Anzahl der Treffer: 13 Studien
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
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. Updated per Amendment 1
2.1 Updated per Amendment 1/DEU-1
2.2 Diagnosis of acute myeloid leukemia (AML) according to World Health Organization 2016 criteria,
- De novo or secondary AML
- Relapsed /refractory (Arm A)
- Harboring KMT2A or NPM1 alterations

3. Criterion deleted per Amendment 1/DEU-1

4. Criterion deleted per Amendment 1/DEU-1

5. Updated per Amendment 1/DEU-1
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 for select participants)

Chemistry
Aspartate aminotransferase (AST) and alanine aminotransferase (ALT): a. <= 2.5 x upper limit of normal (ULN)

Total bilirubin: a. < 1.5 x ULN (participants with elevated bilirubinemia, such as Gilbert’s syndrome, may enroll if conjugated bilirubin is within clinically acceptable range).

Renal function: Estimated or measured glomerular filtration rate >= 40 mL/min per MDRD formula (Levey 2006; see Section 11.14)

6. ECOG performance status grade of 0, 1 or 2 (See Appendix 13; Oken 1982).

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

8. Updated per Amendment 1
8.1 Updated per Amendment 1/DEU-1
8.2 A woman of childbearing potential must agree to all the following during the study and for6 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. A male must agree to all the following during the study and for 90 days after the last dose of study treatment:
- 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. Any prior treatment with a menin-KMT2A inhibitor

5. Updated per Amendment 1/DEU-1
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. Uncontrolled (persistent) hypertension (eg, blood pressure >= 140/90 mmHg)
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)

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 > 100.4oF/38oC 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. Updated per Amendment 1/DEU-1
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.

