Bevacizumab, Sorafenib Tosylate, and Temsirolimus in Treating Patients With Metastatic Kidney Cancer

PRIMARY OBJECTIVES:

I. To assess progression-free survival on each arm of combination targeted therapy (CTT)
compared to that of bevacizumab alone.

SECONDARY OBJECTIVES:

I. To assess the significance of changes in tumor size over early time points as a predictor
of progression-free survival (PFS).

II. To quantify the number and percent of patients who have stable disease at 6 months of
therapy (failure to progress) in each treatment arm of CTT in patients with metastatic renal
cell carcinoma (RCC).

III. To evaluate the safety of each treatment arm of combination targeted therapy (CTT) in
patients with metastatic RCC.

IV. To assess overall survival in each arm of the study. V. To assess the objective response
rate in each treatment arm of CTT in patients with metastatic RCC.

VI. To assess pathology, angiogenesis histology and to assess activation status of mitogen
activated protein (MAP) kinase and vascular endothelial growth factor receptor 2 (VEGFR2)
pathways and relate to clinical outcome.

TERTIARY OBJECTIVES:

I. To analyze the pharmacokinetic and pharmacogenetic properties of sorafenib (sorafenib
tosylate) including angiogenesis, monooxygenases polymorphisms and multi-drug resistance
(MDR).

II. To relate changes in tumor perfusion and vascular permeability on serial dynamic
contrast-enhanced magnetic resonance imaging (MRI) to clinical outcome and radiologic
regression detected by other standard methods.

III. To assess the potential of dynamic contrast-enhanced (DCE)-MRI imaging as a biomarker
for response to therapy and/or as a prognostic indicator of disease progression.

IV. To assess site readiness and ability in acquiring DCE-MRI data. V. To determine the
relationship between tumor and blood biomarkers and clinical outcomes of patients treated
with the combination of targeted agents.

OUTLINE: Patients are randomized to 1 of 4 treatment arms.

ARM A: Patients receive bevacizumab intravenously (IV) over 30-90 minutes on days 1 and 15.

ARM B: Patients receive temsirolimus IV over 30 minutes on days 1, 8, 15, and 22 and
bevacizumab as in Arm A.

ARM C: Patients receive bevacizumab as in Arm A and sorafenib tosylate orally (PO) twice
daily (BID) on days 1-5, 8-12, 15-19, and 22-26.

ARM D: Patients receive sorafenib tosylate PO BID on days 1-28 and temsirolimus as in Arm B.

In all arms, courses repeat every 28 days in the absence of disease progression or
unacceptable toxicity.

After completion of study treatment, patients are followed up periodically for 5 years.

Inclusion Criteria:

- Patients will be required to have the clear cell variant of renal cell carcinoma with
less than 25% of any other histology (including, but not limited to, papillary or
chromophobe or oncocytic); there must be histologic confirmation by treating center of
either primary or metastatic lesion

- Patients will be required to have measurable metastatic disease that is not curable by
standard radiation therapy or surgery; all sites must be assessed within 4 weeks prior
to study entry

- Previous nephrectomy is required with the following exceptions:

- Primary tumor =< 5 cm, or

- Extensive liver (> 30% of liver parenchymal) or multiple (> 5) bone metastases,
making nephrectomy a clinically questionable procedure

- Unresectable primary tumor due to invasion into adjacent organs or encasing the
aorta or vena cava

- No prior cytotoxic chemotherapy; a maximum of one prior regimen of either vaccine or
cytokine-based immunotherapy disease is permitted

- No prior anti-angiogenic therapy including, but not limited to, SU11248, ZD6474 or
VEGF Trap; no prior therapy with bevacizumab, mammalian target of rapamycin (mTOR)
inhibitors (including, but not limited to, temsirolimus), or sorafenib will be
allowed; thalidomide or interferon alpha (IFNalpha) are allowed either for adjuvant
therapy or stage IV disease

