A Multicenter Phase I/II Trial of Abiraterone Acetate + BEZ235 in Metastatic, Castration-Resistant Prostate Cancer

Prostate Cancer Overview:

Prostate cancer is the second most common cancer in men representing approximately 30% of all
cancers diagnosed in men. When confined to the prostate gland the disease is curable with
local therapy. However approximately 50% of men fail local therapy and develop incurable
metastatic disease. Androgen deprivation (AD) therapy remains the mainstay of treatment, not
only for advanced disease but also in the adjuvant and neo-adjuvant settings. Androgen
deprivation therapy induces a remission in 80 to 90% of patients with advanced disease and
results in a median progression-free survival of 12 to 33 months, at which time an
androgen-independent phenotype usually emerges. This accounts for the median overall survival
of 23 to 37 months from the initiation of androgen deprivation.

Androgen deprivation can be achieved surgically with orchiectomy, or using some form of drug
treatment. Current approaches to AD utilize leutinizing hormone releasing hormone (LHRH)
agonists. These act by continuous stimulation of the anterior pituitary resulting in
inhibition of leutinizing hormone (LH) secretion, and hence a fall in testicular production
of testosterone. Although AD is clinically effective in the majority of patients, studies
have shown that extratesticular sources of testosterone represent an important alternative
source of androgen stimulation in a significant proportion of prostate cancer patients. As
much as 10% of baseline circulating testosterone remains in castrate men, due to the
peripheral conversion of adrenal steroids to testosterone. Increased levels of androgen
receptor confer resistance to antiandrogens in prostate cancer xenograft models. This could
result in amplified signal output from circulating low levels of adrenal androgens and
suggests a role for agents that target the adrenal androgen synthesis pathway.

As prostate cancer progresses to castration-resistant prostate cancer genetic events
accumulate. One of the most consistent genetic findings in CRPC is amplification and
over-expression of the androgen receptor (AR). Multiple groups have demonstrated that
up-regulation of AR expression along with de novo synthesis of androgens by the adrenals
and/or prostate cancer cells themselves is perhaps the most common mechanism by which
prostate cancer cells progress despite castrate levels of circulating testosterone. This
underlying biology is likely the mechanism explaining the recent success of Abiraterone
Acetate.

An important genetic event found to be associated with progression of prostate cancer is loss
of heterozygosity and subsequent homozygous deletion at the 10q23 locus containing the PTEN
tumor suppressor gene. PTEN functions, in part, as a negative regulator of the
phosphatidylinositol 3' (PI3) kinase - AKT pathway. Targeting the PI3K pathway and/or
downstream targets of PI3K has been recognized as an important therapeutic strategy for some
time. An important aspect of PI3K signaling is the PTEN mutation and the downstream events
associated with PI3K signaling are not mutually exclusive with the aforementioned AR
signaling pathway aberrancies that have yielded important therapeutic consequences.
Preclinical data has demonstrated that PI3K inhibition upregulates AR expression, but that
the net effect is antiproliferative and that concomitant anti androgen therapy is
synergistic.

Introduction to BEZ235 and Abiraterone Acetate:

Preclinical data has demonstrated that PI3K inhibition upregulates AR expression, and that
concomitant anti-androgen therapy has synergistic anti-tumor effects with PI3K inhibition.
This study seeks to enhance the efficacy of Abiraterone Acetate in CRPC by concomitantly
targeting PI-3Kinase activity with the novel agent BEZ-235.

BEZ235 is a potent pan-class I PI3K and mammalian target of rapamycin (mTOR) inhibitor
belonging to the class of imidazoquinoline derivatives. BEZ235 is the investigational agent
utilized in this study.

Abiraterone Acetate is now considered a standard of care for the treatment of Castration
Resistant Prostate Cancer (CRPC) following docetaxel, and is likely to be considered such in
the pre-chemotherapy setting based on recent results. Despite benefits in survival resistance
to this therapy develops in virtually all patients.

Study rationale and purpose:

It is hypothesized that signaling through the PI3Kinase pathway is a major mechanism of
resistance to Abiraterone Acetate therapy (and castration based therapy in general) and that
inhibition of this pathway will enhance the clinical benefit of Abiraterone Acetate.

The addition of BEZ 235 to Abiraterone Acetate provides an opportunity to test if inhibition
of PI3K along with TORC1 will attenuate the survival mechanisms co-opted by CRPC when treated
with Abiraterone Acetate. We will conduct a Phase I study to determine the MTD for this
combination and use that dose for this Phase II study. Biopsies of metastatic disease prior
to and during treatment with BEZ235 plus Abiraterone Acetate will allow for the determination
if mutations in the PTEN and/or PI3kinase axis in biopsied tumors are associated with
response to therapy with the combination of BEZ235 and Abiraterone Acetate.

While PSA decline remains an imperfect surrogate marker for overall survival it remains a
useful means of determining whether a positive clinical "signal" exists for a given treatment
strategy and can be an efficient means of determining if an approach could proceed to more
definitive testing according the standards of the Prostate Cancer Working Group 2 (PCWG2).

Inclusion Criteria:

Patients eligible for inclusion in this study have to meet all of the following criteria:

1. Patient has provided a signed study Informed Consent Form prior to any screening
procedure.

2. Patient is ≥ 18 years of age on the day of consenting to the study.

3. Patients must have histologically confirmed adenocarcinoma of the prostate.

4. Radiographic evidence of disease (bone scan, CT scan, ultrasound or MRI acceptable)
that is amenable to image-guided biopsy must be present.

5. Patients must have castrate levels of testosterone (< 50 ng/dL) on GnRH analogues or
have had prior orchiectomy. GnRH analogues must be continued while on study.

