A dose-finding study of zoledronate in hypercalcemic cancer patients

Zoledronate is a new heterocyclic imidazole bisphosphonate that is the most potent bisphosphonate administered in humans because it is 100-850 times m ore potent than pamidronate, according to in vitro or animal models of bone resorption. We conducted an open-label, dose-finding, single-dose phase I study in tumor-induced hypercalcemia (TIH), which has been similarly used a s a model to determine the active doses of other bisphosphonates. The prima ry objective was to determine, with a dose escalation schedule, two nontoxi c dose levels of zoledronate able to induce normocalcemia in at least 80% o f patients with TM after rehydration (corrected Ca for albumin levels great er than or equal to 2.75 mmol/l). Based on estimates of potency, the starti ng dose was 0.002 mg/kg, and further tested doses were 0.005, 0.01, 0.02, a nd 0.04 mg/kg. To obtain a more precise estimate of the response rate, we t reated 10 more patients at the highest of the two effective dose levels. Th e median infusion time of zoledronate was 30 minutes. Thirty out of the 33 treated patients were evaluable for efficacy. Thirty percent of the patient s had breast cancer and 54% had metastatic bone involvement. For all groups combined, mean Ca levels at baseline was 3.0 mmol/l. The two effective dos e levels were 0.02 mg/kg and 0.04 mg/kg. Five out of five patients became n ormocalcemic after 0.02 mg of zoledronate/kg and 14 out of 15 after 0.04 mg of zoledronate/kg. The success rate of the latter dose was thus 93% (95% c onfidence interval [CI] 68-100%). At this dose, the first day of normocalce mia was day 2 or 3 for all but one patient. The duration of normocalcemia f or the two effective doses could be assessed in nine patients; seven patien ts remained normocalcemic throughout the trial (32-39 days). The fall in se rum Ca was accompanied by a marked fall in fasting urinary Ca excretion. Zo ledronate was well tolerated: 7 out of 33 patients developed transient hypo phosphatemia, and 3 developed transient hypocalcemia. The only clinically d etectable side effect was an increase in body temperature occurring in 10 ( 30%) patients. In summary, very low doses of zoledronate (0.02 mg/kg and 0. 04 mg/kg, i.e., 1.2 mg and 2.4 mg for a 60-kg individual, respectively) adm inistered by a short-time infusion effectively treated patients with TM. Th e fall in serum Ca was rapid, and normocalcemia was often maintained for se veral weeks. Zoledronate was well tolerated. Future trials will determine w hether prolonged treatment with this potent compound can have greater effec ts on the skeletal morbidity rate in patients with tumor bone disease than can be achieved with currently available bisphosphonates.