A Sequential Phase I Study of MEK1/2 Inhibitors PD-0325901 or Binimetinib Combined With cMET Inhibitor PF-02341066 in Patients With RAS Mutant and RAS Wild Type (With Aberrant c-MET) Colorectal Cancer
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 82
- 试验地点
- 1
- 主要终点
- Maximal Tolerated Dose (MTD) of Binimetinib and PF-02341066
研究概览
简要总结
This trial is designed to try two new cancer drugs together for the first time. The investigators think that they might be effective in some types of bowel cancer. The first part of the trial will see what doses of the two drugs can safely be given together. Once the investigators have identified a suitable dose combination they will look at how effective treatment is in bowel cancers where either the RAS gene is mutated, or MET is over-active. In the trial the investigators will look at samples of blood, skin and tumour to check the drugs are working in the way expected. The trial will take place in three sites in the UK and 5 sites in Europe. The trial is funded as part of the European commission's FP7 program.
详细描述
This is a two stage study. Firstly a dose escalation step is used to define the best dose for the drug combination, using the rolling 6 design where up to 6 patients are recruited at each dose level, and increasing the dose of one or other agent according to the side effects of treatment. An initial dose escalation phase was completed where 25 patients were enrolled, using the study treatment combination of PD-0325901 with PF-02341066. Following discontinuation of the MEKi (inihibitor), PD-0325901, the study was updated to include a further dose escalation phase using the new combination study treatment, MEKi, Binimetinib with METi, PF-02341066. The effects of this drug combination will be assessed to define the recommended dose level for the dose expansion phase of the study.
Second the new drug combination is observed in 42-98 patients with bowel cancer for its efficacy and tolerability. Patients who give consent will have their archival tumour samples tested for RAS and c-MET status.
Potential participants will, after giving consent, undergo screening tests to ensure that it is safe for them to take part. These involve a detailed medical history, physical exam, blood tests, ophthalmology exam, ECG and ultrasound and skin biopsies. The size and extent of tumours is also assessed by CT and/or MRI scan.
For the initial dose escalation phase, on assurance that the test results are satisfactory, patients start on PD-0325901 first for one week. On Day -7 a physical exam, ECG and blood test is performed, with a repeat blood test on Day -6. End of first week PD samples of blood are taken to observe the level of PD-0325901. Day 1 PF-02341066 is introduced after further clinical safety assessments. There are further blood samples taken over 24 hours to measure levels of PD-0325901 and PF-02341066 on days 21 and 28 of the first cycle.
For the further dose escalation phase, again assuming that the screening test results are satisfactory, patients start on Day 1 with the combined treatment of PF-02341066 with Binimetinib. A physical exam, ECG and blood test is performed, with a repeat blood test on Day 2. There are further blood samples taken over 24 hours to measure levels of Binimetinib and PF-02341066 on day 21of the first cycle.
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
- 16 Years 至 —（Child, 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
Dose Escalation Phase Cohort 1 Dose level 1
Crizotinib 250mg OD Days 1-28 continuously PD-0325901 2mg BD Run in Day -7 to Cycle 1 Day1, then Day 1-21 every 28 day cycle
干预措施: PF-02341066 (Drug)
Dose Escalation Phase Cohort 1 Dose level 1
Crizotinib 250mg OD Days 1-28 continuously PD-0325901 2mg BD Run in Day -7 to Cycle 1 Day1, then Day 1-21 every 28 day cycle
干预措施: PD-0325901 (Drug)
