Phase I trial and pharmacokinetic analysis of ifosfamide in cats with sarcomas.
OBJECTIVE
To determine the maximally tolerated dose (MTD) and dose-limiting toxicosis (DLT) of ifosfamide in tumor-bearing cats.


METHODS
38 cats with resected, recurrent, or metastatic sarcomas.


METHODS
The starting dosage of ifosfamide was 400 mg/m(2) of body surface area, IV, and dosages were increased by 50 to 100 mg/m(2) in cohorts of 3 cats. To protect against urotoxicosis, mesna was administered at a dosage equal to 20% of the calculated ifosfamide dosage. Diuresis with saline (0.9% NaCl) solution before and after administration of ifosfamide was used to minimize nephrotoxicosis. Samples for pharmacokinetic analysis were obtained after the MTD was reached.


RESULTS
38 cats were entered into this phase I study and were administered a single dose of ifosfamide at various dosages. The MTD was 1,000 mg/m(2), and neutropenia was the DLT. Seven of 8 episodes of neutropenia were on day 7 after treatment, and 1 cat developed severe neutropenia on day 5. Adverse effects on the gastrointestinal tract were generally mild and self-limiting, the most common of which was nausea during ifosfamide infusion. One cat had signs consistent with a drug-induced hypersensitivity reaction. There were no episodes of hemorrhagic cystitis or nephrotoxicosis. Correlations between pharmacokinetic variables and ifosfamide-associated toxicoses were not found. Preliminary evidence of antitumor activity was observed in 6 of 27 cats with measurable tumors.


CONCLUSIONS
The dosage of ifosfamide recommended to treat tumor-bearing cats is 900 mg/m(2) every 3 weeks. This dosage should be used in phase II clinical trials.
Rassnick
Kenneth M
KM
Department of Clinical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY 14853, USA.
Moore
Antony S
AS
Northrup
Nicole C
NC
Kristal
Orna
O
Beaulieu
Bernard B
BB
Lewis
Lionel D
LD
Page
Rodney L
RL
D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000009:adverse effects / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use*; D019540:Area Under Curve; D002371:Cat Diseases / Q000188:drug therapy*; D002415:Cats; D004305:Dose-Response Relationship, Drug; D005260:Female; D006207:Half-Life; D007069:Ifosfamide / Q000009:adverse effects / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use*; D008297:Male; D008956:Models, Chemical; D015394:Molecular Structure; D012509:Sarcoma / Q000188:drug therapy / Q000662:veterinary*
D018906:Antineoplastic Agents, Alkylating; D007069:Ifosfamide