Clinical Trials /

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



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. Monoclonal antibodies, such as trastuzumab, may interfere with the ability of HER2+ tumor cells to grow and spread. Giving tucatinib and trastuzumab in combination may work better in treating patients with HER2+ metastatic CRC.

Related Conditions:
  • Colorectal Carcinoma
Recruiting Status:



Phase 2

Trial Eligibility



  • Brief Title: Tucatinib (ONT-380) and Trastuzumab for Patients With HER2-positive Metastatic Colorectal Cancer (MOUNTAINEER)
  • Official Title: A Phase II, Open Label Study of Tucatinib Combined With Trastuzumab in Patients With HER2+ Metastatic Colorectal Cancer

Clinical Trial IDs

  • SECONDARY ID: P30CA015083
  • NCT ID: NCT03043313


  • Colorectal Cancer
  • Colorectal Carcinoma
  • Colorectal Tumors
  • Neoplasms, Colorectal
  • HER-2 Gene Amplification
  • Metastatic Cancer
  • Metastatic Colon Cancer
  • Adenocarcinoma of the Colon
  • Adenocarcinoma of the Rectum


TucatinibONT-380, ARRY-380Tucatinib + Trastuzumab
TrastuzumabHerceptinTucatinib + Trastuzumab


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.

Trial Arms

Tucatinib + TrastuzumabExperimentalTucatinib 300 mg by mouth twice daily on days 1-21 of all cycles. Trastuzumab 8 mg/kg body weight given intravenously on Day 1 of Cycle 1. Trastuzumab 6 mg/kg body weight given intravenously on Day 1 of Cycle 2 and all subsequent cycles. Cycle length = 21 days.
  • Tucatinib
  • Trastuzumab

Eligibility Criteria

        Inclusion Criteria:

          -  Histologically and/or cytologically confirmed and radiographically measurable
             adenocarcinoma of the colon or rectum that is metastatic and/or unresectable. Subjects
             must have been treated with a fluoropyrimidine (e.g., 5-fluorouracil or capecitabine),
             oxaliplatin, irinotecan, and an anti-VEGF monoclonal antibody (bevacizumab,
             ramucirumab, or ziv-aflibercept), or have contraindication to such treatment.

          -  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 amplification by in situ hybridization assay (FISH or CISH signal ratio >2.0
                  or gene copy number >6).

               -  HER2 amplification by CLIA-certified Next Generation Sequencing (NGS) sequencing

          -  RAS (KRAS and NRAS) wild-type in primary or metastatic tumor tissue.

          -  At least one site of disease that is measurable by RECIST criteria as defined in
             Section 11.0 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

          -  ECOG Performance Status (PS) of 0, 1, or 2. (Form is available on the ACCRU web site

          -  Life expectancy greater than 3 months.

          -  Absolute neutrophil count (ANC) ≥1000/mm3

          -  Platelet count ≥75,000/mm3

          -  Hemoglobin >8.0 g/dL

          -  Total bilirubin ≤1.5 x upper limit of normal (ULN)

          -  AST/ALT ≤ 2.5 X upper limit of normal (ULN) (≤5 ULN if liver metastases are present)

          -  Calculated creatinine clearance must be ≥50 ml/min using the Cockcroft-Gault formula

          -  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 within 4 weeks prior to first dose
             of study treatment

          -  Sexually active subjects (men and women) must agree to use medically accepted barrier
             methods of contraception (e.g., male or female condom) during the course of the study
             and for 1 month after the last dose of study drug(s), even if oral contraceptives are
             also used.

          -  Negative pregnancy test done ≤7 days prior to registration for women of childbearing
             potential only. 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. Note: women who have
             been amenorrheic for 12 or more months are still considered to be of childbearing
             potential if the amenorrhea is possibly due to prior chemotherapy, anti-estrogens,
             ovarian suppression or any other reversible treatment.

          -  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/or blood samples for correlative research

        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

               -  Pregnant women

               -  Nursing women

               -  Men or women of childbearing potential who are unwilling to employ adequate

          -  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)

          -  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

          -  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.
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Objective Response Rate (ORR) defined as achieving Complete Response (CR) or Partial Response (PR)
Time Frame:Through study completion, an average of 7 months
Safety Issue:
Description:ORR is defined as a complete response (CR) or partial response (PR) measured by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 over the treatment period, with the exception that 4-week confirmatory scans will not be required. The primary hypothesis will be tested in the cohort of eligible patients.

Secondary Outcome Measures

Measure:Clinical Best Response (CBR)
Time Frame:Up to 3 years
Safety Issue:
Description:Stable disease (SD) ≥6 months or best response of CR or PR estimated by 95% confidence interval estimates
Measure:Overall Survival (OS)
Time Frame:Up to 3 years
Safety Issue:
Description:Time from registration to time of death
Measure:Progression Free Survival (PFS)
Time Frame:Up to 3 years
Safety Issue:
Description:Time from registration to earliest date documentation off disease progression
Measure:Duration of Response
Time Frame:Up to 3 years
Safety Issue:
Description:For all eligible patients who have achieved an objective response, duration of response is defined as time from patient's earliest best objective status noted to be either CR or PR to the earliest date progression is documented.


Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Academic and Community Cancer Research United

Last Updated

July 3, 2017