Phase I clinical study of the novel epothilone B analogue BMS-310705 given on a weekly schedule.
BACKGROUND
BMS-310705, a water-soluble semi-synthetic analogue of epothilone B, was selected for clinical development because of its in vivo anti-tumour activity and toxicity profile similar to that of ixabepilone, currently the most extensively evaluated and promising epothilone B analogue. The improved solubility of BMS-310705 allowed a cremophore-free formulation that avoided the need for pre-medication.


METHODS
Two schedules were tested, one with drug administrations on days (D) 1, 8 and 15 followed by 1-week's rest, the other with administrations on D1 and 8 (D1&8 schedule) followed by 1-week's rest. Treatment was given as a 15-min infusion without pre-medication against hypersensitivity. The plasma pharmacokinetics of BMS-310705 was studied in 30 patients. An accelerated titration design 2B was applied for dose escalations. Twenty-seven patients were accrued in the D1, 8, 15 and 32 in the D1&8 schedule.


RESULTS
The dose was escalated from 5-30 mg/m(2)/week with diarrhoea as dose-limiting toxicity; 15 and 20 mg/m(2) were the recommended doses in the D1, 8, 15 and D1&8 schedule, respectively. Other frequent non-haematological toxicities were neurotoxicity, mainly paraesthesia, asthenia and myalgia. Preliminary results showed linear pharmacokinetics along the range of doses tested with a short half-life. Five objective responses were reported.


CONCLUSIONS
Further clinical development of BMS-310705 might be worthwhile in solid tumours where ixabepilone or other epothilones are not indicated.
Sessa
C
C
IOSI, Bellinzona, Switzerland.
Perotti
A
A
Lladò
A
A
Cresta
S
S
Capri
G
G
Voi
M
M
Marsoni
S
S
Corradino
I
I
Gianni
L
L
D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D003967:Diarrhea / Q000139:chemically induced; D004334:Drug Administration Schedule; D034261:Epothilones / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D009422:Nervous System Diseases / Q000139:chemically induced; D009503:Neutropenia / Q000139:chemically induced; D050257:Tubulin Modulators / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics
D000970:Antineoplastic Agents; C478223:BMS 310705; D034261:Epothilones; D050257:Tubulin Modulators