Phase I clinical and pharmacokinetic study of the glucose-conjugated cytotoxic agent D-19575 (glufosfamide) in patients with solid tumors.
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.
Shimizu
Toshio
T
Department of Medical Oncology, Kinki University School of Medicine, Ohno-higashi, Osaka-Sayama, Japan.
Okamoto
Isamu
I
Tamura
Kenji
K
Satoh
Taroh
T
Miyazaki
Masaki
M
Akashi
Yusaku
Y
Ozaki
Tomohiro
T
Fukuoka
Masahiro
M
Nakagawa
Kazuhiko
K
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
D000970:Antineoplastic Agents; D010752:Phosphoramide Mustards; C092028:beta-D-glucosylisophosphoramide mustard; D005947:Glucose; D007069:Ifosfamide