**ZOMETA^^ (Zoledronic acid for injection)**

**ONCOLOGIC DRUGS ADVISORY COMMITTEE**

**BRIEFING DOCUMENT**

**Date of Meeting: January 31, 2002**

**NDA \# 21-386**

**Treatment of bone metastases**

Version: Final

Release date: January 3, 2002

**AVAILABLE FOR PUBLIC DISCLOSURE WITHOUT REDACTION.**

Summary

Many forms of cancer can originate in or metastasize to bone. Cancers
that involve bone can cause a variety of skeletal problems for patients,
ranging from pain to fractures to spinal cord compression. The majority
of patients living with bone metastases have breast cancer or prostate
cancer (since these cancers are common in our population, frequently
metastasize to bone, and are often associated with a relatively longer
survival than other cancers following metastasis to bone). Other cancers
associated with frequent metastasis to bone include lung cancers, renal
cancer, melanoma and thyroid cancer. Bone complications are also common
in patients with multiple myeloma, a hematologic malignancy that
originates in bone. In the US, it is thought that over 250,000 patients
are living with bone metastasis at any time.

Damage to bone by cancer can result from direct effects of tumor growth
(replacing/weakening the bone and/or compromising adjacent structures)
and from indirect effects mediated by factors released by the tumor
(which may promote osteoclast resorption of bone or abnormal bone
growth/remodeling). Effective systemic anticancer treatments can control
tumor growth which, for a time, may stem the bony destruction with
improvement in related signs and symptoms. Unfortunately, many types of
cancer that involve bone are poorly responsive to current antineoplastic
treatments. Patients with this diagnosis may often suffer from morbid
skeletal events, requiring palliative treatments such as pain
medication, radiation therapy, or surgery. These palliative treatments
have their own limitations and potential for adverse consequences, and
patients may be left with significant disability and loss of mobility
and independence

An alternative approach to control bone damage due to cancer has been to
utilize intravenous bisphosphonate therapy to block tumor-stimulated
osteoclast activity. Aredia (pamidronate disodium for injection) is
marketed for treatment of patients with multiple myeloma or breast
cancer metastatic to bone, where it has been shown to delay or reduce
the occurrence of skeletal-related morbid events. The utility of
bisphosphonate treatment in reducing skeletal-related morbid events in
patients with other forms of cancer has not previously been established,
and there is no U.S.-approved bisphosphonate treatment for these
patients. In particular, prospective studies in prostate cancer failed
to detect a beneficial effect of Aredia on skeletal-related events (1).
It is nonetheless anticipated that effective inhibition of osteoclast
activity should have beneficial effects regardless of tumor type, since
excessive osteoclast activity plays a central role in the
pathophysiology of all (osteolytic, mixed, and osteoblastic) malignant
bone lesions. The magnitude of the observed benefit, however, may depend
on many factors, including the potency of the bisphosphonate, the types
and levels of osteoclast-activating factors elaborated by different
tumor types, and the biology of the patient's disease in other tissues
(with competing causes of early morbidity/mortality in patients with
rapid disease progression in other tissues).

Intravenous bisphosphonates are generally well tolerated and can be
administered safely to patients with a variety of advanced tumor types.
The most commonly noted side effect is a transient flu-like syndrome
characterized by fever, arthralgias, myalgias, and chills. Nausea,
fatigue, and headache are among the other more common adverse events.
Bisphosphonate administration may also be associated with impairment of
renal function, a complication that may be related to complexes between
bisphosphonate and minerals in the kidneys. Elevation of serum
creatinine and (rarely) renal failure may occur in some patients. Risk
factors are believed to include insufficient hydration of the patient,
rapid infusion, and higher bisphosphonate dosages.

ZOMETA (Zometa for infusion, Novartis Pharmaceuticals Corporation, East
Hanover, NJ) is a new-generation bisphosphonate that was selected for
clinical development based on its high pharmacological potency. In
previous clinical trials, Zometa has been shown to be superior to Aredia
in the treatment of hypercalcemia of malignancy, providing a higher
response rate and longer response duration. Zometa is registered
worldwide for this indication (2,3).

The Zometa clinical development program is the largest and most
comprehensive bisphosphonate clinical trial program conducted to date in
patients with malignancies involving the skeletal system. The study
designs and clinical endpoints were discussed with the FDA prior to the
start of the clinical trials discussed The clinical trials reported in
this application evaluated Zometa versus Aredia in patients with
multiple myeloma or breast cancer metastatic to bone (study 010). Zometa
was compared with placebo in patients with prostate cancer (study 039)
and lung cancer or other solid tumors (study 011) metastatic to bone.
The study data are consistent in demonstrating a clinical benefit for
Zometa in delaying and reducing the occurrence of skeletal related
events (SREs) for the broad range of tumor types studied. The primary
analyses compared the proportions of patients who experienced any SRE in
the respective arms of each study. Analyses of the time to first SRE and
recurrence rate of SREs over time on study (secondary analyses of this
primary endpoint) provided further support for Zometa effectiveness
across all tumor types studied.

Overall, no significant efficacy differences were observed between 4 mg
and 8 mg Zometa doses in these studies, suggesting that the 4 mg dose is
sufficient to provide maximal effectiveness. Renal safety concerns
resulted in a decision to increase the Zometa administration time from 5
minutes (in the original study protocols) to 15 minutes. Over the course
of these studies, the 8 mg dose was associated with an increased
incidence of creatinine elevations, and in the later stages of this
research all 8 mg Zometa patients were converted to the 4 mg dose. The
safety profile of Zometa 4 mg administered over 15 minutes is comparable
to that of Aredia. The incidence of serum creatinine elevations in
patients receiving Zometa 4 mg over 15 minutes was similar to that seen
with administration of Aredia 90 mg over 2 hours in breast cancer and
multiple myeloma patients and was similar to that seen with placebo in
prostate cancer patients. It was only slightly greater than that seen
with placebo in the other solid tumor patients. Finally a practical
benefit associated with Zometa is the short 15 minute infusion time
compared with the 2-4 hours required to administer Aredia to breast
cancer or multiple myeloma patients.

In conclusion, the studies provided in this application demonstrate the
safety and effectiveness of Zometa 4 mg infused over 15 minutes
(repeated at 3-4 week intervals) to delay or reduce the occurrence of
skeletal-related events in patients with cancer metastatic to bone or
multiple myeloma. The results were consistent in that both Zometa
treatment arms in all three protocols reduced the proportion of patients
having at least one SRE. This reflects the benefit patients receive by
having a longer initial period free of skeletal complications, and by
having fewer additional complications over time.

Table of Contents

1 Background [10](#background)

1.1 Clinical consequence of skeletal related events
[10](#clinical-consequence-of-skeletal-related-events)

1.2 Pathophysiology [10](#pathophysiology)

1.3 Overview of Zometa [11](#overview-of-zometa)

2 Clinical Pharmacokinetics and Metabolism
[12](#clinical-pharmacokinetics-and-metabolism)

2.1. Clinical pharmacology studies [12](#__RefHeading___Toc533676648)

2.2. Metabolism and drug-drug interactions
[14](#metabolism-and-drug-drug-interactions)

2.3. Pharmacokinetics in renal impairment
[14](#pharmacokinetics-in-renal-impairment)

3 Use in Hypercalcemia of Malignancy
[15](#use-in-hypercalcemia-of-malignancy)

3.1 Efficacy in HCM [15](#efficacy-in-hcm)

3.2 Safety in HCM [15](#safety-in-hcm)

4 Phase II Trial in treatment of bone metastases
[15](#phase-ii-trial-in-treatment-of-bone-metastases)

4.1 Efficacy [16](#efficacy)

4.2 Safety [16](#safety)

5 Phase III Trials [16](#phase-iii-trials)

5.1 Study Design [16](#__RefHeading___Toc533676658)

5.2 Breast cancer and multiple myeloma -- Aredia-controlled trial (010)
[25](#__RefHeading___Toc533676659)

5.2.1 Patient disposition [25](#__RefHeading___Toc533676660)

5.2.2 Demographics and disease characteristics
[25](#__RefHeading___Toc533676661)

5.2.3 Primary efficacy analysis [27](#primary-efficacy-analysis)

5.2.4 Secondary skeletal endpoints analyses
[28](#secondary-skeletal-endpoints-analyses)

5.2.5 Analysis of Other Endpoints [30](#analysis-of-other-endpoints)

5.2.6 Survival [32](#survival)

5.2.7 Efficacy Summary (breast cancer / multiple myeloma)
[33](#efficacy-summary-breast-cancer-multiple-myeloma)

5.3 Prostate Cancer -- Placebo-controlled trial (039)
[34](#prostate-cancer-placebo-controlled-trial-039)

5.3.1 Patient Disposition [34](#patient-disposition-1)

5.3.2 Demographic and Disease Characteristics
[35](#demographic-and-disease-characteristics)

5.3.3 Primary efficacy analysis [36](#primary-efficacy-analysis-1)

5.3.4 Secondary skeletal endpoint analyses
[37](#secondary-skeletal-endpoint-analyses)

5.3.5 Analyses of Other Endpoints [39](#analyses-of-other-endpoints)

5.3.6 Survival [40](#survival-1)

5.3.7 Efficacy Summary (prostate study)
[41](#efficacy-summary-prostate-study)

5.4 Lung Cancer and Other Solid Tumors -- Placebo-Controlled Trial (011)
[43](#lung-cancer-and-other-solid-tumors-placebo-controlled-trial-011)

5.4.1 Patient Disposition [43](#patient-disposition-2)

5.4.2 Demographics and Disease Characteristics
[43](#demographics-and-disease-characteristics-1)

5.4.3 Primary efficacy analysis [45](#primary-efficacy-analysis-2)

5.4.4 Secondary skeletal endpoint analyses
[46](#secondary-skeletal-endpoint-analyses-1)

5.4.5 Analyses of Other Endpoints [49](#analyses-of-other-endpoints-1)

5.4.7 Efficacy Summary (other solid tumors)
[51](#efficacy-summary-other-solid-tumors)

6 Phase III Studies -- Safety [53](#phase-iii-studies-safety)

6.1 Adverse Events [53](#adverse-events)

6.1.1 Overall Incidence in Phase II/III bone metastases studies
[53](#overall-incidence-in-phase-iiiii-bone-metastases-studies)

6.1.2 Grade 3 and 4 Adverse Events [54](#grade-3-and-4-adverse-events)

6.1.3 Serious Adverse Events [56](#serious-adverse-events)

6.2 NCI Grade 3 and 4 Laboratory Abnormalities
[56](#nci-grade-3-and-4-laboratory-abnormalities)

6.3 Renal Effects [58](#renal-effects)

6.3.1 Renal Adverse Events in Phase II/III Bone Metastases Studies
[58](#renal-adverse-events-in-phase-iiiii-bone-metastases-studies)

6.3.4 Grade 3 and 4 Creatinine Values
[60](#grade-3-and-4-creatinine-values)

6.3.5 Renal Function Deterioration -- Advisory Board Criteria
[61](#renal-function-deterioration-advisory-board-criteria)

6.3.6 Time to Creatinine Increase [62](#time-to-creatinine-increase)

6.4 Deaths [67](#deaths)

6.4.1 Primary Cause of Death [67](#primary-cause-of-death)

7\. Summary of Safety [68](#summary-of-safety)

8\. Summary of Effectiveness [68](#summary-of-effectiveness)

9\. Benefit-Risk Assessment [71](#benefit-risk-assessment)

10\. Overall Conclusion [72](#overall-conclusion)

11\. References [73](#references)

ATTACHMENT 1: COMPOSITION OF DATA SAFETY MONITORING BOARD (DSMB)
[75](#attachment-1-composition-of-data-safety-monitoring-board-dsmb)

ATTACHMENT 2: COMPOSITION OF RENAL ADVISORY BOARD (RAB)
[76](#attachment-2-composition-of-renal-advisory-board-rab)

ATTACHMENT 3: [77](#attachment-3)

PROPOSED ZOMETA LABELING (including HCM)
[77](#proposed-zometa-labeling-including-hcm)

List of tables

Table 2-1. Human pharmacokinetic studies
[12](#table-2-1.-human-pharmacokinetic-studies)

Table 5-1. Overview of Phase III studies
[17](#table-5-1.-overview-of-phase-iii-studies)

Table 5-2. Efficacy parameters used in Phase III studies
[20](#table-5-2.-efficacy-parameters-used-in-phase-iii-studies)

Table 5-3. Patient disposition by treatment group, Aredia-controlled
trial
[25](#table-5-3.-patient-disposition-by-treatment-group-aredia-controlled-trial)

Table 5-4. Baseline demographic characteristics -- Aredia-controlled
trial -- ITT population
[26](#table-5-4.-baseline-demographic-characteristics-aredia-controlled-trial-itt-population)

Table 5-5. Baseline disease characteristics of multiple myeloma patients
[26](#table-5-5.-baseline-disease-characteristics-of-multiple-myeloma-patients)

Table 5-6. Baseline disease characteristics of breast cancer patients
[27](#table-5-6.-baseline-disease-characteristics-of-breast-cancer-patients)

Table 5-7. Proportion of patients with SREs, multiple myeloma and breast
cancer
[28](#table-5-7.-proportion-of-patients-with-sres-multiple-myeloma-and-breast-cancer)

Table 5-8. Time to the first SRE up to Month 13 (Median and hazard
ratio), multiple myeloma and breast cancer
[29](#table-5-8.-time-to-the-first-sre-up-to-month-13-median-and-hazard-ratio-multiple-myeloma-and-breast-cancer)

Table 5-9. Multiple-event analysis of time to SRE up to Month 13,
multiple myeloma and breast cancer (010)
[30](#table-5-9.-multiple-event-analysis-of-time-to-sre-up-to-month-13-multiple-myeloma-and-breast-cancer-010)

Table 5-10. Mean/Median changes from baseline in quality of life scores
at Month 13 by treatment group
[31](#table-5-10.-meanmedian-changes-from-baseline-in-quality-of-life-scores-at-month-13-by-treatment-group)

Table 5-11. Time to progression of disease up to Month 13, multiple
myeloma and breast cancer
[31](#table-5-11.-time-to-progression-of-disease-up-to-month-13-multiple-myeloma-and-breast-cancer)

Table 5-12. Best bone lesion response up to Month 13, multiple myeloma
and breast cancer
[32](#table-5-12.-best-bone-lesion-response-up-to-month-13-multiple-myeloma-and-breast-cancer)

