A phase 1 study of BMS-275183, a novel oral analogue of paclitaxel given on a daily schedule to patients with advanced malignancies.
OBJECTIVE
BMS-275183 is an oral C-4 methyl carbonate analogue of paclitaxel that has the same mechanism of action, stabilization of tubulin polymerization. The present study was designed to: (i) assess the safety and tolerability of BMS-275183, and (ii) determine a suitable Phase II dose of BMS-275183 when given on a continuous daily schedule to patients with advanced solid tumor(s).


METHODS
This was a multi-institutional, open-label, Phase I, single-arm dose escalation study in which cohorts of eligible patients with advanced malignancies were treated with BMS-275183 orally on a continuous daily schedule. The starting dose level was 6 mg/m(2)/day administered once daily. Cohorts of 3 patients were treated at each dose level provided no dose-limiting toxicities (DLTs) were observed. Each cycle of treatment lasted 28 days.


RESULTS
Twenty patients were enrolled in dose cohorts ranging from the initial dose level of 6 mg/m(2)/day to 18 mg/m(2)/day. Overall, the most frequent (>20% of patients) treatment-related adverse events (AEs) were nausea (40%), constipation (20%), diarrhea (20%), and fatigue (20%). There were 2 fatal events of neutropenic sepsis one each at the 15 mg/m(2)/day and 18 mg/m(2)/day dose level, respectively. There were no objective responses; 4 of 20 patients experienced stable disease. Pharmacokinetic data indicated no clear correlation between dose and exposure following daily oral administration of BMS-275183 doses between 6 and 18 mg/m(2). Substantial inter-patient variability was observed, and high drug exposure was associated with fatal neutropenic sepsis.


CONCLUSIONS
BMS-275183 is a novel oral analogue of paclitaxel with high inter-patient variability in exposure. The lack of evidence of clinical benefit and the occurrence of two fatal events of neutropenic sepsis, coupled with high drug exposure, argues against further evaluation of BMS-275183 on a daily dosing schedule.
Heath
Elisabeth I
EI
Wayne State University/Karmanos Cancer Institute, Detroit, MI 48201, USA. heathe@karmanos.org
Lorusso
Patricia
P
Ramalingam
Suresh S
SS
Awada
Ahmad
A
Egorin
Merrill J
MJ
Besse-Hamer
Tatiana
T
Cardoso
Fatima
F
Valdivieso
Manuel
M
Has
Teresa
T
Alland
Leila
L
Zhou
Xiaofei
X
Belani
Chandra P
CP
D000284:Administration, Oral; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics; D001952:Bridged-Ring Compounds / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D009503:Neutropenia / Q000139:chemically induced; D018805:Sepsis / Q000139:chemically induced; D016896:Treatment Outcome
D000970:Antineoplastic Agents; C437188:BMS-275183; D001952:Bridged-Ring Compounds