A Study of Tazemetostat in Adult Participants With Soft Tissue Sarcoma

Study Overview
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Brief Summary
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This study will include participants with various types of cancer known as soft-tissue sarcomas. Tissues that can be affected by soft tissue sarcomas include fat, muscle, blood vessels, deep skin tissues, tendons and ligaments. Soft tissue cancers are rare and can occur almost anywhere in the body. Part 1 of this trial will study the safety and the level that adverse effects of the study drug tazemetostat in combination with doxorubicin (current front line treatment) can be tolerated (known as tolerability). It is also designed to establish a recommended study drug dosage for the next part of the study. Part 2 will evaluate and compare how long participants live without their disease getting worse when receiving the study drug plus doxorubicin versus doxorubicin plus placebo (dummy treatment).

Detailed Description
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This is a Phase II, multicenter, open-label, single arm, 2-stage study of tazemetostat 800 mg BID (twice daily) and 1600 mg QD (once daily). Subjects will be screened for eligibility within 21 days of the planned date of the first dose of tazemetostat and enrolled into one of 8 cohorts: Cohort using tazemetostat 800 mg BID Cohort 1 (Closed for enrollment): malignant rhabdoid tumor (MRT), rhabdoid tumor of the kidney (RTK), atypical teratoid rhabdoid tumor (ATRT), and selected tumors with rhabdoid features, including small cell carcinoma of the ovary hypercalcemic type (SCCOHT), also known as malignant rhaboid tumor of the ovary (MRTO) Cohort 2 (Closed for enrollment): Relapsed or refractory synovial sarcoma with SS18-SSX rearrangement Cohort 3 (Closed for enrollment): Other integrase interactor 1 (INI1) negative tumors or any solid tumor with an enhancer of zeste homologue-2 (EZH2) gain of function (GOF) mutation, including: epithelioid malignant peripheral nerve sheath tumor (EMPNST), extraskeletal myxoid chondrosarcoma (EMC), myoepithelial carcinoma, other INI1-negative malignant tumors with Sponsor approval (e.g., dedifferentiated chordoma) any solid tumor with an EZH2 GOF mutation including but not limited to Ewing's sarcoma and melanoma Cohort 4 (Closed for enrollment): Renal medullary carcinoma (RMC) Cohort 5 (Closed for enrollment): Epithelioid sarcoma (ES) Cohort 6 (Closed for enrollment): Epithelioid sarcoma (ES) undergoing mandatory tumor biopsy Cohort 7 (Closed for enrollment): Poorly differentiated chordoma (or other chordoma with Sponsor approval) Cohort using tazemetostat 1600 mg QD • Cohort 8 (Closed for enrollment): Epitheliod sarcoma Participants will be dosed in continuous 28-day cycles. (Note: if treatment with study drug is discontinued prior to completing 2 years, subjects will be followed for a maximum duration of 2 years from start of study drug dosing.) Response assessment will be performed every 8 weeks while on study. Treatment with tazemetostat will continue until disease progression, unacceptable toxicity or withdrawal of consent, or termination of the study.

Official Title
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A Phase II, Multicenter Study of the EZH2 Inhibitor Tazemetostat in Adult Subjects With INI1-Negative Tumors or Relapsed/Refractory Synovial Sarcoma

Conditions
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Malignant Rhabdoid Tumors (MRT), Rhabdoid Tumors of the Kidney (RTK), Atypical Teratoid Rhabdoid Tumors (ATRT), Selected Tumors With Rhabdoid Features, Synovial Sarcoma, INI1-negative Tumors, Malignant Rhabdoid Tumor of Ovary, Renal Medullary Carcinoma, Epithelioid Sarcoma, Poorly Differentiated Chordoma (or Other Chordoma With Sponsor Approval), Any Solid Tumor With an EZH2 GOF Mutation

Intervention / Treatment
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* Drug: Tazemetostat