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 45927
Kurztitel Amgen 20150161
EudraCT-Nr 2015-004777-32
Titel Erste Studie am Menschen (Phase I) zur Beurteilung der Sicherheit, Verträglichkeit, Pharmakokinetik und Pharmakodynamik von AMG 176 bei Patienten mit rezidiviertem oder refraktärem multiplem Myelom und bei Patienten mit rezidivierter oder refraktärer akuter myeloischer Leukämie
Studiendesign Interventionsstudie , nicht randomisiert , Phase I
Strategie 2nd line
Einschlusskriterien
Subjects are eligible to be included in the study only if all of the following criteria apply:
- Subject has provided informed consent prior to initiation of any study-specific activities/procedures.
- (Multiple myeloma subjects only) Pathologically documented, definitively diagnosed, MM relapse or refractory progressive disease and have received at least 2 therapeutic treatments or regimens for MM. The investigator must be of the opinion that no other treatment option will result in a durable response.
- Must be willing and able to undergo a core bone marrow biopsy (multiple myeloma subjects only) and bone marrow aspirate (MM and AML subjects) at screening.
- (Multiple myeloma subjects only) Measurable disease per the IMWG response criteria (assessed within 28 days prior to enrollment), as indicated by one or more of the following:
- Serum M-protein >= 0.5 g/dL
- Urine M-protein >= 200 mg/24 hours
- Subjects who do not meet 1 of the 2 prior criteria: serum free light chain (SFLC) >= 10 mg/dL (>= 100 mg/L) and an abnormal SFLC ratio (< 0.26 or > 1.65) as per the IMWG response criteria
- Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2
- Age >= 18 years old
- For subjects in Japan only: if a subject is younger than 20 years at the time of signing the informed consent form, informed consent must be obtained from both the subject and his/her legal representative
- Life expectancy of > 3 months, in the opinion of the investigator
- (Multiple myeloma subjects only) Hematological function, as follows without transfusion or growth factor support:
- Absolute neutrophil count (ANC) >= 1.0 x 10^9/L
- Platelet count >= 50 x 10^9/L (in subjects where < 50 % of bone marrow nucleated cells were plasma cells) or >= 30 x 10^9/L (in subjects where >= 50 % of bone marrow nucleated cells were plasma cells) without transfusion or growth factor support
- Subjects should not have received platelet transfusions for at least 1 week prior to screening
- Hemoglobin > 8 g/dL
- Screening ANC should be independent of granulocyte- and granulocyte/macrophage colony stimulating factor (G-CSF and GM-CSF) support for at least 1 week and of pegylated G-CSF for >= 2 weeks
- Hepatic function, as follows; total bile acid (TBA) < 5 x upper limit of normal (ULN), aspartate aminotransferase (AST) and alanine aminotransferase (ALT) <= 3 x ULN, total bilirubin <= 1.5 x ULN (except subjects with Gilbert’s syndrome).
- Cardiac function, as follows; left ventricular ejection fraction (LVEF) > 50 % 2-D transthoracic echocardiogram (ECHO) is the preferred method of evaluation. Multigated Acquisition Scan (MUGA) is acceptable if ECHO is not available.
- Calculated or measured creatinine clearance (CrCl) of >= 30 mL/minute calculated using the formula of Cockcroft and Gault [(140 – Age) x Mass (kg) / (72 x Creatinine mg/dL)]. Multiply result by 0.85 if female.
- Female subjects of childbearing potential must have a negative serum or urine pregnancy test within 3 days of the first dose (see Section 11.5 for definition of females of childbearing potential).
- (Acute myeloid leukemia subjects) AML as defined by the World Health Organization (WHO) Classification (Section 11.14) persisting or recurring following one or more treatment courses, and for subjects in Japan, determined by the investigator to be not eligible for approved anticancer drug therapy in Japan; EXCEPT acute promyelocytic leukemia (APL). The investigator must be of the opinion that no other treatment option will result in a durable response.
- (Acute myeloid leukemia subjects only) More than 5 % blasts in bone marrow.
- (Acute myeloid leukemia subjects only) Circulating white blood cells (WBCs) < 25,000/MikroL.
Ausschlusskriterien
Subjects are excluded from the study if anyof the following criteria apply:
- Previously received an allogeneic stem cell transplant within 6 months OR having received immunosuppressive therapy within the last 3 months OR having signs or symptoms of acute or chronic graft-versus-host disease.
- Autologous stem cell transplant less than 90 days prior to enrollment.
- (Multiple myeloma only) Multiple myeloma with IgM subtype.
- (Multiple myeloma only) POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes).
- (Multiple myeloma only) Existing plasma cell leukemia or rapidly proliferating extra medullary disease unless discussed and approved by Amgen medical monitor prior to enrollment.
- (Multiple myeloma only) Waldenstrom’s macroglobulinemia.
- (Multiple myeloma only) Amyloidosis.
- (Multiple myeloma only) Glucocorticoid therapy (prednisone > 30 mg/day or equivalent) within 7 days prior to enrollment. Topical or inhaled corticosteroids are permitted.
- Currently receiving treatment in another investigational device or drug study. Other investigational procedures while participating in this study will be allowed if approved by Amgen medical monitor.
- History of other malignancy within the past 2 years prior to enrollment, 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
- Known sensitivity to any of the products or component to be administered during dosing.
- Myocardial infarction within 6 months of enrollment, symptomatic congestive heart failure (New York Heart Association > class II).
- History of arterial thrombosis (eg, stroke or transient ischemic attack) in the past 6 months prior to enrollment.
- Active infection requiring IV anti-infective treatments within 1 week of enrollment
- Known or suspected human immunodeficiency virus (HIV) infection or subjects who are HIV seropositive. Testing will be performed if required by local regulatory authorities.
- Exclusion of hepatitis B and C infection based on the following results:
- Positive for hepatitis B surface antigen (HbsAg) (indicative of chronic hepatitis B or recent acute hepatitis B)
- Negative HbsAg and positive for hepatitis B core antibody (HbcAb) and/or hepatitis B surface antibody (HBsAb; Japan only): hepatitis B virus DNA by polymerase chain reaction (PCR) is necessary. Detectable hepatitis B virus DNA suggests occult hepatitis B. Negative for PCR test can be enrolled in the study
- Positive Hepatitis C virus antibody (HCVAb): hepatitis C virus RNA by PCR is necessary. Detectable hepatitis C virus RNA suggests chronic hepatitis C. Negative for PCR test can be enrolled in the study
- Unresolved toxicities from prior anti-tumor therapy, defined as not having resolved to Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 grade 1, or to levels dictated in the eligibility criteria with the exception of grade 2 peripheral neuropathy, alopecia or toxicities from prior anti-tumor therapy that are considered irreversible (defined as having been present and stable for > 4 weeks may be allowed if they are not otherwise described in the exclusion criteria AND there is agreement to allow by both the investigator and sponsor).
- Treatment with medications known to cause QT interval corrected (QTc) interval prolongation within 1 week prior to enrollment unless approved by the Amgen Medical Team.
- Anti-tumor therapy: chemotherapy within 14 days (or 5 half-lives, whichever is shorter) of enrollment, antibody therapy, molecular targeted therapy, or investigational agent within 21 days (or 5 half-lives, whichever is shorter) of enrollment. Exceptions: hydroxyurea to control peripheral blood leukemic cell counts is allowed until prior to receiving the first dose of AMG 176. Hydroxyurea is unapproved for AML in Japan.
- Prior systemic radiation therapy must have been completed at least 28 days prior to enrollment. Prior focal radiotherapy completed at 14 days prior to enrollment.
- Major surgery within 28 days of enrollment.
- Women of reproductive potential who are unwilling to practice an acceptable method of highly effective birth control while on study through 3 months after receiving the last dose of study drug. Men who are unwilling to practice sexual abstinence (refrain from heterosexual intercourse) or use a condom with spermicide during treatment and for an additional 4 months following the last dose of study drug if sexually active with a female of childbearing potential. For acceptable methods of highly effective birth control, and definition of females of childbearing potential see Section 11.5.
- Women planning to become pregnant or breastfeed while on study through 3 months after receiving the last dose of study drug. Subjects who suspend breastfeeding prior to starting treatment with study drug and do not intend to resume breastfeeding before 3 months after receiving the last dose of study drug can be enrolled
- Male subjects who are unwilling to abstain from donating sperm during treatment and for an additional 4 months following the last study drug administration
- History or evidence of any other clinically significant disorder, condition or disease 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.
- Use of any medications (except anti-tumor medications), including herbal medicines (eg, St. John’s wort), vitamins, or supplements consumed by the subject within the 30 days prior to enrollment, and continuing use if applicable, that was not reviewed and approved by the principal investigator and the Amgen medical monitor prior to enrollment. Written documentation of this review and Amgen acknowledgment is required for subject participation.
- Use of known strong inhibitors of CYP3A4/P-gp within the 14 days or 5 half-lives (whichever is longer) or products containing grapefruit juice, Seville oranges, or St. John’s wort within 7 days, prior to enrollment unless reviewed and approved by the principal investigator and the Amgen medical monitor prior to enrollment. Written documentation of this review and Amgen acknowledgment is required for subject participation. Exception: use of itraconazole for subjects enrolled in Part 3d.
- Use of known CYP3A4 sensitive substrates with a narrow therapeutic window within 5 half-lives of the drug or its major active metabolite, whichever is longer, following the last dose of the drug prior to receiving the first dose of AMG 176 unless reviewed and approved by the principal investigator and the Amgen medical monitor prior to enrollment. Written documentation of this review and Amgen acknowledgment is required for subject participation. Refer to prescribing information for any concomitant medications
- Use of known OATP1B1 and/or OATP1B3 or BCRP substrates with a narrow therapeutic window within 5 half-lives of the drug or its major active metabolite, whichever is longer, following the last dose of the drug prior to enrollment unless reviewed and approved by the principal investigator and the Amgen medical monitor prior to enrollment. Written documentation of this review and Amgen information for any concomitant medications.
- 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, Patient Reported Outcomes) to the best of the subject and investigator’s knowledge.
- Subjects with elevated cardiac troponin above the manufacturer’s 99th percentile upper reference limit for ADVIA Centaur XP assay at screening performed by the central laboratory (Covance).
- Subjects with evidence of recent cardiac injury at screening based on creatine kinase-muscle/brain (CK-MB), N-terminal prohormone of brain natriuretic peptide (NT-pro-BNP), and electrocardiogram (ECG) assessments at screening.
- DDI assessment cohort with itraconazole only: History of QT prolongation, torsades de pointes, ventricular tachycardia, and cardiac arrest
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Ansprechpartner Email: ectu.cooperation@uniklinik-ulm.de , Tel. 0731 500 45927
Klinik Innere Medizin III
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 45927
Klinik Innere Medizin III
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 ClinicalTrials.gov   ICH GCP NETWORK  
Ansprechpartner Email: ectu.cooperation@uniklinik-ulm.de , Tel. 0731 500 45927
Kurztitel CADPT01C12101
EudraCT-Nr 2019-004688-27
Titel Eine offene multizentrische Phase Ib Plattform Studie mit Eskalation und Expansion mit ausgewählten Substanzkombinationen in erwachsenen Patienten mit fortgeschrittenem oder metastasiertem BRAF V600 Kolorektalkarzinom
Studiendesign Interventionsstudie , nicht randomisiert , Phase I
Strategie 2nd line , 3rd line
Einschlusskriterien
POPULATION:
The study will be conducted in adult patients with BRAF V600 CRC in dose escalation and expansion as outlined in Section 1.2, Section 3, and Section 4.
The investigator or designee must ensure that only patients who meet all the following inclusion and none of the exclusion criteria are offered treatment in the study. Please note that eligibility criteria are divided into two categories: (1) applicable for all combination treatment arms, (2) specific to triplet combination treatment arms; both should be followed.

