MEK and MET Inhibition in Colorectal Cancer

University of Oxford82 enrolled

Overview

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.

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.

Eligibility

Sex: ALLMin age: 16 Years

Medical Language ↔ Plain English

INCLUSION CRITERIA (Inclusion criteria for the completed initial dose escalation phase using PF-02341066/PD-0325901 are listed in Appendix 7.) All patients * Age ≥ 16 years (\>18 years in France) * ECOG performance status 0-1 (Appendix 1) * Adequate respiratory function on clinical assessment * Left ventricular ejection fraction (LVEF) ≥ 50% as determined by a multigated acquisition (MUGA) scan or echocardiogram┼ * Able to give informed consent prior to any screening procedures being performed and be capable of complying with the protocol and its requirements * Haematological and biochemical indices within the ranges shown below: * Haemoglobin (Hb) ≥ 9g/dl (transfusion to achieve this allowed ), * Neutrophils ≥ 1,500/μl, * Platelet count ≥ 100,000/μl, * AST or ALT ≤ 2.5 x ULN, patient with liver metastases ≤ 5 × ULN, * Alkaline phosphatase ≤ 5 x ULN, * Serum Bilirubin ≤ 1.5 x ULN, * Creatinine Clearance ≥ 50ml/min (Calculated by Cockcroft Gault equation, or by EDTA) (Appendix 2) * Able to swallow oral medication * Life expectancy of at least 3 months. Dose escalation phase: * Patients with any advanced solid tumours * Patients for whom the combination of PF-02341066 with Binimetinib is a reasonable option. Dose expansion phase: Patients will be eligible for pre-screening for this phase provided that: * They have given informed consent to screening. * They are willing to undergo a biopsy for assessment of tumour RAS mutation status and c-MET assessment. * The Investigator anticipates that they are likely to satisfy the eligibility criteria for the trial. Formal screening should not be performed until the tumour pre-screening result is known. Eligibility for the trial, in patients passing pre-screening, requires: * Histologically confirmed colorectal adenocarcinoma that is either a) RASMT (KRAS codon 12, 13, 61, 117, 146; NRAS codon 12, 13, 61, 117, 146) or b) RASWT/c-MET mutated/amplified or c) RASWT/c-MET over-expressed with progressive disease on or within 6 months of completion of adjuvant therapy or after chemotherapy and/or targeted therapies for metastatic disease. * Prior treatment with an EGFR targeted monoclonal antibody for patients with RASWT/c-MET mutated or amplified CRC or c) RASWT/c-MET over-expressed CRC. * No evidence for a mutation in BRAF at codon600 * Metastases accessible for biopsy on 2-3 occasions * At least one other measurable lesion (according to RECIST v1.1). * Unsuitable for potential curative resection. ┼For non-UK territories: if echocardiogram (ECHO) cannot be performed, a MUGA scan may be performed in compliance with local policy, applicable national legislation and relevant approvals. Cardiac ejection fraction must be determined as measured by ECHO in the UK. EXCLUSION CRITERIA (Exclusion criteria for the completed initial dose escalation phase using PF-02341066/PD-0325901 are listed in Appendix 7.) All patients * Unstable ischaemic heart disease, cardiac dysrhythmias, coronary/peripheral artery bypass graft or cerebrovascular accident within 6 months prior to starting treatment. * Uncontrolled arterial hypertension despite medical treatment. * Ongoing congestive heart failure or cardiac dysrhythmias of NCI CTCAE Grade ≥2 or uncontrolled atrial fibrillation. * History of extensive disseminated/bilateral or known presence of Grade 3 or 4 interstitial fibrosis or interstitial lung disease, including a history of pneumonitis, hypersensitivity pneumonitis, interstitial pneumonia, interstitial lung disease (ILD), obliterative bronchiolitis, and pulmonary fibrosis. A history of prior radiation pneumonitis is allowed. * Any active central nervous system (CNS) lesion (i.e., those with radiographically unstable, symptomatic lesions) and/or leptomeningeal metastases. However, patients treated with stereotactic radiotherapy or surgery are eligible if the patient remained without evidence of CNS disease progression ≥ 3 months. Patients must be off corticosteroid therapy for ≥ 3 weeks. * Patients who have neuromuscular disorders that are associated with elevated CK (e.g., inflammatory myopathies, muscular dystrophy, amyotrophic lateral sclerosis, spinal muscular atrophy); * Patients who are planning on embarking on a new strenuous exercise regimen after first dose of study treatment. NB: Muscular activities, such as strenuous exercise, that can result in significant increases in plasma CK levels should be avoided while on Binimetinib treatment * Spinal cord compression unless treated with the patient attaining good pain control and stable or recovered neurologic function. * Carcinomatous meningitis or leptomeningeal disease. * History of hypoalbuminaemia, or patients with peritoneal disease or pleural disease, where there is a requirement for ascitic or pleural taps. * History of retinal vein occlusion, intraocular pressure \> 21 mmHg or patient considered at risk of retinal vein thrombosis (e.g. history of hyperviscosity or hypercoagulability syndromes). * History of retinal degenerative disease. * History of Gilbert's syndrome. * Active infections (including chronic hepatitis type B or C and HIV infection if status known), severe immunologic defect, compromised bone marrow function. * Other severe acute or chronic medical (including severe gastro-intestinal disorders e.g. partial bowel obstruction, malabsorption, active inflammatory bowel disease) or psychiatric conditions or laboratory abnormalities that the investigator considers would make the patient a poor trial candidate, would impart excess risk associated with study participation or drug administration or could interfere with protocol compliance or the interpretation of trial results. * Patients who have undergone major surgery ≤ 3 weeks prior to starting study drug or who have not recovered from side effects of such procedure. * Use of drugs or foods that are known potent CYP3A4 inhibitors or inhibitors or are CYP3A4 substrates with narrow therapeutic indices (see Appendix 5). * Radiotherapy (except for palliative reasons), endocrine therapy, immunotherapy or chemotherapy during the previous four weeks (six weeks for nitrosoureas, Mitomycin-C) and four weeks for investigational medicinal products before treatment. Patients with prostate cancer may continue to receive endocrine therapy to maintain castrate levels of androgens. * Resting ECG with QTc \> 480msec at 2 or more time points within a 24h period (using Fredericia correction). * Requirement for medication known to prolong QT interval (Appendix 5). * History of other malignancy less than 3 years before the diagnosis of current cancer, EXCLUDING the following: Non-melanoma skin cancer, in situ carcinoma of the cervix treated surgically with curative intent, other malignant tumours that have been treated curatively and patient is deemed disease-free * Women with the ability to become pregnant (or already pregnant or lactating). However, those female patients who have a negative serum pregnancy test before enrolment and agree to use one highly effective form of contraception (oral, injected or implanted hormonal contraception or intra-uterine device) in addition to condom plus spermicide for four weeks before entering the trial, during the trial and for six months afterwards are considered eligible. * Male patients with partners of child-bearing potential unless they agree to take measures not to father children by using one form of highly effective contraception including oral, injected or implanted hormonal contraception or intra-uterine device in addition to condom plus spermicide, during the trial and for six months afterwards). Men with pregnant or lactating partners should be advised to use barrier method contraception (condom plus spermicidal gel) to prevent exposure to the foetus or neonate. * Prior exposure to any of a HGF, cMET or a MEK inhibitor.

