Phase I Trial of Bevacizumab Plus Escalated Doses of Sunitinib in Patients With Metastatic Renal Cell Carcinoma

Abstract

PurposeBoth bevacizumab and sunitinib target the vascular endothelial growth factor pathway and demonstrate activity against advanced renal cell carcinoma (RCC). In this phase I study, the maximum-tolerated dose (MTD) and safety of sunitinib in combination with bevacizumab were examined in patients with advanced RCC.Patients and MethodsThree cohorts of three to six patients were treated with escalated doses of daily oral sunitinib (ie, 25 mg, 37.5 mg, 50 mg) for 4 weeks followed by a 2-week break and with fixed doses of bevacizumab (10 mg/kg) intravenously once every 2 weeks. Dose-limiting toxicities (DLTs) were assessed during the first cycle to determine the MTD, and an expanded cohort was treated to obtain additional safety information.ResultsOf 26 study participants, 25 received treatment at one of three dose levels. Grade 4 hemorrhage, identified as a DLT, occurred in one patient in each of cohorts 2 and 3. The MTD was determined to be sunitinib 50 mg/bevacizumab 10 mg/kg, but chronic therapy at this dose level frequently resulted in grades 3 to 4 hypertension and hematologic and vascular toxicities. Overall, 48% of patients discontinued treatment because of adverse events. One complete and 12 partial responses were observed, which provided an objective response rate of 52%.ConclusionIn this phase I trial of patients with metastatic RCC, the combination of sunitinib and bevacizumab caused a high degree of hypertension and vascular and hematologic toxicities at the highest dose level. We do not plan to pursue additional study of this regimen at these doses in patients with RCC.

Combination therapy: intermittent sorafenib with bevacizumab yields activity and decreased toxicity

“…In a Phase I study of the combination of bevacizumab and sunitinib in 25 patients with metastatic renal cell cancer (mRCC), Feldman et al (2009) reported that the MTD was sunitinib 50 mg and bevacizumab 10 mg kg À1 every 2 weeks. Although a high objective response rate (52%) was observed, 48% discontinued study because of grade 3 or 4 hypertension, haematologic, or vascular toxicities.…”

Unexpected Hematologic Effects of Biotherapeutics in Nonclinical Species and in Humans

“…In most cases, thrombosis has been confined to the kidney, likely due to the importance of VEGF in maintaining glomerular endothelial integrity (Eremina et al 2008). Combination therapy of bevacizumab and sunitinib (a small molecule receptor tyrosine kinase inhibitor that inhibits VEGF) was associated with TMA characterized by proteinuria and neurologic signs in 5 of 25 renal cell carcinoma patients (Feldman et al 2009). …”

Practical Insights and Challenges in the Rational Use of Targeted Agents in Metastatic Clear Cell Renal Carcinoma

“…Combining available established therapies may or may not increase the response rate at the expense of increased toxicity (Feldman et al, 2009;Sosman et al, 2006;Negrier et al, 2011). Combination of VEGF and mTOR inhibition is currently being tested in two trials.…”