Trial of Ibrutinib Plus Trastuzumab in HER2-amplified Metastatic Breast Cancer

Ado-trastuzumab emtansine (T-DM1) is approved by the FDA for patients with HER2-positive
metastatic breast cancer (MBC) previously treated with a taxane and trastuzumab, and is
currently listed as the preferred second-line therapy in the NCCN guidelines (NCCN 2014).
While the benefit of continued HER2 inhibition has been conclusively established for disease
that has progressed on a trastuzumab-containing regimen, there are currently no data
regarding the efficacy of HER2- targeted therapies following progression on T-DM1.

With the population of T-DM1-treated patients steadily growing, clinical trials are needed to
investigate novel therapies in this setting,to meet the medical need for effective,
evidence-based therapies for these patients.

The oral small-molecule Bruton's Tyrosine Kinase (BTK) inhibitor ibrutinib has also
demonstrated the ability to inhibit erythroblastosis virus oncogene B (ErbB)/HER receptor
family kinases in preclinical studies at clinically relevant concentrations, with an
equivalent or greater potency than other HER2-directed tyrosine kinase inhibitors (TKIs) with
demonstrated activity in HER2-positive MBC, including lapatinib, neratinib, and afatinib. Of
note, in preclinical HER2-positive cell model systems the growth inhibitory ability of
ibrutinib was substantially greater in HER2-amplified breast cancer cells versus those that
simply overexpressed the HER2 protein.

Ibrutinib is currently approved for use in patients with Chronic lymphocytic leukemia (CLL)
or Mantle cell lymphoma (MCL), and has an established safety record from clinical trials in
these patient populations. Thus there is a reasonable rationale to investigate ibrutinib in
patients with HER2- amplified MBC, in the setting of T-DM1-pretreated disease. Previous
studies have demonstrated that combined targeting of HER2 with multiple HER2-directed agents
is more effective that single agent therapy and therefore this study will explore the safety
and efficacy of ibrutinib in combination with trastuzumab.

This is a Phase I/II, open-label, unblinded, nonrandomized, standard 3+3 dose-escalation
study designed to evaluate the maximum tolerated dose (MTD) and dose-limiting toxicities
(DLT) of ibrutinib (560 or 840 or 420 mg QD) given orally in combination with trastuzumab (8
mg/kg loading dose followed by 6 mg/kg q3w) administered intravenously (IV) in patients with
HER2-amplified MBC that has progressed on prior therapy with ado-trastuzumab emtansine.

Once the recommended phase II dose of ibrutinib plus trastuzumab has been determined (no more
than 1 of 6 patients with dose-limiting toxicity) in the required 6 to 18 patients over the 3
possible dose levels, additional patients will be enrolled on the phase II part of the study
at the recommended phase II dose of ibrutinib plus trastuzumab, for a maximum of 51 patients
total.

Inclusion Criteria:

- 1. Female, Age ≥ 18 years

- 2. Histologic or cytologic confirmation of HER2-amplified breast cancer according to
most recent biopsy (local testing permitted)

- a. HER2-amplified status is defined as a HER2/CEP17 ratio ≥2 or an average of ≥6
HER2 gene copies per cell by in situ hybridization (ISH) according to the 2013
American Society of Clinical Oncology (ASCO)/CAP guidelines

- 3. Measurable or evaluable metastatic disease by RECIST (v1.1).

- 4. Progression of disease on or ≤6 months of completing prior TDM1 therapy

- 5. ≤ 4 prior chemotherapy regimens for MBC (Phase I portion) or ≤ 3 prior chemotherapy
regimens for MBC (Phase II portion)

- 6. Adequate hematologic function independent of transfusion and growth factor support
for ≤7 days prior to screening, with the exception of pegylated G-CSF (pegfilgrastim)
and darbepoetin which require discontinuation at least 14 days prior to screening,
defined as:

- Absolute neutrophil count >1500 cells/mm3 (0.75 x 10^9/L).

- Platelet count >100,000 cells/mm3 (50 x 10^9/L).

- Hemoglobin >9.0 g/dL.

- 7. Adequate hepatic and renal function defined as:

- Serum aspartate transaminase (AST) and/or alanine transaminase (ALT) ≤5.0 x upper
limit of normal (ULN) if liver metastases, or ≤3 x ULN in the absence of liver
metastases.

