title: Phase I and pharmacologic study of 9-aminocamptothecin given by 72-hour infusion in adult cancer patients.
abstract: OBJECTIVE
  To conduct a phase I and pharmacologic study of the new topoisomerase I inhibitor, 9-aminocamptothecin (9-AC).
  
  
  METHODS
  A 72-hour infusion of 9-AC was administered every 14 days to 48 solid-tumor patients at doses of 5 to 59 microg/m2/h without granulocyte colony-stimulating factor (G-CSF) and 47 to 74 microg/m2/h with G-CSF.
  
  
  RESULTS
  Without G-CSF, two of eight patients who received 47 microg/m2/h had dose-limiting neutropenia in their initial cycle, as did both patients who received 59 microg/m2/h (with a platelet count < 25,000/microL in one). With G-CSF, zero of seven patients treated with 47 microg/m2/h had dose-limiting neutropenia in their first cycle, while dose-limiting neutropenia occurred in six of 14 patients (with platelet count < 25,000/microL in five) entered at 59 microg/m2/h. Among 39 patients entered at > or = 25 microg/m2/h 9-AC with or without G-CSF, fatigue, diarrhea, and nausea/vomiting of grade 2 severity ultimately occurred in 54%, 30%, and 38%, respectively, while grade 3 toxicities of each type occurred in 8% of patients. Steady-state 9-AC lactone concentration (Css) increased linearly from 0.89 to 10.6 nmol/L, and correlated strongly with leukopenia ( r = .85).
  
  
  CONCLUSIONS
  The recommended phase II dose of 9-AC given by 72-hour infusion every 2 weeks is 35 microg/m2/h without G-CSF or 47 microg/m2/h with G-CSF support. Dose escalation in individual patients may be possible according to their tolerance.
authors.affiliation: National Cancer Institute-Navy Medical Oncology Branch, National Naval Medical Center, Bethesda, MD, USA.
authors.forename: W
authors.initials: W
authors.lastname: Dahut
authors.forename: N
authors.initials: N
authors.lastname: Harold
authors.forename: C
authors.initials: C
authors.lastname: Takimoto
authors.forename: C
authors.initials: C
authors.lastname: Allegra
authors.forename: A
authors.initials: A
authors.lastname: Chen
authors.forename: J M
authors.initials: JM
authors.lastname: Hamilton
authors.forename: S
authors.initials: S
authors.lastname: Arbuck
authors.forename: M
authors.initials: M
authors.lastname: Sorensen
authors.forename: F
authors.initials: F
authors.lastname: Grollman
authors.forename: H
authors.initials: H
authors.lastname: Nakashima
authors.forename: R
authors.initials: R
authors.lastname: Lieberman
authors.forename: M
authors.initials: M
authors.lastname: Liang
authors.forename: W
authors.initials: W
authors.lastname: Corse
authors.forename: J
authors.initials: J
authors.lastname: Grem
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D002166:Camptothecin / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D004334:Drug Administration Schedule; D005260:Female; D016179:Granulocyte Colony-Stimulating Factor / Q000627:therapeutic use; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D009503:Neutropenia / Q000139:chemically induced / Q000628:therapy; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D016179:Granulocyte Colony-Stimulating Factor; C080125:9-aminocamptothecin; D002166:Camptothecin