A Study of Tazemetostat in Adult Participants With Soft Tissue Sarcoma

Synovial Sarcoma Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02601950
• Other study ID #: EZH-202
• Secondary ID: 2015-002469-41
• Status: Completed
• Phase: Phase 2
• Start date: December 22, 2015
• Est. completion date: February 26, 2024

Study information

• Verified date: April 2024
• Source: Ipsen
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This study will include participants with various types of cancer known as soft-tissue sarcomas. Tissues that can be affected by soft tissue sarcomas include fat, muscle, blood vessels, deep skin tissues, tendons and ligaments. Soft tissue cancers are rare and can occur almost anywhere in the body. Part 1 of this trial will study the safety and the level that adverse effects of the study drug tazemetostat in combination with doxorubicin (current front line treatment) can be tolerated (known as tolerability). It is also designed to establish a recommended study drug dosage for the next part of the study. Part 2 will evaluate and compare how long participants live without their disease getting worse when receiving the study drug plus doxorubicin versus doxorubicin plus placebo (dummy treatment).

Description:

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): malignant rhabdoid tumor (MRT), rhabdoid tumor of the kidney (RTK), atypical teratoid rhabdoid tumor (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 integrase interactor 1 (INI1) negative tumors or any solid tumor with an enhancer of zeste homologue-2 (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 (Closed 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 Participants 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 267
• Est. completion date: February 26, 2024
• Est. primary completion date: February 26, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

1. Age (at the time of consent/assent): =18 years of age

2. Has an Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2

3. Has provided signed written informed consent

4. Has a life expectancy of >3 months

5. 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)

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. 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

8. 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)

9. 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

10. For Cohort 6 (subjects with ES undergoing optional tumor biopsy) only:

• Morphology and immunophenotypic panel consistent with ES (e.g., CD34, EMA, Keratin, and INI1)

11. 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.

12. 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)

13. Has sufficient tumor tissue (slides or blocks) available for central confirmatory testing

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

15. Has adequate hematologic (bone marrow [BM] and coagulation factors), renal and hepatic function.

16. 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

17. 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

18. Has a QT interval corrected by Fridericia's formula (QTcF) =480 msec

19. Female subjects of childbearing potential must:

• Have a negative beta-human chorionic gonadotropin (ß-hCG) pregnancy test at time of screening and within 14 days prior to planned first dose of tazemetostat and
• Agree to use effective contraception 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 or have a male partner who is vasectomized

20. 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

Exclusion Criteria:

1. Has had prior exposure to tazemetostat or other inhibitor(s) of enhancer of zeste homologue-2 (EZH2)

2. Has participated in another interventional clinical study and received investigational drug within 30 days or 5 half-lives, whichever is longer, prior to the planned first dose of tazemetostat

3. Has known active CNS or any leptomeningeal metastasis of primary extra-cranial tumor.

4. Has had a prior malignancy other than the malignancies under study - EXCEPTION: A subject who has been disease-free for 5 years, or a subject with a history of a completely resected non-melanoma skin cancer or successfully treated in situ carcinoma is eligible

5. Has had major surgery within 3 weeks prior to enrollment

6. Has Thrombocytopenia, neutropenia, or anemia of Grade =3 (per CTCAE 4.03 criteria) or any prior history of myeloid malignancies, including myelodysplastic syndrome (MDS). Has abnormalities known to be associated with MDS (e.g. del 5q, chr 7 abn) and MPN (e.g. JAK2 V617F) observed in cytogenetic testing and DNA sequencing.

7. Has a prior history of T-LBL /T-ALL

8. Is unwilling to exclude grapefruit juice, Seville oranges and grapefruit from the diet

9. Has cardiovascular impairment, history of congestive heart failure greater than NYHA Class II, uncontrolled arterial hypertension, unstable angina, myocardial infarction, or stroke within 6 months prior to the planned first dose of tazemetostat; or ventricular cardiac arrhythmia requiring medical treatment

10. Is currently taking any prohibited medication(s)

11. Has an active infection requiring systemic treatment

12. Is immunocompromised (i.e. has congenital immunodeficiency), including subjects known history of infection with human immunodeficiency virus (HIV)

13. Has known active infection with hepatitis B virus or hepatitis C virus

14. Has had a symptomatic venous thrombosis within 2 weeks prior to study enrollment -

15. For subjects with CNS involvement (primary tumor or metastatic disease), have any active bleeding or new intratumoral hemorrhage of more than punctuate size of screening MRI obtained within 14 days of starting study drug or known bleeding diathesis or treatment with anti-platelet or anti-thrombotic agents

16. Has known hypersensitivity to any of the component of tazemetostat or other inhibitor(s)of EZH2

17. Is unable to take oral medications, or has a malabsorption syndrome or any uncontrolled gastrointestinal condition (e.g., nausea, diarrhea or vomiting) that would limit compliance with study requirements.

18. Has an uncontrolled intercurrent illness including, but not limited to, uncontrolled infection, or psychiatric illness/social situations that would limit compliance with study requirements.

19. For female subjects of childbearing potential: Is pregnant or nursing

20. For male subjects: Is unwilling to adhere to contraception criteria from time of enrollment in the study to at least 3 months after last dose of tazemetostat.

