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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details. Identifier: NCT03043313
Recruitment Status : Recruiting
First Posted : February 6, 2017
Last Update Posted : November 4, 2019
National Cancer Institute (NCI)
Academic and Community Cancer Research United
Information provided by (Responsible Party):
Seattle Genetics, Inc.

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
ERBB2 Gene Amplification HER2/Neu Positive KRAS wt Allele Metastatic Colon Adenocarcinoma Metastatic Colorectal Adenocarcinoma Metastatic Rectal Adenocarcinoma NRAS wt Allele Recurrent Colorectal Carcinoma Stage III Colon Cancer AJCC v7 Stage III Colorectal Cancer AJCC v7 Stage III Rectal Cancer AJCC v7 Stage IIIA Colon Cancer AJCC v7 Stage IIIA Colorectal Cancer AJCC v7 Stage IIIA Rectal Cancer AJCC v7 Stage IIIB Colon Cancer AJCC v7 Stage IIIB Colorectal Cancer AJCC v7 Stage IIIB Rectal Cancer AJCC v7 Stage IIIC Colon Cancer AJCC v7 Stage IIIC Colorectal Cancer AJCC v7 Stage IIIC Rectal Cancer AJCC v7 Stage IV Colon Cancer AJCC v7 Stage IV Colorectal Cancer AJCC v7 Stage IV Rectal Cancer AJCC v7 Stage IVA Colon Cancer AJCC v7 Stage IVA Colorectal Cancer AJCC v7 Stage IVA Rectal Cancer AJCC v7 Stage IVB Colon Cancer AJCC v7 Stage IVB Colorectal Cancer AJCC v7 Stage IVB Rectal Cancer AJCC v7 Unresectable Colon Adenocarcinoma Unresectable Rectal Adenocarcinoma Biological: Trastuzumab Drug: Tucatinib Phase 2

Detailed Description:


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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 40 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: MOUNTAINEER: A Phase II, Open Label Study of Tucatinib Combined With Trastuzumab in Patients With HER2+ Metastatic Colorectal Cancer
Actual Study Start Date : June 23, 2017
Estimated Primary Completion Date : June 30, 2020
Estimated Study Completion Date : June 30, 2022

Resource links provided by the National Library of Medicine

Drug Information available for: Trastuzumab

Arm Intervention/treatment
Experimental: Treatment (tucatinib, trastuzumab)
Patients receive tucatinib PO BID on days 1-21 and trastuzumab IV on day 1. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.
Biological: Trastuzumab
Given IV
Other Names:
  • ABP 980
  • ALT02
  • Anti-c-ERB-2
  • Anti-c-erbB2 Monoclonal Antibody
  • Anti-ERB-2
  • Anti-erbB-2
  • Anti-erbB2 Monoclonal Antibody
  • Anti-HER2/c-erbB2 Monoclonal Antibody
  • Anti-p185-HER2
  • c-erb-2 Monoclonal Antibody
  • HER2 Monoclonal Antibody
  • Herceptin
  • Herceptin Biosimilar PF-05280014
  • Herceptin Trastuzumab Biosimilar PF-05280014
  • Herzuma
  • MoAb HER2
  • Monoclonal Antibody c-erb-2
  • Monoclonal Antibody HER2
  • Ogivri
  • Ontruzant
  • PF-05280014
  • rhuMAb HER2
  • RO0452317
  • SB3
  • Trastuzumab Biosimilar ABP 980
  • Trastuzumab Biosimilar ALT02
  • trastuzumab biosimilar EG12014
  • Trastuzumab Biosimilar HLX02
  • Trastuzumab Biosimilar PF-05280014
  • Trastuzumab Biosimilar SB3
  • Trastuzumab-dkst
  • Trastuzumab-dttb
  • Trastuzumab-pkrb
  • Trastuzumab-QYYP
  • Trazimera

Drug: Tucatinib
Given PO
Other Names:
  • ARRY-380
  • Irbinitinib
  • ONT-380

Primary Outcome Measures :
  1. Objective response rate [ Time Frame: Up to 4 months ]
    Defined as a complete response (CR) or partial response (PR) measured by Response Evaluation Criteria in Solid Tumors 1.1. Objective response rate over at most two post-baseline scans (approximately 4 months) with the exception that the 4-week confirmatory scans will not be required. The proportion of unconfirmed tumor responses (successes) will be estimated by the number of successes divided by the total number of evaluable patients. The null hypothesis that the proportion of evaluable patients with CR or PR (p) equals 0.2 (H0: p=0.2) will be tested against the alternative that this proportion equals 0.4 (HA: p=0.4). Confidence intervals for the true success proportion will be calculated using the normal approximation.

Secondary Outcome Measures :
  1. Clinical best response [ Time Frame: Up to 2 years ]
    Defined as the proportion of patients who experience stable disease for >= 6 months, or a best response of complete or Partial response. Will be estimated by the 95% confidence interval estimates.

