A Phase I Study of Safety, Pharmacokinetics and Efficacy of HMPL-523 With Azacitidine in Elderly Patients With Previously Untreated Acute Myeloid Leukemia
概览
- 阶段
- 1 期
- 状态
- 终止
- 发起方
- Hutchison Medipharma Limited
- 入组人数
- 7
- 试验地点
- 1
- 主要终点
- Adverse Event (AE) monitoring of HMPL-523 in combination with azacitidine
概览
简要总结
This is a Phase I, open-label, non-randomized, multicenter study to evaluate the safety, pharmacokinetics and preliminary efficacy of HMPL-523 in combination with Azacitidine in previously untreated elderly patients with AML who are not eligible for standard induction therapy.
详细描述
There are two stages in this study: a dose-escalation stage (stage 1) and a dose-expansion stage (stage 2).
Dose-escalation stage (stage 1):
The conventional 3+3 design (3 patients per dose cohort, with the potential to add additional 3 patients to the same cohort to further evaluate toxicity) will be applied for dose escalation and maximum tolerated dosage determination. Approximately 12 to 18 dose limited toxicities evaluable patients will be enrolled. A dose of HMPL-523 up to 800mg will be taken orally once daily continuously through a 28-day Cycle of study treatment. Azacitidine will be administered subcutaneously, beginning on Day 1 through Day 7 of each Cycle.
Dose-expansion stage (stage 2):
This phase is to further evaluate the safety, pharmacokinetics and preliminary efficacy of HMPL-523 in combination with Azacitidine in approximately 28 previously untreated elderly patients with AML. Patients will receive HMPL-523 in combination with Azacitidine in a 28-day cycle continuously until disease progression/relapse, death, or intolerable toxicity, whichever comes first.
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
- 65 Years 至 —（Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Subject must have confirmation of AML by WHO criteria, except for APL (M3)
- •Subject must be ≥ 65 years of old and be ineligible for treatment with a standard cytarabine and anthracycline induction regimen due to co-morbidity or other factors
- •Subject must have received no prior treatment for AML with the exception of hydroxyurea
- •ECOG performance status of 0-
- •For dose-expansion stage, ECOG PS of 2 will also be eligible
排除标准
- •Subject has received treatment of hypomethylating agent and/or chemo therapeutic agent for MDS or MPN
- •Subject has known active CNS involvement or extramedullary sarcoma from AML
- •Subject has favorable risk cytogenetics as categorized by the NCCN Guidelines Version 1, 2018 for Acute Myeloid Leukemia, such as inv(16) or t(16;16) or t(8;21) or t(15;17)
- •Subject has a white blood cell count \> 25 × 109/L (Hydroxyurea is permitted to meet this criterion)
- •Subject with serum amylase or lipase \> the ULN
- •Subject is known to be positive for hepatitis B or C infection with the exception of those with an undetectable viral load.
- •Subject who don't have enough liver or renal function
- •Subject with New York Heart Association (NYHA) Class III or greater congestive heart failure
- •Subject received herbal therapy ≤ 1 week prior to initiation of study treatment
- •Subject received prior treatment with any SYK inhibitors (Fostamatinib) or FLT3 inhibitor (Quizartinib) or multi-target inhibitor with SYK or FLT3 inhibition activity (Midostaurin)
研究组 & 干预措施
HMPL-523 & Azacitidine
HMPL-523 will be taken orally once daily continuously through a 28-days Cycle of study treatment. Azacitidine will be administered subcutaneously, beginning on Day 1 through Day 7 of each Cycle.
干预措施: HMPL-523 (Drug)
HMPL-523 & Azacitidine
HMPL-523 will be taken orally once daily continuously through a 28-days Cycle of study treatment. Azacitidine will be administered subcutaneously, beginning on Day 1 through Day 7 of each Cycle.
干预措施: Azacitidine (Drug)
结局指标
主要结局
Adverse Event (AE) monitoring of HMPL-523 in combination with azacitidine
时间窗: Measured from the first dose to within 30 days after the last dose.
AE monitoring will be assessed by evaluation of study drug exposure, AEs , serious AEs, all deaths, as well as laboratory determinations and vital sign parameters.
Overall response rate (ORR)
时间窗: Measured up to 1 year after the last subject has enrolled or all the subjects have finished their last EFS follow up, whichever comes first.
Overall response rate will be defined as the proportion of subjects who achieve a complete remission (CR), complete remission incomplete (CRi), Morphologic leukemia-free state (MLFS), or partial remission(PR) per 2017 European Leukemia Net (ELN) recommendations
次要结局
- Half-life (t1/2) of HMPL-523(Measured on the cycle 1 day 7, cycle 1 day 8, cycle 1 day 28 and cycle 2 day 1.)
- The area under the plasma concentration-time curve (AUC) from 0 to the time of the last measurable concentration (AUCt) of HMPL-523(Measured on the cycle 1 day 7, cycle 1 day 8, cycle 1 day 28 and cycle 2 day 1.)
- Clearance (CL) of Azacitidine(Measured on the cycle 1 day 7 and Cycle 1 day 8.)
- Complete Remission Rate of Minimal Residual Disease (MRD) Negativity （CR MRD- rate）(Measured up to 1 year after the last subject has enrolled or all the subjects have finished their last EFS follow up, whichever comes first.)
- Disease-free Survival (DFS)(Measured up to 1 year after the last subject has enrolled or all the subjects have finished their last EFS follow up, whichever comes first.)
- Overall Survival (OS)(Measured up to 1 year after the last subject has enrolled or all the subjects have finished their last EFS follow up, whichever comes first.)
- Maximum plasma concentration (Cmax) of HMPL-523(Measured on the cycle 1 day 7, cycle 1 day 8, cycle 1 day 28 and cycle 2 day 1.)
- The area under the plasma concentration-time curve (AUC) from 0 to the time of the last measurable concentration (AUCt) of Azacitidine(Measured on the cycle 1 day 7 and Cycle 1 day 8.)
- Cumulative incidence of relapse (CIR)(Measured up to 1 year after the last subject has enrolled or all the subjects have finished their last EFS follow up, whichever comes first.)
- The time to Cmax (peak time, Tmax) of HMPL-523(Measured on the cycle 1 day 7, cycle 1 day 8, cycle 1 day 28 and cycle 2 day 1.)
- Steady-state concentration(Css) of Azacitidine(Measured on the cycle 1 day 7 and Cycle 1 day 8.)
- Half-life (t1/2) of Azacitidine(Measured on the cycle 1 day 7 and Cycle 1 day 8.)
- Event Free Survival (EFS)(Measured up to 1 year after the last subject has enrolled or all the subjects have finished their last EFS follow up, whichever comes first.)