Advanced Soft-tissue Sarcoma, Advanced Epithelioid Sarcoma
Conditions
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 Recommended Phase 3 Dose (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 Epithelioid Sarcoma (ES). The Phase 3 portion was planned but never initiated due to early termination during Phase 1b. Participants with confirmed Soft-tissue Sarcoma (STS) were enrolled in phases 1b.
Interventions
DRUGTazemetostat
400 mg, 600 to 800 mg of Tazemetostat will be administered twice daily.
DRUGDoxorubicin HCl
75mg/m2 intravenous injection day 1 of each cycle for up to 6 cycles
Sponsors
Epizyme, Inc.
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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. Eastern Cooperative Oncology Group Performance Status (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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Dose Limiting Toxicities (DLTs) | 1 Cycle/21 days | Determined by Adverse Events (AEs) and clinical laboratory tests. |
| Progression free survival (PFS) | Through study completion, an average of two years. | Phase 3: Assessed by Independent Review Committee. Phase 3 was planned but never initiated; therefore, no data were collected for these endpoints |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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 Participants 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 was planned but never initiated; therefore, no data were collected for these endpoints |
| Phase 3: Incidence of Adverse Events (AEs) | Through study completion, an average of two years. | All AEs, including clinically significant laboratory parameters will be graded by the investigator according to the Common Terminology Criteria for Adverse Events (CTCAE). Phase 3 was planned but never initiated; therefore, no data were collected for these endpoints |
| Phase 3: PFS | Through study completion, an average of two years. | Assessed by the investigator. Phase 3 was planned but never initiated; therefore, no data were collected for these endpoints |
| Disease control rate (DCR) | Through study completion, an average of two years | Defined as the number of participants who achieve response complete response (CR) + partial response (PR) or who have stable disease (SD). Phase 3 was planned but never initiated; therefore, no data were collected for these endpoints. |
| Objective response rate (ORR) | Through study completion, an average of two years | 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 |
| Progression-Free Survival on Next Line of Therapy (PFS2) | Through study completion, an average of two years | Defined as time from randomization to objective tumor progression on next-line treatment or death, whichever occurs first |
| Change from baseline in European Organisation for Research and Treatment of Cancer (EORTC) Core Quality of Life Questionnaire (QLQC) (EORTC QLQC-30) | Through study completion, an average of two years | The EORTC QLQC-30 physical function, role function, and global health status domains will be assessed |
| Time to first subsequent anti-cancer therapy ((TFST) | Through study completion, an average of two years | Defined as the time from randomization to the time to first subsequent therapy |
| Population PK parameters of tazemetostat when administered in combination with doxorubicin: Oral clearance (CL/F) | Cycles 1, 2, 3, and 5 of the first continuous 21-day cycles of combination therapy | CL/F is defined as the apparent oral clearance following administration of tazemetostat when administered in combination with doxorubicin |
| 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 | — |
| Duration of treatment (DOR) | Through study completion, an average of two years | 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 |
| 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 | — |
Countries
Canada, Taiwan, United Kingdom, United States
Outcome results
None listed