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

Trial Status: Active

This is a multicenter, double-blind, placebo-controlled, randomized phase 3 study with phase 1b portion designed to establish a recommended phase 3 dose (RP3D) and to evaluate the efficacy, PK, and safety of tazemetostat + doxorubicin vs placebo + doxorubicin in subjects with advanced epithelioid sarcoma (ES). This study will be conducted in 2 parts.

Inclusion Criteria

  • Have voluntarily agreed to provide written informed consent and demonstrated willingness and ability to comply with all aspects of the protocol.
  • Are aged 18 years at the time of providing voluntary written informed consent. informed consent. 18 years at the time of providing voluntary written informed consent.
  • Life expectancy 3 months before enrollment. 3 months before enrollment.
  • Phase 1b: Have histologically confirmed STS.
  • Phase 3: Have histologically confirmed epithelioid sarcoma, with 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
  • Have measurable disease as defined by the Response Evaluation Criteria in Solid
  • ECOG performance status of 0, 1, or 2.
  • Females must not be lactating or pregnant at Screening or Baseline
  • Females of childbearing potential must not have had unprotected sexual intercourse within 30 days prior to study entry and must agree to use a highly effective method of contraception, from the last menstrual period prior to randomization, during Treatment cycles, and for 6 months after the final dose of study treatment, and have a male partner who uses a condom.
  • Male subjects must have had either a successful vasectomy OR they and their female partner must meet the criteria above (ie, not of childbearing potential OR practicing highly effective contraception and use a condom throughout the study period and for 6 months after doxorubicin discontinuation or 30 days after oral study treatment [tazemetostat or placebo] discontinuation, whichever is later).
  • Subjects with diagnosed human immunodeficiency virus (HIV) are eligible to participate in the study if they meet the following criteria:
  • No history of AIDS-defining opportunistic infections or have not had an opportunistic infection within the past 12 months prior to enrollment.
  • No history of AIDS-defining cancers (eg Kaposi's sarcoma, aggressive B-cell lymphoma, and invasive cervical cancer).
  • Subjects may take prophylactic antimicrobials, however subjects that are taking specific antimicrobial drugs where there may be drug-drug interaction or overlapping toxicities should be excluded from study participation.
  • Subjects should be on established anti-retroviral therapy for at least 4 weeks and have an HIV viral load of < 400 copies/mL prior to enrollment.

Exclusion Criteria

  • Prior exposure to tazemetostat or other inhibitor(s) of enhancer of zeste homologue-2 (EZH2).
  • Prior systemic anticancer therapy.
  • Subjects must not have any of the contraindications noted in the local doxorubicin label (ie, Summary of Product Characteristics [SmPc] or United States Prescribing Information [USPI]).
  • 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. 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 treatment 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 treatment. NOTE: Subjects with asymptomatic brain metastases found on screening magnetic resonance imaging (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.
  • Subjects 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 while on study.
  • Major surgery within 4 weeks before the first dose of study treatment. Subjects 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.
  • Has either a shortening fraction of <27% or an ejection fraction of ≤50% by either echocardiogram (ECHO) or multi-gated acquisition (MUGA) scan, and has heart failure greater than New York Heart Association (NYHA) Class II.
  • Has cardiovascular impairment: history of congestive heart failure greater than NYHA Class II, uncontrolled arterial hypertension (ie, systolic BP >150 mm Hg and/or diastolic BP >110 mm Hg), unstable angina, myocardial infarction, or stroke within 6 months prior to the planned first dose of tazemetostat; or ventricular cardiac arrhythmia requiring medical treatment.
  • Prolongation of corrected QT interval using Fridericia's formula (QTcF) to > 480 msec.
  • Venous thrombosis or pulmonary embolism within the last 1 month before starting study treatment.
  • Have an active infection requiring systemic therapy.
  • Are immunocompromised (ie, has a congenital immunodeficiency), including subjects with known history of infection with human immunodeficiency virus (HIV).
  • Have known hypersensitivity to any component of tazemetostat or doxorubicin.
  • 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), human immunodeficiency virus, OR human T-cell lymphotropic virus 1.
  • Any other major illness that, in the Investigator's judgment, will substantially increase the risk associated with the subject's participation in this study OR interfere with their ability to receive study treatment or complete the study.
  • Female subjects who are pregnant or breastfeeding.
  • Subjects who have undergone a solid organ transplant.
  • Subjects with malignancies other than STS (phase 1b) or ES (Phase 3 only).

Colorado

Aurora
University of Colorado Hospital
Status: ACTIVE

New York

New York
NYP / Columbia University Medical Center / Herbert Irving Comprehensive Cancer Center
Status: ACTIVE

Ohio

Columbus
Ohio State University Comprehensive Cancer Center
Status: APPROVED

Washington

Seattle
Fred Hutch / University of Washington Cancer Consortium
Status: APPROVED

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.

Trial Phase Phase III

Trial Type Treatment

Lead Organization
Epizyme, Inc.

  • Primary ID EZH-301
  • Secondary IDs NCI-2020-00071
  • Clinicaltrials.gov ID NCT04204941