INCLUSION CRITERIA APPLICABLE FOR ALL COMBINATION TREATMENT ARMS
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. Patients must be >= 18 years of age.
3. ECOG performance status <= 1.
4. Patients must have a site of disease amenable to biopsy, and be a candidate for tumor biopsy according to the treating institution’s guidelines. Patients must be willing to undergo a new tumor biopsy at baseline and during therapy on study. Exceptions may be considered after documented discussion with Novartis.
5. All patients must have a BRAF V600 mutation confirmed by local assessment.
6. Patients with unresectable advanced/metastatic BRAF V600 cancer of the colon or rectum with measurable disease as determined by RECIST v1.1 (refer to Section 16.1).
7. Dose escalation part: Patients must have documented disease progression following, or are intolerant to, 1 or 2 lines of chemotherapy for advanced/metastatic disease.
8. Dose expansion part:
a. Group A (all arms as currently outlined in the protocol): Patients who have not previously received MAPK pathway-directed therapy (MAPKi naive). Patients must have documented disease progression following, or are intolerant to, 1 or 2 lines of chemotherapy for advanced/metastatic disease.
i. Additional inclusion for the spartalizumab-containing arm only:
Microsatellite stable (MSS) as determined by local testing in addition to above
b. Group B (all arms as currently outlined in the protocol): Patients who have previously received and progressed on MAPK pathway-directed therapy (MAPKi prior treated). Patients must have documented disease progression following, or are intolerant to, 1 or 2 lines of chemotherapy for advanced/metastatic disease.
c. Group C (spartalizumab containing arms only): Patients with BRAF V600 CRC that is MSI-H (as determined by local testing), and who are MAPKi naive and immune-checkpoint inhibitor naive. Patients must have documented disease progression following, or are intolerant to, 1 or 2 lines of chemotherapy for advanced/metastatic disease.

