SYMPHONY-II: A Phase II Open-Label, Multicenter Trial of Oral Tazemetostat in Combination With Rituximab in Subjects With Relapsed/Refractory Follicular Lymphoma
试验速览
- 阶段
- 2 期
- 状态
- 终止
- 入组人数
- 5
- 试验地点
- 17
- 主要终点
- Objective Response Rate (ORR)
研究概览
简要总结
This study evaluates the safety and efficacy of combining the EZH2 inhibitor tazemetostat with rituximab in R/R FL subjects previously treated with at least 2 standard prior systemic treatment regimens where at least 1 anti-CD20-based regimen was used.
详细描述
This is a phase 2, multicenter, open-label study of oral tazemetostat in combination with rituximab in subjects with relapsed or refractory (R/R) follicular lymphoma (FL). This study is designed to evaluate the safety and efficacy of tazemetostat in combination with rituximab in subjects previously treated with at least 2 standard prior systemic treatment regimens where at least 1 anti-CD20-based regimen was used, and used and features early futility stopping to maintain subject safety.
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
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
- •Men and women of 18 years of age and older
- •Voluntary agreement to provide written informed consent and the willingness and ability to comply with all aspects of the protocol
- •Eastern Cooperative Oncology Group (ECOG) score of 0 </=, 1 or 2
- •Life expectancy (in the opinion of the investigator) of >3 months before enrollment
- •Have histologically confirmed FL, Grade 1 to 3a. Subjects may have R/R disease following at least 2 standard prior systemic treatment regimens where at least 1 anti- CD20-based regimen was used
- •Treatment recommended in accordance with the Groupe d'Etude des Lymphomes b Folliculaires (GELF) criteria
- •Meet the following laboratory parameters:
- •Absolute neutrophil count (ANC) ≥ 750 cells/μL (0.75 x 109/L), or ≥ 500 cells/μL (0.50 x 109/L) in subjects with documented bone marrow involvement
- •Platelet count ≥ 50,000 cells/μL (50 x 109/L), or ≥ 30,000 cells/μL (30 x 109/L) in subjects with documented bone marrow involvement, and without transfusion dependence
- •Hemoglobin ≥ 8 g/dL
- •Serum alanine aminotransferase (AST) and aspartate aminotransferase (ALT) ≤ Incl3.0 x ULN, unless related to disease involvement
- •Total bilirubin ≤ 1.5 x ULN, unless due to disease involvement, Gilbert's syndrome, or hemolytic anemia
- •Estimated creatinine clearance (ie, estimated glomerular filtration rate [eGFR] using Cockcroft-Gault) ≥ 40 mL/min
- •At least one bi-dimensionally measurable nodal lesion > 1.5 cm in its longest diameter by computed tomography (CT) scan or magnetic resonance imaging (MRI)
- •Any clinically significant toxicity related to a prior anticancer treatment (ie, chemotherapy, immunotherapy, and/or radiotherapy), except for alopecia, either resolved to ≤ Grade 1 per National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0 or is clinically stable and no longer clinically significant
- •Negative serologic or polymerase chain reaction (PCR) test results for acute or chronic hepatitis B virus (HBV) infection
- •Negative test results for hepatitis C virus (HCV) and human immunodeficiency virus (HIV).
- •Females of childbearing potential (FCBP) must have a negative serum pregnancy test (beta-human chorionic gonadotropin [β-hCG] test with a minimum sensitivity of 25 mIU/mL or equivalent units of β-hCG) at screening and within 24 hours prior to the first dose of study drug.
- •FCBP must either practice complete abstinence or agree to use a highly effective method of contraception beginning at least 28 days prior to the first dose of study drug, during study treatment (including during dose interruptions), for 6 months after tazemetostat discontinuation, and for 12 months after rituximab discontinuation. .
- •Male subjects must have had a successful vasectomy (with medically confirmed azoospermia) OR must either practice complete abstinence or agree to use a latex or synthetic condom during sexual contact with a FCBP from the first dose of study drug, during study treatment (including during dose interruptions), and for 3 months after study drug discontinuation.
