A Phase 1 Study to Determine the Safety, and Pharmacokinetics of the Selective MET Kinase Inhibitor, DO-2 in Patients With Advanced or Refractory Solid Tumours
试验速览
- 阶段
- 1 期
- 状态
- 进行中（未招募）
- 发起方
- 入组人数
- 25
- 试验地点
- 8
- 主要终点
- Number of subjects who experience specific treatment-related adverse events (TRAEs)
研究概览
简要总结
This study is a first-in-human, open-label, 2-part, Phase 1 dose escalation study of DO-2, administered orally to patients with advanced or refractory solid tumours, with MET aberrations, and no available, approved therapeutic alternative.
详细描述
In Part 1, a Simon Design 3 accelerated titration design will be followed. One patient will be enrolled per cohort, until grade 2 toxicity is observed. Three sequential patients per cohort will be enrolled thereafter, with a minimum of 1 week between first dose administration in the first patient and the subsequent ones, in those latter cohorts.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Sequential
- 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
- •18 years or older
- •histologically or cytologically confirmed advanced or refractory solid tumour and no longer eligible for approved, available standard therapies. Tumour types must have:
- •proven MET activating mutations, determined by previous next generation sequencing (NGS), whole exome sequencing (WES), whole transcriptome sequencing (WTS) or other genomic analysis methods, or
- •proven amplification (≥ 10 copies) on archived tumour tissue. or
- •Hereditary Renal Papillary Cancer
- •measurable disease in accordance with RECIST 1.1
- •Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1
- •adequate bone marrow function, without the support of cytokines
- •adequate liver function
- •adequate renal function
- •agree to follow the contraception requirements of the trial
- •signed informed consent, indicating study patients understand the purpose of and procedures required for the study and are willing to participate in the study.
排除标准
- •major surgery within 3 weeks before enrollment
- •chemotherapy (in the case of nitrosoureas and mitomycin C within 6 weeks), radiotherapy, immunotherapy, or any other study drug within 3 weeks before study drug administration
- •antibody based cancer therapy within 4 weeks before administration of the first dose of DO-2
- •patients who became progressive on previous treatment with a MET-kinase inhibitor
- •patients with brain metastases are excluded unless all of the following criteria are met:
- •CNS lesions are asymptomatic and previously treated
- •No ongoing requirement for corticosteroids as therapy for CNS metastases
- •Imaging demonstrates stability of disease > 28 days from last treatment for CNS metastases
- •leptomeningeal involvement (leptomeningeal carcinomatosis)
- •history of uncontrolled heart disease including unstable angina, congestive heart failure, myocardial infarction within preceding 12 months, clinically significant rhythm or conduction abnormality, congenital long QT syndrome, obligate use of a cardiac pacemaker, QTc at screening greater than 450 milliseconds in males and greater than 470 milliseconds in females
- •uncontrolled arterial hypertension despite appropriate therapy
- •positive pregnancy test (urinary beta-hCG) at screening (applicable to women of child-bearing potential who are sexually active)
- •mental status alteration or history of major psychiatric illness, which may potentially impair patient's compliance with study procedures
- •signs and symptoms of active infection requiring systemic therapy
- •other medical condition (e.g. pre-existing kidney dysfunction) that in the opinion of the investigator makes it undesirable for a patient to participate
研究组 & 干预措施
Cohort 1 (starting dose)
Oral administration, once a day for 28 days, in a 4-week cycle
干预措施: DO-2 (Drug)
Cohort 2 (dose level 2)
Oral administration, once a day for 28 days, in a 4-week cycle
干预措施: DO-2 (Drug)
Cohort 3 (dose level 3)
Oral administration, once a day for 28 days, in a 4-week cycle
干预措施: DO-2 (Drug)
Cohort 4 (dose level 4)
Oral administration, once a day for 28 days, in a 4-week cycle
干预措施: DO-2 (Drug)
Cohort 5 (dose level 5)
Oral administration, once a day for 28 days, in a 4-week cycle
干预措施: DO-2 (Drug)
Cohort 6 (dose level 6)
Oral administration, once a day for 28 days, in a 4-week cycle
干预措施: DO-2 (Drug)
Cohort 7 (dose level 7)
Oral administration, once a day for 28 days, in a 4-week cycle
干预措施: DO-2 (Drug)
结局指标
主要结局
Number of subjects who experience specific treatment-related adverse events (TRAEs)
时间窗: Baseline up to Week 36
Number of subjects with specific treatment-related adverse events for each dose group. AE refers to any untoward medical occurrence or deterioration of existing medical event after the subject signed the ICF, whether or not considered related to the study treatment. TRAEs are any event that occurs after the subject has received study treatment. AE grading will be performed in accordance with NCI-CTC Version 5.0.
Number of subjects who experience Dose Limiting Toxicities (DLTs)
时间窗: Baseline up to Week 4
Only toxicities that occur during Cycle 1 will be considered for the purposes of defining DLT and for dose escalation, but toxicities that occur in all cycles will be recorded and considered in decisions about the Maximum Tolerated Dose. DLTs are defined as toxicities that meet pre-defined severity criteria. Toxicity grading will be performed in accordance with NCI-CTC Version 5.0.
Determination of the Maximum Tolerated Dose (MTD)
时间窗: Baseline up to Week 4
The MTD in milligram is defined as the highest dose at which less than one third of the subjects in a dose level cohort experience DLT.
次要结局
- Overall survival (OS)(Baseline through study completion, an average of 36 weeks)
- Maximum observed concentration (Cmax) and Area under the curve (AUC) of DO-2(Baseline up to Day 23)
- Objective responses seen in Part I and objective response rate (ORR) in Part II(Baseline through study completion, an average of 36 weeks)
- Time over treshold (ToT) for DO-2(Baseline up to Day 23)
- Progression-free survival (PFS)(Baseline through study completion, an average of 36 weeks)
- Duration of response (DoR)(Baseline through study completion, an average of 36 weeks)