Phase Ib/II Evaluation of RAD001 With Docetaxel and Bevacizumab in Patients With Metastatic Androgen Independent Prostate Cancer

Inclusion Criteria:

- Age ≥ 18 years.

- Signed informed consent

- ECOG performance status: 0-2

- Histologically documented adenocarcinoma of the prostate

- Progressive disease despite androgen deprivation therapy. Progressive disease is
defined as any one of the following:

- Measurable Disease: Objective evidence of increase > 20% in the sum of the longest
diameters of target lesions from the time of maximal regression or the appearance of
one or more new lesions (Modified RECIST Criteria)

- Bone Scan Progression: Appearance of one or more new lesions on bone scan
attributable to prostate cancer

- PSA Progression: An elevated PSA (≥ 5 ng/ml) which has risen serially from baseline
on two occasions each at least one week apart

- At least 4 weeks since any other hormonal therapy. Flutamide and megestrol acetate
(any dose) must be discontinued at least 4 weeks prior to initiating treatment.
Bicalutamide or nilutamide must be discontinued at least 6 weeks prior to initiating
treatment. If improvement following antiandrogen withdrawal is noted, progression
must be established using the criteria above. Androgen suppression should be
continued

- ≥ 4 weeks since major surgery and fully recovered

- ≥ 8 weeks since high risk surgery and fully recovered

- ≥ 4 weeks since any prior radiation and fully recovered

- ≥ 6 weeks since the last dose of bone targeted radiopharmaceutical

- Men of child-bearing potential are required to use an effective means of
contraception

- Required Initial Laboratory Values:

- ANC ≥ 1500/µL

- Platelet count ≥ 100,000/µL

- Creatinine ≤ 1.5 x ULN

- Bilirubin ≤ 1.5 x ULN

- AST ≤ 1.5 x ULN

- Urine protein to creatinine ratio < 1.0

- Serum Testosterone ≤ 50 ng/dL (For patients who have not had bilateral
orchiectomy.)

Exclusion Criteria:

- Prior treatment with cytotoxic chemotherapy for metastatic disease

- Prior treatment with anti-angiogenic agents, including thalidomide and bevacizumab

- Prior treatment with any investigational drug within 4 weeks of initiating treatment

- Prior treatment with an mTor inhibitor

- Chronic treatment with systemic steroids or another immunosuppressive agent

- Known history of HIV seropositivity

- Known brain metastases (brain imaging is not required)

- Congestive heart failure

- Uncontrolled hypertension. Patients with history of hypertension must be well
controlled (< 150/100) on a regimen of anti-hypertensive therapy

- Any prior history of hypertensive crisis or hypertensive encephalopathy

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

- History of abdominal fistula, gastrointestinal perforation, or intra-abdominal
abscess within 6 months prior to study enrollment

- Active bleeding diathesis or on oral anti-vitamin K medications (except low dose
coumarin)

- Arterial thrombotic events, including transient ischemic attack (TIA),
cerebrovascular accident (CVA), at any time

- History of unstable angina or angina requiring surgical or medical intervention in
the past 12 months, or myocardial infarction (MI)

- Patients with clinically significant peripheral artery disease or any other arterial
thrombotic event

- Significant vascular disease

- Other concurrent severe and/or uncontrolled medical disease which could compromise
participation in the study

- Proteinuria at screening as demonstrated by either

- Urine protein:creatinine (UPC) ratio ≥ 1.0 OR

- Urine dipstick for proteinuria ≥ 2+

- Serious or non-healing wound, ulcer or bone fracture

- Peripheral neuropathy ≥ grade 2

- Known hypersensitivity to Chinese hamster ovary cell products or other recombinant
human antibodies

- Herbal medications and food supplements must be discontinued before registration.
Patients may continue on daily vitamins and calcium supplements

- History of noncompliance to medical regimens

- Unwilling to or unable to comply with the protocol