Temsirolimus and Bevacizumab in Hormone-Resistant Metastatic Prostate Cancer That Did Not Respond to Chemotherapy

PRIMARY OBJECTIVES:

I. The primary objective of the Phase I portion of this study is to determine the maximum
tolerated dose (MTD) of temsirolimus in combination with AVASTIN in subjects with
chemotherapy refractory metastatic CRPC.

II. The primary objective for the Phase II portion of this study is to evaluate the
objective response frequency (PSA and RECIST-Response Evaluation Criteria in Solid
Tumors-defined) of the combination of temsirolimus and AVASTIN in patients with chemotherapy
refractory metastatic CRPC.

SECONDARY OBJECTIVES:

I. To evaluate the effect of the combination of temsirolimus and AVASTIN on time to clinical
progression and overall survival in patients with chemotherapy refractory metastatic CRPC.

II. To further evaluate the safety of temsirolimus given in combination with AVASTIN in
chemotherapy refractory metastatic CRPC patients at the dose established in our phase I
safety phase.

III. To determine the presence of circulating tumor cells (CTCs) and status of single
nucleotide polymorphism (SNPs) in CRPC patients. (Exploratory)

OUTLINE: Patients receive temsirolimus IV over 30-60 minutes once weekly and bevacizumab IV
over 30-90 minutes once every two weeks . Treatment repeats every 4 weeks for 6 courses in
the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed for 28 days.

Inclusion

- Understand and voluntarily sign an informed consent form

- Patients with histologically confirmed adenocarcinoma of the prostate

- Patients must have evidence of chemotherapy-refractory metastatic CRPC following
standard antiandrogen withdrawal (AAWD); CRPC will be defined as patients with
metastatic prostate cancer with radiologic evidence of metastases on either bone
scan, plain x-rays, CT scans, chest x-ray, and castrate levels of testosterone ( =<
50 mg/dL)

- All patients must be receiving ongoing therapy to ensure testicular androgen
suppression (LHRH therapy or bilateral orchiectomy)

- Patients must have received prior Docetaxel-based or Mitoxantrone-based chemotherapy;
previous chemotherapy treatments must be completed at least 4 weeks prior to
screening, and patients must not have any residual therapy-related toxicity present
at screening

- Patients must be off any steroids 7 days prior to the initiation of treatment

- Patients must have evidence of disease progression defined as any of the following:

- a) New sites of metastatic disease on radiographic imaging (bone scan or CT scan of
chest/abdomen/pelvis) as determined by the referring physician

- b) PSA progression, defined as 2 consecutive PSA rise at least 2 weeks apart with PSA
value over a baseline level of at least 5.0 ng/mL, confirmed after an interval of at
least two weeks

- ECOG performance status 0-2 (Eastern Cooperative Oncology Group)

- Absolute neutrophil count >= 1500/uL

- Hemoglobin >= 8 g/dL (blood transfusion not permitted within 2 weeks prior to first
dose of treatment)

- Platelets >= 100,000/uL

- Serum creatinine =< 1.5 x ULN

- Total bilirubin =< 1.5 x ULN

- AST (aspartate aminotransferase-SGOT) and ALT (SGPT) that are =< 2.5 x ULN (5 x ULN
in patients with liver metastasis)

- Fasting cholesterol =< 350mg/dL and fasting triglycerides =< 400mg/dL

- Hemoglobin A1c (HgbA1c) < 10% (optimal therapy permitted)

- Therapeutic INR/PT for those patients receiving oral anticoagulation

- Urine protein:creatinine ratio (UPC) =< 1.0 at screening

- QTc interval =< 450 msec for males and =< 470 msec for females

- The use of cholesterol medications is allowed during the study

- Patients with a history of a prior malignancy are eligible provided they were treated
with curative intent and have been disease-free for the time period considered
appropriate by the treating physician

- Sexually active men whose sexual partners are women of childbearing potential must
agree to use a medically acceptable form of barrier contraception or abstinence
during their participation in the study and for at least six weeks after study drug
discontinuation

- Patients on stable doses of bisphosphonates that show subsequent tumor progression
may continue on this medication; however, patients are not allowed to initiate
bisphosphonate therapy within 4 weeks prior to starting therapy or throughout the
study

- Prior radiopharmaceuticals (strontium, samarium) must be completed at least 8 weeks
prior to treatment initiation in this study and all major side effects resolved to =<
grade 1

- Patients receiving any other hormonal therapy, including any dose of Megestrol
acetate (Megace), Proscar (finasteride), any herbal product known to decrease PSA
levels (e.g., Saw Palmetto and PC-SPES), must discontinue the agent for at least 4
weeks prior to enrollment

- Life expectancy of at least 12 weeks

- Written informed consent/HIPAA (Health Insurance Portability and Accountability
Act)authorization must be provided prior to the performance of any study-related
procedures

Exclusion

- Prior treatment with AVASTIN, temsirolimus, everolimus or sirolimus

- Evidence of current or prior central nervous system (CNS) metastases or any imaging
abnormality indicative of CNS metastases; patients with history of cord compression
are eligible provided they had either palliative radiation therapy or surgery, have
NO neurologic symptoms (as determined by treating physician), have stable spinal
disease by scans and are off any steroids prior to initiating study drug (at least 7
days)

- Major surgery or radiation therapy within 28 days prior to screening (Palliative
radiotherapy to painful bone lesions is allowed within 14 days prior to study entry);
subject must have recovered from prior surgery and radiation

- Significant cardiovascular disease defined as congestive heart failure (NYHA Class
II, III, or IV), angina pectoris requiring nitrate therapy, or myocardial infarction
within the last 6 months

- Inadequately controlled hypertension (defined as a blood pressure of >= 150 mmHg
systolic and/or >= 100 mmHg diastolic on medication), or any prior history of
hypertensive crisis or hypertensive encephalopathy

- History of stroke or transient ischemic attack within 6 months prior to screening

- Significant vascular disease (e.g., aortic aneurysm, aortic dissection), or
symptomatic peripheral vascular disease

- Known congenital long QT syndrome, history of Torsade de pointes or ventricular
tachycardia

- Known pulmonary hypertension or pneumonitis

- More than 1 episode of DVT/PE within the last 6 months

- Evidence or history of bleeding diathesis or coagulopathy

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

- Supplements or complementary medicines/botanicals are not permitted while on protocol
therapy, except for any combination of the following: conventional multivitamin
supplements; selenium; lycopene; soy supplements; patients should review the label
with their doctor prior to enrollment, and discontinue disallowed agents prior to
study enrollment; patients taking St. John's Wort need to discontinue its use at
least 7 days prior to initiating trial

- Serious intercurrent infections or non-malignant medical illnesses including
uncontrolled autoimmune disorders

- Psychiatric illnesses/social situations that would limit compliance with protocol
requirements

- Known contraindication to receive temsirolimus or AVASTIN

- Use of any other experimental drug or therapy within 28 days of baseline

- Immunocompromised subjects, including known seropositivity for human immunodeficiency
virus (HIV), or current or chronic hepatitis B and/or hepatitis C infection (as
detected by positive testing for hepatitis B surface antigen [HbsAg] or antibody to
hepatitis C virus [anti HCV] with confirmatory testing) (testing is not mandatory to
be eligible for the study)

- Anticancer therapies such as biologic therapy and chemotherapy, as well as radiation
therapy or cancer surgery

- Other current or recent (within 4 weeks prior to randomization) investigational agent

- Rifampicin

- Immunosuppressive therapies except steroids

- Prophylactic use of white blood growth factors to support neutrophils

- Concomitant treatment with agents that have CYP3A4 induction or inhibition potential
should be voided