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Phase I clinical and pharmacokinetic study of the glucose-conjugated cytotoxic agent d-19575 (glufosfamide) in patients with solid tumors

  • Toshio Shimizu
  • Isamu OkamotoEmail author
  • Kenji Tamura
  • Taroh Satoh
  • Masaki Miyazaki
  • Yusaku Akashi
  • Tomohiro Ozaki
  • Masahiro Fukuoka
  • Kazuhiko Nakagawa
Original Article

Abstract

Purpose

d-19575 (glufosfamide: β-d-glucosylisophosphoramide mustard) is an alkylating agent in which isophosphoramide mustard, the cytotoxic metabolite of ifosfamide, is covalently linked to β-d-glucose. We have performed a phase I study to determine the safety profile, pharmacokinetics, and antitumor activity of d-19575 in Japanese patients with advanced solid tumors

Methods

Patients were treated with escalating doses of d-19575 administered by a two-step (fast–slow) intravenous infusion over 6 h every 3 weeks. Thirteen patients received 43 treatment cycles (median 3; range 1–11) at d-19575 doses of 3,200, 4,500, or 6,000 mg/m2.

Results

Hematologic toxicities and other side effects were generally mild. The maximum tolerated dose of d-19575 was 6,000 mg/m2, at which two patients experienced dose-limiting toxicities (hypophosphatemia, hypokalemia, and metabolic acidosis each of grade 3). Pharmacokinetic analysis revealed a linear relation between the area under the concentration-versus-time curve (AUC) and dose. The AUC values for isophosphoramide mustard were substantially greater than those achieved by bolus administration or continuous infusion of ifosfamide in conventional therapy. One patient with gallbladder cancer previously treated with cisplatin and gemcitabine achieved a partial response lasting for >5 months, and eight patients achieved disease stabilization.

Conclusions

Our results show that d-19575 can be safely administered by infusion over 6 h at 4,500 mg/m2 every 3 weeks. The safety profile and potential antitumor activity of d-19575 show that phase II studies of this drug are warranted.

Keywords

Glufosfamide Isophosphoramide mustard Glucose transporter Pharmacokinetics 

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Copyright information

© Springer-Verlag 2009

Authors and Affiliations

  • Toshio Shimizu
    • 1
  • Isamu Okamoto
    • 1
    Email author
  • Kenji Tamura
    • 2
  • Taroh Satoh
    • 1
  • Masaki Miyazaki
    • 1
  • Yusaku Akashi
    • 3
  • Tomohiro Ozaki
    • 3
  • Masahiro Fukuoka
    • 4
  • Kazuhiko Nakagawa
    • 1
  1. 1.Department of Medical OncologyKinki University School of MedicineOsaka-SayamaJapan
  2. 2.Outpatient Treatment CenterNational Cancer Center HospitalTokyoJapan
  3. 3.Department of Medical OncologyKinki University Nara HospitalIkomaJapan
  4. 4.Department of Medical OncologyKinki University Sakai Hospital Minami-ku Sakai, OsakaJapan

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