Related Conditions & MeSH terms

• Any Solid Tumor With an EZH2 GOF Mutation
• Atypical Teratoid Rhabdoid Tumors (ATRT)
• Chordoma
• Epithelioid Sarcoma
• INI1-negative Tumors
• Kidney Neoplasms
• Malignant Rhabdoid Tumor of Ovary
• Malignant Rhabdoid Tumors (MRT)
• Neoplasms
• Poorly Differentiated Chordoma (or Other Chordoma With Sponsor Approval)
• Renal Medullary Carcinoma
• Rhabdoid Tumor
• Rhabdoid Tumors of the Kidney (RTK)
• Sarcoma
• Sarcoma, Synovial
• Selected Tumors With Rhabdoid Features
• Synovial Sarcoma

Intervention

Drug:
• Tazemetostat
Tazemetostat (EPZ-6438) is a selective small molecule inhibitor of the histone-lysine methyltransferase EZH2 gene

Locations

Country	Name	City	State
Australia	Chris O'Brien Lifehouse	Camperdown	New South Wales
Australia	Metro South Hospital and Health Service via Princess Alexandra Hospital	Woolloongabba
Belgium	Institut Jules Bordet Medical Oncology Clinic	Brussels
Belgium	University Hospital Leuven	Leuven
Canada	Alberta Health Services	Edmonton	Alberta
Canada	McGill University Health Centre - Royal Victoria Hospital	Montreal	Quebec
Canada	Princess Margaret Hospital	Toronto	Ontario
France	Institut Bergonie	Bordeaux
France	Centre Leon Berard	Lyon
France	Institut Curie	Paris
France	Hospital Pitie Salpetriere	Paris Cedex 13
France	Institut Gustave Roussy	Villejuif
Germany	Children's Hospital Augsburg Klinikum	Augsburg
Germany	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
United Kingdom	University College London Hospital	London
United States	University of Michigan	Ann Arbor	Michigan
United States	University of Colorado Denver	Aurora	Colorado
United States	Dana Farber Cancer Institute	Boston	Massachusetts
United States	Massachusetts General Hospital - Cancer Center	Boston	Massachusetts
United States	Northwestern Memorial Hospital	Chicago	Illinois
United States	Cincinnati Children's Hospital Medical Center	Cincinnati	Ohio
United States	MD Anderson Cancer Center	Houston	Texas
United States	Mayo Clinic - Jacksonville	Jacksonville	Florida
United States	Memorial Sloan Kettering Cancer Center	New York	New York
United States	Oregon Health Sciences University	Portland	Oregon
United States	Washington University	Saint Louis	Missouri
United States	University of California San Francisco	San Francisco	California
United States	Fred Hutchinson Cancer Research Center	Seattle	Washington
United States	Seattle Children's Hospital	Seattle	Washington

Sponsors (1)

Lead Sponsor	Collaborator
Epizyme, Inc.

Countries where clinical trial is conducted

United States,  Australia,  Belgium,  Canada,  France,  Germany,  Italy,  Taiwan,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Objective response rate (ORR) in Cohorts 1,3,4,5,6 and 7	Defined as the percentage of participants achieving a confirmed response (CR) or partial Response (PR) from the start of treatment until disease progression or the start of subsequent anti-cancer therapy, as per RANO criteria for primary brain tumors or RECIST 1.1 criteria for all other solid tumors. Participants with a best response of unknown/non-evaluable response will be treated as non-responders, i.e., they will be included in the denominator when calculating the percentage.	Day 1 and 15 of Cycle 1 and Cycle 2, Day 1 of Cycle 3, every 28 Days thereafter assessed maximum up to 2 years
Primary	Progression-free survival (PFS) rate in Cohort 2	Defined as the interval of time between the date of the first dose of study drug and the earliest date of disease progression or death due to any cause	16 weeks of treatment
Primary	Number of participants with adverse events (AEs) in Cohort 8	Severity of AEs experienced by all participants will be evaluated by the Investigator based on the Common Terminology Criteria for Adverse Events (CTCAE) CTCAE, version 5.0.	Through study completion, an average of 2 years
Primary	Percentage of Participants with Clinically Significant changes in Laboratory Parameters (blood chemistry, hematology and coagulation)	Percentage of participants with clinically significant change in laboratory parameters (blood chemistry, hematology and coagulation) will be reported. The clinical significance will be evaluated by the investigator	Up to 2 years.
Secondary	Duration of response (DOR) in all Cohorts	Defined as the time from the first documented evidence of a response of at least partial remission (including partial remission and complete remission) to the time of first documented disease progression or death due to any cause, whichever comes first, using disease-appropriate standardized response criteria.	Assess every 8 weeks for duration of study participation which is estimated to be 2 years.
Secondary	Disease control rate (DCR) in Cohort 5, 6 and 8	Defined as the percentage of participants who achieve a CR or PR (as per RECIST 1.1 criteria) or who have stable disease (SD) lasting at least 32 weeks from the start of treatment until disease progression or the start of subsequent anti-cancer therapy	32 weeks of treatment
Secondary	Objective Response Rate (ORR) in Cohort 2	Defined as the percentage of participants achieving a CR and PR from the start of treatment until disease progression or the start of subsequent anti-cancer therapy, as per RECIST 1.1 criteria for all other solid tumors (Appendix 5). Participants with a best response of unknown/non-evaluable response will be treated as non-responders, i.e., they will be included in the denominator when calculating the percentage.	Day 1 and 15 of Cycle 1 and Cycle 2, Day 1 of Cycle 3, every 28 Days thereafter assessed maximum up to 2 years
Secondary	Overall survival (OS) in all cohorts	Defined as the interval of time between the date of the first dose of study drug and the date of death due to any cause.	24, 32 and 56 weeks of treatment
Secondary	Overall survival for each cohort	The time from the date of the first dose of study treatment to the date of death due to any cause	Weeks 24, 32, 56, and at end of study, an average of 2 years.