title: A phase I and pharmacokinetic study of exisulind and docetaxel in patients with advanced solid tumors.
abstract: 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.
authors.affiliation: University of Colorado Health Sciences Center, Denver, Colorado 80262, USA.
authors.forename: Samir E
authors.initials: SE
authors.lastname: Witta
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Gustafson
authors.forename: A Scott
authors.initials: AS
authors.lastname: Pierson
authors.forename: Alexander
authors.initials: A
authors.lastname: Menter
authors.forename: Scott N
authors.initials: SN
authors.lastname: Holden
authors.forename: Michele
authors.initials: M
authors.lastname: Basche
authors.forename: Martha
authors.initials: M
authors.lastname: Persky
authors.forename: Cindy L
authors.initials: CL
authors.lastname: O'Bryant
authors.forename: Chan
authors.initials: C
authors.lastname: Zeng
authors.forename: Anna
authors.initials: A
authors.lastname: Baron
authors.forename: Michael E
authors.initials: ME
authors.lastname: Long
authors.forename: Amy
authors.initials: A
authors.lastname: Gibbs
authors.forename: Karen
authors.initials: K
authors.lastname: Kelly
authors.forename: Paul A
authors.initials: PA
authors.lastname: Bunn
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Chan
authors.forename: Patrick
authors.initials: P
authors.lastname: Pallansch
authors.forename: S Gail
authors.initials: SG
authors.lastname: Eckhardt
mesh_terms: 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
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D043823:Taxoids; D000077143:Docetaxel; D013467:Sulindac; C025463:sulindac sulfone