Dose Escalation Phase Cohort 2 Dose level 2
Crizotinib 200mg BD Days 1-28 continuously PD-0325901 2mg BD Run in Day -7 to Cycle 1 Day1, then Day 1-21 every 28 day cycle
干预措施: PF-02341066 (Drug)
Dose Escalation Phase Cohort 2 Dose level 2
Crizotinib 200mg BD Days 1-28 continuously PD-0325901 2mg BD Run in Day -7 to Cycle 1 Day1, then Day 1-21 every 28 day cycle
干预措施: PD-0325901 (Drug)
Dose Escalation Phase Cohort 3 Dose level 3
Crizotinib 200mg BD Days 1-28 continuously PD-0325901 4mg BD Run in Day -7 to Cycle 1 Day 1, then Day 1-21 every 28 day cycle
干预措施: PF-02341066 (Drug)
Dose Escalation Phase Cohort 3 Dose level 3
Crizotinib 200mg BD Days 1-28 continuously PD-0325901 4mg BD Run in Day -7 to Cycle 1 Day 1, then Day 1-21 every 28 day cycle
干预措施: PD-0325901 (Drug)
Dose Escalation Phase Cohort 4 Dose level 4
Crizotinib 200mg BD Days 1-28 continuously PD-0325901 8mg BD Run in Day -7 to Cycle 1 Day1, then Day 1-21 every 28 day cycle
干预措施: PF-02341066 (Drug)
Dose Escalation Phase Cohort 4 Dose level 4
Crizotinib 200mg BD Days 1-28 continuously PD-0325901 8mg BD Run in Day -7 to Cycle 1 Day1, then Day 1-21 every 28 day cycle
干预措施: PD-0325901 (Drug)
Dose Escalation Phase Cohort 7 Dose level 5
Binimetinib 30mg BD continuous administration or Days 1-21 every 28 days. PF-02341066 200mg BD continuous administration
干预措施: PF-02341066 (Drug)
Dose Escalation Phase Cohort 7 Dose level 5
Binimetinib 30mg BD continuous administration or Days 1-21 every 28 days. PF-02341066 200mg BD continuous administration
干预措施: PD-0325901 (Drug)
Dose Escalation Phase Cohort 7 Dose level 5
Binimetinib 30mg BD continuous administration or Days 1-21 every 28 days. PF-02341066 200mg BD continuous administration
干预措施: Binimetinib (Drug)
Dose Escalation Phase Cohort 13 Dose level 5a
Binimetinib 30mg BD interval dose administration Days 1-21 every 28 days. PF-02341066 250mg OD continuous administration
干预措施: PF-02341066 (Drug)
Dose Escalation Phase Cohort 13 Dose level 5a
Binimetinib 30mg BD interval dose administration Days 1-21 every 28 days. PF-02341066 250mg OD continuous administration
干预措施: Binimetinib (Drug)
Dose Expansion Phase
Binimetinib 30mg BD interval dose administration Days 1-21 every 28 days PF-02341066 (Crizotinib) 250mg OD Days 1-28 continuously Dosage determined following the recommended Phase II dose identification in the dose escalation phase.
干预措施: PF-02341066 (Drug)
Dose Expansion Phase
Binimetinib 30mg BD interval dose administration Days 1-21 every 28 days PF-02341066 (Crizotinib) 250mg OD Days 1-28 continuously Dosage determined following the recommended Phase II dose identification in the dose escalation phase.
干预措施: Binimetinib (Drug)
Dose Escalation Phase Cohort 12 Dose level 5 (Interval dosing)
Binimetinib 30mg BD interval dose administration days 1-21 every 28 days. PF-02341066 200mg BD continuous administration
干预措施: PF-02341066 (Drug)
Dose Escalation Phase Cohort 12 Dose level 5 (Interval dosing)
Binimetinib 30mg BD interval dose administration days 1-21 every 28 days. PF-02341066 200mg BD continuous administration
干预措施: Binimetinib (Drug)
结局指标
主要结局
Maximal Tolerated Dose (MTD) of Binimetinib and PF-02341066
时间窗: Dose Escalation Phase: treatment Cycle 1 28 days
To determine the maximal tolerated dose (MTD) of Binimetinib with PF-02341066 according to toxicities graded by NCI CTCAE V4.03 in cycle 1 of treatment.
Maximal Tolerated Dose (MTD) of PD-0325901 and PF-02341066 /PF-02341066 or Binimetinib With PF-02341066
时间窗: Dose Escalation Phase: treatment Cycle 1 28 days (plus 7 day run-in for PD-0325901/PF-02341066 combination)
Determine maximum tolerated dose (MTD) of PD-0325901 with Crizotinib (PF-02341066) according to toxicities graded by NCI CTCAE v4.03, in patients with advanced solid tumours.
Clinical Response to Binimetinib Combined With PF-02341066
时间窗: Dose Expansion phase: change from baseline and up to 12 months.
