A Study of Tazemetostat in Adult Participants With Soft Tissue Sarcoma

Phase 2

Completed

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

Interventions: Drug: Tazemetostat

Registration Number: NCT02601950

Lead Sponsor: Epizyme, Inc.

Brief Summary: 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: 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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 267

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.

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Open-label Tazemetostat	Tazemetostat	All cohorts will receive 800 mg oral Tazemetostat twice a day in continuous 28-day cycles.

Primary Outcome Measures

Name	Time	Method
Cohorts 1, 3, 4, 5, 6 and 7: Objective Response Rate (ORR)	Tumor assessment performed at screening and every 8 weeks beginning at Cycle 3 Day 1, until disease progression or the start of subsequent anti-cancer therapy, whichever occurred first, up to 5.75 years (cycle duration: 28 days)	ORR was defined as percentage of participants who achieved a confirmed complete response (CR) or partial response (PR) based on the investigator review from start of treatment until progressive disease (PD) or start of subsequent anti-cancer therapy or cancer-related surgery, whichever was earlier, as per response assessment in neuro-oncology (RANO) criteria for primary brain tumors or response evaluation criteria in solid tumors (RECIST) version (v) 1.1 criteria for all other solid tumors. CR was defined as disappearance of all target and non-target lesions. Any pathological lymph nodes must be \<10 millimeter (mm) in short axis. PR was defined as at least 30% decrease in sum of diameters of target lesions, taking as a reference, baseline sum of diameters. PD was defined as at least a 20% increase in sum of diameters of target lesions, taking as a reference, smallest sum of diameters recorded since treatment started. In addition, sum must have an absolute increase from nadir of 5 mm.
Cohort 2: Progression-Free Survival (PFS) Rate at 16 Weeks of Treatment With Tazemetostat	At 16 Weeks	PFS was defined as the interval of time between the date of the first dose of study treatment and the earliest date of PD or death due to any cause, whichever comes first, as per RECIST v 1.1 criteria. PFS rate at 16 week was estimated. PD was defined as at least a 20% increase in the sum of diameters of target lesions, taking as a reference, smallest sum of diameters recorded since the treatment started. In addition, the sum must have an absolute increase from nadir of 5 mm.
Cohort 8: Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs)	From first dose of study treatment (Day 1) up to 30 days after the last dose of study treatment, approximately 148 weeks	An AE was defined as any untoward medical occurrence in a participant or clinical investigation participant administered a medicinal product and which did not necessarily have a causal relationship with this treatment. An SAE was defined as any untoward medical occurrence that, at any dose: resulted in death, was life threatening, required hospitalization or prolongation of existing hospitalization, resulted in disability/incapacity, was a congenital anomaly/birth defect or was medically significant. TEAEs were defined as AEs if one of the following conditions met: emerged after the time of first dose administration, having been absent prior to the first dose; re-emerged, having been present but stopped prior to the time of first dose administration; worsened in severity after the time of first dose administration relative to the pretreatment state, when the AE was continuous.