Table 5-13. Summary of median survival (days) by stratum and treatment
group
[32](#table-5-13.-summary-of-median-survival-days-by-stratum-and-treatment-group)

Table 5-14. Summary of analysis of skeletal related events in Study 010
(Breast Cancer and Multiple Myeloma)
[34](#table-5-14.-summary-of-analysis-of-skeletal-related-events-in-study-010-breast-cancer-and-multiple-myeloma)

Table 5-15. Patient disposition -- prostate cancer study
[35](#table-5-15.-patient-disposition-prostate-cancer-study)

Table 5-16 Demographics in prostate cancer patients -- ITT population
[35](#table-5-16-demographics-in-prostate-cancer-patients-itt-population)

Table 5-17. Baseline characteristics in prostate cancer patients (ITT
population)
[36](#table-5-17.-baseline-characteristics-in-prostate-cancer-patients-itt-population)

Table 5-18. Proportion of patients with prostate cancer with an SRE up
to Month 15
[37](#table-5-18.-proportion-of-patients-with-prostate-cancer-with-an-sre-up-to-month-15)

Table 5-19. Time to the first SRE up to Month 15 in prostate cancer
patients
[38](#table-5-19.-time-to-the-first-sre-up-to-month-15-in-prostate-cancer-patients)

Table 5-20. Skeletal morbidity rate (risk set definition) of any SRE
(-HCM) up to Month 15
[38](#table-5-20.-skeletal-morbidity-rate-risk-set-definition-of-any-sre--hcm-up-to-month-15)

Table 5-21. Multiple-event analysis of time to SRE up to Month 15 in
prostate cancer patients (039)
[39](#table-5-21.-multiple-event-analysis-of-time-to-sre-up-to-month-15-in-prostate-cancer-patients-039)

Table 5-22. Summary of time to progression of disease at Month 15 in
prostate cancer patients
[40](#table-5-22.-summary-of-time-to-progression-of-disease-at-month-15-in-prostate-cancer-patients)

Table 5-23. Frequency distribution of best response by treatment group
[40](#table-5-23.-frequency-distribution-of-best-response-by-treatment-group)

Table 5-24. Summary of median survival (days) by stratum and treatment
group
[41](#table-5-24.-summary-of-median-survival-days-by-stratum-and-treatment-group)

Table 5-25. Summary of analysis of skeletal related events in Study 039
(Prostate cancer)
[42](#table-5-25.-summary-of-analysis-of-skeletal-related-events-in-study-039-prostate-cancer)

Table 5-26. Patient disposition, lung cancer and other solid tumors
(011)
[43](#table-5-26.-patient-disposition-lung-cancer-and-other-solid-tumors-011)

Table 5-27. Demographic characteristics by treatment group, Study 011
(ITT population)
[44](#table-5-27.-demographic-characteristics-by-treatment-group-study-011-itt-population)

Table 5-28. Baseline disease characteristics in patients with lung
cancer or other solid tumors (011)
[45](#table-5-28.-baseline-disease-characteristics-in-patients-with-lung-cancer-or-other-solid-tumors-011)

Table 5-29. Proportion of patients with lung cancer or other solid
tumors having any SRE (011)
[46](#table-5-29.-proportion-of-patients-with-lung-cancer-or-other-solid-tumors-having-any-sre-011)

Table 5-30. Time to first SRE in patients with lung cancer and other
solid tumors (011)
[47](#table-5-30.-time-to-first-sre-in-patients-with-lung-cancer-and-other-solid-tumors-011)

Table 5-31. Skeletal morbidity rate of any SRE in patients with lung
cancer and other solid tumors (011)
[48](#table-5-31.-skeletal-morbidity-rate-of-any-sre-in-patients-with-lung-cancer-and-other-solid-tumors-011)

Table 5-32. Proportion of patients with lung cancer or other solid
tumors having any SRE (+HCM)
[48](#table-5-32.-proportion-of-patients-with-lung-cancer-or-other-solid-tumors-having-any-sre-hcm)

Table 5-33. Multiple-event analysis of time to SRE up to Month 9 in
patients with lung cancer and other solid tumors (011)
[49](#table-5-33.-multiple-event-analysis-of-time-to-sre-up-to-month-9-in-patients-with-lung-cancer-and-other-solid-tumors-011)

Table 5-34. Time to progression of disease in patients with lung cancer
and other solid tumors (011)
[50](#table-5-34.-time-to-progression-of-disease-in-patients-with-lung-cancer-and-other-solid-tumors-011)

Table 5-35. Frequency distribution of best bone lesion response (011)
[50](#table-5-35.-frequency-distribution-of-best-bone-lesion-response-011)

Table 5-36. Summary of median survival (days) by stratum and treatment
group
[51](#table-5-36.-summary-of-median-survival-days-by-stratum-and-treatment-group)

Table 5-37. Summary of analysis of skeletal related events in Study 011
(Lung cancer and other solid tumors)
[52](#table-5-37.-summary-of-analysis-of-skeletal-related-events-in-study-011-lung-cancer-and-other-solid-tumors)

Table 6-1. No. (%) of patients with most frequent adverse events (≥ 15%)
-- Phase II/III studies
[54](#table-6-1.-no.-of-patients-with-most-frequent-adverse-events-15-phase-iiiii-studies)

Table 6-2. No. (%) of patients with grade 3 or 4 AEs (≥ 5%) -- Phase
II/III studies
[55](#table-6-2.-no.-of-patients-with-grade-3-or-4-aes-5-phase-iiiii-studies)

Table 6-3. No (%) of patients with SAEs (≥ 5%) -- Phase II/III Studies
[56](#table-6-3.-no-of-patients-with-saes-5-phase-iiiii-studies)

Table 6-4. No. (%) of patients with grade 3 or 4 serum chemistry values
-- Phase II/III studies
[57](#table-6-4.-no.-of-patients-with-grade-3-or-4-serum-chemistry-values-phase-iiiii-studies)

Table 6-5. No. (%) of patients with grade 3 or 4 hematology laboratory
abnormalities -- Phase II/III bone metastases studies
[58](#table-6-5.-no.-of-patients-with-grade-3-or-4-hematology-laboratory-abnormalities-phase-iiiii-bone-metastases-studies)

Table 6-6. No. (%) of patients with AEs (≥ 1%) of the renal and urinary
system -- pre-15-minute infusion amendment
[59](#table-6-6.-no.-of-patients-with-aes-1-of-the-renal-and-urinary-system-pre-15-minute-infusion-amendment)

Table 6-7. No. (%) of patients with AEs (≥ 1%) of the renal and urinary
system -- post-15-minute infusion patients
[60](#table-6-7.-no.-of-patients-with-aes-1-of-the-renal-and-urinary-system-post-15-minute-infusion-patients)

Table 6-8. No. (%) of patients with grade 3 or 4 serum creatinine values
pre- and post-15-minute infusion amendment -- Phase II/III bone
metastases studies
[61](#table-6-8.-no.-of-patients-with-grade-3-or-4-serum-creatinine-values-pre--and-post-15-minute-infusion-amendment-phase-iiiii-bone-metastases-studies)

Table 6-9. No. (%) of patients with notable serum creatinine values pre-
and post-15-minute infusion amendment -- Phase II/III bone metastases
studies
[62](#table-6-9.-no.-of-patients-with-notable-serum-creatinine-values-pre--and-post-15-minute-infusion-amendment-phase-iiiii-bone-metastases-studies)

Table 6-11. Primary causes of death (by body system) in Phase II/III
studies
[67](#table-6-11.-primary-causes-of-death-by-body-system-in-phase-iiiii-studies)

Table 8-1. Proportion of patients with one or more SREs (Phase III
trials, primary analyses)
[69](#table-8-1.-proportion-of-patients-with-one-or-more-sres-phase-iii-trials-primary-analyses)

Table 8-2. Median Time to first SRE (Phase III trials)
[69](#table-8-2.-median-time-to-first-sre-phase-iii-trials)

Table 8-3. Skeletal Morbidity Rate (rate of SREs over time, Phase III
studies)
[70](#table-8-3.-skeletal-morbidity-rate-rate-of-sres-over-time-phase-iii-studies)

Table 8-4. Risk ratios compared to control, Multiple Event Analyses of
SREs (Phase III studies)
[70](#table-8-4.-risk-ratios-compared-to-control-multiple-event-analyses-of-sres-phase-iii-studies)

List of figures

Figure 2-1. Mean Zometa plasma concentrations over 4 hours (left panel)
and 24 hours (right panel)
[13](#figure-2-1.-mean-zometa-plasma-concentrations-over-4-hours-left-panel-and-24-hours-right-panel)

Figure 2-2. Relationship between the renal clearance of Zometa (Clr) and
creatinine clearance (CLcr) in 64 patients in 3 clinical pharmacology
studies
[14](#figure-2-2.-relationship-between-the-renal-clearance-of-zometa-clr-and-creatinine-clearance-clcr-in-64-patients-in-3-clinical-pharmacology-studies)

Figure 5-1 Individual SREs in breast/myeloma patients
[28](#figure-5-1-individual-sres-in-breastmyeloma-patients)

Figure 5.2 Mean skeletal morbidity rate by treatment group
[29](#figure-5.2-mean-skeletal-morbidity-rate-by-treatment-group)

Figure 5-3. Kaplan-Meier curve of survival by treatment group
[33](#figure-5-3.-kaplan-meier-curve-of-survival-by-treatment-group)

Figure 5-4. Individual SREs in patients with prostate cancer
[37](#figure-5-4.-individual-sres-in-patients-with-prostate-cancer)

Figure 5-5. Kaplan-Meier curve of survival by treatment group
[41](#figure-5-5.-kaplan-meier-curve-of-survival-by-treatment-group)

Figure 5-6. Individual SREs in patients with lung cancer or other solid
tumors
[47](#figure-5-6.-individual-sres-in-patients-with-lung-cancer-or-other-solid-tumors)

Figure 5-7. Kaplan-Meier curve for survival by treatment group
[51](#figure-5-7.-kaplan-meier-curve-for-survival-by-treatment-group)

Figure 6-1. Kaplan-Meier curve for time to the first renal function
deterioration by treatment group for the pre 15-minute infusion
Amendment patients (Protocol 010, Safety evaluable patients)
[64](#figure-6-1.-kaplan-meier-curve-for-time-to-the-first-renal-function-deterioration-by-treatment-group-for-the-pre-15-minute-infusion-amendment-patients-protocol-010-safety-evaluable-patients)

Figure 6-2. Kaplan-Meier curve for time to the first renal function
deterioration by treatment group for the post 15-minute infusion
Amendment patients (Protocol 010, Safety evaluable patients)
[64](#figure-6-2.-kaplan-meier-curve-for-time-to-the-first-renal-function-deterioration-by-treatment-group-for-the-post-15-minute-infusion-amendment-patients-protocol-010-safety-evaluable-patients)

Figure 6-3. Kaplan-Meier curve for time to the first renal function
deterioration by treatment group for the pre 15-minute infusion
Amendment patients (Protocol 011, Safety evaluable patients)
[65](#figure-6-3.-kaplan-meier-curve-for-time-to-the-first-renal-function-deterioration-by-treatment-group-for-the-pre-15-minute-infusion-amendment-patients-protocol-011-safety-evaluable-patients)

Figure 6-4. Kaplan-Meier curve for time to the first renal function
deterioration by treatment group for the post 15-minute infusion
Amendment patients (Protocol 011, Safety evaluable patients)
[65](#__RefHeading___Toc533676768)

Figure 6-5. Kaplan-Meier curve for time to the first renal function
deterioration by treatment group for the pre 15-minute infusion
Amendment patients (Protocol 039, Safety evaluable patients)
[66](#figure-6-5.-kaplan-meier-curve-for-time-to-the-first-renal-function-deterioration-by-treatment-group-for-the-pre-15-minute-infusion-amendment-patients-protocol-039-safety-evaluable-patients)

Figure 6-6. Kaplan-Meier curve for time to the first renal function
deterioration by treatment group for the post 15-minute infusion
Amendment patients (Protocol 039, Safety evaluable patients)
[66](#figure-6-6.-kaplan-meier-curve-for-time-to-the-first-renal-function-deterioration-by-treatment-group-for-the-post-15-minute-infusion-amendment-patients-protocol-039-safety-evaluable-patients)

**Glossary of Abbreviations and Definition of Terms**

  ----------------- -----------------------------------------------------
  AE                Adverse Event

  ANCOVA            Analysis of covariance

  ANOVA             Analysis of variance

  b.i.d.            Bis in diem/Twice daily

  BMD               Bone mineral density

  BP                Bisphosphonate

  BPI               Brief Pain Inventory (composite score)

  CMH               Cochran-Mantel Haenszel

  CR                Complete response

  CRF               Case report form

  DSMB              Drug Safety Monitoring Board

  ECOG              Eastern Cooperative Oncology Group

  FACT-G            Functional Assessment of Cancer Therapy-General

  GLM               General linear model

  HCM               Hypercalcemia of malignancy (also known as TIH)

  IEC               Independent Ethics Committee

  IMN               International Medical Nomenclature

  IRB               Institutional Review Board

  ISE               Integrated Summary of Efficacy

  ISS               Integrated Summary of Safety

  ITT               Intent-to-treat (population)

  i.v.              intravenous

  KM                Kaplan-Meier

  NDA               New Drug Application

  NSLC              Non - small cell lung cancer

  o.d.              Omni die/once per day

  OST               Other solid tumor

  pam               Pamidronate (Aredia)

  p.o.              Per os/by mouth/orally

  PSA               Prostate specific antigen

  QOL               Quality of life

  RAB               Renal Advisory Board

  SAE               Serious Adverse Event

  SMR               Skeletal-morbidity rate

  SOP               Standard operating procedures

  S.D.              Standard deviation

  SRE               Skeletal-related event

  SRE (- HCM)       Skeletal-related events excluding HCM

  SRE (+ HCM)       Skeletal-related events including HCM

  TIH               Tumor-induced hypercalcemia (also known as HCM)

  WHO               World Health Organization

  ZOL               Zometa (ZOMETA)
  ----------------- -----------------------------------------------------

# 1 Background

## 1.1 Clinical consequence of skeletal related events

In patients with advanced cancer, the events defined as Skeletal Related
Events (SREs) are the clinical complications of bone metastases. The
time that is necessary to treat these complications and the additional
pain and suffering subtract from the time in which a patient can live
free from symptoms and independent of additional medical care.

