Open-Label, Multicenter, Phase 1 / 2 Study of Tazemetostat (EZH2 Histone Methyl Transferase [HMT] Inhibitor) as a Single Agent in Subjects With Adv. Solid Tumors or With B-cell Lymphomas and Tazemetostat in Combination With Prednisolone in Subjects With DLBCL

This is a multicenter, open-label, Phase 1 / 2 study that is being conducted in two parts. The Phase 1 part (closed to accrual as of January 25, 2016) is comprised of dose escalation and expansion parts to establish the MTD and / or the recommended Phase 2 dose (RP2D) when tazemetostat is given BID (twice daily) orally on a continuous basis. Additionally, in separate cohorts in Phase 1, the effect of food on the bioavailability of tazemetostat as well as the drug-drug interaction (DDI) potential of tazemetostat are being evaluated. The Phase 2 part was initiated once the MTD and / or RP2D was established. Phase 2 enrolls subjects with DLBCL (Cohorts 1-3 and 6) and FL (Cohorts 4 and 5) for the determination of efficacy and safety of tazemetostat monotherapy (Cohorts 1-5) and of tazemetostat in combination with prednisolone (Cohort 6) with placement determined by centrally confirmed histology, cell of origin (COO), and EZH2 mutation status.

Inclusion Criteria

• Inclusion Criteria All Subjects: 1. Phase 1: Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1. Phase 2: ECOG performance status of 0 to 2. 2. Life expectancy ≥ 3 months before starting tazemetostat. 3. Subjects with Hepatitis B or C are eligible on the condition that subjects have adequate liver function as defined by Inclusion Criterion #6 and are hepatitis B surface antigen negative and/or have undetectable hepatitis C virus (HCV) RNA. 4. Adequate renal function defined as calculated creatinine clearance greater than or equal to 40 mL/min per the Cockcroft and Gault formula or the local institutional standard formula. 5. Adequate bone marrow function: 1. Absolute neutrophil count (ANC) ≥750/mm3 (≥0.75 x 10^9/L) - Without growth factor support (filgrastim or pegfilgrastim) for at least 14 days 2. Platelets greater ≥ 75,000/mm3 (≥75 x 10^9/L) - Evaluated after at least 7 days since last platelet transfusion 3. Hemoglobin greater than or equal to 9.0 g/dL - May receive transfusion 6. Adequate liver function: 1. Total bilirubin less than or equal to 1.5 x the upper limit of normal (ULN) except for unconjugated hyperbilirubinemia of Gilbert's syndrome 2. Alkaline phosphatase (ALP) (in the absence of bone disease), alanine aminotransferase (ALT), and aspartate aminotransferase (AST) less than or equal to 3 x ULN (less than or equal to 5 x ULN if subject has liver metastases) 7. Time between prior anticancer therapy and first dose of tazemetostat as below: 1. Cytotoxic chemotherapy - At least 21 days 2. Non-cytotoxic chemotherapy (eg. Small molecule inhibitor) - At least 14 days 3. Nitrosoureas - At least 6 weeks 4. Monoclonal antibody (ies) - At least 28 days 5. Radiotherapy- At least 14 days from local site radiation therapy/At least 6 weeks from prior radioisotope therapy/At least 12 weeks from 50% pelvic or total body irradiation 6. High dose therapy with autologous hematopoietic cell infusion - At least 60 days 7. High dose therapy with allogeneic transplant - At least 90 days (if graft versus host disease [GVHD] is present, must be < Grade 2) and no prohibited medications per Exclusion Criteria #3) Note: Starting at Cycle 1 Day 1, subjects may receive no more than 10 mg of prednisone daily (or equivalent corticosteroid, excluding protocol-defined prednisolone dosing for subjects enrolled in Cohort 6) when used for treatment of lymphoma related symptoms, with the intent to taper by the end of Cycle 1. 8. Males or females aged ≥ 18 years at the time of informed consent (Phase 2). Males and females aged ≥ 16 years at time of informed consent (Phase 1). 9. Females must not be lactating or pregnant at screening or baseline (as documented by a negative beta-human chorionic gonadotropin [beta-hCG] test with a minimum sensitivity of 25 IU/L or equivalent units of beta-hCG). A separate baseline assessment is required if a negative screening pregnancy test was obtained more than 72 hours before the first dose of study drug. All females will be considered to be of childbearing potential unless they are postmenopausal (at least 12 months consecutive amenorrheic, in the appropriate age group, and without other known or suspected cause) or have been sterilized surgically (ie, bilateral tubal ligation, total hysterectomy or bilateral oophorectomy, all with surgery at least 1 month before dose). Females of childbearing potential must not have had unprotected sexual intercourse within 30 days prior to study entry and must agree to use a highly effective method of contraception, from the last menstrual period prior to randomization, during Treatment Cycles, and for 30 days after the last final dose of study treatment, and have a male partner who uses a condom. Highly effective contraception includes: 1. Double barrier methods of contraception such as condom plus diaphragm or cervical/vault cap with spermicide. 2. Placement of an intrauterine device. 3. Established hormonal contraceptive methods: oral, injectable, or implant. Females who are using hormonal contraceptives must have been on a stable dose of the same hormonal contracept

