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.

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 (IHC)

   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 sponsor.

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 enrollment.
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 criteria
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/µL
    2. Platelet count ≥ 75 x 103/µL
    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 treatment
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 disease
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