A phase I trial of the novel farnesyl protein transferase inhibitor, BMS-214662, in combination with paclitaxel and carboplatin in patients with advanced cancer.
OBJECTIVE
This phase I study was conducted to determine the toxicities, pharmacokinetics, and pharmacodynamics of BMS-214662, a farnesyl transferase inhibitor, in combination with paclitaxel and carboplatin, in patients with advanced solid tumors.


METHODS
Patients with solid tumors received one of six escalating dose levels of BMS-214662 infused over 1 hour given following paclitaxel and carboplatin on the first day of a 21-day cycle. Toxicities were graded by the National Cancer Institute common toxicity criteria and recorded as maximum grade per patient for each treatment cycle. Inhibition of farnesyl transferase activity in peripheral blood mononuclear cells (PBMCs) was evaluated. Accumulation of unfarnesylated HDJ-2 in PBMCs of patients was evaluated as a marker of farnesyl transferase inhibition by BMS-214662.


RESULTS
Thirty patients received 141 cycles of treatment through six dose levels. Dose-limiting toxicities were neutropenia, thrombocytopenia, nausea, and vomiting. There was no pharmacokinetic interaction between BMS-214662 and paclitaxel. The maximum tolerated dose was established as BMS-214662 (160 mg/m(2)), paclitaxel (225 mg/m(2)) and carboplatin (area under the curve = 6 on day 1), every 21 days. Inhibition of HDJ-2 farnesylation in PBMCs of patients was shown. One measurable partial response was observed in a patient with taxane-resistant esophageal cancer. There was partial regression of evaluable disease in two other patients (endometrial and ovarian cancer). Stable disease (> 4 cycles) occurred in eight other patients.


CONCLUSIONS
The combination of BMS-214662 with paclitaxel and carboplatin was well tolerated, with broad activity in solid tumors. There was no correlation between dose level and accumulation of unfarnesylated HDJ-2 in PBMCs nor tumor response.
Dy
Grace K
GK
Department of Oncology, Mayo Clinic and Foundation, 200 First Street SW, Rochester, MN 55905, USA.
Bruzek
Laura M
LM
Croghan
Gary A
GA
Mandrekar
Sumithra
S
Erlichman
Charles
C
Peethambaram
Prema
P
Pitot
Henry C
HC
Hanson
Lorelei J
LJ
Reid
Joel M
JM
Furth
Alfred
A
Cheng
Shinta
S
Martell
Robert E
RE
Kaufmann
Scott H
SH
Adjei
Alex A
AA
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D001569:Benzodiazepines / Q000009:adverse effects* / Q000493:pharmacokinetics* / Q000494:pharmacology; D016190:Carboplatin / Q000008:administration & dosage; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000009:adverse effects* / Q000493:pharmacokinetics* / Q000494:pharmacology; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D017239:Paclitaxel / Q000008:administration & dosage
D007093:Imidazoles; D001569:Benzodiazepines; D016190:Carboplatin; C415151:7-cyano-2,3,4,5-tetrahydro-1-(1H-imidazol-4-ylmethyl)-3-(phenylmethyl)-4-(2-thienylsulfonyl)-1H-1,4-benzodiazepine; D017239:Paclitaxel