A Randomized Phase II Study of Peripheral Androgen Blockade With Bicalutamide Followed by Placebo or Treatment With the Gamma Secretase Inhibitor RO4929097 in Men With Rising PSA After Definitive Local Therapy for Adenocarcinoma of the Prostate

Inclusion Criteria:

- Histologically confirmed prostate cancer

- Stage D0 OR D1 disease (i.e., tumor originally diagnosed as being limited to the
prostate and regional lymph nodes)

- Has a rising PSA value after definitive local therapy (i.e., prostatectomy or
radiotherapy) and no radiographic evidence of disease

- PSA progression after local treatment:

- PSA values for patients after surgery must be ≥ 0.2 ng/mL, determined by two
measurements, ≥ 1 month apart and ≥ 6 months after prostatectomy

- PSA values for patients after radiotherapy must be ≥ 2.0 ng/mL above the nadir
PSA achieved after radiotherapy, determined by two measurements at 1 month apart
and ≥ 6 months after completion of the radiotherapy treatment (patients who
received adjuvant or salvage radiotherapy after prostatectomy must have PSA of ≥
0.2 ng/mL)

- The first two PSA values, along with a third (study baseline) value must all be
rising (i.e., there must be an overall rising trajectory, such that the third
value cannot be lower than the first value)

- No metastatic disease on baseline bone scan and CT scan of the abdomen/pelvis

- ECOG performance status 0-2

- Life expectancy ≥ 6 months

- WBC ≥ 3,000/mm^3

- ANC ≥ 1,500/mm^3

- Platelet count ≥ 100,000/mm^3

- Hemoglobin ≥ 9 g/dL

- Serum creatinine ≤ 1.5 times upper limit of normal (ULN) OR creatinine clearance ≥ 40
mL/min for patients with creatinine levels above normal

- Bilirubin normal

- AST and/or ALT ≤ 2.5 times ULN

- Serum total testosterone level ≥ 150 ng/dL

- No uncontrolled electrolyte abnormalities including hypocalcemia, hypomagnesemia,
hyponatremia, hypophosphatemia, or hypokalemia, defined as less than the lower limit
of normal despite adequate electrolyte supplementation

- Fertile patients must use two effective forms of contraception (i.e., barrier
contraception and one other method of contraception) for 1 week before, during, and
for ≥ 12 months after completion of study treatment

- Able to swallow tablets

- No malabsorption syndrome or other condition that would interfere with intestinal
absorption

- No uncontrolled concurrent illness including, but not limited to, any of the
following:

- Ongoing or active infection

- Symptomatic congestive heart failure

- Unstable angina pectoris

- A history of torsades de pointes

- Cardiac arrhythmia other than chronic, stable atrial fibrillation

- Psychiatric illness or social situation that would limit compliance with study
requirements

- Baseline QTc ≤ 450 msec

- No serologic positivity for acute hepatitis A, acute or chronic hepatitis B, or acute
or chronic hepatitis C

- No history of liver disease or other forms of hepatitis or cirrhosis

- No HIV-positive patients on combination antiretroviral therapy

- No serious concurrent systemic disorder that would compromise the safety of the
patient or compromise the patient's ability to complete the study, at the discretion
of the investigator

- No history of allergic reactions attributed to compounds of similar chemical or
biologic composition to gamma-secretase inhibitor RO4929097 or bicalutamide

- Patients may not donate sperm or blood during or for ≥ 12 months after completion of
study treatment

- No concurrent medications or food that may interfere with the metabolism of RO4929097
including grapefruit and fresh-squeezed grapefruit juice

- Recovered from adverse events to < CTCAE grade 2

- At least 3 months since prior and no concurrent androgen-deprivation therapy (ADT)

- Hormone-ablative treatment is only allowed in the neoadjuvant setting or in the
setting of primary or salvage radiotherapy

- No more than 36 months of neoadjuvant/ adjuvant ADT

- More than 4 weeks since prior chemotherapy or radiotherapy (6 weeks for nitrosoureas
or mitomycin C)

- More than 4 weeks since prior and no concurrent estrogens, estrogen-like substances
(i.e., PC-SPES, saw palmetto, or other herbal product that may contain
phytoestrogens), or any other hormonal therapy (including flutamide, nilutamide,
finasteride, ketoconazole, systemic corticosteroids, megestrol acetate, or
cyproterone acetate)

- No other concurrent investigational agents

- No concurrent medications with narrow therapeutic indices that are metabolized by
cytochrome P450 (CYP450), including warfarin sodium (Coumadin®)

- No concurrent medications that are strong inducers/inhibitors or substrates of CYP3A4

- No other investigational or commercial agents or therapies administered with the
intent to treat the patient's malignancy, including chemotherapy, immunotherapy,
hormonal cancer therapy, radiotherapy, or surgery for cancer

- No concurrent hormonal therapy with a leuteinizing hormone-releasing hormone (LHRH)
agonist therapy (e.g., leuprolide or goserelin) or LHRH antagonist (e.g., abarelix)

- No concurrent growth factors (e.g., G-CSF), packed RBC transfusions, or platelet
transfusions

- No concurrent antiarrhythmics or other medications known to prolong QTc