Aktuelle Klinische Studien

Patients 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. Male or female patients must be = 18 years of age.

3. Eastern Cooperative Oncology Group (ECOG) performance status of = 2. (Inclusion criterion 3 has been replaced with 3a and is no longer applicable with protocol amendment v03).
3a. Eastern Cooperative Oncology Group (ECOG) performance status of = 1.

4. Patients with one of the following indications:

- Histologically and/or cytologically confirmed diagnosis of estrogen-receptor positive and/or progesterone receptor positive and HER2-negative breast cancer based on the most recently analyzed tissue sample; all tested by a local laboratory using an assay that meets applicable local regulations and all data must be available in the patient’s medical record. HER2-negative breast cancer is defined as a negative in situ hybridization (ISH) test or an IHC status of 0 or 1+, or an IHC status of 2+ in conjunction with a negative in situ hybridization test [such as fluorescence in situ hybridization (FISH), chromogenic in situ hybridization (CISH), silver-enhanced in situ hybridization (SISH) or dual in situ hybridization (DISH)].

- Histologically and/or cytologically confirmed diagnosis of cancer with a CCNE1 amplification (only solid tumor data is allowed). CCNE1 amplifications must have been previously identified through local molecular assays that meet applicable local regulations and data must be available in the patient’s medical record.

Phase I:

- BC: Patients with HR+/HER2- breast cancer must have had disease progression on or following, or have been intolerant to, at least one line of hormone-based therapy in combination with a CDK4/6 inhibitor (CDK4/6i) and at least one additional line of systemic therapy (including cytotoxic chemotherapy, targeted therapies, and/or antibody-drug conjugate therapies) for metastatic disease and not be a candidate for any available standard therapy, in the investigator's judgement.

- CCNE1 amplified solid tumors: Patients must have received, but are not benefitting from standard therapies, are intolerant or ineligible to receive such therapy, or have no standard therapy option. For dose expansion only: no more than 3 prior lines of therapy for advanced or metastatic disease are allowed.

- OC: Patients must have received platinum-based chemotherapy and be considered to have platinum-resistant or refractory disease. If appropriate, they should have received prior treatment with anti-VEGF therapy or PARP inhibitor in accordance with local standard of care, unless the patient was ineligible to receive such therapies. In addition, patients must have received at least one line of chemotherapy in the platinum-resistant setting and not be a candidate for any available standard therapy, in the investigator's judgement.

- GEA: Patients must have received one line of therapy with a fluoropyrimidine and platinum-based regimen, and, if appropriate, prior treatment with HER2 targeted therapy or anti-PD-(L)1 therapy in accordance with local standard of care, unless the patient was ineligible to receive such therapy or not be a candidate for any available standard therapy, in the investigator's judgement.

Phase II:

- BC: Patients with HR+/HER2- breast cancer who have received an aromatase inhibitor or tamoxifen in combination with a CDK4/6 inhibitor (palbociclib, ribociclib, or abemaciclib) for unresectable or metastatic disease and demonstrated evidence of disease progression. They must not have received more than two lines of endocrine therapy in the unresectable/metastatic setting. Patients whose disease progressed while on an adjuvant CDK4/6 inhibitor are permitted without a CDK4/6 inhibitor in the metastatic setting; such patients are permitted only one additional line of endocrine therapy in the unresectable/metastatic setting.

5. Measurable disease as determined by RECIST version 1.1 (refer to Appendix 8).
Tumor lesions previously irradiated or subjected to other locoregional therapy will only be considered measurable if there is documented disease progression at the treated site after completion of therapy.

- BC only: If no measurable disease is present, then at least one predominantly lytic bone lesion must be present that can be accurately assessed at baseline and is suitable for repeated assessment (patients with no measurable disease and only one predominantly lytic bone lesion that has been previously irradiated are eligible if there is documented evidence of disease progression of the bone lesion after irradiation).

6. Patients must be suitable and willing to undergo study required biopsies if safe and medically feasible according to the treating institution’s own guidelines and requirements.
Patient must be willing to undergo a new tumor biopsy at screening (and additionally during treatment for Phase I additional escalation cohorts). If a newly obtained biopsy cannot be safely performed at screening, a recent archival sample may be substituted from patients that have not received systemic therapy since the collection of the biopsy.
Exceptions to the mandatory baseline tumor sample requirement may be allowed following documented discussion with Novartis.

Patients meeting any of the following criteria are not eligible for inclusion in this study.

1. Treatment with any of the following anti-cancer therapies prior to the first dose of study treatment within the stated timeframes:
- Previous treatment with a CDK2 inhibitor at any time.
- = 2 weeks for fluoropyrimidine therapy
- = 4 weeks for extended-field radiotherapy or = 2 weeks for limited field radiation for palliation. For the combination treatment, patients in whom = 25% of the bone marrow has been previously irradiated are also excluded.
- = 4 weeks or = 5 half-lives (whichever is shorter) for chemotherapy or biological therapy (including monoclonal antibodies) or continuous or intermittent small molecule therapeutics or any other investigational agent.
- = 6 weeks for cytotoxic agents with major delayed toxicities, such as nitrosoureas and mitomycin C.
- For the combination treatment: = 5 half-lives wash out period after treatment with tamoxifen or toremifene.

