Phase I Study of Oral PQR309 in Patients With Advanced Solid Tumors
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 70
- 试验地点
- 1
- 主要终点
- To identify the Maximum Tolerated Dose (MTD) of PQR309 administered in different (continuous and intermittent) dosing schedules. To evaluate efficacy of PQR309 in selected patient population: • Solid tumors with PI3K/mTOR activation • Human Papilloma
研究概览
简要总结
This is an open-label, multi-center, non-randomized, dose escalation Phase 1 study evaluating safety, tolerability, PK (pharmacokinetics) and efficacy of PQR309 in the treatment of selected patients with advanced solid tumors.
详细描述
This is an open-label, multi-center, non-randomized, dose escalation Phase 1 study evaluating safety, tolerability, PK (pharmacokinetics)and efficacy of PQR309 in the treatment of selected patients with advanced solid tumors.
In the initial phase of the study, patients will be treated once daily until disease progression, unacceptable toxicity, patient's request for withdrawal, investigator judgment or death whichever comes first. Enrollment of an initial patient cohort of 3 or 6 patients will follow the traditional 3 + 3 dose escalation scheme to evaluate Dose Levels 1 - 5 with continuous q.d dosing schedule. Patients will be treated with PQR309 at starting Dose Level 1 enrolling exceptionally 6 patients (only applicable for continuous dosing schedule). Subsequent patient cohort(s) will be enrolled depending on the safety and tolerability of the initial cohort. If < 33% patients treated at Dose Level 1 (80 mg) experience Dose Limiting Toxicities (DLT - see definition below) by the end of first treatment cycle (21 days), next cohort of 3 patients will be enrolled and treated at Dose Level 2 of the continuous dosing schedule, if 2 or more treatment-related DLTs are observed at Dose Level 1, patients will be accrued to Dose Level -1. If 2 or more patients experience a DLT during dose Level 2 (120 mg), the dose of 100 mg will be explored next.The MTD is defined as the maximum dose level at which ≤ 1/6 patients have DLTs. After the MTD has been established with the continuous dosing schedule, the study will be expanded to evaluate the MTD of intermittent dosing schedules. Initially 2 additional dosing schedules, intermittent schedule A and B, will be evaluated in parallel. Patients will be assigned to the two schedules in an alternating manner.
Patients will be treated only within dose and schedule cohort they have been enrolled in. No within-patient dose escalation or alteration of dosing schedule will be allowed.Both schedules A and B will evaluate intermittent dosing in 21 day cycles:
Intermittent schedule A:
Two days of once daily PQR309 administration followed by no treatment for 5 days.
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
- 未提供
研究组 & 干预措施
PQR309
Different dose Evaluation (continous and intermittent) 20-160mg daily
干预措施: PQR 309 (Drug)
结局指标
主要结局
To identify the Maximum Tolerated Dose (MTD) of PQR309 administered in different (continuous and intermittent) dosing schedules. To evaluate efficacy of PQR309 in selected patient population: • Solid tumors with PI3K/mTOR activation • Human Papilloma
时间窗: In average 1 year
MTD based on the rate of dose-limiting toxicities. The MTD is defined as the maximum dose level at which ≤ 1/6 patients have dose limiting toxicities (DLTs).
Objective response rate (ORR) according to the response evaluation• Solid tumors with PI3K/mTOR activation • Human Papilloma Virus (HPV) positive Head and neck squamous cell carcinoma (HNSCC) containing activating PIK3CA mutations
时间窗: in average 2 years
Expansion part criteria in solid tumors (RECIST), version 1.1
次要结局
- Number of patients with adverse Events and serious adverse events(Assessment on Day 1 after basline, Cycle1 on Day 8,15, Cycle 2 and subsequent cycles on Day 1, End of the treatment up to 3 days and as follow up 30 days after last dosing)
- Physical examination according to ECOG (Eastern Cooperative Oncology Group) Performance Status(Assessment on Day1,2, Cycle 1 on Day 4,8,9,15)
- Change in ECG(After Cycle 2 and subsequent cycles on Day1, end of treatment up to 3 days after last medication)
- Depression test (PHQ-9)(Cycle 1 on Day 8,15, Cycle 2 and subsequent cycles on Day1, end of treatment up to 3 days after last medication)
- Generalized anxiety disorder mood scale score (GAD7)(Cycle 1 on Day 8,15, Cycle 2 and subsequent cycles on Day1, end of treatment up to 3 days after last medication)
- Changes in routine blood chemistry(Assessment on Day 1 after baseline, Cycle 1 on Day 8,15, Cycle 2 and subsequent cycles on Day1, end of treatment up to 3 days after last medication)
- Changes of hematology(Assessment on Day 1 after baseline, Cycle 1 on Day 8,15, Cycle 2 and subsequent cycles on Day1, end of treatment up to 3 days after last medication)
- Changes of insulin/Glucose/ C-peptide(Assessment on Day 1,2 after baseline, Cycle1 on Day 4, 8,9,15)
- Changes of haemostasis(Assessment on Day 1 after baseline, Cycle 1 on Day 1,15 Cycle 2 and subsequent cycles on Day1, end of treatment up to 3 days after last medication)
- Determination of Cmax(Assessment on Day 1,2 after baseline, Cycle 1 on Day 4,8,9,15)
- Determination of AUC 0-24(Assessment on Day 1,2 after baseline, Cycle 1 on Day 4,8,9,15)
- Determination of tmax(Assessment on Day 1,2 after baseline, Cycle 1 on Day 4,8,9,15)
- Determination of AUClast (area under the curve)(Assessment on Day 3,2,1 after baseline, Cycle 1 on Day 8,15, Cycle 2 on Day1)
- Determination of AUClast(Assessment on Day 1,2 after baseline, Cycle 1 on Day 4,8,9,15)
- Change in Pulse Rate(Assessment on Day1,2,Cycle 1 on Day 4,8,9,15)
- Change in Temperature(Assessment on Day1,2,Cycle 1 on Day 4,8,9,15)
- Change in Respiratory Rate(Assessment on Day1,2,Cycle 1 on Day 4,8,9,15)
- Change in Blood Pressure(Assessment on Day1,2,Cycle 1 on Day 4,8,9,15)
- Change in Blood Body Weight(Assessment on Day1,2,Cycle 1 on Day 4,8,9,15)
- Determination of AUC0-∞(Assessment on Day 1,2 after baseline, Cycle 1 on Day 4,8,9,15)
- Determination of t 1/2(Assessment on Day 1,2 after baseline, Cycle 1 on Day 4,8,9,15)
- Determination of RAC (Accumulation Ratio)(Assessment on Day 1,2 after baseline, Cycle 1 on Day 4,8,9,15)
- Determine Time to Response (TTR)(up to 2 years)
- Determine Duration of Response (DOR)(baseline and on Day 1 of every subsequential cycle which can be up to 24 months)
- Time to Treatment Failure (TTF)(Tumor Measurement preferably with a ruler and/or MRI scans e.g. and incorporated clinical signs will be assesses at baseline and on Day 1 of every subsequential cycle which can be up to 24 months)
- Determine Progression Free Survival (PFS)(baseline and on Day 1 of every subsequential cycle which can be up to 24 months)
- 1- year Survival Rate(baseline and on Day 1 of every subsequential cycle which can be up to 36 months)