Tucatinib (ONT-380) and Trastuzumab for Patients With HER2-positive Metastatic Colorectal Cancer (MOUNTAINEER)

Overview

About this study

This is a phase II trial that will study how well tucatinib (ONT-380) and trastuzumab work in treating patients with colorectal cancer with a specific genetic marker (human epidermal growth factor receptor 2 - HER2) that has spread to other places in the body or has come back and cannot be removed by surgery. Tucatinib has been found to specifically target and inhibit HER2.

Participation eligibility

Participant eligibility includes age, gender, type and stage of disease, and previous treatments or health concerns. Guidelines differ from study to study, and identify who can or cannot participate. There is no guarantee that every individual who qualifies and wants to participate in a trial will be enrolled. Contact the study team to discuss study eligibility and potential participation.

Inclusion Criteria:

  • Age  ≥ 18 years.
  • Histologically and/or cytologically confirmed and radiographically measurable adenocarcinoma of the colon or rectum that is metastatic and/or unresectable.
  • Prior progression on or intolerance to treatment with a fluoropyrimidine (e.g., 5-fluorouracil or capecitabine), oxaliplatin, irinotecan, an anti-VEGF monoclonal antibody (bevacizumab, ramucirumab, or ziv-aflibercept), and an anti-PD-1 monoclonal antibody (nivolumab or pembrolizumab) if tumor has deficient mismatch repair proteins or is MSIHigh, or contraindication to such treatment(s).
  • Molecular testing result from CLIA-certified laboratory confirming that the tumor tissue has at least one of the following:
    • HER2 overexpression (3+ IHC). Note: HER2 2+ IHC is eligible if the tumor is amplified by FISH;
    • HER2 (ERBB2) amplification by in situ hybridization assay (FISH or CISH signal ratio > 2.0 or gene copy number > 6);
    • HER2 (ERBB2) amplification by CLIA-certified Next Generation Sequencing (NGS) sequencing assay.
  • RAS (KRAS and NRAS) wild-type in primary or metastatic tumor tissue.
  • At least one site of disease that is measurable by RECIST criteria that has not been previously irradiated; if the patient has had previous radiation to the target lesion(s), there must be evidence of progression since the radiation.
  • ECOG Performance Status (PS) of 0, 1, or 2.
  • Life expectancy greater than 3 months.
  • The following laboratory values obtained ≤  7 days prior to registration:
    • Absolute neutrophil count (ANC) ≥ 1000/mm^3;
    • Platelet count ≥ 75,000/mm3;
    • Hemoglobin ≥ 8.0 g/dL;
    • Total bilirubin ≤ 1.5 x upper limit of normal (ULN).  Patients with known history of Gilbert Syndrome and total bilirubin < 3 x ULN and normal AST/ALT are eligible;
    • AST and ALT ≤ 2.5 x ULN (≤ 5 x ULN if liver metastases are present);
    • Calculated creatinine clearance must be ≥ 50 ml/min using the the Cockcroft-Gault formula below:
      • Cockcroft-Gault Equation:
        • Creatinine clearance for males = (140 – age)(weight in kg) (72)(serum creatinine in mg/dL);
        • Creatinine clearance for females = (140 – age)(weight in kg)(0.85) (72)(serum creatinine in mg/dL).
  • International normalized ratio (INR) and activated partial thromboplastin time (aPTT).
  • Left ventriulcar ejection fraction (LVEF) ≥ 50% as assessed by echocardiogram (ECHO) or multi-gated acquisition scan (MUGA) documented ≤ 28 days prior to registration.
  • Women of child bearing potential and male partners of women of child bearing potential must agree to use two medically accepted methods of contraception, one of them being a barrier method during the study and for 7 months after last study drug administration.
    • Note: Women of child bearing potential include women who have experienced menarche who have not undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or are not postmenopausal. Post menopause is defined as amenorrhea ≥ 12 consecutive months.
  • Negative serum pregnancy test done ≤ 7 days prior to registration for women of childbearing potential only.
  • Capable of understanding and complying with the protocol requirements and has signed the informed consent document.
  • Willing to return to enrolling institution for follow-up (during the Active Monitoring Phase of the study).
  • Willing to provide mandatory tissue and blood samples for correlative research purposes.

