A Phase 1, Open-Label, Multicenter Study of HMPL-306 in Advanced Hematological Malignancies With Isocitrate Dehydrogenase (IDH) Mutations
试验速览
- 阶段
- 1 期
- 状态
- 终止
- 发起方
- Hutchmed
- 入组人数
- 46
- 试验地点
- 15
- 主要终点
- Dose Escalation Part: Recommended Phase 2 Dose (RP2D) of HMPL-306
研究概览
简要总结
An open label single-arm clinical trial to evaluate the safety, tolerability, PK, PD, and preliminary efficacy of HMPL-306 in subjects with advanced relapsed, refractory, or resistant hematological malignancies that harbor IDH mutations.
详细描述
HMPL-306 is a dual IDH1/2 inhibitor
This is a phase 1, open-label, multicenter, single-arm study to evaluate safety, tolerability, PK, PD, and preliminary efficacy of HMPL-306 administered orally in treatment of subjects with advanced relapsed, refractory, or resistant hematological malignancies that harbor IDH mutations (or co-mutations).
The study consists of 2 parts: a dose-escalation part (Part 1) and a dose-expansion part (Part 2). The dose-escalation part will determine the MTD/R2PD. The dose-expansion part will administer the MTD/RP2D to subjects with mIDH-positive AML
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
- •Subjects may be enrolled in this study only if they satisfy all the following criteria (NOTE: This is not an exhaustive list):
- •Subjects aged ≥18 years.
- •ECOG performance status ≤ 2
- •Subjects with advanced relapsed, refractory, or resistant hematological malignancies, as defined below:
- •Subjects with documented IDH mutation per local or institutional next generation sequence (NGS).
- •Subjects must be refractory to or intolerant of established therapies.
- •Subjects who have received prior IDH inhibitor treatment may be enrolled in the escalation phase.
- •Subjects with documented IDH mutation of any of these subsets: IDH1 (R132C), IDH1 (R132H), IDH (R140Q), and IDH2 (R172K), including co-mutations and any combination thereof per local and institutional NGS.
- •Patients must have received at least 1 prior line of therapy with an IDH inhibitor. An established standard of care with proven benefit for which the patient is eligible, must not be available at the time of enrollment.
- •Patients with AML must not have standard therapeutic options available (including IDH inhibitors where approved) and have the following:
- •i. Relapsed AML unsuitable for intensive chemotherapy or venetoclax-based regimen or target agents;
- •ii. Primary refractory AML unsuitable for intensive chemotherapy or venetoclax-based regimen or target agents.
- •iii. Relapsed/refractory AML that has progressed on prior IDH treatment
排除标准
- •Subjects are not eligible for enrollment into this study if they meet any of the following criteria (NOTE: This is not an exhaustive list):
- •Subjects who received an investigational agent <14 days prior to their first day of study drug administration.
- •Subjects who are pregnant or breastfeeding.
- •Subjects with an active severe infection, some treated infections and with an expected or with an unexplained fever >38.3°C during screening visits or on their first day of study drug administration.
- •Subjects with some current or prior heart conditions.
- •Subjects taking medications that are known to prolong the QT interval may not be eligible.
- •Subjects with immediately life-threatening, severe complications of leukemia such as uncontrolled bleeding, pneumonia with hypoxia or shock, and/or disseminated intravascular coagulation.
- •Some subjects with some current or prior gastrointestinal or liver diseases.
- •Subjects with inadequate organ function as defined by the protocol.
- •Subjects with a medical condition, physical examination finding, or clinical laboratory finding that, in the Investigators opinion, contraindicates the use of an investigational drug or that may affect the interpretation of the results or renders the subject at high risk from treatment complications.
- •Subjects with a known hypersensitivity to HMPL-306 or to any of its excipients.
- •Subjects with presence of second primary malignant tumors within the last 2 years, with the exception of the following, if medically controlled: basal cell carcinoma of the skin, squamous cell carcinoma of the skin, carcinoma in situ of the cervix, and carcinoma in situ of the breast.
- •Part 2 Only: The time since the last dose of prior IDH inhibitor treatment is within 30 days prior to the first day of study drug administration
研究组 & 干预措施
Treatment
All patients will be administered HMPL-306 orally QD
干预措施: HMPL-306 (Drug)
结局指标
主要结局
Dose Escalation Part: Recommended Phase 2 Dose (RP2D) of HMPL-306
时间窗: From the first dose of study drug (Day 1) up to Day 28 of Cycle 1
RP2D determination took the following criteria under consideration: determination of maximum tolerated dose (MTD) achieved during the dose escalation part and assessment of safety, PK and pharmacodynamics (PD).
