Clinical Trials

Inclusion Criteria:

• Have histologically and/or cytologically documented adenocarcinoma of the colon or rectum, which is metastatic and/or unresectable.
• Unless otherwise contraindicated, subjects must have received and failed regimens containing the following agents:
  • fluoropyrimidines (e.g., 5-fluorouracil or capecitabine), oxaliplatin, irinotecan, an anti-VEGF mAb (bevacizumab, ramucirumab, or ziv-aflibercept), and an anti-PD-(L)1 therapy (nivolumab or pembrolizumab) if the tumor has dMMR proteins or is MSI-H.
• Have progression of unresectable or mCRC after last systemic therapy (as confirmed by investigator), or be intolerant of last systemic therapy.
• Have RAS wild-type in primary or metastatic tumor tissue, based on expanded RAS testing including KRAS exon 2 (codons 12 and 13), exon 3 (codons 59 and 61), and exon 4 (codons 117 and 146), and NRAS exon 2 (codons 12 and 13), exon 3 (codons 59 and 61), and exon 4 (codons 117 and 146).
• Subjects must be willing and able to provide the most recently available tissue blocks (or slides, with Medical Monitor’s approval), 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.
• Have confirmed HER2-positive mCRC, as defined by having tumor tissue tested at a Clinical Laboratory Improvement Amendments (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 Européenne (CE)-marked HER2 IHC test following the package insert’s interpretational manual for breast cancer;
  • HER2 2+ IHC is eligible if the tumor is amplified by an FDA-approved or CE-marked HER2 in situ hybridization assay (fluorescence in situ hybridization [FISH] or chromogenic in situ hybridization [CISH]) following the package insert’s interpretational manual for breast cancer;
  • HER2 (ERBB2) amplification by CLIA-certified or ISO-accredited Next Generation Sequencing (NGS) sequencing assay.
• Age ≥ 18 years at time of consent.
• 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 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, 1, or 2.
• Life expectancy greater than 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 the first study treatment:
  • Absolute neutrophil count (ANC) ≥ 1.0 × 10^3 /µL;
  • Platelet count ≥ 75 × 10^3 /µL;
  • Hemoglobin ≥ 8.0 g/dL;
  • Total bilirubin ≤ 1.5 × upper limit of normal (ULN). Subjects with known history of Gilbert’s Syndrome and normal direct bilirubin, aspartate aminotransferase (AST), and alanine aminotransferase (ALT) are eligible;
  • AST and ALT ≤ 2.5 × ULN (≤ 5 × ULN if liver metastases are present);
  • Calculated creatinine clearance ≥ 50 mL/min using the Cockcroft-Gault formula;
  • 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 drug administration;
  • Must agree not to breastfeed or donate ova, starting at time of informed consent and continuing through 7 months after the final dose of study drug 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 highly effective methods of birth control, starting at the time of informed consent and continuing throughout the study and for at least 7 months after the final dose of any study drug.
• For subjects who can father children, the following stipulations apply:
  • Must agree not to donate sperm starting at time of informed consent and continuing throughout the study period and for at least 7 months after the final study drug administration;
  • If sexually active with a person of childbearing potential in a way that could lead to pregnancy, must consistently use 2 highly effective methods of birth control, starting at time of informed consent and continuing throughout the study and for at least 7 months after the final dose of any study drug;
  • If sexually active with a person who is pregnant or breastfeeding, must consistently use one of 2 contraception options starting at time of informed consent and continuing throughout the study and for at least 7 months after the final dose of any study drug.
• 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 that are not part of standard-of-care for the subject’s disease.
• Subject must be willing and able to comply with study procedures.

Exclusion Criteria:

• Have previously been treated with anti-HER2 targeting therapy.
• Have received treatment with any systemic anticancer therapy (including hormonal and biologic therapy), non-central nervous system (CNS) radiation, or experimental agent ≤ 3 weeks of first dose of study treatment or are currently participating in another interventional clinical trial.
• Have any 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 4.
• 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, left ventricular systolic dysfunction or decrease in ejection fraction;
  • Severe dyspnea at rest (CTCAE 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 on screening electrocardiogram (ECG).
• 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 course of 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 (positive by polymerase chain reaction 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.
• 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 a 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.
• 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 drug, 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 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).
• Have a hypersensitivity to tucatinib or any of its excipients, to trastuzumab or any of its excipients, or to murine proteins.

Eligibility last updated 8/12/21. Questions regarding updates should be directed to the study team contact.