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.
Mary Babb Randolph Cancer Center, West Virginia University, Morgantown, USA.
Jame
J
Abraham
Manish
M
Agrawal
Susan
S
Bakke
Ann
A
Rutt
Maureen
M
Edgerly
Frank M
FM
Balis
Brigitte
B
Widemann
Louis
L
Davis
Bharat
B
Damle
Daryl
D
Sonnichsen
David
D
Lebwohl
Susan
S
Bates
Herb
H
Kotz
Tito
T
Fojo
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