Clinical Trials

Inclusion Criteria:

• Have histologically and/or cytologically documented adenocarcinoma of the colon or rectum, which is locally advanced unresectable or metastatic.
• Subjects must be willing and able to provide the most recently available formalin-fixed paraffin-embedded tumor tissue blocks (or freshly sectioned slides, see laboratory manual for details), obtained prior to treatment initiation, to a sponsor-designated central laboratory for biomarker analysis. If archival tissue is not available, then a newly-obtained baseline biopsy of an accessible tumor lesion is required within 35 days prior to the Cycle 1 Day 1 timeframe. Biopsy must provide adequate tissue for analysis; the following biopsy types are acceptable: resection, excision, punch (skin lesions only) and core needle biopsies.
• Have HER2+ disease as determined by tissue-based investigational HER2 IHC and ISH assays performed at a sponsor-defined central laboratory. HER2 amplification will be determined using ASCO/CAP guidelines for gastric and gastroesophageal cancer with IHC 3+ or IHC 2+/ISH+ result.
• Have RAS WT disease as determined by local or central testing (if local testing is unavailable or is not preferred). For central RAS analysis, tissue sample must be analyzed within 1 year of biopsy date.
• Age ≥18 years at time of consent and ≥ the age of majority per regional requirements.
• Have radiographically measurable disease per RECIST v1.1 according to INV assessment, with at least one site of disease that is measurable and that has not been previously irradiated; or, if the subject has had previous radiation to the target lesion(s), there must be evidence of progression since the radiation.
• Have an Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) of 0 or 1.
• Life expectancy of ≥ 3 months, in the opinion of the investigator.
• Have adequate hematological, hepatic, renal, coagulation, and cardiac function, as defined below, obtained ≤ 7 days prior to enrollment (Cycle 1 Day 1):
  • Absolute neutrophil count (ANC) ≥ 1.5 × 10^3 /µL;
  • Platelet count ≥ 100 × 10^3 /µL;
  • Hemoglobin ≥ 9.0 g/dL;
  • Total bilirubin ≤ 1.5 × upper limit of normal (ULN);
  • Subjects with known history of Gilbert’s Syndrome may enroll if direct bilirubin is ≤ 1.5 × ULN;
  • Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3 × ULN (≤ 5 × ULN if liver metastases are present);
  • Creatinine level ≤ 1.5 × institutional ULN or estimated creatinine clearance ≥60 mL/min for subjects with creatinine levels > 1.5 × institutional ULN;
  • International normalized ratio (INR) and activated partial thromboplastin time (aPTT) ≤ 1.5 × 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 (MUGA) scan documented ≤ 28 days prior to study treatment.
• For subjects of childbearing potential, the following stipulations apply:
  • Must have a negative serum pregnancy test (minimum sensitivity of 25 mIU/mL or equivalent units of beta human chorionic gonadotropin [β-hCG]) result within 7 days prior to the first dose of study treatment. A subject with a false positive result and documented verification that the subject is not pregnant is eligible for participation;
  • Must agree not to try to become pregnant during the study and for at least 7 months after the final dose of study treatment administration;
  • Must agree not to breastfeed or donate ova, starting at time of main informed consent and continuing through 7 months after the final dose of study treatment administration;
  • May choose to practice complete abstinence, if consistent with the subject’s preferred lifestyle, as an acceptable form of contraception;
  • If sexually active in a way that could lead to pregnancy, must consistently use 2 methods of birth control, as defined in Appendix B, starting at the time of main informed consent and continuing throughout the study and for at least 7 months after the final dose of any study treatment administration.
• For subjects who can father children, the following stipulations apply:
  • Must agree not to donate sperm starting at time of main informed consent and continuing throughout the study period and for at least 7 months after the final study treatment administration;
  • If sexually active with a person of childbearing potential in a way that could lead to pregnancy, must consistently use 2 methods of birth control, as defined in Appendix B, starting at time of main informed consent and continuing throughout the study and for at least 7 months after the final dose of study treatment administration;
  • If sexually active with a person who is pregnant or breastfeeding, must consistently use one of 2 contraception options, as defined in Appendix B, starting at time of main informed consent and continuing throughout the study and for at least 7 months after the final dose of study treatment administration;
  • May choose to practice complete abstinence, if consistent with the subject’s preferred lifestyle, as an acceptable form of contraception.
• Subject must provide signed informed consent that has been approved by an institutional review board/independent ethics committee (IRB/IEC) prior to initiation of any study-related tests or procedures. 
• Subject must be willing and able to comply with study procedures.
• Subject must be willing and able to adhere to mandatory antidiarrheal prophylaxis.
• CNS Inclusion—Based on screening contrast brain magnetic resonance imaging (or CT with contrast if MRI is contraindicated), subjects may have any of the following:
  • No evidence of brain metastases;
  • Previously treated brain metastases which are asymptomatic.
  • Brain metastases previously treated with local therapy must not have progressed since treatment;
  • Time since whole brain radiation therapy (WBRT) is ≥ 14 days prior to enrollment, time since stereotactic radiosurgery (SRS) is ≥ 7 days prior to enrollment, or time since surgical resection is ≥ 28 days prior to enrollment;
  • Relevant records of any CNS treatment must be available to allow for classification of target and non-target lesions.

