Tucatinib (ONT-380) and Trastuzumab in Treating Patients with HER2+ Metastatic Colorectal Cancer

Status: Active


This phase II trial studies how well the HER2 inhibitor tucatinib (ONT-380, ARRY-380) works in combination with trastuzumab in treating patients with HER2-positive (HER2+) metastatic colorectal cancer (CRC). Tucatinib may stop the growth of tumor cells by blocking HER2, a receptor needed for cell growth in patients with HER2+ tumors. Trastuzumab is a form of “targeted therapy” because it works by attaching itself to specific molecules (receptors) on the surface of cancer cells, known as HER2 receptors. When trastuzumab attaches to HER2 receptors, the signals that tell the cells to grow are blocked and the cancer cell may be marked for destruction by the body’s immune system. Giving tucatinib and trastuzumab in combination may work better in treating patients with HER2+ metastatic CRC.

Eligibility Criteria

Inclusion Criteria

  • 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 MSI-High, or contraindication to such treatment(s)
  • Molecular testing result from Clinical Laboratory Improvement Act (CLIA)-certified laboratory confirming that the tumor tissue has at least one of the following: * HER2 overexpression (3+ immunohistochemistry [IHC]); Note: HER2 2+ IHC is eligible if the tumor is amplified by fluorescence in situ hybridization (FISH) * HER2 (ERBB2) amplification by in situ hybridization assay (FISH or chromogenic in situ hybridization [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 Response Evaluation Criteria in Solid Tumors (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
  • Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0, 1, or 2
  • Life expectancy greater than 3 months
  • Absolute neutrophil count (ANC) >= 1000/mm^3 (obtained =< 7 days prior to registration)
  • Platelet count >= 75,000/mm^3 (obtained =< 7 days prior to registration)
  • Hemoglobin >= 8.0 g/dL (obtained =< 7 days prior to registration)
  • 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 aspartate aminotransferase (AST)/alanine aminotransferase (ALT) are eligible, (obtained =< 7 days prior to registration)
  • AST and ALT =< 2.5 x ULN (=< 5 x ULN if liver metastases are present) (obtained =< 7 days prior to registration)
  • Calculated creatinine clearance must be >= 50 ml/min using the Cockcroft-Gault formula (obtained =< 7 days prior to registration)
  • International normalized ratio (INR) and activated partial thromboplastin time (aPTT) =< 1.5 X 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 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 the last study drug administration * Note: women of childbearing potential include women who have experienced menarche and who have not undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or are not postmenopausal; postmenopause 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 Common Terminology Criteria for Adverse Events (CTCAE) =< grade 1 from toxicity due to all prior therapies except alopecia and neuropathy; alopecia and neuropathy must have resolved to =< grade 2; congestive heart failure (CHF) must have been =< grade 1 in severity at the time of occurrence and must have resolved completely prior to registration
  • Clinically significant cardiac disease such as history of ventricular arrhythmia requiring therapy, currently uncontrolled hypertension (defined as persistent systolic blood pressure > 150 mmHg and/or diastolic blood pressure > 100 mmHg on antihypertensive medications), or any history of symptomatic CHF
  • Any of the following: * Pregnant women * Nursing women * Men or women of childbearing potential who are unwilling to employ adequate contraception
  • Patient with known active central nervous system (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 inhibitor within 2 weeks prior to registration or strong CYP3A4 inducer within 5 days prior to registration
  • Use of a strong CYP2C8 inhibitor within 2 weeks prior to registration of study treatment or strong CYP2C8 inducer within 5 days prior to registration
  • Use of sensitive CYP3A substrates within two weeks before registration
  • Major surgical procedure, open biopsy, or significant traumatic injury =< 28 days prior to registration (=< 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 registration
  • Immunocompromised patients and patients known to be human immunodeficiency virus (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 local 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

Locations & Contacts


Mayo Clinic Hospital
Status: Active
Contact: Clinical Trials Referral Office
Phone: 855-776-0015
Email: mihalik.laurie@mayo.edu
Mayo Clinic in Arizona
Status: Active
Contact: Clinical Trials Referral Office
Phone: 855-776-0015
Email: mihalik.laurie@mayo.edu


Emory University Hospital / Winship Cancer Institute
Status: Active
Contact: Meredith Renfroe
Phone: 404-778-2670
Email: meredith.ann.renfroe@emory.edu


Dana-Farber Cancer Institute
Status: Active
Contact: Christopher Graham
Phone: 617-632-5960
Email: Christopher_Graham@DFCI.harvard.edu


Mayo Clinic
Status: Active
Contact: Clinical Trials Referral Office
Phone: 855-776-0015
Email: klocke.jodi@mayo.edu

New York

Roswell Park Cancer Institute
Status: Active
Contact: Karen A Hicks
Phone: 716-845-8947
Email: karen.hicks@roswellpark.org
New York
Memorial Sloan Kettering Cancer Center
Status: Active
Contact: Derek Alexander
Phone: 646-888-1381
Email: alexandd@mskcc.org

North Carolina

Duke University Medical Center
Status: Active
Contact: John Howard Strickler
Phone: 919-668-1861
Email: john.strickler@duke.edu


Aurora Cancer Care-Milwaukee West
Status: Active
Contact: Jennifer Mathieu
Phone: 414-302-2312
Email: jennifer.mathieu@aurora.org

Trial Objectives and Outline


I. To assess the objective response rate (ORR) of tucatinib in combination with trastuzumab in patients with HER2 positive (+) metastatic CRC.


I. To assess the clinical benefit rate (CBR) (stable disease [SD] for >= 6 months, or best response of complete response [CR] or partial response [PR]) of tucatinib in combination with trastuzumab.

II. To assess the progression free survival (PFS) of tucatinib in combination with trastuzumab.

III. To assess the duration of response of tucatinib in combination with trastuzumab.

IV. To assess the overall survival (OS) of tucatinib in combination with trastuzumab.

V. To assess the safety and tolerability of tucatinib in combination with trastuzumab.


I. To determine whether the combination of tucatinib and trastuzumab eliminates HER2 amplified circulating tumor deoxyribonucleic acid (DNA) (ctDNA) from peripheral blood.

II. To explore any correlation between tissue and blood based biomarkers and clinical outcomes.


Patients receive tucatinib orally (PO) twice daily (BID) on days 1-21 and trastuzumab intravenously (IV) on day 1. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 30 days and then every 12 weeks.

Trial Phase & Type

Trial Phase

Phase II

Trial Type


Lead Organization

Lead Organization
Academic and Community Cancer Research United

Principal Investigator
John Howard Strickler

Trial IDs

Primary ID ACCRU-GI-1617
Secondary IDs NCI-2017-01107
Clinicaltrials.gov ID NCT03043313