Clinical Trials /

A Study of Tucatinib vs. Placebo in Combination With Capecitabine & Trastuzumab in Patients With Advanced HER2+ Breast Cancer



This study is being done to see if tucatinib works better than placebo to help patients who have a specific type of breast cancer called HER2 positive breast carcinoma. The breast cancer in this study is either metastatic (spread into other parts of the body) or cannot be removed completely with surgery. All patients in the study will get capecitabine and trastuzumab, two drugs that are often used to treat this cancer. There are two parts to this study. The first part of the study is already complete. Patients were randomly assigned to get either tucatinib or placebo (a pill with no medicine). Since this part was "blinded," neither patients nor their doctors knew whether a patient got tucatinib or placebo. The second part of the study is called the Unblinded Phase. In this part of the study, participants and their doctors know which drugs are being given. Participants who used to get or are currently getting placebo may be able to start taking tucatinib instead. Each treatment cycle lasts 21 days. Patients will swallow tucatinib pills two times every day. They will swallow capecitabine pills two times a day during the first two weeks of each cycle. Patients will get trastuzumab injections from the study site staff on the first day of every cycle.

Related Conditions:
  • Breast Carcinoma
Recruiting Status:

Active, not recruiting


Phase 2

Trial Eligibility


Study of ONT-380 vs <span class="go-doc-concept go-doc-intervention">Placebo</span> in Combo w/ <span class="go-doc-concept go-doc-intervention">Capecitabine</span> & <span class="go-doc-concept go-doc-intervention">Trastuzumab</span> in Patients w/ Metastatic <span class="go-doc-concept go-doc-biomarker">HER2</span>+ Breast Cancer


  • Brief Title: Study of ONT-380 vs Placebo in Combo w/ Capecitabine & Trastuzumab in Patients w/ Metastatic HER2+ Breast Cancer
  • Official Title: Phase 2 Randomized, Double-Blinded, Controlled Study of ONT-380 vs Placebo in Combination With Capecitabine and Trastuzumab in Patients With Pretreated Unresectable Locally Advanced or Metastatic HER2+ Breast Carcinoma
  • Clinical Trial IDs

    NCT ID: NCT02614794

    ORG ID: ONT-380-206

    Trial Conditions

    HER2 Positive Breast Cancer

    Trial Interventions

    Drug Synonyms Arms
    ONT-380 ONT-380 in combo w/ cape & tras
    Capecitabine Xeloda ONT-380 in combo w/ cape & tras, Placebo in combo w/ cape & tras
    Trastuzumab Herceptin ONT-380 in combo w/ cape & tras, Placebo in combo w/ cape & tras
    Placebo Placebo in combo w/ cape & tras

    Trial Purpose

    The purpose of this study is to assess the effect of ONT-380 vs. placebo in combination with
    capecitabine and trastuzumab on both central nervous system (CNS) and non-CNS
    progression-free survival (PFS) based on independent central review.

    Detailed Description

    This is a Phase 2 randomized, international, multi-center, double-blinded study of ONT-380
    or placebo in combination with capecitabine and trastuzumab in patients with progressive
    unresectable locally recurrent or metastatic HER2+ breast cancer who have had prior
    treatment with a taxane, trastuzumab, pertuzumab and T-DM1. After signing informed consent
    and meeting all eligibility criteria, including assessments based on screening brain MRI,
    patients will be randomized in a 2:1 ratio to receive ONT-380 or placebo in combination with
    capecitabine and trastuzumab.

    Randomization will be made using a dynamic hierarchical randomization schema. Stratification
    factors will include known history of treated or untreated CNS metastases (yes/no), Eastern
    Cooperative Oncology Group Performance Status (ECOG PS) (0 vs. 1), and region of world (US
    vs Canada vs Western Europe). Stratification for presence of CNS metastases will be based
    upon investigator assessment of screening MRI. Patients who have a documented history of
    prior CNS metastases or unequivocal presence of CNS lesions on screening MRI will be
    considered a "Yes" for stratification purposes, and subsequent efficacy assessments.
    Patients with no prior history of CNS metastases and lesions of equivocal significance on
    screening MRI will also be considered a "Yes" for purposes of stratification and follow-up.

