Zoledronic acid in the treatment of hypercalcemia of malignancy: results of the international clinical development program.

This report summarizes results of the clinical development program evaluating zoledronic acid (Zometa; Novartis Pharmaceuticals Corp, East Hanover, NJ) in the treatment of hypercalcemia of malignancy (HCM). In addition to a phase I dose escalation trial, two randomized, double-blind, double-dummy studies were conducted in parallel to investigate the clinical efficacy and safety of 4 mg and 8 mg zoledronic acid in patients with moderate to severe HCM. Patients were treated with a single dose of zoledronic acid (4 or 8 mg) via 5-minute infusion or a control treatment, 90 mg pamidronate via 2-hour infusion. Patients who relapsed or had refractory HCM after initial treatment could be re-treated with 8 mg zoledronic acid. End points included rate of complete response, defined as normalization of corrected serum calcium by day 10, change in corrected serum calcium, time to relapse, duration of response, and bone biochemical markers. Doses of > or =0.02 mg/kg were effective and nontoxic in the phase I study. In the controlled studies, 287 patients were randomized and evaluated for safety and 275 patients were evaluable for efficacy. The proportions of patients with a complete response by day 10 were 88.4% and 86.7% in the 4 mg and 8 mg zoledronic acid groups, respectively, compared with 69.7% in the 90 mg pamidronate group. Corrected serum calcium normalization occurred by day 4 in 45.3% of patients treated with 4 mg zoledronic acid, 55.6% of patients treated with 8 mg zoledronic acid, and 33.3% of patients treated with pamidronate. Mean change from baseline in corrected serum calcium also was greater with zoledronic acid than with pamidronate. Median times to relapse were significantly longer in both the zoledronic acid 4 mg and 8 mg groups compared with the pamidronate group. There were no significant differences in efficacy between the 4 mg and 8 mg zoledronic acid doses. Retreatment in 69 patients with relapsing or refractory hypercalcemia with 8 mg zoledronic acid resulted in a 52% complete response rate. Fever, hypophosphatemia, and asymptomatic hypocalcemia were the most common drug-related adverse events. These studies have shown that a short single intravenous dose of 4 mg or 8 mg zoledronic acid is effective in treating moderate to severe HCM. Zoledronic acid produced a higher rate of calcium normalization, faster onset of action, and longer time to relapse than pamidronate, while maintaining an excellent safety profile. The lower dose of 4 mg is recommended as initial therapy, with the 8 mg dose reserved for patients requiring retreatment.