Weekly administration of sagopilone (ZK-EPO), a fully synthetic epothilone, in patients with refractory solid tumours: results of a phase I trial.
BACKGROUND
Epothilones are a novel class of microtubule-stabilising agents, and sagopilone is a fully synthetic epothilone that has shown marked in vivo and in vitro preclinical activity.


METHODS
This phase I, open-label study investigated the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs) of weekly sagopilone. Twenty-three patients with malignancy resistant or refractory to standard treatment were enrolled into this study evaluating sagopilone doses from 0.6 to 7.0 mg m(-2).


RESULTS
The incidence of drug-related haematological adverse events (AEs) was low, with two grade 3 events observed. Nonhaematological AEs were generally mild and reversible; increased gamma-GT was the only grade 4 event and grade 3 events comprised peripheral neuropathy (n=2), diarrhoea (n=1) and fatigue (n=1). Two grade 3 events were DLTs (diarrhoea and peripheral neuropathy at 7.0 mg m(-2)). The MTD of weekly sagopilone was therefore established as 5.3 mg m(-2). Stable disease was the best overall response (n=3). Microtubule bundle formation in peripheral blood mononuclear cells increased post-treatment, peaking after 1 h. Sagopilone disposition was similar across treatment courses and showed rapidly decreasing serum concentrations after infusion end and a long terminal disposition phase with no obvious accumulation in the serum, probably reflecting a fast uptake into tissues followed by a slow release.


CONCLUSIONS
Weekly administration of sagopilone could represent an alternative to the 3-weekly administration currently evaluated in phase II trials.
Department of Hematology and Oncology, Martin Luther University, Halle/Saale, Germany. dirk.arnold@medizin.uni-halle.de
D
D
Arnold
W
W
Voigt
P
P
Kiewe
C
C
Behrmann
S
S
Lindemann
S
S
Reif
H
H
Wiesinger
M
M
Giurescu
E
E
Thiel
H-J
HJ
Schmoll
D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D052160:Benzothiazoles / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D004334:Drug Administration Schedule; D034261:Epothilones / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D005260:Female; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*
D000970:Antineoplastic Agents; D052160:Benzothiazoles; D034261:Epothilones; C530494:sagopilone