Secondary Outcome Measures

Name	Time	Method
Cohorts 2 and 8: Objective Response Rate (ORR)	Tumor assessment performed at screening and every 8 weeks beginning at Cycle 3 Day 1, until disease progression or the start of subsequent anti-cancer therapy, whichever occurred first, up to 5.75 years (cycle duration: 28 days)	ORR was defined as percentage of participants who achieved a confirmed CR or PR based on investigator assessment from start of treatment until PD or start of subsequent anti-cancer therapy or cancer-related surgery, whichever was earlier, as per RANO criteria for primary brain tumors or RECIST v 1.1 criteria for all other solid tumors. CR was defined as disappearance of all target and non-target lesions. Any pathological lymph nodes must be \<10 mm in the short axis. PR was defined as at least 30% decrease in sum of diameters of target lesions, taking as a reference, baseline sum of diameters. PD was defined as at least a 20% increase in the sum of diameters of target lesions, taking as a reference, smallest sum of diameters recorded since the treatment started. In addition, the sum must have an absolute increase from nadir of 5 mm.
All Cohorts: Duration of Response (DOR)	Tumor assessment performed at screening and every 8 weeks beginning at Cycle 3 Day 1, until disease progression or the start of subsequent anti-cancer therapy, whichever occurred first, up to 5.75 years (cycle duration 28 days)	DOR was defined as time from the first documented evidence of CR or PR based on investigator review to the time of first documented PD or death due to any cause, whichever came first, as per RECIST v 1.1 criteria. CR was defined as disappearance of all target and non-target lesions. Any pathological lymph nodes must be \<10 mm in the short axis. PR was defined as at least 30% decrease in sum of diameters of target lesions, taking as a reference, baseline sum of diameters. PD was defined as at least a 20% increase in the sum of diameters of target lesions, taking as a reference, smallest sum of diameters recorded since the treatment started. In addition, the sum must have an absolute increase from nadir of 5 mm.
All Cohorts: Progression-Free Survival (PFS)	Tumor assessment performed at screening and every 8 weeks beginning at Cycle 3 Day 1, until disease progression or the start of subsequent anti-cancer therapy, whichever occurred first, up to 5.75 years (cycle duration 28 days)	PFS was defined as the interval of time between the date of the first dose of study treatment and the earliest date of PD or death due to any cause, whichever comes first, as per RECIST v 1.1 criteria. PD was defined as at least a 20% increase in the sum of diameters of target lesions, taking as a reference, smallest sum of diameters recorded since the treatment started. In addition, the sum must have an absolute increase from nadir of 5 mm.
All Cohorts: Progression-Free Survival (PFS) Rate at Weeks 24, 32 and 56	At Weeks 24, 32 and 56	PFS was defined as the interval of time between the date of the first dose of study treatment and the earliest date of PD or death due to any cause, whichever comes first, as per RECIST v 1.1 criteria. PFS rate at 24, 32 and 56 weeks were estimated. PD was defined as at least a 20% increase in the sum of diameters of target lesions, taking as a reference, smallest sum of diameters recorded since the treatment started. In addition, the sum must have an absolute increase from nadir of 5 mm. Estimates were calculated with Kaplan-Meier analysis and 95% CIs using the complementary log-log transformation.
All Cohorts: Overall Survival (OS)	Tumor assessment performed at screening and every 8 weeks beginning at Cycle 3 Day 1, until disease progression or the start of subsequent anti-cancer therapy, whichever occurred first, up to 5.75 years (cycle duration: 28 days)	OS was defined as the interval of time between the date of the first dose of study treatment and the date of death due to any cause.
All Cohorts: Overall Survival (OS) Rate at Weeks 24, 32 and 56	At Weeks 24, 32 and 56	OS was defined as the interval of time between the date of the first dose of study treatment and the date of death due to any cause. OS rate at 24, 32 and 56 weeks were estimated. Estimates were calculated with Kaplan-Meier analysis and 95% CIs using the complementary log-log transformation.
All Cohorts: Disease Control Rate (DCR) at Weeks 12, 24, 32 and 48	At Weeks 12, 24, 32 and 48	DCR was defined as the percentage of participants who achieved a confirmed response (CR or PR, as per RECIST v 1.1 criteria) or who have SD lasting at least 32 weeks from the start of treatment until disease progression or the start of subsequent anti-cancer therapy. CR was defined as disappearance of all target and non-target lesions. Any pathological lymph nodes must be \<10 mm in the short axis. PR was defined as at least 30% decrease in sum of diameters of target lesions, taking as a reference, baseline sum of diameters. SD was defined neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease.

Trial Locations

Locations (32): Institut Curie
🇫🇷
Paris, France
University Hospital Leuven
🇧🇪
Leuven, Belgium
Centre Leon Berard
🇫🇷
Lyon, France
Alberta Health Services
🇨🇦
Edmonton, Alberta, Canada
Memorial Sloan Kettering Cancer Center
🇺🇸
New York, New York, United States
Hospital Pitie Salpetriere
🇫🇷
Paris Cedex 13, France
Institut Gustave Roussy
🇫🇷
Villejuif, France
Institut Jules Bordet Medical Oncology Clinic
🇧🇪
Brussels, Belgium
Instituto Nazionale Tumori - National Cancer Institute Via Giacomo Venezian
🇮🇹
Milano, Italy
Children's Hospital Augsburg Klinikum
🇩🇪
Augsburg, Germany
Sarcoma Center HELIOS Klinikum Berlin
🇩🇪
Berlin, Germany
Royal Marsden Foundation Trust
🇬🇧
London, United Kingdom
University of California San Francisco
🇺🇸
San Francisco, California, United States
Fred Hutchinson Cancer Research Center
🇺🇸
Seattle, Washington, United States
Northwestern Memorial Hospital
🇺🇸
Chicago, Illinois, United States
Massachusetts General Hospital - Cancer Center
🇺🇸
Boston, Massachusetts, United States
Dana Farber Cancer Institute
🇺🇸
Boston, Massachusetts, United States
Chris O'Brien Lifehouse
🇦🇺
Camperdown, New South Wales, Australia
MD Anderson Cancer Center
🇺🇸
Houston, Texas, United States
Seattle Children's Hospital
🇺🇸
Seattle, Washington, United States
Princess Margaret Hospital
🇨🇦
Toronto, Ontario, Canada
Mayo Clinic - Jacksonville
🇺🇸
Jacksonville, Florida, United States
University of Colorado Denver
🇺🇸
Aurora, Colorado, United States
Washington University
🇺🇸
Saint Louis, Missouri, United States
University of Michigan
🇺🇸
Ann Arbor, Michigan, United States
Cincinnati Children's Hospital Medical Center
🇺🇸
Cincinnati, Ohio, United States
Oregon Health Sciences University
🇺🇸
Portland, Oregon, United States
McGill University Health Centre - Royal Victoria Hospital
🇨🇦
Montreal, Quebec, Canada
Metro South Hospital and Health Service via Princess Alexandra Hospital
🇦🇺
Woolloongabba, Australia
National Taiwan University Hospital
🇨🇳
Taipei City, Taiwan
Institut Bergonie
🇫🇷
Bordeaux, France
University College London Hospital
🇬🇧
London, United Kingdom