Tucatinib Plus Trastuzumab in Patients With HER2+ Colorectal Cancer
Condition: Metastatic Colorectal Adenocarcinoma
MeSH terms: Colorectal Neoplasms
Intervention: Trastuzumab; Tucatinib
Intervention description: Given intravenously (into the vein; IV); Given orally
Intervention MeSH terms: Trastuzumab; Tucatinib
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 117.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: HER2; ERBB2; Colorectal cancer; Seattle Genetics

Summary:

      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.
    

Eligibility criteria:

        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