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

Epizyme

Status and phase: Enrolling; Phase 3

Conditions: Advanced Epithelioid Sarcoma; Advanced Soft-tissue Sarcoma

Treatments: Drug: Doxorubicin HCl; Drug: Tazemetostat; Drug: Placebo

Study type: Interventional

Funder types: Industry

Identifiers

NCT04204941

2019-003648-55 (EudraCT Number)

EZH-301

Details and patient eligibility

About

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

Full 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.

Enrollment: 164 estimated patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

Inclusion and exclusion criteria

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. 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-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.
8. Participants 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 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.

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Quadruple Blind

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164 participants in 2 patient groups, including a placebo group

Phase 1b: Open-label Tazemetostat and Phase 3: Tazemetostat + Doxorubicin Arm

Experimental group

Description:

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. Phase 3: Tazemetostat (800 mg) administered orally twice daily in continuous 21-day cycles during cycles 1-6 and in continuous 28-day cycles during cycle 7 and beyond. Doxorubicin 75 mg/m2 IV on day 1 of cycles 1-6.

Treatment:

Drug: Tazemetostat

Drug: Tazemetostat

Drug: Doxorubicin HCl

Drug: Doxorubicin HCl

Phase 3: Placebo + Doxorubicin Arm

Placebo Comparator group

Description:

Placebo administered orally twice daily in continuous 21-day cycles during cycles 1-6 and in continuous 28-day cycles during cycles 7 and beyond. Doxorubicin 75 mg/m2 IV on day 1 of cycles 1-6.

Treatment:

Drug: Placebo

Drug: Doxorubicin HCl

Drug: Doxorubicin HCl