2. Having out of range laboratory values defined as:
- Creatinine clearance (calculated using CKD-EPI 2021 formula, or measured) < 50 mL/min
- Total bilirubin > 1 x ULN, (except for patients with Gilbert’s syndrome who are excluded if total bilirubin > 3.0 x ULN) and direct bilirubin > 1.5 x ULN
- Alanine aminotransferase (ALT) > 2.5 x ULN, except for patients with liver metastasis, who are excluded for ALT = 5 x ULN.
- Aspartate aminotransferase (AST) > 2.5 x ULN except for patients with liver metastasis, who are excluded for AST = 5 x ULN.
- Absolute neutrophil count (ANC) < 1.5 x 10^9/L
- Platelet count < 100 x 109/L
- Hemoglobin < 9 g/dL
- QTcF = 450 msec (as a mean value of triplicates) on screening ECGs, or inability to determine the QTcF interval
- Clinically significant electrolyte abnormalities, including any grade of hypocalcemia, hypokalemia, or hypomagnesemia, that are not corrected before the first dose of the study medication

3. Clinically significant, uncontrolled heart disease and/or cardiac repolarization abnormality, including any of the following:
- History of documented myocardial infarction (MI), angina pectoris, symptomatic pericarditis, or coronary artery bypass graft (CABG) within 6 months prior to study entry
- Documented cardiomyopathy
- Long QT syndrome or family history of idiopathic sudden death or congenital long QT syndrome, or any of the following:
- Risk factors for Torsades de Pointe (TdP) including uncorrected hypocalcemia, hypokalemia or hypomagnesemia, history of cardiac failure, or history of clinically significant/symptomatic bradycardia
- Clinically significant cardiac arrhythmias (e.g., ventricular tachycardia, complete left bundle branch block, high-grade atrioventricular (AV) block, Mobitz type II and third-degree AV block)
- Uncontrolled arterial hypertension with systolic blood pressure (SBP) > 160 mmHg.

4. Presence of Grade = 2 toxicity due to prior cancer therapy according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) that has not resolved, with the exception of Grade 2 neuropathy, any grade alopecia, amenorrhea, skin rash that is adequately treated or endocrinopathies that are adequately treated with replacement therapy.

5. Presence of symptomatic central nervous system (CNS) metastases or CNS metastases that require local CNS-directed therapy (such as radiotherapy or surgery) or increasing doses of corticosteroids within 2 weeks prior to study entry. Patients with treated symptomatic brain metastases must be neurologically stable (for 4 weeks post-treatment and prior to study entry) and at a dose of = 10 mg per day prednisone or equivalent for at least 2 weeks before administration of any study treatment.

6. 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.

7. For the combination treatment:
- Patients with symptomatic visceral disease or any disease burden that makes the patient ineligible for endocrine-based therapy per the investigator’s judgment.
- Patients who could not tolerate the prescribed dose of ribociclib during a previous course of treatment, requiring dose reduction or permanent discontinuation due to adverse events.

8. For patients with breast cancer: Patient is concurrently using hormone replacement therapy.

9. Any serious uncontrolled infection (acute or chronic), such as but not limited to those caused by bacteria, viruses, or fungi, confirmed by clinical evidence, imaging, and/or relevant positive laboratory tests (e.g., blood cultures, Polymerase Chain Reaction (PCR) for DNA/RNA, etc.). Patients with active Hepatitis B (HBV) or Hepatitis C (HCV) infection whose disease is controlled (defined as positive anti-HBc and negative hepatitis B virus surface antigen (HBsAg) for HBV and undetectable viral load by real-time PCR for HCV) under antiviral therapy should not be excluded. Testing for HBV or HCV status is not necessary unless clinically indicated or if the patient has a history of HBV or HCV infection.

10. Impairment of gastrointestinal function or gastrointestinal disease that may significantly alter the absorption of study drugs (e.g., gastrointestinal perforation, ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome). Patients who have undergone gastrectomy are eligible.

11. Unable or unwilling to swallow oral drugs as per dosing schedule.

12. Patients who have undergone major surgery = 4 weeks prior to first dose of study treatment or who have not recovered from the surgical procedure (mediastinoscopy, insertion of a central venous access device and insertion of a feeding tube are not considered major surgery).

13. Any medical condition that would, in the investigator’s judgment, prevent the patient’s participation in the clinical study due to safety concerns, compliance with clinical study procedures or interpretation of study results.

14. Use of hematopoietic growth factors or transfusion support = 2 weeks prior to start of study treatment. If growth factors 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.

15. History of hypersensitivity to any of the study treatments or its excipients (for the combination treatment arm: including to peanut and soy) or to drugs of similar chemical classes.

16. Patients taking prohibited therapies as listed in Section 6.6.2 that cannot be stopped within 7 days or 5 half-lives (whichever is longer) prior to study treatment and for the duration of the study treatment.

- Medications with a known risk to prolong the QT interval and/or known to cause TdP that cannot be discontinued or replaced by safe alternative medication
- Strong or moderate inhibitors or inducers of CYP3A4/5
- Substrates of CYP3A4/5 with a narrow therapeutic index
- Proton pump inhibitors (PPIs)
- Herbal products
- Other investigational and antineoplastic therapies

17. Women of childbearing potential (WOCBP), defined as all women physiologically capable of becoming pregnant from menarche until becoming post-menopausal, unless they are using highly effective methods of contraception (failure rate < 1% per year) while taking study treatment and for 7 days plus six (6) months after the last dose of ECI830 if receiving ECI830 alone or in combination with ribociclib, or for 1 year after the last dose of fulvestrant or per approved local label requirements (e.g. fulvestrant USPI, SmPC) if receiving any combination treatment with fulvestrant. WOCBP must not donate eggs for 7 days + 6 months or 1 year after the last dose of study treatment as defined above.

