A Phase II Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Preliminary Efficacy of Tazemetostat in Combination With HMPL-689 in Patients With Relapsed/Refractory Lymphoma
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 发起方
- Hutchmed
- 入组人数
- 61
- 试验地点
- 1
- 主要终点
- Dose Expansion Phase (Phase IIb):To evaluate the PFS of Tazemetostat in combination with HMPL-689 in patients with lymphoma
研究概览
简要总结
A phase II clinical study of tazemetostat combined with HMPL-689 in patients with R/R lymphoma. The study includes 2 phases: dose escalation phase (phase IIa) and expansion phase (phase IIb).
详细描述
Dose Escalation Phase (Phase IIa ):Including 10-20 patients for dose escalation, the enrollment will continue until about 10 patients in the dose group with response, as to determine Recommended Phase II dose (RP2D).
Dose Expansion Phase (Phase IIb):Multiple expansion cohorts will be set up according to different tumor types, and about 15-20 patients will be enrolled in each cohort to further observe the anti-tumor effect of Tazemetostat combined with HMPL-689 in different pathological types of R/R lymphoma.
This study is expected to enroll 85-140 patients total in Phase IIa and phase IIb.
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
- •Willing and able to give informed consent, as documented by signed ICF
- •Age ≥ 18 years
- •Patients with histologically confirmed R/R lymphoma:
- •Phase IIa （dose escalation study）: patients with relapsed or refractory lymphoma who have failed standard treatment and have no standard treatment options
- •Phase IIb（ expansion Study ）: Cohort 1 (DLBCL, FL 3b) Histologically confirmed DLBCL, FL 3b (including primary mediastinal B-cell lymphoma) with relapsed/refractory disease
- •Cohort 2 (FL) patients with histologically confirmed R/R FL (Grade 1, 2, 3a)
- •Cohort 3 (MCL): Patients with R/R MCL who had prior therapies
- •Cohort 4 (PTCL): Patients with histologically confirmed R/R PTCL who have failed or cannot tolerate standard therapy
- •Patients must have at least one measurable lesion
- •Life expectancy ≥ 12 weeks
- •Eastern Cooperative Oncology Group (ECOG) performance status of 0-2
- •Adequate bone marrow function, renal function and hepatic function:
- •Currently human immunodeficiency virus (HIV), hepatitis B virus (HBV), hepatitis C virus (HCV), or cytomegalovirus (CMV) is inactive
- •Female patients of childbearing potential must agree to use a double contraception method and male patients with partners of childbearing potential must also use an effective double contraception method during the study period and for 3 months after the final dose
排除标准
- •Patients who have previously used EZH2 inhibitors and PI3K inhibitors, or previously could not tolerate EZH2 inhibitors or PI3K inhibitors
- •Patients with brain metastases or leptomeningeal invasion
- •Has thrombocytopenia, neutropenia, or anemia of Grade ≥3 (per CTCAE 5.0 criteria) and any prior history of myeloid malignancies, including myelodysplastic syndrome (MDS / AML/MPN)
- •Has abnormalities known to be associated with MDS (e.g. del 5q, chr 7 abn) and multiple primary neoplasms (MPN) (e.g. JAK2 V617F) observed in cytogenetic testing and DNA sequencing
研究组 & 干预措施
tazemetostat combined with HMP689 open-label treatment arm
Dose Escalation Phase (Phase IIa):
patients with relapsed or refractory lymphoma who have failed standard treatment and have no standard treatment options
Dose Expansion Phase (Phase IIb):
Cohort 1 (DLBCL, FL 3b): Histologically confirmed DLBCL, FL 3b (including primary mediastinal B-cell lymphoma) with relapsed/refractory disease ；
Cohort 2 (FL) patients with histologically confirmed R/R FL (Grade 1, 2, 3a)；
Cohort 3 (MCL): Patients with R/R MCL who had prior therapies ；
Cohort 4 (PTCL): Patients with histologically confirmed R/R PTCL who have failed or cannot tolerate standard therapy
干预措施: tazemetostat (Drug)
tazemetostat combined with HMP689 open-label treatment arm
Dose Escalation Phase (Phase IIa):
patients with relapsed or refractory lymphoma who have failed standard treatment and have no standard treatment options
Dose Expansion Phase (Phase IIb):
Cohort 1 (DLBCL, FL 3b): Histologically confirmed DLBCL, FL 3b (including primary mediastinal B-cell lymphoma) with relapsed/refractory disease ；
Cohort 2 (FL) patients with histologically confirmed R/R FL (Grade 1, 2, 3a)；
Cohort 3 (MCL): Patients with R/R MCL who had prior therapies ；
Cohort 4 (PTCL): Patients with histologically confirmed R/R PTCL who have failed or cannot tolerate standard therapy
干预措施: HMPL-689 (Drug)
结局指标
主要结局
Dose Expansion Phase (Phase IIb):To evaluate the PFS of Tazemetostat in combination with HMPL-689 in patients with lymphoma
时间窗: from Cycle 1 Day 1 to PFS (each cycle is 28 days)
the proportion of patients with CR or PR or stable disease (SD) as the best response with Lugano2014
Dose Escalation Phase (Phase IIa):To evaluate the safety, tolerability, and determine the maximum tolerated dose (MTD) and/or RP2D of Tazemetostat in combination with HMPL-689 in patients with R/R lymphoma
