A Pharmacodynamic Study of Pre-prostatectomy BKM120 in Men With High-risk, Localized Prostate Cancer

Inclusion Criteria

INCLUSION CRITERIA

1. Histologically confirmed adenocarcinoma of the prostate

2. Candidate for radical prostatectomy

3. Prostate cancer with the following pathological characteristics:

1) Gleason sum > 8 AND at least 2 discrete core biopsies containing a minimum of 20%
cancer OR 2) Gleason pattern 4 + 3 = 7 AND greater than 50% of biopsies positive for
prostate cancer 4. Age ≥ 18 years 5. ECOG performance status £ 2 6. Ability to take oral
medications (capsule must be swallowed with liquid) 7. Adequate bone marrow function as
shown by: ANC ≥ 1.5 x 109/L, Platelets ≥ 100 x 109/L, Hgb > 9 g/dL 8. Total calcium
(corrected for serum albumin) within normal limits (biphosphonate use for malignant
hypercalcemia control is not allowed) 9. Magnesium ≥ the lower limit of normal 10.
Potassium within normal limits for the institution 11. Alanine aminotransferase (ALT) and
aspartate aminotransferase (AST) within normal range 12. Serum bilirubin within normal
range (or total bilirubin ≤ 3.0 x ULN with direct bilirubin within normal range in
patients with well documented Gilbert Syndrome) 13. Serum creatinine ≤ 1.5 x ULN or
24-hour clearance ≥ 50 mL/min 14. Serum amylase ≤ ULN 15. Serum lipase ≤ ULN 16. Fasting
plasma glucose ≤ 120 mg/dL (6.7 mmol/L) 17. INR ≤ 2 18. Men of reproductive potential and
their female partners must use highly effective contraception during treatment, for 5
half-lives (8 days) after stopping treatment and for additional 12 weeks (3 months in
total after study drug discontinuation) and should not father a child in this period The
highly effective contraception is defined as either:

1. True abstinence: When this is in line with the preferred and usual lifestyle of the
subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal,
post-ovulation methods) and withdrawal are not acceptable methods of contraception.

2. Sterilization: Female partners have had surgical bilateral oophorectomy (with or
without hysterectomy) or tubal ligation at least six weeks ago. In case of
oophorectomy alone, only when the reproductive status of the woman has been confirmed
by follow up hormone level assessment.

3. Male participant sterilization (with the appropriate post-vasectomy documentation of
the absence of sperm in the ejaculate).

4. Use of a combination of any two of the following (a+b):

1. Female partner with prior placement of an intrauterine device (IUD) or
intrauterine system (IUS)

2. Barrier methods of contraception: Condom or Occlusive cap (diaphragm or
cervical/vault caps) with spermicidal foam/gel/film/cream/vaginal suppository

- Oral contraception use by female partners, injected or implanted hormonal
methods are not allowed as BKM120 potentially decreases the effectiveness
of hormonal contraceptives.

- Fertile males, defined as all males physiologically capable of conceiving
offspring must use condom during treatment, for 5 T1/2 (8 days) after
stopping treatment and for additional 12 weeks (3 months in total after
study drug discontinuation) and should not father a child in this period.

19. Ability to understand and the willingness to sign a written informed consent document

EXCLUSION CRITERIA

1. Prior treatment with a PI3K inhibitor

2. Known hypersensitivity to BKM120 or to its excipients

3. History of another malignancy within 3 years, except cured basal cell carcinoma of
the skin

4. Hormonal therapy with GnRH agonists, GnRH antagonists or high dose biclutamide within
1 month of enrollment unless serum testosterone is within normal limits.

