adhere to the study visit schedule and other protocol requirements.

6. All subjects must agree to refrain from donating blood while on study drug and for 28 days after discontinuation from this study treatment.

7. Patients with Karnofsky performance score > 50 %

8. Diagnosis of LMD by CSF and/or MRI

a. A thorough CSF evaluation must be performed in every patient prior to the inclusion in this trial. The reason is that a positive CSF cytology is considered the gold standard for LMD diagnosis. Furthermore, a thorough CSF evaluation will allow the thorough assessment of potential differential diagnosis (for example, viral meningitis, bacterial meningitis, aseptic meningitis, sarcoidosis etc.)

b. Presence of malignant cells on CSF cytology. The frequency of CSF evaluation is based on guideline of the German Society of Neurology: Please note that the first lumbar puncture is only 50-60 % sensitive. Repeat collection increases sensitivity up to approximately 80 %. Thus, a negative first CSF evaluation should at least be repeated once. According to guidelines from the German Society for Neurology each CSF collection should draw enough, i.e. at least 5-10 ml CSF and should be processed within one hour of collection.

c. MRI diagnosis of LMD: pial enhancement, pial nodular manifestations (as defined per LANO criteria, see appendix).

d. A positive CSF cytology and an MRI evidence is enough to determine the LMD diagnosis.

e. Please note that approximately 20 % of patients with symptomatic LMD might lack positive CSF cytology even upon repeated puncture. In these cases, the LMD diagnosis can also be performed based on cerebral/spinal MRI manifestations and by exclusion of differential diagnosis

f. In the absence of diagnostic findings for LMD in the CSF: patients must present with typical clinical and MRI signs of LMD (Le Rhun et al., 2017). If the CSF has signs of pleocytosis (BUT NOT any malignant, atypical or suspicious cells) the differential diagnoses for CSF pleocytosis (aseptic meningitis, viral meningitis, bacterial meningitis) must be excluded.

g. Some centers perform biopsies of leptomeninges for obtaining a LMD diagnosis. The LMD diagnosis will be based on histology and should be documented accordingly. Yet, a histological diagnosis of LMD is NOT required for the inclusion in this trial.

9. If radiation therapy had occurred: Please make sure that a documentation of the past radiation therapy is available (including applied dosage and radiation therapy fields):

a. Participants eligible for IT-PD1 should have completed their radiation therapy due to clinical indication > 2 weeks prior to enrollment into the trial

b. All LMD patients without an indication for radiation therapy (per investigator s choice) can be enrolled immediately

10. Neurological examination (NANO scale) (Nayak et al., 2017)

11. MRI: the assessment at baseline and for subsequent time points should be based on the LANO scorecard (see appendix) according to (Le Rhun et al., 2019)
12. Ability to undergo intrathecal therapy via an intraventricular catheter (e.g. Ommaya reservoir)

13. Primary tumor tissue for the assessment of PD1 and PD-L1 should be available but does not need to be shipped before enrollment of patient into the trial.

14. Female Patient of childbearing potential^1 and male patients with female partner of childbearing potential^1 is willing to use highly effective contraceptive methods during treatment and for 150 days (male or female, see SmPC) after the last dose.
Recommendations highly effective contraceptive methods are:

a. combined hormonal contraception associated with inhibition of ovulation (oral-, intravaginal, -transdermal)

b. progestogen-only hormonal contraception associated with inhibition of ovulation (pral injectable, implantable),

c. intrauterine device (IUD),

d. intrauterine hormone - releasing system (IUS),

e. bilateral tubal occlusion,

f. vasectomized partner^2,

g. sexual abstinence^3

^1 For the purpose of this document, a female is considered of childbearing potential (FCBP), i.e. fertile, following menarche and until becoming post-menopausal unless permanently sterile. Permanent sterilisation methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy. A postmenopausal state is defined as no menses for 12 months without an alternative medical cause. A high follicle stimulating hormone (FSH) level in the postmenopausal range may be used to confirm a post-menopausal state in women not using hormonal contraception or hormonal replacement therapy. However, in the absence of 12 months of amenorrhea, a single FSH measurement is insufficient. For the purpose of this document, a man is considered fertile after puberty unless permanently sterile by bilateral orchidectomy.

