Ibrutinib as Neoadjuvant Therapy in Localized Prostate Cancer

Inclusion Criteria:

- 18 years of age or older

- ECOG performance status 0 or 1

- Histologically documented adenocarcinoma of the prostate

- Patients must be suitable for and willing to undergo a radical prostatectomy at the
completion of study therapy.

- Adequate bone marrow function, defined as:

- WBC >2,500 cells/mm3

- ANC >1,500 cells/mm3

- Hemoglobin >9 mg/dL

- Platelet count >100,000 cells/mm3

- Adequate renal function, defined as serum creatinine <2 mg/dL or CrCl >30 mL/min

- Adequate liver function, defined as:

- AST and ALT <2.5x institutional ULN

- Serum bilirubin <1.5x institutional ULN

- Adequate coagulation function, defined as normal PT/INR and PTT

- Ability to understand and willingness to sign a written informed consent document

- Available evaluable archival tumor tissue for correlative studies including assessment
of immune infiltration and Btk expression is required. If archival tissue is
unavailable, patients must be willing to undergo repeat prostate biopsy. Tissue is
considered sufficient for correlative endpoint analyses if they are obtained from at
least 2 prostate cores and consist of at least 15 unstained slides from the largest
tumor volume and/or highest Gleason score. The availability of archival tissue or
consent for repeat prostate biopsy is required for study eligibility; determination of
tissue sufficiency is not required for study eligibility.

- The effects of ibrutinib on the developing human fetus is unknown. Men treated or
enrolled on this protocol must agree to use adequate contraception prior to the study,
for the duration of the study participation, and for 3 months after completion of
treatment.

Exclusion Criteria:

- Patients with neuroendocrine or small cell features are not eligible.

- Any evidence of metastatic disease. Pre-operative staging will be undertaken per
urologic standard of care.

- Any prior use of hormonal therapy, including:

- GNRH agonists or GNRH antagonists (e.g., leuprorelin, degarelix)

- Antiandrogens (e.g., bicalutamide, flutamide, nilutamide)

- Novel androgen-directed therapies (e.g., abiraterone, enzalutamide)

- Any estrogen containing compounds

- 5-alpha reductase inhibitors (e.g., finasteride, dutasteride)

- PC-SPES or PC-x products. Other herbal therapies or supplements will be
considered by the Principle Investigator on a case by case basis based on their
potential for hormonal or anti-cancer therapies.

- Chemotherapy ≤ 21 days prior to first administration of study treatment and/or
monoclonal antibody ≤ 6 weeks prior to first administration of study treatment

- Prior radiation therapy for prostate cancer

- Prior exposure to BTK inhibitors

- Prior investigational therapy for prostate cancer

- Patients may not receive any other concurrent investigational agents while on study.

- Use of systemic steroid therapy within 28 days of study screening. Patients on inhaled
or topical steroids are eligible.

- Concurrent systemic immunosuppressive therapy within 21 days of the first dose of
study drug.

- Major surgery requiring the use of general anesthetic within 4 weeks of study
enrollment

- HIV, active hepatitis B (HBV) or active hepatitis C (HCV)

- Patients with past HBV infection or resolved HBV infection, defined as the
presence of hepatitis B core antibody (HBc Ab) and absence of hepatitis B surface
antigen (HBsAg) are eligible. HBV DNA must be obtained in these patients prior to
day 1 of ibrutinib therapy, but detection of HBV DNA in these patients will not
exclude study participation.

- Patients positive for HCV antibody are eligible only if polymerase chain reaction
is negative for HCV RNA.

- Inability to swallow capsules or presence of malabsorption syndromes, disease
significantly affecting gastrointestinal function, history of resection of the stomach
or small bowel, symptomatic inflammatory bowel disease or ulcerative colitis, or
partial or complete small obstruction.

- 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 Function Classification; or a history of myocardial infarction, unstable
angina, or acute coronary syndrome within 6 months prior to screening.

- Uncontrolled concurrent illness, or any underlying medical condition, which in the
Principal Investigator's opinion will make the administration of ibrutinib hazardous
or obscure the interpretation of adverse events.

- Recent infection requiring systemic treatment that was completed within 14 days prior
to the first dose of study drug

- Concurrent active malignancy other than non-melanoma skin cancers. Patients are
considered to be free of active malignancy if they have completed curative therapy and
have a <30% risk of relapse.

- Moderate or severe hepatic impairment defined as Child-Pugh Class B or C.

- History of congenital bleeding diathesis.

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

- Concomitant use of anticoagulants including warfarin, other Vitamin K antagonists, and
enoxaparin.

- Subjects who received a strong or moderate cytochrome P450 (CYP) 3A4 inhibitor within
7 days prior to the first dose of ibrutinib or patients who require treatment with a
strong or moderate cytochrome P450 (CYP) 3A inhibitor.

- Vaccination with live, attenuated vaccines within 4 weeks of first dose of study drug.

- Major surgery within 4 weeks of the first dose of study drug.

- Patients on anti-platelet agents including clopidogrel and glycoprotein IIb/IIIa
inhibitors. Aspirin is allowed, but should be held before surgery according to
standard practices.

- Currently active, clinically significant hepatic impairment Child-Pugh class B or C
according to the Child-Pugh classification

- 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.

- Unresolved toxicities from prior anti-cancer therapy, defined as having not resolved
to CTCAE v 4.03 grade 0 or 1 or to the levels dictated in the eligibility criteria
with the exception of alopecia.