A Phase II, Multicenter Study of the EZH2 Inhibitor Tazemetostat in Adult Subjects With INI1-Negative Tumors or Relapsed/Refractory Synovial Sarcoma
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|ClinicalTrials.gov Identifier: NCT02601950|
Recruitment Status : Active, not recruiting
First Posted : November 11, 2015
Last Update Posted : January 19, 2023
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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): MRT, RTK, 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 INI1 negative tumors or any solid tumor with an 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
Subjects 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.
|Condition or disease||Intervention/treatment||Phase|
|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||Drug: Tazemetostat||Phase 2|
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||250 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|Official Title:||A Phase II, Multicenter Study of the EZH2 Inhibitor Tazemetostat in Adult Subjects With INI1-Negative Tumors or Relapsed/Refractory Synovial Sarcoma|
|Study Start Date :||December 22, 2015|
|Estimated Primary Completion Date :||June 2024|
|Estimated Study Completion Date :||December 2024|
Experimental: Open-label Tazemetostat
All Cohorts [Cohort 1 - MRT, RTK, ATRT, or tumors with rhabdoid features, including small cell carcinoma of the ovary hypercalcemic type [SCCOHT], also known as malignant rhabdoid tumor of the ovary [MRTO] Cohort 2 - Relapsed/refractory synovial sarcoma (SS18-SSX rea), Cohort 3 - Other INI1-negative tumors or any solid tumor with an EZH2 GOF mutation, Cohort 4 - Renal medullary carcinoma, Cohort 5 - Epithelioid sarcoma, Cohort 6 - Epithelioid sarcoma undergoing mandatory tumor biopsy and Cohort 7 - Poorly differentiated chordoma (or other chordoma with Sponsor approval)] will receive 800 mg oral Tazemetostat BID x 28 days
Tazemetostat (EPZ-6438) is a selective small molecule inhibitor of the histone-lysine methyltransferase EZH2 gene
- Progression-free survival (PFS) rate for Cohort 2 (Relapsed/Refractory Synovial Sarcoma) [ Time Frame: 16 weeks of treatment ]The proportion of patients with documented disease progression or death due to any cause at the 16-week assessment.
- Safety and tolerability of tazemetostat 1600 mg once daily for Cohort 8 (Epithelioid Sarcoma) [ Time Frame: Through study completion, an average of 2 years ]To determine the safety and tolerability based on the number of adverse events and results of clinical laboratory tests.
- Objective response rate (ORR) for all other cohorts [ Time Frame: Assessed every 8 weeks for duration of study participation which is estimated to be 24 months ]The proportion of patients with a best response of at least partial remission (including partial remission and complete remission) using disease appropriate standardized response criteria.
- ORR for Cohort 2 (Relapsed/Refractory Synovial Sarcoma) [ Time Frame: Assess every 8 weeks for duration of study participation which is estimated to be 24 months ]The proportion of patients with a best response of at least partial remission (including partial remission and complete remission) using disease appropriate standardized response criteria.
- Duration of response (DOR) for all cohorts [ Time Frame: Assess every 8 weeks for duration of study participation which is estimated to be 24 months ]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
- Disease control rate (DCR) for all patients with Epithelioid Sarcoma (ES): Cohort 5 (ES treated twice daily), Cohort 6 (ES with optional tumor sampling treated twice daily), and Cohort 8 (ES treated once daily) [ Time Frame: 32 weeks of treatment ]The proportion of patients with a confirmed response of partial remission, complete remission, or stable disease at the 32-week assessment.
- PFS rate for each cohort [ Time Frame: 24, 32 and 56 weeks of treatment ]The proportion of patients with documented disease progression or death due to any cause
- Overall survival for each cohort [ Time Frame: 24, 32 and 56 weeks of treatment ]The time from the date of the first dose of study treatment to the date of death due to any cause
- Incidence of treatment-emergent adverse events as a measure of safety and tolerability [ Time Frame: Adverse events assessed from first dose through 30 days post last dose ]
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|Ages Eligible for Study:||18 Years and older (Adult, Older Adult)|
|Sexes Eligible for Study:||All|
|Accepts Healthy Volunteers:||No|
- 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
- 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.
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02601950
|Responsible Party:||Epizyme, Inc.|
|Other Study ID Numbers:||
|First Posted:||November 11, 2015 Key Record Dates|
|Last Update Posted:||January 19, 2023|
|Last Verified:||January 2023|
|Studies a U.S. FDA-regulated Drug Product:||Yes|
|Studies a U.S. FDA-regulated Device Product:||No|
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