Note: For the purposes of inclusion criteria number 7 and number 8, regorafenib will not be considered a MAPKi. Chemotherapy is defined as a treatment regimen containing a fluoropyrimidine, and as medically indicated and tolerated, oxaliplatin or irinotecan. Adjuvant therapy containing a fluoropyrimidine and oxaliplatin may count as 1 prior line of chemotherapy, if disease recurrence has occurred within 6 months following completion of adjuvant chemotherapy.
Ausschlusskriterien
EXCLUSION CRITERIA APPLICABLE FOR ALLCOMBINATION TREATMENT ARMS
Subjects meeting any of the following criteria are not eligible for inclusion in this study.
1. History of hypersensitivity to any of the study treatments or its excipients or to drugs of similar chemical classes.
2. Treatment with any of the following anti-cancer therapies prior to the first dose of study treatment within the stated timeframes:
a. <= 4 weeks fo radiation therapy, or limited-field radiation for palliation within <= 2 weeks prior to the first dose of study treatment.
b. <= 2 weeks or <=5 half-lives (whichever is longer) for chemotherapy or biological therapy (including monoclonal antibodies) or continuous or intermittent small molecule therpeutics or any other investigational agent.
biological therapy (including monoclonal antibodies) or continuous or
intermittent small molecule therapeutics or any other investigational agent.
Note: for anti-VEGF antibodies, a washout period of at least 2 weeks will be used.
c. <= 6 weeks for cytotoxic agents with major delayed toxicities, such as nitrosoureas and mitomycin C.
d. Patients who have undergone major surgery <= 4 weeks prior to first dose of study treatment or who have not recovered from the surgical procedure.
Exceptions may be considered after documented discussion with Novartis (mediastinoscopy, insertion of a central venous access device and insertion of a feeding tube are not considered major surgery).
e. Use of immunotherapy treatment must have ended at least 4 weeks prior to first dose of study treatment (For the spartalizumab triplet combination treatment arm, refer to Section 5.2.5 for additional restrictions)
3. Patients who required discontinuation of treatment due to treatment-related toxicities during prior therapy directed against the same target as the drug(s) under study in this protocol.
4. Has a known additional malignancy that is progressing or requires active treatment.
Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the skin that has undergone potentially curative therapy, or in-situ cervical cancer, or other tumors that will not affect life expectancy.
5. Patients participating in additional parallel investigational drug or medical device studies.
6. Presence of Grade >= 2 toxicity according to National Cancer Institute (NCI) CTCAE, with the exception of neuropathy (inclusion of patients with neuropathy of Grade 2 or less is permitted in the treatment arms that do not contain LXH254) and alopecia. (For the LXH254 arm, see Section 5.2.3 for exclusion criteria for neurological disease)
7. Impairment of gastrointestinal function or gastrointestinal disease that may significantly alter the absorption of study drugs, with the exception of prior gastrectomy (e.g., ulcerative disease, uncontrolled nausea, vomiting, malabsorption syndrome, ongoing diarrhea requiring medication [e.g., loperamide, bile acid sequestrant such as cholestyramine] within 7 days).
8. Unable or unwilling to swallow the oral drug as per dosing schedule.
9. Current evidence/known risk of uveitis in the opinion of the investigator.
10. A history of or current evidence/risk of retinal vein occlusion (RVO) or serous retinopathy including:
- Presence of predisposing factors to RVO or serous retinopathy (e.g., uncontrolled glaucoma or ocular hypertension, uncontrolled hypertension, uncontrolled diabetes mellitus, or a history of hyperviscosity or hypercoagulability syndromes); or
Visible retinal pathology as assessed by ophthalmic examination that is considered a risk factor for RVO or central serous retinopathy such as:
Evidence of new optic disc cupping;
Evidence of new visual field defects on automated perimetry;
Intraocular pressure > 21 mmHg as measured by tonometry.
11. History of or current interstitial lung disease or non-infectious pneumonitis.
12. Patients with CNS tumor involvement. However, patients with metastatic CNS tumors may participate in this study if at the time of first study treatment the patient is:
a. 2 weeks from post completion of prior CNS-directed therapy (including radiation and/or surgery)
b. Clinically stable with respect to the CNS tumor involvement
c. Not receiving steroid therapy or, if receiving glucocorticoid therapy, the patient must have been maintained on a stable dose <= 10 mg per day prednisone or equivalent for at least 2 weeks
13. Patients with a history of diabetes requiring medical therapy that is not well-controlled on a stable regimen in the opinion of the investigator.
14. Any medical condition that would, in the investigator’s judgment, prevent the patient’s participation in the clinical study due to safety concerns or compliance with clinical study procedures. Any severe, acute, or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or study treatment administration or that may interfere with the interpretation of study results and, in the judgment of the investigator, would make the patient inappropriate for the study.
15. Insufficient bone marrow function prior to start of treatment:
a. Absolute Neutrophil Count (ANC) < 1.5 x 10^9/L
b. Hemoglobin (Hgb) < 9.0 g/dL
c. Platelets < 75 x 10^9/L
16. Insufficient hepatic or renal function prior to start of treatment:
a. Serum total bilirubin > 1.5 x upper limit of normal (ULN), except for patients with Gilbert’s syndrome who are excluded if total bilirubin > 3.0 x ULN or direct bilirubin > 1.5 x ULN (For the LXH254 arm, see Section 5.2.3)
b. Asparate aminotransferase (AST) > 3 x ULN
c. Alanine aminotransferase (ALT) > 3 x ULN
d. Serum creatinine > 1.5 x ULN OR Creatinine Clearance < 60 mL/min (calculated using Cockcroft-Gault equation, see Section 16.3)
17. Patients who have the following laboratory values outside of the laboratory normal limits (treatment may be given during screening to correct values):
a. Potassium
b. Magnesium
c. Calcium (corrected for serum albumin)
d. Phosphate
18. Patients who are taking a prohibited medication (See Section 6.2.1.2 and Section 17), including herbal medicines known to cause liver toxicity, that cannot be discontinued at least seven days prior to the first dose of study treatment and for the duration of the study.
19. Patients with known history of testing positive for Human Immunodeficiency Virus (HIV).
20. Patients with active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection.
- Patients with serologic evidence of chronic HBV infection but have an HBV viral load below the limit of quantification can be enrolled with concurrent viral suppressive therapy.
- Active hepatitis C is defined by quantitative HCV RNA results greater than the lower limits of detection of the assay.
21. Clinically significant cardiac disease at screening including any of the following:
a. Congestive heart failure (New York Heart Association Class >= 2)
b. Left ventricular ejection fraction (LVEF) < 50 % or below the institutional standard lower limit, whichever is higher, as determined by multiple gated acquisition (MUGA) scan or trans-thoracic echocardiography (TTE)
c. Uncontrolled hypertension defined by blood pressure >= 140 (systolic) / 90 (diastolic) mmHg at rest (average of 3 consecutive readings) despite medical treatment. Initial or adjustment of antihypertensive medication(s) is allowed prior to screening.
d. History or presence of clinically significant ventricular arrhythmias, atrial fibrillation, resting bradycardia, conduction abnormality, transient ischemic attack or stroke, including:
i. Unstable angina pectoris or acute myocardial infarction 6 months prior to starting study drug
ii. QT interval corrected by Fridericia’s formula (QTcF) > 470 msec on screening ECGs (as a mean of triplicate ECGs)
iii. Patients receiving a drug with a known risk of Torsades de Pointes (TdP) that cannot be discontinued or replaced by safe alternative medication (Table 6-3 and Section 17)
iv. Symptomatic cardiac arrhythmias (e.g., sustained ventricular tachycardia, and clinically significant second or third-degree atrioventricular block without a pacemaker)

For the trametinib- and TNO155-containing arms, see additional cardiac criteria in Sections 5.2.2, Section 5.2.4, and Section 5.2.6, respectively.