Women are considered post-menopausal and not of childbearing potential if they have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g., age-appropriate [should be generally age = 40 years], history of vasomotor symptoms [e.g., hot flush]) in the absence of other medical justification or have had surgical bilateral oophorectomy (with or without hysterectomy), total hysterectomy at least six weeks prior to enrollment on study. 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 not considered to be of childbearing potential.

Highly effective contraception methods include:

- Total abstinence (when this is in line with the preferred and usual lifestyle of the patient). Note that periodic abstinence (e.g., calendar, ovulation, symptothermal, post ovulation methods) and withdrawal are not acceptable methods of contraception.
- Bilateral oophorectomy with or without hysterectomy, total hysterectomy or bilateral salpingectomy 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 are they considered to be not of childbearing potential.
- Bilateral tubal occlusion, bilateral tubal ligation (at least six weeks before taking study treatment)
- Sterilization (vasectomy) of male partner(s) of the female patient at least 6 months prior to screening provided partner(s) has(have) received medical confirmation of surgical success.
- For breast cancer patients: Placement of non-hormonal intrauterine device (IUD).
- For non-breast cancer patients: Placement of hormonal or non-hormonal IUD, or IUS, or hormonal vaginal ring.

Note: Use of oral (estrogen and progesterone), injected, or implanted hormonal methods of contraception or any other forms of hormonal contraception (which result in systemic exposure) is not allowed in this study.
If local regulations are more stringent than the contraception methods listed above, local regulations apply and will be described in the informed consent.

18. Sexually active males unwilling to use a condom during intercourse while taking study treatment and for 7 days + three (3) months after stopping study treatment. A condom is required for all sexually active male patients to prevent them from fathering a child AND/OR to prevent delivery of study treatment via seminal fluid to their partner.
In addition, male patients must not donate sperm for the time period specified above.
Male patients must inform female partner(s) of the potential risks of ECI830 and any combination study treatment and the requirement to use a method of highly effective contraception.

19. Pregnant or nursing (breast feeding) women.

- Any patients with histologically confirmed localized or metastatic EwS
- Any patients with histologically confirmed related small round cell sarcomas (SRCSs), so called Ewing-like sarcomas, with rare translocations
- Informed consent form (ICF) according to national /GCP guidelines signed prior to registration

- Withdrawal from ICF

Participants are eligible to be enrolled in the study only if the following criteria are met:

Demographic characteristics

1a. Participant aged =18 years old.

General criteria

2. ECOG PS of 0 to 1. Participants with an ECOG PS of 2 due to functional limitations as a result of prior surgical resections or due to the anatomical location of the tumor will be permitted.

3a. Be willing to complete HRQoL (EORTC-QLQ-C30, EQ-5D-5L, and PROMIS) assessments.

Sex and contraceptive/barrier requirements

4a. Women of childbearing potential must agree to undergo medically supervised pregnancy blood tests prior to starting the IMP. The first pregnancy test will be performed at Screening (within 7 days prior to the first IMP administration) and another on the day of the first IMP administration, the result of which must be confirmed negative prior to dosing.

Women of childbearing potential must agree to abstain from sexual intercourse or use 2 effective methods of birth control (a highly effective method and a barrier method; both described in Appendix 7) from the time of giving informed consent and during study treatment until at least 90 days after the last dose of IMP. Hormonal contraception alone is not considered an acceptable method of contraception and should be combined with a barrier method.

Women of childbearing potential, as well as fertile men with partners who are female with reproductive potential, must agree to use 2 effective forms of contraception (one of them a highly effective method and the other one a barrier method) from the time of giving informed consent throughout the study and for 90 days (both females and males) following the last dose of IMP. Sperm/egg donation will not be allowed during the study and for 90 days after the last dose of IMP.

Please refer to Appendix 7 for further contraception considerations.

Informed consent

5a. Obtained prior to any study-specific procedure as described in Section 13.3 of the protocol. Participants will sign a prescreening and/or main informed consent form depending on when their IDH1 mutation testing is performed.

Medical and therapeutic criteria

6a. Histopathological diagnosis consistent with locally advanced or metastatic conventional chondrosarcoma Grades 1, 2, or 3 and not eligible for curative resection or other local therapeutic options as per standard of care such as definitive radiotherapy for skull base lesions.

7. At least one BICR-confirmed measurable lesion as defined by RECIST v1.1.
Participants who have received prior radiation therapy are eligible provided measurable disease falls outside of the treatment field or within the field and has shown = 20% growth in size since post-treatment assessment.

8a. Received 0 to 2 prior systemic treatment regimens in the advanced/metastatic setting (adjuvant/maintenance/consolidation treatment during which metastatic disease recurrence/progression occurred will be considered as prior systemic treatment) for chondrosarcoma.

9a. Participants must have radiographic progression/recurrence of disease according to RECIST v1.1 defined as:
- Radiographic progression of disease (local and/or distant) documented by 2 imaging assessments performed no more than 6 months (+3 weeks) apart within 12 months before randomization.

OR

- Any recurrence of disease (local and/or distant) after complete surgical resection and documented by imaging within 6 months (+3 weeks) before randomization.

10a. Documented IDH1 gene-mutated disease (from a fresh tumor biopsy or banked tumor tissue available that was sourced from either a primary or metastatic tumor lesion) based on central laboratory testing (R132C/L/G/H/S mutation variants; see Section 9.1).

11. Adequate renal function defined as:
- Creatinine clearance =30 mL/min, based on using the Cockcroft & Gault formula (Appendix 4)

12a. Adequate hepatic function defined as:
- Total serum/plasma bilirubin = 1.5 x ULN (unless considered due to Gilbert disease where it must be = 3.0 x ULN.)
- Aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase (ALP) = 2.5 x ULN. For participants with bone metastases and/or disease-related hepatic involvement, ALP must be = 5 x ULN.

