- 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.
- 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
- RAS (KRAS and NRAS) wild-type in primary or metastatic tumor tissue.
- 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
- ECOG Performance Status (PS) of 0, 1, or 2. (Form is available on the ACCRU web site
- 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
- 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
- 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
- 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
- Pregnant women
- Nursing women
- Men or women of childbearing potential who are unwilling to employ adequate
- 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
- 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
- Unable or unwilling to abide by the study protocol or cooperate fully with the
investigator or designee.