Phase I/II trial of CCI-779 and bevacizumab in stage IV renal cell carcinoma: Phase I safety and activity results

Abstract

5034 Background: The mammalian target of rapamicin (mTOR) and vascular endothelial growth factor (VEGF) pathways are critically involved in the pathogenesis and progression of clear cell renal cell carcinoma. Methods: The goal of the phase I portion of the trial was to determine the maximum tolerated dose (MTD) and dose limiting toxicity (DLT) of the combination of the mTOR inhibitor CCI-779 (C) and the anti-VEGF monoclonal antibody Bevacizumab (B). Patients with measurable stage IV clear cell RCC, performance status 0–2 and good organ function were eligible. Up to two prior treatment regimens were allowed. Treatment consisted of 25 mg IV weekly C and escalating IV doses of B (level 1= 5 mg/kg; level 2= 10 mg/kg) every other week. A cycle was defined as 4 weeks. Results: A total of 10 male and 2 female patients, median age 66 yrs (50–77) were enrolled to the phase I portion of the trial. PS: 0/1= 6/6; prior nephrectomy = 10; prior systemic therapy = 7 (prior cytokine therapy = 6); Number of metastatic sites: 1/2/≥3 = 2/2/8; one patient (out of 6) in dose level 1 experienced DLT which consisted of grade 3 hypertriglyceridemia. 1/6 patient in dose level 2 experienced DLT with grade 3 mucositis. Other grade 3 toxicities that were not DLTs included hypertension, proteinuria, hemorrhage, nausea/vomiting, dehydration, anorexia, pneumonitis, anemia, and hypophosphatemia. The best responses in the 12 evaluable patients included 7 PRs and 3 SDs. One patient had PD due to symptomatic deterioration and in one patient response information is not available at the time of this submission. Conclusions: Combination therapy with CCI-779 and Bevacizumab is safe and shows promising clinical antitumor activity. The recommended phase II dose is CCI-779 25 mg/week with bevacizumab 10 mg/kg every other week. The phase II study in stage IV renal cell cancer patients refractory to FDA approved receptor tyrosine kinase inhibitors is under way. The goals of the phase II portion are to determine the proportion of patients who have not had disease progression at 6 months, safety, response rates and correlative biomarker studies including determination of the tumor’s VHL-HIF-VEGF status, PTEN/AKT expression, plasma angiogenic activity and angiogenic cytokines. Supported by NCI N01-CM-62205 No significant financial relationships to disclose.