A Phase II, Multicentre Study of the EZH2 Inhibitor Tazemetostat in Adult Subjects With INI1-Negative Tumours or Relapsed/Refractory Synovial Sarcoma

Official Title

A Phase II, Multicentre Study of the EZH2 Inhibitor Tazemetostat in Adult Subjects With INI1-Negative Tumours or Relapsed/Refractory Synovial Sarcoma

Summary:

This is a Phase II, multicentre, open-label, single arm, 2-stage study of tazemetostat 800 mg BID (twice daily) and 1600 mg QD (once daily). Subjects will be screened for eligibility within 21 days of the planned date of the first dose of tazemetostat and enrolled into one of 8 cohorts: Cohort using tazemetostat 800 mg BID - Cohort 1 (Closed for enrollment): MRT, RTK, ATRT, and selected tumours with rhabdoid features, including small cell carcinoma of the ovary hypercalcemic type [SCCOHT], also known as malignant rhaboid tumour of the ovary [MRTO] - Cohort 2 (Closed for enrollment): Relapsed or refractory synovial sarcoma with SS18-SSX rearrangement - Cohort 3 (Closed for enrollment): Other INI1 negative tumours or any solid tumour with an EZH2 gain of function (GOF) mutation, including: epithelioid malignant peripheral nerve sheath tumour (EMPNST), extraskeletal myxoid chondrosarcoma (EMC), myoepithelial carcinoma, other INI1-negative malignant tumours with Sponsor approval (e.g., dedifferentiated chordoma) any solid tumour with an EZH2 GOF mutation including but not limited to Ewing's sarcoma and melanoma - Cohort 4 (Closed for enrollment): Renal medullary carcinoma (RMC) - Cohort 5 (Closed for enrollment): Epithelioid sarcoma (ES) - Cohort 6 (Opened for enrollment): Epithelioid sarcoma (ES) undergoing mandatory tumour biopsy - Cohort 7 (Opened for enrollment): Poorly differentiated chordoma (or other chordoma with Sponsor approval) Cohort using tazemetostat 1600 mg QD • Cohort 8 (Opened for enrollment): Epitheliod sarcoma Subjects will be dosed in continuous 28-day cycles. (Note: if treatment with study drug is discontinued prior to completing 2 years, subjects will be followed for a maximum duration of 2 years from start of study drug dosing.) Response assessment will be performed every 8 weeks while on study. Treatment with tazemetostat will continue until disease progression, unacceptable toxicity or withdrawal of consent, or termination of the study.

Trial Description

Primary Outcome:

• Number of subjects with objective response using disease appropriate standardized response criteria
• Progression-free survival (PFS) rate for Cohort 2 (Relapsed/Refractory Synovial Sarcoma)
• Assess the effects of tazemetostat on tumour immune priming for Cohort 6
• Assess the safety and tolerability of tazemetostat 1600 mg QD for Cohort 8

• Duration of response in subjects in Cohorts 1, 2, 3, 4, 5, 6 and 7 and in Cohorts 1, 3, 4, 5, 6 and 7 combined for subjects achieving a complete response (CR) and partial response (PR) following oral administration of tazemetostat 800 mg BID
• Disease control rate (DCR) in subjects with epithelioid sarcoma (Cohort 5) and epithelioid sarcoma undergoing mandatory biopsy (Cohort 6) following oral administration of tazemetostat 800 mg BID
• Overall response rate ORR for Cohort 2 (relapsed/refractory synovial sarcoma) and Cohort 6 (epithelioid sarcoma undergoing mandatory biopsy) following oral administration of tazemetostat 800 mg BID
• PFS for each cohort
• OS for each cohort
• Incidence of treatment-emergent adverse events as a measure of safety and tolerability
• Pharmacokinetics profile of tazemetotstat and its metabolite (plasma): Cmax
• Pharmacokinetics profile of tazemetotstat and its metabolite (plasma): Tmax
• Pharmacokinetics profile of tazemetotstat and its metabolite (plasma): AUC(0-t)
• Pharmacokinetics profile of tazemetotstat and its metabolite (plasma): AUC(0-12)
• Pharmacokinetics profile of tazemetotstat and its metabolite (plasma): t1/2
• Pharmacokinetics profile of tazemetotstat and its metabolite (plasma): CL/F
• Pharmacokinetics profile of tazemetotstat and its metabolite (plasma): Vd/F
• Pharmacokinetics profile of tazemetotstat and its metabolite (plasma): Ka
• Pharmacokinetics profile of tazemetotstat and its metabolite (plasma): Ctrough
• Investigate the pharmacodynamics (PD) effects of tazemetostat in tumour tissue
• Duration of response in subjects with epithelioid sarcoma in Cohort 8 at 1600 mg QD.
• Disease control rate (DCR) in subjects with epithelioid sarcoma (Cohort 8) following oral administration of tazemetostat 1600 mg QD
• Overall response rate ORR for subjects with epithelioid sarcoma (Cohort 8) following oral administration of tazemetostat 1600 mg QD

View this trial on ClinicalTrials.gov