Dose-finding Trial of a Combined Regsimen With Bevacizumab, Immunotherapy, and Chemotherapy in Patients With Metastatic Renal Cell Cancer: An Italian Oncology Group for Clinical Research (GOIRC) Study

Abstract

The aim of this study was to look for the maximum tolerated dose (MTD) of gemcitabine and 5-fluorouracil in a new regimen also containing the antiangiogenic bevacizumab and immunotherapy (IT) for the treatment of metastatic renal cell cancer. The primary objective of this multicenter dose-finding study was to establish the MTD of chemotherapy (CT) in combination with fixed doses of IT and bevacizumab. The secondary objective was to assess the combination's activity. Five escalated dose levels of CT with intravenous gemcitabine and 5-fluorouracil (days 1 and 8 every 28 d), were associated together with intravenous bevacizumab (10 mg/kg on days 1 and 15 every 28 d), subcutaneous interleukin-2 (1 MIU/m² bid on days 8, 9, 15, 16, and 1 MIU/m²/d on days 10-12 and 17-19), and interferon-α-2a (3 MIU on days 10, 12, 17, 19). Of the 27 enrolled patients, 59% had been pretreated. The MTD was not reached. The highest CT dose studied was gemcitabine 1000 mg/m² and 5-fluorouracil 600 mg/m². More frequent grade 3 to 4 toxicities included neutropenia (63%), thrombocytopenia (33%), and fever (26%). The response rate was 33% according to the Response Evaluation Criteria in Solid Tumors. This is the first study that explored the feasibility and safety of combined bevacizumab, IT, and CT in metastatic renal cell cancer. The activity of this regimen is interesting and its efficacy warrants further trials.

Dose-finding/phase II trial: bevacizumab, immunotherapy, and chemotherapy (BIC) in metastatic renal cell cancer (mRCC). Antitumor effects and variations of circulating T regulatory cells (Treg)

“…In the dose-finding portion, five incremental doses of the chemotherapeutic drugs (gemcitabine and 5-fluorouracil) were used to determine the maximum dose tolerated (MTD) [7]. In the phase II portion, an additional cohort was treated at the recommended dose level, as established in dose-finding portion, to assess safety and feasibility further.…”

“…Among the exclusion criteria are the following: cerebral metastases untreated by surgery or radiotherapy; a history of inflammatory intestinal disease and/or acute/subacute intestinal occlusion; a severe wound or ulcer that will not heal; evidence of hemorrhagic diathesis or coagulopathy; arterial hypertension uncontrolled by medical therapy; significant cardiovascular disease ongoing or in the previous 6 months; and major surgery, within the 28 days preceding the study treatment [7].…”

“…Details of the doseescalation plan have been previously reported: maximum tolerated dose (MTD) was not achieved and we used for phase II portion the fifth level of dose [7]: gemcitabine (Gemzar, Eli Lilly, Indianapolis, IN, USA) was administered at the recommended dose of 1,000 mg/m 2 intravenously (i.v.) over 1 h, before the administration of 5-fluorouracil; undiluted 5-fluorouracil (Fluorouracile, Teva Pharma Italia, Milan, Italy) was administered at the recommended dose of 600 mg/m 2 exclusively as an i.v.…”

“…After completion of the dose-finding portion of this study [7], the phase II portion was carried out according to minimax Simon two-stage design. Following this approach, we chose the lower activity (p0) of 0.12 and target activity level (p1) of 0.32.…”

“…This was the first study investigating CT-IT combined with bevacizumab (called BIC). Data of the dose-finding of this study were yet published [7]. An expanded cohort (phase II study) was treated at the recommended doses to assess further tolerability and efficacy of the combination.…”