^2Vasectomized partner is a highly effective birth control method provided that partner is the sole sexual partner of the WOCBP trial participant and that the vasectomized partner has received medical assessment of the surgical success

^2 In the context of this guidance sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual intercourse during the entire period of risk associated with the study treatments. The reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the subject.
Ausschlusskriterien
Subjects presenting with any of the following criteria will not be included in the trial:

1. Women during pregnancy and lactation.

2. Previous intrathecal nivolumab application.

3. Patient at poor risk (NCCN guidelines version 1.2021)

4. The following differential diagnoses to LMD are exclusion criteria

a. Aseptic meningitis

b. Viral meningitis

.c. Bacterial meningitis

5. History of hypersensitivity to monoclonal antibodies

6. Participation in other clinical trials or observation period of competing trials.

7. A clinical condition that in the opinion of the investigator would interfere with the evaluation or interpretation of patient safety or trial results or that would prohibit the understanding of informed consent and compliance with the requirements of the protocol

8. Any treatment-related toxicities from prior systemic anti-tumor or immune therapy not having resolved to CTCAE version 5.0 grade 1, with the exception of alopecia

9. Patient with confirmed history of current autoimmune disease

10. Patients with any disease resulting in permanent immunosuppression or requiring permanent immunosuppressive therapy

11. Clinically significant active infection, for example:

a. Presence of human immunodeficiency virus

b. Active hepatitis B virus/hepatitis C virus. HIV infection or active Hepatitis B or C infection, PCR-based detection of SARS-Cov2 or active infections requiring oral or intravenous antibiotics or that can cause a severe disease and pose a severe danger to lab personnel working on patients’ blood or tissue (e.g. rabies) *.

12. Inability to undergo MRI with contrast agent

13. The underlying primary tumor has not a registered and authorized indication in the European Union for intravenous treatment with nivolumab, pembrolizumab or atezolizumab. The solide tumor registered are, i.e. melanoma, non-small cell lung cancer, renal cell carcinoma, squamous cell carcinoma of the head and neck region, urrothelial carcinoma, squamous cell carcinoma of the oesophagus tumours, triplenegative breast carcinoma

14. Abnormal laboratory values for the following values in haematology, coagulation parameters, liver and renal function:

a. Haemoglobin < 8 g/dl

b. White blood cell count < 2.0 x 10^9/L)

c. Platelet count decrease < 50 x 10^9/L

d. Bilirubin > 2.5 x upper limit of normal (ULN) according to the performing laboratory s reference range. Note that benign hereditary hyperbilirubinemia e.g. Gilbert s syndrome is permitted.

e. Alanine aminotransferase > 3 x ULN

f. Aspartate aminotransferase > 3 x ULN

g. Serum creatinine increase > 1.5 x ULN

15. Patients who have received live or attenuated vaccine therapy used for prevention of infectious disease within 4 weeks of the first IT application of nivolumab

16. Patients requiring chronic systemic corticosteroid therapy (> 10 mg prednisone or equivalent per day) or any other immunosuppressive therapies (including anti-TNF-a therapies).

