Cohort 1: Rhabdoid tumors (INI1 or SMARCA4 negative) Cohort 2: Relapsed or refractory synovial sarcoma with SS18-SSX rearrangement Cohort 3: Other INI1-deficient/aberrant tumors, including: •Epithelioid sarcoma (ES) •Epithelioid malignant peripheral nerve sheath tumor (EMPNST) •Extraskeletal myxoid chondrosarcoma (EMC) •Myoepithelial carcinoma •Renal medullary carcinoma (RMC) •Other INI1-negative malignant tumors (e.g., dedifferentiated chordoma) with Sponsor approval MedDRA version: 18.1 Lev
Conditions
Interventions
Product Name: tazemetostat
Product Code: EPZ-6438 (E7438)
Pharmaceutical Form: Tablet
INN or Proposed INN: TAZEMETOSTAT
Current Sponsor code: EPZ-6438
Other descriptive name: ESQR
Concentration unit:
Sponsors
Epizyme, Inc.
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1.Age (at the time of consent/assent): =16 years of age 2.Has an Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2 (Appendix 1) NOTE: If subject is unable to walk due to paralysis, but is mobile in a wheelchair, subject is considered to be ambulatory for the purpose of assessing their performance status. 3.Has provided signed written informed consent 4.Has a life expectancy of >3 months 5.Has a malignancy: •For which there are no standard therapies available (Cohorts 1 & 3) •That is relapsed or refractory after treatment with an approved therapy(ies) (Cohort 2) 6.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 7.For Cohort 1 (subjects with 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 8.For Cohort 2 (subjects with relapsed/refractory synovial sarcoma only): The following test results must be available by local laboratory: •Morphology consistent with synovial sarcoma, and •Cytogenetics or Fluorescence in situ hybridization (FISH) and/or molecular confirmation (e.g., DNA sequencing) of SS18 rearrangement t(X;18)(p11;q11) 9.For Cohort 3 (subjects with INI1-negative/aberrant tumor only): The following test results must be available by local laboratory: •Morphology and immunophenotypic panel consistent with INI1-negative tumors, 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 10.Has all prior treatment (i.e., chemotherapy, immunotherapy, radiotherapy) related clinically significant toxicities resolve to = Grade 1 per CTCAE, version 4.03 or are clinically stable, at time of enrollment 11.Has completed a prior therapy(ies) according to the criteria described in the protocol. 12.Has sufficient tumor tissue (slides or blocks) available for central confirmatory testing of IHC and/or cytogenetics/FISH and/or DNA mutation analysis (required for study entry but enrollment based on local results). 13.Has measurable disease based on either RECIST 1.1 for solid tumors or RANO for CNS tumors as defined in the protocol. 14.Has adequate hematologic (bone marrow [BM] and coagulation factors), renal and hepatic function as defined by criteria in the protocol. 15.For subjects with ATRT 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 16.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 less than or equal to 2 17.Has a QT interval corrected by Fridericia's formula (QTcF) =480 msec 18.Female subjects of childbearing potential must: •Have a negative beta-human chorionic gonadotropin (ß-hCG) pregnancy test at time of Screening and within 14 days prior to planned first dose of tazemetostat, and •Agree to use effective contraception, as defined in the protocol, from start of screening until 30 days followi
Exclusion criteria
Exclusion criteria: 1.Has had prior exposure to tazemetostat or other inhibitor(s) of enhancer of zeste homologue-2 (EZH2) 2.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 3.Has CNS or leptomeningeal metastasis of primary extra-cranial tumor. NOTE: Only subjects with ATRT as the primary tumor are permitted. 4.Has had a prior malignancy other than the malignancies under study Exception: 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 are eligible. 5.Has had major surgery within 3 weeks prior to enrollment NOTE: Minor surgery (e.g., minor biopsy of extracranial site, central venous catheter placement, shunt revision) is permitted within 3 weeks prior to enrollment. 6.Is unwilling to exclude grapefruit juice, Seville oranges and grapefruit from the diet and all foods that contain those fruits from time of enrollment to while on study. 7.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 8.Is currently taking any prohibited medication(s) as described in the protocol. 9.Has an active infection requiring systemic treatment 10.Is immunocompromised (ie has a congential immunodeficiency), including subjects known history of infection with human immunodeficiency virus (HIV) NOTE: HIV positive subjects who are taking antiretroviral therapy are ineligible due to potential PK interactions with tazemetostat. 11.Has known history of chronic infection with hepatitis B virus (hepatitis B surface antigen positive) or hepatitis C virus (detectable HCV RNA) 12.Has had a symptomatic venous thrombosis within the 3 months prior to study enrollment. NOTE: Subjects with a history of a deep vein thrombosis >3 months prior to study enrollment who are on anticoagulation therapy with low molecular weight heparin are eligible for this study. 