22. Pregnant or lactating women, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive hCG laboratory test. In rare cases of an endocrine-secreting tumor, hCG levels may be above normal limits but with no pregnancy in the subject. In these cases, there should be a repeat serum hCG test (with a non-rising result) and a vaginal/pelvic ultrasound to rule out pregnancy.
Upon confirmation of results and discussion with the Novartis medical monitor, these subjects may enter the study.
23. Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using highly effective methods of contraception while taking study treatment and for 150 days after the last dose of spartalizumab, for 120 days after the last dose of trametinib, for 30 days after the last dose of TNO155, for 14 days after the last dose of dabrafenib, for 7 days after the last dose of LXH254, or for 4 days after the last dose of LTT462, whichever is later. Highly effective contraception methods include:
- Total abstinence (when this is in line with the preferred and usual lifestyle of the subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal, postovulation methods) and withdrawal are not acceptable methods of contraception.
- Female sterilization (have had surgical bilateral oophorectomy with or without hysterectomy), total hysterectomy, or bilateral tubal ligation at least six weeks before taking study treatment. In case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment.
- Male sterilization (at least 6 months prior to screening). For female subjects on the study, the vasectomized male partner should be the sole partner for that subject.
- Placement of an intrauterine device (IUD) or intrauterine system (IUS) that have comparable efficacy (failure rate < 1 %).
- Note: Hormonal-based methods (e.g., oral contraceptives) alone are not considered to be highly effective methods of contraception due to potential drug-drug interactions.Women are considered post-menopausal and not of child bearing potential if they have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g., age- appropriate history of vasomotor symptoms) or have had surgical bilateral oophorectomy (with or without hysterectomy), total hysterectomy or bilateral tubal ligation at least six weeks ago.
In the case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment is she considered not of child-bearing potential.

Sexually active males unwilling to use a condom during intercourse while taking study treatment and for 120 days after the last dose of trametinib, or 14 days after the last dose of dabrafenib, or 10 days after the last dose of TNO155, or 7 days after the last dose of LXH254, or 4 days after the last dose of LTT462, whichever is later. A condom is required for all sexually active male participants to prevent them from fathering a child AND to prevent delivery of study treatment via seminal fluid to their partner. In addition, male participants must not donate sperm for the time period specified above.
If local regulations deviate from the contraception methods listed above to prevent pregnancy, local regulations apply and will be described in the informed consent form (ICF).

ADDITIONAL EXCLUSION CRITERIA FOR COMBINATION ARM DARAFENIB + LTT462 + TRAMETINIB
24. Clinically significant cardiac disease or risk factors at screening including any of the following:
a. Any history of congestive heart failure.
b. Troponin I/T elevation > Grade 1.
c. Supraventricular and nodal arrhythmias not controlled with medication
d. Other cardiac arrhythmias not controlled with medication
e. Complete left bundle branch block or high grade AV block (e.g., bifascicular block, Mobitz type II and third degree AV block).
f. Clinically significant/symptomatic bradycardia.
g. QTcF > 450 ms for males and > 460 ms for females on screening ECGs (as a
mean of triplicate ECGs), history of TdP, or a history of congenital long QT syndrome.
h. Inability to determine the QT interval.
i. Cumulative lifetime anthracycline exposure greater than 250 mg/m^2 doxorubicin or equivalent (See Section 16.4)
25. Patients who have had a grade >= 3 bleed in the last 6 month.

ADDITIONAL EXCLUSION CRITERIA FOR COMBINATION ARM DARAFENIB + LTT462 + LXH254
26. Patients with neurological disease, including grade >= 1 peripheral neuropathy
27. Patients with Gilbert’s syndrome or other heritable disease of bile processing
28. Insufficient hepatic function prior to start of treatment:
a. Total bilirubin > ULN or > 1.5 x ULN if liver metastases are present at baseline

ADDITIONAL EXCLUSION CRITERIA FOR COMBINATION ARM DARAFENIB + LTT462 + TNO155
29. Clinically significant cardiac disease or risk factors at screening including any of the following:
a. Any history of congestive heart failure.
b. Supraventricular and nodal arrhythmias not controlled with medication
c. Other cardiac arrhythmias not controlled with medication
d. Complete left bundle branch block or high grade AV block (e.g., bifascicular block, Mobitz type II and third degree AV block).
e. Clinically significant/symptomatic bradycardia.
f. QTcF > 450 ms for males and > 460 ms for females on screening ECGs (as a mean of triplicate ECGs), history of TdP, or a history of congenital long QT syndrome.
g. Inability to determine the QT interval.
h. Cumulative lifetime anthracycline exposure greater than 250 mg/m^2 doxorubicin or equivalent (See Section 16.4)

ADDITIONAL EXCLUSION CRITERIA FOR COMBINATION ARM DARAFENIB + LTT462 + SPARTALIZUMAB
30. Active, known or suspected autoimmune disease. Patients with vitiligo, type I diabetes, residual hypothyroidism only requiring hormone replacement, psoriasis not requiring systemic treatment or conditions not expected to recur may be considered.
31. Dose escalation only: Patients previously exposed to anti-PD-1/PD-L1 treatment who are not adequately treated for skin rash or with replacement therapy for endocrinopathies.
32. Dose expansion only: Prior anti-PD-1/PD-L1 treatment
33. Systemic chronic steroid therapy (> 10 mg/day prednisone or equivalent) or any other immunosuppressive therapy within 7 days of the first dose of study treatment.
Topical, inhaled, nasal and ophthalmic steroids are allowed.
34. Use of any live vaccines against infectious diseases within 4 weeks of initiation of study treatment.
35. Use of hematopoietic colony-stimulating growth factors (e.g., G-CSF, GM-CSF, M-CSF), thrombopoietin mimetics or erythroid stimulating agents <= 2 weeks prior to start of study treatment. If thrombopoietin mimetics or erythroid stimulating agents were initiated more than 2 weeks prior to the first dose of study treatment and the patient is on a stable dose, they can be maintained.

