Clinical Trial: A Phase II, Multicenter Study of the EZH2 Inhibitor Tazemetostat in Adult Subjects With INI1-Negative Tumors or Relapsed/Refractory Synovial Sarcoma

Study Status: Recruiting
Recruit Status: Recruiting
Study Type: Interventional

Official Title: A Phase II, Multicenter Study of the EZH2 Inhibitor Tazemetostat in Adult Subjects With INI1-Negative Tumors or Relapsed/Refractory Synovial Sarcoma

Brief Summary:

This is a Phase II, multicenter, open-label, single arm, 2-stage study of tazemetostat 800 mg BID administered orally in continuous 28 day cycles. Screening of subjects to determine eligibility for the study will be performed within 21 days of the first planned dose of tazemetostat. Eligible subjects will be enrolled into one of fivecohorts based on tumor type:

  • Cohort 1: MRT, RTK, ATRT, or selected tumors with rhabdoid features, including small cell carcinoma of the ovary hypercalcemic type [SCCOHT], also known as malignant rhaboid tumor of the ovary [MRTO]
  • Cohort 2: Relapsed or refractory synovial sarcoma with SS18-SSX rearrangement
  • Cohort 3: Other INI1 negative tumors or any solid tumor with an EZH2 gain of function (GOF) mutation, including: epithelioid malignant peripheral nerve sheath tumor (EMPNST), extraskeletal myxoid chondrosarcoma (EMC), myoepithelial carcinoma, other INI1-negative malignant tumors with Sponsor approval (e.g., dedifferentiated chordoma) any solid tumor with an EZH2 GOF mutation including but not limited to Ewing's sarcoma and melanoma
  • Cohort 4: Renal medullary carcinoma (RMC)
  • Cohort 5: Epithelioid sarcoma (ES)

Treatment with tazemetostat will continue until disease progression, unacceptable toxicity or withdrawal of consent, or termination of the study. Response assessment will be evaluated after 8 weeks of treatment and then every 8 weeks thereafter while on study.


Detailed Summary:
Sponsor: Epizyme, Inc.

Current Primary Outcome:

  • Number of subjects with objective response using disease appropriate standardized response criteria [ Time Frame: Assessed every 8 weeks for duration of study participation which is estimated to be 24 months ]
  • Progression-free survival (PFS) rate for Cohort 2 (Relapsed/Refractory Synovial Sarcoma) [ Time Frame: 16 weeks of treatment ]
    The number of subjects with CR, PR, or stable disease (SD) at 16 week assessment
  • Disease control rate (DCR) in subjects in Cohort 5 (Epithelioid Sarcoma) following oral administration of tazemetostat 800 mg BID [ Time Frame: 32 weeks of treatment ]
    The number of subjects with a confirmed CR or PR, or SD at 32 week assessment


Original Primary Outcome:

  • Number of subjects with objective response using disease appropriate standardized response criteria [ Time Frame: Assessed every 8 weeks for duration of study participation which is estimated to be 24 months ]
  • Progression-free survival (PFS) rate for Cohort 2 (Relapsed/Refractory Synovial Sarcoma) [ Time Frame: 16 weeks of treatment ]
    The number of subjects with CR, PR, or stable disease (SD) at 16 week assessment


Current Secondary Outcome:

