PRIMARY OBJECTIVES:~I. To evaluate the progression-free survival (PFS) of v-raf murine sarcoma viral oncogene homolog B (BRAF) mutant metastatic colorectal cancer patients treated with irinotecan (irinotecan hydrochloride), cetuximab, and vemurafenib, compared to a control arm of irinotecan and cetuximab.~SECONDARY OBJECTIVES:~I. To evaluate the frequency and severity of toxicity associated with each of the treatment arms in this patient population.~TERTIARY OBJECTIVES:~I. To evaluate overall survival (OS) in treatment Arms 1 and 2. II. To evaluate the overall response rate (ORR), including confirmed and unconfirmed, complete and partial response, in treatment Arms 1 and 2 in the subset of patients with measurable disease.~III. To estimate rates of OS, ORR, and PFS in patients who register to Arm 3 after disease progression on Arm 1.~IV. To evaluate low-frequency Kirsten rat sarcoma viral oncogene homolog (KRAS) or neuroblastoma RAS viral (v-ras) oncogene homolog (NRAS) mutations as detected by high-depth sequencing as predictive biomarkers of efficacy.~V. To evaluate phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA) pathway activation through PIK3CA mutations or phosphatase and tensin homolog (PTEN) protein loss as a predictive biomarker of innate resistance to this regimen.~VI. To evaluate gene expression signatures from screened patients with v-raf murine sarcoma viral oncogene homolog B wild type (BRAFWT) and BRAFV600E tumors.~VII. To provide validation of BRAF immunohistochemistry (IHC) using complementary sequencing methodology from screened patients with BRAFWT and BRAFV600E tumors.~VIII. To confirm the estimated sensitivity of detectable BRAF V600E circulating cell-free deoxyribonucleic acid (DNA) as a non-invasive biomarker for BRAF V600E mutation as detected by IHC in the primary tumor.~IX. To correlate radiographic tumor response with change in quantification of BRAFV600E alleles in circulating cell-free DNA.~X. To monitor for known mechanism of acquired resistance to epidermal growth factor receptor (EGFR) inhibition in circulating cell-free DNA (KRAS, NRAS mutations).~OUTLINE: Patients are randomized to 1 of 2 treatment arms.~ARM I: Patients receive cetuximab intravenously (IV) and irinotecan hydrochloride IV on days 1 and 14. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients with disease progression may cross over to Arm II.~ARM II: Patients receive cetuximab and irinotecan hydrochloride as in Arm I and vemurafenib orally (PO) twice daily (BID) on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.~After completion of study treatment, patients are followed up every 2-6 months for 3 years.
This randomized phase II trial studies how well irinotecan hydrochloride and cetuximab with or without vemurafenib works in treating patients with colorectal cancer that has spread to nearby tissue or lymph nodes, that has spread to other places in the body, or cannot be removed by surgery. Irinotecan hydrochloride and vemurafenib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Monoclonal antibodies, such as cetuximab, may block the ability of tumor cells to grow and spread. It is not yet known whether irinotecan hydrochloride and cetuximab are more effective with or without vemurafenib in treating colorectal cancer.