ADDITIONAL EXCLUSION CRITERIA FOR COMBINATION ARM DARAFENIB + TRAMETINIB + TNO155
36. Clinically significant cardiac disease or risk factors at screening including any of the
following:
a. Any history of congestive heart failure.
b. Troponin I/T elevation > Grade 1.
c. Supraventricular and nodal arrhythmias not controlled with medication
d. Other cardiac arrhythmias not controlled with medication
e. Complete left bundle branch block or high grade AV block (e.g., bifascicular block, Mobitz type II and third degree AV block).
f. Clinically significant/symptomatic bradycardia.
g. QTcF > 450 ms for males and > 460 ms for females on screening ECGs (as a mean of triplicate ECGs), history of TdP, or a history of congenital long QT syndrome.
h. Inability to determine the QT interval.
i. Cumulative lifetime anthracycline exposure greater than 250 mg/m^2 doxorubicin or equivalent (See Section 16.4)
37. Patients who have had a grade >= 3 bleed in the last 6 months.
Weitere Info ClinicalTrials.gov  
Ansprechpartner Email: ectu.cooperation@uniklinik-ulm.de , Tel. 0731 500 45927
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 45927
Klinik Innere Medizin III
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.
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Ansprechpartner Email: ectu.cooperation@uniklinik-ulm.de , Tel. 0731 500 45927
Klinik Innere Medizin III
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 kurativ , 2nd line
Einschlusskriterien
Subjects are eligible to be included in the study only if all of the following criteria apply:

01. Subject has provided informed consent/assent before initiation of any study specific activities/procedures.

02. Age >= 18 years.

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

04. 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 up to 2 prior lines of systemic therapy for metastatic/locally advanced disease, to 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 up to 2 prior lines of systemic therapy for metastatic/locally advanced disease, to include PD1 or PD-L1 inhibitors and platinum-based chemotherapy, and 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 up 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 up to 2 prior lines of systemic therapy for metastatic/locally advanced disease, to include platinum-based chemotherapy.

- Part 1g: MTAP-null or lost MTAP expression pancreatic adenocarcinoma, treated with up to 2 prior lines of systemic therapy.

- 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 up to 2 prior lines of systemic therapy for locally advanced/metastatic disease, to include PD1 or PD-L1 inhibitors and platinum-based chemotherapy.

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

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

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

08.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.

09. Adequate renal function per local laboratory, defined as:

- estimated glomerular filtration rate based on Modification of Diet in Renal Disease calculation > 45 mL/min/1.73 m^2.

10.Adequate glucose control per local laboratory (Part 1 only), defined as:

- fasting blood glucose <= 160 mg/dL.

11.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).

12.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.

13. 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.

14. 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 for women or 350 msec <= baseline QTc <= 450 msec for men (based on average of screening triplicates, confirmed by central cardiology read).

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

16. 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.

17. 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 anyof the following criteria apply:

Disease Related

01. 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.

02. Presence of primary brain cancer.

03. Presence of hematological malignancy or lymphoma.

Other Medical Conditions

04. 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.

05. Evidence of interstitial lung disease or active, non-infectious pneumonitis.

06. Active infection requiring systemic therapy.

07. 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.

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

09. 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.

10. 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).

11. 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.

12. History of solid organ transplant.

13. Diagnosis of Congenital Short QT Syndrome.

Prior/Concomitant Therapy

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

15. 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).

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

17. Prior treatment with docetaxel (Part 2 only).

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

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

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

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

22. 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.

23. 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.
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Ansprechpartner Email: ectu.cooperation@uniklinik-ulm.de , Tel. 0731 500 45927
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
Strategie palliativ
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)
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Ansprechpartner Email: ectu.cooperation@uniklinik-ulm.de , Tel. 0731 500 45927
Kurztitel PANTAX-Ib
EudraCT-Nr 2020-002627-11
Titel Eine offene, prospektive klinische Studie der Phase Ib zur Untersuchung der Sicherheit,Verträglichkeit und maximal verträglichen Dosis von SCO-101 in Kombination mitGemcitabin und Nab-Paclitaxel bei Patienten mit inoperablem Bauchspeicheldrüsenkrebs - PANTAX-Ib
Studiendesign Interventionsstudie , nicht randomisiert , Phase I
Strategie 1st line
Einschlusskriterien
Patienten, die in die Studie eingeschlossen werden, müssen alle folgenden Kriterien erfüllen:

1. Fähigkeit, die Einwilligung nach Aufklärung zu verstehen und Bereitschaft die Einwilligung schriftlich zu geben bevor studienspezifische Aktivitäten durchgeführt werden.

2. Alter >= 18 Jahre.

3. Histologisch oder zytologisch bestätigtes Adenokarzinom des Pankreas.

4. Inoperables lokal begrenztes, lokal fortgeschrittenes oder metastasiertes Pankreaskarzinom bei Patienten, für die eine kurative Therapie nicht in Frage kommt, und die für eine Chemotherapie mit Gemcitabin und nab-Paclitaxel vorgesehen sind.

5. Messbare oder nicht-messbare Läsionen gemäß RECIST 1.1 bestimmt anhand CT oder MRT.

6. ECOG Performance Status <= 2 und Eignung für die standardmäßig empfohlene (100 %) Gemcitabin- und nab-Paclitaxel-Dosis.

