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

Sponsors

Lead Sponsor: Epizyme, Inc.

Source 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.

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.

Overall Status Recruiting
Start Date December 19, 2019
Completion Date May 1, 2029
Primary Completion Date September 15, 2020
Phase Phase 3
Study Type Interventional
Primary Outcome
Measure Time Frame
Incidence of Treatment-Emergent Adverse Events following administration of Tazemostat in Combination with Doxorubicin 1 Cycle/21 days
Progression free survival (PFS) up to 5 years
Secondary Outcome
Measure Time Frame
Peak Plasma Concentration (AUC0-24) days -1,1, 21 in cycle 1 and day 1 in cycle 2.
Peak Plasma Concentration (AUC0-last) days -1,1, 21 in cycle 1 and day 1 in cycle 2.
Peak Plasma Concentration (Cmax) up to 5 years
Overall survival up to 5 years
Disease Control Rate (DCR) up to 5 years
Overall Response Rate (ORR) up to 5 years
Duration of Response (DOR) up to 5 years
European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC-QLQ-C30) up to 5 years
Enrollment 154
Condition
Intervention

Intervention Type: Drug

Intervention Name: Tazemetostat

Description: 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..

Arm Group Label: Tazemetostat + Doxorubicin Arm

Other Name: EPZ-6438

Intervention Type: Drug

Intervention Name: Placebo

Description: 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.

Arm Group Label: Placebo + Doxorubicin Arm

Intervention Type: Drug

Intervention Name: Doxorubicin HCl

Description: 75mg/m2 intravenous injection cycles 1 to 6

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).

Gender: All

Minimum Age: 18 Years

Maximum Age: N/A

Healthy Volunteers: No

Overall Contact

Last Name: Study Director, MD

Phone: 855-500-1011

Email: [email protected]

Location
Facility: Status: Contact:
Sarcoma Oncology Research Center | Santa Monica, California, 90403, United States Recruiting Victoria Chua-Alcala
Sarah Cannon Research Institute at HealthONE | Denver, Colorado, 80218, United States Recruiting Shiraj Sen, MD
Sarah Cannon and HCA Research Institute | Nashville, Tennessee, 37203, United States Recruiting Meredith Ann McKean, MD
Location Countries

United States

Verification Date

January 2020

Responsible Party

Type: Sponsor

Has Expanded Access Yes
Condition Browse
Number Of Arms 2
Arm Group

Label: Tazemetostat + Doxorubicin Arm

Type: Experimental

Description: 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.

Label: Placebo + Doxorubicin Arm

Type: Experimental

Description: 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.

Study Design Info

Allocation: Randomized

Intervention Model: Parallel Assignment

Primary Purpose: Treatment

Masking: None (Open Label)

Source: ClinicalTrials.gov