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

Who is this study for? Patients with Tumors
What treatments are being studied? Tazemetostat
Status: Active, not recruiting
Location: See all (32) locations...
Intervention Type: Drug
Study Type: Interventional
Study Phase: Phase 2
SUMMARY

This is a Phase II, multicenter, 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 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 (Closed for enrollment): Relapsed or refractory synovial sarcoma with SS18-SSX rearrangement Cohort 3 (Closed for enrollment): 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 (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 tumor biopsy Cohort 7 (Closed for enrollment): Poorly differentiated chordoma (or other chordoma with Sponsor approval) Cohort using tazemetostat 1600 mg QD • Cohort 8 (Closed 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.

Eligibility
Participation Requirements
Sex: All
Minimum Age: 18
Healthy Volunteers: No
View:

⁃ Age (at the time of consent/assent): ≥18 years of age

⁃ Has an Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2 NOTE: If subject is unable to walk due to paralysis, but is mobile in a wheelchair subject is considered to be ambulatory for the purpose of assessing their performance status.

⁃ Has provided signed written informed consent

⁃ Has a life expectancy of >3 months

⁃ Has a malignancy:

⁃ For which there are no standard therapies available (Cohorts 1, 3, 4 and 5)

⁃ That is relapsed or refractory after treatment with an approved therapy(ies), defined as metastatic or non-resectable, locally advanced disease that has previously been treated with and progressed following approved therapy(ies) (Cohort 2)

⁃ That has progressed within 6 months prior to study enrollment (Cohort 5 Expansion, Cohort 6 and Cohort 8 ONLY)

⁃ 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

⁃ For Cohort 1 (rhabdoid tumors only), the following test results must be available by local laboratory: morphology and immunophenotypic panel consistent with rhabdoid tumors, and loss of INI1 or SMARCA4 confirmed by IHC, or molecular confirmation of tumor bi-allelic INI1 or SMARCA4 loss or mutation when INI1 or SMARCA4 IHC is equivocal or unavailable

⁃ For Cohort 2 (subjects with relapsed/refractory synovial sarcoma only), the following tests must be available by local laboratory: Morphology consistent with synovial sarcomas, and cytogenetics or fluorescence in situ hybridization (FISH) and/or molecular confirmation (e.g., DNA sequencing) of SS18 rearrangement t(X;18)(p11;q11)

⁃ For Cohort 3, 4, 5, 7 and 8 (subjects with INI1-negative/aberrant tumors or any solid tumor with EZH2 GOF mutation only), the following test results must be available by local laboratory: Morphology and immunophenotypic panel consistent with INI1-negative tumors (not applicable for solid tumors with EZH2 GOF mutation), 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, or molecular evidence of EZH2 GOF mutation

⁃ For Cohort 6 (subjects with epithelioid sarcoma undergoing optional tumor biopsy):

⁃ Morphology and immunophenotypic panel consistent with epithelioid sarcoma (e.g., CD34, EMA, Keratin, and INI1)

⁃ If providing optional biopsy: Willingness to provide informed consent to undergo pre- and post-dose biopsy

⁃ Has all prior treatment (I.e. chemotherapy, immunotherapy, radiotherapy) related clinically significant toxicities resolve to ≤Grade 1 per CTCAE version 4.0.3 or are clinically stable and not clinically significant, at time of enrollment.

⁃ Prior anti-cancer therapy(ies), if applicable, must be completed according to the criteria below:

⁃ Chemotherapy: cytotoxic (At least 14 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 28 days since the last dose of any monoclonal antibody prior to first dose of tazemetostat)

⁃ Immunotherapy (e.g. tumor vaccine) (At least 42 days 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 stereostatic 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)

⁃ High dose therapy with autologous hematopoietic cell infusion (At least 60 days from last infusion 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)

⁃ Has sufficient tumor tissue (slides or blocks) available for central confirmatory testing of IHC and/or cytogenetics/FISH and/or DNA mutation analysis (required for study entry but enrollment based on local results)

⁃ Has measurable disease based on either RECIST 1.1 for solid tumors or RANO for CNS tumors

⁃ Has adequate hematologic (bone marrow [BM] and coagulation factors), renal and hepatic function as defined by criteria below:

⁃ Hematologic (BM Function):

⁃ Hemoglobin ≥9 mg/dL

⁃ Platelets ≥100,000/mm^3 (≥100x10^9/L)

⁃ ANC ≥1,000/mm^3 (≥1.0x10^9/L)

⁃ Hematologic (Coagulation Factors):

⁃ INR/PT₫ <1.5 ULN

⁃ PTT>1.5 ULN

⁃ Renal Function:

• Serum creatinine ≤1.5 x ULN

⁃ Hepatic Function:

⁃ Total bilirubin <1.5 x ULN(Eligibility can be determined by conjugated or total bilirubin)

⁃ AST and ALT <3 x ULN NOTE: Laboratory results obtained during screening should be used to determine eligibility criteria. In situations where laboratory results are outside the permitted range, the Investigator may retest the subject and the subsequent within range screening result may be used to determine the subject's eligibility.

