title: A phase I and pharmacologic study of 9-aminocamptothecin administered as a 120-h infusion weekly to adult cancer patients.
abstract: OBJECTIVE
  To define the toxicity profile and the recommended phase II doses of 9-aminocamptothecin (9-AC) administered as a weekly 120-h infusion.
  
  
  METHODS
  9-AC was administered over 120 h weekly to 55 adult cancer patients with solid tumors over doses ranging from 0.41 to 0.77 mg/m2 per day in a phase I and pharmacologic study. 9-AC formulated in dimethylacetamide/polyethylene glycol (DMA) was administered on a 3 of 4-week schedule, and the newer colloidal dispersion (CD) formulation was given on a 2 of 3-week schedule.
  
  
  RESULTS
  Overall, 193 courses of therapy were administered over 122 dose levels. On the 3 of 4-week schedule, 9-AC DMA infused at > or = 0.6 mg/m2 per day for 120 h weekly produced dose-limiting neutropenia, thrombocytopenia, and diarrhea, or resulted in 1-2-week treatment delays. Shortening treatments to 2 of 3 weeks resulted in dose-limiting neutropenia and fatigue at infusion rates > 0.72 mg/m2 per day. The ratio of 9-AC lactone to total (carboxylate + lactone) drug plasma concentrations at steady-state was 0.15 +/- 0.07. Clinical toxicities and drug pharmacokinetics were not substantially different between the DMA and CD formulations. One objective response was observed in a patient with bladder cancer and minor responses were observed in patients with lung and colon cancers. Plasma area under the concentration versus time curve for 9-AC lactone modestly correlated with the degree of thrombocytopenia (r=0.51) using a sigmoid Emax pharmacodynamic model.
  
  
  CONCLUSIONS
  The recommended phase II dose for the 9-AC DMA formulation is 0.48 mg/m2 per h over 120 h for 3 of 4 weeks and for the 9-AC CD formulation is 0.6 mg/m2 per day over 120 h for 2 of 3 weeks. Both regimens were well tolerated and feasible to administer.
authors.affiliation: Developmental Therapeutics Department, Medicine Branch, Division of Clinical Sciences, National Cancer Institute, Bethesda, MD 20889, USA.
authors.forename: R R
authors.initials: RR
authors.lastname: Thomas
authors.forename: W
authors.initials: W
authors.lastname: Dahut
authors.forename: N
authors.initials: N
authors.lastname: Harold
authors.forename: J L
authors.initials: JL
authors.lastname: Grem
authors.forename: B P
authors.initials: BP
authors.lastname: Monahan
authors.forename: M
authors.initials: M
authors.lastname: Liang
authors.forename: R A
authors.initials: RA
authors.lastname: Band
authors.forename: J
authors.initials: J
authors.lastname: Cottrell
authors.forename: V
authors.initials: V
authors.lastname: Llorens
authors.forename: J A
authors.initials: JA
authors.lastname: Smith
authors.forename: W
authors.initials: W
authors.lastname: Corse
authors.forename: S G
authors.initials: SG
authors.lastname: Arbuck
authors.forename: J
authors.initials: J
authors.lastname: Wright
authors.forename: A P
authors.initials: AP
authors.lastname: Chen
authors.forename: J D
authors.initials: JD
authors.lastname: Shapiro
authors.forename: J M
authors.initials: JM
authors.lastname: Hamilton
authors.forename: C J
authors.initials: CJ
authors.lastname: Allegra
authors.forename: C H
authors.initials: CH
authors.lastname: Takimoto
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics; D019540:Area Under Curve; D002166:Camptothecin / Q000008:administration & dosage* / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D004305:Dose-Response Relationship, Drug; D005260:Female; D005500:Follow-Up Studies; D006403:Hematologic Tests; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D010976:Platelet Count
chemical_list: D000970:Antineoplastic Agents; C080125:9-aminocamptothecin; D002166:Camptothecin