- No immunotherapy within 4 weeks of randomization; toxicities from immunotherapy must
have resolved and a minimum of two weeks must pass prior to enrollment

- Prior radiation therapy is permitted, but toxicities from radiation must have resolved
and a minimum of 2 weeks must pass prior to randomization

- No history or clinical evidence of central nervous system (CNS) disease, including
primary brain tumor, seizures not controlled with standard medical therapy, any brain
metastasis, or history of stroke within the past 48 weeks

- Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1

- Life expectancy of greater than 12 weeks

- Hemoglobin (Hgb) >= 9.0 g/dL (transfusions allowed prior to enrollment)

- White blood count (WBC) >= 3,000/mm^3

- Absolute granulocyte count (AGC) >= 1,200/mm^3

- Platelet count >= 100,000/mm^3

- Serum creatinine =< 1.5 x upper limit of normal (ULN) or serum creatinine clearance
(CrCl) >= 55 ml/min

- Total bilirubin =< 1.5 x ULN

- Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x ULN (or
=< 5.0 x ULN in the presence of liver metastases)

- International normalized ratio (INR) =< 1.5

- Activated partial thromboplastin time (aPTT) within normal limits

- Fasting cholesterol < 350 mg/dL (9.0 mmol/L)

- Fasting triglycerides < 400 mg/dL (4.56 mmol/L)

- Patients must not have other current malignancies, other than basal cell skin cancer,
squamous cell skin cancer, in situ cervical cancer, and ductal or lobular carcinoma in
situ of the breast; patients with other malignancies are eligible if they have been
continuously disease-free for >= 5 years prior to the time of randomization

- No history of allergic reactions attributed to Chinese hamster ovary cell products,
other recombinant human antibodies, or compounds of similar chemical or biologic
composition to sorafenib, temsirolimus or bevacizumab

- No history of bleeding diathesis or coagulopathy

- Any condition that impairs patient's ability to swallow pills will make patient
ineligible

- No major surgical procedure, open biopsy or significant traumatic injury within 28
days prior to randomization

- No anticipated need for major surgery during the course of the study

- No current or recent (within 4 weeks of enrollment) use of full-dose of anticoagulants
or thrombolytic agents (except as required to maintain patency of preexisting or
permanent indwelling IV catheters, for those patients receiving warfarin, INR must be
=< 1.5)

- No clinically significant cardiovascular disease, defined as one of the following:

- Patients with uncontrolled hypertension (blood pressure > 150/100 mm/Hg at the
time of enrollment); patients with hypertension and blood pressure =< 150/100
mm/Hg on stable antihypertensive regimen are eligible

- Myocardial infarction or unstable angina < 24 weeks prior to registration

- New York Heart Association grade II or greater congestive heart failure, serious
cardiac arrhythmia requiring medication, unstable angina pectoris

- Grade II or greater peripheral vascular disease

- No serious, non-healing wound, ulcer, or bone fracture

- No significant proteinuria at baseline; urine protein must be screened within 2 weeks
prior to randomization by urine analysis for urine protein creatinine (UPC) ratio; if
UPC ratio is > 0.5, 24-hour urine protein is to be obtained and the level must be <
1000 mg for patient enrollment

- NOTE: UPC ratio of spot urine is an estimation of the 24 urine protein excretion;
a UPC ratio of 1 is roughly equivalent to a 24-hour urine protein of 1 gm

- No uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection requiring parenteral antibiotics on day 0 or psychiatric illness/social
situations that would limit compliance with study requirements

- Patients currently taking any of the following cytochrome P450 enzyme-inducing drugs
are ineligible:

- Phenytoin

- Carbamazepine

- Phenobarbital

- Rifampin

- Pregnant and breastfeeding women are excluded from the study; breastfeeding should be
discontinued while receiving therapy; patients must have pregnancy test within 7 days
prior to patient randomization if woman is of child-bearing capacity

- Human immunodeficiency virus (HIV)-positive patients receiving combination
anti-retroviral therapy are excluded from the study