Tucatinib Plus Trastuzumab in Patients With HER2+ Colorectal Cancer

MOUNTAINEER: A Phase II, Open Label Study of Tucatinib Combined With Trastuzumab in Patients With HER2+ Metastatic Colorectal Cancer

This trial studies how well the drug tucatinib works when given with trastuzumab and when given by itself. The participants in this trial have HER2-positive (HER2+) metastatic colorectal cancer (mCRC). 'Metastatic' means that the cancer has spread to other parts of the body.

In the first part of this study, participants enrolled into Cohort A and received both tucatinib and trastuzumab. In the second part of this study, participants are randomly assigned to either Cohort B or Cohort C. Participants in Cohort B will receive tucatinib and trastuzumab. Participants in Cohort C will receive tucatinib. Participants in Cohort C who do not respond to therapy may have an option to receive tucatinib plus trastuzumab.

Inclusion Criteria

• Histologically and/or cytologically documented adenocarcinoma of the colon or rectum that is metastatic and/or unresectable

• Unless contraindicated, participants must have received and failed regimens containing the following agents: fluoropyrimidine (e.g., 5-fluorouracil or capecitabine), oxaliplatin, irinotecan, an anti-VEGF monoclonal antibody (bevacizumab, ramucirumab, or ziv-aflibercept), and an anti-PD-(L)1 therapy (nivolumab or pembrolizumab) if tumor has deficient mismatch repair proteins or is MSI-High.

• Have progression of unresectable or metastatic CRC after the last systemic therapy, or be intolerant of last systemic therapy

• Have RAS wild-type in primary or metastatic tumor tissue, based on expanded RAS testing

• Willing and able to provide the most recently available tissue blocks obtained prior to treatment initiation. If archival tissue is not available, then a newly-obtained baseline biopsy of an accessible tumor

• Have confirmed HER2-positive mCRC, as defined by having tumor tissue tested at a Clinical Laboratory Improvement Act (CLIA)-certified or International Organization for Standardization (ISO)-accredited laboratory, meeting at least one of the following criteria:

  • HER2+ overexpression (3+ immunohistochemistry [IHC]) by an FDA-approved or Conformité Européene (CE)-marked HER2 ICH test
  • HER2 2+ IHC is eligible if the tumor is amplified by an FDA-approved or CE-marked HER2 in situ hybridization assay (FISH or chromogenic in situ hybridization [CISH]))
  • HER2 (ERBB2) amplification by CLIA-certified or ISO-accredited next generation sequencing (NGS) sequencing assay

• Have radiographically measurable disease assessable by RECIST 1.1, with at least one site of disease that is measurable and that has not been previously irradiated; or, if the participant has had previous radiation to the target lesion(s), there must be evidence of progression since the radiation

• Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0, 1, or 2

• Life expectancy greater than 3 months

• Have adequate hematological, hepatic, renal, coagulation, and cardiac function

Exclusion Criteria

• Previous treatment with anti-HER2 targeting therapy

• Previous treatment with any systemic anticancer therapy, non-central nervous system radiation, or experimental agent within 3 weeks of first dose of study treatment

• Toxicity related to prior cancer therapies that has not resolved to ≤ Grade 1, with the following exceptions:

  • Alopecia and neuropathy, which must have resolved to ≤ Grade 2
  • Congestive heart failure (CHF), which must have been ≤ Grade 1 in severity at the time of occurrence, and must have resolved completely
  • Anemia, which must have resolved to ≤ Grade 2
  • Decreased ANC, which must have resolved to ≤ Grade 2

• Have clinically significant cardiopulmonary disease

• Have known myocardial infarction, unstable angina, cardiac or other vascular stenting, angioplasty, or cardiac surgery within 6 months prior to first dose of study treatment

• Major surgical procedure, open biopsy, 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 study

• Serious, non-healing wound, ulcer, or bone fracture

• Known to be positive for hepatitis B by surface antigen expression

• Known to have active hepatitis C infection

  • Exception for participants with a documented sustained virologic response of 12 weeks

• Known to be positive for human immunodeficiency virus (HIV)

• Subjects who are pregnant, breastfeeding, or planning a pregnancy

• Inability to swallow pills or any significant gastrointestinal disease which would preclude the adequate oral absorption of medications

• Have used strong CYP2C8 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

• History of another malignancy within 3 years before the first dose of study drug, or any evidence of residual disease from a previously diagnosed malignancy.

  • Exceptions are malignancies with a negligible risk of metastasis or death

• Subjects with known active CNS metastasis

  • Irradiated or resected lesions are permitted, provided the lesions are fully treated and inactive, subject is asymptomatic, and no steroids have been administered for at least 30 days