13.For subjects with ATRT only: Have =3 foci of punctate hemorrhage, any active bleeding, or intratumoral hemorrhage at time of enrollment or known bleeding diathesis or treatment with anti-platelet or anti-thrombotic agents. 14.Has known hypersensitivity to any of the components of tazemetostat or other inhibitor(s) of EZH2 15.Is unable to take oral medications, malabsorption syndrome or any other uncontrolled gastrointestinal condition (e.g., nausea, diarrhea or vomiting) that might impair the bioavailability of tazemetostat 16.Has an uncontrolled intercurrent illness including, but not limited to, uncontrolled infection, or psychiatric illness/social situations that would limit compliance with study requirements. 17.For female subjects of childbearing potential: Is pregnant or nursing 18.For male subjects: Is unwilling to adhere to contraception criteria from time of enrollment in study to at least 30 days after last dose of tazemetostat.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: To assess the overall response rate (ORR) in subjects with rhabdoid tumors (Cohort 1) and other INI1-negative tumors (Cohort 3) following oral administration of tazemetostat 800 mg twice daily (BID) To determine the progression-free survival (PFS) rate after 16 weeks of treatment with tazemetostat in subjects with relapsed/refractory synovial sarcoma (Cohort 2) following oral administration of tazemetostat 800 mg BID;Secondary Objective: To assess the ORR in subjects with synovial sarcoma (Cohort 2) following oral administration of tazemetostat 800 mg twice daily (BID) To determine the PFS and overall survival (OS) at Weeks 24 and 56 and overall in subjects with rhabdoid tumors (Cohort 1), relapsed/refractory synovial sarcoma (Cohort 2) or other INI1-negative tumors (Cohort 3) following oral administration of tazemetostat 800 mg BID. To evaluate the duration of response in subjects with rhabdoid tumors (Cohort 1), relapsed/refractory synovial sarcoma (Cohort 2), or other INI1-negative tumors (Cohort 3) and in Cohorts 1 and 3 combined achieving a CR or PR according to the disease-appropriate criteria following oral administration of tazemetostat 800 mg BID To assess the safety and tolerability of orally administered tazemetostat 800 mg BID To assess the population PK parameters of tazemetostat To investigate the PD effects of tazemetostat in tumor tissue;Primary end point(s): Cohorts 1 (rhabdoid tumors) and 3 (other INI1-negative tumors): Overall response rate (ORR) (confirmed complete response (CR) and partial response (PR)) to tazemetostat in subjects with INI1-negative tumors using disease-appropriate standardized response criteria. Cohort 2 (relapsed/refractory synovial sarcoma): Progression-free survival (PFS) rate which is the number of subjects with complete response (CR), partial response (PR) or stable disease (SD).;Timepoint(s) of evaluation of this end point: Cohorts 1 (rhabdoid tumors) and 3 (INI1-negative/aberrant)- ORR: every 8 weeks f | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): Progressive-free survival (PFS) which is defined as the time from date of first dose of study treatment to the earlier of the date of first documented disease progression or date of death due to any cause. Overall Survival (OS) which is defined as the time from the date of the first dose of study treatment to the date of death due to any cause. Response duration for each cohort and Cohorts 1 and 3 combined. Response duration, for the subset of subjects with a confirmed CR or PR, is defined as the time from the first documented evidence of CR or PR to the time of first documented disease progression or death due to any cause, using disease-appropriate standardized response criteria Safety and tolerability of tazemetostat Population PK parameters oral clearance (CL/F), oral volume of distribution (Vd/F), and first-order absorption rate constant (Ka) for tazemetostat. PD effects of tazemetostat in tumor tissue in IHC assessments of changes in the level of H3K27-Me3 following tazemetostat dosing;Timepoint(s) of evaluation of this end point: Cohort 2 (synovial sarcoma) – ORR: every 8 weeks until disease progression All Cohorts - •PFS: every 8 weeks until disease progression and analyzed at 24 and 56 weeks. OS: continuously throughout the treatment period and then every 16 weeks until death or study completion •Response duration: every 8 weeks from the time of confirmed response (CR or PR) until disease progression or death. •Safety: At each visit or required timepoint during treatment and until for 30 days after last treatment or until new anti-cancer therapy •PK: Days 1, 15, 29, 43 and 57 •PD: Any time after week 8 | — |
Countries
Australia, Belgium, France, Germany, Italy, United Kingdom, United States
Contacts
Public ContactClinical Trials Information
Epizyme, Inc.
Outcome results
None listed