Phase I study of a novel taxane BMS-188797 in adult patients with solid malignancies.
OBJECTIVE
Preclinical studies show that BMS-188797 has a broad spectrum of antitumor activity in in vitro cytotoxicity assays and tumor xenograft models. We did a phase I trial designed to determine the maximum tolerated dose and the pharmacokinetics of BMS-188797 when administered i.v.


METHODS
BMS-188797 was administered i.v. over 60 minutes once every 21 days to 51 patients. The initial dose cohort of 3.75 mg/m(2) was set at approximately one third the lethal dose in dogs. Doses were subsequently escalated in cohorts according to a modified Fibonacci design.


RESULTS
Fifty-one patients received a total of 160 cycles of therapy. The dose-limiting toxicity of febrile neutropenia occurred in two patients at the 200 mg/m(2) cohort. Moderate to severe sensory neuropathy occurred in 12 patients (24%). Four radiographic partial responses based on the Response Evaluation Criteria in Solid Tumors occurred: two in subjects with breast cancer, one in a subject with non-small cell lung cancer, and one in a subject with renal cell carcinoma. The duration of the partial responses observed were 24.1 months (renal cell carcinoma), 5.7 and 4.3 months (breast cancer), and 4.5 months (non-small cell lung cancer). Pharmacokinetics appear linear at doses through 110 mg/m(2) but not at higher doses.


CONCLUSIONS
The dose-limiting toxicity in this single-agent study of BMS-188797 was febrile neutropenia. The recommended phase II dose of BMS-188797 as a single agent is 175 mg/m(2) i.v. for 1 hour administered every 3 weeks.
Garrett
Christopher R
CR
Experimental Therapeutics and Phase I Programs, Department of Interdisciplinary Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida 33612-9497, USA.
Fishman
Mayer N
MN
Rago
Randall R
RR
Williams
Charles C
CC
Dellaportas
Anne M
AM
Mahany
J Joseph
JJ
Lush
Richard M
RM
Dalton
William S
WS
Gollerkeri
Ashwin
A
Cohen
Marvin B
MB
Sullivan
Daniel M
DM
D000328:Adult; D000368:Aged; D019540:Area Under Curve; D015331:Cohort Studies; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D043823:Taxoids / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D016896:Treatment Outcome
C436443:BMS188797; D043823:Taxoids