Phase I study of eribulin mesylate administered once every 21 days in patients with advanced solid tumors.
OBJECTIVE
To evaluate the maximum tolerated dose (MTD), dose-limiting toxicities (DLT), and pharmacokinetics of eribulin mesylate (E7389), a halichondrin B analogue, administered every 21 days in patients with advanced solid tumors.


METHODS
Eribulin mesylate was given as a 1-hour infusion every 21 days at doses of 0.25, 0.5, 1, 2, 2.8, and 4 mg/m(2). The MTD was identified using an accelerated titration design. The pharmacokinetics of eribulin were evaluated in the plasma and urine with the first dose.


RESULTS
Twenty-one patients were enrolled. At 4 mg/m(2), three patients experienced a DLT of febrile neutropenia on day 7. The dose level was reduced to 2.8 mg/m(2) where two of three patients experienced dose-limiting febrile neutropenia. Six additional patients were enrolled at 2 mg/m(2) (seven patients in total received this dose) and one of these patients experienced a neutropenic DLT. The MTD of eribulin mesylate was therefore 2 mg/m(2). Nonhematologic toxicities included alopecia, fatigue, anorexia, and nausea. Pharmacokinetic analysis showed linear kinetics for eribulin over the dose range studied and a terminal half-life of 2 days. The plasma-concentration-time profile exhibited a rapid distribution phase followed by a slow elimination phase. Drug clearance was nonrenal. One patient with non-small cell lung cancer achieved an unconfirmed partial response and 12 patients had stable disease.


CONCLUSIONS
Eribulin mesylate administered as a 1-hour infusion every 21 days has a manageable toxicity profile at 2 mg/m(2), with further dose escalation limited by neutropenia.
Tan
Antoinette R
AR
The Cancer Institute of New Jersey, New Brunswick, New Jersey 08901, USA. tanan@umdnj.edu
Rubin
Eric H
EH
Walton
Diana C
DC
Shuster
Dale E
DE
Wong
Y Nancy
YN
Fang
Fang
F
Ashworth
Simon
S
Rosen
Lee S
LS
D000328:Adult; D000368:Aged; D000505:Alopecia / Q000139:chemically induced; D000855:Anorexia / Q000139:chemically induced; D004334:Drug Administration Schedule; D005221:Fatigue / Q000139:chemically induced; D005260:Female; D005663:Furans / Q000008:administration & dosage* / Q000009:adverse effects; D006801:Humans; D007659:Ketones / Q000008:administration & dosage* / Q000009:adverse effects; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009325:Nausea / Q000139:chemically induced; D009369:Neoplasms / Q000188:drug therapy*; D009503:Neutropenia / Q000209:etiology; D050257:Tubulin Modulators / Q000008:administration & dosage* / Q000009:adverse effects; D000095662:Polyether Polyketides
D005663:Furans; D007659:Ketones; D050257:Tubulin Modulators; C490954:eribulin; D000095662:Polyether Polyketides