Phase I study of the multidrug resistance inhibitor zosuquidar administered in combination with vinorelbine in patients with advanced solid tumours.
BACKGROUND
Zosuquidar (LY335979) is an oral P-glycoprotein modulator. This phase I study was designed to determine the maximum tolerated dose (MTD) of zosuquidar in combination with vinorelbine. The effects of zosuquidar on vinorelbine pharmacokinetics were also examined.


METHODS
Patients with advanced solid tumours were treated with escalating doses of zosuquidar administered every 8-12 h on days 7-9 and 14-16 during cycle 1 then days 0-2, 7-9, and 14-16 from cycle 2 onwards, with vinorelbine 22.5-30 mg/m2 IV on days 1, 8 and 15 every 28 days.


RESULTS
Of 21 patients registered, 19 were treated at four dose levels (zosuquidar 100-300 mg/m2). Two patients had prolonged and febrile neutropenia at the second dose level resulting in a reduction of the dose of vinorelbine in subsequent dose levels. There was another patient with dose-limiting febrile neutropenia at dose level four which resulted in the expansion of the dose level three. Eight patients had stable disease and no objective responses were seen. Vinorelbine pharmacokinetic studies showed reduced clearance when given with zosuquidar.


CONCLUSIONS
The MTD was zosuquidar 300 mg/m2 orally every 12 h for 3 days weekly for 3 weeks with vinorelbine 22.5 mg/m2 IV weekly for 3 weeks every 28 days. Zosuquidar may inhibit vinorelbine clearance to a modest degree.
Lê
Lyly H
LH
Princess Margaret Hospital, 610 University Ave., Toronto, ON, M5G 2M9, Canada.
Moore
Malcolm J
MJ
Siu
Lillian L
LL
Oza
Amit M
AM
MacLean
Martha
M
Fisher
Bryn
B
Chaudhary
Ajai
A
de Alwis
Dinesh P
DP
Slapak
Christopher
C
Seymour
Lesley
L
D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects* / Q000627:therapeutic use*; D003986:Dibenzocycloheptenes / Q000008:administration & dosage* / Q000009:adverse effects* / Q000494:pharmacology; D018432:Drug Resistance, Multiple; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy; D011804:Quinolines / Q000008:administration & dosage* / Q000009:adverse effects* / Q000494:pharmacology; D014747:Vinblastine / Q000008:administration & dosage* / Q000009:adverse effects* / Q000031:analogs & derivatives* / Q000494:pharmacology; D000077235:Vinorelbine
D003986:Dibenzocycloheptenes; D011804:Quinolines; D014747:Vinblastine; C095179:zosuquidar trihydrochloride; D000077235:Vinorelbine