Atypical teratoid rhabdoid tumor (ATRT), Malignant rhabdoid tumor (MRT), Rhabdoid tumor of kidney (RTK), selected tumors with rhabdoid features. Epithelioid sarcoma, Epithelioid malignant peripheral nerve sheath tumor, Extraskeletal myxoid chondrosarcoma, Myoepithelial carcinoma, Renal medullary carcinoma, Other INI1-negative malignant tumors (e.g., dedifferentiated chordoma) with Sponsor approval, Synovial Sarcoma with a SS18-SSX rearrangement MedDRA version: 21.1 Level: LLT Classification co
Conditions
Sponsors
Epizyme, Inc.
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1.Age (at the time of consent/assent): =6 months to 50% ,If =12 y of age: Karnofsky Performance Status >50% 3.Has provided signed written ICF 4. Has a life expectancy of >3 months. 5.Has relapsed or refractory disease and no standard treatment options. 6.Is ineligible for other treatment regimens. 7.Has a documented local diagnostic pathology of original biopsy. 8.Has all prior treatment related clinically significant toxicities resolve to = Grade 1 per CTCAE, version 4.03 or are clinically stable& not clinically significant. 9.Prior therapies must be completed according to the protocol. 10.Has adequate hemat. BM & coagulation factors, renal&hepatic function as defined by criteria in the protocol 11.Specific requirements for subjects with CNS involvement eg: stable deficits within certain timeframe, stable seizure, treated brain metastases without evidence of progression. 12. Has a LV fractional shortening of >27% or an LV ejection fraction of =50% by ECHO or MUGA scan & NYHAC =2. 13. Has a QT interval corrected by Fridericia's formula (QTcF) =450 msec. 14.Is able to swallow and retain orally administered medication and does not have any uncontrolled GI condition that may alter absorption. 15.Has sufficient tumor tissue for central confirmatory testing of IHC and/or cytogenetics/FISH and/or DNA mutation analysis. 16.Is willing and able to comply with all aspects of the protocol. 17.18. For female subjects of childbearing potential and for male subjects with a female partner of childbearing potential Subject must adhere to contraception methods described in the protocol. For Dose Escalation Only: ALL criteria above and the following: 1.Has evaluable disease as defined as lesions that can be accurately measured at least in one dimension by radiographic examination or physical examination or and other lesions such as bone lesions, leptomeningeal disease, ascites, pleural/pericardial effusions, lymphangitis cutis/pulmonitis or hepatosplenomegaly from disease 2.Has one of the following histologically confirmed tumors: Rhabdoid tumor: ATRT (closed to enrollment), MRT, RTK, selected tumors with rhabdoid features, INI1-negative tumor: (Epithelioid sarcoma, Epithelioid malignant peripheral nerve sheath tumor, EMC, Myoepithelial carcinoma, Renal medullary carcinoma), other INI1-negative malignant tumors, Synovial sarcoma with SS18-SSX rearrangement (closed to enrollment). 3. For subjects with ATRT, MRT, and RTK or tumors with rhabdoid features only: the following test results must be available: •Morphology and immunophenotypic panel consistent with rhabdoid tumor, and •Loss of INI1 or SMARCA 4 confirmed by IHC, or •Molecular confirmation of tumor bi-allelic INI1 or SMARCA 4 loss or mutation when INI1 or SMARCA4 IHC is equivocal or unavailable 4. For subjects with INI1 negative tumor only the following test results must be available: •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 5.For subjects with synovial sarcoma with SS18-SSX rearangement only the following test results must be available: •Morphology consistent with synovial sarcoma, and •Cytogenetics or FISH and/or molecular confirmation (e.g.DNA sequencing) of SS18 rearrangement t
Exclusion criteria
Exclusion criteria: 1.Has had prior exposure to tazemetostat or other inhibitor(s) of enhancer of zeste homolog2 (EZH2) 2.Is being actively treated for another concurrent malignancy or is less than five years from completion of treatment for another malignancy 3.Has participated in another interventional clinical study and received investigational drug within 30 days or five half-lives, whichever is longer, prior to the planned first dose of tazemetostat 4.Has had major surgery within 2 weeks prior to enrollment 5.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 at Screening. Cytogenetic testing and DNA sequencing will be conducted by a central laboratory following an abnormal result of bone marrow aspirate/biopsy. 6.Has a prior history of T-LBL/T-ALL. 7.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 8.Has clinically active heart disease including prolonged QTcF QTcF (>450 msec). 9.Is currently taking any prohibited medication(s) as described in section 7.3. 10.Has an active infection requiring systemic treatment. 11.Is immunocompromised (ie congenital immunodeficiency), including subjects with a known history of infection with human immunodeficiency virus (HIV). 12.Has known history of chronic infection with hepatitis B virus (hepatitis B surface antigen positive) or hepatitis C virus (detectable HCV RNA). 