RAD001 and Bicalutamide for Androgen Independent Prostate Cancer

Bicalutamide, an androgen receptor (AR) antagonist, is frequently used as the first
'secondary hormonal therapy' in combination with another established agent (LHRH: luteinizing
hormone-releasing hormone agonist/antagonist) to treat CRPC. A series of studies have shown
that RAD001 through inhibition of mammalian target of rapamycin (mTOR) pathway has antitumor
and anti-angiogenic activities. The hypothesis is that the combination of an antiandrogen and
mTOR inhibitor would have additive and clinically significant effects in CRPC.

STATISTICAL CONSIDERATIONS:

The regimen will be considered promising if the rate of response/favorable outcome is 40% or
greater. A rate of 20% (similar to that observed for bicalutamide alone) will not be
considered worthy of further study. 38 patients (of whom 36 are assumed to be eligible) will
be accrued to the study. If 11 or more patients have a favorable outcome (stable disease > 6
months or response), the combination will be considered worthy of further study. Given this
design, there is a 9% probability of declaring the combination effective if the true
favorable outcome rate is 20% and a 91% probability of declaring the combination effective if
the true favorable outcome rate is 40%.

Inclusion Criteria:

- 18 years of age or older

- Histologically documented prostate cancer

- Castration resistant prostate cancer defined as two rising PSAs on castration therapy

- Baseline PSA of 2ns/mL or greater

- Testosterone of 50ng/mL or less

- Patients on LHRH agonist/antagonist must continue therapy at the recommended dosing
intervals

- Prior bicalutamide is allowed as long as treatment was for 6 months or longer

- Metastatic disease is not required

- Minimum of four weeks since any major surgery, completion of radiation, or completion
of all prior systemic anticancer therapy

- ECOG Performance Status equal to or less than 2

- Adequate bone marrow and liver function as outlined by parameters in the protocol

Exclusion Criteria:

- Prior treatment with any investigational drug within the preceding 4 weeks

- Prior treatment with an mTOR inhibitor

- Fasting lipids over the parameters outlined in the protocol

- Chronic treatment with systemic steroids or another immunosuppressive agent

- Patients should not receive immunization with attenuated live vaccines during study
period or within one week of study entry

- Uncontrolled brain or leptomeningeal metastases, including patients who continue to
require glucocorticoids for brain or leptomeningeal metastases

- Other malignancies within the past 3 years except for adequately treated or basal
squamous cell carcinomas of the skin

- Patients who have any severe and/or uncontrolled medical conditions or other
conditions that could affect their participation in the study

- Known history of HIV seropositivity

- Impairment of gastrointestinal function or gastrointestinal disease that may
significantly alter the absorption of RAD001

- Patients with an active, bleeding diathesis or on oral anti-vitamin K medication
(except low dose coumarin)

- Men able to conceive and unwilling to practice an effective method of birth control

- Known hypersensitivity to RAD001 or other rapamycins or to its excipients

- History of noncompliance to medical regimens