Study Description

The open-label phase 1b portion is designed to evaluate the safety of the combination of tazemetostat + doxorubicin, as well as to establish the maximum tolerated dose (MTD) and the RP3D. The phase 3 portion of the clinical trial aims to compare tazemetostat + doxorubicin to the current front-line standard treatment, single-agent doxorubicin + placebo, when used as first-line treatment in locally advanced unresectable or metastatic ES.

Condition or Disease	Intervention/Treatment
Advanced Soft-tissue Sarcoma Advanced Epithelioid Sarcoma	Drug: Tazemetostat Drug: Doxorubicin HCl Drug: Tazemetostat Drug: Placebo Drug: Doxorubicin HCl

Study Design

Study Type	Interventional
Anticipated Enrollment	164 participants
Design Allocation	Randomized
Interventional Model	Parallel Assignment
Masking	Quadruple
Primary Purpose	Treatment
Official Title	A Phase 1b/3 Global, Randomized, Double-blind, Placebo-Controlled Trial of Tazemetostat in Combination With Doxorubicin as Frontline Therapy for Advanced Epithelioid Sarcoma
Study Start Date	December 19, 2019
Anticipated Primary Completion Date	January 28, 2029
Anticipated Study Completion Date	January 1, 2030

Groups and Cohorts

Group/ Cohort	Intervention/ Treatment
Phase 1b: Open-label Tazemetostat and Phase 3: Tazemetostat + Doxorubicin Arm Phase 1b: On cycle 1 day -1, participants will receive a single morning dose of tazemetostat at the assigned dose level. Participants will receive doxorubicin 75 mg/m2 intravenously (IV) on day 1 of each cycle for up to 6 cycles. Tazemetostat will be escalated from a starting dose of 400 mg twice daily PO to 600 mg twice daily PO to 800 mg twice daily. Phase 3: Tazemetostat (800 mg) administered orally twice daily in continuous 21-day cycles during cycles 1-6 and in continuous 28-day cycles during cycle 7 and beyond. Doxorubicin 75 mg/m2 IV on day 1 of cycles 1-6.	Drug: Tazemetostat 400 mg, 600 to 800 mg of Tazemetostat will be administered twice daily. Drug: Doxorubicin HCl
Phase 3: Placebo + Doxorubicin Arm Placebo administered orally twice daily in continuous 21-day cycles during cycles 1-6 and in continuous 28-day cycles during cycles 7 and beyond. Doxorubicin 75 mg/m2 IV on day 1 of cycles 1-6.	Drug: Placebo Drug: Doxorubicin HCl

Outcome Measures

Primary Outcome Measures

1. Dose Limiting Toxicities (DLTs) [1 Cycle/21 days]
   Determined by Adverse Events (AEs) and clinical laboratory tests.
2. Progression free survival (PFS) [Through study completion, an average of two years.]
   Phase 3: Assessed by Independent Review Committee.