  2. Overall survival [ Time Frame: From registration to death due to any cause, assessed up to 2 years ]
    The distribution of overall survival will be estimated using the method of Kaplan-Meier.

  3. Progression free survival [ Time Frame: From registration to the earliest date of documented disease progression, assessed up to 2 years ]
    The distribution of time to progression will be estimated using the method of Kaplan-Meier.

  4. Duration of response [ Time Frame: Up to 2 years ]
    Defined for all evaluable patients who have achieved an objective response as the date at which the patient's earliest best objective status is first noted to be either a complete or partial response to the earliest date progression is documented. The duration of response will be assessed descriptively.

  5. Incidence of adverse events of grade 2 and above [ Time Frame: Up to 2 years ]
    Adverse events will be described by grade for grade 2 and above with and without attribution considered. All eligible patients that have initiated treatment will be considered evaluable for assessing adverse event rate(s). The maximum grade for each type of adverse event will be recorded for each patient, and frequency tables will be reviewed to determine patterns. Additionally, the relationship of the adverse event(s) to the study treatment will be taken into consideration.

Other Outcome Measures:
  1. Archived tumor tissue analysis [ Time Frame: Up to 2 years ]
    Analyses may include, but are not limited to, immunohistochemistry for HER2 expression, florescence in situ hybridization for HER2 amplification, and next generation sequencing.

  2. Circulating tumor deoxyribonucleic acid [ Time Frame: Up to 2 years ]
    These analyses will be descriptive.

  3. Blood biomarker analysis [ Time Frame: Up to 2 years ]
    Biomarker analyses will be considered exploratory. Analyses of interest will be correlated with progression free survival and tumor response using univariate and multivariate Cox models. P values will be reported but will be considered descriptive.

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT03043313

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Contact: Seattle Genetics Trial Information Support 866-333-7436

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United States, Arizona
Mayo Clinic Arizona Recruiting
Phoenix, Arizona, United States, 85054
Contact: Theresa Araque    480-301-2048   
Principal Investigator: Tanios Bekaii-Saab         
United States, Georgia
Winship Cancer Institute / Emory University School of Medicine Recruiting
Atlanta, Georgia, United States, 30322
Contact: Trafina Jadhav    404-778-1900   
Principal Investigator: Christina Wu         
United States, Massachusetts
Dana Farber Cancer Institute Recruiting
Boston, Massachusetts, United States, 02215
Contact: Larissa Masnyk    617-632-3000   
Principal Investigator: Kimmie Ng         
United States, Minnesota
Mayo Clinic Rochester Recruiting
Rochester, Minnesota, United States, 55905
Contact: Lucas Hamann    507-284-0923   
Principal Investigator: Joleen Hubbard, MD         
United States, New York
Roswell Park Cancer Institute Recruiting
Buffalo, New York, United States, 14263
Contact: Karen Hicks    716-845-8556   
Principal Investigator: Christos Fountzilas         
Memorial Sloan Kettering Cancer Center Recruiting
New York, New York, United States, 10065
Contact: Asha Krishnan    646-227-3010   
Principal Investigator: Andrea Cercek         
United States, North Carolina
Duke University Medical Center Recruiting
Durham, North Carolina, United States, 27710
Contact: Ireka Burrus    919-668-1861   
Principal Investigator: John Strickler         
United States, Wisconsin
Aurora Research Institute Cancer Center Recruiting
Milwaukee, Wisconsin, United States, 53215
Contact: Karen Globke    414-302-2304   
Principal Investigator: Federico Sanchez         
Sponsors and Collaborators
Seattle Genetics, Inc.
National Cancer Institute (NCI)
Academic and Community Cancer Research United
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Study Chair: John H Strickler Academic and Community Cancer Research United
Study Director: Michael Stecher, MD Seattle Genetics, Inc.

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Responsible Party: Seattle Genetics, Inc. Identifier: NCT03043313     History of Changes
Other Study ID Numbers: SGNTUC-017
NCI-2017-01107 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
ACCRU-GI-1617 ( Other Identifier: Academic and Community Cancer Research United )
P30CA015083 ( U.S. NIH Grant/Contract )
First Posted: February 6, 2017    Key Record Dates
Last Update Posted: November 4, 2019
Last Verified: October 31, 2019

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Seattle Genetics, Inc.:
Colorectal cancer
Additional relevant MeSH terms:
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Colorectal Neoplasms
Colonic Neoplasms
Rectal Neoplasms
Intestinal Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Digestive System Diseases
Gastrointestinal Diseases
Colonic Diseases
Intestinal Diseases
Rectal Diseases
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Antineoplastic Agents, Immunological
Antibodies, Monoclonal
Immunologic Factors
Physiological Effects of Drugs
Antineoplastic Agents