6. Progressive disease as demonstrated by a rising PSA or radiographic progression per
PCWG2 criteria.

7. Asymptomatic or minimally symptomatic disease: No use of opiate analgesics (EXCLUDING
codeine or dextromethorphan) for cancer related pain within 28 days of day 1, cycle 1.

8. Phase II Cohort 1: No prior Abiraterone Acetate therapy

9. Phase II Cohort 2: Immediate prior Abiraterone Acetate therapy is required. No
intervening therapy is allowed between Abiraterone Acetate therapy and study therapy.

10. Patient has an Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2.

11. Men of reproductive potential who have not had a radical prostatectomy must agree to
use an effective contraceptive method. Patients who have had a prostatectomy are
sterile and do not need to use contraception.

12. Patient has adequate bone marrow and organ function as shown by:

- Absolute neutrophil count (ANC) ≥ 1.0 x 109/L

- Platelets ≥ 100 x 109/L

- Hemoglobin (Hgb) ≥ 9.0 g/dL

- INR ≤ 2

- Serum creatinine ≤ 1.5 x ULN

- Total serum bilirubin ≤ 1.5 x ULN (in patients with known Gilbert Syndrome, a
total bilirubin ≤ 3.0 x ULN, with direct bilirubin ≤ 1.5 x ULN)

- AST and ALT ≤ 3 x ULN (or ≤ 5.0 x ULN if hepatic metastases are present)

- Fasting plasma glucose (FPG) ≤ 140mg/dL [7.8 mmol/L]

- HgbA1c ≤8% (Patients with diabetes mellitus not actively being treated and
patients with an HgbA1c level between 7-8% will be required to have home glucose
monitoring three times weekly during the first cycle. Patients may also be
referred to a diabetes specialist as indicated.)

Exclusion Criteria:

Patients eligible for this study must not meet any of the following criteria:

1. Patient has received previous treatment with PI3K and/or mTOR inhibitors.

2. Phase II Cohort 1: Prior Abiraterone Acetate therapy is an exclusion

3. Prior therapy with any of the following for >1 month: MDV-3100, Orteronel,
ketoconazole or other drugs given with the intention to inhibit CYP 17.

4. Patient has active uncontrolled or symptomatic CNS metastases. Note: A patient with
controlled and asymptomatic CNS metastases may participate in this trial. As such, the
patient must have completed any prior treatment for CNS metastases > 90 days
(including radiotherapy and/or surgery) prior to start of treatment in this study and
should not be receiving chronic corticosteroid therapy for the CNS metastases.

5. Patient has a concurrent malignancy or has had a malignancy in the last 3 years prior
to start of study treatment (with the exception of adequately treated basal or
squamous cell carcinoma or cervical carcinoma in situ).

6. Patient has received wide field radiotherapy (including therapeutic radioisotopes such
as strontium 89) ≤ 28 days or limited field radiation for palliation ≤ 14 days prior
to starting study drug or has not recovered from side effects of such therapy.

7. Patient has had major surgery within 28 days prior to starting study drug or has not
recovered from major side effects of the surgery.

8. Patient has active cardiac disease including any of the following:

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

- QTcF > 480 msec on screening ECG

- Unstable angina pectoris

- Ventricular arrhythmias except for benign premature ventricular contractions

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

- Conduction abnormality requiring a pacemaker

- Valvular disease with documented compromise in cardiac function

- Symptomatic pericarditis

9. Patient has a 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

10. Family history of congenital long or short QT, or known history of QT/QTc prolongation
or Torsades de Pointes (TdP).

11. Patient with medically documented history of active major depressive episodes, bipolar
disorder (I or II), obsessive-compulsive disorder, schizophrenia, a history of
suicidal attempt or ideation, or homicidal ideation.

12. Active or uncontrolled infection of hepatitis B or hepatitis C.

13. Inadequately controlled hypertension (i.e., SBP > 180 mmHg or DBP > 100 mmHg).

14. Patient has impairment of gastrointestinal (GI) function or GI disease that may
significantly alter the absorption of BEZ235 (e.g. ulcerative diseases, uncontrolled
nausea, vomiting, diarrhea grade ≥ 2, malabsorption syndrome or small bowel
resection).

15. Use of any chemotherapy, investigational agents, immunotherapy, or hormonal therapy
other LHRH agonists within 28 days of the start of treatment on protocol. Use of bone
targeted agents including bisphosphanates and RANK ligand inhibitors is allowed if on
stable dose; Xgeva or Zometa cannot be started within 28 days of initiating study
therapy.

16. Systemic corticosteroids except as part of on label treatment prostate cancer
regimens.

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

17. Patient is undergoing active treatment for diabetes mellitus.

18. Patient is being treated at start of study treatment with any of the following drugs:

- Drugs known to be moderate and strong inhibitors or inducers of isoenzyme CYP3A4
including herbal medications (see Appendix 1 for a list of prohibited CYP3A4
inhibitors and inducers)

- Drugs with a known risk to induce Torsades de Pointes (see Appendix 3 for a list
of prohibited drugs)

- Warfarin and coumadin analogues

19. Patient is consuming Seville oranges, grapefruit, grapefruit hybrids, pomelos and
exotic citrus fruits (as well as their juices) during the last 7 days prior to start
of treatment. Regular orange juice is permitted.

20. Immunocompromised patients, including known seropositivity for HIV (testing is not
mandatory).

21. Patient has other concurrent severe and/or uncontrolled medical condition that would,
in the investigator's judgment contraindicate his participation in the clinical study
(e.g. uncontrolled diabetes, chronic pancreatitis, active chronic hepatitis etc.).

22. Patient is not able to understand or to comply with study instructions and
requirements or has a history of non-compliance to medical regimen.

23. Patients in whom, in the opinion of the treating physician, should receive cytotoxic
chemotherapy with docetaxel.