7. Nebenwirkungen Grad <= 1 von vorheriger Operation, Akuttoxizitäten einer vorherigen Radiotherapie oder Behandlung mit Zytostatika oder Biologika.

8. Zeitintervall von >= 2 Wochen seit vorheriger Operation oder Radiotherapie.

9. Angemessener Zustand basierend auf folgenden klinischen Laborparametern:
- Neutrophile (ANC) >= 1,5 x 10^9/L
- Hämoglobin >= 6,0 mmol/L
- Thrombozyten >= 100 x 10^9/L
- Alanin-Aminotransferase (ALT) <= 2,5 x ULN und Aspartat-Aminotransferase (AST) <= 2,5 x ULN*
- Serumbilirubin <= 1,0 ULN
- Alkalische Phosphatase <= 2,5 x ULN*
- Kreatinin <= 1,5 ULN
- eGFR im Normbereich
- Adäquate Blutgerinnung definiert als INR (International Normalized Ratio) <= 1,2

10. Lebenserwartung > 3 Monate.

11. Sexuell aktive Männer und Frauen, die Kinder bekommen können, müssen während der Studienbehandlung und für mindestens 6 Monate nach Beendigung der Studienbehandlung sichere Verhütungsmethoden (Kupferspirale oder hormonale Methoden wie Antibabypille, Hormonspirale, Vaginalring, Dreimonatsspritze, Implantat oder Hormonpflaster) anwenden.

12. Unterschriebene Einverständniserklärung.

*AST ist nicht vorgeschrieben. Bei Vorhandensein von Lebermetastasen mit ALT und AST <= 5 x ULN und/oder alkalischer Phosphatase <= 5 x ULN: Patienten, die die Kriterien zu Transaminasen und/oder alkalischer Phosphatase verletzen, aber lt. Prüfer in gutem Allgemeinzustand und ansonsten für die Studie geeignet sind, und eine Erhöhung der Transaminasen und/oder alkalischer Phosphatase auf andere Gründe als eine eingeschränkte Leberfunktion zurückzuführen ist, können, basierend auf einer Übereinkunft zwischen Prüfer und Sponsor, für einen Einschluss in die Studie berücksichtigt werden.
Ausschlusskriterien
Patienten dürfen nicht in die Studie eingeschlossen werden, wenn eines der folgenden Kriterien zutrifft:

1. Gleichzeitige Chemotherapie, Radiotherapie oder Therapie mit einem anderen Prüfpräparat während der Studie.

2. Vorherige Operationen mit Entfernung des kompletten Magens oder dem Großteil des Dünndarms (außer Duodenum), welche die Resorption von SCO-101 beeinträchtigen könnte. Behandlung mit Kreon o. ä. ist erlaubt.

3. Schwierigkeit Tabletten zu schlucken.

4. ZNS-Metastasen, die eine Behandlung mit Steroiden benötigen.

5. Antibiotika zur Behandlung von Infektionen oder klinische Symptome einer aktiven Infektion. Patienten mit CoViD19-Symptomen müssen auf eine aktive CoViD19-Infektion getestet werden.

6. HIV-positive Diagnose.

7. Aktive Infektion mit Hepatitis B oder C.

8. Klinisch signifikante (i. e. aktive) kardiovaskuläre Erkrankung:
- Schlaganfall, transitorische ischämische Attacke (TIA) oder Herzinfarkt innerhalb von <= 6 Monaten vor Tag 1.
- Instabile Angina oder Herzinsuffizienz (CHF) = Grad II (NYHA Klassifikation).
- Schwerwiegende Herzrhythmusstörung, die eine medikamentöse Behandlung benötigt.

9. Psychischer Zustand, symptomatische Epilepsie oder andere ZNSErkrankung, welche(r) nach Einschätzung des Prüfarztes eine Teilnahme an der Studie nicht zulässt.

10. Weitere medikamentöse Behandlung oder Erkrankung, die nach Einschätzung des Prüfarztes aus Sicherheitsgründen eine Teilnahme nicht zulässt oder die Interpretation der Studienergebnisse beeinträchtigen würde. Weitere schwerwiegende Erkrankungen einschließlich schwerwiegende Herzerkrankung, instabiler Diabetes, unkontrollierte Hyperkalzämie oder vorherige Organtransplantation.
Teilnahme an weiterer klinischer Prüfung mit Prüfmedikament innerhalb von 30 Tagen vor Registrierung.

11. Bekannte Überempfindlichkeit gegen Gemcitabin und/oder nab-Paclitaxel.

12. Für Patientinnen: Schwangerschaft oder Stillzeit.

13. Vorherige oder derzeitige Neuropathie > Grad I (NCI-CTCAE v.5.0).

14. Kurativer Behandlungsansatz.
Weitere Info ClinicalTrials.gov  
Ansprechpartner Email: ectu.cooperation@uniklinik-ulm.de , Tel. 0731 500 45927
Klinik Innere Medizin I
Kurztitel TAPISTRY
EudraCT-Nr 2020-001847-16
Titel Tumordiagnostische Präzisionsimmunoonkologie und somatisches Targeting rational rational for you (TAPISTRY) Phase II - Plattformversuch - TAPISTRY
Studiendesign Interventionsstudie , nicht randomisiert , Phase II
Strategie kurativ
Einschlusskriterien
General Inclusion Criteria
Patients must meet the following general inclusion criteria to be eligible to enroll in any cohort.

