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

Study Overview
=================
Brief Summary
-----------------
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

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.

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

Conditions
-----------------
Advanced Soft-tissue Sarcoma, Advanced Epithelioid Sarcoma

Intervention / Treatment
-----------------
* Drug: Tazemetostat
* Drug: Doxorubicin HCl
* Drug: Tazemetostat
* Drug: Placebo
* Drug: Doxorubicin HCl


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria Participants must meet ALL the following inclusion criteria to be eligible to enroll in this study: 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. Life expectancy ≥ 3 months before enrollment Phase 1b: 18-65 years old histologically confirmed Soft Tissue Sarcoma Phase 3: ≥18 years old with unresectable locally advanced or metastatic Epithelioid Sarcoma and tumor tissue available Have measurable disease ECOG performance status of 0, 1, or 2 Have adequate hematologic (bone marrow [BM] and coagulation factors), renal and hepatic function as required per protocol Females must not be lactating or pregnant at Screening or Baseline 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 Male participants of child-bearing potential must have had either a successful vasectomy or practice highly effective contraception 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: Prior exposure to tazemetostat or other inhibitor(s) of enhancer of zeste homologue-2 (EZH2). Prior systemic anticancer therapy. Contraindications noted in the doxorubicin label 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. Participants 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 through the duration of study participation. Major surgery within 4 weeks before the first dose of study treatment. Participants 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. Have an active infection requiring systemic therapy. Are immunocompromised (ie, has a congenital immunodeficiency). Have known hypersensitivity to any component of tazemetostat or doxorubicin. Cardiovascular impairment as stated in the protocol 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). 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. Female participants who are pregnant or breastfeeding. Participants who have undergone a solid organ transplant. Participants with malignancies other than STS (phase 1b) or ES (Phase 3 only). Participants housed in an institution by order of the authorities or courts.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase 1b: Open-label Tazemetostat and Phase 3: Tazemetostat + Doxorubicin Arm<br>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. | Drug: Tazemetostat<br>* 400 mg, 600 to 800 mg of Tazemetostat will be administered twice daily.<br>* Other names: IPN60200;Drug: Doxorubicin HCl<br>* 75mg/m2 intravenous injection day 1 of each cycle for up to 6 cycles<br>Drug: Tazemetostat<br>* 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.<br>* Other names: Tazverik®;|
| Placebo Comparator: Phase 3: Placebo + Doxorubicin Arm<br>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. | Drug: Placebo<br>* 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<br>Drug: Doxorubicin HCl<br>* 75mg/m2 intravenous injection day 1 of each cycle for up to 6 cycles<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dose Limiting Toxicities (DLTs) | Determined by Adverse Events (AEs) and clinical laboratory tests. | 1 Cycle/21 days | 
| Progression free survival (PFS) | Phase 3: Assessed by Independent Review Committee. | Through study completion, an average of two years. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 1b: Pharmacokinetics (PK) of tazemetostat when administered in combination with doxorubicin in participants with soft tissue sarcoma (STS): Area under the Plasma Concentration Time Curve from time 0 to 24 hours (AUC0-24) |  | Cycles 1, 2, 3, and 5 of the first continuous 21-day cycles of combination therapy | 
| Phase 1b: PK of tazemetostat when administered in combination with doxorubicin in participants with STS: Area under the Plasma Concentration Time Curve From time 0 to the last observable concentration (AUC0- last) |  | Cycles 1, 2, 3, and 5 of the first continuous 21-day cycles of combination therapy | 
| Phase 1b: PK of tazemetostat when administered in combination with doxorubicin in Pparticipants with STS: The maximum observed concentration (Cmax). |  | Cycles 1, 2, 3, and 5 of the first continuous 21-day cycles of combination therapy | 
| Phase 3: Overall Survival (OS) |  | Through study completion, an average of two years. | 
| Phase 3: Incidence of Adverse Events (AEs) | All AEs, including clinically significant laboratory parameters will be graded by the investigator according to the Common Terminology Criteria for Adverse Events (CTCAE) | Through study completion, an average of two years. | 
| Phase 3: PFS | Assessed by the investigator | Through study completion, an average of two years. | 
| Disease control rate (DCR) | Defined as the number of participants who achieve response complete response (CR) + partial response (PR) or who have stable disease (SD) | Through study completion, an average of two years | 
| Objective response rate (ORR) | ORR is defined as the proportion of participants achieving complete or partial response. Determined based on the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 | Through study completion, an average of two years | 
| Duration of treatment (DOR) | Defined as the time from first documented evidence of CR or PR to the time of first documented disease progression or death, whichever occurs first | Through study completion, an average of two years | 
| Change from baseline in European Organisation for Research and Treatment of Cancer Core Quality of Life Questionnaire (EORTC QLQC-30) | The EORTC QLQC-30 physical function, role function, and global health status domains will be assessed | Through study completion, an average of two years | 
| PFS2 | Defined as time from randomization to objective tumor progression on next-line treatment or death, whichever occurs first | Through study completion, an average of two years | 
| Time to first subsequent anti-cancer therapy ((TFST | Defined as the time from randomization to the time to first subsequent therapy | Through study completion, an average of two years | 
| Population PK parameters of tazemetostat when administered in combination with doxorubicin: Oral clearance (CL/F) | CL/F is defined as the apparent oral clearance following administration of tazemetostat when administered in combination with doxorubicin | Cycles 1, 2, 3, and 5 of the first continuous 21-day cycles of combination therapy | 
| Population PK parameters of tazemetostat when administered in combination with doxorubicin: oral volume of distribution (Vss). |  | Cycles 1, 2, 3, and 5 of the first continuous 21-day cycles of combination therapy | 
| Population PK parameters of tazemetostat when administered in combination with doxorubicin: Area Under the Curve at steady state (AUCss) |  | Cycles 1, 2, 3, and 5 of the first continuous 21-day cycles of combination therapy | 
| Population PK parameters of tazemetostat when administered in combination with doxorubicin: trough concentration (Ctrough) |  | Cycles 1, 2, 3, and 5 of the first continuous 21-day cycles of combination therapy | 
| Population PK parameters of tazemetostat when administered in combination with doxorubicin: Cmax |  | Cycles 1, 2, 3, and 5 of the first continuous 21-day cycles of combination therapy |