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

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

Sponsors

Lead Sponsor: Epizyme, Inc.

Source Epizyme, Inc.
Brief 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 (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.

Overall Status Recruiting
Start Date December 22, 2015
Completion Date May 2023
Primary Completion Date May 2023
Phase Phase 2
Study Type Interventional
Primary Outcome
Measure Time Frame
Number of subjects with objective response using disease appropriate standardized response criteria 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) 16 weeks of treatment
Assess the effects of tazemetostat on tumor immune priming for Cohort 6 Through study completion, an average of 2 years
Assess the safety and tolerability of tazemetostat 1600 mg QD for Cohort 8 Through study completion, an average of 2 years
Secondary Outcome
Measure Time Frame
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 Assess every 8 weeks for duration of study participation which is estimated to be 24 months
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 32 weeks of treatment
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 Assessed every 8 weeks for duration of study participation which is estimated to be 24 months
PFS for each cohort 24, 32 and 56 weeks of treatment
OS for each cohort 24, 32 and 56 weeks of treatment
Incidence of treatment-emergent adverse events as a measure of safety and tolerability Adverse events assessed from first dose through 30 days post last dose
Pharmacokinetics profile of tazemetotstat and its metabolite (plasma): Cmax Days 1 and 15
Pharmacokinetics profile of tazemetotstat and its metabolite (plasma): Tmax Days 1 and 15
Pharmacokinetics profile of tazemetotstat and its metabolite (plasma): AUC(0-t) Days 1 and 15
Pharmacokinetics profile of tazemetotstat and its metabolite (plasma): AUC(0-12) Days 1 and 15
Pharmacokinetics profile of tazemetotstat and its metabolite (plasma): t1/2 Days 1 and 15
Pharmacokinetics profile of tazemetotstat and its metabolite (plasma): CL/F Days 1, 15, 29, 43, and 57
Pharmacokinetics profile of tazemetotstat and its metabolite (plasma): Vd/F Days 1, 15, 29, 43, and 57
Pharmacokinetics profile of tazemetotstat and its metabolite (plasma): Ka Days 1, 15, 29, 43, and 57
Pharmacokinetics profile of tazemetotstat and its metabolite (plasma): Ctrough Days 29, 43 and 57
Investigate the pharmacodynamics (PD) effects of tazemetostat in tumor tissue At week 8
Duration of response in subjects with epithelioid sarcoma in Cohort 8 at 1600 mg QD. Assess every 8 weeks for duration of study participation which is estimated to be 24 months
Disease control rate (DCR) in subjects with epithelioid sarcoma (Cohort 8) following oral administration of tazemetostat 1600 mg QD 32 weeks of treatment
Overall response rate ORR for subjects with epithelioid sarcoma (Cohort 8) following oral administration of tazemetostat 1600 mg QD Assessed every 8 weeks for duration of study participation which is estimated to be 24 months
Enrollment 250
Condition
Intervention

Intervention Type: Drug

Intervention Name: Tazemetostat

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

Arm Group Label: Open-label Tazemetostat

Eligibility

Criteria:

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 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.

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 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

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 of IHC and/or cytogenetics/FISH and/or DNA mutation analysis (required for study entry but enrollment based on local results)

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 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.

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 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

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 (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

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. Subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging 4 weeks prior to the first dose of study drug and any neurologic symptoms have stabilized), have no evidence of new or enlarging brain metastases, and are on stable or tapering doses of steroids for at least 7 days prior to first dose of study drug. NOTE: Subjects with asymptomatic brain metastases found on screening MRI may be entered into the study without prior radiation therapy to the brain if they do not require immediate surgical or radiation therapy in the opinion of the treating investigator and in the opinion of a radiation therapy or neurosurgical consultant.

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 Note: Minor surgery (e.g., minor biopsy of extracranial site central venous catheter placement, shunt re-vision) is permitted 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.

NOTE: Bone marrow aspirate/biopsy will be conducted following abnormal peripheral blood smear morphology assessment conducted by central laboratory. Cytogenetic testing and DNA sequencing will be conducted following an abnormal result of bone marrow aspirate/biopsy.

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

8. Is unwilling to exclude grapefruit juice, Seville oranges and grapefruit from the diet and all foods that contain those fruits from time of enrollment to while on study

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

- Note - Subjects with a history of hepatitis B or C with normal ALT and undetectable HBV DNA or HCV RNA are eligible for this study

14. Has had a symptomatic venous thrombosis within 2 weeks prior to study enrollment - NOTE: Subjects with a history of a deep vein thrombosis >2 weeks prior to study enrollment who are on anticoagulation therapy with low molecular weight heparin are eligible for this study

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.