    Treatment will be administered in cycles of 21 days each. ONT-380 or placebo will be given
    PO BID. Capecitabine will be given at 1000 mg/m2 PO BID on Days 1-14 of each 21-day cycle.
    Trastuzumab will be given as a loading dose of 8 mg/kg IV followed by 6 mg/kg once every 21
    days, except in specific circumstances where it may be given weekly to compensate for
    modifications in treatment schedule. Dose modifications of ONT-380 or placebo and
    capecitabine will be allowed. Dose holding or discontinuation of ONT-380 or placebo,
    capecitabine, and trastuzumab will also be allowed as needed for patient safety. Patients
    who discontinue either capecitabine or trastuzumab (but not both) may remain on study
    treatment. Patients who discontinue ONT-380 or placebo, or both capecitabine and trastuzumab
    will not be allowed to remain on study treatment.

    Treatment will continue until unacceptable toxicity, disease progression, withdrawal of
    consent, or study closure. After discontinuing study treatment, patients may receive further
    care as determined by their physician. In the absence of clear evidence of clinical
    progression, development of CNS symptoms, or radiographic changes thought to pose potential
    immediate risk to patient, all efforts should be made to continue treatment until
    unequivocal evidence of radiologic or clinical progression occurs, as defined in RECIST 1.1
    and Response Assessment in Neuro-Oncology - Brain Metastases (RANO-BM) criteria. No
    crossover from placebo to ONT-380 will be allowed.

    Patients will be assessed throughout the study for safety. Safety assessments including
    physical exam, collection of adverse events (AEs), and laboratory assessments will be
    performed at a minimum of once every three weeks throughout study treatment and 30 days
    after the last dose of study drugs. Laboratory assessments will be performed locally at
    sites. Cardiac ejection fraction will be assessed by multiple-gated acquisition scan (MUGA)
    or echocardiogram (ECHO) at screening and once every 12 weeks thereafter.

    Brain MRI will be performed at baseline in all patients regardless of prior history of CNS
    metastases. Efficacy assessments will include measurement of all known sites of metastatic
    or locally advanced unresectable disease (including at a minimum the chest, abdomen, and
    pelvis) by high quality spiral computed tomography (CT), positron emission tomography
    (PET)/CT (if high quality CT scan included) and/or MRI scan as appropriate, as well as
    appropriate imaging of any other known sites of disease (e.g. bone scans) at baseline, every
    6 weeks for the first 24 weeks, and then every 9 weeks thereafter. Repeat MRI of the brain
    will be required on this same schedule only in those patients with prior history of brain
    metastases, brain metastases found at screening, or brain lesions of equivocal significance
    found at screening. Brain MRI may also be performed in patients without known CNS metastases
    if there is clinical suspicion of new brain lesions. Additional imaging such as nuclear
    medicine bone scan or other unscheduled scans may be performed at the discretion of the
    investigator. Treatment decisions will be made based upon investigator assessment of
    radiologic scans. All patients will undergo a repeat MRI of the brain within 30 days of the
    end of treatment, unless an MRI of the brain has already been performed within 30 days or
    prior documentation of progression in the brain on study. Patients in both arms of the study
    will continue to be followed for OS after completion of study treatment.

    Trial Arms

    Name Type Description Interventions
    ONT-380 in combo w/ cape & tras Experimental ONT-380 in combo w/ capecitabine & trastuzumab ONT-380, Capecitabine, Trastuzumab
    Placebo in combo w/ cape & tras Active Comparator Placebo in combo w/ capecitabine & trastuzumab Capecitabine, Trastuzumab, Placebo

    Eligibility Criteria

    Inclusion Criteria

    Patients must meet the following criteria to be eligible for the study:

    1. Have histologically confirmed HER2+ breast carcinoma, with HER2+ defined by
    fluorescence in situ hybridization (FISH) and/or 3+ staining by immunohistochemistry

    a. Tissue blocks or slides must be submitted to confirm HER2 positivity
    (FISH-positive or IHC 3+) by a sponsor-designated central laboratory prior to
    randomization. Centrally confirmed HER2 results (either IHC or FISH) from a previous
    study can be used to determine eligibility for this study with approval from the

    2. Have received previous treatment with a taxane, trastuzumab, pertuzumab, and T-DM1

    3. Have one of the following:

    1. If both pertuzumab and T-DM1 were administered for metastatic or locally
    advanced unresectable breast cancer, must be at least 6 months since diagnosis
    of metastatic or locally advanced unresectable breast cancer.

