A phase I study of the dolastatin-15 analogue tasidotin (ILX651) administered intravenously daily for 5 consecutive days every 3 weeks in patients with advanced solid tumors.
OBJECTIVE
To determine the maximum tolerated dose, dose-limiting toxicity, and pharmacokinetics of the dolastatin-15 analogue, tasidotin (ILX651), when administered i.v. daily for 5 days every 3 weeks.


METHODS
Thirty-six patients with advanced solid tumors received a total of 114 courses through eight dose levels ranging from 2.3 to 36.3 mg/m(2). Pharmacokinetic samples were collected in cycle 1.


RESULTS
Neutropenia was the principal dose-limiting toxicity at 36.3 mg/m(2)/d along with grade 3 ileus and elevated aspartate amino transaminase/alanine amino transaminase (n = 1). At the maximum tolerated dose, 27.3 mg/m(2), 4 of 14 patients experienced dose-limiting grade 4 neutropenia. The other principal toxicities consisted of mild-to-moderate elevated transaminases, alopecia, fatigue, and nausea. One patient with melanoma metastatic to liver and bone treated at 15.4 mg/m(2)/d experienced a complete response and received 20 courses of tasidotin. Two other patients with melanoma had mixed responses of cutaneous metastases at 27.3 mg/m(2)/d associated with either stable or progressive visceral disease. In addition, nine patients had stable disease. There was no accumulation of tasidotin following repeated daily dosing. Tasidotin decayed from plasma in a biphasic fashion with a half-life of <45 minutes in most cases.


CONCLUSIONS
The maximum tolerated dose and recommended phase II dose for tasidotin when administered on this schedule was 27.3 mg/m(2)/d. The favorable toxicity profile of tasidotin compared with other antitubulin agents (particularly the lack of severe cumulative neuropathy, peripheral edema, and fatigue), the observed antitumor activity of tasidotin, and its novel mechanism of action support further disease-directed evaluations of this agent on this 5-day schedule every 3 weeks.
Ebbinghaus
Scot
S
Arizona Cancer Center, University of Arizona, Tucson, USA.
Rubin
Eric
E
Hersh
Evan
E
Cranmer
Lee D
LD
Bonate
Peter L
PL
Fram
Robert J
RJ
Jekunen
Antti
A
Weitman
Steve
S
Hammond
Lisa A
LA
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000737:chemistry; D019540:Area Under Curve; D047630:Depsipeptides / Q000008:administration & dosage* / Q000737:chemistry; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D020714:Maximum Tolerated Dose; D008545:Melanoma / Q000188:drug therapy; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000188:drug therapy*; D009842:Oligopeptides / Q000008:administration & dosage* / Q000737:chemistry; D013997:Time Factors; D014057:Tomography, X-Ray Computed
D000970:Antineoplastic Agents; D047630:Depsipeptides; D009842:Oligopeptides; C504233:tasidotin; C075610:dolastatin 15