Gender: All

Minimum Age: 18 Years

Maximum Age: N/A

Healthy Volunteers: No

Overall Contact

Last Name: Shefali Agarwal, MD

Phone: 855-500-1011

Email: [email protected]

Location
Facility: Status: Contact: Investigator:
University of California San Francisco | San Francisco, California, 94115, United States Recruiting Anish Pal [email protected] Thierry Jahan, MD Principal Investigator
University of Colorado Denver | Aurora, Colorado, 80045, United States Recruiting Siobhan Collins [email protected] Victor Villalobos, MD Principal Investigator
Mayo Clinic - Jacksonville | Jacksonville, Florida, 32224, United States Recruiting Steven Attia 904-953-7292 [email protected] Steven Attia, MD Principal Investigator
Northwestern Memorial Hospital | Chicago, Illinois, 60611, United States Recruiting Rasima Cehic [email protected] Mark Agulnik, MD Principal Investigator
Massachusetts General Hospital - Cancer Center | Boston, Massachusetts, 02114, United States Recruiting Greg Cote, MD Principal Investigator
Dana Farber Cancer Institute | Boston, Massachusetts, 02215, United States Recruiting Melissa Hohos, RN [email protected] George Demetri, MD Principal Investigator
University of Michigan | Ann Arbor, Michigan, 48109, United States Recruiting Paige Crawford [email protected] Rashmi Chugh, MD Principal Investigator
Washington University | Saint Louis, Missouri, 63130, United States Recruiting Michele Landeau [email protected] B Van Tine, MD Principal Investigator
Memorial Sloan Kettering Cancer Center | New York, New York, 10065, United States Recruiting Sarah Lundell [email protected] Mrinal Gounder, MD Principal Investigator
Cincinnati Children's Hospital Medical Center | Cincinnati, Ohio, 45229, United States Recruiting Lori Backus [email protected] Joseph Pressey, MD Principal Investigator
Oregon Health Sciences University | Portland, Oregon, 97239, United States Recruiting Laura Carter [email protected] Lara Davis, MD Principal Investigator
MD Anderson Cancer Center | Houston, Texas, 77030, United States Recruiting Cherie A. Perez [email protected] Nizar Tannir, MD Principal Investigator
Seattle Children's Hospital | Seattle, Washington, 98105, United States Completed
Fred Hutchinson Cancer Research Center | Seattle, Washington, 98109, United States Recruiting Taylor Hain [email protected] Elizabeth Loggers, MD Principal Investigator
Chris O'Brien Lifehouse | Camperdown, New South Wales, 2050, Australia Recruiting Jacquie Harvey [email protected] Peter Grimison, MD Principal Investigator
Metro South Hospital and Health Service via Princess Alexandra Hospital | Woolloongabba, QLD 4102, Australia Recruiting Jennifer Suffolk [email protected] Warren Joubert, MD Principal Investigator
Institut Jules Bordet Medical Oncology Clinic | Brussels, 1000, Belgium Recruiting Nathalie De Naeijer [email protected] Thierry Gil, MD Principal Investigator
University Hospital Leuven | Leuven, 3000, Belgium Recruiting An De Guchtenaere Patrick Schoffski, MD Principal Investigator
Alberta Health Services | Edmonton, Alberta, T6G 1Z2, Canada Completed
Princess Margaret Hospital | Toronto, Ontario, M5G 1X8, Canada Recruiting Ragitha Ellenchery [email protected] Abha Gupta, MD Principal Investigator
McGill University Health Centre - Royal Victoria Hospital | Montreal, Quebec, H4A 3J1, Canada Completed
Institut Bergonie | Bordeaux, 33076, France Recruiting Marjorie Pouyles [email protected] Antoine Italiano, MD Principal Investigator
Centre Leon Berard | Lyon, 69008, France Recruiting William Sebag [email protected] Jean-Yves Blay, MD Principal Investigator
Hospital Pitie Salpetriere | Paris Cedex 13, 75651, France Completed
Institut Curie | Paris, 75248, France Recruiting Soraya Dib [email protected] Valerie Laurence, MD Principal Investigator
Institut Gustave Roussy | Villejuif, 94800, France Recruiting Camille Ruiz [email protected] Olivier Mir, MD Principal Investigator
Children's Hospital Augsburg Klinikum | Augsburg, 86156, Germany Completed
Sarcoma Center HELIOS Klinikum Berlin | Berlin, 13125, Germany Recruiting Marie Wicklein [email protected] Peter Reichardt, MD Principal Investigator
Instituto Nazionale Tumori - National Cancer Institute Via Giacomo Venezian | Milano, 20133, Italy Recruiting Daniela Morrone [email protected] Silvia Stacchiotti, MD Principal Investigator
National Taiwan University Hospital | Taipei City, 10002, Taiwan Recruiting Wei-Wu Chen, MD Principal Investigator
London Sarcoma Service Department of Oncology | London, NW1 2PG, United Kingdom Recruiting Michelle Hung [email protected] Palma Dileo, MD Principal Investigator
Royal Marsden Foundation Trust | London, SW3 6JJ, United Kingdom Recruiting Galina Petrikova [email protected] Robin Jones, MD Principal Investigator
Location Countries

Australia

Belgium

Canada

France

Germany

Italy

Taiwan

United Kingdom

United States

Verification Date

March 2019

Responsible Party

Type: Sponsor

Has Expanded Access No
Condition Browse
Number Of Arms 1
Arm Group

Label: Open-label Tazemetostat

Type: Experimental

Description: 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

Study Design Info

Allocation: N/A

Intervention Model: Single Group Assignment

Primary Purpose: Treatment

Masking: None (Open Label)

Source: ClinicalTrials.gov