Many SREs are related to pathological fractures. A pathological fracture
can occur in bone that has been eroded by a bone metastasis, to the
point that a slight trauma is sufficient to break the bone, cause pain,
loss of mobility and the need for possible surgical intervention. If the
metastasis has eroded into the structure of a vertebra, the vertebral
body may collapse. The resulting tissue mass may bulge inward, into the
spinal canal, and compress the spinal cord, leading to paralysis below
the level of the fracture, a devastating complication. Fractures are
generally painful and require analgesic medication to treat pain.
Pathological fractures will not heal spontaneously when immobilized,
unlike traumatic fractures. Therefore, most patients will require
additional procedures, such as orthopedic surgery, for curettage of the
malignant tissue and to insert a metallic rod or plate to immobilize the
bone and reduce pain.

A course of radiotherapy may be administered as part of the treatment of
a pathological fracture. Localized radiotherapy may eradicate the tumor
tissue in a bone metastasis and is used to prevent pathological
fractures, including the collapse of a vertebra, when a significant
amount of bone has been destroyed by cancer. Radiotherapy is also used
to treat bone pain due to bone metastases, but frequently entails daily
visits to a radiotherapy department for two to three weeks. The need to
undergo radiotherapy is therefore a significant burden on a patient.
Radiotherapy itself may lead to osteopenia with the increased risk of
new fractures.

Hypercalcemia of malignancy is often a late complication of cancer.
Symptoms include nausea, vomiting, dehydration, weakness and coma,
culminating in death. Emergency treatment at a clinic is required, which
again subtracts from the time a patient has free from the need for
additional medical care. Finally, even though a change in antineoplastic
therapy to treat bone pain appears to be of lesser significance compared
to other SREs, it means to the patient that their cancer is advancing
and may have a large psychological impact.

Each of these SREs is a serious debilitating event to anyone with
cancer, threatening their independence and requiring additional medical
treatment. Psychologically, an SRE is another reminder to the patient of
the fact that she or he must deal with cancer. The ability to postpone
any of these events leads to a longer time for the patient to be free
from the complications of bone metastases, which together with the
reduction in the rate of subsequent events, results in a lower
proportion of patients suffering from these SREs.

## 1.2 Pathophysiology

The osteoclast is thought to be the final common pathway in the
pathophysiology of bone metastases. Osteoclasts are specialized bone
cells which erode mineralized bone by secreting acids and lysosomal
enzymes. The lytic bone destruction associated with malignancy develops
because tumor cells synthesize and release soluble factors that
stimulate osteoclasts to resorb bone (4,5,6). The osteoclastic
activating factors released by tumor cells include parathyroid
hormone-related peptide (PTHrP), growth factors, and cytokines (7-10).
The activation of osteoclasts is revealed by the increase in urinary
NTX/creatinine ratio seen in patients with osteolytic bone metastases.
The same assay reveals that the highest levels of osteoclast activation
occur in prostate cancer patients who have predominantly osteoblastic
bone metastases(11).

In patients with malignant bone lesions, the activation of osteoclasts
results in disruption of normal bone remodeling so that the equilibrium
between bone resorption and bone formation is shifted towards increased
bone resorption. Thus, the predominant role of the osteoclast in the
pathogenesis of bone destruction and the inhibitory effects of
bisphosphonates on osteoclast function have formed the rationale for the
use of bisphosphonates in the treatment of osteolytic bone metastases.
The common role, regardless of tumor type, of osteoclasts as mediators
of bone destruction in metastatic skeletal disease is indicated by the
effectiveness of bisphosphonates in the therapy of hypercalcemia of
malignancy arising from any type of cancer (12-16).

Bisphosphonates are effective inhibitors of bone resorption, and have
the potential to delay or reduce the occurrence of SREs in patients with
malignant bone lesions. Aredia (pamidronate), given in addition to
standard anticancer therapy, is the only bisphosphonate currently
approved in the United States (U.S.) for the treatment of patients with
multiple myeloma or bone metastases from breast cancer. Studies which
established the current standard of care have shown that therapy with
the bisphosphonate pamidronate (Aredia) combined with anti-neoplastic
therapy significantly reduces the proportion of patients having skeletal
complications due to the lytic bone disease associated with multiple
myeloma and breast cancer compared to anti-neoplastic therapy alone
(17,18). The new Zometa trials reported here have improved on the
clinical and statistical methodologies that had been employed in the
original phase III program demonstrating the efficacy of Aredia in
breast cancer and multiple myeloma. For example the methodology for
assessment of skeletal related events was more conservative than in the
Aredia program, taking into account newer statistical insights which
avoid overcounting events.

The established safety profile of intravenous bisphosphonates includes
transient acute phase reactions (fever, arthralgias, myalgias,
lymphopenia), injection site reactions (erythema, swelling, and/or
induration), and renal insufficiency (19,20,21).

## 1.3 Overview of Zometa

Zometa is a third generation bisphosphonate,
2-(imidazol-l-yl-hydroxyethane-1, 1-bisphosphonic acid), characterized
by a side chain consisting of an imidazole ring group. Zometa, a more
potent inhibitor of osteoclasts than earlier bisphosphonates, has the
largest in vitro therapeutic ratio between the desired inhibition of
bone resorption and the unwanted inhibition of normal mineralization of
all the bisphosphonates. It can be infused over a shorter time (15
minutes rather than 2 hours) than Aredia. Zometa is approved worldwide
for treatment of hypercalcemia of malignancy; in the U.S., the NDA for
this use of Zometa was approved on August 20, 2001 \[see Attachment 3,
Proposed Product Labeling for Zometa (including HCM)\].

This briefing document presents the results of an extensive program of
clinical pharmacology, phase II, and phase III trials, which have
examined the use of Zometa as a treatment for patients with myeloma or
with bone metastases due to a broad range of cancer types. These data
provide the basis of a supplemental NDA for the use of Zometa in a new
indication, treatment of patients with myeloma or with cancer metastatic
to bone.

# 2 Clinical Pharmacokinetics and Metabolism

[]{#__RefHeading___Toc533676648 .anchor}2.1. Clinical pharmacology
studies

The pharmacokinetics of Zometa were derived from plasma and urine Zometa
concentrations determined by specific radioimmunoassay in 64 cancer
patients with bone metastases in three studies, J001, CZOL446D 0503, and
CZOL446E 0506 (Table 2-1).

###### Table 2-1. Human pharmacokinetic studies

+----------+---------------+-------------+-----------------------------+
| Study    | Study         | Zometa      | Pharmacokinetic evaluations |
|          | Objective     | doses       |                             |
+==========+===============+=============+=============================+
| J001     | PK/PD in      | 2 mg, 5     | Plasma and quantitative     |
|          | patients with | min.        | urine sampling 0-48 h post  |
| (Japan)  | bone          |             | dose on day 1 (1^st^        |
|          | metastases    | 4 mg, 5     | infusion).                  |
|          |               | min.        |                             |
|          |               |             |                             |
|          |               | 8 mg, 5     |                             |
|          |               | min.        |                             |
+----------+---------------+-------------+-----------------------------+
| CZOL446D | PK/PD in      | 4 mg, 5     | Plasma and quantitative     |
| 0503     | patients with | min.        | urine sampling 0-24 h post  |
|          | bone          |             | dose on days 1, 29, and 57  |
| (USA)    | metastases    | 4 mg, 15    | (1^st^, 2^nd^, 3^rd^        |
|          |               | min.        | infusion); blood and spot   |
|          |               |             | urine days 8, 15, 29 post   |
|          |               | 8 mg, 15    | dose.                       |
|          |               | min.        |                             |
|          |               |             |                             |
|          |               | 16 mg, 15   |                             |
|          |               | min.        |                             |
+----------+---------------+-------------+-----------------------------+
| CZOL446E | PK/PD in      | 4 mg, 15    | Plasma and quantitative     |
| 0506     | patients with | min.        | urine sampling 0-72 h post  |
|          | bone          |             | dose day 1 (1^st^ inf.),    |
| (USA and | metastases    |             | and 0-24 h post dose days   |
| Canada)  | and differing |             | 29 and 57 (2^nd^ and 3^rd^  |
|          | degrees of    |             | inf.); blood and spot urine |
|          | renal         |             | days 8, 15, 36, 43, 64, 71, |
|          | function      |             | and 85.                     |
|          |               |             |                             |
|          | ADME in       |             | ^14^C-Zometa plasma, blood, |
|          | patients with |             | and urine samples were      |
|          | normal renal  |             | obtained on days 1, 2,3, 8, |
|          | function      |             | 15, 29, 36, 43, 57, 64, 71, |
|          |               |             | and 85.                     |
+----------+---------------+-------------+-----------------------------+

The pharmacokinetics of Zometa were consistent across the three studies,
demonstrating an overall pattern similar to that of other
bisphosphonates. After initiating the infusion of Zometa, the plasma
concentrations of drug rapidly increased, achieving their peak at the
end of the infusion period, followed by a rapid, multiphasic decline to
\<1% of peak after 24 hours post end infusion. The rapid decline of
Zometa plasma concentrations is illustrated in Figure 2-1, which shows
the mean concentration data after a single 4 mg dose infused over 15
minutes, in three groups of cancer patients with normal, mild, and
moderate to severe renal impairment (study CZOL446 0506).

####### Figure 2-1. Mean Zometa plasma concentrations over 4 hours (left panel) and 24 hours (right panel)

  ---------------------------------------------------- ---------------------------------------------------
  Cartesian plot showing rapid decline of Zometa early Semi-logarithmic plot showing prolonged low
  post infusion                                        concentrations at later timepoints

  ![](media/image2.wmf){width="3.3201388888888888in"   ![](media/image3.wmf){width="2.879861111111111in"
  height="1.925in"}                                    height="1.9347222222222222in"}
  ---------------------------------------------------- ---------------------------------------------------

After the steep, about 100-fold decline in the plasma concentration
within the first 24 hours post-drug administration, which is
characterized by population half-lives of t~½α~ = 0.24 hours and t~½β~ =
1.87 hours, there was a long period of detectable Zometa in plasma
characterized by t~½γ~ = 146 hours. This pattern of early and rapid
decline in plasma drug concentration, followed by a prolonged period of
very low concentrations results from the injected drug either rapidly
binding to osseous tissue or being removed by renal excretion. The very
low Zometa concentrations in plasma at later timepoints presumably
represent the small amounts of drug continually released from bone into
the systemic circulation during the remodeling process.

The pharmacokinetics of Zometa assessed by AUC~(0-24h)~ were dose
proportional within the dose range of 2 to 16 mg. The accumulation of
Zometa following the repetitive 28-day dosing schedule was low. There
was no evidence of dose or cycle effect on accumulation properties of
Zometa over the three administrations of Zometa studied. Increasing the
infusion period from 5 minutes to 15 minutes had no statistically
significant effect on the drug exposure (area under the plasma
concentration vs. time curve), but as expected lowered the peak Zometa
concentration by about 30% (CZOL446D 0503).

Generally, between 10% to 65% of Zometa is excreted in urine within 24
hours post infusion. Based on the average (±s.d.) estimate from all 64
patients evaluated in the clinical pharmacology studies, a total of 39 ±
16% of the administered dose is excreted in the urine within 24 hours.
The remainder is retained in the body, subject to slow release from bone
governed by the rate of bone remodeling.

The renal clearance of Zometa is significantly positively correlated and
proportional to the creatinine clearance, as would be expected for this
renally excreted drug (see Figure 2-2).

####### Figure 2-2. Relationship between the renal clearance of Zometa (Clr) and creatinine clearance (CLcr) in 64 patients in 3 clinical pharmacology studies

![](media/image4.wmf)As

## 2.2. Metabolism and drug-drug interactions

Data from a study using ^14^C labeled Zometa (4 patients in CZOL446E
0506) showed that Zometa is not metabolized and is eliminated by renal
excretion.

No specific clinical drug-drug interaction studies have been conducted
with Zometa. Since Zometa is not metabolized in humans and the drug was
found to have little or no capacity as a direct acting and/or
irreversible metabolism-dependent inhibitor of P450 enzymes *in vitro*,
Zometa is unlikely to reduce the metabolic clearance of drugs of drugs
which are metabolized via the cytochrome P-450 enzyme systems.

Zometa is not highly bound to human plasma proteins (56% bound) and
binding is concentration independent. Therefore, interactions resulting
from displacement of highly protein-bound drugs are unlikely.

## 2.3. Pharmacokinetics in renal impairment

There are no relevant differences in exposure to Zometa between renally
impaired patients and patients with normal renal function (study
CZOL446E 0506), evidenced by similar concentration versus time profiles
in plasma (see Fig. 2-1), and no changes in the ratio of renal clearance
to creatinine clearance. In patients mild renal impairment, and moderate
to severe renal impairment, the AUC~(0-24h)~ was increased by 26-37%,
and 27-41%, respectively. Cmax was increased by 11-15% and 0-17%,
respectively, compared to patients with normal renal function. The
increases in AUC and Cmax were the same after the first, or after
subsequent doses (every 28 days) of Zometa. The small increase in
systemic exposure, and lack of accumulation of drug with multiple doses
irrespective of renal function, suggest that dose adjustments of Zometa
in mild (Cl~cr~=50-80mL/min) and moderate renal impairment
(Cl~cr~=30-50mL/min) are not necessary. As only limited data are
available in severe renal impairment (creatinine clearance \<30 mL/min),
no dosing recommendations are possible for this population.

# 3 Use in Hypercalcemia of Malignancy

Two identical multicenter, randomized, double-blind, double-dummy
studies of Zometa 4 mg or 8 mg given as a 5-minute intravenous infusion
or pamidronate 90 mg given as a 2-hour intravenous infusion were
conducted in 287 patients with hypercalcemia of malignancy (HCM). This
was the largest HCM clinical program ever done. In these studies, HCM
was defined as a corrected serum calcium (CSC) concentration of ≥ 12.0
mg/dL (3.00 mmol/L). The primary efficacy variable was the proportion of
patients having a complete response, defined as the lowering of the CSC
to ≤ 10.8 mg/dL (2.70 mmol/L) within 10 days after drug infusion.