Dose Escalation Part: Number of Patients With Dose-Limiting Toxicities (DLTs)
时间窗: From the first dose of study drug (Day 1) up to Day 28 of Cycle 1
DLT was defined as occurrence of any of the following treatment-emergent adverse events (TEAEs) during the DLT assessment window, unless clearly unrelated to the study drug as per investigator's discretion: nonhematologic toxicity: TEAEs of Grade \>=4, Grade \>=3 with the exception of those that resolved within 72 hours (h) of onset; hematologic toxicity with the exception of neutropenia or thrombocytopenia that occurred with active leukemic disease: Grade 3 or 4 neutropenia lasting more than 7 days, Grade 4 thrombocytopenia or Grade 3 thrombocytopenia with bleeding or any requirement for platelets (PLT) transfusion, Grade 3 or greater febrile neutropenia defined as absolute neutrophil count (ANC) 1000 per cubic millimeter with a single temperature of \>38.3 degree Celsius (°C) or a sustained temperature of \>=38°C for more than 1 h; any TEAE requiring a dose delay of \>=14 days or cases of confirmed Hy's law.
Number of Patients With Treatment-Emergent Adverse Events and Treatment-Emergent Serious Adverse Events (TESAEs)
时间窗: From the first dose of study drug (Day 1) up to 30 days after the last dose of study drug, approximately 25.25 months
AE:unfavorable and unintended sign,symptom or disease temporally associated with use of study drug or other protocol-imposed intervention, whether or not considered related to study drug. SAE:AE that resulted in death,life-threatening AE,inpatient hospitalization/prolongation of existing hospitalization,persistent/significant incapacity or substantial disruption of ability to conduct normal life functions, abnormal pregnancy outcome in child born to female patient or female partner of male patient exposed to study drug or was important medical event that jeopardized patient and required medical/surgical intervention to prevent above outcome. TEAE:AE with onset on/after start of study drug until 30 days after last dose or prior to start of subsequent anti-tumor therapy, or AE with onset before start of study drug but worsened in severity after study drug administration, or AE onset after 30 days after last dose or after start of subsequent anti-tumor therapy and treatment-related SAEs.
次要结局
- Number of Patients With Best Overall Response (BOR)(Tumor assessments performed every 8 weeks (+/-7 days) for the first 24 weeks and every 12 weeks (+/-14 days) thereafter until end of treatment, or end of efficacy follow-up period, approximately 45 months)
- Objective Response Rate (ORR)(Tumor assessments performed every 8 weeks (+/-7 days) for the first 24 weeks and every 12 weeks (+/-14 days) thereafter until end of treatment, or end of efficacy follow-up period, approximately 45 months)
- Time to Objective Response (TTOR)(Tumor assessments performed every 8 weeks (+/-7 days) for the first 24 weeks and every 12 weeks (+/-14 days) thereafter until end of treatment, or end of efficacy follow-up period, approximately 45 months)
- Duration of Objective Response (DoOR)(Tumor assessments performed every 8 weeks (+/-7 days) for the first 24 weeks and every 12 weeks (+/-14 days) thereafter until end of treatment, or end of efficacy follow-up period, approximately 45 months)
- Clinical Benefit Rate (CBR)(Tumor assessments performed every 8 weeks (+/-7 days) for the first 24 weeks and every 12 weeks (+/-14 days) thereafter until end of treatment, or end of efficacy follow-up period, approximately 45 months)
- Progression-Free Survival (PFS)(Tumor assessments performed every 8 weeks (+/-7 days) for the first 24 weeks and every 12 weeks (+/-14 days) thereafter until end of treatment, or end of efficacy follow-up period, approximately 45 months)
- Overall Survival (OS)(From the first dose of study drug (Day 1) up to date of death due to any cause, approximately 45 months)
- Event-Free Survival (EFS)(Tumor assessments performed every 8 weeks (+/-7 days) for the first 24 weeks and every 12 weeks (+/-14 days) thereafter until end of treatment, or end of efficacy follow-up period, approximately 45 months)
- Number of Patients With Post-Baseline Transfusion Independence (TI)(From the first dose of study drug (Day 1) up to 30 days after the last dose of study drug, approximately 25.25 months)
- Plasma Concentrations of HMPL-306(PK Week: Pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 24, 48, 72, 96, 120, 144, 168 hours post-dose on Day 1 PK week; Cycle 2 Day 1: Pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 24 hours post-dose on Cycle 2 Day 1)
- Maximum Observed Plasma Concentration (Cmax) of HMPL-306(PK Week: Pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 24, 48, 72, 96, 120, 144, 168 hours post-dose on Day 1 PK week; Cycle 2 Day 1: Pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 24 hours post-dose on Cycle 2 Day 1)
- Time to Reach the Maximum Plasma Concentration (Tmax) of HMPL-306(PK Week: Pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 24, 48, 72, 96, 120, 144, 168 hours post-dose on Day 1 PK week; Cycle 2 Day 1: Pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 24 hours post-dose on Cycle 2 Day 1)
- Area Under the Plasma Concentration-Time Curve From 0 to 24 Hours (AUC0-24) of HMPL-306(PK Week: Pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 24 hours post-dose on Day 1 PK week; Cycle 2 Day 1: Pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 24 hours post-dose on Cycle 2 Day 1)
- Maximum Inhibition Rate of Plasma 2-Hydroxyglutaric Acid (2-HG)(From PK Week Day 2 until end of treatment, approximately 24.25 months)