MEK and MET Inhibition in Colorectal Cancer

Phase 1

Completed

Conditions: Solid Tumor
Colorectal Cancer

Interventions: Drug: PF-02341066
Drug: PD-0325901
Drug: Binimetinib

Registration Number: NCT02510001

Lead Sponsor: University of Oxford

Brief Summary: 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.

Detailed Description: 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.

Patients have weekly visits when side effects are reviewed and a physical examination is performed. On Day 15 a second skin biopsy is taken along with blood tests to assess liver and renal function. At the end of the first 4 weeks cycle, for the initial dose escalation phase, and at end of 8 weeks for the new combination therapy dose escalation phase, an ophthalmology exam is compared with the baseline assessment.

For subsequent cycles in both the initial dose escalation and further dose escalation phases, visits remain weekly and include safety assessments as per Day 1. Blood levels of PD-0325901 or Binimetinib and PF-02341066 are measured on day 21 of even numbered cycles. In addition the tumour size is checked every second cycle, and the study treatment stopped if the tumour continues to grow.

When patients stop taking the study treatment they will be reviewed after 4 weeks for any side effects and have a physical examination and other safety tests performed.

For patients entering the expansion phase of the trial the procedures are similar, except that there is a pre-screening stage where tumour biopsies are required. Patients will have a sample of their tumour assessed, following consent, to determine their RAS and cMET status. This may involve a fresh biopsy. If suitable, the patient will be entered into the screening for the dose expansion phase and a fresh tumour biopsy may be taken if not already done so. The study schedule is the same as for the escalation phase using Binimetinib with PF-02341066. At the end of treatment a further, optional, tumour biopsy may be taken.

After trial participation patients will be offered further care with the trial team or their referring oncology team as appropriate.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 82

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
Dose Escalation Phase Cohort 13 Dose level 5a	PF-02341066	Binimetinib 30mg BD interval dose administration Days 1-21 every 28 days. PF-02341066 250mg OD continuous administration
Dose Escalation Phase Cohort 1 Dose level 1	PF-02341066	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
Dose Escalation Phase Cohort 4 Dose level 4	PF-02341066	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
Dose Escalation Phase Cohort 2 Dose level 2	PF-02341066	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
Dose Escalation Phase Cohort 3 Dose level 3	PF-02341066	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
Dose Escalation Phase Cohort 7 Dose level 5	PF-02341066	Binimetinib 30mg BD continuous administration or Days 1-21 every 28 days. PF-02341066 200mg BD continuous administration
Dose Escalation Phase Cohort 12 Dose level 5 (Interval dosing)	PF-02341066	Binimetinib 30mg BD interval dose administration days 1-21 every 28 days. PF-02341066 200mg BD continuous administration
Dose Expansion Phase	PF-02341066	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.
Dose Escalation Phase Cohort 7 Dose level 5	Binimetinib	Binimetinib 30mg BD continuous administration or Days 1-21 every 28 days. PF-02341066 200mg BD continuous administration
Dose Escalation Phase Cohort 13 Dose level 5a	Binimetinib	Binimetinib 30mg BD interval dose administration Days 1-21 every 28 days. PF-02341066 250mg OD continuous administration
Dose Escalation Phase Cohort 12 Dose level 5 (Interval dosing)	Binimetinib	Binimetinib 30mg BD interval dose administration days 1-21 every 28 days. PF-02341066 200mg BD continuous administration
Dose Expansion Phase	Binimetinib	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.
Dose Escalation Phase Cohort 1 Dose level 1	PD-0325901	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
Dose Escalation Phase Cohort 2 Dose level 2	PD-0325901	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
Dose Escalation Phase Cohort 3 Dose level 3	PD-0325901	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
Dose Escalation Phase Cohort 4 Dose level 4	PD-0325901	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
Dose Escalation Phase Cohort 7 Dose level 5	PD-0325901	Binimetinib 30mg BD continuous administration or Days 1-21 every 28 days. PF-02341066 200mg BD continuous administration

Primary Outcome Measures

Name	Time	Method
Maximal Tolerated Dose (MTD) of Binimetinib and PF-02341066	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	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	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