- Alkaline phosphatase <2.5 x ULN, unless bone metastases are present and in the
absence of liver metastases

- Estimated Creatinine Clearance ≥30 ml/min (Cockcroft-Gault)

- Bilirubin ≤1.5 x ULN (unless bilirubin rise is due to Gilbert's syndrome or of
non-hepatic origin, such as hemolysis)

- 8. Prothrombin time (PT)/international normalized ratio (INR) < 1.5xULN and PTT (aPTT)
< 1.5x ULN

- 9. Left Ventricular Ejection Fraction (LVEF) ≥ 50% at baseline as determined by either
ECHO or multiple gated acquisition scan (MUGA) and within normal limits per
institutional guidelines

- 10. Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2.

- 11. Negative urine/serum pregnancy test within 72 hours before starting study
medications for women of childbearing potential

- 12. Women of childbearing potential who agree to use two highly effective methods of
birth control (e.g., some intrauterine devices [IUD], diaphragm with spermicide,
condom with spermicide, sterilized partner, or complete abstinence) for the duration
of the study and for 30 days after the last dose of study drug

o Note: Women are considered postmenopausal and not of childbearing potential if they
have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical
profile (e.g. age appropriate, history of vasomotor symptoms), or if they have
undergone surgical sterilization

- 13. Signed informed consent obtained prior to any screening procedures.

- 14. Signed Patient Authorization Form (HIPAA) obtained prior to any screening
procedures.

Exclusion Criteria:

- 1. Uncontrolled or untreated central nervous system metastases, defined as clinical or
radiologic evidence of progression of brain metastases or clinical signs of
leptomeningeal disease

1. Patients with treated brain metastases are eligible provided they do not have
clinical or radiologic evidence of disease progression and have been off of
dexamethasone for ≥2 weeks prior to first dose of study drugs

2. Brain MRI at baseline required for patients with known brain metastases at study
entry

- 2. Chemotherapy ≤ 21 days prior to first administration of study treatment

- 3. History of other malignancies, except:

- Malignancy treated with curative intent and with no known active disease present
for ≥3 years before the first dose of study drug and felt to be at low risk for
recurrence by treating physician.

- Adequately treated non-melanoma skin cancer or lentigo maligna without evidence
of disease.

- Adequately treated carcinoma in situ without evidence of disease.

- 4. Concurrent systemic immunosuppressant therapy (e.g., cyclosporine A, tacrolimus,
etc., or chronic administration days] [ > 14 days] of >5 mg/day of prednisone) ≤28
days of the first dose of study drug.

- 5. Vaccinated with live, attenuated vaccines ≤4 weeks of first dose of study drug.

- 6. Recent infection requiring systemic treatment that was completed ≤14 days before
the first dose of study drug.

- 7. Unresolved toxicities from prior anti-cancer therapy, defined as having not
resolved to Common Terminology Criteria for Adverse Event (CTCAE, version 4), grade 0
or 1, or to the levels dictated in the inclusion/exclusion criteria with the exception
of alopecia.

- 8. Known bleeding disorders (e.g., von Willebrand's disease) or hemophilia.

- 9. History of stroke or intracranial hemorrhage ≤6 months prior to first dose of study
drug.

- 10. Known history of human immunodeficiency virus (HIV) or active with hepatitis C
virus (HCV) or hepatitis B virus (HBV). Patients who are positive for hepatitis B core
antibody or hepatitis B surface antigen must have a negative polymerase chain reaction
(PCR) result before enrollment. Those who are PCR positive will be excluded.

- 11. Any uncontrolled active systemic infection.

- 12. Major surgery ≤ 4 weeks of first dose of study drug.

- 13. Any life-threatening illness, medical condition, or organ system dysfunction that,
in the investigator's opinion, could compromise the subject's safety or put the study
outcomes at undue risk.

- 14. Currently active, clinically significant cardiovascular disease, such as
uncontrolled arrhythmia or Class 3 or 4 congestive heart failure as defined by the New
York Heart Association Functional Classification; or a history of myocardial
infarction, unstable angina, or acute coronary syndrome within 6 months prior to
randomization.

- 15. Unable to swallow capsules or malabsorption syndrome, disease significantly
affecting gastrointestinal function, or resection of the stomach or small bowel,
symptomatic inflammatory bowel disease or ulcerative colitis, or partial or complete
bowel obstruction.

- 16. Concomitant use of warfarin or other Vitamin K antagonists.

- 17. Receipt of a strong cytochrome P450 (CYP) 3A inhibitor within 7 days prior to the
first dose of ibrutinib or requirement for continuous treatment with a strong CYP3A
inhibitor.

- 18. Chronic liver disease with hepatic impairment Child-Pugh class B or C.

- 19. Lactating or pregnant.

- 20. Unwilling or unable to participate in all required study evaluations and
procedures.

- 21. Unable to understand the purpose and risks of the study and to provide a signed
and dated informed consent form (ICF) and authorization to use protected health
information (in accordance with national and local subject privacy regulations).