A phase I trial of the oral, multikinase inhibitor sorafenib in combination with carboplatin and paclitaxel.
OBJECTIVE
This study evaluated the safety, maximum tolerated dose, pharmacokinetics, and antitumor activity of sorafenib, a multikinase inhibitor, combined with paclitaxel and carboplatin in patients with solid tumors.


METHODS
Thirty-nine patients with advanced cancer (24 with melanoma) received oral sorafenib 100, 200, or 400 mg twice daily on days 2 to 19 of a 21-day cycle. All patients received carboplatin corresponding to AUC6 and 225 mg/m(2) paclitaxel on day 1. Pharmacokinetic analyses were done for sorafenib on days 2 and 19 of cycle 1 and for paclitaxel on day 1 of cycles 1 and 2. Pretreatment tumor samples from 17 melanoma patients were analyzed for BRAF mutations.


RESULTS
Sorafenib was well tolerated at the doses evaluated. The most frequent severe adverse events were hematologic toxicities (grade 3 or 4 in 33 patients, 85%). Twenty-seven (69%) patients had sorafenib-related adverse events, the most frequent of which were dermatologic events (26 patients, 67%). Exposure to paclitaxel was not altered by intervening treatment with sorafenib. Treatment with sorafenib, paclitaxel, and carboplatin resulted in one complete response and nine partial responses, all among patients with melanoma. There was no correlation between BRAF mutational status and treatment responses in patients with melanoma.


CONCLUSIONS
The recommended phase II doses are oral 400 mg twice daily sorafenib, carboplatin at an AUC6 dose, and 225 mg/m(2) paclitaxel. The tumor responses observed with this combined regimen in patients with melanoma warrant further investigation.
Flaherty
Keith T
KT
The Abramson Cancer Center of the University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA. ktflaherty@aol.com
Schiller
Joan
J
Schuchter
Lynn M
LM
Liu
Glenn
G
Tuveson
David A
DA
Redlinger
Maryann
M
Lathia
Chetan
C
Xia
Chenghua
C
Petrenciuc
Oana
O
Hingorani
Sunil R
SR
Jacobetz
Michael A
MA
Van Belle
Patricia A
PA
Elder
David
D
Brose
Marcia S
MS
Weber
Barbara L
BL
Albertini
Mark R
MR
O'Dwyer
Peter J
PJ
D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001557:Benzenesulfonates / Q000008:administration & dosage*; D001706:Biopsy; D016190:Carboplatin / Q000008:administration & dosage*; D005260:Female; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009536:Niacinamide / Q000031:analogs & derivatives; D017239:Paclitaxel / Q000008:administration & dosage*; D010671:Phenylurea Compounds; D011725:Pyridines / Q000008:administration & dosage*; D000077157:Sorafenib; D013997:Time Factors; D016896:Treatment Outcome
D001557:Benzenesulfonates; D010671:Phenylurea Compounds; D011725:Pyridines; D009536:Niacinamide; D000077157:Sorafenib; D016190:Carboplatin; D017239:Paclitaxel