## 3.1 Efficacy in HCM

The two multicenter HCM studies were combined in a pre-planned analysis
to assess the effects of Zometa versus those of pamidronate. The
proportions of patients that had normalization of corrected serum
calcium by Day 10 were 88% and 70% for Zometa 4 mg and pamidronate 90
mg, respectively (P=0.002). Median time to relapse of HCM was
significantly longer with Zometa 4 mg vs pamidronate 90 mg (30 vs 17
days P\<0.001). Thus Zometa is superior to pamidronate in the treatment
of HCM, in the normalization of serum calcium and time to relapse. These
endpoints are clinically meaningful in that more patients will recover
quickly and early relapse is less likely. In these studies, no
additional efficacy benefit was seen for Zometa 8 mg over Zometa 4 mg.

## 3.2 Safety in HCM

Adverse reactions to Zometa^®^ (Zoledronic acid for injection) in these
trials were usually mild and transient and similar to those reported for
other bisphosphonates. Intravenous administration has been most commonly
associated with fever. Occasionally, patients experience a flu-like
syndrome consisting of fever, chills, bone pain and/or arthralgias, and
myalgias. Gastrointestinal reactions such as nausea and vomiting have
been reported following intravenous infusion of Zometa. Local reactions
at the infusion site, such as redness or swelling, were observed
infrequently. In most cases, no specific treatment was required and the
symptoms subsided after 24-48 hours.

Grade 3 or 4 creatinine values were reported in 2 (2.3%), 5 (5.2%), and
4 (4.0%) of patients in the Zometa 4 mg, Zometa 8 mg, and Aredia 90 mg
groups, respectively.

# 4 Phase II Trial in treatment of bone metastases

A phase II dose ranging trial was performed. This study was a
randomized, double-blind, double dummy, parallel group trial in 280
patients aged at least 18 years with metastatic breast cancer or
multiple myeloma with at least one osteolytic lesion (confirmed on plain
film X-ray). For patients with multiple myeloma, the study eligibility
criteria specified that patients must have had a previous skeletal event
or must have experienced failure of first-line chemotherapy. All
patients had to have ECOG performance scores of 0, 1 or 2. Patients
received either 0.4 mg, 2 mg, or 4 mg Zometa administered as 5-minute
infusions, or Aredia 90 mg given as a 2-hour i.v. infusion every 3-4
weeks for 9 months.

## 5 Efficacy

The primary efficacy endpoint was the proportion of patients receiving
radiation to bone. This endpoint was selected based on data from the
pamidronate breast cancer and multiple myeloma studies. Radiation
therapy to bone was consistently affected in the pamidronate treatment
arms in these studies. This consistent efficacy effects was seen
throughout the course of these trials. The secondary parameters used in
this trial were similar to the primary and secondary endpoints
(proportion of patients with SREs, time to first SRE and rate of
SREs/time). This study is part of an overall Zometa clinical trial
program culminating in larger Phase III trials in cancer patients with
metastatic bone disease. Of the three Zometa doses evaluated here, 0.4
mg was clearly ineffective compared with Zometa at doses of 2.0 mg to
4.0 mg and pamidronate at 90 mg. Although results for the primary
efficacy criterion were similar for the 2.0- and 4.0-mg doses of Zometa,
several trends in the secondary efficacy parameters favor the 4.0-mg
Zometa dose. Skeletal events as a whole and pathologic fractures
occurred slightly less frequently in patients treated with 4.0 mg than
2.0 mg Zometa. The 4.0-mg Zometa group was the only one in which no
patient developed hypercalcemia during the 10 months of the study. Also,
time to the first skeletal event was almost 2 months longer for patients
in the 2.0-mg group. Although this trial was not designed to detect
statistically significant differences between treatment groups, these
data suggest that, assuming similar safety profiles, the 4.0-mg dose was
the better choice for confirmatory Phase III trials.

  -------------------- ------------- ------------ ------------ -----------
                                                               

                                                               

                                                               

                                                               
  -------------------- ------------- ------------ ------------ -----------

## 6 Safety

The nature and frequency of commonly reported adverse events (≥15% of
patients) were similar for the Zometa and Aredia treatment groups. The
incidence of renal adverse events was low and was similar for the Zometa
and Aredia treatment groups. The percentage of patients experiencing
injection site reactions with the 5-minute Zometa infusion was slightly
lower than that with that 2-hour Aredia infusion. The overall reporting
of eye-related adverse events was low (12.5%) and was similar in all the
treatment groups. Conjunctivitis occurred more frequently in the Aredia
and Zometa 0.4 mg groups than in the Zometa 2.0 and 4.0 mg groups. The
incidence of hypocalcemia and other metabolic or electrolyte
abnormalities was low and similar in the treatment groups.

# 7 Phase III Trials 

## 8 Study Design

Three pivotal phase III Zometa trials (2 placebo- and 1
pamidronate-controlled) were performed (Table 5-1). The primary analysis
for these trials was the proportion of patients having at least one
skeletal-related event (SRE). This trial design has been shown to be
effective in the phase III Aredia development program. Secondary
analyses of the primary SRE endpoint included time to first SRE,
skeletal morbidity rate (SMR, the number of events divided by the time
on trial), and multiple event analysis of time to each SRE
(Anderson-Gill). Both the proportion of patients having at least one SRE
and the time to first SRE are conservative endpoints which only take
into account the information of the first event. The SMR and
Anderson-Gill analyses also utilize information on subsequent events, in
cases where patients had more than one event over the course of their
study participation, and thus help to evaluate the longer-term effects
of treatment with the study drug.

###### 

###### Table 5-1. Overview of Phase III studies

  --------------------------------------------------------------------------------
  Study\   No. of\    Treatment   Zometa*\    Control     Patient population
  No.      Patients   Duration    *dose                   
  -------- ---------- ----------- ----------- ----------- ------------------------
  010      1648       13 months   4 and 8\*   Aredia 90   Multiple myeloma or
                                  mg Q3 -     mg Q3 - 4   metastatic breast cancer
                                  4weeks      weeks       

  039      643        15 months   4 and 8\*   Placebo     Metastatic prostate
                                  mg Q3 weeks             cancer

  011      773        9 months    4 and 8\*   Placebo     Metastatic solid tumor
                                  mg Q3 weeks             other than breast or
                                                          prostate cancer
  --------------------------------------------------------------------------------

\*All patients on 8 mg Zometa were switched to 4 mg following a protocol
amendment

The different study durations were based both on the skeletal related
event analysis of previous pamidronate trials and the estimated survival
of the cancer population being investigated.

#### Study Histories

In the original pivotal study protocols, patients were to be randomized
to either of two Zometa doses, 4 mg or 8 mg, administered as 5-minute
i.v. infusions. Following a protocol amendment issued in June 1999 by
Novartis, the infusion time was increased to 15 minutes, and the volume
increased from 50 mL to 100 mL. Following protocol amendments issued in
June 2000, all patients on 8 mg were switched to 4 mg, and monitoring of
serum creatinine was initiated. These latter amendments were made on the
suggestion of a Data Safety Monitoring Board (DSMB) and Renal Advisory
Board (RAB) appointed to monitor overall and renal safety. Throughout
this document, any treatment group that was originally assigned to
treatment with 8 mg Zometa but later was switched to 4 mg following the
protocol amendments is referred to as an 8/4 mg group.

Due to the higher incidence of renal adverse events observed in the
Zometa 8 mg group at the time of the amendment (reduce 8 mg to 4 mg) and
the inhomogeneity of the treatment duration in the Zometa 8/4 mg group,
Novartis made the decision that the Zometa 8/4 mg will not be part of
the application for the indication as documented in the amendment.
However, analysis results of the Zometa 8/4 mg will be included in the
presentation for the completeness of the study results.

#### Entry Criteria

Entry criteria were generally similar across the 3 trials, except for
tumor-specific considerations.

#### Aredia- controlled trial

Study 010 was a randomized, double-blind, double-dummy, multicenter,
parallel-group Phase III study in 1648 patients. Patients had multiple
myeloma with at least one osteolytic bone lesion or breast cancer with
at least one bone metastasis, and were receiving anti-cancer therapy.
Breast cancer patients receiving hormonal therapy had to be using first-
or second-line hormonal therapy. Patients had an ECOG performance status
of 0, 1, or 2, and no significant hepatic, renal or cardiac impairment,
hypercalcemia, brain metastases, or lymphangitic lung metastases (breast
cancer patients).

#### Placebo-controlled trials

Study 039 was a randomized, double-blind, multicenter, parallel-group,
placebo-controlled, Phase III study in 643 patients with bone metastases
due to prostate cancer. Patients had biochemical evidence (rising serum
PSA concentration) of disease progression despite hormonal therapy, and
an ECOG performance status of 0, 1 or 2. Patients who had received, or
were receiving, cytotoxic chemotherapy, or who had radiation therapy
within 3 months prior to entry were excluded, as were those who had bone
pain requiring strong narcotics. Patients with hypercalcemia,
significant renal or cardiac impairment, or a history of other cancers
within the previous 5 years were also excluded.

Study 011 was a randomized, double-blind, multicenter, parallel-group,
placebo-controlled, Phase III study in 773 patients with bone metastases
from solid tumors other than breast or prostate cancers. Patients had to
have ECOG scores of 0, 1 or 2; those with ECOG scores of 2 had to have
bone metastases diagnosed within 6 weeks of study entry. Patients were
excluded for significant hepatic, renal or cardiac impairment,
hypercalcemia, or symptomatic brain metastases.

#### Randomization Procedures: treatment assignments and blinding

Randomization procedures were the same for all three double-blind
trials. The pharmacist, who was the only unblinded person during the
studies, was provided with allocation cards linking the randomization
number with the treatment group and was responsible for maintaining the
blind at each center. Emergency drug codes were also supplied to the
investigator and kept on file at Novartis in Clinical Safety and
Epidemiology (CS&E). The randomization scheme was performed by Novartis
Drug Supply management using a validated system that automates the
random assignment of treatment groups to randomization numbers. The
randomization scheme was then reviewed by Quality Management
Biostatistics and locked by them after approval.

In the placebo-controlled trials, patients were randomized to treatment
with Zometa 4 mg, Zometa 8 mg, or placebo every 3 weeks for 15 months in
the prostate cancer study and 9 months in the study of other solid
tumors. Following a protocol amendment (dated June 24 and 25, 1999 for
039 and 011, respectively), the infusion time was increased from 5 to 15
minutes and infusate volume increased from 50 to 100 mL. In another
protocol amendment (dated June 7, 2000), all patients on 8 mg Zometa
were switched to 4 mg and creatinine monitoring was instituted.

In the prostate cancer study, patients were stratified into two groups:
patients with no metastatic disease present at the time of the
[initial]{.underline} diagnosis of prostate cancer (TMN stage MX or MO)
and patients with metastatic disease present at initial diagnosis (stage
D2 disease or TMN Stage M1). Per protocol, all patients had bone
metastases at study entry. In the study of other solid tumors, patients
were also stratified into two groups: patients with lung cancer and
patients with all other cancers.

In the study in patients with breast cancer or multiple myeloma,
patients were randomized to Zometa 4 mg, Zometa 8 mg or Aredia 90 mg
every 3-4 weeks for 12 months. Following a protocol amendment dated June
25, 1999, the infusion time for Zometa or matching double-dummy placebo
was increased from 5 to 15 minutes and infusate volume was increased
from 50 to 100 mL. To maintain blinding, Zometa was infused in a total
volume of 100 mL, followed by 250 mL of normal saline given over 2
hours. Aredia was administered as a 2-hour i.v. infusion in a total
volume of 250 mL, preceded by a 100 mL 15-minute normal saline infusion.
Following a protocol amendment dated June 7, 2000, all patients on 8 mg
Zometa were switched to 4 mg and creatinine monitoring was instituted.
Patients were stratified into three groups: Stage III multiple myeloma
patients, Stage IV breast cancer patients receiving chemotherapy with or
without combination hormonal therapy, and Stage IV breast cancer
patients receiving first-line or second-line hormonal therapy for
metastatic disease at the time of randomization.

Treatment Administration: Study Drug

Zometa was packaged in open-label fashion and shipped to the pharmacist
at each center. Medication labels complied with the legal requirements
of each country and printed in the local language. Zometa was supplied
in 4mg lyophilized vials. The pharmacist was responsible for the
preparation of study drug. Zometa 4 or 8 mg was given in 100 mL of
normal saline and administered by intravenous infusion.

Efficacy Endpoints and Statistical Analysis

All efficacy analyses reported here were performed on intent-to-treat
(ITT) populations. The three pivotal studies utilized a common primary
efficacy endpoint, the proportion of patients with at least one
skeletal-related event (SRE), which had been demonstrated to be a
relevant parameter in the phase III Aredia trials. These studies also
shared most secondary efficacy parameters.

###### Table 5-2. Efficacy parameters used in Phase III studies

+---------------------+------------------------------------------------+
| **Primary**         | **Major Secondary**                            |
+---------------------+------------------------------------------------+
| Proportion of       | *Skeletal*: Proportion of patients having at   |
| patients having at  | least one SRE including HCM, time to first     |
| least one SRE       | SRE, SMR, proportion of patients with each     |
| (exclusive of HCM)  | SRE, bone biochemical markers^1^, bone mineral |
|                     | density^2^                                     |
|                     |                                                |
|                     | *Quality of Life*: Changes from baseline in    |
|                     | pain score (BPI), analgesic score, ECOG        |
|                     | performance score, quality of life (FACT-G and |
|                     | EURO QOL-5D^3^)                                |
|                     |                                                |
|                     | *Cancer*: Time to progression of bone lesions, |
|                     | time to progression of disease, best response  |
|                     | of bone lesions                                |
+---------------------+------------------------------------------------+
| SRE:                |                                                |
| skeletal-related    |                                                |
| events; SMR:        |                                                |
| skeletal morbidity  |                                                |
| rate; BPI: basic    |                                                |
| pain inventory      |                                                |
| composite score\    |                                                |
| ^1^ In breast       |                                                |
| cancer/multiple     |                                                |
| myeloma study, some |                                                |
| biochemical markers |                                                |
| were only evaluated |                                                |
| in selected         |                                                |
| US/Canadian centers |                                                |
|                     |                                                |
| ^2^ In prostate     |                                                |
| cancer study and    |                                                |
| selected            |                                                |
| US/Canadian centers |                                                |
| in breast           |                                                |
| cancer/multiple     |                                                |
| myeloma study only\ |                                                |
| ^3^ In prostate     |                                                |
| cancer study only   |                                                |
+---------------------+------------------------------------------------+

*Skeletal related events (SREs)* were defined as follows:

*Radiation therapy to bone* including irradiation of bone to palliate
painful lesions, to treat or prevent a pathologic fracture, to treat or
prevent a spinal cord compression, and the use of i.v. strontium-89 (or
other radioisotopes) to treat metastatic bone pain.

