Phase I trial of bevacizumab plus escalated doses of sunitinib in patients with metastatic renal cell carcinoma

Abstract

Purpose: Both 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 methods: Three 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.

Results: Of 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%.

Conclusion: In 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.

Fig 1.

Two patients on study developed severe microangiopathic hemolytic anemia and reversible posterior leukoencephalopathy syndrome (RPLS). (A) The peripheral blood smear for patient 1 showed schistocytes (blue arrows) consistent with microangiopathy. (B) Brain magnetic resonance imagine (MRI; flair images) obtained within a few days of the peripheral smear was consistent with RPLS (red arrows denote flair intensity). (C) Repeat MRI taken 6 weeks later after a break from therapy and with hypertension controlled showed complete resolution of RPLS. (D) The peripheral smear of patient 2 again showed schistocytes (blue arrows), and (E) brain MRI (flair images) showed RPLS (red arrows denote flair intensity). (F) Eight weeks later, a repeat brain MRI confirmed resolution of RPLS concurrent with the patient's clinical recovery.

Fig A1.

Changes in the (A) median serum vascular endothelial growth factor (VEGF) level of the entire study population during treatment with the combination of sunitinib and bevacizumab; and (B) median serum VEGF level for patients separated by response type. The blue line corresponds to patients whose best responses were either stable disease (SD) or progressive disease (PD), whereas the red line corresponds to patients who achieved a partial (PR) or complete response (CR). The baseline median VEGF level was significantly lower for patients who achieved a PR or CR compared with those who experienced SD or PD. The median value for each time point is provided along the data line; the number of patients who had VEGF levels drawn at each time point is in parentheses. C, cycle; D, day.