Exclusion Criteria:

  • Radiation therapy, hormonal therapy, biologic therapy, experimental therapy, or chemotherapy for cancer ≤ 21 days prior to registration.
  • Prior anti-HER2 targeting therapy.
  • Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
  • Not recovered to baseline or CTCAE ≤ Grade 1 from toxicity due to all prior therapies except alopecia and neuropathy, which must have resolved to ≤ Grade 2; and congestive heart failure (CHF), which must have been ≤ Grade 1 in severity at the time of occurrence, and must have resolved completely.
  • Clinically significant cardiac disease such as history of ventricular arrhythmia requiring therapy, currently uncontrolled hypertension (defined as persistent systolic blood pressure > 150 mm Hg and/or diastolic blood pressure > 100 mm Hg on antihypertensive medications), or any history of symptomatic CHF.
  • Any of the following because this study involves an investigational agent whose genotoxic, mutagenic and teratogenic effects on the developing fetus and newborn are unknown:
    • Pregnant women;
    • Nursing women;
    • Men or women of childbearing potential who are unwilling to employ adequate contraception.
  • Patient with known CNS metastasis (radiated or resected lesions are permitted, provided the lesions are fully treated and inactive, patient is asymptomatic, and no steroids have been administered for at least 30 days).
  • Require therapy with warfarin or other coumarin derivatives (non-coumarin anticoagulants are allowed)
  • Inability to swallow pills or any significant gastrointestinal disease which would preclude the adequate oral absorption of medications.
  • Use of a strong CYP3A4 inducer or inhibitor, or strong CYP2C8 inducer or inhibitor within 3 elimination half-lives of the inhibitor or inducer prior to first dose of study treatment.
  • Use of sensitive CYP3A substrates within two weeks before registration
  • Major surgical procedure, open biopsy, or significant traumatic injury ≤ 28 days prior to study enrollment (56 days for hepatectomy, open thoracotomy, major neurosurgery) or anticipation of need for major surgical procedure during the course of the study.
  • Serious, non-healing wound, ulcer, or bone fracture.
  • History of myocardial infarction, unstable angina, cardiac or other vascular stenting, angioplasty, or cardiac surgery ≤ 6 months prior to study enrollment.
  • Immunocompromised patients and patients known to be HIV positive and currently receiving antiretroviral therapy.
    • NOTE: Patients known to be HIV positive, but without clinical evidence of an immunocompromised state, are eligible for this trial.
  • Acute or chronic active hepatitis B or C infection, or other serious chronic infection requiring ongoing treatment.
  • Known chronic liver disease, autoimmune hepatitis, or sclerosing cholangitis.
  • Receiving any other investigational agent which would be considered as a treatment for the primary neoplasm.
  • Other active malignancy ≤ 2 years prior to registration which required systemic treatment.
    • EXCEPTIONS: Non-melanotic skin cancer or carcinoma-in-situ of the cervix.
  • Co-morbid systemic illnesses or other severe concurrent disease which, in the judgment of the investigator, would make the patient inappropriate for entry into this study or interfere significantly with the proper assessment of safety and toxicity of the prescribed regimens.
  • Unable or unwilling to abide by the study protocol or cooperate fully with the investigator or designee.

Participating Mayo Clinic locations

Study statuses change often. Please contact the study team for the most up-to-date information regarding possible participation.

Mayo Clinic Location Status Contact

Scottsdale/Phoenix, Ariz.

Mayo Clinic principal investigator

Tanios Bekaii-Saab, M.D.

Open for enrollment

Contact information:

Cancer Center Clinical Trials Referral Office

(855) 776-0015

Rochester, Minn.

Mayo Clinic principal investigator

Joleen Hubbard, M.D.

Open for enrollment

Contact information:

Cancer Center Clinical Trials Referral Office

(855) 776-0015

More information

Publications

Publications are currently not available

Study Results Summary

Not yet available

Supplemental Study Information

Not yet available

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CLS-20366158

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