*Surgery to bone***,** including surgical procedures performed to set or
stabilize pathologic fractures or areas of spinal cord compression, or
to prevent an imminent pathologic bone fracture or spinal cord
compression.

*Pathologic bone fractures* were defined as bone fractures (vertebral
and non-vertebral) which occurred spontaneously or resulted from trivial
trauma and documented via radiographs. Each pathologic fracture was to
be documented by a plain X-ray film. A new vertebral compression
fracture was defined as a decrease in total, anterior or posterior
vertebral height of ≥ 25% from baseline. Vertebral compression fractures
and non-vertebral fractures were evaluated by a central radiologist who
was not aware of the treatment regimens.

*Spinal cord compression* occurs due to impingement of tumor on the
spinal cord, and is associated with neurologic impairment or back pain.
If spinal cord compression was associated with one or more vertebral
compression fractures, each fracture was recorded as an SRE, in addition
to the spinal cord compression itself.

*Change of antineoplastic therapy* to treat bone pain included any
change of anticancer agents (to a different hormonal regimen or to a
cytotoxic chemotherapy regimen) to palliate bone pain. This was only
included as an SRE in the study in prostate cancer patients where
changes in antineoplastic therapy maybe more commonly used to achieve
bone pain relief. An alteration of analgesic medication for bone pain
was captured as an analgesic score and was not recorded as an SRE in any
study.

*Hypercalcemia of malignancy (HCM)* also termed tumor-induced
hypercalcemia (TIH), was included as an SRE for some secondary efficacy
analyses. HCM/TIH was defined as a corrected serum calcium level of ≥
3.00 mmol/L (12.0 mg/dL) or a lower level of hypercalcemia which was
symptomatic and required active treatment other than rehydration.

**Other skeletal assessments** **(data not shown):**

*Biochemical markers of bone resorption and formation* were measured by
a central laboratory (Mayo Medical Laboratories) in the pivotal studies
(in study 010, US/Canadian centers only):

-   Urinary N-telopeptide/creatinine ratio

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-   Urinary pyridinoline/creatinine ratio

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-   Urinary deoxypyridinoline/creatinine ratio

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-   Serum bone alkaline phosphatase

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-   Serum PTH

*Bone mineral density (BMD)* was determined in studies 010 (breast
cancer and multiple myeloma patients) and 039 (prostate cancer patients)
by dual-energy X-ray absorptiometry (DEXA). Scanning sites were the AP
lumbar spine (L2-L4), the proximal femur (neck, trochanteric region and
Ward's triangle) and the non-dominant forearm. Total body bone mineral
density was also calculated.

#### Analysis of primary endpoint and other skeletal endpoints

A placebo group was not utilized in the breast/multiple myeloma study,
since Aredia has previously been shown to significantly delay or reduce
the incidence of skeletal-related morbid events in these patients. If
Zometa and Aredia were equal in effectiveness, statistical power
calculations indicated that the planned study enrollment (1600 patients)
would have had power to exclude an 8% or greater inferiority for Zometa
in the proportion of patients experiencing an SRE (the primary study
endpoint), compared with anticipated beneficial treatment effect of
13.5% for Aredia (based on historical data). The study results revealed
a small difference in the proportion of patients experiencing an SRE,
favoring Zometa 4 mg, and the lower confidence bound for this comparison
with Aredia was 3.9% (indicating that Zometa was at least within 3.9% of
the effectiveness seen with Aredia as measured by this statistic). For
the placebo-controlled studies (prostate cancer; solid tumors other than
breast/prostate), the proportion of patients with at least one SRE was
compared between groups using a Cochran-Mantel-Haenszel (CMH) test.

The proportion of patients having any SRE (including HCM) and the
proportion of patients having each individual type of SRE were analyzed
as described above for the primary variable.

Time to first SRE was compared between treatment groups using survival
analysis, including Kaplan-Meier product-limit estimates of the
'survival functions', the log-rank test, and Cox regression stratified
by the stratum. The Anderson-Gill approach was used to analyze the time
from randomization to each occurrence of the events (multiple event
analysis). The information of each patient from the study entry to the
end of the follow-up was fully utilized in the Anderson-Gill approach to
estimate the rate of recurrence over the course of the study and the
test was aimed in detecting whether one group of study subjects had a
higher recurrence rate than the other group. The difference between the
time to the first event analysis and the Anderson-Gill approach is that
the former ignores the information after the occurrence of the first
event (the number of events and the time when each of these recurrent
events occurs) and the latter utilizes the information ignored by the
former.

The SMR was defined as the number of SREs divided by the time at risk in
years, counted from the randomization date with every counted event
followed by a 20-day period during which no SRE experienced by the
patient would be counted, nor the time be counted as at risk. This was a
more conservative approach than was used in the phase III Aredia
program, where all events were counted. If a patient had no SRE, the
whole study period was counted as at risk. The SMRs were compared
between treatment groups using a CMH test.

The same definition in counting the number of events and the time at
risk as defined in SMR was used in the Anderson-Gill approach. In the
case where patients did not experience any SRE, the SMR analysis made no
distinction for the length of follow up of each patient (i.e. SMR had a
value of 0) while the Anderson-Gill approach takes this into account of
the length of the follow-up.

#### Analysis of Quality of Life parameters

*Pain* was measured by the Brief Pain Inventory (BPI) composite score,
which was derived from items 3 to 6 from the BPI. Changes from baseline
in BPI composite score were compared between treatment groups using
analysis of covariance (ANCOVA) with baseline value as a covariate and
stratum and treatment group as factors at 3, 6, 9, etc. months.

*Analgesic score* captured the use of pain medication in a five-point
ordinal scale ranging from 0 (no analgesics used) to 4 (strong
narcotics, e.g. morphine or hydromorphone, used). Change from baseline
in analgesic score was compared between treatment groups using the
stratified Cochran-Mantel-Haenszel test with modified ridit scores at 3,
6, 9 etc., months. Within-treatment differences from baseline were
analyzed using the Wilcoxon signed-rank test.

*ECOG performance scores* measured performance on a five-point ordinal
scale from 0 (fully active and able to carry out all pre-disease
performance without restriction to 4 (completely disabled, cannot carry
on any self care and totally confined to bed or chair).Changes from
baseline in performance status were compared between treatment groups
using the stratified Cochran-Mantel-Haenszel test with modified ridit
scores at 3, 6, 9, etc., months. Within-treatment differences from
baseline were analyzed using the Wilcoxon signed-rank test.

Two *quality of life* instruments were used: FACT-G (in all three
studies) and EURO QOL EQ-5D (in the prostate cancer study only). FACT-G
(version 4) uses a questionnaire with four subscales: physical
well-being, social/family well-being, emotional well-being and
functional well-being. The sum of these provides the total score. EURO
QOL EQ-5D uses a questionnaire with 6 dimensions: mobility, self-care,
usual activities, pain/discomfort, anxiety/depression, and overall
health state. Changes from baseline in FACT-G total scores and the four
subscales were analyzed using ANCOVA with baseline value as covariate
and disease as a factor. Changes in EURO QOL scores were analyzed as for
FACT-G.

#### Analysis of Other Disease Parameters

*Progression of bone lesions* was defined in the protocols as the
appearance of new osteolytic or osteoblastic lesions, and/or a
significant increase in the size of one or more existing osteolytic or
osteoblastic lesions. For 'measurable' lesions (those with greatest
diameter \>2 cm), progression was defined as an increase of \>25% in the
lytic or blastic area as measured by the product of the greatest
diameter and the diameter perpendicular to the greatest diameter. For
'evaluable' lesions (defined as those with \<2 cm greatest diameter),
progression was defined as a linear increase of 1 cm or more in the
unidimensional measurement. Time to progression of disease was compared
between the treatment groups using survival analysis methods, including
Kaplan-Meier product-limit estimates of the 'survival functions', the
log-rank test, and Cox regression stratified by the stratum.

Time to progression of disease was analyzed using the same method used
for time to progression of bone lesions.

*Objective response of bone lesions*, on the basis of radiologic
evidence, was determined as follows:

-   *Complete response*, i.e. resolution of all osteoblastic lesions and
    complete recalcification of all osteolytic lesions.

-   *Partial response*, i.e. resolution of some but not all osteoblastic
    lesions or decreased size of one or more osteoblastic lesions (for
    'measurable' lesions a decrease of ≥ 50% in blastic area, for
    'evaluable' lesions a decrease of ≥ 30% of the unidimensional
    measurement) or at least partial recalcification of one or more
    osteolytic lesions and no appearance of new osteolytic or
    osteoblastic lesions or progression of existing osteolytic or
    osteoblastic lesions.

-   *No change*, i.e. no change in number or size of osteoblastic
    lesion, no evidence of recalcification of, or change in number or
    size of, osteolytic lesions.

-   *Progressive disease*, defined as above in the description of time
    to progression of bone lesions.

-   *Not evaluable*.

The best response of objective bone lesion response was summarized by
treatment group.

All skeletal X-rays and bone scans from the patients in the three
pivotal trials were read by a central radiologist who was blinded to the
patient's treatment assignment.

#### Sample Size and Power Considerations

*Aredia-controlled trial*

A placebo group was not utilized in this study, since Aredia has
previously been shown to significantly delay or reduce the incidence of
skeletal-related morbid events in these patients. If Zometa and Aredia
were equal in effectiveness, statistical power calculations indicated
that the planned study enrollment (1600 patients) would have had power
to exclude an 8% or greater inferiority for Zometa in the proportion of
patients experiencing an SRE (the primary study endpoint), compared with
anticipated beneficial treatment effect of 13.5% for Aredia (based on
historical data). The study results revealed a small difference in the
proportion of patients experiencing an SRE, favoring Zometa 4 mg, and
the lower confidence bound for this comparison with Aredia was 3.7%
(indicating that Zometa was at least within 3.7% of the effectiveness
seen with Aredia as measured by this statistic).

*Placebo controlled trials*

The studies in lung cancer or other solid tumors and in prostate cancer
were designed to have 80% power which allowed to detect a 14% and a 16%
difference in the proportion of patients reporting any "skeletal-related
episode" (during the first nine and the first fifteen months of
treatment) between the two Zometa dose levels (4-mg and 8-mg) and
placebo, respectively. The sample size for both protocols were
calculated using the Bonferroni's adjustment formula.

For the prostate cancer study, based on the Bonferroni's adjustment, the
sample size calculation assumed a 40% incidence rate on placebo
treatment; a 24% incidence rate on either dose level of Zometa, with an
overall Type I error rate of 0.05 (two-sided). The total sample size was
determined to be 519 patients (173 on each arm). It was recommended that
550 patients be enrolled to allow for 5% noise due to the inclusion of
the intent-to-treat patient population.

For the lung cancer and other solid tumors study, the sample size was
calculated, assuming a 38% incidence rate on placebo; a 24% incidence
rate on either dose level of Zometa, with an overall Type I error rate
of 0.05 (two-sided). The total sample size was determined to be 663
patients (221 on each arm). Therefore, it was recommended that 700
patients be enrolled in order to allow for the 5% noise from the
inclusion of the intent-to-treat patient population.

To determine the final patient accrual number, patient drop-out and SRE
rates were monitored on an ongoing basis using blinded data. In the
study in lung cancer and other solid tumors, there was a higher than
expected drop-out rate (40%) and a lower than expected SRE rate (\<30%)
in the first 400 randomized patients. Therefore, there was a need to
increase the sample size to achieve the established 80% power. Amendment
4, effective 16-Feb-2000, increased the sample size from 600 to 700
patients. There was no need to increase the sample size in the prostate
cancer study.

## 9 Breast cancer and multiple myeloma -- Aredia-controlled trial (010)

### 10 Patient disposition

A total of 1648 patients were randomized between 16-October-1998 and
18-December-1999 at 248 centers in 20 countries including centers in
North and South America, Europe, South Africa, the Middle East, and
Australia and New Zealand. The intent-to-treat (ITT) population excluded
eight patients from one center because of GCP/ICH violations.

###### Table 5-3. Patient disposition by treatment group, Aredia-controlled trial

  -------------------------------- ------------ ------------ ------------
  **\                              **Zometa 4   **Zometa 8/4 **Aredia 90
  Number of patients**             mg\          mg\          mg\
                                   N = 564**    N = 526**    N = 558**

  Randomized\                      564\         526\         558\
  Included in efficacy analysis    561          524          555
  (ITT)                                                      

  Multiple myeloma                 183 (32.4%)  160 (30.4%)  167 (29.9%)

  Breast cancer with chemotherapy  178 (31.6%)  172 (32.7%)  181 (32.4%)

  Breast cancer with hormonal      200 (35.5%)  192 (36.5%)  207 (37.1%)
  therapy                                                    

  Completed 12 months              353 (62.9%)  313 (59.7%)  337 (60.7%)

  Discontinued prematurely from    208 (37.1%)  211 (40.3%)  218 (39.3%)
  ITT n (%)                                                  

  Adverse events                   57 (10.2%)   70 (13.4%)   51 (9.2%)

  Abnormal laboratory values       6 (1.1%)     3 (0.6%)     4 (0.7%)

  Abnormal test procedure results  0 (0.0%)     2 (0.4%)     2 (0.4%)

  Unsatisfactory therapeutic       18 (3.2%)    18 (3.4%)    22 (4.0%)
  effect                                                     

  Condition no longer requires     6 (1.1%)     7 (1.3%)     8 (1.4%)
  study drug                                                 

  Protocol violation               6 (1.1%)     4 (0.8%)     4 (0.7%)

  Withdrew consent                 47 (8.4%)    45 (8.6%)    56 (10.1%)

  Lost to follow-up                3 (0.5%)     4 (0.8%)     3 (0.5%)

  Administrative problems          5 (0.9%)     2 (0.4%)     4 (0.7%)

  Death                            60 (10.7%)   56 (10.7%)   64 (11.5%)
  -------------------------------- ------------ ------------ ------------

### 11 Demographics and disease characteristics

The majority of patients in all treatment groups in the breast
cancer/multiple myeloma study were female and Caucasian, with a mean age
of 59 to 60 years (see Table 5-4 below).

