Phase I study of the farnesyltransferase inhibitor lonafarnib with paclitaxel in solid tumors.
OBJECTIVE
To establish the maximum tolerated dose of lonafarnib, a novel farnesyltransferase inhibitor, in combination with paclitaxel in patients with solid tumors and to characterize the safety, tolerability, dose-limiting toxicity, and pharmacokinetics of this combination regimen.


METHODS
In a Phase I trial, lonafarnib was administered p.o., twice daily (b.i.d.) on continuously scheduled doses of 100 mg, 125 mg, and 150 mg in combination with i.v. paclitaxel at doses of 135 mg/m(2) or 175 mg/m(2) administered over 3 h on day 8 of every 21-day cycle. Plasma paclitaxel and lonafarnib concentrations were collected at selected time points from each patient.


RESULTS
Twenty-four patients were enrolled; 21 patients were evaluable. The principal grade 3/4 toxicity was diarrhea (5 of 21 patients), which was most likely due to lonafarnib. dose-limiting toxicities included grade 3 hyperbilirubinemia at dose level 3 (100 mg b.i.d. lonafarnib and 175 mg/m(2) paclitaxel); grade 4 diarrhea and grade 3 peripheral neuropathy at dose level 3A (125 mg b.i.d. lonafarnib and 175 mg/m(2) paclitaxel); and grade 4 neutropenia with fever and grade 4 diarrhea at level 4 (150 mg b.i.d. lonafarnib and 175 mg/m(2) paclitaxel). The maximum tolerated dose established by the continual reassessment method was lonafarnib 100 mg b.i.d. and paclitaxel 175 mg/m(2). Paclitaxel appeared to have no effect on the pharmacokinetics of lonafarnib. The median duration of therapy was eight cycles, including seven cycles with paclitaxel. Six of 15 previously treated patients had a durable partial response, including 3 patients who had previous taxane therapy. Notably, two of five patients with taxane-resistant metastatic non-small cell lung cancer had partial responses.


CONCLUSIONS
When combined with paclitaxel, the recommended dose of lonafarnib for Phase II trials is 100 mg p.o. twice daily with 175 mg/m(2) of paclitaxel i.v. every 3 weeks. Additional studies of lonafarnib in combination regimens appear warranted, particularly in patients with non-small cell lung cancer.
Khuri
Fadlo R
FR
Winship Cancer Institute, Emory University, Atlanta, Georgia 30322, USA. fkhuri@emory.edu
Glisson
Bonnie S
BS
Kim
Edward S
ES
Statkevich
Paul
P
Thall
Peter F
PF
Meyers
Michael L
ML
Herbst
Roy S
RS
Munden
Reginald F
RF
Tendler
Craig
C
Zhu
Yali
Y
Bangert
Sandra
S
Thompson
Elizabeth
E
Lu
Charles
C
Wang
Xue-Mei
XM
Shin
Dong M
DM
Kies
Merrill S
MS
Papadimitrakopoulou
Vali
V
Fossella
Frank V
FV
Kirschmeier
Paul
P
Bishop
W Robert
WR
Hong
Waun Ki
WK
D000328:Adult; D000368:Aged; D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors; D000740:Anemia / Q000139:chemically induced; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D019540:Area Under Curve; D004305:Dose-Response Relationship, Drug; D051231:Farnesyltranstransferase; D005221:Fatigue / Q000139:chemically induced; D005260:Female; D006323:Heart Arrest / Q000139:chemically induced; D006801:Humans; D007970:Leukopenia / Q000139:chemically induced; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D009503:Neutropenia / Q000139:chemically induced; D017239:Paclitaxel / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D010880:Piperidines / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D011725:Pyridines / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D016896:Treatment Outcome; D003986:Dibenzocycloheptenes
D019883:Alkyl and Aryl Transferases; D051231:Farnesyltranstransferase; D017239:Paclitaxel; D010880:Piperidines; D011725:Pyridines; C115354:lonafarnib; D003986:Dibenzocycloheptenes