A Study of the Effect of Tazemetostat (study drug) in Patients with INI1-Negative Tumors or Relapsed/Refractory Synovial Sarcoma

Phase 1

Conditions: Cohort 1: Rhabdoid tumors (malignant rhabdoid tumors, rhabdoid tumors of the kidney, atypical teratoid rhabdoid tumors, and selected tumorsCohort 2: Relapsed/refractory synovial sarcoma with SS18-SSX rearrangementCohort 3: Other INI1-negative tumors or any solid tumor with EZH2 GOF (gain of function) mutationCohort 4: Renal medullary carcinomaCohort 5 and 8: Epithelioid sarcomaCohort 6: Epithelioid sarcoma undergoing optional tumour biopsyCohort 7: Poorly differentiated chordoma
MedDRA version: 20.0Level: LLTClassification code 10007284Term: CarcinomaSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
MedDRA version: 21.1Level: LLTClassification code 10064886Term: Renal medullary carcinomaSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
MedDRA version: 21.0Level: PTClassification code 10073134Term: Extraskeletal myxoid chondrosarcomaSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
MedDRA version: 21.1Level: LLTClassification code 10026667Term: Malignant peripheral nerve sheath tumorSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
MedDRA version: 21.1Level: LLTClassification code 10073335Term: Rhabdoid tumorSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
MedDRA version: 20.0Level: PTClassification code 10042863Term: Synovial sarcomaSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
MedDRA version: 20.0Level: HLTClassification code 10015100Term: Epithelioid sarcomasSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Therapeutic area: Diseases [C] - Cancer [C04]

Registration Number: EUCTR2015-002469-41-GB

Lead Sponsor: Epizyme, Inc.

Brief Summary: Not available

Detailed Description: Not available

Recruitment & Eligibility

Status: Authorised-recruitment may be ongoing or finished

Sex: All

Target Recruitment: 291

Inclusion Criteria

1.Age (at the time of consent/assent): =18 years of age
2.Has an Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2
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, 4 & 5)
• That is relapsed or refractory, defined as metastatic or non-resectable, locally advanced disease that has previously been treated with and progressed following approved therapy(ies), if therapy(ies) exists (Cohort 2)
• That has progressed within 6 months prior to study enrollment (Cohort 5 Expansion, Cohort 6 and 8 ONLY)
6.Has a documented local diagnostic pathology of original biopsy confirmed by a Clinical Laboratory Improvement Amendments (CLIA)/College of American Pathologists (CAP) or other sponsor-approved 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 3,4, 5, 7 and 8 (subjects with INI1-negative tumor or any other solid tumour 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
10.For Cohort 6 (subjects with epithelioid sarcoma undergoing optional tumor biopsy):•Morphology and immunophenotypic panel consistent with epithelioid sarcoma (e.g., CD34, EMA, Keratin, and INI1) •If providing optional biopsy: Willingness to provide informed consent to undergo pre- and post-dose biopsy
11. 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 and not clinically significant, at time of enrollment
12.Prior anti-cancer therapy(ies) according to the criteria as in the protocol.
13.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).
14.Has measurable disease based on either RECIST 1.1 for solid tumors or RANO for CNS tumors as defined in the protocol.
15.Has adequate hematologic (bone marrow [BM] and coagulation factors), renal and hepatic function as defined by criteria in the protocol.
16.For subjects with CNS tumors only: must have stable seizures, not increasing in freque

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 known active CNS or any leptomeningeal metastasis of primary extra-cranial tumor. Subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging 4 weeks prior to the first dose of study drug and any neurologic symptoms have stabilized), have no evidence of new or enlarging brain metastases, and are on stable or tapering doses of steroids for at least 7 days prior to first dose of study drug.
NOTE: Subjects with asymptomatic brain metastases found on screening MRI may be entered into the study without prior radiation therapy to the brain if they do not require immediate surgical or radiation therapy in the opinion of the treating Investigator and in the opinion of a radiation therapy or neurosurgical consultant.
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 is 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. 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. NOTE: Bone marrow aspirate/biopsy will be conducted following abnormal peripheral blood smear morphology assessment conducted by central laboratory. Cytogenetic testing and DNA sequencing will be conducted following an abnormal result of bone marrow aspirate/biopsy.
7. Has prior history of T-LBL/T-ALL
8.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.
9.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
10.Is currently taking any prohibited medication(s) as described in the protocol.
11.Has an active infection requiring systemic treatment
12.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.
13.Has known active infection with hepatitis B virus (hepatitis B surface antigen positive) or hepatitis C virus (detectable HCV RNA)
14.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 molec

Study & Design

Study Type: Interventional clinical trial of medicinal product

Study Design: Not specified

Primary Outcome Measures

Name	Time	Method

Secondary Outcome Measures

Name	Time	Method

Related Trials