QUILT-3.031: AMG 337 in Subjects With Advanced or Metastatic Clear Cell Sarcoma

A Phase 2 Study of AMG 337 in Subjects With Advanced or Metastatic Clear Cell Sarcoma That Contains the Ewing Sarcoma Breakpoint Region 1-activating Transcription Factor-1 (EWSR1-ATF1) Gene Fusion

This is a phase 2 study that will assess the efficacy of AMG 337 in subjects with advanced or metastatic clear cell sarcoma that contains the EWSR1-ATF1 gene fusion.

The phase 2 single arm study will assess efficacy of AMG 337 (based on confirmed ORR) in subjects with advanced or metastatic clear cell sarcoma that contains the EWSR1-ATF1 gene fusion, as determined by fluorescent in situ hybridization (FISH) or other diagnostic methods and confirmed by RNA sequencing (RNAseq).

Inclusion Criteria:

1. Able to understand and provide a signed informed consent that fulfills the relevant Institutional Review Board (IRB) or Independent Ethics Committee (IEC) guidelines.

2. Able to attend required study visits and return for adequate follow-up, as required by this protocol.

3. Able to self-administer AMG 337 as a whole capsule by mouth every day.

4. Age ≥ 16 years.

5. Histologically confirmed, unresectable, locally advanced or metastatic tumors that contain the EWSR1-ATF1 gene fusion, as determined by fluorescent in situ hybridization (FISH) or other diagnostic methods and confirmed by RNA sequencing (RNAseq).

6. Have measurable disease evaluable in accordance with RECIST Version 1.1.

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

8. Must have a recent Formalin-fixed paraffin-embedded (FFPE) tumor biopsy specimen that was obtained following the conclusion of the most recent anticancer treatment. If an historic specimen is not available, the subject must be willing to undergo a biopsy during the screening period.

9. Must be willing to undergo a biopsy during the treatment period, if considered safe by the investigator.

10. Ability to attend required study visits and return for adequate follow-up, as required by this protocol.

11. Hematologic function, as follows:

    1. Absolute neutrophil count (ANC) ≥ 1.5 × 109/L.
    2. Platelet count ≥ 50 × 109/L.
    3. Hemoglobin > 8 g/dL.
    4. Prothrombin time (PT) or partial thromboplastin time (PTT) < 1.5 × upper limit of normal (ULN), except for subjects on anticoagulation therapy for venous thromboembolism.

12. Renal function, as follows:

    a. Calculated creatinine clearance > 30 mL/min.

13. Hepatic function, as follows:

    1. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < 2.5 × ULN and total bilirubin < 1.5 × ULN.
    2. Alkaline phosphatase (ALP) < 2 × ULN (≤ 5 × ULN if bone or liver metastases are present)

14. Agreement to practice effective contraception (both male and female subjects, if the risk of conception exists).

Exclusion Criteria:

1. Assessed by the investigator to be unable or unwilling to comply with the requirements of the protocol.

2. Inability to attend required study visits and return for adequate follow-up, as required for this protocol.

3. Known hypersensitivity to any component of the study medication(s).

4. Women who are nursing, pregnant, or planning to become pregnant during the duration of the study.

5. Current diagnosis or history of a second neoplasm, except the following:

   a. Adequately treated non-melanoma skin cancer, curatively treated in situ disease, or other solid tumors curatively treated with no evidence of disease for ≥ 2 years.

6. History of bleeding diathesis.

7. Uncontrolled hypertension (systolic > 160 mmHg and/or diastolic > 100 mmHg) or clinically significant cardiovascular disease, cerebrovascular accident/stroke, or myocardial infarction within 6 months before study day 1; unstable angina; congestive heart failure of New York Heart Association grade 2 or higher; or serious cardiac arrhythmia requiring medication.

8. Baseline ECG Fridericia's formula QTcF > 470 ms.

9. Active infection requiring intravenous (IV) antibiotics within 2 weeks before study day 1.

10. Significant gastrointestinal disorder (eg, Crohn's disease, ulcerative colitis, extensive gastrointestinal resection) that in the opinion of the Investigator may influence drug absorption.

11. Positive result of screening test for human immunodeficiency virus (HIV).

12. Evidence of acute hepatitis B and C. Subjects with chronic hepatitis B or C are eligible if their condition is stable and, in the opinion of the investigator, would not pose a risk to subject safety.

13. Toxicities from prior anti-tumor therapy not resolved to CTCAE Version 4.03 grade 0 or 1.

    a. Grade 2 toxicities from prior anti-tumor therapy that are considered irreversible (defined as having been present or stable for > 4 weeks), such as stable grade 2 peripheral neuropathy or ifosfamide-related proteinuria, may be allowed if they are not otherwise described in the exclusion criteria.

14. Participation in this study or in an investigational study and/or procedure with any molecularly targeted agents reported to inhibit Mesenchymal epithelial transition factor (MET) within 14 days before study day 1.

15. Anti-tumor therapy, including chemotherapy, antibody therapy, retinoid therapy, or other investigational therapy within 14 days before study day 1.

16. Therapeutic or palliative radiation therapy within 14 days before study day 1.

17. Major surgery within 28 days before study day 1.

18. Any comorbidity that in the opinion of the investigator may increase the risk of toxicity.

19. Concurrent or prior use of a strong CYP3A4 inhibitor within 14 days before study day 1, including the following: ketoconazole, itraconazole, clarithromycin, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, and voriconazole.

20. Concurrent or prior ingestion of grapefruit or grapefruit products, or other foods known to inhibit CYP3A4 within 7 days before study day 1.

21. Concurrent or prior use of strong CYP3A4 inducers within 28 days before study day 1, including the following: phenytoin, carbamazepine, rifampin, rifabutin, rifapentin, phenobarbital, or the herbal supplement St. John's Wort.