Phase I clinical and plasma and cellular pharmacological study of topotecan without and with granulocyte colony-stimulating factor

Clin Cancer Res. 1996 Sep;2(9):1489-97.

Abstract

Topotecan, a semisynthetic water-soluble analogue of camptothecin, inhibits human topoisomerase I (topo I). We performed a Phase I clinical and plasma pharmacological study of topotecan administered by 24-h continuous infusion without and with granulocyte colony-stimulating factor (G-CSF). We also measured topo I-DNA complexes in peripheral blood mononuclear cells (PBMCs) in an attempt to correlate formation of topo I-DNA complexes in patients treated with topotecan with toxicity and/or response. One hundred four courses of topotecan at doses of 2.5-15.0 mg/m2 were administered to 44 patients with solid tumors. The maximum tolerated dose without G-CSF was 10.0 mg/m2; granulocytopenia was the dose-limiting toxic effect. The maximum tolerated dose could not be increased with G-CSF because of severe thrombocytopenia. Plasma pharmacology was obtained in 11 patients treated at 12.5 mg/m2 and 15.0 mg/m2. The topotecan lactone end-infusion plasma levels correlated strongly with the area under the curve. Lactone elimination was biexponential with a mean t1/2alpha of 28 min and a t1/2beta of 3.8 h at 12.5 mg/m2. Topo I-DNA complexes were measured before and after treatment in PBMCs from seven patients. Pretopotecan topo I-DNA complexes were available on two additional patients treated at 15 mg/m2. The mean increase in topo I-DNA complexes at the end of the topotecan infusion was 1.25 times the pretreatment value. There was a statistically significant relationship (P = 0.02) between lack of disease progression and the level of topo I-DNA complexes measured in PBMCs before therapy. For Phase II studies of minimally treated adults with solid tumors, the recommended topotecan starting dose administered by 24-h continuous infusion is 10 mg/m2 without G-CSF.

Publication types

  • Clinical Trial
  • Clinical Trial, Phase I
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adult
  • Aged
  • Antineoplastic Agents / adverse effects
  • Antineoplastic Agents / pharmacokinetics*
  • Antineoplastic Agents / therapeutic use
  • Area Under Curve
  • DNA Topoisomerases, Type I / metabolism
  • DNA Topoisomerases, Type II / metabolism
  • DNA, Neoplasm / drug effects
  • DNA, Neoplasm / metabolism
  • Diarrhea / chemically induced
  • Drug Therapy, Combination
  • Female
  • Granulocyte Colony-Stimulating Factor / administration & dosage
  • Granulocyte Colony-Stimulating Factor / therapeutic use*
  • Headache / chemically induced
  • Humans
  • Infusions, Intravenous
  • Leukocytes, Mononuclear / cytology
  • Leukocytes, Mononuclear / drug effects
  • Leukocytes, Mononuclear / metabolism
  • Male
  • Middle Aged
  • Nausea / chemically induced
  • Neoplasms / blood
  • Neoplasms / drug therapy
  • Neutropenia / chemically induced
  • Skin Diseases / chemically induced
  • Thrombocytopenia / chemically induced
  • Topoisomerase I Inhibitors
  • Topoisomerase II Inhibitors
  • Topotecan / blood
  • Topotecan / pharmacokinetics*
  • Topotecan / therapeutic use
  • Treatment Outcome
  • Vomiting / chemically induced

Substances

  • Antineoplastic Agents
  • DNA, Neoplasm
  • Topoisomerase I Inhibitors
  • Topoisomerase II Inhibitors
  • Granulocyte Colony-Stimulating Factor
  • Topotecan
  • DNA Topoisomerases, Type I
  • DNA Topoisomerases, Type II