A phase I and pharmacokinetic study of exisulind and docetaxel in patients with advanced solid tumors.
OBJECTIVE
Exisulind (sulindac sulfone, FGN-1, Aptosyn) is a sulindac metabolite that induces apoptosis via inhibition of cyclic GMP-phosphodiesterase. This agent demonstrated tumor growth inhibition in rodent models of colon, breast, prostate, and lung carcinogenesis. In an orthotopic model of human non-small-cell lung cancer, the combination of exisulind and docetaxel prolonged survival in athymic nude rats, forming the basis of this phase I combination study.


METHODS
This study evaluated the toxicity and pharmacokinetics of combining exisulind (150-250 mg) given orally twice daily and docetaxel (30-36 mg/m2) administered intravenously on days 1, 8, and 15 of a 4-week cycle.


RESULTS
Twenty patients with a range of advanced solid tumors (median age, 59 years; age range, 35-77 years; median performance status, 1) received a total of 70 courses. Observed adverse events were mild to moderate, and there was no dose-limiting toxicity at any level. Grade 3 gastrointestinal toxicities were present in 10 of the 70 cycles (10%) and included nausea, vomiting, dyspepsia, and elevated alkaline phosphatase. Neutropenia was present in four cycles in patients treated with a docetaxel dose of 36 mg/m2. Pharmacokinetic analysis did not demonstrate a clear effect of exisulind on docetaxel pharmacokinetics and vice versa. Relationships were evident between the plasma concentration of exisulind and the development of grade 2 or greater toxicities. One third of patients maintained stable disease for 3 to 12 cycles, but no objective responses were observed.


CONCLUSIONS
The combination of docetaxel (36 mg/m2, weekly) and exisulind (500 mg/d) was reasonably well tolerated, and it is undergoing phase II testing in patients with non-small-cell lung cancer.
Witta
Samir E
SE
University of Colorado Health Sciences Center, Denver, Colorado 80262, USA.
Gustafson
Daniel L
DL
Pierson
A Scott
AS
Menter
Alexander
A
Holden
Scott N
SN
Basche
Michele
M
Persky
Martha
M
O'Bryant
Cindy L
CL
Zeng
Chan
C
Baron
Anna
A
Long
Michael E
ME
Gibbs
Amy
A
Kelly
Karen
K
Bunn
Paul A
PA
Chan
Daniel C
DC
Pallansch
Patrick
P
Eckhardt
S Gail
SG
D000328:Adult; D000368:Aged; D000972:Antineoplastic Agents, Phytogenic / Q000493:pharmacokinetics; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D017209:Apoptosis; D000077143:Docetaxel; D004305:Dose-Response Relationship, Drug; D005260:Female; D041981:Gastrointestinal Tract / Q000187:drug effects; D006801:Humans; D008297:Male; D008875:Middle Aged; D013467:Sulindac / Q000008:administration & dosage* / Q000031:analogs & derivatives* / Q000493:pharmacokinetics*; D043823:Taxoids / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D013997:Time Factors; D016896:Treatment Outcome
D000972:Antineoplastic Agents, Phytogenic; D043823:Taxoids; D000077143:Docetaxel; D013467:Sulindac; C025463:sulindac sulfone