Sponsor: University of Oxford
EudraCT number: 2014-000463-40
A Sequential Phase I study of MEK 1/2 inhibitors PD-0325901 or Binimetinib combined with cMET inhibitor PF-02341066 in Patients with RAS Mutant and RAS Wild Type (with aberrant c-MET) Colorectal Cancer
Opened to recruitment: since November 2014. (Temporarily closed Dec2015 - July2016 due to change in IMP combination)
Recruitment re-started July 2016.
- Dose Escalation phase: Up to 25 patients using PF-02341066 and Binimetinib. (25 patients already recruited to the previous PD-0325901 and PF-02341066 combination).
- Dose Expansion phase: 3 cohorts where up to 22-40 patients will be required for the RASMT cohort, and 10-29 patients each for the RASWT/c-MET mut/amplified CRC, and RASWT/c-MET over-expressed CRC cohorts.
- The total patient number for the study will be between 92-148.
Dose Escalation Phase sites:
- Churchill Hospital, Oxford, UK
- Antwerp University Hospital, Belgium
- Instituto de Oncologia Vall d’Hebron, Spain
- Belfast City Hospital, Northern Ireland
- Velindre Cancer Centre, Cardiff, Wales
Dose Expansion Phase sites:
As above, plus:
- Beaumont Hospital, Dublin, Rep. of Ireland
- Hopital Saint Antoine, Paris, France
- Hopital European Georges Pompidou, Paris, France
− Age ≥ 16 years
− 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, 62, 227, 146) mutations) or b) RASWT/c-METmutated or amplified CRC 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-METmutated or amplified CRC or RASWT/c-MET over-expressed.
− 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.
− 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 or urine 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.
Dose Escalation Phase: To assess the safety and toxicity profile of PD-0325901 or Binimetinib/PF-02341066 combination in patients with advanced solid tumours using the NCI CTCAE V4.03, and determine the maximum tolerated dose (MTD).
Dose Expansion Phase: To investigate the response to treatment with RPII dose of PF-02341066 in combination with Binimetinib in patients with RASMT and RASWT/c-MET+ CRC.
Oncology Clinical Trial Office
Department of Oncology, Old Road Campus Research Building
University of Oxford, Old Road Campus, Off Roosevelt Drive, Headington
Oxford, OX3 7DQ
Tel: +44 (0)1865 227194