Avastin and Temsirolimus Following Tyrosine Kinase Inhibitor Failure in Patients With Advanced Renal Cell Carcinoma

Avastin, a humanized IgG1 monoclonal antibody (MAb), inhibits vascular endothelial growth
factor (VEGF). VEGF is one of the most potent and specific proangiogenic factors and has been
identified as a crucial regulator of both normal and pathological angiogenesis. Temsirolimus
specifically inhibits the mammalian target of rapamycin (mTOR), a highly conserved
serine/threonine kinase which regulates cell growth and metabolism in response to
environmental factors. The combination avastin and temsirolimus has already demonstrated
efficacy in the phase I setting

STATISTICAL CONSIDERATIONS:

The primary endpoint is 4-month PFS. The null and alternative hypotheses are 50% vs. 70%.
Assuming 2 ineligible patients, the target sample size is 41 patients (39 eligible patients).
The probability of concluding that the treatment is effective was >0.90 if the true rate is
at least 70%. The probability of concluding that the treatment is effective was ≤ 0.10 if the
true rate was 50% or less. If 24 or more patients are alive and progression-free at 4 months,
then this regimen would be considered for further study.

Inclusion Criteria:

- Histologically confirmed renal cell carcinoma in either primary or metastatic lesions.
Non-clear histology will be allowed.

- Disease progression on a VEGF-targeted tyrosine kinase inhibitor as the most recent
therapy or have experienced intolerable toxicity so as require discontinuation. Only
one prior VEGF-targeted tyrosine kinase inhibitor.

- Must be off of VEGF-targeted tyrosine kinase inhibitor for 2 weeks or greater.

- One measurable lesion which is not curable by standard radiation therapy or surgery.

- The enrolling site must agree to obtain paraffin-embedded tumor blocks or at least 10
unstained, paraffin-embedded slides for submission for correlative studies.

- 18 years of age or older

- ECOG Performance Status of 0 or 1

- Baseline laboratory values as outlined in the protocol

- Life expectancy of greater than 3 months

- No prior malignancy diagnosed within the past three years, other than superficial
basal cell and superficial squamous cell, or carcinoma in situ of the cervix.

Exclusion Criteria:

- Known CNS disease, except for treated brain metastases

- Previously treated with avastin or mTOR inhibitors

- Other then VEFG-targeted TKI, patients may only have had prior immunotherapy or
chemotherapy for stage IV disease

- History of allergic reaction to Chinese hamster ovary cell products, other recombinant
antibodies, or compounds of similar chemical or biologic composition to avastin or
temsirolimus

- History of bleeding diathesis or coagulopathy. Therapeutic anticoagulants are allowed

- Patients with clinically significant cardiovascular disease

- Patients receiving enzyme-inducing antiepileptic drugs or any other CYP3A4 inducer
such as rifampin or St. John's wort

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

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

- HIV-positive receiving combination anti-retroviral therapy

- Major surgical procedure, open biopsy, or significant traumatic injury within 28 days
prior to study enrollment or anticipation of need for major surgical procedure during
the course of the study

- Core biopsy or other minor surgical procedure, excluding placement of vascular access
device, within 7 days prior to enrollment on study

- History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess
within 6 months prior to study enrollment

- Known hypersensitivity to any component of avastin or temsirolimus

- Life expectancy of less than 12 weeks

- History of hemoptysis within 1 month prior to day 1