Phase I trial with BMS-275183, a novel oral taxane with promising antitumor activity.
OBJECTIVE
BMS-275183 is an orally administered C-4 methyl carbonate analogue of paclitaxel. We did a dose-escalating phase I study to investigate its safety, tolerability, pharmacokinetics, and possible antitumor activity.


METHODS
A cycle consisted of four weekly doses of BMS-275183. The starting dose was 5 mg, which was increased by 100% increments (i.e., 5, 10, 20 mg/m2, etc.) in each new cohort consisting of one patient. Cohorts were expanded when toxicity was encountered, and 20 patients were treated at the maximum tolerated dose (MTD). Plasma pharmacokinetics were done on days 1 and 15.


RESULTS
A total of 48 patients were enrolled in this trial. Dose-limiting toxicities consisted of neuropathy, fatigue, diarrhea, and neutropenia. First cycle severe neuropathy was reported in four patients treated at 320 (n = 1), 240 (n = 2), and 160 mg/m2 (n = 1), whereas eight patients treated at dose levels ranging from 160 to 320 mg/m2 experienced grade 2 neuropathy in cycle one. The MTD was 200 mg/m2, as 3 of 20 patients experienced grade 3 or 4 toxicity in cycle one [fatigue (n = 2), and neutropenia/diarrhea (n = 1)]. BMS-275183 was rapidly absorbed with a mean plasma half-life of 22 hours. We observed a significant correlation between drug-exposure and toxicity. Tumor responses were observed in 9 of 38 evaluable patients with non-small cell lung cancer, prostate carcinoma, and other tumor types.


CONCLUSIONS
BMS-275183 is generally well tolerated on a weekly schedule. The main toxicity is peripheral neuropathy, and the MTD is 200 mg/m2. Promising activity was observed in several tumor types, and a phase II trial in non-small cell lung cancer has been initiated.
Bröker
Linda E
LE
VU University Medical Center, Amsterdam, the Netherlands.
de Vos
Filip Y F L
FY
van Groeningen
Cees J
CJ
Kuenen
Bart C
BC
Gall
Helen E
HE
Woo
Michael H
MH
Voi
Maurizio
M
Gietema
Jourik A
JA
de Vries
Elisabeth G E
EG
Giaccone
Giuseppe
G
D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D019540:Area Under Curve; D001952:Bridged-Ring Compounds / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000473:pathology; D015331:Cohort Studies; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005221:Fatigue / Q000139:chemically induced; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D009503:Neutropenia / Q000139:chemically induced; D010146:Pain / Q000139:chemically induced; D016896:Treatment Outcome
D000970:Antineoplastic Agents; C437188:BMS-275183; D001952:Bridged-Ring Compounds