Phase I study of BCX1777 (forodesine) in patients with relapsed or refractory peripheral T/natural killer-cell malignancies

Cancer Sci. 2012 Jul;103(7):1290-5. doi: 10.1111/j.1349-7006.2012.02287.x. Epub 2012 Apr 30.

Abstract

BCX1777 (forodesine), a novel purine nucleoside phosphorylase inhibitor, induces apoptosis, mainly in T cells. To evaluate the safety, tolerability, and pharmacokinetics of BCX1777, we conducted a phase I study in patients with relapsed or refractory peripheral T/natural killer-cell malignancies. Eligible patients had relapsed or refractory peripheral T/natural killer-cell malignancies without any major organ dysfunction. BCX1777 was administered orally once daily (dose escalation: 100, 200, and 300 mg) until disease progression requiring new therapy or unacceptable adverse events occurred. A total of 13 patients were enrolled and treated in three dose cohorts (100 mg/day, five patients; 200 mg/day, three patients; 300 mg/day, five patients). Although none of the patients developed dose-limiting toxicities, further dose escalation was not performed based on data from overseas. Therefore, the maximum tolerated dose was not determined. Adverse events of grade 3 or greater (≥2 patients) included lymphopenia (62%), anemia (15%), leukopenia (8%), and pyrexia (8%). Plasma pharmacokinetics parameter of BCX1777 (area under the plasma concentration-time curve) at day 1 in each cohort was 1948 ± 884, 4608 ± 1030, and 4596 ± 939 ng•h/mL, respectively. Disease control was achieved in approximately half of patients. One patient with anaplastic large cell lymphoma, which was negative for anaplastic lymphoma kinase, achieved a complete response, and two patients with cutaneous T-cell lymphoma achieved partial responses. BCX1777 was well tolerated at doses up to 300 mg once daily and showed preliminary evidence of activity in relapsed or refractory peripheral T/natural killer-cell malignancies, warranting further investigation.

Trial registration: ClinicalTrials.gov NCT00823355.

Publication types

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

MeSH terms

  • Administration, Oral
  • Adult
  • Aged
  • Antineoplastic Agents / administration & dosage
  • Antineoplastic Agents / pharmacokinetics
  • Antineoplastic Agents / therapeutic use
  • Area Under Curve
  • Cohort Studies
  • Dose-Response Relationship, Drug
  • Drug Administration Schedule
  • Drug Resistance, Neoplasm / drug effects
  • Exanthema / chemically induced
  • Female
  • Humans
  • Lymphoma, Large-Cell, Anaplastic / drug therapy
  • Lymphoma, T-Cell / drug therapy*
  • Lymphoma, T-Cell, Peripheral / drug therapy
  • Lymphopenia / chemically induced
  • Male
  • Metabolic Clearance Rate
  • Middle Aged
  • Mycosis Fungoides / drug therapy
  • Natural Killer T-Cells / pathology*
  • Purine Nucleosides / adverse effects
  • Purine Nucleosides / pharmacokinetics
  • Purine Nucleosides / therapeutic use*
  • Pyrimidinones / adverse effects
  • Pyrimidinones / pharmacokinetics
  • Pyrimidinones / therapeutic use*
  • Recurrence
  • Skin Neoplasms / drug therapy
  • Treatment Outcome

Substances

  • Antineoplastic Agents
  • Purine Nucleosides
  • Pyrimidinones
  • forodesine

Associated data

  • ClinicalTrials.gov/NCT00823355