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


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%.


CONCLUSIONS
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.
Feldman
Darren R
DR
Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA.
Baum
Michael S
MS
Ginsberg
Michelle S
MS
Hassoun
Hani
H
Flombaum
Carlos D
CD
Velasco
Susanne
S
Fischer
Patricia
P
Ronnen
Ellen
E
Ishill
Nicole
N
Patil
Sujata
S
Motzer
Robert J
RJ
D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000009:adverse effects; D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000009:adverse effects*; D000068258:Bevacizumab; D002292:Carcinoma, Renal Cell / Q000097:blood / Q000188:drug therapy*; D015331:Cohort Studies; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007211:Indoles / Q000008:administration & dosage / Q000009:adverse effects; D007680:Kidney Neoplasms / Q000097:blood / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D011758:Pyrroles / Q000008:administration & dosage / Q000009:adverse effects; D000077210:Sunitinib; D042461:Vascular Endothelial Growth Factor A / Q000097:blood
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D007211:Indoles; D011758:Pyrroles; D042461:Vascular Endothelial Growth Factor A; D000068258:Bevacizumab; D000077210:Sunitinib