MEK and MET Inhibition in Colorectal Cancer
Condition: Solid Tumor; Colorectal Cancer
MeSH terms: Colorectal Neoplasms
Intervention: PF-02341066; PD-0325901; Binimetinib
Intervention description: PF-02341066 (Crizotinib) 250mg OD or 200mg BD or 250mg BD Days 1-28 continuously; PD-0325901 2mg - 8mg BD with Run in Day -7 to Day-1 on Cycle 1 Day1, then Day 1-21 every 28 day cycle.; Binimetinib 30mg or 45 mg BD either continuously or Days 1-21 every 28 days
Intervention MeSH terms: Crizotinib
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Sequential Assignment
Masking: None (Open Label)
Enrollment: 82.0
Sex: All
Minimum age: 16 Years
Healthy volunteers: No
Keywords: RASMT CRC; RASWT/c-MET CRC; Dose Escalation; Histologically or cytologically confirmed; Dose Expansion

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.
    

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.