Secondary Outcome Measures

1. Phase 1b: Pharmacokinetics (PK) of tazemetostat when administered in combination with doxorubicin in participants with soft tissue sarcoma (STS): Area under the Plasma Concentration Time Curve from time 0 to 24 hours (AUC0-24) [Cycles 1, 2, 3, and 5 of the first continuous 21-day cycles of combination therapy]
2. Phase 1b: PK of tazemetostat when administered in combination with doxorubicin in participants with STS: Area under the Plasma Concentration Time Curve From time 0 to the last observable concentration (AUC0- last) [Cycles 1, 2, 3, and 5 of the first continuous 21-day cycles of combination therapy]
3. Phase 1b: PK of tazemetostat when administered in combination with doxorubicin in Pparticipants with STS: The maximum observed concentration (Cmax). [Cycles 1, 2, 3, and 5 of the first continuous 21-day cycles of combination therapy]
4. Phase 3: Overall Survival (OS) [Through study completion, an average of two years.]
5. Phase 3: Incidence of Adverse Events (AEs) [Through study completion, an average of two years.]
   All AEs, including clinically significant laboratory parameters will be graded by the investigator according to the Common Terminology Criteria for Adverse Events (CTCAE)
6. Phase 3: PFS [Through study completion, an average of two years.]
   Assessed by the investigator
7. Disease control rate (DCR) [Through study completion, an average of two years]
   Defined as the number of participants who achieve response complete response (CR) + partial response (PR) or who have stable disease (SD)
8. Objective response rate (ORR) [Through study completion, an average of two years]
   ORR is defined as the proportion of participants achieving complete or partial response. Determined based on the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1
9. Duration of treatment (DOR) [Through study completion, an average of two years]
   Defined as the time from first documented evidence of CR or PR to the time of first documented disease progression or death, whichever occurs first
10. Change from baseline in European Organisation for Research and Treatment of Cancer Core Quality of Life Questionnaire (EORTC QLQC-30) [Through study completion, an average of two years]
    The EORTC QLQC-30 physical function, role function, and global health status domains will be assessed
11. PFS2 [Through study completion, an average of two years]
    Defined as time from randomization to objective tumor progression on next-line treatment or death, whichever occurs first
12. Time to first subsequent anti-cancer therapy ((TFST [Through study completion, an average of two years]
    Defined as the time from randomization to the time to first subsequent therapy
13. Population PK parameters of tazemetostat when administered in combination with doxorubicin: Oral clearance (CL/F) [Cycles 1, 2, 3, and 5 of the first continuous 21-day cycles of combination therapy]
    CL/F is defined as the apparent oral clearance following administration of tazemetostat when administered in combination with doxorubicin
14. Population PK parameters of tazemetostat when administered in combination with doxorubicin: oral volume of distribution (Vss). [Cycles 1, 2, 3, and 5 of the first continuous 21-day cycles of combination therapy]
15. Population PK parameters of tazemetostat when administered in combination with doxorubicin: Area Under the Curve at steady state (AUCss) [Cycles 1, 2, 3, and 5 of the first continuous 21-day cycles of combination therapy]
16. Population PK parameters of tazemetostat when administered in combination with doxorubicin: trough concentration (Ctrough) [Cycles 1, 2, 3, and 5 of the first continuous 21-day cycles of combination therapy]
17. Population PK parameters of tazemetostat when administered in combination with doxorubicin: Cmax [Cycles 1, 2, 3, and 5 of the first continuous 21-day cycles of combination therapy]

Eligibility Criteria

Ages Eligible for Study	18 Years and Older (Adult, Older Adult)
Sexes Eligible for Study	All
Accepts Healthy Volunteers	No
Inclusion Criteria	articipants must meet ALL the following inclusion criteria to be eligible to enroll in this study: Have voluntarily agreed to provide written informed consent and demonstrated willingness and ability to comply with all aspects of the protocol. Study related activities will not start until written consent is obtained. Life expectancy ≥ 3 months before enrollment Phase 1b: 18-65 years old histologically confirmed Soft Tissue Sarcoma Phase 3: ≥18 years old with unresectable locally advanced or metastatic Epithelioid Sarcoma and tumor tissue available Have measurable disease ECOG performance status of 0, 1, or 2 Have adequate hematologic (bone marrow [BM] and coagulation factors), renal and hepatic function as required per protocol Females must not be lactating or pregnant at Screening or Baseline Females must not be pregnant or breast feeding and agree to use highly effective contraception during the clinical trial and for 6 months following the final dose of study Male participants of child-bearing potential must have had either a successful vasectomy or practice highly effective contraception Participants diagnosed with human immunodeficiency virus (HIV) are eligible to participate in the study if their infection is well controlled on anti-retroviral therapy.
Exclusion Criteria	articipants meeting ANY of the following exclusion criteria are NOT eligible to enroll in this study: Prior exposure to tazemetostat or other inhibitor(s) of enhancer of zeste homologue-2 (EZH2). Prior systemic anticancer therapy. Contraindications noted in the doxorubicin label Have any prior history of myeloid malignancies, including myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML). Have prior history of T-cell lymphoblastic lymphoma/T-cell acute lymphoblastic leukemia (T- LBL/T-ALL). Have 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 study treatment. Have known active central nervous system (CNS) or any leptomeningeal metastasis of primary extracranial tumor. Participants taking medications that are known potent cytochrome P450 (CYP)3A4 inducers/inhibitors (including St. John's Wort) Are unwilling to exclude Seville oranges, grapefruit juice, AND grapefruit from the diet and all foods that contain those fruits from time of enrollment to through the duration of study participation. Major surgery within 4 weeks before the first dose of study treatment. Participants must have recovered from surgery prior to enrollment to this study. Are unable to take oral medication OR have malabsorption syndrome or any other uncontrolled gastrointestinal condition (eg, nausea, diarrhea, vomiting) that might impair the bioavailability of study treatment. Have an active infection requiring systemic therapy. Are immunocompromised (ie, has a congenital immunodeficiency). Have known hypersensitivity to any component of tazemetostat or doxorubicin. Cardiovascular impairment as stated in the protocol Have a known active infection with hepatitis B virus (HBV, as measured by positive hepatitis B surface antigen), hepatitis C virus (HCV, as measured by positive hepatitis C antibody). Any other major illness that, in the Investigator's judgment, will substantially increase the risk associated with the participant's participation in this study OR interfere with their ability to receive study treatment or complete the study. Female participants who are pregnant or breastfeeding. Participants who have undergone a solid organ transplant. Participants with malignancies other than STS (phase 1b) or ES (Phase 3 only). Participants housed in an institution by order of the authorities or courts.