13 Adequate bone marrow function without transfusions or growth factors for at least 2 weeks prior to the blood test.
- Absolute neutrophil count = 1,500/mm3 or 1.5 x 10^9/L
- Hemoglobin = 8 g/dL
- Platelets = 75,000/mm^3 or 75 x 10^9/L

14. Recovered from any clinically relevant sequelae and toxic effects of any prior surgery, radiotherapy, or other therapy intended for the treatment of cancer.

Participants are excluded from the study if any of the following criteria apply:

General criteria

15. Unable to swallow oral medication.

16. Pregnant or lactating women.

17. Unlikely to cooperate in the study.

18. Participating in another interventional study at the same time; participation in noninterventional registries or epidemiological studies is allowed.

19. Participant already enrolled in the study (informed consent signed) and had received at least one dose of IMP.

Medical and therapeutic criteria

20.Prior therapy with an IDH1 inhibitor.

21.Received systemic anticancer therapy < 2 weeks prior to randomization (washout from prior investigational or immune-based anticancer therapy is 4 weeks).

22.Received radiotherapy < 2 weeks prior to randomization.

23.Have known symptomatic brain metastases requiring steroids > 10 mg per day prednisone (or equivalent). Participants with previously diagnosed brain metastases are eligible if they have completed their treatment and have recovered from the acute effects of radiation therapy or surgery prior to randomization, have discontinued or reduced corticosteroid treatment to = 10 mg per day for these metastases for at least 4 weeks and have radiographically stable disease of brain lesions for at least 3 months prior to randomization.

24.Have a history of another primary cancer, with the exception of: a) curatively resected non-melanoma skin cancer; b) curatively treated carcinoma in situ; or c) pT1- 2 prostatic cancer Gleason score = 6 or d) participant is free of other primary solid or liquid tumor for = 1 year prior to the start of study treatment and, in the opinion of the Investigator, the disease will not affect participant’s outcome in the setting of current chondrosarcoma diagnosis.

25.Major surgery within 4 weeks prior to randomization.

26.Are taking known strong cytochrome P450 (CYP) 3A4 inducers or sensitive CYP3A4 substrate medications with a narrow therapeutic window, unless (after at least 5 half-lives have elapsed) they can be transferred to other medications prior to randomization.

27.Have an active infection requiring systemic anti-infective therapy or with an unexplained fever > 38.5 Grad C within 7 days prior to randomization (at the discretion of the Investigator, participants with tumor fever may be enrolled).

28.Have any known hypersensitivity to any of the components of ivosidenib or the matched placebo.

29.Have significant active cardiac disease within 6 months prior to randomization, including New York Heart Association (NYHA) Class III or IV congestive heart failure; myocardial infarction; unstable angina; and/or stroke.

30.Have LVEF < 40% by ECHO scan (or by other methods according to institutional practice) obtained within 28 days prior to randomization.

31a. Have a heart-rate corrected QT interval (using Fridericia’s formula, Appendix 4) (QTcF) = 450 msec or other factors that increase the risk of QT prolongation or arrhythmic events (eg, heart failure, hypokalemia, family history of long QT interval syndrome, familial history of sudden death or polymorphic ventricular arrhythmia).
Participants with a bundle branch block combined with a prolonged QTcF interval may be permitted based on local cardiology assessment.

32. Are taking medications that are known to prolong the QT interval unless (after at least 5 half-lives have elapsed) they can be transferred to other medications prior to randomization or unless the medications can be properly monitored during the study.
If equivalent medication is not available, QTcF should be closely monitored.

33. Have known active hepatitis B (HBV) or hepatitis C (HCV) infections, known positive HIV antibody results, or AIDS-related illness. Participants with a sustained viral response to HCV treatment or immunity to prior HBV infection will be permitted. Participants with chronic HBV or HIV that are adequately suppressed per institutional practice will be permitted.

34. Have any other acute or chronic medical or psychiatric condition, including recent (within last 12 months) or active suicidal ideation or behavior, or a laboratory abnormality that may increase the risk associated with study participation or IMP administration or may interfere with the interpretation of study results and, in the judgment of the Investigator, would make the participant inappropriate for entry into this study.

35. Have known active inflammatory gastrointestinal disease, chronic diarrhea, previous gastric resection or lap band, dysphagia, short-gut syndrome, gastroparesis, or other conditions that limit the ingestion or gastrointestinal absorption of drugs administered orally. Gastroesophageal reflux disease under medical treatment is allowed (assuming no drug interaction potential).

36. Have known medical history of progressive multifocal leukoencephalopathy (PML).

Prior/Concomitant therapy

For prior and prohibited concomitant medication, refer to Section 6.3.

Alle Patienten, unabhängig von Geschlecht, Alter, Tumorstadium / -ausbreitung oder einer aktuellen / bereits beendeten / zukünftigen Studienteilnahme, mit pathologisch-anatomisch
bewiesener Diagnose eines der folgenden Tumore:

- Hochmalignes Osteosarkom jeden Subtyps
- Konventionell
- osteoblastisch (inkl. sklerosierend)
- chondroblastisch
- fibroblastisch
- riesenzellreich (engl.: giant cell rich)
- osteoblastom-ähnlich
- epithelioid
- klarzellig (engl.: clear cell)
- chondroblastom-ähnlich
- Nicht-konventionell
- teleangiektatisch
- kleinzellig
- high grade surface
- Sonderformen
- parosteal
- periosteal
- extraossär
- Niedrig-malignes Osteosarkom (engl.: low grade central)
- Andere Knochensarkome
- ossäres undifferenziertes pleomorphes Sarkom (UPS)
- ossäres Leiomyosarkom
- ossäres dedifferenziertes Chondrosarkom
- ossäres mesenchymales Chondrosarkom
- ossäres Fibrosarkom
- ossäres Angiosarkom

- Patientenmeldungen erfolgen durch Kliniken oder Behandlungszentren, die ihren Sitz in Deutschland haben

Für dieses Register sind keine Ausschlusskriterien definiert. Jeder Patient, der gemeldet wird und die oben definierten Einschlusskriterien erfüllt, kann registriert werden. Es bestehen keine Meldefristen.