###### Table 5-4. Baseline demographic characteristics -- Aredia-controlled trial -- ITT population

+--------------------+---------------+---------------+---------------+
|                    | **Zometa 4    | **Zometa 8/4  | **Aredia 90   |
|                    | mg**          | mg**          | mg**          |
|                    |               |               |               |
|                    | **N=561**     | **N=524**     | **N=555**     |
+====================+===============+===============+===============+
| Age (years)        |               |               |               |
+--------------------+---------------+---------------+---------------+
| Mean ± SD          | 59.7 ± 12.00  | 58.9 ± 12.32  | 58.7 ± 12.66  |
+--------------------+---------------+---------------+---------------+
| Sex -- n (%)       |               |               |               |
+--------------------+---------------+---------------+---------------+
| Male               | 104 (18.5)    | 96 (18.3)     | 92 (16.6)     |
+--------------------+---------------+---------------+---------------+
| Female             | 457 (81.5)    | 428 (81.7)    | 463 (83.4)    |
+--------------------+---------------+---------------+---------------+
| Race -- n (%)      |               |               |               |
+--------------------+---------------+---------------+---------------+
| Caucasian          | 493 (87.9)    | 443 (84.5)    | 484 (87.2)    |
+--------------------+---------------+---------------+---------------+
| Black              | 34 (6.1)      | 42 (8.0)      | 43 (7.7)      |
+--------------------+---------------+---------------+---------------+
| Other              | 34 (6.1)      | 39 (7.4)      | 28 (5.0)      |
+--------------------+---------------+---------------+---------------+
| Weight (kg)        |               |               |               |
+--------------------+---------------+---------------+---------------+
| N                  | 536           | 504           | 538           |
+--------------------+---------------+---------------+---------------+
| Mean ± SD          | 72.7 ± 16.43  | 72.9 ± 16.20  | 73.5 ± 16.43  |
+--------------------+---------------+---------------+---------------+
| Median             | 70.2          | 70.7          | 72.0          |
+--------------------+---------------+---------------+---------------+
| ECOG performance   |               |               |               |
| status - n (%)     |               |               |               |
+--------------------+---------------+---------------+---------------+
| ECOG 0-1           | 474 (84.5)    | 428 (81.7)    | 436 (78.6)    |
+--------------------+---------------+---------------+---------------+
| ECOG 2             | 86 (15.3)     | 95 (18.1)     | 116 (20.9)    |
+--------------------+---------------+---------------+---------------+
| Missing            | 1 (0.2)       | 1 (0.2)       | 3 (0.5)       |
+--------------------+---------------+---------------+---------------+

Other baseline characteristics are presented by tumor type (multiple
myeloma or breast cancer patients) in the tables below.

###### Table 5-5. Baseline disease characteristics of multiple myeloma patients

+-----------------------------+------------+------------+------------+
|                             | **Zometa 4 | **Zometa   | **Aredia   |
|                             | mg**       | 8/4 mg**   | 90 mg**    |
+-----------------------------+------------+------------+------------+
| Disease characteristic      | **N=186**  | **N=160**  | **N=167**  |
+-----------------------------+------------+------------+------------+
| Previous SRE                |            |            |            |
+-----------------------------+------------+------------+------------+
| Yes                         | 150        | 130        | 136        |
|                             | (80.6%)    | (81.3%)    | (81.4%)    |
+-----------------------------+------------+------------+------------+
| Time from initial cancer    | 18.3 ±     | 13.6 ±     | 17.3 ±     |
| diagnosis to Visit 2        | 32.28      | 22.30      | 28.54      |
| (months, mean ± SD)\*       |            |            |            |
|                             |            |            |            |
| Visit 2 (months, median ±   |            |            |            |
| SD)\*                       |            |            |            |
+-----------------------------+------------+------------+------------+
| Baseline serum creatinine   |            |            |            |
+-----------------------------+------------+------------+------------+
| Normal (\<1.4 mg/dL)        | 147        | 127        | 145        |
|                             | (79.0%)    | (79.4%)    | (86.8%)    |
+-----------------------------+------------+------------+------------+
| Abnormal (≥1.4 mg/dL)       | 36 (19.4%) | 32 (20.0%) | 22 (13.2%) |
+-----------------------------+------------+------------+------------+
| Missing                     | 3 (1.6%)   | 1 (0.6%)   | 0 (0.0%)   |
+-----------------------------+------------+------------+------------+

\* 28 days in a month.

###### Table 5-6. Baseline disease characteristics of breast cancer patients

  -------------------------- -------------- -------------- --------------
                             **Zometa 4     **Zometa 8/4   **Aredia 90
                             mg**           mg**           mg**

                             **N=377**      **N=364**      **N=389**

  First-line anti-neoplastic 161 (42.7%)    180 (49.5%)    182 (46.8%)
  therapy                                                  

  Previous SRE               232 (61.5%)    207 (56.9%)    244 (62.7%)

  Site of metastases:                                      

  Bone                       377 (100%)     364 (100%)     389 (100%)

  Liver                      82 (21.8%)     69 (19.0%)     97 (24.9%)

  Lung                       69 (18.3%)     81 (22.3%)     80 (20.6%)

  Brain                      6 (1.6%)       5 (1.4%)       9 (2.3%)

  \` Other                   82 (21.8%)     76 (20.9%)     97 (24.9%)

  Time from initial cancer   78.6 ± 67.19   79.1± 74.89    71.9 ± 63.69
  diagnosis to Visit 2                                     
  (months, mean ± SD)\*                                    

  Time from initial cancer   57.0 ± 57.40   60.4± 65.83    54.4 ± 57.73
  diagnosis to 1st                                         
  metastasis (months, mean                                 
  ±SD)\*\*                                                 

  Time from 1st bone         17.5 ± 33.85   14.1± 22.87    12.6 ± 21.68
  metastasis to Visit 2                                    
  (months, mean ±SD)\*                                     

  Baseline serum creatinine                                

  Normal (\<1.4 mg/dL)       364 (96.6%)    348 (95.6%)    369 (94.9%)

  Abnormal (≥1.4 mg/dL)      11 (2.9%)      11 (3.0%)      15(3.9%)

  Missing                    2 (0.5%)       5 (1.4%)       5 (1.3%)
  -------------------------- -------------- -------------- --------------

\* 28 days in a month\
\*\* Time from initial diagnosis of cancer to bone metastases or 1st
metastatic disease is assigned to 0 when metastatic disease occurred
before initial cancer diagnosis.

### Primary efficacy analysis

The primary efficacy analysis in this study was aimed to demonstrate
non-inferiority of the selected Zometa doses to 90 mg Aredia in the
proportion of patients with SREs (where hypercalcemia would not be
considered an SRE). The non-inferiority margin was prospectively defined
as 8%. This criterion was met by both the Zometa groups (Table 5-7
below). This table shows that the lower bound was 3.7% for the 4 mg
group, and 5.8% for the 8/4 group, indicating that the predefined
non-inferiority criteria were substantially exceeded. In the analysis of
proportion of patients with SREs including hypercalcemia, a similar
result was seen.

###### Table 5-7. Proportion of patients with SREs, multiple myeloma and breast cancer

  ------------- ---------------- --------------------- ---------------------
                                 **95% C.I.** **for    
                                 the difference**      

                **Proportion**   **Zometa 4 mg**       **Zometa 8/4 mg**

  Excluding TIH                                        

  Aredia 90 mg  257/555 (46%)    (-7.9%, 3.7%)         (-6.1%, 5.8%)

  Zometa 4 mg   248/561 (44%)    \-                    (-3.9%, 7.9%)

  Zometa 8/4 mg 242/524 (46%)    \-                    \-
  ------------- ---------------- --------------------- ---------------------

### 5.2.4 Secondary skeletal endpoints analyses

#### Proportion of patients with each type of SRE

The proportion of patients receiving radiation therapy to bone was
significantly lower for patients in the Zometa 4 mg group than for
patients in the Aredia 90 mg group (p=0.031).

The proportion of patients with a pathological fracture, vertebral or
non-vertebral, was comparable for all treatment groups. Spinal cord
compression, surgery to bone, and hypercalcemia (not shown) occurred for
a small and comparable percentage of patients in each treatment group.

####### Figure 5-1 Individual SREs in breast/myeloma patients

![](media/image5.wmf)

#### Time to first skeletal-related event

The median time to the first occurrence of a SRE and the event rate at
day 364 was similar for patients in all treatment groups (see Table 5-8
below). The upper limit of the 95% CI for the hazard ratio for the 4 mg
group is 1.090, with the hazard ratio of 0.915, indicates that Zometa 4
mg is likely to influence the time to first SRE at least as strongly as
Aredia.

###### Table 5-8. Time to the first SRE up to Month 13 (Median and hazard ratio), multiple myeloma and breast cancer

+------------+-----+-------+-------+-----------+-------+-------------+
|            |     |       | **Z   |           | **Z   |             |
|            |     |       | ometa |           | ometa |             |
|            |     |       | 4 mg  |           | 8/4   |             |
|            |     |       | v     |           | mg    |             |
|            |     |       | .s.** |           | v     |             |
|            |     |       |       |           | .s.** |             |
+------------+-----+-------+-------+-----------+-------+-------------+
|            | **  | **Me  | **H   | **95% CI  | **H   | **95% CI    |
|            | N** | dian\ | azard | for       | azard | for Hazard  |
|            |     | (da   | rati  | Hazard    | rati  | ratio**     |
|            |     | ys)** | o\*** | ratio**   | o\*** |             |
+------------+-----+-------+-------+-----------+-------+-------------+
| > Aredia   | 555 | 363   | 0.915 | (0.786,   | 0.994 | (0.834,     |
| > 90 mg    |     |       |       | 1.090)    |       | 1.185)      |
+------------+-----+-------+-------+-----------+-------+-------------+
| > Zometa 4 | 561 | 373   | \-    | \-        | 1.087 | (0.910,     |
| > mg       |     |       |       |           |       | 1.299)      |
+------------+-----+-------+-------+-----------+-------+-------------+
| > Zometa   | 524 | 353   | \-    | \-        | \-    | \-          |
| > 8/4 mg   |     |       |       |           |       |             |
+------------+-----+-------+-------+-----------+-------+-------------+

\* Hazard ratio is the ratio of column versus row. The hazard ratio and
the 95% C.I. are from Cox-regression for the pairwise comparison of the
time to the first event.

B. Time to the first SRE up to Month 13, multiple myeloma and breast
cancer

  ------------ ---- --------- ---------- -------- ------------ ------------
                                                               

                                                               

                                                               

                                                               

                                                               
  ------------ ---- --------- ---------- -------- ------------ ------------

#### 

#### Skeletal morbidity rate

The mean SMR of all SREs up to Month 13 was lower for patients in the
Zometa 4 mg and Zometa 8/4 mg groups than in the Aredia 90 mg group, but
the differences were not statistically significant.

####### Figure 5.2 Mean skeletal morbidity rate by treatment group 

![](media/image6.wmf)

Multiple event analysis of all SREs

The analysis results of multiple events analysis of all SRE (-HCM),
using Anderson and Gill's approach, showed that there was a trend toward
statistical significance (p=0.155), favoring Zometa 4 mg over Aredia 90
mg

The difference seen between the SMR analysis and the multiple event
analysis was partially due to patients experiencing no events during the
study. In the case of the SMR analysis, all patients contributed equal
information regardless of a patient's duration in the study, whereas the
multiple event analysis took into account the length of stay in the
study.

###### Table 5-9. Multiple-event analysis of time to SRE up to Month 13, multiple myeloma and breast cancer (010)

  ------------- ----------- ------------- ------------- -- ----------- ------------- -------------
                **Zometa 4                                 **Zometa                  
                mg v.s.**                                  8/4 mg                    
                                                           v.s.**                    

                **Hazard    **95% CI for  **P-value**      **Hazard    **95% CI for  **P-value**
                ratio\***   Hazard                         ratio\***   Hazard        
                            ratio**                                    ratio**       

  Aredia 90 mg  0.885       (0.748,       0.155            0.910       (0.768,       0.277
                            1.047)                                     1.079)        

  Zometa 4 mg                                              1.025       (0.863,       0.775
                                                                       1.218)        
  ------------- ----------- ------------- ------------- -- ----------- ------------- -------------

\* Hazard ratio is the ratio of column versus row. Hazard ratios and
p-values are from Anderson-Gill approach for time to multiple events

P-value and the 95% C.I. are computed using the robust variance estimate

### 5.2.5 Analysis of Other Endpoints

### 

### Pain

The change from baseline in mean BPI was compared between treatment
groups at Months 3, 6, 9 and 13. The composite pain score was decreased
for all treatment groups at each analysis time point. The mean change
from baseline in BPI composite pain scores was comparable between the
treatment groups at Month 13, regardless of whether the patient had pain
at baseline or not. For the patient population as a whole and for the
patients with pain at baseline, the BPI score decreased slightly over
the period of the trial, in spite of the fact that many patients
experienced progressive disease.

Analgesics

Analgesic scores ranged from 0 to 4, higher scores indicate that
stronger analgesics were used. The mean change from baseline in
analgesic score decreased at Month 3 and remained lower up to Month 13
for the three treatment groups. There was no statistically significant
difference between any treatment groups in the change from baseline in
analgesic score.

ECOG performance status

The mean change from baseline in ECOG score increased from baseline to
Month 13 for all three treatment groups. There was no statistically
significant difference between any treatment groups in the change from
baseline in ECOG score. However, the within treatment change from
baseline in ECOG score was statistically significant in all treatment
groups.

Quality of Life (FACT-G)

The FACT-G total score is the sum of four subscales, with a maximum
possible score of 108**.** An increase in the score from baseline
indicated improvement. The mean increase from baseline in the FACT-G
total score was statistically significant between Zometa 8/4 mg and
Aredia 90 mg compared with Zometa 4 mg. The mean change from baseline
was similar for Zometa 4 mg and Aredia 90 mg in the physical and
emotional subscales. There was a significant difference in the mean
change from baseline in the functional and social subscales, with Aredia
90 mg showing a greater increase than Zometa 4 mg. These small changes
however, were not clinically meaningful.