⁃ For subjects with CNS Tumors only, subject must have seizures that are stable, not increasing in frequency or severity and controlled on current anti-seizure medication(s) for a minimum of 21 days prior to the planned first dose of tazemetostat NOTE: Subjects may receive glucocorticoids (at stable or tapering dose) to control CNS symptoms prior to enrollment; however, subjects should receive a stable or tapering dose for at least 7 days prior to planned first dose of tazemetostat

⁃ Has a shortening fraction of >27% or an ejection fraction of ≥50% by echocardiogram (ECHO) or multi-gated acquisition (MUGA) scan and New York Heart Association (NYHA) Class ≤2

⁃ Has a QT interval corrected by Fridericia's formula (QTcF) ≤480 msec

⁃ Female subjects of childbearing potential must:

⁃ Have a negative beta-human chorionic gonadotropin (β-hCG) pregnancy test at time of screening and within 14 days prior to planned first dose of tazemetostat (urine or serum test is acceptable however, positive urine tests must be confirmed with serum testing), and

⁃ Agree to use effective contraception, as defined in Section 8.6.1, from a minimum of 7 days prior to first dose until 6 months following the last dose of tazemetostat and have a male partner who uses a condom, or

⁃ Practice true abstinence (when this is in line with the preferred and usual lifestyle of the subject, see Section 8.6.1), or Have a male partner who is vasectomized

⁃ Male subjects with a female partner of childbearing potential must:

⁃ Be vasectomized, or

⁃ Agree to use condoms as defined in Section 8.6.2, from first dose of tazemetostat until 3 months following the last dose of tazemetostat, or

⁃ Have a female partner who is NOT of childbearing potential

Locations
United States
California
University of California San Francisco
San Francisco
Colorado
University of Colorado Denver
Aurora
Florida
Mayo Clinic - Jacksonville
Jacksonville
Illinois
Northwestern Memorial Hospital
Chicago
Massachusetts
Dana Farber Cancer Institute
Boston
Massachusetts General Hospital - Cancer Center
Boston
Michigan
University of Michigan
Ann Arbor
Missouri
Washington University
Saint Louis
New York
Memorial Sloan Kettering Cancer Center
New York
Ohio
Cincinnati Children's Hospital Medical Center
Cincinnati
Oregon
Oregon Health Sciences University
Portland
Texas
MD Anderson Cancer Center
Houston
Washington
Fred Hutchinson Cancer Research Center
Seattle
Seattle Children's Hospital
Seattle
Other Locations
Australia
Chris O'Brien Lifehouse
Camperdown
Metro South Hospital and Health Service via Princess Alexandra Hospital
Woolloongabba
Belgium
Institut Jules Bordet Medical Oncology Clinic
Brussels
University Hospital Leuven
Leuven
Canada
Alberta Health Services
Edmonton
McGill University Health Centre - Royal Victoria Hospital
Montreal
Princess Margaret Hospital
Toronto
France
Institut Bergonie
Bordeaux
Centre Leon Berard
Lyon
Institut Curie
Paris
Hospital Pitie Salpetriere
Paris Cedex 13
Institut Gustave Roussy
Villejuif
Germany
Children's Hospital Augsburg Klinikum
Augsburg
Sarcoma Center HELIOS Klinikum Berlin
Berlin
Italy
Instituto Nazionale Tumori - National Cancer Institute Via Giacomo Venezian
Milano
Taiwan
National Taiwan University Hospital
Taipei City
United Kingdom
Royal Marsden Foundation Trust
London
University College London Hospital
London
Time Frame
Start Date: December 22, 2015
Estimated Completion Date: June 2023
Participants
Target number of participants: 250
Treatments
Experimental: Open-label Tazemetostat
All Cohorts [Cohort 1 - MRT, RTK, ATRT, or 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/refractory synovial sarcoma (SS18-SSX rea), Cohort 3 - Other INI1-negative tumors or any solid tumor with an EZH2 GOF mutation, Cohort 4 - Renal medullary carcinoma, Cohort 5 - Epithelioid sarcoma, Cohort 6 - Epithelioid sarcoma undergoing mandatory tumor biopsy and Cohort 7 - Poorly differentiated chordoma (or other chordoma with Sponsor approval)] will receive 800 mg oral Tazemetostat BID x 28 days
Sponsors
Leads: Epizyme, Inc.

This content was sourced from clinicaltrials.gov

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