Phase I and pharmacokinetics study of topotecan, a new topoisomerase I inhibitor.
OBJECTIVE
A phase I study with topotecan (SKF 104864-A, NSC 609699), a semisynthetic analog of camptothecin, was performed using a daily-times-5 regimen, given i.v. q 3 weeks, to evaluate the pharmacokinetics and toxicities of the compound.


METHODS
Patients with a histologically confirmed diagnosis of a solid tumor no longer amenable to established forms of treatment were eligible for the study. Topotecan was given as a 30 min. infusion daily on 5 successive days, repeated every three weeks. In subsequent patient cohorts the dose was escalated from 0.5 to 1.5 mg/m2/day. Weekly evaluations included hematology and biochemistry. Response to treatment was assessed every 2 cycles. Pharmacokinetics were performed using a HPLC method.


RESULTS
Forty-eight patients were entered. The maximal tolerated dose was 1.5 mg/m2/day. The dose limiting toxicity was leucocytopenia. Other major toxicities were alopecia and moderate nausea/vomiting. Partial remissions were observed in one patient with pretreated small-cell lung cancer, one with non-small-cell lung cancer and one with no-pretreated pancreatic cancer, lasting 130-240 days. Pharmacokinetics showed a t 1/2 (alpha) of 8.1 +/- 7.6 min., t 1/2 (beta) of 132 +/- 48 min., Vd,ss 72.7 +/- 26.9 L/m2 and Cltot of 0.57 +/- 0.16 L/min/m2.


CONCLUSIONS
Topotecan is an interesting new topoisomerase I inhibitor exerting antitumor activity in this phase I trial. Leucocytopenia is dose-limiting. The recommended dose for phase II studies is 1.5 mg/m2/day for 5 consecutive days every 3 weeks.
Verweij
J
J
Dept. of Medical Oncology, Rotterdam Cancer Institute, The Netherlands.
Lund
B
B
Beijnen
J
J
Planting
A
A
de Boer-Dennert
M
M
Koier
I
I
Rosing
H
H
Hansen
H
H
D000328:Adult; D000368:Aged; D000505:Alopecia / Q000139:chemically induced; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D002166:Camptothecin / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D005260:Female; D006801:Humans; D007970:Leukopenia / Q000139:chemically induced; D008175:Lung Neoplasms / Q000188:drug therapy; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000188:drug therapy; D012074:Remission Induction; D059004:Topoisomerase I Inhibitors; D019772:Topotecan
D000970:Antineoplastic Agents; D059004:Topoisomerase I Inhibitors; D019772:Topotecan; D002166:Camptothecin