Randomized Phase II Study of Irinotecan and Cetuximab with or without Vemurafenib in BRAF Mutant Metastatic Colorectal Cancer

STEP 1: Must have histologically or cytologically documented adenocarcinoma of the color or rectum that is either metastatic or locally advanced and unresectable; must have BRAF-V600E mutant status; brain metastases are allowed if adequately treated with RT or surgery and stable at least 90 days prior to reg. Pts should be neurologically asymptomatic and without corticosteroid treatment at least 7 days prior to reg; Must have had one or two prior regimens of systemic chemo for metastatic or locally advanced, unresectable disease; prior treatment with iriontecan is allowed; prior treatment for metastatic disease is not required for pts w/disease recurrence w/in 6 mo of completion of adjuvant chemo; Must not have been treated w/any of the following: cetuximab, panitumumab, other monoclonal antibody against EGFR or inhibitor of EGFR, BRAF inhibitor, or MEK inhibitor; previous chemo, immunotherapy, or RT must be completed at least 14 days prior to reg with all toxicity resolved to Grade 1; No known mutation in codon 12 or 13 of KRAS and, if tested, no mutation in codons 61 or 146 in KRAS or codons 12, 13, 61, or 146 in NRAS; Must have tumor available for V600E BRAF testing and have additional tumor available & be willing to submit tissue and blood samples.

STEP 2: Must have BRAF-V600E mutation; must have measurable or non-measurable metastatic disease within 28 days prior to Step 2 reg; Zubrod PS 0-1; must be >/= 18 years old; must have complete physical exam & medical history within 28 days prior to Step 2 reg; adequate hematologic function w/in 14 days prior to Step 2 reg: ANC >/= 1,500/mcL, platelets >/= 100,000/mcL, and hemoglobin >/= 9 g/dL; adequate hepatic function within 14 days prior to Step 2 reg: AST and ALT </= 2.5 x IULN or </= 5 x IULN if liver mets are present, total bilirubin </= 1.5 x IULN; adequate kidney function within 14 days prior to Step 2 reg: serum creatinine </= 1.5 x IULN or calculated creatinine clearance > 60 ml/min; QTc </= 500 sec within 14 days prior to Step 2 reg; no known history of Gilbert's Syndrome or known homozygosity for UGT1A1*28 allele; no interstitial pneumonia or extensive symptomatic interstitial fibrosis of the lung; no uncontrolled intercurrent illness including active bleeding diathesis, uncontrolled infection/disorders including, nonmalignant medical illnesses, or psychiatric illness/social situation which would limit compliance with study requirements; must be able to swallow pill/tablet and have no refractory nausea, vomiting, malabsorption, external biliary shunt, or significant bowel resection; must not be pregnant or nursing during and for at least 60 days after study treatment; no other prior malignancy allowed except: adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, adequately treated Stage I or II cancer from which pt is currently in complete remission, or any other cancer from which pt has been disease free for three years.

STEP 3: Must have documented progression while on Arm 1; Step 3 reg must be within 28 days of discontinuation of Arm 1; Zubrod PS 0-1; adequate hematologic function w/in 14 days prior to Step 2 reg: ANC >/= 1,500/mcL, platelets >/= 100,000/mcL, and hemoglobin >/= 9 g/dL; adequate hepatic function within 14 days prior to Step 2 reg: AST and ALT </= 2.5 x IULN or </= 5 x IULN if liver mets are present, total bilirubin </= 1.5 x IULN; adequate kidney function within 14 days prior to Step 2 reg: serum creatinine </= 1.5 x IULN or calculated creatinine clearance > 60 ml/min.