Clinical Trial Details
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NCT02614794 : Study of ONT-380 vs Placebo in Combo w/ Capecitabine & Trastuzumab in Patients w/ Metastatic HER2+ Breast Cancer
PhasePhase 2
AgesMin: 18 Years Max: N/A
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. If pertuzumab and/or T-DM1 were given in the neo-adjuvant or adjuvant setting, must
have completed that treatment at least 12 months prior to start of treatment

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

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) ? 1.5 x 103/µL

2. Platelet count ? 100 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 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 brain metastases

19. Untreated CNS brain metastases not needing immediate local therapy. For patients with
untreated CNS lesions > 2.0 cm on screening MRI, discussion with and approval from
the medical monitor is required prior to enrollment.

20. Previously treated brain metastases

1. Brain metastases previously treated with local therapy may either be stable
since treatment or may have progressed since prior local CNS therapy, provided
that there is no clinical indication for immediate re-treatment with local
therapy in the opinion of the investigator.

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:

i. 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

ii. Non-CNS sites of evaluable disease are present

c. 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:

1. lapatinib within 12 months of starting study treatment or

2. neratinib, afatinib, or other investigational HER2/epidermal growth factor
receptor (EGFR) or HER2 TKI at any time previously.

2. Have previously been treated with capecitabine for metastatic disease. Note: Patients
who have received capecitabine for adjuvant or neoadjuvant treatment at least 12
months prior to starting study treatment are eligible.

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

4. Idarubicin > 90 mg/m2

5. Other anthracyclines (e.g., liposomal doxorubicin) > the equivalent of 360 mg/m2
of doxorubicin

6. 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 therapy with warfarin or other coumarin derivatives (other non-coumarin
anticoagulants are allowed)

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

18. History of other malignancy within the previous 3 years, except for appropriately
treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, Stage 1 uterine
cancer, synchronous or previously diagnosed HER2-positive breast cancer, or cancers
with a similar curative outcome as those mentioned above

CNS Exclusion

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

19. Any untreated lesions > 2.0 cm in size

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

21. 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

22. 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

23. Have poorly controlled seizures
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