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

This is a single-arm phase II trial evaluating the combination of avastin and temsirolimus in patients with metastatic renal cell cancer (RCC) including both histologically confirmed clear cell (cc) or non-clear cell (ncc) subtypes. Patients must have experienced disease progression or intolerable toxicity with a vascular endothelial growth factor (VEGF)-targeted tyrosine kinase inhibitor (TKI) (e.g. sorafenib, sunitinib, pazopanib). Only 2 prior VEGF therapies are allowed. The purpose of this research study is to evaluate efficacy of the combination against an historical control. Temsirolimus has been approved by the Food and Drug Administration (FDA) in the treatment of renal cell carcinoma. Avastin has been approved by the FDA for other types of cancers but not 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.

Eligibility Criteria:
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