*) These parameters are necessary in immunotherapy studies, as they in turn may have an impact on immune parameters (independent of study treatment)
Weitere Info ClinicalTrials.gov  
Ansprechpartner Email: ectu.cooperation@uniklinik-ulm.de , Tel. 0731 500 56070
Klinik ECTU (Early Clinical Trials Unit)
Kurztitel UC02-123-01
EudraCT-Nr 2019-001339-30
Titel Multizentrische, offene Phase I Studie mit Dosissteigerungen für die Behandlung von Patienten mit CD123 positiven hämatologischen und lymphatischen Malignomen mittels gentechnisch veränderten T-Zellen, die universelle chimäre Antigen-Rezeptoren (UniCAR02-T) auf der Oberfläche tragen, und in Kombination mit einem CD123-spezifischen Zielmodul (TM123) verabreicht werden
Studiendesign Interventionsstudie , nicht randomisiert , Phase I
Strategie 2nd line
Einschlusskriterien
1. Male or female patients, age >= 18 years
2. Documented definitive diagnosis at screening of AML (according to standard of care testing) and CD123 positivity of more than 20 % of blasts.
- Relapsed or refractory AML, defined as:
a. Patients having received standard induction chemotherapy: either refractory to standard induction treatment,
b. or relapse within 6 months after achieving 1st CR, or relapse later than 6 months after 1st CR and refractory to standard salvage regimen,
c. or relapse after >= 2nd CR and not eligible for curative treatment (i.e. allogeneic blood stem cell transplantation).
d. first relapse after allogeneic HSCT; subjects must be at least 2 months from HSCT at the time of screening and off immunosuppressant medication for at least 1 month at the time of screening (with the exception of low-dose steroids (<= 20 mg prednisone or equivalent), and have no active graft versus host disease (GvHD).
e. Patients not eligible for standard induction chemotherapy: either refractory or progressive after at least 1 cycle of demethylating agents in AML patients not qualifying for intensive induction chemotherapy
3. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1
4. Life expectancy of at least 2 months
5. Adequate renal and hepatic laboratory assessments:
a. Aspartate aminotransferase (AST), alanine aminotransferase (ALT) and alkaline phosphatase (ALP) <= 2.5 x upper limit of normal (ULN)
b. Total bilirubin <= 1.5 x ULN
c. Serum creatinine <= 1.5 x ULN or Serum creatinine clearance > 60 mL/min (male); > 50 m L/min (female) (only if creatinine > 1.5 ULN)
6. Adequate cardiac function, i.e. left ventricular ejection fraction (LVEF) of >= 45 % as assessed by transthoracal two-dimensional echocardiography
7. Permanent venous access existing (e.g. port-system) resp. acceptance of implantation of a device
8. Able to give written informed consent
9. Weight >= 45 kg
10. A female of childbearing potential may be enrolled providing she has a negative pregnancy test at screening visit and is routinely using a highly effective method of birth control (pearl index of <= 1 required) resulting in a low failure rate (e.g. hormonal contraception, intrauterine device, total sexual abstinence or sterilization) as long as UniCAR02-T persistence is measured but at least until 12 months from lymphodepletion therapy. Male patients must also practice a highly effective method of birth control and should not father a child at least until 6 months after end of lymphodepletion therapy.
Ausschlusskriterien
1. Acute promyelocytic leukemia (t15;17)
2. Refractory disease under anti-leukemic treatment lasting longer than 6 months
3. Manifestation of AML in central nervous system
4. Bone marrow failure syndromes (e.g. Fanconi anemia, Kostman syndrome, Shwachman syndrome)
5. Cardiac disease: i.e. heart failure (NYHA III or IV); unstable coronary artery disease, myocardial infarction or serious cardiac ventricular arrhythmias requiring anti-arrhythmic therapy within the last 6 months prior to study entry
6. Patients undergoing renal dialysis
7. Pulmonary disease with clinical relevant hypoxia (need for oxygen inhalation)
8. Parkinson, epilepsy and, stroke or presence or history of seizures, paresis, aphasia or intracranial hemorrhage
9. History or presence of disseminated intravascular coagulation (DIC) or thromboembolism
10. Hemolytic anemia
11. Multiple sclerosis
12. Active infectious disease considered by investigator to be incompatible with protocol or being contraindications for lymphodepletion therapy (in individual cases, after consultation with the sponsor, this does not include past, non-acute, non-clinically significant infectious diseases for which there is still serological evidence)
13. Presence of urotoxicity from previous chemo- or radiotherapy or urinary outflow obstruction
14. Allogeneic stem cell transplantation within last two months or GvHD requiring immunosuppressive therapy
15. Vaccination with live viruses less than 2 weeks prior lymphodepletion therapy
16. Major surgery within 28 days (prior start of TM123 infusion)
17. Other malignancy requiring active therapy but adjuvant endocrine therapy is allowed
18. Treatment with any investigational drug substance or experimental therapy within 4 weeks or 5 half-lives (whatever is shorter) of the substance prior to the day of apheresis
19. Prior treatment with gene therapy products
20. Use of checkpoint inhibitors within 5 half-lives of the respective substance
21. Autoimmune diseases requiring systemic steroids or other systemic immunosuppressants (note that physiologic steroid replacement not exceeding 10 mg prednisolone equivalent per day is allowed)
22. Pregnant or breastfeeding women
23. Psychologic disorders, drug and/or significant active alcohol abuse
24. Known history of human immunodeficiency virus (HIV) or active/chronic infection with hepatitis C virus (HCV) or hepatitis B virus (HBV)
25. Presence of autoantibodies against La/SS-B or presence or history of autoimmune diseases (e.g. systemic lupus erythematosus, SS/SLE overlap syndrome, subacute cutaneous lupus erythematosus, neonatal lupus, primary biliary cirrhosis, Sjögren's syndrome)
