Bicalutamide and RO4929097 in Treating Patients With Previously Treated Prostate Cancer

PRIMARY OBJECTIVES:

I. To determine the difference in the time to PSA progression in patients with adenocarcinoma
of the prostate who have rising PSA after definitive local therapy treated with bicalutamide
with vs without gamma-secretase/Notch signalling pathway inhibitor RO4929097 (RO4929097).

SECONDARY OBJECTIVES:

I. To determine the proportion of patients from each arm who achieve complete response (by
PSA) during the combination phase.

II. To determine the proportion of patients from each arm with PSA progression during the
combination phase.

III. To determine the time to PSA nadir during the combination phase for patients in each
arm.

IV. To determine the time to PSA progression during the combination phase for patients in
each arm.

V. To determine the time to PSA progression during the observation phase. VI. To determine
the proportion of patients with PSA progression during the observation phase.

VII. To assess the safety and tolerability of gamma-secretase inhibitor RO4929097 in
combination with bicalutamide.

VIII. To evaluate expression for targets of gamma secretase inhibitor in a prostate tissue
microarray.

IX. To collect serum for future evaluation of soluble markers of gamma-secretase inhibition
and angiogenesis.

OUTLINE: This is a multicenter study.

INDUCTION PHASE: All patients receive induction therapy comprising oral bicalutamide once
daily for at least 16 weeks. Patients whose PSA declines at least 50% continue to the
randomization phase.

RANDOMIZATION PHASE: Patients are stratified according to prior therapy (radiotherapy vs
surgery) and randomized to 1 of 2 treatment arms.

ARM I: Patients receive oral placebo once daily on days 1-3, 8-10, and 15-17. Treatment
repeats every 21 days for 18 courses in the absence of PSA progression.

ARM II: Patients receive oral gamma-secretase/Notch signalling pathway inhibitor RO4929097
(RO4929097) once daily on days 1-3, 8-10, and 15-17. Treatment repeats every 21 days for 18
courses in the absence of PSA progression.

Patients with no disease progression continue to the combination phase. Patients with disease
progression undergo imaging studies to verify the absence of metastatic disease before
continuing to the combination phase.

COMBINATION PHASE: All patients then receive oral bicalutamide once daily on days 1-21 and
oral RO4929097 once daily on days 1-3, 8-10, and 15-17. Courses repeat every 21 days for 12
months in the absence of disease progression or unacceptable toxicity.

Blood and tumor tissue samples may be collected periodically for correlative studies. After
completion of study treatment, patients are followed up every 6 weeks for 12 months.

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