CCI-779 and Bevacizumab in Treating Patients With Metastatic or Unresectable Kidney Cancer

PRIMARY OBJECTIVES:

I. To determine the maximally tolerated dose (MTD) and recommended dosing for the
combination of CCI-779 and Bevacizumab in patients with metastatic renal cell cancer. (Phase
I) II. To determine the proportion of patients with metastatic renal cell cancer who are
progression free at 6 months. (Phase II)

SECONDARY OBJECTIVES:

I. To determine the toxicity of the combination of CCI 779 and Bevacizumab in patients with
metastatic renal cell cancer. (Phase II) II. To determine the clinical response rate of CCI
779 and Bevacizumab in patients with metastatic renal cell cancer. (Phase II) III. To
determine the time to progression (TTP), disease free survival, and overall survival of CCI
779 and Bevacizumab in patients with metastatic renal cell cancer. (Phase II)

TERTIARY OBJECTIVES:

I. To identify predictive molecular markers of response, both at the tumor level and in the
plasma/serum level, in an exploratory manner.

II. To correlate blood markers of angiogenesis with clinical activity of the combination of
CCI-779 and Bevacizumab.

OUTLINE: This is a multicenter, phase I dose-escalation study followed by a phase II study.
Patients are stratified according to study phase (I vs II).

Phase I: Patients receive CCI-779 IV on days 1, 8, 15, and 22 and bevacizumab IV on days 1
and 15.

Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Cohorts of 3-6 patients receive escalating doses of CCI-779 and bevacizumab until the
maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at
which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity. Phase II: Patients
receive CCI-779 and bevacizumab as in phase I at the MTD determined in phase I. After
completion of study treatment, patients are followed every 3 months until disease
progression and then every 6 months for up to 3 years after study entry.

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 chemotherapy for 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