Inclusion Criteria:

          -  STEP 1 INITIAL REGISTRATION: HER2 TESTING

          -  Patients must have histologically or cytologically documented adenocarcinoma of the
             colon or rectum that is metastatic or locally advanced and unresectable

          -  Mutation results:

               -  All patients must have molecular testing performed in a Clinical Laboratory
                  Improvement Act (CLIA) certified lab which includes which includes KRAS and NRAS
                  gene and exon 15 of BRAF gene (BRAF V600E mutation); patients with any known
                  activating mutation in exon 2 [codons 12 and 13], exon 3 [codons 59 and 61] and
                  exon 4 [codons 117 and 146]) of KRAS/NRAS genes and in exon 15 (BRAFV600E
                  mutation) of BRAF gene are not eligible

          -  Patients must not have been treated with any of the following prior to step 1 initial
             registration:

               -  Cetuximab, panitumumab, or any other monoclonal antibody against EGFR or
                  inhibitor of EGFR

               -  HER-2 targeting for treatment of colorectal cancer; patients who have received
                  prior trastuzumab or pertuzumab for other indications such as prior history of
                  adjuvant or neoadjuvant breast cancer treatment prior to the development of
                  advanced colorectal cancer are eligible

          -  Patients must not have had history of severe toxicity and intolerance to or
             hypersensitivity to irinotecan or any other study drug; patients must not have had a
             severe infusion-related reaction during any prior therapy with pertuzumab or
             trastuzumab

          -  Patients must have tumor slides available for submission for HER-2 testing; HER-2
             testing must be completed by the central lab prior to step 2 randomization

          -  Patients must be informed of the investigational nature of this study and must sign
             and give informed consent in accordance with institutional and federal guidelines; for
             step 1 initial registration, the appropriate consent form is the step 1 consent form

          -  As a part of the OPEN registration process the treating institution's identity is
             provided in order to ensure that the current (within 365 days) date of institutional
             review board approval for this study has been entered in the system

          -  STEP 2 RANDOMIZATION

          -  Patients must have HER-2 amplification as determined by central testing (3+ or 2+ by
             immunohistochemistry and HER-2 gene amplification by in situ hybridization with a
             ratio of HER-2 gene signals to centromere 17 signals >= 2.0)

          -  Patients must have measurable disease that is metastatic or locally advanced and
             unresectable; imaging used to assess all disease per RECIST 1.1 must have been
             completed within 28 days prior to step 2 randomization; all disease must be assessed
             and documented on the Baseline Tumor Assessment Form

          -  Patients must have had at least one prior regimen of systemic chemotherapy for
             metastatic or locally advanced, unresectable disease; patients must have progressed
             following the most recent therapy; prior treatment with irinotecan is allowed; for
             patients that received adjuvant chemotherapy: prior treatment for metastatic disease
             is not required for patient who experienced disease recurrence during or within 6
             months of completion of adjuvant chemotherapy; if the patient received one line of
             adjuvant treatment and had disease recurrence after 6 months of completing
             chemotherapy, patients will only be eligible after failing one additional line of
             chemotherapy used to treat the metastatic or locally advanced, unresectable disease;
             patients who have received >= 3 lines of systemic chemotherapy for metastatic or
             locally advanced, unresectable disease are not eligible

          -  Patients must have completed prior chemotherapy, immunotherapy, or radiation therapy
             at least 14 days prior to step 2 randomization and all toxicity must be resolved to
             Common Terminology Criteria for Adverse Events (CTCAE) version (v)4.0 grade 1 (with
             the exception of CTCAE v4.0 grade 2 neuropathy) prior to step 2 randomization

          -  Brain metastases are allowed if they have been adequately treated with radiotherapy or
             surgery and stable for at least 30 days prior to step 2 randomization; eligible
             patients must be neurologically asymptomatic and without corticosteroid treatment for
             at least 7 days prior to step 2 randomization

          -  Patients must have a Zubrod performance status of 0 or 1

          -  Patients must have a complete physical examination and medical history within 28 days
             prior to step 2 randomization

          -  Absolute neutrophil count (ANC) >= 1,500/mcL

          -  Platelets >= 75,000/mcL

          -  Hemoglobin >= 9 g/dL

          -  Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) both =< 5 x
             institutional upper limit of normal (IULN)

          -  Bilirubin =< 1.5 mg/dL

          -  Calculated creatinine clearance > 30 ml/min within 14 days prior to step 2
             randomization

          -  Patients who have had an echocardiogram performed within 6 months prior to step 2
             randomization must have ventricular ejection fraction (left ventricular ejection
             fraction [LVEF]) >= 50% or >= within normal limits for the institution

