A Phase 1b, Open-label, Multi-center Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Efficacy of HS-10382 Combination Therapy in Patients With Chronic Myeloid Leukemia
试验速览
- 阶段
- 1 期
- 状态
- 尚未招募
- 发起方
- 入组人数
- 100
- 主要终点
- Maximum tolerated dose (MTD) for HS-10382 combined treatment
研究概览
简要总结
HS-10382 is a small molecular, oral potent, allosteric inhibitor. By binding a myristoyl site of the BCR-ABL1 protein, HS-10382 locks BCR-ABL1 into an inactive conformation. Flumatinib is the first approved second generation TKI in China and a derivative of imatinib.
The primary objective of this study is to evaluation the safety and tolerability and of HS-10382 combination therapy in patients with chronic myeloid leukemia (CML).
The secondary objectives is to evaluate the PK profile, major metabolites and efficacy of HS-10382 in CML-CP/AP subjects after combination therapy, and to explore the kinase domain mutations associated with TKI resistance
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 75 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Signed informed consent form.
- •Men or women aged more than or equal to (≥) 18 years, and less than (<) 75 years.
- •CML-CP/AP patients with the Ph chromosome or BCR-ABL1 fusion genes.
- •Patient with CML-CP/AP who are resistant to or intolerant to previous TKIs therapy.
- •ECOG performance status of 0-1 and no worsening within 2 weeks before the first dose.
- •Life expectancy ≥ 12 weeks.
- •Men or women should be using adequate contraceptive measures throughout the study; Females should not be breastfeeding at the time of screening, during the study and until 6 months after completion of the study.
- •Females must have evidence of non-childbearing potential.
排除标准
- •CML-CP patients who have acquired CCyR and have not lost it.
- •Patients with CML-CP who have progressed to AP or blast phase(BP.)
- •Patients with CML-AP who have obtained CHR or no evidence of CML in peripheral blood.
- •Patients with CML-AP who have progressed to BP.
- •Previous treatment with a BCR-ABL1 TKI allosteric inhibitor .
- •Impaired cardiac function including any one of the following:
- •Resting corrected QT interval (QTc) > 470 ms obtained from electrocardiogram (ECG), using the screening clinic's ECG machine and Fridericia's formula for QT interval correction (QTcF).
- •Any clinically important abnormalities in rhythm, conduction, or morphology of the resting ECG.
- •Any factors that increase the risk of QTc prolongation or risk of arrhythmic events,
- •Left ventricular ejection fraction (LVEF) ≤ 50%.
- •Myocardial infarction occurred within 6 months of the first scheduled dose of study drug.;
- •Congestive heart failure occurred within 6 months of the first scheduled dose of study drug.;
- •Uncontrollable angina.
- •History of acute pancreatitis within 1 year of study entry or past medical history of chronic pancreatitis
- •Any severe or uncontrolled systemic diseases (i.e. uncontrolled hypertension or diabetes).
- •Clinically severe gastrointestinal dysfunction that may affect drug intake, transport or absorption.
- •Severe infection within 4 weeks prior to the first scheduled dose of study drug
- •Inadequate other organ function.
- •History of other malignancies.
- •History of hypersensitivity to any active or inactive ingredient of HS-10382 and flumatinib.
- •History of neuropathy or mental disorders, including epilepsy and dementia.
- •Judgment by the investigator that the patient should not participate in the study if the patient is unlikely to comply with study procedures, restrictions, and requirements
研究组 & 干预措施
HS-10382+Flumatinib
Subjects with resistant or intolerant CML CP/AP will be enrolled in dose-escalation stage.Dose escalation of HS-10382 combined flumatinib will be done to determine maximum tolerated dose(Part 1).
Depending on data obtained from the dose-escalation stage,dose expansion may proceed with in subjects with newly diagnosed CML-CP.The safety and efficacy will be evaluated at the target dose.(Part 2)
干预措施: HS-10382+Flumatinib (Drug)
结局指标
主要结局
Maximum tolerated dose (MTD) for HS-10382 combined treatment
时间窗: Up to day 28 from the first dose
MTD was defined as the previous dose level at which 2 out of 3 subjects or 2 out of 6 subjects experienced a DLT
次要结局
- Time to reach maximum plasma concentration of HS-10382 or Flumatinib(and its major metabolite) after HS-10382 combination therapy(Cycle 1 day 1 up to 28 days after the last dose)
- Progression-free survival (PFS)(From the first dose to disease progression or withdrawal from study, whichever came first,up to 24 months)
- Area under the curve (AUC) of HS-10382 combination therapy(Cycle 1 day 1 up to 28 days after the last dose)
- Hematologic Response of combination therapy with HS-10382(up to 24 months)
- Cytogenetic Response of combination therapy with HS-10382(up to 24 months)
- Incidence and severity of treatment-emergent adverse events(Cycle 1 day 1 up to 28 days after the last dose)
- Event-free survival (EFS)(up to 24 months)
- maximum plasma concentration of HS-10382 or Flumatinib(and its major metabolite ) after HS-10382 combination therapy(Cycle 1 day 1 up to 28 days after the last dose)
- half-life (T1/2) of HS-10382 combination therapy(Cycle 1 day 1 up to 28 days after the last dose)
- Molecular Response of combination therapy with HS-10382(up to 24 months)
- Overall survival (OS)(From the first dose up to death or withdrawal from study, whichever came first, up to 24 months)