A Phase 1 Study of the EZH2 Inhibitor Tazemetostat in Pediatric Subjects With Relapsed or Refractory INI1-Negative Tumors or Synovial Sarcoma

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Status: Active

Description

This is a Phase I, open-label, dose escalation and dose expansion study with a BID oral dose of tazemetostat. Subjects will be screened for eligibility within 14 days of the planned first dose of tazemetostat. A treatment cycle will be 28 days. Response assessment will be evaluated after 8 weeks of treatment and subsequently every 8 weeks while on study. The study has two parts: Dose Escalation and Dose Expansion. Dose escalation for subjects with the following relapsed / refractory malignancies: - Rhabdoid tumors: - Atypical teratoid rhabdoid tumor (ATRT) - Malignant rhabdoid tumor (MRT) - Rhabdoid tumor of kidney (RTK) - Selected tumors with rhabdoid features - INI1-negative tumors: - 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 Dose Expansion at the MTD or the RP2D - Cohort 1 - ATRT - Cohort 2 - MRT / RTK / selected tumors with rhabdoid features - Cohort 3 - INI-negative tumors: - Epithelioid sarcoma - Epithelioid malignant peripheral nerve sheath tumor - Extraskeletal myxoid chondrosarcoma - Myoepithelial carcinoma - Renal medullary carcinoma - Chordoma (poorly differentiated or de-differentiated) - Other INI1-negative malignant tumors (e.g., dedifferentiated chordoma) with Sponsor approval - Cohort 4 - Tumor types eligible for Cohorts 1 through 3 or synovial sarcoma with SS18-SSX rearrangement

Eligibility Criteria

Inclusion Criteria

  • Inclusion Criteria: 1. Age (at the time of consent/assent): ≥6 months to ≤21 years - Cohort 4 only: ≥10 years to ≤21 years 2. Performance Status: - If <12 years of age: Lanksy Performance Status >50% - If ≥12 years of age: Karnofsky Performance Status >50% 3. Has a life expectancy of >3 months 4. Has relapsed or refractory disease and no standard treatment options as determined by locally or regionally available standards of care and treating physician's discretion 5. Is ineligible or inappropriate for other treatment regimens known to have effective potential 6. 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 7. Has completed a prior therapy (ies) according to the criteria below: - Other investigational study agent (any medicinal product that is not approved in the country of treatment for any indication, adult or pediatric) (At least 30 days or five half-lives, whichever is longer, since last dose prior to the first dose of tazemetostat) - Chemotherapy: cytotoxic (At least 21 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 3 half-lives since the last dose of any monoclonal antibody prior to first dose of tazemetostat) - Immunotherapy (e.g., tumor vaccine) At least 6 weeks 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 stereotactic 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) - Hematopoietic growth factor (At least 14 days from last dose of hematopoietic growth factor prior to first dose of tazemetostat) - Hematopoietic cell transplantation (At least 60 days from infusion of hematopoietic cells prior to first dose of tazemetostat) 8. Has adequate hematologic (bone marrow and coagulation factors), renal and hepatic function as defined by criteria below: - Hematologic (BM Function): - Hemoglobin ≥ 8 g/dL - Platelets ≥100,000/mm^3 (≥100 x 10^9/L) - ANC ≥1,000/mm^3 (≥1.0 x 10^9/L) - Hematologic (Coagulation Factors): - PT ≤1.5 ULN - PTT ≤1.5 ULN - Fibrinogen ≥0.75 LLN - Renal Function (creatinine clearance or serum creatinine): - Calculated creatinine clearance ≥60 mL/min/1.73m^2 - Serum creatinine 6 months to 1 year: male 0.6 mg/dL (53 µmol/L) female 0.5 mg/dL (44 µmol/L) - Serum creatinine 1 to < 2 years: male 0.6 mg/dL (53 µmol/L) female 0.6 mg/dL (53 µmol/L) - Serum creatinine 2 to < 6 years: male 0.8 mg/dL (71 µmol/L) female 0.8 mg/dL (71 µmol/L) - Serum creatinine 6 to <10 years: male 1 mg/dL (88 µmol/L) female 1 mg/dL (88 µmol/L) - Serum creatinine 10 to <13 years: male 1.2 mg/dL (106 µmol/L) female 1.2 mg/dL (106 µmol/L) - Serum creatinine 13 to <16 years: male 1.5 mg/dL (133 µmol/L) female 1.4 mg/dL (125 µmol/L) - Serum creatinine ≥16 years: male 1.7 mg/dL (150 µmol/L) female 1.4 mg/dL (125 µmol/L) - Hepatic Function: - Total bilirubin <1.5 x ULN - ALT or AST <3 x ULN 9. For subjects with CNS involvement: Subjects must have deficits that are stable for a minimum of 14 days prior to enrollment, or seizures that are stable, not increasing in frequency or severity and controlled on current anti-seizure medication(s) for a