- Patients with histologically proven rhabdoid tumors, confirmed by central pathology.
- In general absence of nuclear SMARCB1 staining should have been demonstrated. However, as rhabdoid tumor cases without SMARCB1 mutations have been published, reference pathology may suggest inclusion of tumors with positive SMARCB1 staining, but unequivocal diagnostic criteria for histopathologic diagnosis of a rhabdoid tumor.
- Patients that have been pretreated under the suspicion of a renal tumor (RTK), malignant tumor of the brain (e.g. glioblastoma, sPNET or medulloblastoma) (AT/RT) or soft tissue tumor (MRT).
- Informed consent of the legal guardians concerning data and tumor material transfer.

- Diagnoses other than rhabdoid tumors.
- Missing consent of the legal guardians.

- Histologically (and molecularly) diagnosed primary localised (SR) or metastatic (HR) Ewing sarcoma or so called Ewing-like darcoma ( i.e. translocation-positive small blue round cell sarcoma other than Rhabdomyosarcoma) of bone and / or soft tissue; pathological diagnosis can be performed at the investigatidnal site

- Any sex, age > 2 and < 50 years by the date of diagnostic biopsy (Patients outside this age range may be included in the iEuroEWING registry, please contact the trial office via the following email address: iEuroEwing@uk-essen.de)

- lnformed consent must be obtained according to national and GCP guidelines and signed prior to trial entry. Subjects and when applicable parental or legal representative(s) must understand 1
and voluntarily provide permission to the ICF, prior to conducting any trial-related assessments / procedures. Willingness and abili y to comply with scheduled visits and trial procedures are
required.

- White blood cell (WBC) count > 2000/µI*

- Assessment of cardiac function including LVEF > 40 % and SF > 28 %*

- Serum creatinine < 1.5 x ULN*

- For patients of childbearing potentiaI, a negative pregnancy test must be documented prior to enrolment and repeated every month during therapy. Female and male patients, who are fertile and sexually active, must agree to u e an effective form of contraception from the time of signing the ICF until 6 months after the end of treatment.

*Parameters must be checked within the screening phase of 45 days from biopsy / surgery and after diagnosis of metastatic disease to registration.

- Treatment of more than one cycle of chemotherapy prior to registration

- Concurrent treatment within any other clinical trials, excluding trials with different endpoints, which, due to the nature of their endpoints, must run parallel to iEuroEwing trial, e.g. studies on antiemetics, antimycotics, antibiotics, strategies for psychosocial support, etc.

- Clinically significant and uncontrolled, or active cardiac disease

- Evidence of invasive fungal infection or other severe systemic infection requiring systemic / parenteral therapy

- Hypersensitivity to the active substance or other excipients contained in the investigational medical products listed in the summary of product characteristics (SmPC) or investigators brochure (1B).

- Secondary malignancy

- Pregnancy or lactation

- Female and male subjects with child-bearing potential, who avoid using highly effective contraceptive methods
Any other medical, psychiatric or social condition which is incompatible with the protocol treatment

- Primary diagnosed and histologically confirmend metastatic (HR) Ewing sarcoma or Ewing-like sarcoma of bone and/or soft tissue

- Patients who receive preoperative RTX

- Patients who receive Brachytherapy

- Patients with previous RT in the same region

- Histologically (and molecularly) diagnosed primary localised (SR) or metastatic (HR) Ewing sarcoma or so called Ewing-like sarcoma ( i.e. translocation-positive small blue round cell
sarcoma other than Rhabdomyosarcoma) of bone and / or soft tissue; pathological diagnosis can be performed at the investigational site
- Any sex, age > 2 and < 50 years by the date of diagnostic biopsy (Patients outside this age range may be included in the iEuroEWING registry, please contact the trial office via the
following email address: iEuroEwing@uk-essen.de)

- Informed consent must be obtained according to national and GCP guidelines and signed prior to trial entry. Subjects and when applicable parental or legal representative(s) must understand and voluntarily provide permission to the ICF, prior to conducting any trial-related assessments / procedures. Willingness and ability to comply with scheduled visits and trial procedures are required.
- White blood cell (WBC) count > 2000/µl*
- Assessment of cardiac function including LVEF > 40% and SF > 28%*
- Serum creatinine < 1.5 X ULN*
- For patients of childbearing potential, a negative pregnancy test must be documented prior to enrolment and repeated every month during therapy. Female and male patients, who are fertile and sexually active, must agree to use an effective form of contraception from the time of signing the ICF until 6 months after the end of treatment.

*Parameters must be checked within the screening phase of 45 days from biopsy / surgery and after diagnosis of metastatic disease to registration.

