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