###### Table 5-10. Mean/Median changes from baseline in quality of life scores at Month 13 by treatment group

+-----------------------------+------------+------------+------------+
|                             | **Zometa 4 | **Zometa   | **Aredia   |
|                             | mg**       | 8/4 mg**   | 90 mg**    |
+-----------------------------+------------+------------+------------+
|                             | **N=561**  | **N=524**  | **N=555**  |
+-----------------------------+------------+------------+------------+
| **in FACT-G total score\    | 446        | 418        | 445        |
| ** Total no. of patients \* |            |            |            |
|                             | 76.2 ±     | 75.0 ±     | 76.9 ±     |
| Baseline\                   | 16.3       | 16.9       | 15.8       |
| Mean ± SD                   |            |            |            |
|                             | 0.5 ±      | 3.1 ±      | 2.1 ±      |
| Change from baseline\       | 14.9\      | 14.9\      | 15.6\      |
| Mean ± SD\                  | 0.3        | 3.0        | 2.0        |
| Median                      |            |            |            |
+-----------------------------+------------+------------+------------+

\* Number of patients who had a non-missing score at both baseline and
Month 13 with last observation carried forward.

Time to progression of disease

There was no pairwise statistically significant difference in time to
progression of bone metastases or in time to overall disease progression
between the two treatment groups.

###### Table 5-11. Time to progression of disease up to Month 13, multiple myeloma and breast cancer

+-----------------------------+------------+------------+------------+
|                             | **Zometa 4 | **Zometa   | **Aredia   |
|                             | mg**       | 8/4 mg**   | 90 mg**    |
+-----------------------------+------------+------------+------------+
|                             | **N=561**  | **N=524**  | **N=555**  |
+-----------------------------+------------+------------+------------+
| **Time to progression of    | 61.5%\     | 62.9%\     | 62.4%\     |
| bone lesions**              | 179.0      | 175.0      | 171.0      |
|                             |            |            |            |
| Event rate at day 364\      |            |            |            |
| Median (days)               |            |            |            |
+-----------------------------+------------+------------+------------+
| **Time to progression of    | 72.0%\     | 71.6%\     | 74.9%\     |
| disease**                   | 134.0      | 125.0      | 111.0      |
|                             |            |            |            |
| Event rate at day 364\      |            |            |            |
| Median (days)               |            |            |            |
+-----------------------------+------------+------------+------------+

Event rate and median are derived from KM estimate.

Objective bone lesion response

The best bone lesion response rates were similar for all treatment
groups (see Table 5-12 on next page).

###### Table 5-12. Best bone lesion response up to Month 13, multiple myeloma and breast cancer

  ---------------------------- -------------- -------------- --------------
                               **Zometa 4     **Zometa 8/4   **Aredia 90
                               mg**           mg**           mg**

                               **N=561**      **N=524**      **N=555**

  **Best bone lesion           0 (0%)\        0 (0%)\        0 (0%)\
  response**\                  98 (17%)\      77 (15%)\      102 (18%)\
  Complete response\           170 (30%)\     164 (31%)\     154 (28%)\
  Partial response\            222 (40%)\     219 (42%)\     238 (43%)\
  Stable disease\              71 (13%)       64 (12%)       61 (11%)
  Progression\                                               
  Not evaluable                                              
  ---------------------------- -------------- -------------- --------------

### 

### 

### 5.2.6 Survival

The following survival analysis has been updated to include all data
available from the ongoing extensions up to October 26, 2001. Median
survival is provided in Table 5-13 and Kaplan-Meier curve of survival is
provided in Figure 5-3 below.

In Study 010, median survival has been reached for all treatment groups
in the strata of breast cancer with hormonal therapy of study entry.
Median survival has not been reached for any treatment group in the
multiple myeloma strata. There are no significant differences in
survival between Zometa 4 mg and pamidronate in study 010, either in
each individual stratum or the total.

###### Table 5-13. Summary of median survival (days) by stratum and treatment group

  -------------------------------------------------------------------------
                               **Zometa**\    **Zometa**\    **Aredia**\
                               **4 mg**       **8/4 mg**     **90 mg**
  ---------------------------- -------------- -------------- --------------
  **Stratum**                                                

  Multiple myeloma             NR             NR             NR

  Breast cancer chemotherapy   570.0          637.0          640.0

  Breast cancer hormonal       806.0          910.0          868.0

  Total                        838.0          830.0          811.0
  -------------------------------------------------------------------------

####### Figure 5-3. Kaplan-Meier curve of survival by treatment group

![](media/image7.wmf){width="4.719444444444444in"
height="3.6430555555555557in"}

### 5.2.7 Efficacy Summary (breast cancer / multiple myeloma)

In the Zometa clinical trials program, Study 010 was designed to
evaluate whether Zometa provides the level of benefit seen with Aredia
in patients with multiple myeloma or bone metastases from breast cancer.
A placebo group was not utilized in this study, since Aredia has
previously been shown to significantly delay or reduce the incidence of
skeletal-related morbid events in these patients. If Zometa and Aredia
were equal in effectiveness, statistical power calculations indicated
that the planned study enrollment (1600 patients) would have had power
to exclude an 8% or greater inferiority for Zometa in the proportion of
patients experiencing an SRE (the primary study endpoint), compared with
an anticipated beneficial treatment effect of 13.5% for Aredia (based on
historical data). The study results revealed a small difference in the
proportion of patients experiencing an SRE, favoring Zometa 4 mg, and
the lower confidence bound for this comparison with Aredia was 3.7%
(indicating that Zometa was at least within 3.7 % of the effectiveness
seen with Aredia as measured by this statistic).

Other analyses of skeletal related events, as noted in the study
protocol statistical plan, considered (1) the time to first SRE, (2) the
rate of SREs over time (Skeletal Morbidity Rate, SMR), and (3) Multiple
Event Analysis (Anderson-Gill methodology was used). These analyses
complement the analysis of proportion of patients experiencing an SRE,
and provide useful further information regarding the comparative patient
benefits of Zometa and Aredia (a drug that is known to provide
substantial benefit in this population). The results of these analyses
are provided in table 5-14, below.

Hazard ratios show comparable efficacy for Zometa 4 mg and 8/4 mg to
pamidronate.

###### Table 5-14. Summary of analysis of skeletal related events in Study 010 (Breast Cancer and Multiple Myeloma)

  ------------- -------------- -------------- -------------- --------------
                **\            **Time to      **\            **Multiple
                Proportion     First SRE\     Mean Skeletal  Event
                with SRE**     (Hazard        Morbidity      analysis\
                               ratio)**       Rate**         (Hazard
                                                             ratio)**

  Zometa 4 mg   248/561 (44%)  0.915          1.13           0.885

  Zometa 8/4 mg 242/524 (46%)  0.994          1.08           0.910

  Aredia        257/555 (46%)  \-             1.40           \-
  ------------- -------------- -------------- -------------- --------------

Hazard ratio were Zometa treatment groups versus Aredia treatment group.

While the results do not demonstrate any statistically significant
differences among the treatment groups, it is interesting to note that
all of these analyses of skeletal-related morbid events were consistent
in showing similar to slightly better results for both Zometa study arms
compared to the Aredia study arm. Based on evaluations of the historical
data from placebo-controlled studies of Aredia, and the features of the
patients enrolled in study 010 (data not shown), it is anticipated that
Aredia had substantial benefit for patients in study 010, and thus the
similar findings with Zometa reliably establish the effectiveness of
Zometa in this population.

## 5.3 Prostate Cancer -- Placebo-controlled trial (039)

### 5.3.1 Patient Disposition

This trial was designed with a placebo control, because no
bisphosphonate, including the clinically effective bisphosphonate
Aredia, has demonstrated efficacy in clinical trials in this population.
A total of 643 prostate cancer patients with a history of bone
metastases were randomized: 214 patients in the Zometa 4 mg group, 221
patients in the Zometa 8/4 mg group, and 208 patients in the placebo
group. These patients were randomized between 22-June-1998 and
10-November-1999 at one of 136 centers in 17 countries including centers
in North and South America, Europe, and Australia and New Zealand.

###### Table 5-15. Patient disposition -- prostate cancer study

  --------------------------------------- ----------- ----------- -----------
  **\                                     **Zometa\   **Zometa\   **\
  Number of patients**                    4 mg\       8/4 mg\     Placebo\
                                          N=214**     N=221**     N=208**

  Randomized\                             214\        221\        208\
  Included in efficacy analysis           214         221         208

  Completed 15 months                     81(37.9%)   62(28.1%)   65(31.3%)

  Reason for discontinuation                                      

  Adverse events                          38 (17.8%)  44 (19.9%)  29 (13.9%)

  Abnormal laboratory values              3 (1.4%)    5 (2.3%)    2 (1.0%)

  Abnormal test procedure results         1 (0.5%)    0 (0.0%)    0 (0.0%)

  Unsatisfactory therapeutic effect       19 (8.9%)   17 (7.7%)   34 (16.3%)

  Condition no longer required study drug 1 (0.5%)    3 (1.4%)    3 (1.4%)

  Protocol violation                      1 (0.5%)    0 (0.0%)    0 (0.0%)

  Withdrew consent                        41 (19.2%)  50 (22.6%)  35(16.8%)

  Lost to follow-up                       4 (1.9%)    0 (0.0%)    5 (2.4%)

  Administrative problems                 0 (0.0%)    0 (0.0%)    3 (1.4%)

  Death                                   25 (11.7%)  40(18.1%)   32 (15.4%)
  --------------------------------------- ----------- ----------- -----------

### 5.3.2 Demographic and Disease Characteristics

Baseline patient demographics were generally comparable for all
treatment groups. Most of the randomized patients were \> 60 years of
age.

###### Table 5-16 Demographics in prostate cancer patients -- ITT population

  ------------------------------- ------------- ------------- -------------
                                  **Zometa 4    **Zometa 8/4  **Placebo**
                                  mg**          mg**          

  **Demographic variable**        **(N=214)**   **(N=221)**   **(N=208)**

  Age (years)                                                 

  Mean ± S.D.                     71.8 ± 7.92   71.2 ± 7.99   72.2 ± 7.89

  Range                           45 - 90       43 - 90       37 - 90

  \> 60                           195 ( 91.1)   202 ( 91.4)   193 ( 92.8)

  Race n (%) patients                                         

  Caucasian                       178 (83.2%)   186 (84.2%)   172 (82.7%)

  Black                           24 (11.2%)    19 (8.6%)     19 (9.1%)

  Other                           12 (5.6%)     16 (7.2%)     17 (8.2%)

  Weight (kg)                                                 

  Mean ± S.D.                     82.8 ± 14.16  82.1 ± 14.44  83.4 ± 16.08

  Range                           40 - 120      46 - 126      43 - 138
  ------------------------------- ------------- ------------- -------------

Treatment groups were also comparable with respect to baseline quality
of life variables, and disease characteristics, with some minor
exceptions. Median baseline serum PSA was higher in both Zometa groups
than in the placebo group. Also, the BPI composite pain score and
proportion of patients with pain at baseline were higher in the Zometa
8/4 mg group than in the other two groups.

###### Table 5-17. Baseline characteristics in prostate cancer patients (ITT population)

  --------------------- ---------------- ---------------- ----------------
                        **Zometa 4 mg**  **Zometa 8/4     **Placebo**
                                         mg**             

  Total number of       214              221              208
  patients                                                

  Previous SRE          66 (30.8)        71 (32.1)        78 (37.5)

  Time since initial    62.5             67.6             66.6
  diagnosis of cancer                                     
  (months, mean)                                          

  Time since bone       23.5             25.8             28.4
  metastasis (months,                                     
  mean)                                                   

  PSA (ng/dl)                                             

  mean ± S.D.           276.5 ± 737.1    350.9 ± 1148.9   211.1 ± 464.9

  median                81.7             88.2             61.0

  ECOG status n (%)                                       

  0-1                   197 ( 92.1)      199 ( 91.3)      190 ( 91.3)

  ≥2                    17 ( 7.9)        19 ( 8.7)        18 ( 8.7)

  BPI composite pain                                      
  score                                                   

  N                     193              199              191

  Mean ±SD              2.0 ± 1.98       2.5 ± 2.10       2.1 ± 2.04

  Median                1.8              2.3              1.8

  Analgesic score                                         

  0                     94 ( 43.9)       73 ( 33.0)       77 ( 37.0)

  1                     69 ( 32.2)       84 ( 38.0)       77 ( 37.0)

  2                     9 ( 4.2)         11 ( 5.0)        9 ( 4.3)

  3                     40 ( 18.7)       48 ( 21.7)       41 ( 19.7)

  4                     2 ( 0.9)         3 ( 1.4)         3 ( 1.4)

  FACT-G total score                                      

  N                     193              193              187

  Mean ±SD              81.0 ± 15.30     81.4 ± 13.76     82.2 ± 14.57

  Median                82.5             82.2             82.8

  Baseline creatinine                                     

  \< 1.4 mg/dL          173 (80.8)       170 (76.9)       170 (81.7)

  ≥ 1.4 mg/dL           41 (19.2)        48 (21.7)        33 (15.9)
  --------------------- ---------------- ---------------- ----------------

### Primary efficacy analysis

The proportion of patients having any SRE in the Zometa 4 mg group was
significantly smaller than that in the placebo group (Table 5-18). The
Zometa 8/4 mg group also had a smaller proportion of patients with SREs
than the placebo group, but the difference did not reach statistical
significance. There was also no statistically significant difference
between the two Zometa groups for this comparison. There were two
patients who had HCM during the study, but each had other SREs and was
thus counted in the SRE (-HCM) analysis. Hence the proportion of
patients with prostate cancer having any SRE (-HCM) is identical to the
proportion of patients having any SRE (+HCM).

###### Table 5-18. Proportion of patients with prostate cancer with an SRE up to Month 15

+---------------+-------------+-------------------+---+-------------------+
|               |             | ######## 95% C    |   |                   |
|               |             | .I. and P-value f |   |                   |
|               |             | or the difference |   |                   |
+---------------+-------------+-------------------+---+-------------------+
| ######        | ########    | ###               |   | #####             |
| ## Treatment  |  Proportion | ##### Zometa 4 mg |   | ### Zometa 8/4 mg |
+---------------+-------------+-------------------+---+-------------------+
| > Placebo     | 92/208      | (- 20.3%,- 1.8%), | ( |                   |
|               | (44%)       | p = 0.021         | - |                   |
|               |             |                   | 1 |                   |
|               |             |                   | 5 |                   |
|               |             |                   | . |                   |
|               |             |                   | 1 |                   |
|               |             |                   | % |                   |
|               |             |                   | , |                   |
|               |             |                   | 3 |                   |
|               |             |                   | . |                   |
|               |             |                   | 6 |                   |
|               |             |                   | % |                   |
|               |             |                   | ) |                   |
|               |             |                   | , |                   |
|               |             |                   | p |                   |
|               |             |                   | = |                   |
|               |             |                   | 0 |                   |
|               |             |                   | . |                   |
|               |             |                   | 2 |                   |
|               |             |                   | 2 |                   |
|               |             |                   | 2 |                   |
+---------------+-------------+-------------------+---+-------------------+
| > Zometa 4 mg | 71/214      | \-                |   | (- 3.7%, 14.3%),p |
|               | (33%)       |                   |   | = 0.255           |
+---------------+-------------+-------------------+---+-------------------+
| > Zometa 8/4  | 85/221      | \-                |   | \-                |
| > mg          | (38%)       |                   |   |                   |
+---------------+-------------+-------------------+---+-------------------+

Proportion = (no. of patients with the event)/(total no. in the group)
up to Month 15;\
Confidence interval for the difference (treatment labeled in the column
minus row) of percent of patients with events.\
P-values are based on stratified Cochran-Mantel-Haenszel test for the
proportion.