Exclusion Criteria

• Inclusion Criteria All Subjects: 1. Phase 1: Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1. Phase 2: ECOG performance status of 0 to 2. 2. Life expectancy ≥ 3 months before starting tazemetostat. 3. Subjects with Hepatitis B or C are eligible on the condition that subjects have adequate liver function as defined by Inclusion Criterion #6 and are hepatitis B surface antigen negative and/or have undetectable hepatitis C virus (HCV) RNA. 4. Adequate renal function defined as calculated creatinine clearance greater than or equal to 40 mL/min per the Cockcroft and Gault formula or the local institutional standard formula. 5. Adequate bone marrow function: 1. Absolute neutrophil count (ANC) ≥750/mm3 (≥0.75 x 10^9/L) - Without growth factor support (filgrastim or pegfilgrastim) for at least 14 days 2. Platelets greater ≥ 75,000/mm3 (≥75 x 10^9/L) - Evaluated after at least 7 days since last platelet transfusion 3. Hemoglobin greater than or equal to 9.0 g/dL - May receive transfusion 6. Adequate liver function: 1. Total bilirubin less than or equal to 1.5 x the upper limit of normal (ULN) except for unconjugated hyperbilirubinemia of Gilbert's syndrome 2. Alkaline phosphatase (ALP) (in the absence of bone disease), alanine aminotransferase (ALT), and aspartate aminotransferase (AST) less than or equal to 3 x ULN (less than or equal to 5 x ULN if subject has liver metastases) 7. Time between prior anticancer therapy and first dose of tazemetostat as below: 1. Cytotoxic chemotherapy - At least 21 days 2. Non-cytotoxic chemotherapy (eg. Small molecule inhibitor) - At least 14 days 3. Nitrosoureas - At least 6 weeks 4. Monoclonal antibody (ies) - At least 28 days 5. Radiotherapy- At least 14 days from local site radiation therapy/At least 6 weeks from prior radioisotope therapy/At least 12 weeks from 50% pelvic or total body irradiation 6. High dose therapy with autologous hematopoietic cell infusion - At least 60 days 7. High dose therapy with allogeneic transplant - At least 90 days (if graft versus host disease [GVHD] is present, must be < Grade 2) and no prohibited medications per Exclusion Criteria #3) Note: Starting at Cycle 1 Day 1, subjects may receive no more than 10 mg of prednisone daily (or equivalent corticosteroid, excluding protocol-defined prednisolone dosing for subjects enrolled in Cohort 6) when used for treatment of lymphoma related symptoms, with the intent to taper by the end of Cycle 1. 8. Males or females aged ≥ 18 years at the time of informed consent (Phase 2). Males and females aged ≥ 16 years at time of informed consent (Phase 1). 9. Females must not be lactating or pregnant at screening or baseline (as documented by a negative beta-human chorionic gonadotropin [beta-hCG] test with a minimum sensitivity of 25 IU/L or equivalent units of beta-hCG). A separate baseline assessment is required if a negative screening pregnancy test was obtained more than 72 hours before the first dose of study drug. All females will be considered to be of childbearing potential unless they are postmenopausal (at least 12 months consecutive amenorrheic, in the appropriate age group, and without other known or suspected cause) or have been sterilized surgically (ie, bilateral tubal ligation, total hysterectomy or bilateral oophorectomy, all with surgery at least 1 month before dose). Females of childbearing potential must not have had unprotected sexual intercourse within 30 days prior to study entry and must agree to use a highly effective method of contraception, from the last menstrual period prior to randomization, during Treatment Cycles, and for 30 days after the last final dose of study treatment, and have a male partner who uses a condom. Highly effective contraception includes: 1. Double barrier methods of contraception such as condom plus diaphragm or cervical/vault cap with spermicide. 2. Placement of an intrauterine device. 3. Established hormonal contraceptive methods: oral, injectable, or implant. Females who are using hormonal contraceptives must have been on a stable dose of the same hormonal contracept

Lead Organization
Epizyme, Inc.