Exclusion Criteria:

• Have previously received any systemic anticancer therapy for CRC in the metastatic setting or have participated in any interventional clinical trial for CRC in the metastatic setting; note that subjects may have received a maximum of 2 doses of mFOLFOX6 in the locally advanced/unresectable or metastatic setting prior to randomization.
  • Note: subjects may have received prior chemotherapy for CRC in the adjuvant setting provided that it was completed > 6 months prior to enrollment.
• Have previously received radiation therapy within 14 days prior to enrollment (or within 7 days in the setting of SRS). Subjects who have received prior radiation therapy must have recovered to baseline from any treatment-related adverse events (AEs). Subjects who have received palliative radiotherapy for symptomatic metastases may enter the study without a washout period provided that the subject has recovered from any treatment-related AEs.
• Have previously been treated with anti-HER2 therapy.
• Have any toxicity related to prior cancer therapies that has not resolved to ≤ Grade 1, with the following exceptions:
  • Neuropathy, which must have resolved to ≤ Grade 2;
  • Alopecia;
  • Congestive heart failure (CHF), which must have been ≤ Grade 1 in severity at the time of occurrence, and must have resolved completely;
  • Anemia, hemoglobin must have resolved to a level of ≥9.0 g/dL 5. Have clinically significant cardiopulmonary disease such as:
  • Ventricular arrhythmia requiring therapy;
  • Symptomatic hypertension or uncontrolled asymptomatic hypertension, as determined by the investigator;
  • Any history of symptomatic CHF (Grade 2 or above), symptomatic left ventricular systolic dysfunction or symptomatic decrease in ejection fraction;
  • Severe dyspnea at rest (Grade 3 or above) due to complications of advanced malignancy or hypoxia requiring supplementary oxygen therapy;
  • Presence of ≥ Grade 2 corrected QT interval (QTc) prolongation (>480 ms) on screening electrocardiogram (ECG);
  • Interstitial lung disease or pneumonitis;
  • Have a history of transient ischemic attack, cerebrovascular accident, myocardial infarction, unstable angina, cardiac or other vascular stenting, angioplasty, or cardiac surgery within 6 months prior to enrollment (Cycle 1 Day 1).
  • Have a history of a significant bleeding events within 6 months of enrollment, unless the source of bleeding has been definitively treated.
  • Have a history of gastrointestinal (GI) perforation within 12 months of enrollment.
  • Have ongoing ≥ Grade 2 diarrhea of any etiology.
  • Major surgical procedure or significant traumatic injury ≤ 28 days prior to enrollment (≤ 56 days for hepatectomy, open thoracotomy, or major neurosurgery) or anticipation of need for major surgical procedure during the course of the study.
  • Serious, non-healing wound, ulcer, or bone fracture.
  • Positive for hepatitis B by surface antigen expression.
  • Presence of known chronic liver disease.
  • Have active hepatitis C infection (positive by PCR or on antiviral therapy for hepatitis C within the last 6 months). Subjects who have been treated for hepatitis C infection are permitted if they have documented sustained virologic response of 12 weeks.
• Subjects known to be positive for human immunodeficiency virus (HIV) are excluded if they meet any of the following criteria:
  • CD4+ T-cell count of <350 cells/µL;
  • Detectable HIV viral load;
  • History of an opportunistic infection within the past 12 months;
  • On stable antiretroviral therapy for < 4 weeks.
• Subjects who are pregnant, breastfeeding, or planning a pregnancy.
• Inability to swallow pills or any significant GI disease which would preclude the adequate oral absorption of medications.
• Have used a strong cytochrome p450 (CYP) 2C8 inhibitor within 5 half-lives of the inhibitor, or have used a strong CYP2C8 or CYP3A4 inducer within 5 days prior to first dose of study treatment.
• Have any other medical, social, or psychosocial factors that, in the opinion of the investigator, could impact safety or compliance with study procedures.
• History of another malignancy within 3 years before the first dose of study treatment, or any evidence of residual disease from a previously diagnosed malignancy. Exceptions are malignancies with a negligible risk of metastasis or death (e.g., 5-year OS ≥90%), such as adequately treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, localized prostate cancer, ductal carcinoma in situ, or Stage I uterine cancer.
• Subjects with active CNS metastases (irradiated or resected lesions are permitted).
• Subjects with carcinomatous meningitis are excluded without exception.
• Have a known hypersensitivity or allergy to any of the study treatments or any of their excipients, or to required concomitant medications, or to murine proteins, except for Grade 1 or 2 infusion-related reactions (IRRs) to oxaliplatin that were successfully managed.
• Have received a live vaccine <30 days prior to enrollment.
• Have known dihydropyrimidine dehydrogenase (DPD) deficiency.

Note: Other protocol defined Inclusion/Exclusion Criteria may apply.

Eligibility last updated 10/5/23. Questions regarding updates should be directed to the study team contact.