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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04204941
Recruitment Status : Recruiting
First Posted : December 19, 2019
Last Update Posted : January 18, 2020
Sponsor:
Information provided by (Responsible Party):
Epizyme, Inc.

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Advanced Soft Tissue Sarcoma Advanced Epithelioid Sarcoma Drug: Tazemetostat Drug: Placebo Drug: Doxorubicin HCl Phase 3

Expanded Access : Epizyme, Inc. has indicated that access to an investigational treatment associated with this study is available outside the clinical trial.  

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 154 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
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
Actual Study Start Date : December 19, 2019
Estimated Primary Completion Date : September 15, 2020
Estimated Study Completion Date : May 1, 2029


Arm Intervention/treatment
Experimental: Tazemetostat + Doxorubicin Arm

Tazemetostat 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.

Drug: Tazemetostat

Tazemetostat tablets will be administered orally at the phase 1b or RP3D dose given twice daily. Doses must be administered at least 8 hours apart. An adequate supply will be provided with instructions on home administration.

Tazemetostat/placebo will be administered twice daily..

Other Name: EPZ-6438

Drug: Doxorubicin HCl
75mg/m2 intravenous injection cycles 1 to 6

Experimental: Placebo + Doxorubicin Arm

Placebo 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.

Drug: Placebo

Tazemetostat/placebo tablets will be administered orally at the phase 1b or RP3D dose given twice daily. Doses must be administered at least 8 hours apart. An adequate supply will be provided with instructions on home administration.

Tazemetostat/placebo will be administered twice daily.


Drug: Doxorubicin HCl
75mg/m2 intravenous injection cycles 1 to 6




Primary Outcome Measures :
  1. Incidence of Treatment-Emergent Adverse Events following administration of Tazemostat in Combination with Doxorubicin [ Time Frame: 1 Cycle/21 days ]
    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.

  2. Progression free survival (PFS) [ Time Frame: up to 5 years ]
    Phase 3 Evaluate and compare the PFS by independent review committee in subjects with advanced ES treated with tazemetostat + doxorubicin versus placebo + doxorubicin


Secondary Outcome Measures :
  1. Peak Plasma Concentration (AUC0-24) [ Time Frame: days -1,1, 21 in cycle 1 and day 1 in cycle 2. ]
    Phase 1b: Assess the AUC0-24, of tazemetostat when administered in combination with doxorubicin in subjects with STS

  2. Peak Plasma Concentration (AUC0-last) [ Time Frame: days -1,1, 21 in cycle 1 and day 1 in cycle 2. ]
    Phase 1b: Assess the AUC0-last, of tazemetostat when administered in combination with doxorubicin in subjects with STS

  3. Peak Plasma Concentration (Cmax) [ Time Frame: up to 5 years ]
    Phase 1b: Assess the Cmax of tazemetostat when administered in combination with doxorubicin in subjects with STS

  4. Overall survival [ Time Frame: up to 5 years ]
    Phase 3: Evaluate and compare the OS of tazemetostat + doxorubicin versus placebo + doxorubicin in subjects with advanced ES

  5. Disease Control Rate (DCR) [ Time Frame: up to 5 years ]
    Phase 3: Evaluate and compare the DCR in subjects with advanced ES treated with tazemetostat + doxorubicin or placebo + doxorubicin

  6. Overall Response Rate (ORR) [ Time Frame: up to 5 years ]
    Phase 3: Evaluate and compare the ORR of tazemetostat + doxorubicin versus placebo + doxorubicin in subjects with advanced ES

  7. Duration of Response (DOR) [ Time Frame: up to 5 years ]
    Phase 3: Evaluate and compare the DOR in subjects with advanced ES treated with tazemetostat + doxorubicin or placebo + doxorubicin

  8. European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC-QLQ-C30) [ Time Frame: up to 5 years ]
    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.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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).

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04204941


Contacts
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Contact: Study Director, MD 855-500-1011 clinicaltrials@epizyme.com

Locations
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United States, California
Sarcoma Oncology Research Center Recruiting
Santa Monica, California, United States, 90403
Contact: Victoria Chua-Alcala         
United States, Colorado
Sarah Cannon Research Institute at HealthONE Recruiting
Denver, Colorado, United States, 80218
Contact: Shiraj Sen, MD         
United States, Tennessee
Sarah Cannon and HCA Research Institute Recruiting
Nashville, Tennessee, United States, 37203
Contact: Meredith Ann McKean, MD         
Sponsors and Collaborators
Epizyme, Inc.
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Responsible Party: Epizyme, Inc.
ClinicalTrials.gov Identifier: NCT04204941    
Other Study ID Numbers: EZH-301
First Posted: December 19, 2019    Key Record Dates
Last Update Posted: January 18, 2020
Last Verified: January 2020

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Sarcoma
Neoplasms, Connective and Soft Tissue
Neoplasms by Histologic Type
Neoplasms
Doxorubicin
Liposomal doxorubicin
Antibiotics, Antineoplastic
Antineoplastic Agents
Topoisomerase II Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action