The BeST Trial: A Randomized Phase II Study of VEGF, RAF Kinase, and mTOR Combination Targeted Therapy (CTT) With Bevacizumab, Sorafenib and Temsirolimus in Advanced Renal Cell Carcinoma

Inclusion Criteria:

- Histologically confirmed clear cell renal cell carcinoma

- Primary or metastatic lesion

- Less than 25% of any other histology (papillary, chromophobe, or oncocytic)

- Sufficient pathology material available for diagnostic review

- Core-needle biopsy allowed

- No fine-needle aspirations as only source for diagnosis

- Measurable metastatic disease

- Lesions that can be accurately measured in ≥ 1 dimension(longest diameter to be
recorded) as > 20 mm (2.0 cm) with conventional techniques or as ≥ 10 mm (1.0
cm) with spiral CT scan

- Not curable by standard radiotherapy or surgery

- Prior nephrectomy required, with the following exceptions:

- Primary tumor ≤ 5 cm

- Extensive liver metastases (> 30% of liver parenchymal) or multiple (> 5) bone
metastases

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

- No history or clinical evidence of CNS disease, including primary brain tumor or
brain metastases

- ECOG performance status 0-1

- Life expectancy > 3 months

- WBC ≥ 3,000/mm³

- Absolute granulocyte count ≥ 1,200/mm³

- Platelet count ≥ 100,000/mm³

- Hemoglobin ≥ 9.0 g/dL (transfusions allowed)

- Creatinine ≤ 1.5 times upper limit of normal (ULN) OR creatinine clearance ≥ 55
mL/min

- Bilirubin ≤ 1.5 times ULN

- AST/ALT ≤ 2.5 times ULN (5.0 times ULN in the presence of liver metastases)

- INR ≤ 1.5 and aPTT normal

- Fasting cholesterol < 350 mg/dL

- Fasting triglycerides < 400 mg/dL

- Not pregnant or nursing

- Negative pregnancy test

- Fertile patients must use effective contraception during and for 6 months after
completion of study treatment

- No seizures not controlled with standard medical therapy

- No stroke within the past 12 months

- No other malignancies within the past 5 years except basal cell skin cancer, squamous
cell skin cancer, carcinoma in situ of the cervix, or ductal or lobular carcinoma in
situ of the breast

- 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 tosylate, temsirolimus, or bevacizumab

- No history of bleeding diathesis or coagulopathy

- No condition that impairs ability to swallow pills

- No significant traumatic injury within the past 28 days

- No clinically significant cardiovascular disease, including any of the following:

- Uncontrolled hypertension

- Blood pressure must be ≤ 150/100 mm Hg on a stable antihypertensive regimen

- Myocardial infarction or unstable angina within the past 6 months

- New York Heart Association class II-IV congestive heart failure

- Serious cardiac arrhythmia requiring medication

- Unstable angina pectoris

- Peripheral vascular disease ≥ grade 2

- No serious, nonhealing wound, ulcer, or bone fracture

- No significant proteinuria

- If urine protein: creatinine ratio > 0.5, 24-hour urine protein must be < 1,000
mg

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

- No concurrent prophylactic hematopoietic colony-stimulating factors

- No prior cytotoxic chemotherapy

- No prior antiangiogenic therapy including, but not limited to, sunitinib malate,
ZD6474, or VEGF Trap

- No prior bevacizumab, mTOR inhibitors (including, but not limited to, temsirolimus),
or sorafenib tosylate

- Prior thalidomide or interferon alfa allowed as adjuvant therapy or for metastatic
disease

- More than 4 weeks since prior immunotherapy and recovered

- No more than 1 prior vaccine or cytokine-based immunotherapy regimen for
metastatic disease

- More than 2 weeks since prior radiotherapy and recovered

- More than 4 weeks since prior major surgery or open biopsy

- No concurrent major surgery

- No concurrent or recent full-dose anticoagulants or thrombolytic agents (unless
required to maintain patency of pre-existing or permanent indwelling IV catheters)

- No concurrent cytochrome P450 enzyme-inducing drugs including any of the following:

- Phenytoin

- Carbamazepine

- Phenobarbital

- Rifampin

- No concurrent combination antiretroviral therapy for HIV-positive patients

- No other concurrent anticancer therapies or investigational agents