- Treatment of more than one cycle of chemotherapy prior to registration
- Concurrent treatment within any other clinical trials, excluding trials with different endpoints, which, due to the nature of their endpoints, must run parallel to iEuroEwing trial, e.g. studies on antiemetics, antimycotics, antibiotics, strategies for psychosocial support, etc.
- Clinically significant and uncontrolled, or active cardiac disease
- Evidence of invasive fungal infection or other severe systemic infection requiring systemic / parenteral therapy
- Hypersensitivity to the active substance or other excipients contained in the investigational medical products listed in the summary of product characteristics (SmPC) or investigators
brochure (IB).
- Secondary malignancy
- Pregnancy or lactation
- Female and male subjects with child-bearing potential, who avoid using highly effective contraceptive methods
Any other medical, psychiatric or social condition which is incompatible with the protocol treatment

Exclusion criteria for SR-RT randomisation

- Primary diagnosed and histologically confirmed metastatic (HR) Ewing sarcoma or Ewing-like sarcoma of bone and/or soft tissue
- Patients who receive preoperative RTX
- Patients who receive Brachytherapy
- Patients with previous RT in the same region

Inclusion Criteria; HLA (S1), and Tumor Tissue Collection (S2) and Treatment Eligibility Assessment (VA)

No Inclusion criterion S1 S2 VA

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

2 Patients = 18 years old S1 - X

3 Patients must have pathologically confirmed and documented advanced or metastatic malignancies corresponding to the planned cohort indication. S1 - X

Cohort: Treatment - Indication

Phase Ia: IMA402 monotherapy and IMA402 + pembrolizumab - Cutaneous melanoma, uveal melanoma, endometrial carcinoma (excluding uterine carcinosarcoma), epithelial ovarian, fallopian tube or primary peritoneal cancer (EOFPC)

A1/A2: IMA402 monotherapy RDE1 and RDE2 - Cutaneous melanoma, uveal melanoma, endometrial carcinoma (excluding uterine carcinosarcoma), epithelial ovarian, fallopian tube or primary peritoneal cancer (EOFPC)

restricted to serous, and endometrioid subtypes, with the exception of primary platinum
refractory disease, synovial sarcoma, or sqNSCLC

B: IMA402 + decitabine - Cutaneous melanoma, uveal melanoma, endometrial carcinoma (excluding uterine carcinosarcoma), epithelial ovarian, fallopian tube or primary peritoneal cancer (EOFPC)

C: IMA402 + IMA401 - sqNSCLC

D: IMA402 + bevacizumab - EOFPC restricted to serous, and endometrioid subtypes, with the exception of primary platinum-refractory disease

E: IMA402 + paclitaxel +/- bevacizumab - EOFPC restricted to high-grade serous, and endometrioid subtypes, with the exception of primary platinum-refractory disease
Note: In case of mixed EOFPC histology, > 50% of the primary tumor must be confirmed to be high-grade serous or endometrioid subtype.

F IMA402 + PLD +/- bevacizumab - EOFPC restricted to high-grade serous, and endometrioid subtypes, with the exception of primary platinum-refractory disease
Note: In case of mixed EOFPC histology, > 50% of the primary tumor must be confirmed to be high-grade serous or endometrioid subtype.

G: IMA402 + Opdualag - Cutaneous melanoma with the requirement that patients must have experienced disease progression during or after treatment with a checkpoint inhibitor

Phase IIa: IMA402 + Opdualag - Cutaneous melanoma with the requirement that patients must have experienced disease progression during or after treatment with a checkpoint inhibitor

Phase IIa: IMA402 + pembrolizumab - Cutaneous melanoma with the requirement that patients must have experienced disease progression during or after treatment with a checkpoint inhibitor

Phase IIa: IMA402 monotherapy - Cutaneous melanoma with the requirement that patients must have experienced disease progression during or after treatment with a checkpoint inhibitor or are ineligible for checkpoint inhibitor treatment

4 Patients must have measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST 1.1).
Exception: Measurable disease according to RECIST 1.1 is not required for patients dosed with up to 0.5 mg IMA402. VA - X^2

5 HLA genotype: HLA-A*02:01 positive (repeat assessment allowed; refer to Section 8.2.1).

For cohort C (IMA401) only: In addition, HLA-A*02:05 negative (repeat assessment allowed).

Note: In case the patient is known to be HLA-A*02:01 positive as tested routinely, or in another Immatics-sponsored clinical trial, or an Immatics-supported IIT, or as a trial-specific procedure by a local hospital laboratory or central laboratory with appropriate accreditation (e.g., CLIA, CAP, EFI, ASHI, ISO15189) using a PCR-based or sequencing-based method, S1, S2 and/or VA visits may be conducted on the same day, and treatment can be started (except for cohort C, where in order to start therapy patients also need to be known to be HLA-A*02:05 negative) . In any case, for these patients, HLA genotyping will be reconfirmed at Immatics’ designated ASHI and/or EFI-certified laboratory. S1 - X^4, VA - X

6 ECOG Performance Status of 0 to 1. S1 - X, S2 - X, VA - X^1

7 Hematology parameters need to be within defined range (repeat assessments allowed). S2 - X^5, VA - X^1

Parameter: Threshold - Cohort

Absolute neutrophil count (ANC) without G-CSF support:
= 1.0 x 10^9/L - Phase Ia, cohort A1/2 (monotherapy), B (decitabine), D (bevacizumab), F (PLD +/- bevacizumab), Phase IIa pembrolizumab and monotherapy
= 1.5 x 10^9/L - Cohort C (IMA401), E (paclitaxel +/- bevacizumab), G (Opdualag ) and Phase IIa Opdualag

Platelets:
= 75,000/MikroL - Phase Ia, cohort A1/2 (monotherapy), Phase IIa pembrolizumab and monotherapy
= 100,000/MikroL - Cohort B (decitabine), C (IMA401), D (bevacizumab), E (paclitaxel +/- bevacizumab), F (PLD +/- bevacizumab), G (Opdualag ) and Phase IIa Opdualag

