A phase I and pharmacokinetic study of sunitinib administered daily for 2 weeks, followed by a 1-week off period.
OBJECTIVE
Sunitinib, an oral multitargeted tyrosine kinase inhibitor that inhibits VEGFR, PDGFR, FLT3, KIT, and RET, is currently approved for the treatment of imatinib-refractory GIST and advanced renal cell carcinoma at a dose of 50 mg daily for 4 weeks followed by a 2-week off period (4/2 schedule). This trial was performed to investigate the safety, tolerability, and pharmacokinetics of sunitinib 50 mg daily for 2 weeks followed by a 1-week off period (2/1 schedule).


METHODS
Twelve patients with advanced refractory malignancies were treated with sunitinib on the 2/1 schedule. Intensive safety monitoring included serial measurements of left ventricular ejection fraction (LVEF). Extensive pharmacokinetic sampling was performed on days 1 and 14 of course 1, and on day 14 of courses 2 and 3 to evaluate sunitinib and the SU12662 metabolite.


RESULTS
Twelve patients received a total of 50 courses with an average (+/-SD) off-drug period of 11.5 +/- 5.7 days. Two patients experienced DLT: one patient had asymptomatic grade 4 elevations in lipase and amylase, and another patient had an asymptomatic grade 2 decline in LVEF in course 1. In total, five patients demonstrated asymptomatic grade 2 declines in LVEF. Other principal effects were similar to previous experience with sunitinib, including fatigue, myelosuppression, skin discoloration, and gastrointestinal effects. Pharmacokinetic studies revealed no significant accumulation of sunitinib or SU12662. One patient with papillary thyroid cancer developed a partial response, and was on study for 16 courses, followed by an additional 18 courses on a continuation protocol.


CONCLUSIONS
The 2/1 schedule of sunitinib 50 mg was tolerable, and no significant drug accumulation was demonstrated. The safety profile on this schedule was consistent with the safety profile of sunitinib when administered on a 4-week on, 2-week off schedule.
Britten
Carolyn D
CD
David Geffen School of Medicine at the University of California, Los Angeles 90095, USA. cbritten@mednet.ucla.edu
Kabbinavar
Fairooz
F
Hecht
J Randolph
JR
Bello
Carlo L
CL
Li
Jim
J
Baum
Charles
C
Slamon
Dennis
D
D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use; D019540:Area Under Curve; D001794:Blood Pressure / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005221:Fatigue / Q000139:chemically induced / Q000453:epidemiology; D005260:Female; D005500:Follow-Up Studies; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D007211:Indoles / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy; D010179:Pancreas / Q000201:enzymology; D011758:Pyrroles / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use; D000077210:Sunitinib; D014057:Tomography, X-Ray Computed; D017211:Treatment Failure
D000970:Antineoplastic Agents; D007211:Indoles; D011758:Pyrroles; D000077210:Sunitinib