A dose finding trial of PF-02341066 and Binimetinib in bowel cancer.
- Conditions
- Cancer. Solid tumours in the escalation phase and colorectal cancer in the expansion groups.MedDRA version: 20.0 Level: PT Classification code 10061451 Term: Colorectal cancer System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)Therapeutic area: Diseases [C] - Cancer [C04]
- Registration Number
- EUCTR2014-000463-40-IE
- Lead Sponsor
- niversity of Oxford
- Brief Summary
Not available
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- ot Recruiting
- Sex
- Not specified
- Target Recruitment
- 148
All patients
• 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 x 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 (combination of PF-02341066 with PD-0325901):
• Patients with any advanced solid tumours
• Patients for whom PF-02341066 with PD-0325901 is a reasonable option.
Dose escalation phase (combination of PF-02341066 with Binimetinib):
• Patients with any advanced solid tumours
• Patients for whom PF-02341066 with Binimetinib is a reasonable option.
Dose expansion
Patients will be eligible for pre-screening for MErCuRIC 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-MET mutated or amplified or c) RASWT/c-MET over-expressed with progressive disease on or within 6 months of completion of adjuvant therapy or after chemotherapy/targeted therapies for metastatic disease.
• Prior treatment with an EGFR targeted monoclonal antibody for patients with RASWT/c-MET mutated or amplified CRC or 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.
Are the trial subjects under 18? yes
Number of subjects for this age range: 1
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 90
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 50
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 conditions
• 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
• Radiotherapy (except for palliative reasons), endocrine therapy, immunotherapy or chemotherapy during the previous
four weeks (six weeks for nitrosoureas, Mitomycin-C)
• Resting ECG with QTc >480msec at 2 or more time points within a 24h
Study & Design
- Study Type
- Interventional clinical trial of medicinal product
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method
- Secondary Outcome Measures
Name Time Method