Pertuzumab and Cetuximab in Treating Patients With Previously Treated Locally Advanced or Metastatic Colorectal Cancer

Inclusion Criteria:

* Patients with a history of colorectal cancer (CRC) treated by surgical resection and who develop radiological or clinical evidence of metastatic disease do not require separate histological or cytological confirmation of metastatic disease unless 1 of the following criteria are met:

  * More than 5 years has elapsed between the primary surgery and the development of metastatic disease
  * The primary cancer was stage I
* Patients must have representative tumor specimens in paraffin blocks or at least 15 unstained slides with an associated pathology report obtained at any time prior to study entry:

  * Cytology specimens are not acceptable replacements
* Patients must have their tumor tissue screened for KRAS mutation status, and be found to have a KRAS wild-type tumor:

  * No KRAS-mutated tumor
* Locally advanced or metastatic disease
* Not curable by surgery or amenable to radiotherapy with curative intent
* Must have received an cetuximab-containing regimen for at least 6 weeks for treatment of metastatic disease
* Documented progression of disease or intolerable toxicity during or within 3 months of receiving this regimen
* Patients who have received an cetuximab-containing regimen as adjuvant therapy for resected stage II or III CRC are eligible provided recurrent disease is documented \< 6 months after completion of adjuvant treatment
* Must have received \>= 1 prior chemotherapeutic regimen for treatment of metastatic disease with any of the following:

  * Cetuximab
  * Must have resolution of any skin rash related to prior treatment with cetuximab
  * No prior cetuximab which required a dose reduction for toxicity
  * 5-fluorouracil or capecitabine
  * Irinotecan hydrochloride or oxaliplatin
* Measurable disease by CT scan or physical exam
* ECOG performance status (PS) 0-1 (Karnofsky PS 70-100%)
* Life expectancy \> 12 weeks
* Absolute neutrophil count \>= 1,500/mcL
* Platelet count \>= 100,000/mcL
* Leukocytes \>= 3,000/mcL
* Hemoglobin \>= 9 g/dL (transfusion, erythropoietin, or other approved hematopoietic growth factors allowed)
* Total bilirubin =\< 1.5 times upper limit of normal (ULN)
* AST and ALT =\< 5 times ULN
* Creatinine normal OR Creatinine clearance \>= 60 mL/min
* Not pregnant or nursing
* Negative pregnancy test
* Fertile patients must use effective contraception prior to and during study therapy
* Cardiac left ventricular ejection fraction \>= 50% OR \>= lower limit of normal
* No evidence of left ventricular wall motion abnormalities as measured by ECHO or MUGA scan
* None of the following cardiac conditions:

  * Uncontrolled high blood pressure
  * Unstable angina
  * Symptomatic congestive heart failure
  * Congestive heart failure, cardiac dysfunction, or cardiomyopathy requiring medication treatment
  * Myocardial infarction within the past 6 months
  * Serious uncontrolled cardiac arrhythmia
  * New York Heart Association class III or IV heart disease
* No active or uncontrolled infection
* No predisposing colonic or small bowel disorders in which the symptoms are uncontrolled as indicated by baseline pattern of \> 3 loose stools/day (in patients without a colostomy or ileostomy)
* Patients with a colostomy or ileostomy may be eligible at investigator discretion
* No psychiatric illness/social situation that would limit compliance with study requirements
* No other prior or concurrent malignancy, except for adequately treated basal cell or squamous cell skin cancer, in situ carcinoma of the cervix, lobular carcinoma in situ in one breast, or other cancer from which the patient has been disease-free for at least 5 years
* No other medical or psychiatric disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug or that may affect the interpretation of the study results or render the patient at high risk for treatment complications
* No history of allergic reactions, hypersensitivity, or intolerance to cetuximab, and/or compounds of similar chemical or biologic composition to pertuzumab or cetuximab (i.e., other monoclonal antibodies such as bevacizumab) that led to discontinuation of the drug
* Patients able to tolerate subsequent infusions after a reaction are eligible
* At least 4 weeks since prior major surgery (e.g., laparotomy) and recovered (Insertion of a vascular access device is not considered major or minor surgery)
* At least 2 weeks since prior minor surgery and recovered (Insertion of a vascular access device is not considered major or minor surgery)
* At least 4 weeks since prior major radiotherapy (e.g., chest or bone palliative radiotherapy)
* At least 4 weeks since prior bevacizumab
* More than 4 weeks since prior chemotherapy (6 weeks for nitrosoureas or mitomycin C) and recovered
* No prior agents directed against EGFR and/or HER2
* No more than one prior treatment regimen for metastatic disease; Prior chemotherapy in the adjuvant setting following resection of stage II or III disease allowed provided the regimen did not contain irinotecan hydrochloride and/or an agent directed against EGFR and/or HER2
* No prior doxorubicin or liposomal doxorubicin at doses \> 360 mg/m\^2; epirubicin at doses \> 720 mg/m\^2; mitoxantrone at doses \> 120 mg/m\^2; or idarubicin at doses \> 90 mg/m\^2
* No prior radiotherapy to \> 15% of the bone marrow
* No prior standard adjuvant chemoradiotherapy for rectal cancer
* No phenytoin, phenobarbital, carbamazepine, or any other enzyme-inducing anti-convulsant drugs (EIACDs) for at least 7 days before, during, and for 7 days after the final dose of irinotecan hydrochloride
* Concurrent gabapentin or other non-EIACDs are allowed
* No St. John's wort for at least 14 days before, during, and for 7 days after the final dose of irinotecan hydrochloride
* No concurrent corticosteroids, except for stable doses of prednisone (\< 20 mg/day or equivalent), topical or inhaled corticosteroids, or corticosteroids for reasons unrelated to treatment of colorectal cancer
* No concurrent combination antiretroviral therapy for HIV-positive patients
* No concurrent filgrastim (G-CSF) or sargramostim (GM-CSF) for any of the following reasons:

  * To avoid dose reductions or delays
  * Prophylactic treatment
  * Treatment of febrile neutropenia
* No other concurrent HER family-targeted therapy
* No concurrent rifampin
* No concurrent herbal remedies unless initiated prior to study entry
* No other concurrent investigational agents
* No other concurrent anticancer therapy, including cytotoxic chemotherapy, radiotherapy, immunotherapy, hormonal therapy, or biological anticancer therapy
* Histologically or cytologically confirmed adenocarcinoma of the colon or rectum
* Site of the primary lesion must be or have been confirmed endoscopically, radiologically, or surgically to be or have been in the large bowel
* No known brain metastases
* No concurrent fluconazole