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

Toshio Shimizu, Isamu Okamoto, Kenji Tamura, Taroh Satoh, Masaki Miyazaki, Yusaku Akashi, Tomohiro Ozaki, Masahiro Fukuoka, Kazuhiko Nakagawa

Research output: Contribution to journalArticle

14 Citations (Scopus)

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/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.

Original languageEnglish
Pages (from-to)243-250
Number of pages8
JournalCancer Chemotherapy and Pharmacology
Volume65
Issue number2
DOIs
Publication statusPublished - Jan 1 2010
Externally publishedYes

Fingerprint

Ifosfamide
Pharmacokinetics
Cytotoxins
gemcitabine
Toxicity
Tumors
Glucose
Alkylating Agents
Metabolites
Cisplatin
Neoplasms
Stabilization
Area Under Curve
Pharmaceutical Preparations
Hypophosphatemia
Gallbladder Neoplasms
Safety
Mustard Plant
Maximum Tolerated Dose
Hypokalemia

All Science Journal Classification (ASJC) codes

  • Cancer Research
  • Oncology
  • Pharmacology
  • Pharmacology (medical)
  • Toxicology

Cite this

Phase I clinical and pharmacokinetic study of the glucose-conjugated cytotoxic agent d-19575 (glufosfamide) in patients with solid tumors. / Shimizu, Toshio; Okamoto, Isamu; Tamura, Kenji; Satoh, Taroh; Miyazaki, Masaki; Akashi, Yusaku; Ozaki, Tomohiro; Fukuoka, Masahiro; Nakagawa, Kazuhiko.

In: Cancer Chemotherapy and Pharmacology, Vol. 65, No. 2, 01.01.2010, p. 243-250.

Research output: Contribution to journalArticle

Shimizu, Toshio ; Okamoto, Isamu ; Tamura, Kenji ; Satoh, Taroh ; Miyazaki, Masaki ; Akashi, Yusaku ; Ozaki, Tomohiro ; Fukuoka, Masahiro ; Nakagawa, Kazuhiko. / Phase I clinical and pharmacokinetic study of the glucose-conjugated cytotoxic agent d-19575 (glufosfamide) in patients with solid tumors. In: Cancer Chemotherapy and Pharmacology. 2010 ; Vol. 65, No. 2. pp. 243-250.
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T1 - Phase I clinical and pharmacokinetic study of the glucose-conjugated cytotoxic agent d-19575 (glufosfamide) in patients with solid tumors

AU - Shimizu, Toshio

AU - Okamoto, Isamu

AU - Tamura, Kenji

AU - Satoh, Taroh

AU - Miyazaki, Masaki

AU - Akashi, Yusaku

AU - Ozaki, Tomohiro

AU - Fukuoka, Masahiro

AU - Nakagawa, Kazuhiko

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N2 - 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/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.

AB - 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/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.

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