A Phase I, Open-label, Dose-escalation and Expansion Study to Evaluate the Safety, Tolerability, Pharmacokinetic and Pharmacodynamic of HSK41959 in Patients With MTAP Deletion Locally Advanced or Metastatic Solid Tumors
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 发起方
- 入组人数
- 245
- 试验地点
- 3
- 主要终点
- DLTs
研究概览
简要总结
This is a phase I, open-label, dose-escalation and expansion study to evaluate the safety, tolerability, PK and PD of HSK41959 when given orally in patients with MTAP Deletion locally advanced or metastatic Solid Tumors.
详细描述
The study will contain two phases: Phase Ia is dose escalation phase and Phase Ib is dose expansion phase.
Phase Ia will contain two part: Dose Escalation Part (Part A) and Extension Part (Part B). Part A based on the "3+3" design for dose escalation and safety evaluation requirements. Patient cohorts at selected doses may be extended to further investigate the tolerability, PK and PD of HSK41959. The number of patients to be enrolled will be up to 10 subjects in each Part B cohort. Approximately 30-50 subjects will be enrolled in Phase Ia.
Phase Ib no less than 10-50 subjects will be enrolled in each expansion cohort.
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
- •Age ≥ 18 years，Male and female patients, at time of signing informed consent form (ICF).
- •ECOG performance status 0-
- •Life expectancy ≥ 3 months.
- •Patients with locally advanced or metastatic solid tumors confirmed by histology or cytology, who have failed standard treatment (disease progression after treatment or intolerable treatment).
- •Homozygous deletion of the MTAP gene detected in tumor tissue confirmed prior to the administration of HSK
- •Measurable disease by RECIST 1.1 criteria.
- •Adequate hematologic, hepatic, and renal function.
排除标准
- •Prior treatment with a PRMT5 or MAT2A inhibitor therapy.
- •The presence of unstable, clinically symptomatic central nervous system metastases or leptomeningeal metastases.
- •Malignant tumor within 2 years, with the exception of cutaneous squamous cell carcinoma, cervical carcinoma in situ, papillary thyroid carcinoma, or other tumors with low malignancy.
- •Uncontrollable pleural effusion, ascites, or pericardial effusion per protocol.
- •Treatment with any of the following:
- •Prior treatment with anti-tumor drug within 4 weeks or approximately 5 × t1/2 prior to the first dose of HSK41959, whichever is shorter; Prior treatment with nitrosourea or mitomycin C within 6 weeks prior to the first dose of HSK41959; Prior treatment with palliative radiotherapy or anti-tumor herbs within 2 weeks prior to the first dose of HSK41959; Prior treatment with radiotherapy, electric field therapy, or other anti-tumor therapies within 4 weeks prior to the first dose of HSK
- •Any unresolved toxicities from prior therapy greater than Common Terminology Criteria for Adverse Events (CTCAE) grade 1 at the time of starting study treatment, with the exception of alopecia, dermal toxicity, and other toxicity considering no safety risks by investigator.
- •Any disease which would preclude drug absorption, metabolism or pharmacokinetics, e.g. active peptic ulcer or chronic gastroesophageal reflux disease.
- •Patients who have clinically significant or uncontrolled cardiac disease, include: QTc interval ≥ 450(male)/470(female) msec; any clinically significant arrhythmia; left ventricular ejection fraction < 50%; myocardial infarction, unstable angina, or class III/IV cardiac failure by the NYHA that occurred within 6 months prior to the first dose of HSK
- •Any thromboembolic events within 6 months prior to the first dose of HSK41959; any familial or acquired thrombophilia.
- •Uncontrolled hypertension (systolic pressure≥160mmHg, or diastolic pressure≥100mmHg), diabetes (fasting blood-glucose≥10mmol/L), seizures, chronic obstructive pulmonary disease (COPD), interstitial pneumonia, pulmonary interstitial fibrosis, Parkinson's disease, active bleeding, or systemic active infection.
- •Any unstable systemic disease, e.g. severe metabolic disease: liver cirrhosis, renal failure, or uremia.
- •Patient with cognitive dysfunction, or history of mental illness, other uncontrolled comorbidities, alcohol dependence, hormone dependence or drug abuse.
- •Other protocol-defined Inclusion/Exclusion criteria apply
研究组 & 干预措施
Phase Ia (Part A): HSK41959 as monotherapy
Phase 1a (Part A): dose escalation of HSK41959 as monotherapy at various dose levels
干预措施: HSK41959 (Drug)
Phase Ia (Part B): HSK41959 as monotherapy
Phase 1a (Part B): dose extention of HSK41959 as monotherapy at certain dose levels
干预措施: HSK41959 (Drug)
Phase Ib: HSK41959 as monotherapy
Phase 1b: dose expansion for HSK41959 as monotherapy at a dose determined during Phase 1a (Part B) in patients with MTAP Deletion locally advanced or metastatic solid tumors
干预措施: HSK41959 (Drug)
结局指标
主要结局
DLTs
时间窗: 24 days
Incidence of dose-limiting toxicities (DLTs) at Cycle 0 and Cycle1
MTD
时间窗: 24 days
MTD determination: dose limiting toxicity (DLT) rate
AEs
时间窗: Up to approximately 3 years
Rate and severity of adverse events of HSK41959 as monotherapy
RP2D
时间窗: Up to approximately 1 year
RP2D determination: DLT, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary safety and anticancer activity data
次要结局
- Tmax(Time to maximum plasma concentration) of HSK41959(Up to approximately 6 months)
- Overall response rate (ORR)(Up to approximately 3 years)
- Disease control rate (DCR)(Up to approximately 3 years)
- Duration of response (DOR)(Up to approximately 3 years)
- Progression free survival (PFS)(Up to approximately 3 years)
- Overall survival (OS)(Up to approximately 3 years)
- Area under the curve (AUC) of HSK41959(Up to approximately 6 months)
- maximum plasma concentration (Cmax) of HSK41959(Up to approximately 6 months)
- half-life (t1/2) of HSK41959(Up to approximately 6 months)