study of encorafenib + cetuximab plus or minus binimetinib vs. irinotecan/cetuximab or infusional 5-fluorouracil (5-fu)/folinic acid (fa)/irinotecan (folfiri)/cetuximab with a safety lead-in of encorafenib + binimetinib + cetuximab in patients with braf v600e-mutant metastatic colorectal cancer

Conditions: BRAF V600E-mutant Metastatic Colorectal Cancer

Summary: this is a multicenter, randomized, open-label, 3-arm phase 3 study to evaluate encorafenib + cetuximab plus or minus binimetinib versus investigator's choice of either irinotecan/cetuximab or folfiri/cetuximab, as controls, in patients with brafv600e mcrc whose disease has progressed after 1 or 2 prior regimens in the metastatic setting. the study contains a safety lead-in phase in which the safety and tolerability of encorafenib + binimetinib + cetuximab will be assessed prior to the phase 3 portion of the study.


Eligibility criteria:
key inclusion criteria: * age ≥ 18 years at time of informed consent * histologically- or cytologically-confirmed crc that is metastatic * presence of brafv600e in tumor tissue as previously determined by a local assay at any time prior to screening or by the central laboratory * progression of disease after 1 or 2 prior regimens in the metastatic setting * evidence of measurable or evaluable non-measurable disease per recist, v1.1 * adequate bone marrow, cardiac, kidney and liver function * able to take oral medications * female patients are either postmenopausal for at least 1 year, are surgically sterile for at least 6 weeks, or must agree to take appropriate precautions to avoid pregnancy from screening through follow-up if of childbearing potential * males must agree to take appropriate precautions to avoid fathering a child from screening through follow-up key exclusion criteria: * prior treatment with any raf inhibitor, mek inhibitor, cetuximab, panitumumab or other epidermal growth factor receptor (egfr) inhibitors * prior irinotecan hypersensitivity or toxicity that would suggest an inability to tolerate irinotecan 180 mg/m2 every 2 weeks * symptomatic brain metastasis or leptomeningeal disease * history or current evidence of retinal vein occlusion or current risk factors for retinal vein occlusion (e.g., uncontrolled glaucoma or ocular hypertension, history of hyperviscosity or hypercoagulability syndromes) * known history of acute or chronic pancreatitis * history of chronic inflammatory bowel disease or crohn's disease requiring medical intervention (immunomodulatory or immunosuppressive medications or surgery) ≤12 months prior to randomization * uncontrolled blood pressure despite medical treatment * impaired gi function or disease that may significantly alter the absorption of encorafenib or binimetinib (e.g., ulcerative diseases, uncontrolled vomiting, malabsorption syndrome, small bowel resection with decreased intestinal absorption) * concurrent or previous other malignancy within 5 years of study entry, except cured basal or squamous cell skin cancer, superficial bladder cancer, prostate intraepithelial neoplasm, carcinoma in-situ of the cervix, or other noninvasive or indolent malignancy * history of thromboembolic or cerebrovascular events ≤ 6 months prior to starting study treatment, including transient ischemic attacks, cerebrovascular accidents, deep vein thrombosis or pulmonary emboli * concurrent neuromuscular disorder that is associated with the potential of elevated creatine (phosphor)kinase (ck) (e.g., inflammatory myopathies, muscular dystrophy, amyotrophic lateral sclerosis, spinal muscular atrophy) * residual common terminology criteria for adverse events (ctcae) ≥ grade 2 toxicity from any prior anticancer therapy, with the exception of grade 2 alopecia or grade 2 neuropathy * known history of hiv infection * active hepatitis b or hepatitis c infection * known history of gilbert's syndrome * known contraindication to receive cetuximab or irinotecan at the planned doses

Keywords: colorectal cancer braf brafv600e