title: A study of amsalog (CI-921) administered orally on a 5-day schedule, with bioavailability and pharmacokinetically guided dose escalation.
abstract: OBJECTIVE
  Amsalog is a derivative of 9-aminoacridine. Phase I studies using intravenous (i.v.) amsalog have shown the dose-limiting toxicity (DLT) to be phlebitis and myelosuppression. Phase II studies using a variety of schedules have shown evidence of activity in patients with large-cell lung, breast, and head and neck cancers. Preclinical studies demonstrated that amsalog is active orally: a clinical study of the oral bioavailability of amsalog was therefore performed.
  
  
  METHODS
  A group of 20 patients with refractory malignancies were treated. There were two phases of the study: a pharmacokinetic comparison of i.v. against oral amsalog, followed by a pharmacokinetically guided oral dose escalation study. In the first phase of the study, 11 patients were treated. Amsalog 50 mg/m2 was administered i.v., and 50 mg/m2 and 200 mg/m2 orally. In the second phase of the study, 9 patients were treated in three cohorts of three. On day 1 of a 5-day schedule, amsalog was administered i.v. at the maximum tolerated dose (MTD) of 200 mg/m2. Subsequent doses were given orally, starting at a dose of 200 mg/m2 per day, with intrapatient dose escalation of up to 100% for the second cycle. Doses were escalated further in subsequent cohorts, based on oral bioavailability and toxicity.
  
  
  RESULTS
  Oral bioavailability of 50 mg/m2 amsalog was 34%. In the dose escalation phase, DLT was neutropenia; other toxicities included malaise and nausea. The MTD was 1600 mg/m2 per day for 5 days. The plasma AUC using 1600 mg/m2 by the oral route was higher than that achieved using 200 mg/m2 by the i.v. route.
  
  
  CONCLUSIONS
  Amsalog can be tolerated orally on a 5-day schedule at doses up to 1600 mg/m2. The recommended dose for further evaluation is 800 mg/m2 daily for 5 days, repeated three weekly.
authors.affiliation: CRC Department of Clinical Oncology, Nottingham City Hospital, UK.
authors.forename: D
authors.initials: D
authors.lastname: Fyfe
authors.forename: F
authors.initials: F
authors.lastname: Raynaud
authors.forename: R E
authors.initials: RE
authors.lastname: Langley
authors.forename: D R
authors.initials: DR
authors.lastname: Newell
authors.forename: G
authors.initials: G
authors.lastname: Halbert
authors.forename: C
authors.initials: C
authors.lastname: Gardner
authors.forename: K
authors.initials: K
authors.lastname: Clayton
authors.forename: P J
authors.initials: PJ
authors.lastname: Woll
authors.forename: I
authors.initials: I
authors.lastname: Judson
authors.forename: J
authors.initials: J
authors.lastname: Carmichael
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000677:Amsacrine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics*; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001682:Biological Availability; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007275:Injections, Intravenous; D008297:Male; D008875:Middle Aged; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D000677:Amsacrine; C042315:asulacrine