To investigate response to treatment with RPII dose of Binimetinib with Crizotinib (PF-02341066), in patients with a) RASMT CRC or b) RASWT/cMET mut amplified CRC or c) RASWT/c-MET over-expressed CRC, as defined by stable, partially or completely responding disease, per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by CT: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Stable Disease (SD), Neither sufficient shrinkage to qualify for PR nor sufficient increase (\>=20%) to qualify for Progressive Disease; Overall Response (OR) = CR + PR + SD
次要结局
- Pharmacokinetic Peak Plasma Concentration (Cmax) for PF-02341066 and PD-0325901.(Dose Escalation:Up to 12 months. PK profile at pre-dose and up to 10 hrs post dose on Day - 1, Day 21 and Day 28 of Cycle 1)
- Pharmacokinetic Plasma t1/2 Etc for PF-02341066 and Binimetinib(Dose Expansion phase at Cycle 1 Day 21 up to 10 hours binimetinib and its metabolite, AR00426032, and up to 24 hours for PF-02341066)
- Pharmacokinetic Area Under the Plasma Concentration Versus Time Curve (AUC) for PF-02341066 and Binimetinib.(Dose Escalation :Up to 12 months. PK profile pre-dose and up to 10 hrs post dose on Day 21 of Cycle 1)
- Pharmacokinetic Plasma Oral Clearance for PF-02341066 and Binimetinib(Dose Expansion phase at Cycle 1 Day 21 up to 10 hours binimetinib and its metabolite, AR00426032, and up to 24 hours for PF-02341066)
- Pharmacokinetic Plasma t1/2 for PF-02341066 and Binimetinib.(Dose Escalation: PK profile at up to 10 hrs post dose on Cycle 1 Day 21)
- Pharmacokinetic (PK) Peak Plasma Concentration (Cmax) for PF-02341066 and Binimetinib.(Dose Expansion: PK profile up to 10 hrs at Cycle 1 Day 21)
- Pharmacokinetic Minimum Plasma Trough Concentration (Cmin) for PF-02341066 and Binimetinib.(Dose Expansion: PK profile on Cycle 1 Day 21 up to 10 hrs .)
- Pharmacokinetic Minimum Plasma Trough Concentration (Cmin) for PF-02341066 and PD-0325901(Dose Escalation:Up to 12 mths. Cycle 1 PK profile up to 10 hrs post dose on Day -1, 21 and 28)
- Pharmacokinetic Area Under the Plasma Concentration Versus Time Curve (AUC) for PF-02341066 and PD-0325901(and Its Metabolite)(Dose Escalation:Up to12 months. Cycle 1 PK profile up to 10 hrs on Day -1, 21 and 28)
- Pharmacokinetic Plasma Oral Clearance for PF-02341066 and PD-0325901(Dose Escalation:Up to12 months.PK profile at Cycle 1 up to 10 hrs post dose on Days -1, 21 and 28)
- Overall Survival (Dose Escalation Binimetinib/PF-02341066)(From date of study entry until the date of death, assessed up to study completion, an average of 6 months)
- Pharmacokinetic Peak Plasma Concentration (Cmax) for PF-02341066 and Binimetinib.(Dose Escalation:Up to 12 months. PK profile at pre-dose and up to 10 hrs post dose on Day 21 of Cycle 1)
- Progression Free Survival (Dose Expansion)(From date of study entry until the date of progression or date of death, assessed up to study completion, an average of 6 months (dose expansion)).)
- Overall Survival (Dose Expansion)(From date of study entry until the date of death, assessed up to study completion, an average of 6 months (dose escalation).)
- Pharmacokinetic Oral Clearance for PF-02341066 and Binimetinib.(Dose Escalation: PK profile at up to 10 hrs post dose on Cycle 1 Day 21)
- Pharmacodynamic (PD) Effect of PF-02341066 in Combination With PD-0325901 or Binimetinib in Paired Skin Biopsies - Measurement of phosphoMEK1/2.(Dose Escalation and Expansion: at baseline and Cycle1, D15.)
- Pharmacodynamic (PD) Effect of PF-02341066 in Combination With PD-0325901 or Binimetinib in Paired Tumour Biopsies (Where Possible).(Dose Escalation: Biopsies at baseline and Cycle1 D15 - both optional.)
- Pharmacodynamic (PD) Effect of PF-02341066 in Combination With Binimetinib in Paired Tumour Biopsies (Where Possible).(Dose Expansion: Biopsies at baseline and Cycle1 D15. Optional metastic tumour biopsy within 28 days following radiological confirmation of disease progression.)
- Progression Free Survival (Dose Escalation Binimetinib/PF-02341066).(From date of study entry until the date of progression or date of death, assessed up to study completion, an average of 6 months)
- Pharmacokinetic (PK) Minimum Plasma Trough Concentration (Cmin) for PF-02341066 and Binimetinib.(Dose Escalation phase :Up to 12 months. PK profile at pre-dose and up to 10 hrs post dose on Day 21 of Cycle 1)
- Pharmacokinetic Plasma t1/2 Etc for PF-02341066 and PD-0325901(Dose Escalation:Up to12 months.PK profile at Cycle 1 up to 10 hrs post dose on Days -1, 21 and 28)
- Pharmacodynamic (PD) Effect of PF-02341066 in Combination With PD-0325901 or Binimetinib in Paired Skin Biopsies - Measurement of phosphoERK1/2.(Dose Escalation and Expansion: at baseline and Cycle1, D15.)