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age (at the time of consent/assent): ≥18 years of age Has an Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2 Has provided signed written informed consent Has a life expectancy of >3 months Has a malignancy: For which there are no standard therapies available (Cohorts 1, 3, 4 and 5) That is relapsed or refractory after treatment with an approved therapy(ies), defined as metastatic or non-resectable, locally advanced disease that has previously been treated with and progressed following approved therapy(ies) (Cohort 2) That has progressed within 6 months prior to study enrollment (Cohort 5 Expansion, Cohort 6 and Cohort 8 ONLY) Has a documented local diagnostic pathology of original biopsy confirmed by a Clinical Laboratory Improvement Amendments (CLIA/College of American Pathologists (CAP) or equivalent laboratory certification For Cohort 1 (rhabdoid tumors only), the following test results must be available by local laboratory: morphology and immunophenotypic panel consistent with rhabdoid tumors, and loss of INI1 or SMARCA4 confirmed by IHC, or molecular confirmation of tumor bi-allelic INI1 or SMARCA4 loss or mutation when INI1 or SMARCA4 IHC is equivocal or unavailable For Cohort 2 (subjects with relapsed/refractory synovial sarcoma only), the following tests must be available by local laboratory: Morphology consistent with synovial sarcomas, and cytogenetics or fluorescence in situ hybridization (FISH) and/or molecular confirmation (e.g., DNA sequencing) of SS18 rearrangement t(X;18)(p11;q11) For Cohort 3, 4, 5, 7 and 8 (subjects with INI1-negative/aberrant tumors or any solid tumor with EZH2 GOF mutation only), the following test results must be available by local laboratory: Morphology and immunophenotypic panel consistent with INI1-negative tumors (not applicable for solid tumors with EZH2 GOF mutation), and loss of INI1 confirmed by IHC, or molecular confirmation of tumor bi-allelic INI1 loss or mutation when INI1 IHC is equivocal or unavailable, or molecular evidence of EZH2 GOF mutation For Cohort 6 (subjects with ES undergoing optional tumor biopsy) only: Morphology and immunophenotypic panel consistent with ES (e.g., CD34, EMA, Keratin, and INI1) Has all prior treatment (i.e. chemotherapy, immunotherapy, radiotherapy) related clinically significant toxicities resolve to ≤Grade 1 per CTCAE version 4.0.3 or are clinically stable and not clinically significant, at time of enrollment. Prior anti-cancer therapy(ies), if applicable, must be completed according to the criteria below: Chemotherapy: cytotoxic (At least 14 days since last dose of chemotherapy prior to first dose of tazemetostat) Chemotherapy: nitrosoureas (At least 6 weeks since last dose of nitrosoureas prior to first dose of tazemetostat) Chemotherapy: non-cytotoxic (e.g., small molecule inhibitor) (At least 14 days since last dose of non-cytotoxic chemotherapy prior to first dose of tazemetostat) Monoclonal antibody(ies) (At least 28 days since the last dose of any monoclonal antibody prior to first dose of tazemetostat) Immunotherapy (e.g. tumor vaccine) (At least 42 days since last dose of immunotherapy agent(s) prior to first dose of tazemetostat) Radiotherapy (RT) (At least 14 days from last local site RT prior to first dose of tazemetostat/At least 21 days from stereostatic radiosurgery prior to first dose of tazemetostat/At least 12 weeks from craniospinal, ≥50% radiation of pelvis, or total body irradiation prior to first dose of tazemetostat) High dose therapy with autologous hematopoietic cell infusion (At least 60 days from last infusion prior to first dose of tazemetostat) Hematopoietic growth factor (At least 14 days from last dose of hematopoietic growth factor prior to first dose of tazemetostat) Has sufficient tumor tissue (slides or blocks) available for central confirmatory testing Has measurable disease based on either RECIST 1.1 for solid tumors or RANO for CNS tumors Has adequate hematologic (bone marrow [BM] and coagulation factors), renal and hepatic function. For subjects with CNS Tumors only, subject must have seizures that are stable, not increasing in frequency or severity and controlled on current anti-seizure medication(s) for a minimum of 21 days prior to the planned first dose of tazemetostat Has a shortening fraction of >27% or an ejection fraction of ≥50% by echocardiogram (ECHO) or multi-gated acquisition (MUGA) scan and New York Heart Association (NYHA) Class ≤2 Has a QT interval corrected by Fridericia's formula (QTcF) ≤480 msec Female subjects of childbearing potential must: Have a negative beta-human chorionic gonadotropin (β-hCG) pregnancy test at time of screening and within 14 days prior to planned first dose of tazemetostat and Agree to use effective contraception from a minimum of 7 days prior to first dose until 6 months following the last dose of tazemetostat and have a male partner who uses a condom, or Practice true abstinence or have a male partner who is vasectomized Male subjects with a female partner of childbearing potential must: Be vasectomized, or Agree to use condoms as defined in Section 8.6.2, from first dose of tazemetostat until 3 months following the last dose of tazemetostat, or Have a female partner who is NOT of childbearing potential Exclusion Criteria: Has had prior exposure to tazemetostat or other inhibitor(s) of enhancer of zeste homologue-2 (EZH2) Has participated in another interventional clinical study and received investigational drug within 30 days or 5 half-lives, whichever is longer, prior to the planned first dose of tazemetostat Has known active CNS or any leptomeningeal metastasis of primary extra-cranial tumor. Has had a prior malignancy other than the malignancies under study - EXCEPTION: A subject who has been disease-free for 5 years, or a subject with a history of a completely resected non-melanoma skin cancer or successfully treated in situ carcinoma is eligible Has