Combination of bevacizumab (B) plus immunotherapy, with interleukin-2 (IL-2) and interferon-α (IFN-α) plus chemotherapy (BIC) in patients with metastatic renal cell cancer (mRCC): Dose-finding phase II trial

Background: Treatment with IL-2 and IFN-a is considered as an effective immunotherapy (IT) for mRCC. Bevacizumab (B) proved to have efficacy with different mechanism as regards as IL-2 + IFN-a, and had at least an additive effect with chemotherapy (Ch) in many tumors. On this basis, it is reasonable to search for a synergism between B, IT and Ch. Methods: This is a multicenter dose- finding/phase II study aimed at to investigate: 1) safety, tolerability, dose-limiting toxicity (DLT) and maximum tolerated dose (MTD) of the BIC combination; 2) antitumor activity. Dose-finding study comprised 5 escalation dose levels of Ch: Gemcitabine (G) (initial dose 600 mg/m2 to 1,000 mg/m2) followed by 5FU bolus (initial dose 400 mg/m2 to 600 mg/m2) each one on days 1 and 8 every 28 days, associated with fixed doses of B (10mg/kg on days 1 and 15), IL-2 (1 MUI/m2 bid sc on days 8, 9, 15, 16 and 1 MUI/m2/day sc from days 10 to 12 and from 17 to 19) and IFN-a (3 MUI sc on days 10, 12, 17, 19). Three patients were enrolled at each dose level according to Fibonacci statistical method. Phase II study used the reached MTD and was conducted according to two stage Minimax Simon design. Treatment was repetead for a maximum of 6 cycles followed by a maintenance therapy with B and IT until progressive disease (PD). Results: 32 patients were enrolled (male 75%); median age 58 years (range: 28–75): of these, 23 was assessable for toxicity, 14 were pre-treated and 9 not; there was 1 case of DLT (2° level) due to a transitory grade 3 transaminases rising; phase II used the highest dose level of Ch. Grade 3–4 toxicity during all cycles included: neutropenia non febrile (11/23) and 1 febrile, fever in 5; grade 3 toxicity included: thrombocytopenia in 7, asthenia in 4, hypertension in 2, anemia in 2; no bleeding of grade 3–4. So far there are 20 assessable patients for response: 6 (30%) partial response, 8 (40%) stable disease and 6 (30%) PD for an overall disease control rate of 70%. Conclusion: This is the first study that explored the synergy between antiangiogenic therapy, IT and Ch in mRCC. The BIC combination is generally well tolerated and shows promising activity. The Phase II study is currently ongoing and accrual is still open.