Zoledronic acid in cancer patients with bone metastases: results of Phase I and II trials.

Zoledronic acid (Zometa, Novartis Pharmaceuticals Corp, East Hanover, NJ) is a new, highly potent bisphosphonate that may provide improved management of skeletal complications in cancer patients with bone metastases. A total of 383 cancer patients with osteolytic bone lesions was evaluated in two phase I studies and one phase II study of zoledronic acid. The phase I studies used two dosing regimens, either a 5-minute monthly intravenous infusion of 0.1 to 8 mg administered for 3 or more months or a single 30 to 60 second intravenous bolus of 1 to 16 mg. Zoledronic acid was well tolerated in the two phase I studies and a maximum tolerated dose was not reached in either study. A dose-dependent decrease in urinary markers of bone resorption was observed with the monthly 5-minute infusion. A single intravenous bolus of doses ranging from 2 to 16 mg zoledronic acid suppressed biochemical markers of bone resorption for up to 8 weeks. The phase II study evaluated a 5-minute infusion of 0.4, 2, or 4 mg zoledronic acid and a 2-hour infusion of 90 mg pamidronate in 280 patients with bone metastases and multiple myeloma or breast cancer. Significantly fewer patients receiving the 2 and 4 mg doses of zoledronic acid or 90 mg pamidronate required radiation therapy to bone than those patients receiving a 0.4 mg dose of zoledronic acid. Only 30% to 35% of patients in the 2 and 4 mg zoledronic acid groups or in the pamidronate group experienced any skeletal related event compared with 46% in the 0.4 mg zoledronic acid group. Adverse events consistent with an acute phase reaction were observed with both bisphosphonates. No new, unexpected adverse events were observed with this novel bisphosphonate. These studies support the further evaluation of zoledronic acid in cancer patients with osteolytic metastases. Doses of 0.4 mg or less are ineffective, while rapid infusion of more than 8 mg may increase the risk of renal dysfunction. A 4 mg dose given as a brief infusion appears to offer an excellent benefit/risk ratio for further evaluation in phase III trials.