Cabazitaxel and BKM120 in Patients With Metastatic Castrate-Resistant Prostate Cancer (mCRPC) Previously Treated With Docetaxel

This study will be conducted in two parts. In a lead-in cohort, the feasibility and safety
of administering BKM120 with a standard dose of cabazitaxel will be assessed. If safety is
confirmed, a subsequent Phase II portion will assess the activity of the combination in
patients with mCRPC previously treated with docetaxel. The treatment will consist of 3-week
(21-day) cycles.

The ultimate purpose of this study will be to determine progression-free survival, response
rate, disease control rate and overall survival of patients treated with the combination
regimen and compare outcomes to historical results with single-agent cabazitaxel.

Inclusion Criteria:

1. Adenocarcinoma of the prostate confirmed histologically.

2. Metastatic disease confirmed by biopsy or imaging studies.

3. Patients must have received treatment with docetaxel as the only previous
chemotherapy regimen. In addition, previous treatment with hormonal agents and/or
immune therapy is allowed (e.g., abiraterone). (Previous treatment with MDV3100 will
also be allowed.)

4. Patients must be castrate-resistant (i.e. developed progression of metastases
following surgical castration or during medical androgen ablation therapy) with
documented castrate levels of testosterone (<50 ng/dl).

5. Patients receiving medical castration therapy with gonadotropin-releasing hormone
(GnRH) analogues should continue this treatment during this study.

6. Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) score of 0 to 2.

7. Patient must have progressive metastatic prostate cancer by at least 1 of the
following criteria:

- Soft tissue disease progression defined by Response Evaluation Criteria in Solid
Tumors (RECIST) version 1.1.

- Bone scan progression defined by 2 or more new lesions on bone scan.

- Prostate specific antigen (PSA) progression is determined by a minimum of three
rising PSA levels with an interval of ≥1 week between each determination. The
screening PSA measurement (documenting progression) must be ≥2 ng/mL.

8. Screening PSA ≥2 ng/mL.

9. Adequate hematologic, renal and hepatic function:

10. Adequate serum chemistries.

11. Ability to swallow and retain oral medication.

12. Life expectancy of ≥6 months.

13. Patients must be ≥18 years of age.

14. Patients entering this study must be willing to provide tissue from a previous tumor
biopsy or 15 unstained slides (if available) for correlative testing. If tissue is
not available, a patient will still be eligible for enrollment into the study.

15. Ability to understand the nature of this study and give written informed consent.

Exclusion Criteria:

1. Previous treatment with PI3K inhibitors.

2. Known hypersensitivity to BKM120 or polysorbate-80 or any of the excipients or
taxanes.

3. Use of an investigational drug ≤21 days or 5 half-lives (whichever is shorter) prior
to the first dose of BKM120. For investigational drugs for which 5 half-lives is ≤21
days, a minimum of 10 days between termination of the investigational drug and
administration of BKM120 is required.

4. Previous chemotherapy with any agent other than docetaxel. All patients must be ≥28
days after their most recent chemotherapy and have recovered from side effects.

5. Patient has received wide field radiotherapy (including therapeutic radioisotopes
such as strontium 89) ≤28 days or limited field radiation for palliation ≤7 days
prior to starting study drug or has not recovered from side effects of such therapy.

6. Major surgical procedures ≤28 days of beginning study drug, or minor surgical
procedures ≤7 days. No waiting required following port-a-cath placement.

7. Clinical significant peripheral neuropathy (defined as CTCAE v4.0 Grade ≥2)
regardless of causality.

8. Mood disorders as judged by the Investigator or a Psychiatrist, or who meets the
cut-off score of ≥12 in the Patient Health Questionnaire (PHQ)-9 or a cut-off score
of ≥ 15 in the Generalized Anxiety Disorder (GAD)-7 mood scale, respectively, or
selects a positive response of '1, 2, or 3' to question 9 regarding potential for
suicidal thoughts in the PHQ-9 (independent of the total score or the PHQ-9)

- anxiety or depression ≥ Grade 3

- 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, or patients with active
severe personality disorders (defined according to DSM- IV) are not eligible.
Note: for patients with psychotropic treatments ongoing at baseline, the dose
and the schedule should not be modified

9. Previously untreated brain metastases. Patients who have received radiation or
surgery for brain metastases are eligible if there is no evidence of central nervous
system (CNS) disease progression, and at least 28 days (4 weeks) have elapsed since
treatment. Patients are not permitted to receive enzyme inducing anti-epileptic drugs
(EIAEDs) during the study and should not be receiving chronic corticosteroid therapy
for CNS metastases.