13.Has had a symptomatic venous thrombosis within 14 days prior to study enrollment. 14.For subjects with CNS involvement (primary tumor or metastatic disease): Have any active bleeding, or new intratumoral hemorrhage of more than punctate size on Screening MRI obtained within 14 days of starting study drug or known bleeding diathesis or treatment with antiplatelet or anti-thrombotic agents. 15.Has known hypersensitivity to any of the components of tazemetostat or other inhibitor(s) of EZH2, or hypersensitivity to Ora-sweet or methylparaben. 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.For male subjects: Is unwilling to adhere to contraception criteria from time of enrollment in study to at least 3 months after last dose of
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: Dose Escalation: To determine the maximum tolerated dose (MTD) or the recommended Phase 2 dose (RP2D) of tazemetostat when administered as an oral suspension twice daily (BID) in pediatric subjects with relapsed/refractory rhabdoid tumors, integrase interactor 1 (INI1)-negative tumors or synovial sarcoma Dose Expansion: To evaluate the antitumor activity of tazemetostat as assessed by overall response rate (ORR) in pediatric subjects with relapsed/refractory atypical teratoid rhabdoid tumor (ATRT) (Cohort 1-closed to enrollment), non-ATRT rhabdoid tumors (Cohort 2), INI1-negative tumors (Cohort 3)and tumor types eligible for Cohorts 1 through 3 or synovial sarcoma with SS18-SSX rearrangement (Cohort 4-closed to enrollment) using disease appropriate standardized response criteria. ;Secondary Objective: Dose Escalation: To evaluate the preliminary antitumor activity of tazemetostat as assessed by ORR using disease appropriate standardized response criteria Dose Expansion: To determine the progression-free survival (PFS) and overall survival (OS) at 24 and 56 weeks and overall pediatric subjects with relapsed/refractory atypical teratoid rhabdoid tumor (ATRT) (Cohort 1-closed to enrollment), non-ATRT rhabdoid tumors (Cohort 2), INI1-negative tumors (Cohort3), and tumor types eligible for Cohorts 1 through 3 or synovial sarcoma with SS18-SSX rearrangement (Cohort 4-closed to enrollment) using disease-appropriate standardized response criteria. ALL subjects: -To assess the safety and tolerability &pharmakokinetic (PK) parameters of tazemetostat administered as an oral suspension BID and/or tablets three times daily (TID), in pediatric subjects -To evaluate the duration of response in subjects achieving a PR or CR according to a disease appropriate standardized response criteria ;Primary end point(s): Dose Escalation: •Incidence and severity of treatment -emergent AEs (TEAEs) qualifying as protocol-defined dose-limiting toxicities (DLTs), and es | — |
Secondary
| Measure | Time frame |
|---|---|
| Timepoint(s) of evaluation of this end point: 1.Dose Escalation ORR: every 8 weeks for tumor response until disease progression 2.Dose Expansion PFS: every 8 weeks until disease progression or death OS: throughout the treatment period and then every 16 weeks until death, withdrawal of consent or they are lost to follow up 3.All Groups •Safety: At each visit or required timepoint during treatment and until for 30 days after last dose of tazemetostat or until new anti-cancer therapy •PK parameters: Cycle 1 (Days 1 and 15) and Cycles 2, 3 and 4 (Day 1). •Response duration: every 8 weeks from the time of confirmed response (CR or PR) until disease progression or death. ;Secondary end point(s): Dose Escalation: •Overall response rate (CR+PR) to tazemetostat in pediatric subjects with relapsed or refractory CNS and solid tumors, using disease-appropriate standardized response criteria; Dose Expansion: •Progression-free survival (PFS) and overall survival (OS) at 24 and 56 weeks and overall following receipt of tazemetostat for subjects with relapsed/refractory atypical teratoid rhabdoid tumor (ATRT) (Cohort 1), non-ATRT rhabdoid tumors (Cohort 2), INI1-negative tumors (Cohort 3)and tumor types eligible for Cohorts 1 through 3 or synovial sarcoma with SS18-SSX rearrangement (Cohort 4) using disease-appropriate standardized response; All Parts and Cohorts: •Safety and tolerability parameters including treatment-emergent adverse events (TEAEs), clinical laboratory evaluations, and other safety measures •PK parameters including Cmax, Tmax, t1/2, AUC(0-t), AUC(0-12hr), CL/F, Vd/F, Ka (if data permit) •Response duration, for the subset of subjects with a confirmed CR or PR, defined as the time from the first documented evidence of CR or PR to time of first documented disease progression or death due to any cause, using disease appropriate standardized response criteria. Exploratory Endpoints: •To assess the PK and pharmacodynamic (PD) relationship | — |
Countries
Australia, Canada, Denmark, France, Germany, Italy, Netherlands, United Kingdom, United States
Contacts
Public ContactClinical Trials Information
Epizyme, Inc.
Outcome results
None listed