Safety and Efficacy Study of Neratinib and Cetuximab to Treat Patients With Quadruple Wild-Type Metastatic Colorectal Cancer

Inclusion criteria: * Patients with resected primary must be active participants of the NSABP Patient Registry and Biospecimen Profiling Repository (MPR-1) study. Patients with intact primary and metastatic KRAS wild-type disease at presentation (treatment naive), must have signed consent for quadruple wild-type central testing for treatment-naive tumor sample submission * The Eastern Cooperative Oncology Group (ECOG) performance status must be 0, 1, or 2. * Patients must have the ability to swallow oral medication. * The tumor tissue must have been determined to be KRAS, NRAS, BRAF, PIK3CA wild-type by central CLIA testing. * There must be documentation by PET/CT scan, CT scan, or MRI, that the patient has evidence of measurable metastatic disease per RECIST criteria. * Patients must have an accessible metastatic lesion for pretreatment core biopsy procurement. * Unless either drug is medically contraindicated, patients must have received oxaliplatin and irinotecan as part of standard chemotherapy regimens. (This includes adjuvant therapy.) * Patients must have had at least one prior treatment for metastatic disease with standard chemotherapy and cetuximab in combination or as monotherapy. \[Note: patients who received panitumumab instead of cetuximab are eligible.\] * At the time of study entry, blood counts performed within 4 weeks prior to study entry must meet the following criteria: absolute neutrophil count (ANC) must be greater than or equal to 1000/mm3; Platelet count must be greater than or equal to 100,000/mm3; Hemoglobin must be greater than or equal to 9 g/dL * The following criteria for evidence of adequate hepatic function performed within 4 weeks prior to study entry must be met: Total bilirubin must be less than or equal to 1.5 x upper limit of normal (ULN); aspartate aminotransferase (AST) and ALT must be less than or equal to 2.5 x ULN for the lab or less than or equal to 5 x ULN if liver metastasis; * Serum creatinine performed within 4 weeks prior to study entry must be less than or equal to 1.5 x ULN for the lab. * Female patients and male patients with female partners of reproductive potential must agree to use an effective method of contraception during therapy and for at least 6 months after the last dose of study therapy. * Patients with acquired immunodeficiency syndrome (AIDS-related illnesses) or known human immunodeficiency virus (HIV) disease must: Have a CD4 count greater than or equal to 200 cells/uL within 30 days prior to beginning study therapy; Be off all antiretroviral therapy (prophylaxis/treatment) greater than 60 days prior to beginning study therapy; Have no evidence of opportunistic infections. Exclusion criteria: * Diagnosis of anal or small bowel carcinoma. * Colorectal cancer other than adenocarcinoma, e.g., sarcoma, lymphoma, carcinoid. * Previous therapy with any HER2 TKI (such as trastuzumab, lapatinib, neratinib, etc.) for any malignancy. * Symptomatic brain metastases or brain metastases requiring chronic steroids to control symptoms. * Active hepatitis B or hepatitis C with abnormal liver function tests. * Malabsorption syndrome, ulcerative colitis, inflammatory bowel disease, resection of the stomach or small bowel, or other disease or condition significantly affecting gastrointestinal function. * Persistent Common Toxicity Criteria for Adverse Effects (CTCAE v4.0) greater than or equal to grade 2 diarrhea regardless of etiology. * Chronic daily treatment with corticosteroids with a dose of greater than or equal to 10 mg/day methylprednisolone equivalent (excluding inhaled steroids). * CTCAE v4.0 grade 3 or 4 anorexia or nausea related to metastatic disease. * CTCAE v4.0 greater than or equal to grade 2 vomiting related to metastatic disease. * Any of the following cardiac conditions: Documented congestive heart failure; Myocardial infarction within 6 months prior to study entry; Unstable angina within 6 months prior to study entry; Symptomatic arrhythmia * Serious or non-healing wound, skin ulcer, or bone fracture. * History of bleeding diathesis or coagulopathy. (Patients on stable anticoagulant therapy are eligible.) * Symptomatic interstitial lung disease or definitive evidence of interstitial lung disease described on CT scan, MRI, or chest x-ray in asymptomatic patients; dyspnea at rest requiring current continuous oxygen therapy. * Other malignancies unless the patient is considered to be disease-free and has completed therapy for the malignancy greater than or equal to 12 months prior to study entry. Patients with the following cancers are eligible if diagnosed and treated within the past 12 months: carcinoma in situ of the cervix, colorectal carcinoma in situ, melanoma in situ, and basal cell and squamous cell carcinoma of the skin. * Previous serious hypersensitivity reaction to monoclonal antibodies. (Determination of "serious" hypersensitivity reaction is at the investigator's discretion.) * Psychiatric or addictive disorders or other conditions that, in the opinion of the investigator, would preclude the patient from meeting the study requirements. * Pregnancy or lactation at the time of study entry. * Use of any investigational agent within 4 weeks prior to study entry.