    2. If either pertuzumab or T-DM1 was administered in the neo-adjuvant or adjuvant
    setting (and the other administered for metastatic or locally advanced
    unresectable breast cancer), must be at least 3 months since diagnosis of
    metastatic or locally advanced unresectable breast cancer.

    3. If both pertuzumab and T-DM1 were administered in the neo-adjuvant or adjuvant
    setting, must have completed adjuvant treatment at least 12 months prior to

    4. Have progression of unresectable locally advanced or metastatic breast cancer after
    last systemic therapy (as confirmed by investigator)

    5. Have measurable or non-measureable disease assessable by RECIST 1.1 and/or RANO-BM

    6. Be at least 18 years of age at time of consent

    7. Have Eastern Cooperative Oncology Group Performance Status (ECOG PS) 0 or 1

    8. Have a life expectancy of at least 6 months, in the opinion of the investigator

    9. Have adequate hepatic function as defined by the following:

    1. Total bilirubin 1.5 X ULN, except for patients with known Gilbert's disease,
    who may enroll if the conjugated bilirubin is 1.5X ULN

    2. Transaminases [aspartate aminotransferase/serum glutamic oxaloacetic
    transaminase (AST/SGOT) and alanine aminotransferase/serum glutamic pyruvic
    transaminase (ALT/SGPT)] 2.5 X ULN ( 5 X ULN if liver metastases are present)

    10. Have adequate baseline hematological parameters as defined by:

    1. Absolute neutrophil count (ANC) 1.0 x 103/L

    2. Platelet count 75 x 103/L

    3. Hemoglobin 9 g/dL

    11. Have creatinine clearance 50 mL/min as calculated per institutional guidelines

    12. International normalized ratio (INR) and activated partial thromboplastin time (aPTT)
    1.5 X ULN unless on medication known to alter INR and aPTT. (Note: Warfarin is a
    prohibited concomitant therapy.)

    13. Have 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

    14. If female of childbearing potential, must have a negative result of serum pregnancy
    test performed within 7 days prior to first dose of study treatment. (Females of
    childbearing potential are those who have not undergone surgical sterilization with a
    hysterectomy and/or bilateral oophorectomy; or, are not postmenopausal, as defined as
    12 months of amenorrhea

    15. Women of childbearing potential (as defined above) and men with partners of
    childbearing potential must agree to use a highly effective hormonal form of
    contraception or two effective forms of non-hormonal contraception. [Effective
    methods of contraception include oral, transdermal, injectable, or implantable
    contraceptives; intrauterine device (IUD); female condom; diaphragm with spermicide;
    cervical cap; use of a condom by the sexual partner; or a sterile sexual partner.]
    Male patients with partners of childbearing potential must use barrier contraception.
    All study subjects should practice effective barrier method of contraception starting
    from the signing of informed consent until 6 months after the last dose of study
    medication or investigational medicinal product.

    16. Patient or legally authorized representative of a patient must provide signed
    informed consent per a consent document that has been approved by an institutional
    review board or 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
    patient's disease.

    17. Patients must also be willing and able to comply with study procedures.

    CNS Inclusion

    Based on screening brain magnetic resonance imaging (MRI), patients must have one of
    the following:

    18. No evidence of CNS metastases

    19. Untreated CNS metastases not needing immediate local therapy, where all untreated CNS
    lesions are 2.0 cm on screening MRI

    20. Previously treated CNS metastases

    1. For patients treated with CNS local therapy prior to initiating screening for
    the study, the screening brain MRI must show no increase in any lesion of > 10
    mm compared to a scan obtained at least 4 weeks prior to screening MRI. Relevant
    MRI reports and prior records of treatment of CNS disease (e.g., radiation
    therapy fields or history of surgical resection) must be available to allow for
    classification of target and non-target CNS lesions.

