rhabdoid tumors Soft Tissue sarcoma
Conditions
Interventions
Subjects will receive tazemetostat as an oral agent BID. Treatment may
continue, assuming subject and/or parent/guardian and Investigator consent,
until disease progression or unacceptable toxicity.
Sponsors
Epizyme, Inc.
Eligibility
Age
2 Years to 99 Years
Inclusion criteria
Inclusion criteria: 1. Age (at time of consent/assent): *6 months to *18 years Cohort 4 only: *10 years to *18 years 2. Performance Status: If 50% If *12 years of age: Karnofsky Performance Status >50% 3. Has provided signed written informed consent/assent 4. Has a life expectancy of >3 months 5. Has relapsed or refractory disease and no standard treatment options 6. Is ineligible or inappropriate for other treatment regimens known to have effective potential 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 and not clinically significant, at time of enrollment 9. Prior therapy(ies), must be completed according to the protocol 10. Has adequate hematologic 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 & NYHA *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 available 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 as judged by Investigator 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, 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. 3. For subjects with ATRT, MRT, or 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 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 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 equivo
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 clinically active heart disease including prolonged QTcF (>450 msec) 6. Is currently taking any prohibited medication(s) as described in section 7.3 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 an active infection requiring systemic treatment 9. Is immunocompromised (ie congenital immunodeficiency), including subjects with known history of infection with human immunodeficiency virus (HIV) 10. Has known history of chronic infection with hepatitis B virus (hepatitis B surface antigen positive) or hepatitis C virus (detectable HCV RNA) 11. Has had a symptomatic venous thrombosis within 14 days prior to study enrollment 12. 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 anti-platelet or anti-thrombotic agents 13. Has known hypersensitivity to any of the components of tazemetostat or other inhibitor(s) of EZH2, or hypersensitivity to Ora-sweet or methylparaben 14. Has an uncontrolled intercurrent illness including, but not limited to, uncontrolled infection, or psychiatric illness/social situations that would limit compliance with study requirements 15. For female subjects of childbearing potential: Is pregnant or nursing 16. 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 tazemetostat.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Dose Escalation: * Incidence and severity of treatment-emergent adverse events (AEs) qualifying as protocol-defined DLTs in Cycle 1 * Establishment of the protocol defined RP2D and/or MTD Dose Expansion: Overall response rate (CR + PR) to tazemetostat for each cohort in pediatric subjects with relapsed or refractory atypical teratoid rhabdoid tumor (ATRT) (Cohort 1), non-ATRT rhabdoid tumors (Cohort 2), INI-1 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 criteria | — |
Secondary
| Measure | Time frame |
|---|---|
| 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 - 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 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 permits) * 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 for tazemetostat in pediatric subjects - Tumor target gene expression and phenotypic markers including those for differentiation, apoptosis, inflammation and cell proliferation and their correlation with activity - H3K27 methylation in PBMC population - Somatic mutation analysis of tumor tissue and blood derived circulating DNA | — |
Countries
Netherlands
Outcome results
None listed