          -  Patients must not have an uncontrolled intercurrent illness including, but not limited
             to diabetes, hypertension, severe infection, severe malnutrition, unstable angina,
             class III-IV New York Heart Association (NYHA) congestive heart failure, ventricular
             arrhythmias, active ischemic heart disease, or myocardial infarction within 6 months
             prior to step 2 randomization

          -  Patients must not have any known previous or concurrent condition suggesting
             susceptibility to hypersensitivity or allergic reactions, including, but not limited
             to: known hypersensitivity to any of the study treatments or to excipients of
             recombinant human or humanized antibodies; patients with mild or seasonal allergies
             may be included after discussion with the study chairs

          -  Patients must not be planning treatment with other systemic anti-cancer agents (e.g.,
             chemotherapy, hormonal therapy, immunotherapy) or other treatments not part of
             protocol-specified anti-cancer therapy including concurrent investigational agents of
             any type

          -  No prior malignancy is allowed except for adequately treated basal cell or squamous
             cell skin cancer, in situ cervical cancer, ductal carcinoma in situ, other low grade
             lesions such as incidental appendix carcinoid, or any other cancer from which the
             patient has been disease and treatment free for two years; prostate cancer patients on
             active surveillance are eligible

          -  Patients must not be pregnant or nursing; females of child-bearing potential must have
             a negative serum pregnancy test within 7 days prior to registration; women/men of
             reproductive potential must have agreed to use an effective contraceptive method while
             on study and for at least 7 months after the last dose of study treatment; a woman is
             considered to be of "reproductive potential" if she has had menses at any time in the
             preceding 12 consecutive months; in addition to routine contraceptive methods,
             "effective contraception" also includes heterosexual celibacy and surgery intended to
             prevent pregnancy (or with a side-effect of pregnancy prevention) defined as a
             hysterectomy, bilateral oophorectomy or bilateral tubal ligation; however, if at any
             point a previously celibate patient chooses to become heterosexually active during the
             time period for use of contraceptive measures outlined in the protocol, he/she is
             responsible for beginning contraceptive measures

          -  Patients must be given the opportunity to consent to the optional submission of tissue
             for future research

          -  Patients must be informed of the investigational nature of this study and must sign
             and give written informed consent in accordance with institutional and federal
             guidelines; the appropriate consent form for this registration is the step 2 consent
             form

          -  STEP 2 RANDOMIZATION: As a part of the Oncology Patient Enrollment Network (OPEN)
             registration process the treating institution's identity is provided in order to
             ensure that the current (within 365 days) date of institutional review board approval
             for this study has been entered in the system

          -  STEP 3 CROSSOVER REGISTRATION (OPTIONAL): Patients must have documented disease
             progression while on CETIRI (Arm 2) on this protocol; the Follow-up Tumor Assessment
             Form documenting disease progression must be submitted to Southwest Oncology Group
             (SWOG) prior to step 3 crossover registration; registration to step 3 crossover must
             be within 28 days of discontinuation of CETIRI protocol treatment; patients going off
             treatment for any other reason are not eligible

          -  STEP 3 CROSSOVER REGISTRATION (OPTIONAL): Patients must have a Zubrod performance
             status of 0 or 1

          -  STEP 3 CROSSOVER REGISTRATION (OPTIONAL): ANC >= 1,500/mcL

          -  STEP 3 CROSSOVER REGISTRATION (OPTIONAL): Platelets >= 75,000/mcL

          -  STEP 3 CROSSOVER REGISTRATION (OPTIONAL): Hemoglobin >= 9 g/dL

          -  STEP 3 CROSSOVER REGISTRATION (OPTIONAL): AST and ALT both =< 5 x institutional upper
             limit of normal (IULN)

          -  STEP 3 CROSSOVER REGISTRATION (OPTIONAL): Bilirubin =< 1.5 mg/dL

          -  STEP 3 CROSSOVER REGISTRATION (OPTIONAL): Calculated creatinine clearance > 30 ml/min
             within 14 days prior to step 3 crossover registration

          -  STEP 3 CROSSOVER REGISTRATION (OPTIONAL): Patients must have left ventricular ejection
             fraction (LVEF) >= 50% or >= lower limit of normal for the institution by
             echocardiogram within 14 days prior to step 3 crossover registration

          -  STEP 3 CROSSOVER REGISTRATION (OPTIONAL): Patients must have a magnesium, potassium,
             calcium, sodium, bicarbonate, and chloride performed within 14 days prior to step 3
             crossover registration

          -  STEP 3 CROSSOVER REGISTRATION (OPTIONAL): Patients must be informed of the
             investigational nature of this study and must sign and give written informed consent
             in accordance with institutional and federal guidelines; the appropriate consent form
             for this registration is the step 2 consent form

          -  STEP 3 CROSSOVER REGISTRATION (OPTIONAL): As a part of the OPEN registration process
             the treating institution's identity is provided in order to ensure that the current
             (within 365 days) date of institutional review board approval for this study has been
             entered in the system