Hemoglobin (transfusion permitted):
= 8 g/dL - Phase Ia, cohort A1/2 (monotherapy), G (Opdualag), Phase IIa Opdualag, pembrolizumab and monotherapy
= 9 g/dL - Cohort B (decitabine), C (IMA401), D (bevacizumab), E (paclitaxel +/- bevacizumab), F (PLD +/ bevacizumab)

Absolute lymphocyte count (ALC): = 0.5 x 10^9/L - All cohorts

8 Adequate hepatic function, as defined by a total bilirubin level = 1.5 x upper limit of normal unless the patient is a hepatocellular carcinoma patient or has known Gilbert’s syndrome (total bilirubin level of = 2.5 x ULN), and alanine aminotransferase (ALT)/aspartate aminotransferase (AST) = 2.5 x ULN or = 5 x ULN for patients with liver metastases (repeat assessment allowed). For epithelial ovarian, fallopian tube or primary peritoneal cancer only: Albumin = 3.0 g/dL (repeat assessment allowed). VA - X^1

9 For monotherapy cohorts only: Adequate renal function defined by creatinine clearance = 30 mL/min (as estimated by Cockcroft Gault or other medically acceptable formulars such as MDRD (Modification of Diet in Renal Disease) or CKD-EPI (the Chronic Kidney Disease Epidemiology Collaboration) (repeat assessment allowed).

For combination cohorts only: Adequate renal function defined by creatinine clearance = 45 mL/min (as estimated by Cockcroft Gault or other medically acceptable formulars such as MDRD (Modification of Diet in Renal Disease) or CKD-EPI (the Chronic Kidney Disease Epidemiology Collaboration) (repeat assessment allowed).

In addition for cohort D and patients treated in cohort E and F in combination with bevacizumab: Baseline urine dipstick = 1+ or urine protein/creatinine ratio (UPCR) < 1.0. If dipstick = 2+, eligibility requires 24-hour urine protein < 1 g/24 h (or UPCR < 1.0). Repeat assessment allowed. VA - X^1

10 Acceptable coagulation status defined by an international normalized ratio (INR) of prothrombin time (PT) of blood coagulation = 2.0 x ULN and partial thromboplastin time (PTT) or activated PTT (aPTT) = 2.0 x ULN (repeat assessment allowed).

In addition for cohort D and patients treated in cohorts E and F in combination with bevacizumab: Systemic anticoagulation or chronic aspirin therapy (> 325 mg/day) are not allowed. Patients may receive low dose anti-coagulation therapy for peripheral port patency. S2 - X^3.5, VA - X^1

11 Phase Ia and cohorts A-D: Patients must have recurrent and/or refractory solid tumors and must have received or not be eligible for all available indicated standard-of-care treatments. VA - X

12 The patient must have recovered from any side effects of prior therapy to Grade 1 or lower (except for nonclinically significant toxicities; e.g., alopecia, vitiligo) prior to treatment start. As determined by the investigator, the patient may still be eligible if not fully recovered from Grade = 2 toxicities, in case these toxicities are not anticipated to further improve and such toxicities are not anticipated to worsen with the planned trial treatment, including any combination partner. VA - X

13 Male patients must agree to use highly effective contraception or be abstinent while on treatment and for 6 months after the last trial treatment. VA - X

14 Female patients of childbearing potential must use highly effective contraception or be abstinent, while on treatment and until 6 months after the last trial treatment. For female patients treated with PLD in cohort F, a longer post-treatment contraception period of 8 months is required, in accordance with the PLD SmPC. VA - X

15 Pembrolizumab combination therapy only: Patient must have an indication approved for the treatment with Pembrolizumab as outlined in the (Keytruda) PI/SmPC or EOFPC. VA - X

^1 Assessment to be performed 7 days prior to start of IMA402 treatment
^2 Imaging to be performed as close as possible to baseline, but within 3 weeks prior to start of treatment
^3 Only to be taken in case a biopsy is performed at S2.
^4 Eligibility verification of HLA status at VA at the latest.
^5 Eligibility verification for laboratory values at VA.

Exclusion Criteria; HLA (S1), and Tumor Sample Collection (S2) and Treatment Eligibility Assessment (VA)

No Exclusion criterion S1 S2 VA

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

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

3 History of hypersensitivity to components of IMA402 or rescue medications, if no alternative treatment option is available. S1 - X, VA - X

4 Patients with prior allogeneic stem cell transplantation or organ transplantation. S1 - X, VA - X

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

6 The patient is known to have any of the following clinically relevant cardiac conditions including, but not limited to: uncontrolled hypertension despite optimal therapy, uncontrolled angina, clinically relevant ventricular arrhythmias, congestive heart disease (New York Heart Association Class II or above), baseline left ventricular ejection fraction = 50%, prior or current clinically relevant cardiomyopathy, uncontrolled atrial fibrillation, reoccurrence of pericardial effusion within previous 4 weeks, unstable ischemic heart disease (myocardial
infarction within the last 6 months or angina requiring use of nitrates), known clinically relevant stenosis upon coronary angiography/CT, or with QTcF interval prolongation >480 msec (corrected for heart rate using Fridericia’s formula [QTcF]) or congenital long QT syndrome.