- For patients whose biomarker status is unknown and/or for patients with an ineligible local NGS test result: Signed Biomarker Eligibility Testing Informed Consent Form and willingness to participate in an assigned cohort based on their identified oncogenic biomarker(s)

- For patients with a positive biomarker status: Signed cohort-specific Informed Consent Form

For pediatric patients: Informed Consent Form must be signed by either the parent(s) or a legal representative

- For pediatric patients: Signed Child’s Informed Assent, when appropriate as determined by patient’s age and individual site and country standards

- Histologically or cytologically confirmed diagnosis of advanced and unresectable or metastatic solid malignancy

- Measurable disease as defined by RECIST v1.1, RANO, or INRC

- Performance status as follows:

Patients aged >= 18 years: Eastern Cooperative Oncology Group (ECOG) Performance Status 0-2

Patients aged 16 to < 18 years: Karnofsky score >= 50 %

Patients aged < 16 years: Lansky score >= 50 %

- For patients aged >= 18 years: adequate hematologic and end-organ function as defined below:

ANC >= 1000/MikroL

Platelet count >= 100 x 10^9 /L

Hemoglobin >= 8 g/dL

Total bilirubin <= 1.5 x upper limit of normal (ULN), with the following exception:
Patients with known Gilbert’s syndrome who have a serum bilirubin <= 3 x ULN may be enrolled.

AST and ALT <= 3 x ULN, with the following exception:
Patients with liver metastases who have an AST or ALT <= 5 x ULN may be enrolled.

NOTE: The requirements for enrollment into a specific cohort may be more stringent. Prior to enrollment, patients must also meet the criteria listed in the respective cohort-specific appendix.

- For patients aged < 18 years: adequate hematologic and end-organ function as defined below:

ANC >= 1000/MikroL (without transfusion)

Platelet count >= 75 x 10^9 /L (without transfusion)

Hemoglobin >= 8 g/dL (transfusion permitted)

Bilirubin <= 1.5 x ULN for age

AST and ALT <= 3 x ULN for age

Serum creatinine <= 1.5 x ULN for age or creatinine clearance (or radioisotope glomerular filtration rate) > 70 mL/min/1.73 m^2

INR and aPTT <= 1.5 x ULN for age

NOTE: The requirements for enrollment into a specific cohort may be more stringent. Prior to enrollment, patients must also meet the criteria listed in the respective cohort-specific appendix.

- Disease progression on prior treatment, or previously untreated disease with no available acceptable treatment

- Adequate recovery from most recent systemic or local treatment for cancer

- Life expectancy >= 8 weeks

- Ability to comply with the study protocol, in the investigator's judgment

- For female patients of childbearing potential: Negative serum pregnancy test <= 14 days prior to initiating study treatment, agreement to remain abstinent or use single or combined contraception methods that result in a failure rate of < 1 % per year for the period defined in the cohort-specific inclusion criteria, and agreement to refrain from donating eggs during the same period

Examples of contraception methods with a failure rate of < 1 % per year: vasectomy, bilateral tubal ligation, intrauterine device (IUD), or intrauterine hormone-releasing system (IUS)

Barrier methods such as condoms, diaphragms, caps (with spermicide), or sponges (with spermicide) have a failure rate of > 1 % per year. Contraception methods that have a failure rate of > 1% per year must be combined with a contraception method that has a failure rate of < 1 % per year.

The use of oral contraceptives should be supplemented with a barrier method (preferably a male condom).

A female is considered to be of childbearing potential if she is postmenarcheal, has not reached a postmenopausal state (>= 12 continuous months of amenorrhea with no identified cause other than menopause), and has not undergone surgical sterilization (removal of ovaries and/or uterus). The definition of childbearing potential may be adapted for alignment with local guidelines or requirements

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 patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not acceptable.

- For male patients: Willingness to remain abstinent or use acceptable methods of contraception as defined in the cohort-specific inclusion criteria

In addition to the general inclusion criteria above, in order to be enrolled in a treatment cohort of the study, patients must meet all of the cohort-specific inclusion criteria (including age) for the respective cohort as detailed in the cohort sections below.
Ausschlusskriterien
General Exclusion Criteria
Patients who meet any of the following criteria will be ineligible for NGS biomarker eligibility testing (if required) and excluded from study entry in any cohort:

- Current participation or enrollment in another therapeutic clinical trial

- Any anti-cancer treatment within 2 weeks or 5 half-lives (whichever is longer) prior to start of study treatment

- Whole brain radiotherapy within 14 days prior to start of study treatment

- Stereotactic radiosurgery within 7 days prior to start of study treatment

- Pregnant or breastfeeding, or intending to become pregnant during the study

- History of or concurrent serious medical condition or abnormality in clinical laboratory tests that, in the investigator's judgment, precludes the patient's safe participation in and completion of the study or confounds the ability to interpret data from the study

For patients with HIV, hepatitis A, hepatitis B, or hepatitis C, please refer to the cohort-specific eligibility criteria for requirements on enrollment, if applicable.

- Incomplete recovery from any surgery prior to the start of study treatment that would interfere with the determination of safety or efficacy of study treatment

- Significant cardiovascular disease, such as New York Heart Association cardiac disease (Class II or higher), myocardial infarction, or cerebrovascular accident within 3 months prior to enrollment, unstable arrhythmias, or unstable angina

- History of another active cancer within 5 years prior to screening that may interfere with the determination of safety or efficacy of study treatment with respect to the qualifying solid tumor malignancy

In addition to the general exclusion criteria above, in order to be enrolled in a treatment cohort of the study, patients must not meet any of the cohort-specific exclusion criteria detailed in the cohort sections below. In the event of overlapping eligibility criteria, the cohort-specific eligibility criteria supersede the general criteria.
Weitere Info ClinicalTrials.gov  
Ansprechpartner Email: ectu.cooperation@uniklinik-ulm.de , Tel. 0731 500 45927
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 45927
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
Ansprechpartner Email: ectu.cooperation@uniklinik-ulm.de , Tel. 0731 500 45927
Klinik Innere Medizin III