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

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