Phase I study of the novel, fully synthetic epothilone sagopilone (ZK-EPO) in patients with solid tumors.
BACKGROUND
Sagopilone (ZK-EPO) is a fully synthetic microtubule-stabilizing agent that has demonstrated high antitumor activity in preclinical models. This first-in-human phase I study aimed to determine the maximum tolerated dose (MTD) and dose-limiting toxic effects (DLTs) of 3-weekly sagopilone treatment.


METHODS
A total of 52 patients with advanced solid tumors received a 30-min infusion of escalating doses of sagopilone (0.6-29.4 mg/m(2)) every 3 weeks. Nine additional patients were recruited to a 3-h infusion arm (16.53- or 22.0-mg/m(2) dose) to assess the incidence of neuropathy with prolonged infusion.


RESULTS
The MTD was established as 22.0 mg/m(2). DLTs comprised peripheral sensory neuropathy (PNP), infection, hyponatremia, diarrhea, and central ataxia. PNP was the most common grade 3 event, with a similar incidence in the 30-min and 3-h arms. Hematologic adverse events were rare and of low intensity. One confirmed partial response (PR) and one unconfirmed PR were reported in the 30-min arm, and a further unconfirmed PR was observed in the 3-h arm. Eleven patients achieved disease stabilization. Sagopilone showed high levels of tissue binding and no obvious serum accumulation in both arms.


CONCLUSIONS
These data demonstrate that sagopilone therapy is feasible and well tolerated. The recommended dose for phase II studies is 16.53 mg/m(2), once every 3 weeks.
Schmid
P
P
Hammersmith Early Clinical Trials Unit, Charing Cross Hospital, Imperial College London, London, UK. Electronic address: p.schmid@imperial.ac.uk.
Kiewe
P
P
Department of Oncology, Hematology and Transfusion Medicine, Charité Campus Benjamin Franklin.
Possinger
K
K
Department of Oncology and Hematology, Charité Campus Mitte, Charité Universitätsmedizin Berlin, Berlin.
Korfel
A
A
Department of Oncology, Hematology and Transfusion Medicine, Charité Campus Benjamin Franklin.
Lindemann
S
S
Clinical Pharmacology.
Giurescu
M
M
Global Medical Development Oncology.
Reif
S
S
Clinical Pharmacokinetics, Bayer Schering Pharma AG, Berlin, Germany.
Wiesinger
H
H
Clinical Pharmacokinetics, Bayer Schering Pharma AG, Berlin, Germany.
Thiel
E
E
Department of Oncology, Hematology and Transfusion Medicine, Charité Campus Benjamin Franklin.
Kühnhardt
D
D
Department of Oncology and Hematology, Charité Campus Mitte, Charité Universitätsmedizin Berlin, Berlin.
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000627:therapeutic use*; D052160:Benzothiazoles / Q000493:pharmacokinetics / Q000627:therapeutic use*; D019008:Drug Resistance, Neoplasm; D034261:Epothilones / Q000493:pharmacokinetics / Q000627:therapeutic use*; D005240:Feasibility Studies; D005260:Female; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009367:Neoplasm Staging; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D016879:Salvage Therapy; D015996:Survival Rate; D014018:Tissue Distribution; D016896:Treatment Outcome
D000970:Antineoplastic Agents; D052160:Benzothiazoles; D034261:Epothilones; C530494:sagopilone