Sunitinib in combination with docetaxel in patients with advanced solid tumors: a phase I dose-escalation study.
OBJECTIVE
Sunitinib in combination with docetaxel enhances antitumor activity in xenograft models of human breast and non-small cell lung cancer. We assessed the maximum tolerated doses (MTDs), safety, pharmacokinetic profiles, and preliminary efficacy of sunitinib plus docetaxel in patients with advanced solid tumors.


METHODS
In this phase I study, successive patient cohorts received sunitinib 25, 37.5, or 50 mg/day for 4 weeks of a 6-week cycle (Schedule 4/2, 4 weeks on, 2 weeks off) or for 2 weeks of a 3-week cycle (Schedule 2/1, 2 weeks on, 1 week off) with docetaxel 60 or 75 mg/m(2) IV q21d to determine the MTDs of this treatment combination.


RESULTS
Fifty patients enrolled: 10 on Schedule 4/2 and 40 on Schedule 2/1. MTDs were established as sunitinib 25 mg on Schedule 4/2 with docetaxel 60 mg/m(2) q21d, and as sunitinib 37.5 mg on Schedule 2/1 with docetaxel 75 mg/m(2) q21d. On Schedule 2/1, the most frequent dose-limiting toxicity was neutropenia (+/-fever; grade [G]3/4, n = 5) and the most common G3/4 non-hematologic adverse event (AE) was fatigue (G3, n = 8). Hematologic AEs were managed with growth factor support in 11 of 23 (48%) patients treated at Schedule 2/1 MTD. Three patients achieved a partial response at the Schedule 2/1 MTD. There were no pharmacokinetic drug-drug interactions with either schedule.


CONCLUSIONS
Oral sunitinib 37.5 mg/day on Schedule 2/1 with docetaxel 75 mg/m(2) IV q21d is a clinically feasible regimen with a manageable safety profile, no pharmacokinetic drug-drug interactions, and shows antitumor activity in patients with advanced solid tumors.
Robert
Francisco
F
Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL, USA. pacorobertuab@cs.com
Sandler
Alan
A
Schiller
Joan H
JH
Liu
Glenn
G
Harper
Karen
K
Verkh
Lev
L
Huang
Xin
X
Ilagan
Jennifer
J
Tye
Lesley
L
Chao
Richard
R
Traynor
Anne M
AM
D000328:Adult; D000368:Aged; D020533:Angiogenesis Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D019540:Area Under Curve; D000077143:Docetaxel; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D023381:Endpoint Determination; D005260:Female; D006207:Half-Life; D006801:Humans; D007211:Indoles / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D011758:Pyrroles / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D000077210:Sunitinib; D043823:Taxoids / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*
D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D000972:Antineoplastic Agents, Phytogenic; D007211:Indoles; D011758:Pyrroles; D043823:Taxoids; D000077143:Docetaxel; D000077210:Sunitinib