14CLINICAL STUDIES
14.1 Hypercalcemia of Malignancy
Two identical multicenter, randomized, double-blind, double-dummy studies of Zometa 4mg given as a 5-minute intravenous infusion or pamidronate 90mg given as a 2-hour intravenous infusion were conducted in 185patients with hypercalcemia of malignancy (HCM). NOTE: Administration of Zometa 4mg given as a 5-minute intravenous infusion has been shown to result in an increased risk of renal toxicity, as measured by increases in serum creatinine, which can progress to renal failure. The incidence of renal toxicity and renal failure has been shown to be reduced when Zometa 4mg is given as a 15-minute intravenous infusion. Zometa should be administered by intravenous infusion over no less than 15minutes [see Warnings And Precautions(5.1, 5.2) and Dosage And Administration(2.4)].The treatment groups in the clinical studies were generally well balanced with regards to age, sex, race, and tumor types. The mean age of the study population was 59years; 81% were Caucasian, 15% were Black, and 4% were of other races. 60%of the patients were male. The most common tumor types were lung, breast, head and neck, and renal.

In these studies, HCM was defined as a corrected serum calcium (CSC) concentration of greater than or equal to 12.0mg/dL (3.00mmol/L). The primary efficacy variable was the proportion of patients having a complete response, defined as the lowering of the CSC to less than or equal to 10.8mg/dL (2.70mmol/L) within 10days after drug infusion.

To assess the effects of Zometa versus those of pamidronate, the two multicenter HCM studies were combined in a preplanned analysis. The results of the primary analysis revealed that the proportion of patients that had normalization of corrected serum calcium by Day10 were 88% and 70% for Zometa 4mg and pamidronate 90mg, respectively (P=0.002) (seeFigure1). In these studies, no additional benefit was seen for Zometa 8mg over Zometa 4mg; however, the risk of renal toxicity of Zometa 8mg was significantly greater than that seen with Zometa 4mg.
Figure 1

Secondary efficacy variables from the pooled HCM studies included the proportion of patients who had normalization of corrected serum calcium (CSC) by Day4; the proportion of patients who had normalization of CSC by Day7; time to relapse of HCM; and duration of complete response. Time to relapse of HCM was defined as the duration (in days) of normalization of serum calcium from study drug infusion until the last CSC value less than 11.6mg/dL (less than 2.90mmol/L). Patients who did not have a complete response were assigned a time to relapse of 0days. Duration of complete response was defined as the duration (in days) from the occurrence of a complete response until the last CSC ≤10.8mg/dL (2.70mmol/L). The results of these secondary analyses for Zometa 4mg and pamidronate 90mg are shown in Table11.

Table 11: Secondary Efficacy Variables in Pooled HCM Studies  Zometa 4mg Pamidronate 90mg
Complete Response N Response Rate N Response Rate
By Day 4 86 45.3% 99 33.3%
By Day 7 86 82.6%* 99 63.6%
Duration of Response N Median Duration (Days) N Median Duration (Days)
Time to Relapse 86 30* 99 17
Duration of Complete Response 76 32 69 18
* P less than 0.05 versus pamidronate 90mg.

14.2 Clinical Trials in Multiple Myeloma and Bone Metastases of Solid Tumors
Table12 describes an overview of the effic