Phase I trial and pharmacokinetic study of BMS-247550, an epothilone B analog, administered intravenously on a daily schedule for five days.
OBJECTIVE
The epothilones are a novel class of nontaxane microtubule-stabilizing agents. BMS-247550 is a semisynthetic analog of the natural product epothilone B. We conducted a phase I study administering BMS-247550 as a 1-hour intravenous infusion daily for 5 consecutive days every 21 days.


METHODS
Twenty-one patients received BMS-247550 without filgrastim in the first cycle. An additional six patients were enrolled at a starting dose of 8 mg/m2/d with filgrastim support. Twenty-one of the 27 patients had received prior paclitaxel, docetaxel, or both.


RESULTS
One hundred seven cycles were administered to 27 patients. The maximum-tolerated dose was 6 mg/m2 of BMS-247550 administered as a 1-hour intravenous infusion daily for 5 consecutive days every 21 days. Dose-limiting toxicity at a dose of 8 mg/m2/d was neutropenia with or without filgrastim support. Nonhematologic grade 3 toxicities included fatigue (seven cycles), stomatitis (two cycles), and anorexia (one cycle). The mean terminal half-life of BMS-247550 was 16.8 +/- 6.0 hours, the volume of distribution at steady-state was 798 +/- 375 L, and the clearance was 712 +/- 247 mL/min. Objective responses were observed in patients with breast, cervical, and basal cell cancer. Reductions in CA-125 levels were noted in patients with ovarian cancer.


CONCLUSIONS
The recommended phase II dose of BMS-247550 on the daily schedule for 5 days is 6 mg/m2/d. Neutropenia was dose limiting, but higher doses were tolerated by a large fraction of patients with filgrastim support. Peripheral neuropathy was mild, even after multiple cycles of therapy, and was not dose limiting.
Abraham
Jame
J
Mary Babb Randolph Cancer Center, West Virginia University, Morgantown, USA.
Agrawal
Manish
M
Bakke
Susan
S
Rutt
Ann
A
Edgerly
Maureen
M
Balis
Frank M
FM
Widemann
Brigitte
B
Davis
Louis
L
Damle
Bharat
B
Sonnichsen
Daryl
D
Lebwohl
David
D
Bates
Susan
S
Kotz
Herb
H
Fojo
Tito
T
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D004334:Drug Administration Schedule; D034261:Epothilones / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics*; D005221:Fatigue / Q000139:chemically induced; D005260:Female; D000069585:Filgrastim; D016179:Granulocyte Colony-Stimulating Factor / Q000008:administration & dosage; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy; D009503:Neutropenia / Q000139:chemically induced; D011994:Recombinant Proteins; D013280:Stomatitis / Q000139:chemically induced
D034261:Epothilones; D011994:Recombinant Proteins; D016179:Granulocyte Colony-Stimulating Factor; C430592:ixabepilone; D000069585:Filgrastim