This phase II trial studies how well panitumumab and combination chemotherapy works in treating patients with metastatic colorectal cancer previously treated with combination chemotherapy and bevacizumab. Monoclonal antibodies, such as panitumumab, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. Drugs used in chemotherapy, such as leucovorin calcium, fluorouracil, and irinotecan hydrochloride, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving panitumumab and combination chemotherapy together may kill more tumor cells

PRIMARY OBJECTIVES:

I. To determine the median progression-free survival in patients treated with leucovorin calcium, fluorouracil, and irinotecan hydrochloride (FOLFIRI) and panitumumab for K-ras and NRAS wild-type, metastatic colorectal carcinoma who have already progressed on FOLFIRI + Bevacizumab.

SECONDARY OBJECTIVES:

I. To determine the frequency and severity of toxicities of the regimens. II. To determine overall response rate. III. To determine the median overall survival and the overall survival rate at 1 year.

OUTLINE:

Patients receive panitumumab intravenously (IV) over 60-90 minutes, leucovorin calcium IV over 90 minutes, fluorouracil IV continuously over 46 hours, and irinotecan hydrochloride IV over 90 minutes on days 1 and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up periodically.

Inclusion Criteria:

• Patients with advanced adenocarcinoma of the colon or rectum not curable with surgery or radiotherapy and have been previously treated for their disease with FOLFIRI plus bevacizumab in the first line metastatic setting; patients will only be eligible if their last line of therapy prior to enrolling onto the study was FOLFIRI and bevacizumab received no more than 6 months prior to enrolling in this study; they should have been treated with FOLFIRI plus bevacizumab until disease progression is radiographically documented
• Patients' tumors will need to tested for the K-RAS and N-RAS mutation status; only those patients with wild-type or unmutated K-RAS and N-RAS oncogene are eligible to participate in this study
• Provide written informed consent prior to study-specific screening procedures, with the understanding that the patient has the right to withdraw from the study at any time, without prejudice
• Prior cetuximab is allowed in the adjuvant but not in the metastatic setting, but must have been completed at least 6 months before starting this trial
• Eastern Cooperative Oncology Group (ECOG) performance status =< 1
• Life expectancy greater than 12 weeks
• No active brain metastasis; previously surgically treated or irradiated lesions are allowed if not clinically active
• Has a negative serum pregnancy test within 7 days prior to registration (female patients of childbearing potential)
• Ability to understand and willingness to sign a written informed consent
• No history of severe reactions to fluorouracil (5-FU), irinotecan (irinotecan hydrochloride), or a monoclonal antibody
• Leukocytes >= 3000/uL
• Absolute neutrophil count >= 1500/uL
• Platelets >= 100,000/uL
• Hemoglobin >= 9 mg/dL
• Total bilirubin =< 1.5 X upper limit of normal (ULN)
• Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 3 X ULN (or < 5 x ULN with liver metastases)
• Creatinine clearance (CrCl) >= 30 ml/min (Cockroft-Gault equation)
• Magnesium >= lower limit of normal
• Measurable disease is required according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria
• The effects of Panitumumab on the developing human fetus are unknown; for this reason and because monoclonal antibodies as well as other therapeutic agents used in this trial are known to be teratogenic, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation and up to 6 months after completing therapy; should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately

Exclusion Criteria:

• Pregnant or lactating women; women of childbearing potential with either a positive or no pregnancy test at baseline; woman or men of childbearing potential not using a reliable and appropriate contraceptive method; (postmenopausal woman must have been amenorrheic for at least 12 months to be considered of non-childbearing potential)
• Sexually active males unwilling to practice contraception during the study and 6 months beyond
• Uncontrolled intercurrent illness including but not limited to clinically significant cardiac disease not well controlled with medication (e.g. congestive heart failure, symptomatic coronary artery disease and cardiac arrhythmias) or myocardial infarction within the last 12 months, and serious concurrent infections
• History of interstitial lung disease (eg, pneumonitis or pulmonary fibrosis) or evidence of interstitial lung disease on baseline chest computed tomography (CT) scan
• KRAS or NRAS mutant tumors
• Active inflammatory bowel disease or other bowel disease causing chronic diarrhea (defined as >= Common Toxicity Criteria [CTC] grade 2 [Common Terminology Criteria for Adverse Events (CTCAE) version 4.0])
• Clinically significant cardiovascular disease (including myocardial infarction, unstable angina, symptomatic congestive heart failure, serious uncontrolled cardiac arrhythmia) =< 1 year
• Bevacizumab within the last 4 weeks before starting treatment on trial
• Patient is more than 6 months since the last dose of FOLFIRI
• Patients who have required toxicity related dose reductions of no less than 50% of the original dose of infusional 5-FU and/or irinotecan during the administration of FOLFIRI + bevacizumab
• Prior exposure to panitumumab in any setting
• Prior exposure to cetuximab in the metastatic (stage IV) setting
• Radiotherapy =< 14 days prior to enrollment; patients must have recovered from all radiotherapy-related toxicities
• Prior unanticipated severe reaction to fluoropyrimidine therapy, or known sensitivity to 5-fluorouracil, leucovorin (leucovorin calcium), irinotecan, or panitumumab
• Treatment for other carcinomas within the last three years, except cured non-melanoma skin and treated in-situ cervical cancer
• Participation in any investigational drug study within 4 weeks preceding the start of study treatment
• Other serious uncontrolled medical conditions that the investigator feels might compromise study participation
• Major surgery within 4 weeks of the start of study treatment, without complete recovery
• Unwillingness to give written informed consent
• Unwillingness to participate or inability to comply with the protocol for the duration of the study
• Patients with human immunodeficiency virus (HIV)/acquired immune deficiency syndrome (AIDS) and those severely immunocompromised will be excluded; however, no patients will be tested for HIV