A phase I and pharmacokinetic study of XK469R (NSC 698215), a quinoxaline phenoxypropionic acid derivative, in patients with refractory acute leukemia

Invest New Drugs. 2008 Aug;26(4):331-8. doi: 10.1007/s10637-008-9129-0. Epub 2008 Apr 19.

Abstract

A phase I study was performed to determine the safety and pharmacokinetics of XK469R in patients with refractory acute leukemia. The study aimed to determine the maximum tolerated dose (MTD) and dose limiting toxicity (DLT) of XK469R given intravenously over 30 to 60 min on days 1, 3, and 5 of a 21 day cycle. Patients were treated in successive cohorts of six until DLT was observed. Once the MTD was determined, an additional cohort of six patients was enrolled at the previous dose level and that dose was considered the recommended phase 2 dose (RPTD). Forty-six patients were treated at dose levels of 1,400, 1,750, 2,200, and 2,750 mg. The DLTs were: mucositis, colitis and hyperbilirubinemia. Reversible myelosuppression was noted at all dose levels. One (2%) of 42 patients achieved a complete remission and five patients (11%) had hematologic improvement. The half-life of the drug was long with a mean value of 48 h. The mean clearance was 206 mL/h with a coefficient of variation of 32%. No correlation was observed between the development of DLT and pharmacokinetics. The RTPD is 1,750 mg. XK469R induced hematological responses in patients with refractory leukemia at tolerable doses.

Publication types

  • Clinical Trial, Phase I

MeSH terms

  • Acute Disease
  • Adult
  • Aged
  • Aged, 80 and over
  • Antineoplastic Agents / administration & dosage*
  • Antineoplastic Agents / adverse effects
  • Antineoplastic Agents / pharmacokinetics
  • Dose-Response Relationship, Drug
  • Female
  • Half-Life
  • Humans
  • Infusions, Intravenous
  • Leukemia / drug therapy*
  • Male
  • Maximum Tolerated Dose
  • Middle Aged
  • Quinoxalines / administration & dosage*
  • Quinoxalines / adverse effects
  • Quinoxalines / pharmacokinetics
  • Remission Induction / methods
  • Stereoisomerism
  • Treatment Outcome

Substances

  • Antineoplastic Agents
  • Quinoxalines
  • XK 469