Inclusion Criteria:

• Histologically and/or cytologically confirmed and radiographically measurable adenocarcinoma of the colon or rectum that is metastatic and/or unresectable. Subjects must have been treated with a fluoropyrimidine (e.g., 5-fluorouracil or capecitabine), oxaliplatin, irinotecan, and an anti-VEGF monoclonal antibody (bevacizumab, ramucirumab, or ziv-aflibercept), or have contraindication to such treatment.
• RAS (KRAS and NRAS) wild-type in primary or metastatic tumor tissue. RAS wild-type is defined as tumor tissue with no mutation in exon 2 [codon 12/13], exon 3 [codon 59/61], and exon 4 [codon 117/146] of both KRAS and NRAS genes (local testing permitted).
• Molecular testing result from CLIA-certified laboratory confirming that the tumor tissue has at least one of the following:
  • HER2 overexpression (3+ IHC). Note: HER2 2+ IHC is eligible if the tumor is amplified by FISH.
  • HER2 amplification by in situ hybridization assay (FISH or CISH signal ratio >2.0 or gene copy number >6).
  • HER2 amplification by CLIA-certified Next Generation Sequencing (NGS) sequencing assay.
• At least one site of disease that is measurable by RECIST criteria as defined in Section 11.0 that has not been previously irradiated; if the patient has had previous radiation to the target lesion(s), there must be evidence of progression since the radiation.
• ECOG Performance Status (PS) of 0, 1, or 2. (Form is available on the ACCRU web site https://www.accru.org/accru/forms/NonProtocolSpecificForms/index.html)
• Life expectancy greater than 3 months.
• Absolute neutrophil count (ANC) ≥1000/mm3
• Platelet count ≥75,000/mm3
• Hemoglobin >8.0 g/dL
• Total bilirubin ≤1.5 x upper limit of normal (ULN)
• AST/ALT ≤ 2.5 X upper limit of normal (ULN) (≤5 ULN if liver metastases are present)
• Calculated creatinine clearance must be ≥50 ml/min using the Cockcroft-Gault formula
• International normalized ratio (INR) and activated partial thromboplastin time (aPTT) ≤1.5 X ULN unless on medication known to alter INR and/or aPTT.
• Left ventricular ejection fraction (LVEF) ≥50% as assessed by echocardiogram (ECHO) or multiple-gated acquisition scan (MUGA) documented within 4 weeks prior to first dose of study treatment
• Sexually active subjects (men and women) must agree to use medically accepted barrier methods of contraception (e.g., male or female condom) during the course of the study and for 1 month after the last dose of study drug(s), even if oral contraceptives are also used.
• Negative pregnancy test done ≤7 days prior to registration for women of childbearing potential only. Women of childbearing potential include women who have experienced menarche and who have not undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or are not postmenopausal. Postmenopause is defined as amenorrhea ≥12 consecutive months. Note: women who have been amenorrheic for 12 or more months are still considered to be of childbearing potential if the amenorrhea is possibly due to prior chemotherapy, anti-estrogens, ovarian suppression or any other reversible treatment.
• Capable of understanding and complying with the protocol requirements and has signed the informed consent document.
• Willing to return to enrolling institution for follow-up (during the Active Monitoring Phase of the study).
• Willing to provide mandatory tissue and/or blood samples for correlative research purposes.

Exclusion Criteria:

• Radiation therapy, hormonal therapy, biologic therapy, experimental therapy, or chemotherapy for cancer ≤21 days prior to registration.
• Prior anti-HER2 targeting therapy.
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
• Not recovered to baseline or CTCAE ≤ Grade 1 from toxicity due to all prior therapies except alopecia and neuropathy, which must have resolved to ≤ Grade 2; and congestive heart failure (CHF), which must have been ≤ Grade 1 in severity at the time of occurrence, and must have resolved completely.
• Clinically significant cardiac disease such as history of ventricular arrhythmia requiring therapy, currently uncontrolled hypertension (defined as persistent systolic blood pressure >150 mm Hg and/or diastolic blood pressure >100 mm Hg on antihypertensive medications), or any history of symptomatic CHF.
• Any of the following because this study involves an investigational agent whose genotoxic, mutagenic and teratogenic effects on the developing fetus and newborn are unknown:
  • Pregnant women
  • Nursing women
  • Men or women of childbearing potential who are unwilling to employ adequate contraception
• Patient with known CNS metastasis (radiated or resected lesions are permitted, provided the lesions are fully treated and inactive, patient is asymptomatic, and no steroids have been administered for at least 30 days)
• Inability to swallow pills or any significant gastrointestinal disease which would preclude the adequate oral absorption of medications
• Use of a strong CYP3A4 inducer or inhibitor, or strong CYP2C8 inducer or inhibitor within 3 elimination half-lives of the inhibitor or inducer prior to first dose of study treatment
• Major surgical procedure, open biopsy, or significant traumatic injury ≤28 days prior to study enrollment (56 days for hepatectomy, open thoracotomy, major neurosurgery) or anticipation of need for major surgical procedure during the course of the study.
• Serious, non-healing wound, ulcer, or bone fracture
• History of myocardial infarction, unstable angina, cardiac or other vascular stenting, angioplasty, or cardiac surgery ≤6 months prior to study enrollment
• Immunocompromised patients and patients known to be HIV positive and currently receiving antiretroviral therapy. NOTE: Patients known to be HIV positive, but without clinical evidence of an immunocompromised state, are eligible for this trial.
• Acute or chronic active hepatitis B or C infection, or other serious chronic infection requiring ongoing treatment
• Known chronic liver disease, autoimmune hepatitis, or sclerosing cholangitis
• Receiving any other investigational agent which would be considered as a treatment for the primary neoplasm
• Other active malignancy ≤2 years prior to registration which required systemic treatment. EXCEPTIONS: Non-melanotic skin cancer or carcinoma-in-situ of the cervix.
• Co-morbid systemic illnesses or other severe concurrent disease which, in the judgment of the investigator, would make the patient inappropriate for entry into this study or interfere significantly with the proper assessment of safety and toxicity of the prescribed regimens
• Unable or unwilling to abide by the study protocol or cooperate fully with the investigator or designee.