26. Known hypersensitivity to cellular component (UniCAR02-T) and/or targeting module (TM123) excipients or to compounds of the lymphodepletion therapy, tocilizumab or corticosteroids
27. Evidence suggesting that the patient is not likely to follow the study protocol (e.g. lacking compliance)
28. Incapability of understanding purpose and possible consequences of the trial
29. Patients who should not be included according to the opinion of the investigator
Weitere Info ClinicalTrials.gov  
Ansprechpartner Email: ectu.cooperation@uniklinik-ulm.de , Tel. 0731 500 56070
Klinik Innere Medizin III
Kurztitel UC02-PSMA-01
EudraCT-Nr 2019-004211-32
Titel Multizentrische, offene Phase I Studie mit Dosissteigerungen für die Behandlung von Patienten mit einer fortgeschrittenen PSMA-positiven Tumorerkrankung nach systemischer Standardtherapie mittels gentechnisch veränderten T-Zellen, die universelle chimäre Antigen-Rezeptoren (UniCAR02-T) auf der Oberfläche tragen, und in Kombination mit einem PSMA-spezifischen Zielmodul (TMpPSMA) verabreicht werden
Studiendesign Interventionsstudie , nicht randomisiert , Phase I
Strategie 2nd line
Einschlusskriterien
1. Male or female patients, age >= 18 years
2. PSMA expression positive cancer (i.e. urogenital tract [renal, transitional cell, prostate], nonsmall cell lung, breast and colorectal cancer) refractory to standard treatments and with no other available standard or curative treatment
3. Measurable disease based on Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 and Positron Emission Tomography Response Criteria in Solid Tumors (PERCIST) version 1.0
4. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1
5. Life expectancy of at least 3 months
6. Adequate renal and hepatic laboratory assessments:
a. Aspartate aminotransferase (AST), alanine aminotransferase (ALT) and alkaline phosphatase (ALP) <= 2.5 upper limit of normal (ULN)
b. Total bilirubin <= 1.5 ULN
c. Serum creatinine <= 1.5 ULN or Serum creatinine clearance > 60 mL/min (male); > 50 mL/min (female) if creatinine > 1.5 ULN
7. Adequate cardiac function, i.e. left ventricular ejection fraction (LVEF) of >= 45 % as assessed by transthoracal two-dimensional echocardiography
8. Permanent venous access existing (e.g. port-system) resp. acceptance of implantation of a device
9. Able to give written informed consent
10. Weight >= 45 kg
11. A female of childbearing potential may be enrolled providing she has a negative pregnancy test at screening visit and is routinely using a highly effective method of birth control (pearl index of <= 1 required) resulting in a low failure rate (e.g. hormonal contraception, intrauterine device, total sexual abstinence or sterilization) as long as UniCAR02-T persistence is measured but at least until 12 months from the last study drug administration. Male patients must also practice a highly effective method of birth control and should not father a child at least until 6 months after end of lymphodepletion therapy.
Ausschlusskriterien
1. Central nervous system metastasis or meningeosis carcinomatosa
2. Cardiac disease: i.e. heart failure (NYHA III or IV); unstable coronary artery disease, myocardial infarction or serious cardiac ventricular arrhythmias requiring anti-arrhythmic therapy within the last 6 months prior to study entry
3. Patients undergoing renal dialysis
4. Pulmonary disease with clinical relevant hypoxia (need for continuous oxygen inhalation)
5. Parkinson, epilepsy and stroke or presence or history of seizures, paresis, aphasia, central nervous system (CNS) or intracranial hemorrhage
6. History or presence of disseminated intravascular coagulation (DIC) or thromboembolism
7. Multiple sclerosis
8. Hemolytic anemia
9. Eye diseases with neovascularization
10. Active infectious disease considered by investigator to be incompatible with protocol or being contraindications for lymphodepletion therapy
11. Presence of urotoxicity from previous chemo- or radiotherapy or urinary outflow
Obstruction
12. Vaccination with live viruses less than 2 weeks prior lymphodepletion therapy
13. Any disease requiring immunosuppressive therapy
14. Major surgery within 28 days (prior start of TMpPSMA infusion)
15. Other malignancy requiring active therapy but adjuvant endocrine therapy is allowed
16. Treatment with any investigational drug substance or experimental therapy within 4 weeks or 5 half-lives of the substance (whatever is shorter) prior to administration of TMpPSMA
17. Prior treatment with gene therapy products
18. Use of checkpoint inhibitors within 5 half-lives of the respective substance prior to administration of TMpPSMA
19. Autoimmune diseases requiring systemic steroids or other systemic immunosuppressants (note that physiologic steroid replacement not exceeding 10 mg prednisolone equivalent per day is allowed)
20. Psychologic disorders, drug and/or significant active alcohol abuse
21. Known history of human immunodeficiency virus (HIV) or active/chronic infection with hepatitis C virus (HCV) or hepatitis B virus (HBV)
22. Presence of autoantibodies against La/SS-B or presence or history of autoimmune diseases (e.g. systemic lupus erythematosus, SS/SLE overlap syndrome, subacute cutaneous lupus erythematosus, neonatal lupus, primary biliary cirrhosis, Sjögren's syndrome)
23. Known hypersensitivity to cellular component (UniCAR02-T) and/or targeting peptide module (TMpPSMA) excipients or to compounds of the lymphodepletion therapy, tocilizumab or corticosteroids
24. Evidence suggesting that the patient is not likely to follow the study protocol (e.g. lacking compliance)
25. Incapability of understanding purpose and possible consequences of the trial
26. Patients who should not be included according to the opinion of the investigator
Weitere Info ClinicalTrials.gov   ICH GCP NETWORK  
Ansprechpartner Email: ectu.cooperation@uniklinik-ulm.de , Tel. 0731 500 56070
Klinik Innere Medizin III