Contacts and Locations

Sponsors and Collaborators	Epizyme, Inc.
Locations	City of Hope Comprehensive Cancer Center | Duarte, California, United States, 91010 Sarcoma Oncology Research Center | Santa Monica, California, United States, 90403 University of Colorado Hospital - Anschutz Cancer Pavilion | Aurora, Colorado, United States, 80045 Sarah Cannon Research Institute at HealthONE | Denver, Colorado, United States, 80218 Mayo Clinic-Jacksonville | Jacksonville, Florida, United States, 32224 Massachusetts General Hospital | Boston, Massachusetts, United States, 02214 Dana Farber Cancer Insititute | Boston, Massachusetts, United States, 02215 Dana Farber Cancer Institute | Boston, Massachusetts, United States, 02215 University of Michigan Medical Center | Ann Arbor, Michigan, United States, 48109 Washington University | Saint Louis, Missouri, United States, 63110 Columbia University Irving Medical Center | New York, New York, United States, 10032 Duke University Medical Center | Durham, North Carolina, United States, 27710 The Ohio State University Comprehensive Cancer Center | Columbus, Ohio, United States, 43210 Oregon Health and Science University | Portland, Oregon, United States, 97239 Thomas Jefferson University Hospital | Philadelphia, Pennsylvania, United States, 19107 University of Pittsburgh Medical Center - Hillman Cancer Center | Pittsburgh, Pennsylvania, United States, 15232 Sarah Cannon and HCA Research Institute | Nashville, Tennessee, United States, 37203 Fred Hutchinson Research Center | Seattle, Washington, United States, 98109 McGill University Faculty of Medicine - Royal Victoria Hospital | Montréal, Quebec, Canada, H4A 3J1 National Taiwan University Hospital | Taipei, Taiwan, 100 Royal Marsden Foundation Trust | London, United Kingdom, SW3 6JJ
Investigators

More Information

Publications

• Gounder M, Schoffski P, Jones RL, Agulnik M, Cote GM, Villalobos VM, Attia S, Chugh R, Chen TW, Jahan T, Loggers ET, Gupta A, Italiano A, Demetri GD, Ratan R, Davis LE, Mir O, Dileo P, Van Tine BA, Pressey JG, Lingaraj T, Rajarethinam A, Sierra L, Agarwal S, Stacchiotti S. Tazemetostat in advanced epithelioid sarcoma with loss of INI1/SMARCB1: an international, open-label, phase 2 basket study. Lancet Oncol. 2020 Nov;21(11):1423-1432. doi: 10.1016/S1470-2045(20)30451-4. Epub 2020 Oct 6.

Additional Relevant MeSH Terms

• Sarcoma
• Neoplasms, Connective and Soft Tissue
• Neoplasms by Histologic Type
• Neoplasms