  • 1. Overall response rate ORR for Cohort 2 (relapsed/refractory synovial sarcoma) and Cohort 5 (epithelioid sarcoma) [ Time Frame: Assessed every 8 weeks for duration of study participation which is estimated to be 24 months ]
    ORR (confirmed CR+PR, RECIST 1.1)
  • PFS for each cohort [ Time Frame: 24, 32 and 56 weeks of treatment ]
    The time from date of first dose of study treatment to the earlier of the date of first documented disease progression or date of death due to any cause
  • OS for each cohort [ Time Frame: 24, 32 and 56 weeks of treatment ]
    The time from the date of the first dose of study treatment to the date of death due to any cause
  • Response duration for each cohort and Cohorts 1, 3, 4 and 5 combined [ Time Frame: Every 8 weeks until disease progression or start of new anti-cancer therapy ]
  • Incidence of treatment-emergent adverse events as a measure of safety and tolerability [ Time Frame: Adverse events assessed from first dose through 30 days post last dose ]
  • Pharmacokinetics profile of tazemetotstat and its metabolite (plasma): Cmax [ Time Frame: Days 1 and 15 ]
  • Pharmacokinetics profile of tazemetotstat and its metabolite (plasma): Tmax [ Time Frame: Days 1 and 15 ]
  • Pharmacokinetics profile of tazemetotstat and its metabolite (plasma): AUC(0-t) [ Time Frame: Days 1 and 15 ]
  • Pharmacokinetics profile of tazemetotstat and its metabolite (plasma): AUC(0-12) [ Time Frame: Days 1 and 15 ]
  • Pharmacokinetics profile of tazemetotstat and its metabolite (plasma): t1/2 [ Time Frame: Days 1 and 15 ]
  • Pharmacokinetics profile of tazemetotstat and its metabolite (plasma): CL/F [ Time Frame: Days 1, 15, 29, 43, and 57 ]
  • Pharmacokinetics profile of tazemetotstat and its metabolite (plasma): Vd/F [ Time Frame: Days 1, 15, 29, 43, and 57 ]
  • Pharmacokinetics profile of tazemetotstat and its metabolite (plasma): Ka [ Time Frame: Days 1, 15, 29, 43, and 57 ]
  • Pharmacokinetics profile of tazemetotstat and its metabolite (plasma): Ctrough [ Time Frame: Days 29, 43 and 57 ]
  • Investigate the pharmacodynamics (PD) effects of tazemetostat in tumor tissue [ Time Frame: At week 8 ]
    IHC assessments of changes in the level of H3K27-Me3 following tazemetostat dosing


Original Secondary Outcome:

  • PFS for each cohort [ Time Frame: 24 and 56 weeks of treatment ]
    The time from date of first dose of study treatment to the earlier of the date of first documented disease progression or date of death due to any cause
  • OS for each cohort [ Time Frame: 24 and 56 weeks of treatment ]
    The time from the date of the first dose of study treatment to the date of death due to any cause
  • Response duration for each cohort and Cohorts 1 and 3 combined [ Time Frame: Every 8 weeks until disease progression or start of new anti-cancer therapy ]
  • Incidence of treatment-emergent adverse events as a measure of safety and tolerability [ Time Frame: Adverse events assessed from first dose through 30 days post last dose ]
  • Pharmacokinetics profile of tazemetotstat and its metabolite (plasma): Cmax [ Time Frame: Days 1 and 15 ]
  • Pharmacokinetics profile of tazemetotstat and its metabolite (plasma): Tmax [ Time Frame: Days 1 and 15 ]
  • Pharmacokinetics profile of tazemetotstat and its metabolite (plasma): AUC(0-t) [ Time Frame: Days 1 and 15 ]
  • Pharmacokinetics profile of tazemetotstat and its metabolite (plasma): AUC(0-12) [ Time Frame: Days 1 and 15 ]
  • Pharmacokinetics profile of tazemetotstat and its metabolite (plasma): t1/2 [ Time Frame: Days 1 and 15 ]
  • Pharmacokinetics profile of tazemetotstat and its metabolite (plasma): CL/F [ Time Frame: Days 1, 15, 29, 43, and 57 ]
  • Pharmacokinetics profile of tazemetotstat and its metabolite (plasma): Vd/F [ Time Frame: Days 1, 15, 29, 43, and 57 ]
  • Pharmacokinetics profile of tazemetotstat and its metabolite (plasma): Ka [ Time Frame: Days 1, 15, 29, 43, and 57 ]
  • Pharmacokinetics profile of tazemetotstat and its metabolite (plasma): Ctrough [ Time Frame: Days 29, 43 and 57 ]
  • Investigate the pharmacodynamics (PD) effects of tazemetostat in tumor tissue [ Time Frame: At week 8 ]
    IHC assessments of changes in the level of H3K27-Me3 following tazemetostat dosing


Information By: Epizyme, Inc.

Dates:
Date Received: October 21, 2015
Date Started: December 2015
Date Completion: January 2018
Last Updated: May 16, 2017
Last Verified: May 2017