EUCTR2014-000463-40-GB进行中（未招募）1 期
A Sequential Phase I study of MEK1/2 inhibitors PD-0325901 or Binimetinib combined with cMET inhibitor Crizotinib in RAS Mutant and RAS Wild Type(with aberrant c-MET) Colorectal Cancer - MErCuRIC1: MEK and MET Inhibition in Colorectal Cancer
适应症
相关药物
试验速览
- 阶段
- 1 期
- 状态
- 进行中（未招募）
- 入组人数
- 82
研究概览
简要总结
暂无简介。
研究设计
- 研究类型
- Interventional clinical trial of medicinal product
入排标准
- 性别
- All
入选标准
- •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 a) RASMT (KRAS codon 12, 13, 61,117; NRAS codon 12, 13, 63, 227, 136) 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-MET mutated 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.
- •Are the trial subjects under 18? yes
- •Number of subjects for this age range: 0
- •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
排除标准
- •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 period (using Fredericia correction).
- •Requirement for medication known to prolong QT interval.
- •History of other malignancy less than 3 years before the diagnosis of current cancer
- •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 mo
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