A Phase 1b/3 Global, Randomized, Double-blind, Placebo-Controlled Trial of Tazemetostat in Combination With Doxorubicin as Frontline Therapy for Advanced Epithelioid Sarcoma
试验速览
- 阶段
- 1 期
- 状态
- 终止
- 入组人数
- 25
- 试验地点
- 39
- 主要终点
- Dose Limiting Toxicities (DLTs)
研究概览
简要总结
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
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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
- •Eastern Cooperative Oncology Group Performance Status (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.
排除标准
- •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- LBL/)/T-cell acute lymphoblastic leukemia (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 3A4 (CYP3A4) 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.
研究组 & 干预措施
Phase 1b: Open-label: Tazemetostat + Doxorubicin
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.
干预措施: Tazemetostat (Drug)
Phase 1b: Open-label: Tazemetostat + Doxorubicin
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.
干预措施: Doxorubicin HCl (Drug)
结局指标
主要结局
Dose Limiting Toxicities (DLTs)
时间窗: 1 Cycle/21 days
Determined by Adverse Events (AEs) and clinical laboratory tests.
Progression free survival (PFS)
时间窗: 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
次要结局
- 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 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: Incidence of Adverse Events (AEs)(Through study completion, an average of two years.)
- Phase 3: PFS(Through study completion, an average of two years.)
- Disease control rate (DCR)(Through study completion, an average of two years)
- Objective response rate (ORR)(Through study completion, an average of two years)
- Duration of treatment (DOR)(Through study completion, an average of two years)
- 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)
- Progression-Free Survival on Next Line of Therapy (PFS2)(Through study completion, an average of two years)
- Time to first subsequent anti-cancer therapy ((TFST)(Through study completion, an average of two years)
- 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)
- 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)