Tazemetostat in Combination With Doxorubicin as Frontline Therapy for Advanced Epithelioid Sarcoma

A Phase 1b/3 Global, Randomized, Double-blind, Placebo-Controlled Trial of Tazemetostat in Combination With Doxorubicin as Frontline Therapy for Advanced Epithelioid Sarcoma

The participants of this study will have advanced epithelioid sarcoma. Sarcoma is a cancer of the connective tissues, such as nerves, muscles and bones. Epithelioid sarcoma is an ultra-rare sarcoma of the soft-tissue.

Part 1 of this trial will evaluate the safety and the level of the study drug that the study drug combinations 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 for each of the study drug combinations how long participants live without their disease getting worse.

The study drug is called tazemetostat. The study will test tazemetostat in combination with doxorubicin compared to placebo (dummy treatment) in combination with doxorubicin. Doxorubicin is a current front line treatment for epithelioid sarcoma

Study Overview

• Status: Terminated
• Conditions: Advanced Soft-tissue Sarcoma; Advanced Epithelioid Sarcoma
• Intervention / Treatment: Drug: Tazemetostat; Drug: Doxorubicin HCl

Detailed 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 Recommended Phase 3 Dose (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 Epithelioid Sarcoma (ES).

The Phase 3 portion was planned but never initiated due to early termination during Phase 1b. Participants with confirmed Soft-tissue Sarcoma (STS) were enrolled in phases 1b.

• Study Type: Interventional
• Enrollment (Actual): 25
• Phase: Phase 1

Contacts and Locations

Study Locations

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

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria

Participants must meet ALL the following inclusion criteria to be eligible to enroll in this study:

1. 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.
2. Life expectancy ≥ 3 months before enrollment
3. Phase 1b: 18-65 years old histologically confirmed Soft Tissue Sarcoma
4. Phase 3: ≥18 years old with unresectable locally advanced or metastatic Epithelioid Sarcoma and tumor tissue available
5. Have measurable disease
6. Eastern Cooperative Oncology Group Performance Status (ECOG) performance status of 0, 1, or 2
7. Have adequate hematologic (bone marrow (BM) and coagulation factors), renal and hepatic function as required per protocol
8. Females must not be lactating or pregnant at Screening or Baseline
9. 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
10. Male participants of child-bearing potential must have had either a successful vasectomy or practice highly effective contraception
11. 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

Participants meeting any of the following exclusion criteria are NOT eligible to enroll in this study:

1. Prior exposure to tazemetostat or other inhibitor(s) of enhancer of zeste homologue-2 (EZH2).
2. Prior systemic anticancer therapy.
3. Contraindications noted in the doxorubicin label
4. Have any prior history of myeloid malignancies, including myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML).
5. Have prior history of T-cell lymphoblastic lymphoma (T- LBL/)/T-cell acute lymphoblastic leukemia (T-ALL).
6. 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.
7. Have known active central nervous system (CNS) or any leptomeningeal metastasis of primary extracranial tumor.
8. Participants taking medications that are known potent cytochrome P450 3A4 (CYP3A4) inducers/inhibitors (including St. John's Wort)
9. 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.
10. Major surgery within 4 weeks before the first dose of study treatment. Participants must have recovered from surgery prior to enrollment to this study.
11. 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.
12. Have an active infection requiring systemic therapy.
13. Are immunocompromised (ie, has a congenital immunodeficiency).
14. Have known hypersensitivity to any component of tazemetostat or doxorubicin.
15. Cardiovascular impairment as stated in the protocol
16. 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).
17. 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.
18. Female participants who are pregnant or breastfeeding.
19. Participants who have undergone a solid organ transplant.
20. Participants with malignancies other than STS (phase 1b) or ES (Phase 3 only).
21. Participants housed in an institution by order of the authorities or courts.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Phase 1b: Open-label: Tazemetostat + Doxorubicin; 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.

