Phase I trial and pharmacokinetic study of the farnesyltransferase inhibitor tipifarnib in children with refractory solid tumors or neurofibromatosis type I and plexiform neurofibromas.
OBJECTIVE
This pediatric phase I trial of tipifarnib determined the maximum-tolerated dose (MTD), pharmacokinetics, and pharmacodynamics of tipifarnib in children with refractory solid tumors and neurofibromatosis type 1 (NF1) -related plexiform neurofibromas.


METHODS
Tipifarnib was administered twice daily for 21 days, repeated every 28 days starting at 150 mg/m2/dose (n = 4), with escalations to 200 (n = 12), 275 (n = 12), and 375 (n = 6) mg/m2/dose. The MTD was also evaluated on a chronic continuous dosing schedule (n = 6). Pharmacokinetic sampling was performed for 36 hours after the first dose and peripheral-blood mononuclear cells (PBMCs) were collected at baseline and steady state for determination of farnesyl protein transferase (FTase) activity and HDJ-2 farnesylation.


RESULTS
Twenty-three solid tumor and 17 NF1 patients were assessable for toxicity. The MTD was 200 mg/m2/dose, and dose-limiting toxicities on cycle 1 were myelosuppression, rash, nausea, vomiting, and diarrhea. The 200 mg/m2/dose was also tolerable on the continuous dosing schedule. Cumulative toxicity was not observed in the 17 NF1 patients who received a median of 10 cycles (range, 1 to 32 cycles). The plasma pharmacokinetics of tipifarnib were highly variable but not age dependent. At steady state on 200 mg/m2/dose, FTase activity was 30% compared with baseline, and farnesylation of HDJ-2 was inhibited in PBMCs.


CONCLUSIONS
Oral tipifarnib is well tolerated in children receiving the drug twice daily for 21 days and a continuous dosing schedule at 200 mg/m2/dose, which is equivalent to the MTD in adults. The pharmacokinetic profile of tipifarnib in children is similar to that in adults, and at the MTD, FTase is inhibited in PBMC in vivo.
Widemann
Brigitte C
BC
Pediatric Oncology Branch, National Cancer Institute, Bethesda, MD 20892, USA. widemanb@mail.nih.gov
Salzer
Wanda L
WL
Arceci
Robert J
RJ
Blaney
Susan M
SM
Fox
Elizabeth
E
End
David
D
Gillespie
Andrea
A
Whitcomb
Patricia
P
Palumbo
Joseph S
JS
Pitney
Aaron
A
Jayaprakash
Nalini
N
Zannikos
Peter
P
Balis
Frank M
FM
D000293:Adolescent; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology; D001853:Bone Marrow / Q000187:drug effects; D002648:Child; D002675:Child, Preschool; D004334:Drug Administration Schedule; D003875:Drug Eruptions / Q000209:etiology; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D051231:Farnesyltranstransferase / Q000037:antagonists & inhibitors*; D005260:Female; D041981:Gastrointestinal Tract / Q000187:drug effects; D006801:Humans; D008297:Male; D018318:Neurofibroma, Plexiform / Q000188:drug therapy*; D009456:Neurofibromatosis 1 / Q000188:drug therapy*; D015363:Quinolones / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D016896:Treatment Outcome
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D015363:Quinolones; D051231:Farnesyltranstransferase; C402769:tipifarnib