Secondary Outcome Measures

Name	Time	Method
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	To investigate the pharmacokinetics (PK) plasma Cmax of PD-0325901 (and its metabolite, PD-0315209) with PF-023241066 when administered in combination.
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	To investigate the pharmacokinetics (PK) plasma half life of binimetinib (and its metabolite,AR00426032 ) with PF-023241066 when administered in combination.
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	To investigate the pharmacokinetic (PK) area under the plasma concentration versus time curve (AUC) of PF-02341066 and Binimetinib in blood.
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	To investigate the pharmacokinetics (PK) plasma oral clearance of binimetinib (and its metabolite,AR00426032 ) with PF-023241066 when administered in combination.
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	To investigate pharmacokinetic (PK) t1/2 of PF-02341066 and Binimetinib in blood.
Pharmacokinetic (PK) Peak Plasma Concentration (Cmax) for PF-02341066 and Binimetinib.	Dose Expansion: PK profile up to 10 hrs at Cycle 1 Day 21	To investigate the pharmacokinetic (PK) peak plasma concentration (Cmax) of PF-02341066 and Binimetinib and its metabolite, AR00426032, in blood.
Pharmacokinetic Minimum Plasma Trough Concentration (Cmin) for PF-02341066 and Binimetinib.	Dose Expansion: PK profile on Cycle 1 Day 21 up to 10 hrs .	To investigate pharmacokinetic plasma trough concentration Cmin of PF-02341066 and Binimetinib and its metabolite, AR00426032, in blood.
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	To investigate the pharmacokinetics (PK) plasma Cmin of PD-0325901 (and its metabolite, PD-0315209) with PF-023241066 when administered in combination.
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	To investigate the pharmacokinetics (PK) plasma AUC of PD-0325901 (and its metabolite, PD-0315209) with PF-023241066 when administered in combination.
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	To investigate the pharmacokinetics (PK) plasma oral clearance of PD-0325901 (and its metabolite, PD-0315209) with PF-023241066 when administered in combination.
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	Overall survival (Dose escalation Binimetinib/PF-02341066).
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	To investigate the pharmacokinetics (PK) plasma Cmax of Binimetinib (and its metabolite AR00426032) with PF-023241066 when administered in combination.
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)).	Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1), as a \>=20% increase in the sum of diameters of target lesions (also demonstrating an absolute increase of at least 5mm) or the appearance of new lesions.
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).	Overall survival (dose expansion).
Pharmacokinetic Oral Clearance for PF-02341066 and Binimetinib.	Dose Escalation: PK profile at up to 10 hrs post dose on Cycle 1 Day 21	To investigate pharmacokinetic (PK) oral clearance of PF-02341066 and Binimetinib in blood.
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.	Measurement of phosphoMEK1/2 in skin biopsies to investigate the pharmacodynamic (PD) effect of PF-02341066 in combination with PD-0325901 or Binimetinib in paired skin biopsies to determine objective response to treatment. Western blots are used to measure levels of expression and images are taken of the gels. Image J is used to measure pixels. The minimum is 0 and there is no maximum.
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.	Measurement of pSTAT3Y705 to investigate the pharmacodynamic (PD) effect of PF-02341066 in combination with PD-0325901 or Binimetinib in paired tumour biopsies to determine objective response to treatment. Western blots are used to measure levels of expression and images are taken of the gels. Image J is used to measure pixels. The minimum is 0 and there is no maximum.
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.	Measurement of phosphoERK1/2 to investigate the pharmacodynamic (PD) effect of PF-02341066 in combination with Binimetinib in paired tumour biopsies (where possible) to determine objective response to treatment. Western blots are used to measure levels of expression and images are taken of the gels. Image J is used to measure pixels. The minimum is 0 and there is no maximum.
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	Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1), as a \>=20% increase in the sum of diameters of target lesions (also demonstrating an absolute increase of at least 5mm) or the appearance of new lesions.
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	To investigate the pharmacokinetic (PK) minimum plasma trough concentration (Cmin) of PF-02341066 and binimetinib in blood.
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	To investigate the pharmacokinetics (PK) plasma half life of PD-0325901 (and its metabolite, PD-0315209) with PF-023241066 when administered in combination.
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.	Measurement of phosphoERK1/2 to investigte the pharmacodynamic (PD) effect of PF-02341066 in combination with PD-0325901 or Binimetinib in paired skin biopsies to determine objective response to treatment. Western blots are used to measure levels of expression and images are taken of the gels. Image J is used to measure pixels. The minimum is 0 and there is no maximum.