had major surgery within 3 weeks prior to enrollment Has Thrombocytopenia, neutropenia, or anemia of Grade ≥3 (per CTCAE 4.03 criteria) or any prior history of myeloid malignancies, including myelodysplastic syndrome (MDS). Has abnormalities known to be associated with MDS (e.g. del 5q, chr 7 abn) and MPN (e.g. JAK2 V617F) observed in cytogenetic testing and DNA sequencing. Has a prior history of T-LBL /T-ALL Is unwilling to exclude grapefruit juice, Seville oranges and grapefruit from the diet Has cardiovascular impairment, history of congestive heart failure greater than NYHA Class II, uncontrolled arterial hypertension, unstable angina, myocardial infarction, or stroke within 6 months prior to the planned first dose of tazemetostat; or ventricular cardiac arrhythmia requiring medical treatment Is currently taking any prohibited medication(s) Has an active infection requiring systemic treatment Is immunocompromised (i.e. has congenital immunodeficiency), including subjects known history of infection with human immunodeficiency virus (HIV) Has known active infection with hepatitis B virus or hepatitis C virus Has had a symptomatic venous thrombosis within 2 weeks prior to study enrollment - For subjects with CNS involvement (primary tumor or metastatic disease), have any active bleeding or new intratumoral hemorrhage of more than punctuate size of screening MRI obtained within 14 days of starting study drug or known bleeding diathesis or treatment with anti-platelet or anti-thrombotic agents Has known hypersensitivity to any of the component of tazemetostat or other inhibitor(s)of EZH2 Is unable to take oral medications, or has a malabsorption syndrome or any uncontrolled gastrointestinal condition (e.g., nausea, diarrhea or vomiting) that would limit compliance with study requirements. Has an uncontrolled intercurrent illness including, but not limited to, uncontrolled infection, or psychiatric illness/social situations that would limit compliance with study requirements. For female subjects of childbearing potential: Is pregnant or nursing For male subjects: Is unwilling to adhere to contraception criteria from time of enrollment in the study to at least 3 months after last dose of tazemetostat.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Open-label Tazemetostat<br>All cohorts will receive 800 mg oral Tazemetostat twice a day in continuous 28-day cycles. | Drug: Tazemetostat<br>* Tazemetostat (EPZ-6438) is a selective small molecule inhibitor of the histone-lysine methyltransferase EZH2 gene<br>* Other names: IPN60200;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective response rate (ORR) in Cohorts 1,3,4,5,6 and 7 | Defined as the percentage of participants achieving a confirmed response (CR) or partial Response (PR) from the start of treatment until disease progression or the start of subsequent anti-cancer therapy, as per RANO criteria for primary brain tumors or RECIST 1.1 criteria for all other solid tumors. Participants with a best response of unknown/non-evaluable response will be treated as non-responders, i.e., they will be included in the denominator when calculating the percentage. | Day 1 and 15 of Cycle 1 and Cycle 2, Day 1 of Cycle 3, every 28 Days thereafter assessed maximum up to 2 years | 
| Progression-free survival (PFS) rate in Cohort 2 | Defined as the interval of time between the date of the first dose of study drug and the earliest date of disease progression or death due to any cause | 16 weeks of treatment | 
| Number of participants with adverse events (AEs) in Cohort 8 | Severity of AEs experienced by all participants will be evaluated by the Investigator based on the Common Terminology Criteria for Adverse Events (CTCAE) CTCAE, version 5.0. | Through study completion, an average of 2 years | 
| Percentage of Participants with Clinically Significant changes in Laboratory Parameters (blood chemistry, hematology and coagulation) | Percentage of participants with clinically significant change in laboratory parameters (blood chemistry, hematology and coagulation) will be reported. The clinical significance will be evaluated by the investigator | Up to 2 years. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Duration of response (DOR) in all Cohorts | Defined as the time from the first documented evidence of a response of at least partial remission (including partial remission and complete remission) to the time of first documented disease progression or death due to any cause, whichever comes first, using disease-appropriate standardized response criteria. | Assess every 8 weeks for duration of study participation which is estimated to be 2 years. | 
| Disease control rate (DCR) in Cohort 5, 6 and 8 | Defined as the percentage of participants who achieve a CR or PR (as per RECIST 1.1 criteria) or who have stable disease (SD) lasting at least 32 weeks from the start of treatment until disease progression or the start of subsequent anti-cancer therapy | 32 weeks of treatment | 
| Objective Response Rate (ORR) in Cohort 2 | Defined as the percentage of participants achieving a CR and PR from the start of treatment until disease progression or the start of subsequent anti-cancer therapy, as per RECIST 1.1 criteria for all other solid tumors (Appendix 5). Participants with a best response of unknown/non-evaluable response will be treated as non-responders, i.e., they will be included in the denominator when calculating the percentage. | Day 1 and 15 of Cycle 1 and Cycle 2, Day 1 of Cycle 3, every 28 Days thereafter assessed maximum up to 2 years | 
| Overall survival (OS) in all cohorts | Defined as the interval of time between the date of the first dose of study drug and the date of death due to any cause. | 24, 32 and 56 weeks of treatment | 
| Overall survival for each cohort | The time from the date of the first dose of study treatment to the date of death due to any cause | Weeks 24, 32, 56, and at end of study, an average of 2 years. |