A phase I, dose-finding study of sunitinib in combination with irinotecan in patients with advanced solid tumours.
BACKGROUND
Sunitinib is a multitargeted, oral tyrosine kinase inhibitor with antitumour and antiangiogenic activity. We investigated the safety and pharmacokinetics of sunitinib in combination with irinotecan in patients with advanced, refractory solid tumours.


METHODS
Sunitinib was initially administered once daily at 37.5 mg per day on days 1-14 of a 21-day cycle, in which irinotecan 250 mg m(-2) was given on day 1. In a second cohort, the sunitinib dose was reduced to 25 mg per day. Blood samples were collected for pharmacokinetic studies.


RESULTS
In the sunitinib 37.5 mg per day cohort, 3 out of 10 evaluable patients had objective responses, but dose-limiting toxicities (DLTs) of neutropenia, pneumococcal sepsis, and fatigue were observed. There were no DLTs in the sunitinib 25 mg per day cohort. Paired observations of pharmacokinetic parameter values of sunitinib and irinotecan alone vs the combination did not reveal significant drug-drug interactions. The maximum tolerated dose was defined as sunitinib 25 mg per day (days 1-14) with irinotecan 250 mg m(-2) (day 1), but no activity was observed at this dose.


CONCLUSIONS
Although a higher sunitinib dose of 37.5 mg per day (days 1-14) with irinotecan showed preliminary evidence of antitumour activity, this dose was poorly tolerated. Therefore, this particular combination will not be pursued for further studies.
Boven
E
E
Department of Medical Oncology, VU University Medical Center, De Boelelaan 1117, Amsterdam NL-1081 HV, The Netherlands. e.boven@vumc.nl
Massard
C
C
Armand
J P
JP
Tillier
C
C
Hartog
V
V
Brega
N M
NM
Countouriotis
A M
AM
Ruiz-Garcia
A
A
Soria
J C
JC
D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives*; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D007211:Indoles / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D000077146:Irinotecan; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D011758:Pyrroles / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D000077210:Sunitinib; D016896:Treatment Outcome
D007211:Indoles; D011758:Pyrroles; D000077146:Irinotecan; D000077210:Sunitinib; D002166:Camptothecin