In addition for cohort D and patients treated in cohorts E and F in combination with bevacizumab: Patients with peripheral vascular disease, cerebrovascular accident or transient ischemic attack and patients with systolic blood pressure >150 mmHg or diastolic blood pressure > 100 mmHg.
In addition for cohort G and Phase IIa Opdualag combination cohort only: The patient has troponin levels > 2x ULN and/or a history of myocarditis. S1 - X^1, VA - X

7 Clinically significant pulmonary dysfunction, that, in the investigator’s judgement, would compromise the patient’s ability to tolerate protocol therapy or significantly increase the risk for complications. This includes, but is not limited to, patients with any persisting radiological evidence of prior immunotherapy related pneumonitis who will be excluded from the trial. VA - X

8 The patient has concurrent severe and/or uncontrolled medical disease that could compromise participation in the trial (e.g., uncontrolled diabetes, severe malnutrition). S2 - X, VA - X

9 History of, or current, immunodeficiency disease or prior treatment relevantly compromising immune function, at the discretion of the investigator. S2 - X, VA - X

10 Any other condition that would, in the investigator’s or sponsor’s judgement, contraindicate the patient’s participation in the clinical trial because of safety concerns (e.g., potential intolerance to IMA402) or compliance with clinical trial procedures (e.g., psychiatric disorders or substance dependence, neurological impairment). S1 - X, VA - X

11 Positive for HIV or with active hepatitis B or C infection. S1 - X^1, VA - X

12 The patient has received prior to start of trial treatment live/attenuated vaccines within 1 month, systemic corticosteroids (= 10 mg/day prednisone or equivalent), major surgery, other vaccines, therapeutic radiotherapy, cytotoxic agents, small molecule treatments or treatments with investigational agents within 2 weeks, monoclonal antibodies within 3 weeks or 5 half-lives, or cell therapies within 3 months. No wash-out period is required for hormonal therapy.
In addition for cohort D and patients treated in cohorts E and F in combination with bevacizumab: The patient has not yet recovered from prior minor surgery (insertion of a vascular access device is acceptable), has any serious non-healed wound or bone fracture or has planned major surgical procedure during the treatment phase. The window for major surgery prior to study treatment start is extended to 4 weeks.
In addition for EOFPC patients only: Drainage of ascitic fluid 2 or more times in the 4 weeks prior to the study treatment start, uncontrolled pleural effusion, or permanent drain in place for ascites or pleural effusion.

Note: Use of inhaled or topical steroids is permitted. VA - X

13 Concurrent treatment in another clinical trial or a device study that could interfere with the trial treatment after signature of ICF2. VA - X

14 Patients with active CNS metastases or history of bleeding into brain metastases or with known brain metastases who are receiving therapeutic (treatment-dose) anticoagulation (prophylactic-dose anticoagulation remains acceptable).

Note: Patients with a history of newly detected CNS metastases are eligible if none of the above applies and CNS metastases indicated for treatment were treated and showed no sign of progress, imaging studies performed =4 weeks following treatment indicate stable disease of brain metastasis, the patient is asymptomatic, and steroid therapy has been discontinued for = 2 weeks. VA - X

15 No prior experimental systemic treatment line is allowed.
All cohorts except E and F: Patients who have received more than 4 prior systemic treatment lines for treatment of advanced and/or metastatic disease. Systemic adjuvant and neo-adjuvant treatment lines with curative intent are not considered. Any number of prior systemic treatment lines in the platinum-sensitive setting is allowed.
Cohorts E and F (paclitaxel or PLD +/- bevacizumab) only: Patients who have received more than 2 prior systemic lines of anti-cancer therapy after developing platinum resistance. Systemic adjuvant and neo-adjuvant treatment lines with curative intent are not considered. Any number of prior systemic treatment lines in the platinum-sensitive setting is allowed. VA - X

16 All patients except cutaneous melanoma patients: LDH > 2.0-fold ULN.
Only applicable for cutaneous melanoma patients: LDH > 1.5-fold ULN. VA - X

17 Known presence of leptomeningeal metastases. S1 - X, VA - X

18 Any active infection or ongoing reactivation of infection (e.g., HSV, EBV, CMV) within the last 3 weeks, sepsis within the last 4 weeks. VA - X

19 Rapid clinical deterioration (e.g., worsening of performance status, worsening of clinical symptoms likely associated with rapid disease progression) within 3 weeks. VA - X

20 Patients with clinical or radiological tumor progression on TCR-based therapy, except for Tebentafusp in uveal melanoma. S1 - X, VA - X

21 For all combination cohorts only: Patients with hypersensitivity to or contraindications according to current PI/SmPC for the respective combination drug.
In addition for cohorts Phase Ia pembrolizumab, Phase IIa pembrolizumab and Opdualag and D-G (CPI or bevacizumab combinations) only:
Patients with a history of toxicity leading to permanent discontinuation of the same combination partner. VA - X

22 For cohort D and patients treated in cohort E and F in combination with bevacizumab: Patients with any of the following are excluded
- History of clinically significant bleeding, thrombotic or hemorrhagic disorders or active coagulopathy (regardless of lab values)
- Current bowel obstruction/sub-occlusion; or history of GI perforation, abdominal fistula, or intra-abdominal abscess within 6 months; or rectosigmoid/bowel involvement
- Clinically significant hemoptysis (= 2.5 mL/teaspoon) within 3 months or centrally cavitating lesions at high bleeding risk
- Need for repeated therapeutic drainage > 1x/week without a functioning indwelling cathete. VA - X

^1 Based on medical history

- Patientinnen mit gynäkologischen Sarkomen unabhängig von Therapieform und Therapielinie
- Einverständniserklärung
- Alter > 18 Jahre

- Patientinnen mit nicht-gynäkologischen Sarkomen
- Fehlende Einverständniserklärung