Drug: Tazemetostat; 400 mg, 600 to 800 mg of Tazemetostat will be administered twice daily.; Other Names: EPZ-6438; IPN60200; Drug: Doxorubicin HCl; 75mg/m2 intravenous injection day 1 of each cycle for up to 6 cycles

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Dose Limiting Toxicities (DLTs)	Determined by Adverse Events (AEs) and clinical laboratory tests.	1 Cycle/21 days
Progression free survival (PFS)	Phase 3: Assessed by Independent Review Committee. Phase 3 was planned but never initiated; therefore, no data were collected for these endpoints	Through study completion, an average of two years.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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
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
Objective response rate (ORR)	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	Through study completion, an average of two years
Duration of treatment (DOR)	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	Through study completion, an average of two years
Population PK parameters of tazemetostat when administered in combination with doxorubicin: Oral clearance (CL/F)	CL/F is defined as the apparent oral clearance following administration of tazemetostat when administered in combination with doxorubicin	Cycles 1, 2, 3, and 5 of the first continuous 21-day cycles of combination therapy
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
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
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
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
Phase 1b: PK of tazemetostat when administered in combination with doxorubicin in Participants with STS: The maximum observed concentration (Cmax).		Cycles 1, 2, 3, and 5 of the first continuous 21-day cycles of combination therapy
Phase 3: Overall Survival (OS)	Phase 3 was planned but never initiated; therefore, no data were collected for these endpoints	Through study completion, an average of two years.
Phase 3: Incidence of Adverse Events (AEs)	All AEs, including clinically significant laboratory parameters will be graded by the investigator according to the Common Terminology Criteria for Adverse Events (CTCAE). Phase 3 was planned but never initiated; therefore, no data were collected for these endpoints	Through study completion, an average of two years.
Phase 3: PFS	Assessed by the investigator. Phase 3 was planned but never initiated; therefore, no data were collected for these endpoints	Through study completion, an average of two years.
Disease control rate (DCR)	Defined as the number of participants who achieve response complete response (CR) + partial response (PR) or who have stable disease (SD). Phase 3 was planned but never initiated; therefore, no data were collected for these endpoints.	Through study completion, an average of two years
Change from baseline in European Organisation for Research and Treatment of Cancer (EORTC) Core Quality of Life Questionnaire (QLQC) (EORTC QLQC-30)	The EORTC QLQC-30 physical function, role function, and global health status domains will be assessed	Through study completion, an average of two years
Progression-Free Survival on Next Line of Therapy (PFS2)	Defined as time from randomization to objective tumor progression on next-line treatment or death, whichever occurs first	Through study completion, an average of two years
Time to first subsequent anti-cancer therapy ((TFST)	Defined as the time from randomization to the time to first subsequent therapy	Through study completion, an average of two years

Collaborators and Investigators

• Sponsor: Epizyme, Inc.
• Investigators: Study Director: Ipsen Medical Director, Ipsen

Publications and helpful links

General 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.

Study record dates

Study Major Dates

• Study Start (Actual): December 19, 2019
• Primary Completion (Actual): June 14, 2024
• Study Completion (Actual): June 14, 2024

Study Registration Dates

• First Submitted: December 11, 2019
• First Submitted That Met QC Criteria: December 17, 2019
• First Posted (Actual): December 19, 2019

Study Record Updates

• Last Update Posted (Estimated): January 7, 2026
• Last Update Submitted That Met QC Criteria: January 5, 2026
• Last Verified: January 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms; Neoplasms by Histologic Type; Neoplasms, Connective and Soft Tissue; Sarcoma; Organic Chemicals; Hydrocarbons; Hydrocarbons, Cyclic; Carbohydrates; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Polycyclic Compounds; Glycosides; Anthracyclines; Naphthacenes; Aminoglycosides; Daunorubicin; Doxorubicin; tazemetostat
• Other Study ID Numbers: EZH-301; 2019-003648-55 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD Plan Description

Qualified researchers may request access to patient level data and related study documents including the clinical study report, study protocol with any amendments, annotated case report form, statistical analysis plan, and dataset specifications.

Patient level data will be anonymized and study documents will be redacted to protect the privacy of study participants.

• IPD Sharing Time Frame: Where applicable, data from eligible studies are available 6 months after the studied medicine and indication have been approved in the United States (US) and/or Europe (EU).
• IPD Sharing Access Criteria: Further details on Ipsen's sharing criteria and process for sharing are available here (https://www.ipsen.com/science/clinical-trials/clinical-data-transparency/).

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No