MEK and MET Inhibition in Colorectal Cancer

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 Criteria:
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.