Inclusion Criteria:
- Histologically or cytologically confirmed colon and/or rectal cancer planned for curative intent treatment at gastrointestinal clinics of Emory University's Winship Cancer Institute and collaborating centers
- Tumors must be HER2+ve (human epidermal growth factor receptor 2 \[HER2\] overexpression 3+ immunohistochemistry \[IHC\] or 2+ by IHC and positive fluorescence in situ hybridization \[FISH\] or HER2 amplification by next generation sequencing)
- Tumors must have RAS wildtype genotype
- Radiologically measurable disease based on Response Evaluation Criteria in Solid Tumors (RECIST) 1.1
- Age ≥ 18 years
- Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2 (Karnofsky ≥ 50%)
- Platelet count > 100,000 cells/ ul (within 28 days of cycle 1 day 1, at the discretion of the investigator)
- Hemoglobin > 9g/dl (within 28 days of cycle 1 day 1, at the discretion of the investigator)
- Absolute neutrophil count > 1000 cells/dl (within 28 days of cycle 1 day 1, at the discretion of the investigator)
- Aspartate aminotransferase (AST) ≤ 3 × upper limit of normal (ULN) (within 28 days of cycle 1 day 1, at the discretion of the investigator)
- Alanine aminotransferase (ALT) ≤ 3 × ULN (within 28 days of cycle 1 day 1, at the discretion of the investigator)
- Total bilirubin ≤ 1.5 × ULN, or ≤ 3 × ULN for participants with Gilbert's disease (within 28 days of cycle 1 day 1, at the discretion of the investigator)
- Glomerular filtration rate (GFR) > 60ml/min (based on creatine, and Cystatin C estimation where applicable) (within 28 days of cycle 1 day 1, at the discretion of the investigator)
- Adequate cardiac function with left ventricular ejection fraction of at least 50% (within 28 days of cycle 1 day 1, at the discretion of the investigator)
- Females of child-bearing potential (FCBP) must have a negative serum or urine pregnancy test prior to starting therapy
- FCBP and men treated or enrolled on this protocol must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation, and 3 months after completion of study drug administration. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately
\* A female of childbearing potential (FCBP) is a sexually mature woman who: 1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months)
- Willingness and ability of the subject to comply with scheduled visits, drug administration plan, protocol-specified laboratory tests, other study procedures, and study restrictions. This includes willingness to undergo mandatory blood sample draws for evaluation of correlatives
- Evidence of a personally signed informed consent indicating that the subject is aware of the neoplastic nature of the disease and has been informed of the procedures to be followed, the experimental nature of the therapy, alternatives, potential risks and discomforts, potential benefits, and other pertinent aspects of study participation.
Exclusion Criteria:
- Participants with stage IV colon and rectal cancer even if curative intent resection is planned
- HER2 expression that does not meet documented inclusion criteria
- RAS mutation
- MSI-H or mismatch repair deficient rectal cancer
- Clinically significant cardiac disease, such as ventricular arrhythmia requiring therapy, uncontrolled hypertension or any history of symptomatic congestive heart failure (CHF). Participants with known myocardial infarction or unstable angina within 6 months prior to expected date of cycle 1 day 1 (C1D1) are also excluded. Previous anticancer therapy-related CHF must have been ≤ grade 1 at the time of occurrence and must have completely resolved
- Participants receiving any other investigational agents or an investigational device within 28 days of administering the first dose of study drug
- History of allergic reactions attributed to compounds of similar chemical or biologic composition to the agents used in study
- Uncontrolled current 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.