Clinical Trials /

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

NCT04204941

Description:

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.

Related Conditions:
  • Epithelioid Sarcoma
  • Soft Tissue Sarcoma
Recruiting Status:

Recruiting

Phase:

Phase 3

Trial Eligibility

Document

Title

  • Brief Title: Tazemetostat in Combination With Doxorubicin as Frontline Therapy for Advanced Epithelioid Sarcoma
  • 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

Clinical Trial IDs

  • ORG STUDY ID: EZH-301
  • NCT ID: NCT04204941

Conditions

  • Advanced Soft Tissue Sarcoma
  • Advanced Epithelioid Sarcoma

Interventions

DrugSynonymsArms
TazemetostatEPZ-6438Tazemetostat + Doxorubicin Arm
PlaceboPlacebo + Doxorubicin Arm
Doxorubicin HClTazemetostat + Doxorubicin Arm

Purpose

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.

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
      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 Arms

NameTypeDescriptionInterventions
Tazemetostat + Doxorubicin ArmExperimentalTazemetostat 800 mg (or RP3D from the phase 1b) administered orally twice daily in continuous 21-day cycles. Doxorubicin 75 mg/m2 intravenously (IV) on day 1 cycle 1 then on day 1 of cycles 2-6.
  • Tazemetostat
  • Doxorubicin HCl
Placebo + Doxorubicin ArmExperimentalPlacebo administered orally twice daily in continuous 21-day cycles. Doxorubicin 75 mg/m2 IV on day 1 of cycle 1 then day 1 of cycles 2-6.
  • Placebo
  • Doxorubicin HCl

Eligibility Criteria

        Inclusion Criteria

          1. Have voluntarily agreed to provide written informed consent and demonstrated
             willingness and ability to comply with all aspects of the protocol.

          2. 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.

          3. Life expectancy 3 months before enrollment. 3 months before enrollment.

          4. Phase 1b: Have histologically confirmed STS.

          5. 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

          6. Have measurable disease as defined by the Response Evaluation Criteria in Solid

          7. ECOG performance status of 0, 1, or 2.

          8. Females must not be lactating or pregnant at Screening or Baseline

          9. 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.

         10. 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).

         11. Subjects with diagnosed human immunodeficiency virus (HIV) are eligible to participate
             in the study if they meet the following criteria:

               1. No history of AIDS-defining opportunistic infections or have not had an
                  opportunistic infection within the past 12 months prior to enrollment.

               2. No history of AIDS-defining cancers (eg Kaposi's sarcoma, aggressive B-cell
                  lymphoma, and invasive cervical cancer).

               3. 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.

               4. 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:

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

          2. Prior systemic anticancer therapy.

          3. 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]).

          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-cell acute lymphoblastic
             leukemia (T-LBL/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. 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.

          8. Subjects taking medications that are known potent cytochrome P450 (CYP)3A4
             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 while on
             study.

         10. Major surgery within 4 weeks before the first dose of study treatment. Subjects 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. 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.

         13. 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.

         14. Prolongation of corrected QT interval using Fridericia's formula (QTcF) to > 480 msec.

         15. Venous thrombosis or pulmonary embolism within the last 1 month before starting study
             treatment.

         16. Have an active infection requiring systemic therapy.

         17. Are immunocompromised (ie, has a congenital immunodeficiency), including subjects with
             known history of infection with human immunodeficiency virus (HIV).

         18. Have known hypersensitivity to any component of tazemetostat or doxorubicin.

         19. 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.

         20. 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.

         21. Female subjects who are pregnant or breastfeeding.

         22. Subjects who have undergone a solid organ transplant.

         23. Subjects with malignancies other than STS (phase 1b) or ES (Phase 3 only).
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Incidence of Treatment-Emergent Adverse Events following administration of Tazemostat in Combination with Doxorubicin
Time Frame:1 Cycle/21 days
Safety Issue:
Description:Phase 1b: Evaluate the incidence and CTCAE grade of treatment-emergent of Adverse Events of tazemetostat in combination with doxorubicin in subjects with advanced STS.

Secondary Outcome Measures

Measure:Peak Plasma Concentration (AUC0-24)
Time Frame:days -1,1, 21 in cycle 1 and day 1 in cycle 2.
Safety Issue:
Description:Phase 1b: Assess the AUC0-24, of tazemetostat when administered in combination with doxorubicin in subjects with STS
Measure:Peak Plasma Concentration (AUC0-last)
Time Frame:days -1,1, 21 in cycle 1 and day 1 in cycle 2.
Safety Issue:
Description:Phase 1b: Assess the AUC0-last, of tazemetostat when administered in combination with doxorubicin in subjects with STS
Measure:Peak Plasma Concentration (Cmax)
Time Frame:up to 5 years
Safety Issue:
Description:Phase 1b: Assess the Cmax of tazemetostat when administered in combination with doxorubicin in subjects with STS
Measure:Overall survival
Time Frame:up to 5 years
Safety Issue:
Description:Phase 3: Evaluate and compare the OS of tazemetostat + doxorubicin versus placebo + doxorubicin in subjects with advanced ES
Measure:Disease Control Rate (DCR)
Time Frame:up to 5 years
Safety Issue:
Description:Phase 3: Evaluate and compare the DCR in subjects with advanced ES treated with tazemetostat + doxorubicin or placebo + doxorubicin
Measure:Overall Response Rate (ORR)
Time Frame:up to 5 years
Safety Issue:
Description:Phase 3: Evaluate and compare the ORR of tazemetostat + doxorubicin versus placebo + doxorubicin in subjects with advanced ES
Measure:Duration of Response (DOR)
Time Frame:up to 5 years
Safety Issue:
Description:Phase 3: Evaluate and compare the DOR in subjects with advanced ES treated with tazemetostat + doxorubicin or placebo + doxorubicin
Measure:European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC-QLQ-C30)
Time Frame:up to 5 years
Safety Issue:
Description:Phase 3: Assess health-related Quality of Life as measured by European Organization for Research and Treatment of Cancer instrument in subjects with locally advanced metastatic ES treated with tazemetostat + doxorubicin versus placebo + doxorubicin.

Details

Phase:Phase 3
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Epizyme, Inc.

Last Updated

December 19, 2019