A phase I pharmacokinetic and pharmacodynamic study of the farnesyl transferase inhibitor BMS-214662 in combination with cisplatin in patients with advanced solid tumors.
OBJECTIVE
BMS-214662 is a potent and selective inhibitor of the farnesyl transferase enzyme with in vitro and in vivo antitumor activity. The aims of this study were to characterize the toxicities and to determine the pharmacokinetic profiles of BMS-214662 when administered in combination with cisplatin, and to determine the constitutive farnesyltransferase activity as a surrogate pharmacodynamic end point.


METHODS
Twenty-nine patients with advanced solid malignancy, refractory to conventional therapy, and with adequate hematological, renal, and hepatic function were treated with escalating doses of BMS-214662 administered as a 1-h infusion, followed after an interval of 30 min by 75 mg/m(2) cisplatin administered as a 4-h infusion and repeated every 21 days. Blood and urine samples for pharmacokinetic and pharmacodynamic analyses were collected during the first cycle of treatment only.


RESULTS
Dose-limiting toxicities occurred in 4 of 9 patients enrolled at the 225 mg/m(2) BMS-214662 dose cohort, and included elevation of hepatic transaminases, nausea, vomiting, diarrhea, and renal failure. There was no apparent pharmacokinetic interaction between the two drugs at the recommended dose levels, and a dose-dependent inhibition of farnesyltransferase activity was observed, which returned to control levels within 24 h of drug administration. There were no objective responses, but disease stabilization was observed in 15 patients, including 4 patients with stable disease after 6 cycles of treatment.


CONCLUSIONS
A dose of 200 mg/m(2) of BMS-214662 administered as a 1-h infusion with 75 mg/m(2) cisplatin over 4 h is the recommended dose for additional studies.
Mackay
Helen J
HJ
Cancer Research UK Department of Medical Oncology, Beatson Oncology Centre, Western Infirmary, Glasgow, United Kingdom.
Hoekstra
Ronald
R
Eskens
Ferry A L M
FA
Loos
Walker J
WJ
Crawford
Donna
D
Voi
Maurizio
M
Van Vreckem
Anne
A
Evans
T R Jeffrey
TR
Verweij
Jaap
J
D000328:Adult; D000368:Aged; D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D019540:Area Under Curve; D001569:Benzodiazepines / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D002945:Cisplatin / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D015331:Cohort Studies; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D051231:Farnesyltranstransferase; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D007963:Leukocytes, Mononuclear / Q000201:enzymology; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D013997:Time Factors; D016896:Treatment Outcome
D004791:Enzyme Inhibitors; D007093:Imidazoles; D001569:Benzodiazepines; D019883:Alkyl and Aryl Transferases; D051231:Farnesyltranstransferase; C415151:7-cyano-2,3,4,5-tetrahydro-1-(1H-imidazol-4-ylmethyl)-3-(phenylmethyl)-4-(2-thienylsulfonyl)-1H-1,4-benzodiazepine; D002945:Cisplatin