Phase I pharmacokinetic and pharmacodynamic study of weekly 1-hour and 24-hour infusion BMS-214662, a farnesyltransferase inhibitor, in patients with advanced solid tumors.
OBJECTIVE
BMS-214662 is a potent, nonpeptide, small molecule inhibitor of human farnesyltransferase (FT). We have conducted a phase I pharmacokinetic (PK) and pharmacodynamic study of BMS-214662 administered intravenously weekly with 1- and 24-hour infusions. The objectives were to determine the dose-limiting toxicities and the recommended dose (RD), to describe PKs, and to evaluate the relationships between BMS-214662 exposure, FT inhibition, downstream signaling, and induction of apoptosis in tumor samples.


METHODS
Patients with advanced solid tumors and adequate organ function were eligible. The dose was escalated according to a modified Fibonacci schedule.


RESULTS
high (> 80%) but short-lived (< or = 6 hours) in the 1-hour infusion and moderate (> 40%) but long-lived (24 hours) in the 24-hour infusion. BMS-214662 induced apoptosis in tumors but did not inhibit MAPK signaling.


CONCLUSIONS
BMS-214662 can be safely delivered in both the 1-hour and 24-hour infusions at biologically active doses, with the preclinical, PK, and pharmacodynamic profiles favoring the 24-hour schedule.
Tabernero
Josep
J
Medical Oncology Department, Vall d'Hebron University Hospital, Universitat Autònoma de Barcelona, Barcelona, Spain. jtabernero@vhebron.net [corrected]
Rojo
Fredy
F
Marimón
Irene
I
Voi
Maurizio
M
Albanell
Joan
J
Guix
Marta
M
Vázquez
Federico
F
Carulla
Joan
J
Cooper
Michael
M
Andreu
Jordi
J
Van Vreckem
Anne
A
Bellmunt
Joaquim
J
Manne
Veeraswamy
V
Manning
James A
JA
Garrido
Carmen
C
Felip
Enriqueta
E
Del Campo
Josep Maria
JM
García
Mónica
M
Valverde
Sonia
S
Baselga
José
J
D000328:Adult; D000368:Aged; D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors*; D017209:Apoptosis / Q000187:drug effects; D001569:Benzodiazepines / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D051231:Farnesyltranstransferase; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics* / Q000494:pharmacology; D007262:Infusions, Intravenous; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D015398:Signal Transduction
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