Atypical teratoid rhabdoid tumor (ATRT), Malignant rhabdoid tumor (MRT), Rhabdoid tumor of kidney (RTK). Outside of Germany : - selected tumors with rhabdoid features
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 disease2.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(X;18)(p11;q1
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-cell lymphoblastic lymphoma/T-cell acute lymphoblastic lymphoma (T-LBL/T-ALL). 7.Has clinically active heart disease including prolonged QTcF (>450 msec) 8.Is currently taking any prohibited medication(s) as described in section 7.3 9.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 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 anti-platelet 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 tazemetostat.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| 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) & overall survival (OS) at 24 and 56 weeks & overall pediatric subjects with relapsed/refractory atypical teratoid rhabdoid tumor (ATRT) (Cohort 1), non-ATRT rhabdoid tumors (Cohort 2), INI1-negative tumors or synovial sarcoma ((Cohort 3) outside of Germany),& tumor types eligible for Cohorts 1 through 3 or synovial sarcoma with SS18-SSX rearrangement (Cohort 4 [outside of Germany]) using disease-appropriate standardized response criteria. ALL subjects: - To assess safety&tolerability and PK parameters of tazemetostat administered as an oral suspension BID in pediatric subjects; -To evaluate the duration of response in subjects achieving a PR or CR according to 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 establishment of the protocol-defined RP2D and/or MTD. Dose Expansion: •Overall response rate CR + PR to tazemetostat in pediatric subjects with relapsed or refractory atypical teratoid rhabdoid tumor (ATRT) (Cohort 1), non-ATRT rhabdoid tumors (Cohort 2), (outside of Germany) INI1-negative tumors (Cohort 3), and tumor types eligible for Cohorts 1 through 3 or synovial sarcoma with SS18-SSX rearrangement (Cohort 4 [outside Germany only]) using disease- appropriate standardized response criteria .;Timepoint(s) of evaluation of this end point: Dose Escalation: All DLTs occurring during the first 28 days of exposure summarized. Dose Expansion: Data sets for each cohort will be reviewed as completed. timepoint for every 8 weeks until documented disease progression or new anti-cancer therapy started.;Main Objective: Dose Escalation: To determine the m | — |
Secondary
| Measure | Time frame |
|---|---|
| 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), (outside of Germany) INI1-negative tumors (Cohort 3), and tumor types eligible for Cohorts 1 through 3 or synovial sarcoma with SS18-SSX rearrangement (Cohort 4 [outside of Germany]) 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 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;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 | — |
Countries
Australia, Canada, Denmark, France, Germany, Italy, Netherlands, United Kingdom, United States
Contacts
Public ContactClinical Trials Information
Epizyme, Inc.
Outcome results
None listed