A Phase I/II Trial of CCI-779 and Bevacizumab in Stage IV Renal Cell Carcinoma

Inclusion Criteria:

- Histologically confirmed metastatic or unresectable renal cell cancer

- Must have a component of conventional clear cell histology

- The following histologies are excluded:

- True papillary

- Sarcomatoid features without any clear cell component

- Chromophobe

- Oncocytoma

- Collecting duct tumors

- Transitional cell carcinoma

- Measurable disease, defined as ≥ 1 lesion ≥ 2.0 cm in the longest diameter by
conventional techniques OR ≥ 1.0 cm by spiral CT scan

- Tumor tissue (from primary tumor or metastases) available AND patient is willing to
donate blood for research studies (phase II only)

- No CNS metastases by head CT scan or MRI

- Performance status - ECOG 0-2

- Absolute neutrophil count ≥ 1,500/mm^3

- Platelet count ≥ 100,000/mm^3

- Hemoglobin ≥ 9.0 g/dL

- No evidence of bleeding diathesis or coagulopathy

- No history of clinically significant bleeding or active bleeding

- Bilirubin ≤ 1.5 times upper limit of normal (ULN)

- Alkaline phosphatase ≤ 2.5 times ULN (5 times ULN if liver metastases are present)

- AST ≤ 2.5 times ULN (5 times ULN if liver metastases are present)

- PT/INR ≤ 1.5

- Patients on full-dose warfarin or stable-dose low molecular weight heparin must
have INR > 1.5 but ≤ 3

- Creatinine ≤ 1.5 times ULN

- Urine protein ≤ 1+ by dipstick or urinalysis

- Urine protein < 1,000 mg on a 24-hour urine collection

- No cerebrovascular accident within the past 6 months

- No peripheral vascular disease with claudication on < 1 block

- No New York Heart Association class II-IV congestive heart failure

- No angina pectoris requiring nitrate therapy

- No myocardial infarction within the past 6 months

- No uncontrolled hypertension, defined as systolic blood pressure (BP) ≥ 160 mm Hg
and/or diastolic BP ≥ 90 mm Hg despite medication

- No cardiac arrhythmias

- No other significant cardiovascular disease

- No ongoing hemoptysis

- Not pregnant or nursing

- Negative pregnancy test

- Fertile patients must use effective contraception during and for at least 3-4 months
after study participation

- Fasting cholesterol ≤ 350 mg/dL

- Triglycerides ≤ 1.5 times ULN (may achieve using lipid lowering agents)

- No known hypersensitivity to recombinant human antibodies

- No significant traumatic injury within the past 4 weeks

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

- No abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within
the past 4 weeks

- No pathological conditions that confer a high risk of bleeding (e.g., tumor involving
major vessels or known varices)

- No diabetes

- No other currently active malignancy except nonmelanoma skin cancer

- Patients are not considered to have a currently active malignancy if they have
completed anticancer therapy AND are considered to be at < 30% risk of relapse

- No other uncontrolled serious medical or psychiatric condition

- At least 4 weeks since prior biologic response modifiers for metastatic disease

- No prior bevacizumab or mTOR inhibitors

- At least 4 weeks since prior chemotherapyfor metastatic disease

- Prior palliative radiotherapy to metastatic lesions allowed provided there is ≥ 1
measurable and/or evaluable lesion that has not been irradiated

- At least 4 weeks since prior and no concurrent radiotherapy

- Prior nephrectomy allowed

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

- More than 1 week since prior core biopsy

- No concurrent major surgery

- At least 4 weeks (2 weeks for vascular endothelial growth factor [VEGF] receptor
tyrosine kinase inhibitor [RTKI] therapy) since prior and no more than 2 therapies
(phase II)

- One of these therapies must have included a RTKI agent administered for a
minimum of 4 weeks

- Concurrent full-dose warfarin or low molecular weight heparin allowed provided dose
is stable AND INR requirements are met

- Concurrent zoledronate for bone metastases and/or hypercalcemia allowed provided
therapy was initiated prior to study entry