A Phase 1/2, Open-label, Multicenter Study to Evaluate Safety, Tolerability, Pharmacokinetics, and Efficacy of Single and Multiple Doses of Oral Administration of HS-10365 in Patients With 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
- 306
- 试验地点
- 1
- 主要终点
- Phase 1: To determine the maximum tolerated dose (MTD) or maximum administrated dose(MAD)
研究概览
简要总结
HS-10365 is a small molecular, oral potent, selective RET inhibitor. The purpose of this study is to investigate the safety/tolerability、the pharmacokinetic profile and efficacy of HS-10365 in Chinese advanced solid tumor patients.
详细描述
This is a multicenter, open-label phase 1/2 study in participants with advanced solid tumors, including RET fusion-positive non-small cell lung cancer and other tumors with RET activation. The trial will be conducted in 2 parts: Phase 1 and phase 2. Participants with advanced cancer are eligible if they have progressed on or intolerant to available standard therapies, or no standard or available curative therapy exists. The phase 1 study is a dose-escalation study, which is designed to evaluate the safety, tolerability, pharmacokinetics and preliminary anti-tumor activity of single dose and multiple doses of HS-10365 given once every day (QD) or twice every day (BID). A dose of 160 milligrams (mg) twice a day (BID) has been selected as the recommended phase 2 dose (RP2D). Approximately 273 participants with advanced solid tumors harboring a RET gene alteration will be enrolled to one of nine phase 2 cohorts:
Cohort 1: RET fusion non-small cell lung cancer (NSCLC) that has progressed after at least first-line therapy Cohort 2: RET fusion NSCLC not previously treated for metastatic disease Cohort 3: Medullary thyroid carcinoma that has progressed after at least first-line therapy Cohort 4: RET mutation-positive MTC not previously treated for metastatic disease Cohort 5: RET fusion Radioiodine-refractory thyroid cancer Cohort 6: Advanced solid tumors with RET gene fusion except for cohort 1 to 5 Cohort 7: Advanced solid tumors with RET gene abnormalities and drug resistance or intolerance previously treated with RET inhibitors except for cohort 1 to 6 Cohort 8: Advanced solid tumors with RET gene abnormality except for cohort 1 to 7 Cohort 9: NSCLC with RET gene abnormality except for cohort 1 to 2
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
- 未提供
排除标准
- •For Cohort 1 and Cohort 2，patient's cancer has a known primary driver alteration other than RET.
- •For Cohort 1~6 and Cohort 8~9，patients previously treated with a selective RET inhibitor.
- •Treatment with any of the following:
- •Previous or current treatment with selective RET inhibitors(except for cohort 7). Any cytotoxic chemotherapy, investigational agents and anticancer drugs within 14 days of the first dose of study drug (except for cohort 3 and 7).
- •Radiotherapy with a limited field of radiation for palliation within 2 weeks of the first dose of study drug, or patients received more than 30% of the bone marrow irradiation, or large-scale radiotherapy within 4 weeks of the first dose.
- •Major surgery within 4 weeks of the first dose of study drug.
- •Inadequate bone marrow reserve or organ function.
- •Uncontrolled pleural effusion or ascites or pericardial effusion.
- •Known and untreated, or active central nervous system metastases.
- •Refractory nausea, vomiting, or chronic gastrointestinal diseases, or inability to swallow the study drug that would preclude adequate absorption of HS-
- •History of hypersensitivity to any active or inactive ingredient of HS-10365 or to drugs with a similar chemical structure or class to HS-
- •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.
- •Any disease or condition that, in the opinion of the investigator, would compromise the safety of the patient or interfere with study assessments. Pregnant women, women who are breastfeeding or who believe they may wish to become pregnant during the course of the study.
- •History of neuropathy or mental disorders, including epilepsy and dementia
- •Determined by the physician, any coexisting disease might lead to life threatening complications or avoid the patients from accomplishing the treatment.
研究组 & 干预措施
Multiple doses of HS-10365 and 160mg BID (recommended Phase 2 dose)
Phase 1 : Multiple doses of HS-10365 for oral administration. Phase 2 : 160 mg BID of HS-10365
干预措施: HS-10365 (Drug)
结局指标
主要结局
Phase 1: To determine the maximum tolerated dose (MTD) or maximum administrated dose(MAD)
时间窗: Up to 28 days.
MTD was defined as the previous dose level at which 2 out of 3 subjects or 2 out of 6 subjects experienced a dose limiting toxicity (DLT).
Phase 2: Response Rate (ORR) assessed by independent review committee (IRC)
时间窗: From the date of first occurrence of complete response (CR) or partial response (PR) on 2 consecutive occasions (≥4 weeks), until the date of disease progression or withdrawal from study, whichever came first, up to 24 months.
anti-tumor efficacy will be assessed by best radiographic response based on response evaluation criteria in solid tumors at baseline (Day -28 to -1). For patients that continue on repeating 28-Day cycles after the primary evaluation period, progression will be assessed after each 6 weeks before 18 weeks of therapy and then each 12 weeks. ORR is defined as the percentage of patients with a CR or PR that was confirmed at a subsequent scan at least 4 weeks later, as assessed according to RECIST version 1.1.
次要结局
- Incidence and severity of treatment-emergent adverse events(From baseline until 28 days after the last dose)
- Time to reach maximum plasma concentration (Tmax) after single dose of HS-10365(From pre-dose to 120 hours after single dose on Day 1)
- Area under plasma concentration versus time curve from zero to last sampling time (AUC0-t) after single dose of HS-10365(From pre-dose to 120 hours after single dose on Day 1)
- Observed maximum plasma concentration (Cmax ss) after multiple dose of HS-10365(From pre-dose to 24 hours after the first dose of multiple dosing on Day 1 of the following 21-Day cycles of therapy)
- ORR of HS-10365(From the date of first occurrence of CR or PR on 2 consecutive occasions (≥4 weeks), until the date of disease progression or withdrawal from study, whichever came first, up to 24 months]（Only phase 1）)
- Duration of response of HS-10365 (DoR)(From the date of the first dose to disease progression or death in patients who achieve CR or PR, whichever came first, up to 24 months.)
- Observed maximum plasma concentration (Cmax) after single dose of HS-10365(From pre-dose to 120 hours after single dose on Day 1)
- Apparent terminal half-life (T1/2) after single dose of HS-10365(From pre-dose to 120 hours after single dose on Day 1)
- Disease control rate of HS-10365 (DCR)(From the first occurrence of confirmed CR or PR or SD until the date of disease progression or withdrawal from study, whichever came first, up to 24 months.)
- Progression-free survival of HS-10365 (PFS)(From the date of the first dose until the date of disease progression or death from any cause, whichever came first, up to 24 months.)
- Overall survival (OS)(The time from initial administration to death from any cause, up to 4 years)