排除标准
- •Prior exposure to Tazemetostat or other inhibitor(s) of EZH2
- •Grade 2b, mixed histology, or transformed FL
- •Treatment with any of the following anticancer therapies within the timeframe of a specific treatment prior to first dose of study drug:
- •Cytotoxic chemotherapy within 21 days
- •Noncytotoxic chemotherapy (e.g. small molecule inhibitor) within 14 days
- •Nitrosoureas within 6 weeks
- •Prior immunotherapy within 4 weeks
- •Radiotherapy- within 6 weeks from prior radioisotope therapy; within 12 weeks from 50% pelvic or total body irradiation
- •Any investigational treatment within 4 weeks or at least 5 half lives, whichever is shorter
- •History of solid organ transplant
- •Major surgery within 4 weeks of the start of study treatment
- •Thrombocytopenia, neutropenia, or anemia of Grade > 3 (per CTCAE v5.0 criteria) or any prior history of myeloid malignancies, including MDS/AML or MPN
- •Prior history of T-LBL/T-ALL
- •Unwillingness to exclude grapefruit juice-containing products, Seville oranges, and grapefruits from the diet and/ or consumed within 1 week of the first dose of study drug
- •Subjects taking medications that are known strong cytochrome P450 (CYP)3A inhibitors and strong or moderate CYP3A inducers (including St. John's wort)
- •Any uncontrolled illness
- •History of clinically significant cardiovascular abnormalities
- •History of clinically significant gastrointestinal (GI) conditions
- •Other diagnosis of cancer that is likely to require treatment in the next 2 years
- •Females who are pregnant or lactating/breastfeeding
- •Received a live virus vaccination within 28 days of first dose of rituximab
- •Concurrent participation in a separate investigational therapeutic study
- •Psychiatric illness/social situations that would interfere with study compliance
研究组 & 干预措施
Tazmetostat in combination with rituximab
Tazemetostat 800 mg BID is administered daily starting on Cycle 1 Day 1 (C1D1). Tazemetostat will be administered from C1D1 to the end of Cycle 24, for 24 months of therapy or until disease progression, unacceptable toxicity, or withdrawal of consent. Rituximab will be administered by either subcutaneous injection or IV infusion according to the regional product prescribing information, labeling and institutional guidelines. Rituximab will be administered at a dose of 375 mg/m2 on Day 1, 8, 15, and 22 of Cycle 1, and then on Day 1 of Cycles 3 through 6, accounting for an additional 4 doses, i.e., a total of 8 doses of rituximab in 6 cycles.
干预措施: Tazemetostat (Drug)
Tazmetostat in combination with rituximab
Tazemetostat 800 mg BID is administered daily starting on Cycle 1 Day 1 (C1D1). Tazemetostat will be administered from C1D1 to the end of Cycle 24, for 24 months of therapy or until disease progression, unacceptable toxicity, or withdrawal of consent. Rituximab will be administered by either subcutaneous injection or IV infusion according to the regional product prescribing information, labeling and institutional guidelines. Rituximab will be administered at a dose of 375 mg/m2 on Day 1, 8, 15, and 22 of Cycle 1, and then on Day 1 of Cycles 3 through 6, accounting for an additional 4 doses, i.e., a total of 8 doses of rituximab in 6 cycles.
干预措施: Rituximab (Combination Product)
结局指标
主要结局
Objective Response Rate (ORR)
时间窗: Planned to be assessed during Cycles 3, 6, 12, 18, and 24.
ORR was defined as the percentage of participants with WT EZH2 status who achieved a complete response (CR) or partial response (PR) according to the 2014 Lugano Classification as assessed by investigator and blinded independent review committee (IRC). CR = complete metabolic response per positron emission tomography-computed tomography (PET-CT) based response or complete radiologic response per CT-based response. PR = partial metabolic response per PET-CT-based response or partial remission per CT-based response.
次要结局
- ORR in a Subset of Participants With MT EZH2(Planned to be assessed at the following timepoints: Cycles 3, 6, 12, 18, and 24)
- ORR in Rituximab Refractory Participants(Planned to be assessed at the following timepoints: Cycle 3, Cycle 6, Cycle 12, Cycle 18, and Cycle 24.)
- Duration of Response (DOR)(Planned to be assessed from earliest date of CR or PR to documented progression or death as assessed up to 24 months by an IRC)
- Progression Free Survival (PFS)(Planned to be assessed from first dose of study drug to earliest date of disease progression or death as assessed up to 24 months by an IRC)