title: Phase I clinical and pharmacokinetic study of the glucose-conjugated cytotoxic agent D-19575 (glufosfamide) in patients with solid tumors.
abstract: OBJECTIVE
  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/m(2).
  
  
  RESULTS
  Hematologic toxicities and other side effects were generally mild. The maximum tolerated dose of D-19575 was 6,000 mg/m(2), 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/m(2) every 3 weeks. The safety profile and potential antitumor activity of D-19575 show that phase II studies of this drug are warranted.
authors.affiliation: Department of Medical Oncology, Kinki University School of Medicine, Ohno-higashi, Osaka-Sayama, Japan.
authors.forename: Toshio
authors.initials: T
authors.lastname: Shimizu
authors.forename: Isamu
authors.initials: I
authors.lastname: Okamoto
authors.forename: Kenji
authors.initials: K
authors.lastname: Tamura
authors.forename: Taroh
authors.initials: T
authors.lastname: Satoh
authors.forename: Masaki
authors.initials: M
authors.lastname: Miyazaki
authors.forename: Yusaku
authors.initials: Y
authors.lastname: Akashi
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Ozaki
authors.forename: Masahiro
authors.initials: M
authors.lastname: Fukuoka
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Nakagawa
mesh_terms: D000368:Aged; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D005260:Female; D005947:Glucose / Q000031:analogs & derivatives; D006801:Humans; D007069:Ifosfamide / Q000031:analogs & derivatives; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000473:pathology; D010752:Phosphoramide Mustards / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D014057:Tomography, X-Ray Computed
chemical_list: D000970:Antineoplastic Agents; D010752:Phosphoramide Mustards; C092028:beta-D-glucosylisophosphoramide mustard; D005947:Glucose; D007069:Ifosfamide