MEK and MET Inhibition in Colorectal Cancer

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 wh