Outcomes

Primary Outcomes

Maximal Tolerated Dose (MTD) of PD-0325901 and PF-02341066 /PF-02341066 or Binimetinib With PF-02341066

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.

Time frame: Dose Escalation Phase: treatment Cycle 1 28 days (plus 7 day run-in for PD-0325901/PF-02341066 combination)

Clinical Response to Binimetinib Combined With PF-02341066

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

Time frame: Dose Expansion phase: change from baseline and up to 12 months.

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

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.

Time frame: Dose Escalation Phase: treatment Cycle 1 28 days

Secondary Outcomes

Pharmacokinetic Peak Plasma Concentration (Cmax) for PF-02341066 and PD-0325901.

To investigate the pharmacokinetics (PK) plasma Cmax of PD-0325901 (and its metabolite, PD-0315209) with PF-023241066 when administered in combination.

Time frame: 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 Minimum Plasma Trough Concentration (Cmin) for PF-02341066 and PD-0325901

To investigate the pharmacokinetics (PK) plasma Cmin of PD-0325901 (and its metabolite, PD-0315209) with PF-023241066 when administered in combination.

Time frame: 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)

To investigate the pharmacokinetics (PK) plasma AUC of PD-0325901 (and its metabolite, PD-0315209) with PF-023241066 when administered in combination.