时间窗: from Cycle 1 Day 1 up to Cycle 1 Day 28 (each cycle is 28 days)
Occurrence of Dose Limiting Toxicities (DLTs) During the DLT Observation Period
Dose Expansion Phase (Phase IIb):To evaluate the DCR of Tazemetostat in combination with HMPL-689 in patients with lymphoma
时间窗: from Cycle 1 Day 1 to PFS (each cycle is 28 days)
the proportion of patients with CR or PR or stable disease (SD) as the best response with Lugano2014
Dose Expansion Phase (Phase IIb):To evaluate the DOR of Tazemetostat in combination with HMPL-689 in patients with lymphoma
时间窗: from Cycle 1 Day 1 to PFS (each cycle is 28 days)
as the time from the first appearance of CR or PR to PD or death for any reason (whichever comes first), in the patients with objective response with Lugano2014)
Dose Expansion Phase (Phase IIb):To evaluate the ORR of Tazemetostat in combination with HMPL-689 in patients with lymphoma
时间窗: from Cycle 1 Day 1 to PFS (each cycle is 28 days)
Percentage of patients with Complete Response(CR) or Partial Response(PR) as the best response evaluated in accordance with Lugano2014
次要结局
- Dose Escalation Phase (Phase IIa)-Complete Response Rate (CR rate)(From baseline to final assessment at end of safety follow-up visit(through study completion, an average of 2 years))
- Dose Escalation Phase (Phase IIa)-Disease control rate (DCR)(From baseline to final assessment at end of safety follow-up visit(through study completion, an average of 2 years))
- Dose Escalation Phase (Phase IIa)-Duration of response (DoR)(From baseline to final assessment at end of safety follow-up visit(through study completion, an average of 2 years))
- Dose Escalation Phase (Phase IIa)-Time to response (TTR)(From baseline to final assessment at end of safety follow-up visit(through study completion, an average of 2 years))
- Dose Escalation Phase (Phase IIa)-Progression-free survival (PFS)(From baseline to final assessment at end of safety follow-up visit(through study completion, an average of 2 years))
- Dose Expansion Phase (Phase IIb)-Evaluation of Tazemetostat safety and tolerability in Combination with HMPL-689 in Patients with R/R Lymphoma(From baseline to final assessment at end of safety follow-up visit(through study completion, an average of 2 years))
- Geomean maximum concentration (Cmax) of tazemetostat and its metabolite EPZ-6930 in blood(Cycle (C) 1, Day (D) 1: predose of first administration (PoFA); 0.5, 1, 2, 4, 6, 8, and 12 hours postdose. C1D15: PoFA; 0.5, 1, 2, 4, 6, 8, and 12 hours postdose. C1D2, C1D16, C2D1, C3D1 and C4D1: PoFA)
- Dose Escalation Phase (Phase IIa):Objective Response Rate (ORR)(From baseline to final assessment at end of safety follow-up visit(through study completion, an average of 2 years))
- Dose Escalation Phase (Phase IIa)-Overall survival (OS)(From baseline to final assessment at end of safety follow-up visit(through study completion, an average of 2 years))
- Geomean maximum concentration (Cmax) of HMPL-689 in blood(Cycle (C) 1, Day (D) 1: predose of first administration (PoFA); 0.5, 1, 2, 4, 6, 8, 12 and 24 (C1D2, PoFA) hours postdose. C1D15: PoFA; 0.5, 1, 2, 4, 6, 8, 12 and 24 (C1D16, PoFA) hours postdose. C2D1, C3D1 and C4D1: PoFA)
- Geomean minimum observed concentration at steady-state (Cmin) of HMPL-689 in blood(C1D15, C1D16, C2D1, C3D1 and C4D1: PoFA)
- Median time to reach maximum concentration (Tmax) of tazemetostat and its metabolite EPZ-6930 in blood(Cycle (C) 1, Day (D) 1: predose of first administration (PoFA); 0.5, 1, 2, 4, 6, 8, and 12 hours postdose. C1D15: PoFA; 0.5, 1, 2, 4, 6, 8, and 12 hours postdose. C1D2, C1D16, C2D1, C3D1 and C4D1: PoFA)
- Geomean area under the drug concentration-time curve (AUC) of tazemetostat and its metabolite EPZ-6930 after administration of tazemetostat(Cycle (C) 1, Day (D) 1: PoFA; 0.5, 1, 2, 4, 6, 8, and 12 hours postdose. C1D15: PoFA; 0.5, 1, 2, 4, 6, 8, and 12 hours postdose.)
- Median time to reach maximum concentration (Tmax) of HMPL-689 in blood(Cycle (C) 1, Day (D) 1: predose of first administration (PoFA); 0.5, 1, 2, 4, 6, 8, 12 and 24 (C1D2, PoFA) hours postdose. C1D15: PoFA; 0.5, 1, 2, 4, 6, 8, 12 and 24 (C1D16, PoFA) hours postdose. C2D1, C3D1 and C4D1: PoFA)
- Geomean minimum observed concentration at steady-state (Cmin) of tazemetostat and its metabolite EPZ-6930 in blood(C1D15, C1D16, C2D1, C3D1 and C4D1: PoFA)
- Geomean area under the drug concentration-time curve (AUC) of HMPL-689 after administration of HMPL-689(Cycle (C) 1, Day (D) 1: predose of first administration (PoFA); 0.5, 1, 2, 4, 6, 8, 12 and 24 (C1D2, PoFA) hours postdose. C1D15: PoFA; 0.5, 1, 2, 4, 6, 8, 12 and 24 (C1D16, PoFA) hours postdose)
- To investigate the preliminary efficacy and PK correlation(through study completion, an average of 2 years)
- To investigate the preliminary tolerability and PK relationship(through study completion, an average of 2 years)