Evaluation of satraplatin in dogs with spontaneously occurring malignant tumors.

Abstract

BACKGROUND: Satraplatin is the 1st orally bioavailable platinum anticancer drug. OBJECTIVE: Our objectives were to evaluate efficacy in vitro against a canine cancer cell line, to determine the maximally tolerated dose (MTD) of satraplatin in tumor-bearing dogs, to identify the dose-limiting and other toxicities in dogs, and to record pharmacokinetics (PK). ANIMALS: Dogs with macro- or microscopic malignant neoplasia. METHODS: D17 canine osteosarcoma cells first were evaluated in a clonogenic survival assay. Then, dogs with a diagnosis of malignant neoplasia were prospectively entered in standard 3 + 3 cohorts. Additional patients were entered at the MTD to assess efficacy. Total and free platinum (by ultrafiltrate) concentrations were determined with inductively coupled plasma mass spectroscopy. RESULTS: Satraplatin inhibited clonogenic survival in vitro at clinically relevant and achievable concentrations. Twenty-three dogs were treated, 14 with PK evaluation. The MTD was 35 mg/m(2)/d for 5 days, repeated every 3-4 weeks. Bioavailability was 41%. PK variables (mean ± SD) at the MTD included T(max) 1.8 (± 0.7) hours, C(max) 72 (± 26) ng/mL, area under concentration (AUC)(0-24 h) 316 (± 63) h × ng/mL, and MRT 7 (± 1.3) hours. Higher AUC after the 5th versus the 1st dose suggested drug accumulation. Interestingly, platelets consistently reached nadir sooner than did neutrophils (day 14 versus 19). Myelosuppression was dose-limiting and gastrointestinal toxicity was mild. CONCLUSIONS AND CLINICAL IMPORTANCE: Satraplatin was well tolerated in tumor-bearing dogs, thus warranting further investigation in a phase II trial.