Time frame: 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

To investigate the pharmacokinetics (PK) plasma oral clearance of PD-0325901 (and its metabolite, PD-0315209) with PF-023241066 when administered in combination.

Time frame: Dose Escalation:Up to12 months.PK profile at Cycle 1 up to 10 hrs post dose on Days -1, 21 and 28

Progression Free Survival (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.

Time frame: 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)

Overall survival (dose expansion).

Time frame: From date of study entry until the date of death, assessed up to study completion, an average of 6 months (dose escalation).

Pharmacokinetic (PK) Peak Plasma Concentration (Cmax) for PF-02341066 and Binimetinib.

To investigate the pharmacokinetic (PK) peak plasma concentration (Cmax) of PF-02341066 and Binimetinib and its metabolite, AR00426032, in blood.

Time frame: Dose Expansion: PK profile up to 10 hrs at Cycle 1 Day 21

Pharmacokinetic Minimum Plasma Trough Concentration (Cmin) for PF-02341066 and Binimetinib.

To investigate pharmacokinetic plasma trough concentration Cmin of PF-02341066 and Binimetinib and its metabolite, AR00426032, in blood.

Time frame: Dose Expansion: PK profile on Cycle 1 Day 21 up to 10 hrs .

Pharmacokinetic Area Under the Plasma Concentration Versus Time Curve (AUC) for PF-02341066 and Binimetinib.

To investigate pharmacokinetic area under the plasma concentration versus time curve (AUC) of PF-02341066 and Binimetinib in blood.

Time frame: Dose Expansion: PK profile on Cycle 1 Day 21 up to 10 hrs

Pharmacokinetic Oral Clearance for PF-02341066 and Binimetinib.

To investigate pharmacokinetic (PK) oral clearance of PF-02341066 and Binimetinib in blood.

Time frame: 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.

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.

Time frame: 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).

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.

Time frame: 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).

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.

Time frame: 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).

Time frame: From date of study entry until the date of progression or date of death, assessed up to study completion, an average of 6 months

Overall Survival (Dose Escalation Binimetinib/PF-02341066)

Overall survival (Dose escalation Binimetinib/PF-02341066).

Time frame: 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.

To investigate the pharmacokinetics (PK) plasma Cmax of Binimetinib (and its metabolite AR00426032) with PF-023241066 when administered in combination.

Time frame: Dose Escalation:Up to 12 months. PK profile at pre-dose and up to 10 hrs post dose on Day 21 of Cycle 1

Pharmacokinetic (PK) Minimum Plasma Trough Concentration (Cmin) for PF-02341066 and Binimetinib.

To investigate the pharmacokinetic (PK) minimum plasma trough concentration (Cmin) of PF-02341066 and binimetinib in blood.

Time frame: 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 Area Under the Plasma Concentration Versus Time Curve (AUC) for PF-02341066 and Binimetinib.

To investigate the pharmacokinetic (PK) area under the plasma concentration versus time curve (AUC) of PF-02341066 and Binimetinib in blood.

Time frame: 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

To investigate the pharmacokinetics (PK) plasma oral clearance of binimetinib (and its metabolite,AR00426032 ) with PF-023241066 when administered in combination.

Time frame: 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

Pharmacodynamic (PD) Effect of PF-02341066 in Combination With PD-0325901 or Binimetinib in Paired Skin Biopsies - Measurement of phosphoERK1/2.

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.

Time frame: Dose Escalation and Expansion: at baseline and Cycle1, D15.

Pharmacokinetic Plasma t1/2 Etc for PF-02341066 and PD-0325901

To investigate the pharmacokinetics (PK) plasma half life of PD-0325901 (and its metabolite, PD-0315209) with PF-023241066 when administered in combination.

Time frame: Dose Escalation:Up to12 months.PK profile at Cycle 1 up to 10 hrs post dose on Days -1, 21 and 28

Pharmacokinetic Plasma t1/2 for PF-02341066 and Binimetinib.

To investigate pharmacokinetic (PK) t1/2 of PF-02341066 and Binimetinib in blood.

Time frame: Dose Escalation: PK profile at up to 10 hrs post dose on Cycle 1 Day 21

Pharmacokinetic Plasma t1/2 Etc for PF-02341066 and Binimetinib

To investigate the pharmacokinetics (PK) plasma half life of binimetinib (and its metabolite,AR00426032 ) with PF-023241066 when administered in combination.