Exclusion Criteria

  • Inclusion Criteria: 1. Age (at the time of consent/assent): ≥6 months to ≤21 years - Cohort 4 only: ≥10 years to ≤21 years 2. Performance Status: - If <12 years of age: Lanksy Performance Status >50% - If ≥12 years of age: Karnofsky Performance Status >50% 3. Has a life expectancy of >3 months 4. Has relapsed or refractory disease and no standard treatment options as determined by locally or regionally available standards of care and treating physician's discretion 5. Is ineligible or inappropriate for other treatment regimens known to have effective potential 6. 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 7. Has completed a prior therapy (ies) according to the criteria below: - Other investigational study agent (any medicinal product that is not approved in the country of treatment for any indication, adult or pediatric) (At least 30 days or five half-lives, whichever is longer, since last dose prior to the first dose of tazemetostat) - Chemotherapy: cytotoxic (At least 21 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 3 half-lives since the last dose of any monoclonal antibody prior to first dose of tazemetostat) - Immunotherapy (e.g., tumor vaccine) At least 6 weeks 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 stereotactic 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) - Hematopoietic growth factor (At least 14 days from last dose of hematopoietic growth factor prior to first dose of tazemetostat) - Hematopoietic cell transplantation (At least 60 days from infusion of hematopoietic cells prior to first dose of tazemetostat) 8. Has adequate hematologic (bone marrow and coagulation factors), renal and hepatic function as defined by criteria below: - Hematologic (BM Function): - Hemoglobin ≥ 8 g/dL - Platelets ≥100,000/mm^3 (≥100 x 10^9/L) - ANC ≥1,000/mm^3 (≥1.0 x 10^9/L) - Hematologic (Coagulation Factors): - PT ≤1.5 ULN - PTT ≤1.5 ULN - Fibrinogen ≥0.75 LLN - Renal Function (creatinine clearance or serum creatinine): - Calculated creatinine clearance ≥60 mL/min/1.73m^2 - Serum creatinine 6 months to 1 year: male 0.6 mg/dL (53 µmol/L) female 0.5 mg/dL (44 µmol/L) - Serum creatinine 1 to < 2 years: male 0.6 mg/dL (53 µmol/L) female 0.6 mg/dL (53 µmol/L) - Serum creatinine 2 to < 6 years: male 0.8 mg/dL (71 µmol/L) female 0.8 mg/dL (71 µmol/L) - Serum creatinine 6 to <10 years: male 1 mg/dL (88 µmol/L) female 1 mg/dL (88 µmol/L) - Serum creatinine 10 to <13 years: male 1.2 mg/dL (106 µmol/L) female 1.2 mg/dL (106 µmol/L) - Serum creatinine 13 to <16 years: male 1.5 mg/dL (133 µmol/L) female 1.4 mg/dL (125 µmol/L) - Serum creatinine ≥16 years: male 1.7 mg/dL (150 µmol/L) female 1.4 mg/dL (125 µmol/L) - Hepatic Function: - Total bilirubin <1.5 x ULN - ALT or AST <3 x ULN 9. For subjects with CNS involvement: Subjects must have deficits that are stable for a minimum of 14 days prior to enrollment, or seizures that are stable, not increasing in frequency or severity and controlled on current anti-seizure medication(s) for a

Locations & Contacts

Colorado

Aurora
Children's Hospital Colorado
Status: Active
Contact: Debra Marie Schissel Email: debra.schissel@childrenscolorado.org

Georgia

Atlanta
Children's Healthcare of Atlanta - Egleston
Status: Active
Contact: Dolly Graciela Aguilera
Phone: 404-785-3515

Massachusetts

Boston
Boston Children's Hospital
Status: Active
Contact: Suzanne Ezrre Email: sezrre@partners.org
Dana-Farber Cancer Institute
Status: Active
Contact: Suzanne Ezrre Email: sezrre@partners.org
Charlestown
Massachusetts General Hospital
Status: Active
Name Not Available

Tennessee

Memphis
St. Jude Children's Research Hospital
Status: Active
Contact: Jana Freeman Email: Jana.Freeman@STJUDE.org

Texas

Dallas
UT Southwestern / Simmons Cancer Center-Dallas
Status: Active
Name Not Available

Washington

Seattle
Seattle Children's Hospital
Status: Active
Contact: Sarah Fanizzi Email: sarah.fanizzi@seattlechildrens.org

Trial Phase & Type

Trial Phase

Phase I

Trial Type

Treatment

Lead Organization

Lead Organization
Epizyme, Inc.

Trial IDs

Primary ID EZH-102
Secondary IDs NCI-2015-02224
Clinicaltrials.gov ID NCT02601937