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Tucatinib Plus Trastuzumab in Patients With HER2+ 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.
Colon, Rectal
Phase II
Mol. targeted/Immunotherapy/Biologics
Trastuzumab (Herceptin), Tucatinib (ONT-380)
Ciombor, Kristen
Vanderbilt University


18 Years
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

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