5. Following mood disorders as judged by the investigator and/or symptom management
service co-investigator, or as a result of patient's mood assessment questionnaire:

- Medically documented history of or active major depressive episode, bipolar
disorder (I or II), obsessive-compulsive disorder, schizophrenia, a history of
suicidal attempt or ideation, or homicidal ideation (immediate risk of doing
harm to others)

- Current ≥ CTCAE grade 3 anxiety

- Meets the cut-off score of ≥ 10 in the PHQ-9 or a cut-off of ≥ 15 in the GAD-7
mood scale, respectively, or selects a positive response of "1, 2, or 3" to
question number 9 regarding potential for suicidal thoughts in the PHQ-9
(independent of the total score of the PHQ-9) will be excluded from the study

6. Current diarrhea ≥ CTCAE grade 2

7. Active cardiac disease including any of the following:

- History of left ventricular ejection fraction (LVEF) < 50% as determined by
Multiple Grated acquisition (MUGA) scan or echocardiogram (ECHO)

- QTc > 450 msec on screening ECG (using the QTcF formula)

- Angina pectoris that requires the use of anti-anginal medication

- History of ventricular arrhythmias except for benign premature ventricular
contractions

- Supraventricular and nodal arrhythmias requiring a pacemaker or not controlled
with medication

- Conduction abnormality requiring a pacemaker

- Valvular disease with documented compromise in cardiac function

- Symptomatic pericarditis

8. History of cardiac dysfunction including any of the following:

- Myocardial infarction within the last 6 months, documented by persistent
elevated cardiac enzymes or persistent regional wall abnormalities on assessment
of LVEF function

- History of documented congestive heart failure (New York Heart Association
functional classification III-IV)

- Documented cardiomyopathy

9. Poorly controlled diabetes mellitus or active, steroid-induced diabetes mellitus

10. Other concurrent severe and/or uncontrolled concomitant medical conditions (e.g.,
active or uncontrolled infection) that could cause unacceptable safety risks or
compromise compliance with the protocol

11. Impairment of gastrointestinal (GI) function or GI disease that may significantly
alter the absorption of BKM120 (e.g., ulcerative diseases, uncontrolled nausea,
vomiting, diarrhea, malabsorption syndrome, or small bowel resection). Patients with
unresolved diarrhea will be excluded as previously indicated

12. Treatment with any hematopoietic colony-stimulating growth factors (e.g., G-CSF,
GM-CSF) ≤ 2 weeks prior to starting study drug. Erythropoietin or darbepoetin
therapy, if initiated at least 2 weeks prior to enrollment, may be continued

13. Current treatment with medication with a known risk to prolong the QT interval or
inducing Torsades de Pointes and the treatment cannot either be discontinued or
switched to a different medication prior to starting study drug. Please refer to
section 10.2 for a list of prohibited QT prolonging drugs with risk of Torsades de
Pointes.

14. Current, chronic treatment with steroids or another immunosuppressive agent

• Note: Topical applications (e.g. rash), inhaled sprays (e.g. obstructive airways
diseases), eye drops or local injections (e.g. intr-articular) are allowed. If a
patient stops corticosteroids prior to study participation, a 2-week washout is
required.

15. Taking herbal medications and certain fruits and juices within 7 days prior to
starting study drug. Herbal medications include, but are not limited to St. John's
wort, Kava, ephedra (ma huang), gingko biloba, dehydroepiandrosterone (DHEA),
yohimbe, saw palmetto, and ginseng. Fruits and juice include the CYP3A inhibitors:
Seville oranges, grapefruit, and pomelos.

16. Current treatment with drugs known to be moderate and strong inhibitors or inducers
of isoenzyme CYP3A, and the treatment cannot be discontinued or switched to a
different medication prior to starting study drug. Please refer to Section 10.2 for
a list of prohibited inhibitors and inducers of CYP3A (Please note that co-treatment
with weak inhibitors of CYP3A is allowed)

17. Chemotherapy or targeted anticancer therapy ≤ 4 weeks (6 weeks for nitrosourea,
antibodies or mitomycin-C) prior to starting study drug

18. Any continuous or intermittent small molecule therapeutics (excluding monoclonal
antibodies) ≤ 5 effective half lives prior to starting study drug or patients who
have not recovered from side effects of such therapy

19. Major surgery ≤ 2 weeks prior to starting study drug or who have not recovered from
side effects of such therapy

20. Current treatment with warfarin sodium or any other coumadin-derivative anticoagulant

21. Known diagnosis of human immunodeficiency virus (HIV) infection. Testing is not
required for participation.

22. Unable or unwilling to abide by the study protocol or cooperate fully with the
investigator