A phase I open label study of the farnesyltransferase inhibitor CP-609,754 in patients with advanced malignant tumors.
OBJECTIVE
The purpose of this phase I clinical trial was to determine the maximum-tolerated dose and toxicity of CP-609,754 in patients with solid tumors refractory to standard therapies, to determine the cellular effects of CP-609,754 on its molecular target (farnesyltransferase), and to determine the recommended phase II dose (RP2D) of this agent.


METHODS
Consenting patients with adequate bone marrow, liver, and renal function were enrolled with an accelerated dose strategy with single-patient parallel cohorts in whom the drug was given orally either once or twice daily. Once a dose-limiting toxicity was encountered or two patients developed Common Toxicity Criteria > or = grade 2 toxicities, a modified Fibonacci sequence was initiated. Blood samples were collected during cycle 1 for pharmacokinetic and pharmacodynamic analyses.


RESULTS
A total of 68 cycles of CP-609,754 was administered to 21 patients enrolled in this study. The dose escalation was from 20 mg once daily to 640 mg twice per day, and at the highest dose level, one of six patients developed a dose-limiting toxicity of grade 3 neuropathy. The drug was otherwise well tolerated, and the maximum-tolerated dose was not reached because of the large number of tablets that would have been required for additional dose escalation. Pharmacokinetic analyses showed a proportional increase in exposure with dose, rapid oral absorption, and a half-life of approximately 3 hours. Pharmacodynamic results predict a 95% maximal inhibition of peripheral blood mononuclear cell farnesyltransferase activity 2 hours postdose, on average, with a dose of 400 mg twice per day of CP-609,754.


CONCLUSIONS
On the basis of the safety findings and the pharmacokinetic and pharmacodynamic analyses, the RP2D of CP-609,754 is > or =640 mg twice per day.
Moulder
Stacy L
SL
Experimental Therapeutics and Phase I Programs, Department of Interdisciplinary Oncology, H. Lee Moffitt Cancer Center and Research Institute, University of South Florida, Tampa, Florida, USA.
Mahany
John J
JJ
Lush
Richard
R
Rocha-Lima
Caio
C
Langevin
Michael
M
Ferrante
Karen J
KJ
Bartkowski
Lisa Michele
LM
Kajiji
Shama M
SM
Noe
Dennis A
DA
Paillet
Simone
S
Sullivan
Daniel M
DM
D000368:Aged; D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors*; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D019540:Area Under Curve; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D051231:Farnesyltranstransferase; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D007963:Leukocytes, Mononuclear / Q000201:enzymology; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D008956:Models, Chemical; D009369:Neoplasms / Q000188:drug therapy*; D015363:Quinolones / Q000494:pharmacology*; D013997:Time Factors
D000970:Antineoplastic Agents; C500049:CP 609754; D004791:Enzyme Inhibitors; D007093:Imidazoles; D015363:Quinolones; D019883:Alkyl and Aryl Transferases; D051231:Farnesyltranstransferase