    2. Patients treated with CNS local therapy for newly identified lesions found on
    initial MRI performed during screening for this study may be eligible to enroll
    if all of the following criteria are met:

    1. Time since WBRT is > 21 days prior to first dose of treatment, time since
    stereotactic radiosurgery (SRS) is > 14 days prior to first dose of
    treatment, or time since surgical resection is > 28 days

    2. Non-CNS sites of evaluable disease are present

    3. Relevant records of CNS treatment must be available to allow for
    classification of target and non-target lesions

    Exclusion Criteria

    Patients will be excluded from the study for any of the following reasons:

    1. Have previously been treated with either lapatinib, neratinib, afatinib, or other
    investigational HER2/epidermal growth factor receptor (EGFR) or HER2 TKI. Other prior
    anti-HER2 therapies are allowed.

    2. Have previously been treated with capecitabine

    3. History of exposure to the following cumulative doses of anthracyclines:

    1. Doxorubicin or liposomal doxorubicin > 360 mg/m2

    2. Epirubicin > 720 mg/m2

    3. Mitoxantrone > 120 mg/m2 d. Idarubicin > 90 mg/m2

    e. Other anthracyclines (e.g., liposomal doxorubicin) > the equivalent of 360 mg/m2
    of doxorubicin f. If more than one anthracycline has been used, then the cumulative
    dose must not exceed the equivalent of 360 mg/m2 of doxorubicin

    4. Have history of allergic reactions to trastuzumab, capecitabine, or ONT-380 (or
    compounds chemically or biologically similar), except for Grade 1 or 2 infusion
    related reactions to trastuzumab that were successfully managed

    5. Have received treatment with any systemic anti-cancer therapy (including hormonal
    therapy), non-CNS radiation, or experimental agent 3 weeks of first dose of study

    6. 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; and congestive heart failure (CHF), which must have been Grade 1 in
    severity at the time of occurrence, and must have resolved completely

    7. Have clinically significant cardiac disease such as ventricular arrhythmia requiring
    therapy, 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

    8. Have known myocardial infarction or unstable angina within 6 months prior to first
    dose of study treatment

    9. Are known carriers of Hepatitis B or Hepatitis C or have other known chronic liver

    10. Are known to be positive for human immunodeficiency virus (HIV)

    11. Are pregnant, breastfeeding, or planning a pregnancy

    12. Require warfarin therapy

    13. Have inability to swallow pills or any significant gastrointestinal disease which
    would preclude the adequate oral absorption of medications

    14. Have used 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

    15. Have known dihydropyrimidine dehydrogenase deficiency

    16. Unable for any reason to undergo MRI of the brain

    17. Have any other medical, social, or psychosocial factors that, in the opinion of the
    investigator, could impact safety or compliance with study procedures

    CNS Exclusion

    Based on screening brain MRI, patients must not have any of the following:

    18. Any untreated lesions > 2.0 cm in size

    19. Ongoing use of systemic corticosteroids for control of symptoms of CNS metastases <28
    days prior to first dose of study treatment

    20. Any lesion thought to require immediate local therapy, including (but not limited to)
    a lesion in an anatomic site where increase in size or possible treatment-related
    edema may pose risk to patient (e.g. brain stem lesions). Patients who undergo local
    treatment for such lesions identified by screening MRI may still be eligible for the
    study based on criteria described under CNS inclusion criteria 20b

    21. Known leptomeningeal disease (LMD). If LMD has been reported radiographically on
    baseline MRI but is not suspected clinically by the investigator, patient must be
    free of neurological symptoms of LMD and have a cerebrospinal fluid sample without
    evidence of LMD to be eligible

    22. Have poorly controlled seizures

    Minimum Eligible Age: 18 Years

    Maximum Eligible Age: N/A

    Eligible Gender: Both

    Primary Outcome Measures

    Progression-free survival (PFS) [CNS and non-CNS] based on independent central review

    Secondary Outcome Measures

    Progression free survival (PFS) based on investigator assessment

    Progression free survival (PFS) (CNS vs. non-CNS)

    Time to CNS progression

    Objective response rate (ORR) (CNS vs. non-CNS) (%)

    Duration of response (CNS vs. non-CNS)

    Clinical benefit rate in CNS (the percentage of patients who have achieved complete response, partial response and stable disease as assessed by the RANO-BM criteria)

    Clinical benefit rate in non-CNS (the percentage of patients with advanced or metastatic cancer who have achieved complete response, partial response and stable disease as assessed by the RECIST 1.1 criteria)

    Overall survival (OS)

    Safety and Tolerability of ONT-380 in combination with capecitabine and trastuzumab as assessed by comparison of adverse events

    Trial Keywords