10. Leptomeningeal metastases or spinal cord compression due to disease.

11. Acute or chronic liver, renal disease or pancreatitis.

12. Uncontrolled diabetes mellitus. Type II diabetics are eligible if they require only
oral hypoglycemic agents and fasting blood glucose level is ≤120. Type I diabetics
are eligible if HbAlc is <8.

13. Presence of active gastrointestinal (GI) disease or other condition that will
interfere significantly with the absorption, distribution, metabolism, or excretion
of oral therapy (e.g. ulcerative disease, uncontrolled nausea, vomiting, diarrhea
Grade ≥2, and malabsorption syndrome).

14. Any of the following cardiac diseases currently or within the last 6 months:

- Left Ventricular Ejection Fraction (LVEF) <50% as determined by Multiple Gated
acquisition (MUGA) scan or echocardiogram (ECHO)

- QTc > 480 ms on screening ECG

- Unstable angina pectoris

- Congestive heart failure (New York Heart Association [NYHA] ≥ Grade 2

- Acute myocardial infarction

- Conduction abnormality not controlled with pacemaker or medication

- Significant ventricular or supraventricular arrhythmias (Patients with chronic
rate-controlled atrial fibrillation in the absence of other cardiac
abnormalities are eligible.)

- Valvular disease with significant compromise in cardiac function.

15. Family history of congenital long or short QT, or known history of QT/QTc
prolongation or Torsades de Pointes (TdP). Patients who are currently receiving
treatment with medication that has the potential to prolong the QT interval or induce
TdP and the treatment cannot either be discontinued or switched to a different
medication prior to starting study treatment.

16. Inadequately controlled hypertension (i.e., SBP>180 mmHg or DBP>100mmHg). (Patients
with values above these levels must have their BP controlled with medication prior to
starting treatment)

17. Patient receiving chronic treatment with systemic steroids or another
immunosuppressive agent at the start of study treatment.

Note: Topical applications (e.g. rash), inhaled sprays (e.g. obstructive airways
diseases), eye drops or local injections (e.g. intra-articular) are allowed.

18. Patients receiving drugs known to be moderate and strong inhibitors or inducers or
isoenzyme cytochrome P450 (CYP) 3A (CYP3A) that cannot be discontinued or switched to
different medication prior to starting study drug.

19. Patients who have taken herbal medications and certain fruits ≤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 include the CYP3A inhibitors Seville
oranges, grapefruit, pummelos, or exotic citrus fruits.

20. Patients currently receiving treatment with therapeutic doses of warfarin sodium.
Patients receiving low molecular weight heparin are allowed.

21. A serious active infection at the time of treatment, or another serious underlying
medical condition that would impair the ability of the patient to receive protocol
treatment.

22. Known diagnosis of human immunodeficiency virus (HIV), Hepatitis B (HBV) or Hepatitis
C (HCV).

23. Presence of other active cancers, or history of treatment for invasive cancer ≤5
years. Patients with stage I cancer who have received definitive local treatment at
least 3 years previously, and are considered unlikely to recur are eligible. All
patients with previously treated in situ carcinoma (i.e. non-invasive) are eligible,
as are patients with history of non-melanoma skin cancer.

24. Psychological, familial, sociological, or geographical conditions that do not permit
compliance with the protocol.

25. Inability or unwillingness to comply with study and/or follow-up procedures outlined
in the protocol.

26. Fertile male patients, defined as all males physiologically capable of conceiving
offspring must use a highly effective contraception during dosing any study agent +
[5 x T1/2] +12 weeks = contraception through 16 weeks after final dosing of study
therapy and should not father a child during this period. In addition, female
partners of male patients must use a highly effective contraception during dosing of
any study agent + [5 x T1/2] +12 weeks = contraception through 16 weeks after the
final dose of study therapy.