acy population in three randomized Zometa trials in patients with multiple myeloma and bone metastases of solid tumors. These trials included a pamidronate-controlled study in breast cancer and multiple myeloma, a placebo-controlled study in prostate cancer, and a placebo-controlled study in other solid tumors. The prostate cancer study required documentation of previous bone metastases and 3 consecutive rising PSAs while on hormonal therapy. The other placebo-controlled solid tumor study included patients with bone metastases from malignancies other than breast cancer and prostate cancer, including NSCLC, renal cell cancer, small cell lung cancer, colorectal cancer, bladder cancer, GI/genitourinary cancer, head and neck cancer, and others. These trials were comprised of a core phase and an extension phase. In the solid tumor, breast cancer and multiple myeloma trials, only the core phase was eva luated for efficacy as a high percentage of patients did not choose to participate in the extension phase. In the prostate cancer trials, both the core and extension phases were eva luated for efficacy showing the Zometa effect during the first 15months was maintained without decrement or improvement for another 9months. The design of these clinical trials does not permit assessment of whether more than one-year administration of Zometa is beneficial. The optimal duration of Zometa administration is not known.
The studies were amended twice because of renal toxicity. The Zometa infusion duration was increased from 5minutes to 15minutes. After all patients had been accrued, but while dosing and follow-up continued, patients in the 8mg Zometa treatment arm were switched to 4mg due to toxicity. Patients who were randomized to the Zometa 8mg group are not included in these analyses.
Table 12: Overview of Efficacy Population for Phase III Studies Patient Population No. of Patients Zometa Dose Control Median Duration (Planned Duration) Zometa 4mg
Multiple myeloma or metastatic breast cancer 1,648 4 and 8*mg
Q3-4 weeks Pamidronate 90mg
Q3-4 weeks 12.0 months
(13 months)
Metastatic prostate cancer 643 4 and 8*mg
Q3 weeks Placebo 10.5 months
(15 months)
Metastatic solid tumor other than breast or prostate cancer 773 4 and 8*mg
Q3 weeks Placebo 3.8 months
(9 months)
* Patients who were randomized to the 8mg Zometa group are not included in any of the analyses in this package insert.
Each study eva luated skeletal-related events (SREs), defined as any of the following: pathologic fracture, radiation therapy to bone, surgery to bone, or spinal cord compression. Change in antineoplastic therapy due to increased pain was a SRE in the prostate cancer study only. Planned analyses included the proportion of patients with a SRE during the study and time to the first SRE. Results for the two Zometa placebo-controlled studies are given in Table13.
Table 13: Zometa Compared to Placebo in Patients with Bone Metastases from Prostate Cancer or Other Solid Tumors I. Analysis of Proportion of Patients with a SRE1 II. Analysis of Time to the First SRE
Study Study Arm &
Patient Number Proportion Difference2
& 95% CI P-value Median
(Days) Hazard Ratio3
& 95% CI P-value
Prostate Cancer Zometa 4mg
(n=214) 33% -11%
(-20%, -1%) 0.02 Not Reached 0.67
(0.49, 0.91) 0.011
Placebo
(n=208) 44% 321
Solid Tumors Zometa 4mg
(n=257) 38% -7%
(-15%, 2%) 0.13 230 0.73
(0.55, 0.9