### 5.3.4 Secondary skeletal endpoint analyses

Proportion of patients with individual skeletal-related events

The proportion of patients having each type of SRE was lower in the
Zometa 4 mg group and Zometa 8/4 mg group than in the placebo group
except for the change of antineoplastic therapy (Figure 5-4). The
difference in the proportion of patients with a pathological fracture
between the Zometa 4 mg group and the placebo group was statistically
significant (p=0.015).

####### Figure 5-4. Individual SREs in patients with prostate cancer

Time to first skeletal-related event

The difference in time to the first occurrence of any SRE between the
Zometa 4 mg group and the placebo group was statistically significant.
For Zometa 4 mg treatment group, the median time to the first occurrence
of a SRE was not reached, but it was at least 420 days (the estimated
event rate was less than 50% on day 420), while the median time in the
placebo group was 321 days. Hence the median time to the first
occurrence of a SRE for the Zometa 4 mg group was increased by at least
99 days compared to the patients in the placebo group.

The times to the first SRE (-HCM) and the first SRE (+HCM) are identical
in this study as hypercalcemia was not the first SRE for the two
patients who had hypercalcemia.

###### Table 5-19. Time to the first SRE up to Month 15 in prostate cancer patients

  ------------ ----- ------------ ----------- ----------- -------------- -----------
                                                          **P-values for 
                                                          the between    
                                                          treatment      
                                                          comparison**   

               **\   **Event      **25%       **Median\   **Zometa\      **Zometa\
               N**   rate\        Quartile\   (days)**    4 mg**         8/4 mg**
                     at day 420** (days)**                               

  Placebo      208   57.19%       122         321         0.011          0.491

  Zometa 4 mg  214   44.87%       182         Not Reached \-             0.059

  Zometa 8/4   221   53.17%       127         363         \-             \-
  mg                                                                     
  ------------ ----- ------------ ----------- ----------- -------------- -----------

P-values are from the log-rank test for comparing the distribution of
time to the event.\
For stratum =total, the p-values are from Cox-regression with factor
treatment, stratified by the strata. Event rate is the Kaplan Meier
estimate of the event rate at day 420.\
Event rate, Median and 25%quartile are derived from KM estimate.

Skeletal morbidity rate

The skeletal morbidity rate up to Month 15 was lower for patients in the
Zometa 4 mg and Zometa 8/4 mg groups than in the placebo group (Table
5-20). The difference in the SMR between the Zometa 4 mg group and the
placebo group was statistically significant.

###### Table 5-20. Skeletal morbidity rate (risk set definition) of any SRE (-HCM) up to Month 15

  ----------- ------- --------------- ------------ -------------- -------------
                      **Skeletal                   **p-values for 
                      morbidity                    the between    
                      rates\                       treatment      
                      (no. of events               comparison**   
                      per year)**                                 

              **N**   **Mean ± SD**   **Median**   **Zometa 4     **Zometa 8/4
                                                   mg**           mg**

  Placebo     208     1.49 ± 3.336    0.00         0.006          0.143

  Zometa 4 mg 214     0.80 ± 1.703    0.00         \-             0.191

  Zometa 8/4  221     1.06 ± 2.193    0.00         \-             \-
  mg                                                              
  ----------- ------- --------------- ------------ -------------- -------------

Skeletal morbidity rate (risk set definition) is the number of SREs
divided by the time at risk in years, counted from the date of
randomization, with every counted event followed by a 20 day period
during which any SRE experienced by the patient would not be counted,
nor would the patient be counted as at risk. For patients with no SRE,
the whole study period was counted as at risk.

#### Multiple event analysis of SREs

For SRE (-HCM), there was a statistically significant difference between
the Zometa group and the placebo group in the time to multiple
occurrence of the event in favor of the Zometa 4 mg group (p=0.004). See
Table 5-21 below.

###### Table 5-21. Multiple-event analysis of time to SRE up to Month 15 in prostate cancer patients (039)

  ------------ ----------- ------------ ----------- -- ----------- ------------ -----------
               **Zometa 4                              **Zometa                 
               mg v.s.**                               8/4 mg                   
                                                       v.s.**                   

               **Hazard    **95% CI for **\            **Hazard    **95% CI for **\
               ratio\***   Hazard       P-value**      ratio\***   Hazard       P-value**
                           ratio**                                 ratio**      

  Placebo      0.643       (0.476,      0.004          0.847       (0.640,      0.247
                           0.870)                                  1.122)       

  Zometa 4 mg                                          1.318       (0.966,      0.081
                                                                   1.798)       
  ------------ ----------- ------------ ----------- -- ----------- ------------ -----------

\* Hazard ratio is the ratio of column versus row. Hazard ratios and
p-values are from Anderson-Gill approach for time to multiple events

P-value and the 95% C.I. are computed using the robust variance estimate

### 5.3.5 Analyses of Other Endpoints

#### Pain

Overall, the mean BPI composite pain score increased from baseline to
Month 15 for all three treatment groups. However, the difference in
favor of Zometa between the BPI composite pain scores of both of the
Zometa 4 mg and Zometa 8/4 mg groups and the placebo group at months 3
(p= 0.003 and p= 0.003, respectively) and 9 (p=0.030 and p=0.014,
respectively) was statistically significant. The difference in favor of
Zometa was also statistically significant between the 8/4 mg group and
the placebo group at several other time points.

#### Analgesics

The mean analgesic score increased from baseline to Month 15 for all
three treatment groups. The difference in analgesic score from baseline
for the total of all patients was either similar for all three treatment
groups or the placebo group had a slightly higher score than the two
Zometa groups at all timepoints.

#### Performance status (ECOG)

The mean ECOG score increased from baseline to Month 15 for all three
treatment groups. Overall, there was no statistically significant
difference between any treatment groups in the change from baseline in
ECOG score.

#### Quality of life (FACT-G)

The total score for FACT-G is the sum of the physical, functional,
social and emotional subscales. The EQ-D5 questionnaire consists of the
EURO QOL-5D score and the EURO QOL-5D thermometer. An increase in the
score from baseline indicates improvement while a negative number
indicates worsening.

At Month 15 there was some improvement in the FACT-G social subscale
score and the EURO QOL-5D score for all treatment groups, but there were
no statistically significant differences between treatment groups for
any of the quality of life scores.

#### Time to Progression

There was no statistically significant difference between treatment
groups in the distribution of time to progression of bone metastases or
in the distribution of time to overall disease progression.

###### Table 5-22. Summary of time to progression of disease at Month 15 in prostate cancer patients

  --------------------------------- ------------ ------------ -------------
                                    **Zometa 4   **Zometa 8/4 **Placebo**
                                    mg**         mg**         

                                    **N= 214**   **N= 221**   **N= 208**

  **Time to progression of bone     92.0\        89.0\        87.0\
  lesions\                          0.275\       0.710\       -\
  **Median (days)\                  -            0.342        -
  P-value: vs Placebo\                                        
  P-value: vs Zometa 4mg                                      

  **Time to progression of disease\ 84.0\        84.0\        84.0\
  **Median (days)\                  0.771\       0.408\       -\
  P-value: vs Placebo\              -            0.275        -
  P-value: vs Zometa 4mg                                      
  --------------------------------- ------------ ------------ -------------

Note: Stratified log-rank test is used for the between treatment
comparison. The median is derived from KM estimate.

#### Objective bone lesion response

No patients achieved complete response during the study. In both Zometa
treatment groups, a higher percentage of patients had no change in bone
lesions while a lower percentage had progression of bone lesions
compared with patients in the placebo group.

###### Table 5-23. Frequency distribution of best response by treatment group

  --------------------------------- ------------ ------------ -------------
                                    **Zometa 4   **Zometa 8/4 **Placebo**
                                    mg**         mg**         

                                    **N=214**    **N=221**    **N=208**

  **Best bone lesion response\      0 (0%)\      0 (0%)\      0 (0%)\
  **Complete response**\            9 (4%)\      6 (3%)\      8 (4%)\
  ** Partial response\              47 (22%)\    46 (21%)\    35 (17%)\
  No change\                        118 (55%)\   123 (56%)\   132 (63%)\
  Progression\                      40 (1 9%)    46 (21%)     33 (16%)
  Not evaluable                                               
  --------------------------------- ------------ ------------ -------------

### 5.3.6 Survival

The following survival analysis has been updated to include all data
available from the ongoing extensions up to October 26, 2001. Median
survival is provided in Table 5-24 and Kaplan-Meier curve of survival is
provided in Figure 5-5 below.

######  Table 5-24. Summary of median survival (days) by stratum and treatment group

  -------------------------------------------------------------------------
                            **Zometa**\     **Zometa**\     **\
                            **4 mg**        **8/4 mg**      Placebo**
  ------------------------- --------------- --------------- ---------------
  **Stratum**                                               

  No metastases at initial  515.0           419.0           471.0
  diagnosis                                                 

  Metastases at initial     646.0           377.0           466.0
  diagnosis                                                 

  Total                     563.0           418.0           469.0
  -------------------------------------------------------------------------

####### Figure 5-5. Kaplan-Meier curve of survival by treatment group

![](media/image10.wmf){width="4.819444444444445in"
height="3.720138888888889in"}

### 5.3.7 Efficacy Summary (prostate study)

The primary efficacy variable was compared between the 4 mg Zometa
treatment group and placebo using a stratified Cochran-Mantel-Haenszel
test with modified ridit scores.

For time to the first SRE (-HCM) and each type of SRE, survival analysis
methods, including Kaplan-Meier product-limit estimates of the "survival
functions", and the Cox regression stratified with the stratum were used
to assess the effectiveness of Zometa 4 mg in prolonging the time to the
first event.

For skeletal morbidity rate of SRE (-HCM), SRE (+HCM), and each type of
SREs, stratified Cochran-Mantel-Haenzsel with modified ridit scores were
used to assess the difference between the Zometa 4 mg and the placebo

Zometa 4 mg given as a 15-minute infusion every 3 weeks in addition to
standard antineoplastic therapy was significantly more effective than
placebo in treatment of bone metastases in patients with prostate cancer
(see Table 5-25 below):

-   the proportion of patients having skeletal-related events was
    significantly lower with Zometa 4 mg than with placebo

-   the time to the first skeletal-related event was significantly
    longer with Zometa 4 mg than with placebo

-   the skeletal morbidity rate was significantly lower with Zometa 4 mg
    than with placebo

-   hazard ratio for SRE recurrent rates favored Zometa 4 mg over
    placebo

-   the proportion of patients with individual types of SREs and the SMR
    for each SRE was lower with Zometa compared with placebo

-   patients treated with Zometa had a smaller increase in bone pain
    than patients receiving placebo, with little between group
    difference in analgesic score, in spite of similar deterioration of
    performance status in the three treatment groups

###### Table 5-25. Summary of analysis of skeletal related events in Study 039 (Prostate cancer)

  ------------- -------------- -------------- -------------- ------------------
                **\            **Time to      **\            **\
                \              First SRE      \              SRE Recurrence
                Proportion     (Event Rate)\  Skeletal       (Anderson-Gill)\
                with SRE**     Day 420**      Morbidity      (Hazard ratio)**
                                              Rate**         

  Zometa 4 mg   71/214 (33%)\* 44.87%\*       .80\*          0.643\*

  Zometa 8/4 mg 85/221 (38%)   53.17%         1.06           0.847

  Placebo       92/208 (44%)   57.19%         1.49           \-
  ------------- -------------- -------------- -------------- ------------------

\*P\<0.05 Zometa 4 mg vs. Placebo.

## 5.4 Lung Cancer and Other Solid Tumors -- Placebo-Controlled Trial (011)

### 5.4.1 Patient Disposition

All 773 patients randomized to treatment were included in the analysis
of efficacy (ITT population). Approximately one quarter of patients
completed 9 months of treatment, and the percentage of patients who
discontinued was similar for all treatment groups. Adverse events and
death were the most frequent reasons for discontinuation, followed by
withdrawal of consent.

###### Table 5-26. Patient disposition, lung cancer and other solid tumors (011) 

  -------------------------------- ------------ -------------- ------------
  **\                              **Zometa 4   **Zometa 8/4   **Placebo\
  Number of patients**             mg\          mg\            N=250**
                                   N=257**      N=266**        

  Randomized\                      257\         266\           250\
  Included in efficacy analysis    257          266            250

  Lung cancer                      134 (52.1%)  139 (52.3%)    130 (52.0%)

  Other                            123 (47.9%)  127 (47.7%)    120 (48.0%)

  Completed 9 months               68 (26.5%)   65 (24.4%)     63 (25.2%)

  Discontinued prematurely         189 (73.5%)  201 (75.6%)    187 (74.8%)

  Adverse events                   49 (19.1%)   65 (24.4%)     52 (20.8%)

  Abnormal laboratory values       0 (0.0%)     4 (1.5%)       2 (0.8%)

  Abnormal test procedure results  0 (0.0%)     1 (0.4%)       0 (0.0%)

  Unsatisfactory therapeutic       18 (7.0%)    14 (5.3%)      20 (8.0%)
  effect                                                       

  Condition no longer requires     2 (0.8%)     1 (0.4%)       4 (1.6%)
  study drug                                                   

  Protocol violation               4 (1.6%)     0 (0.0%)       0 (0.0%)

  Withdrew consent                 46 (17.9%)   36 (13.5%)     40 (16.8%)

  Lost to follow-up                2 (0.8%)     4 (1.5%)       0 (0.0%)

  Administrative problems          1 (0.4%)     1 (0.4%)       1 (0.4%)

  Death                            66 (25.7%)   75 (28.2%)     66 (26.4%)

  Not stated                       1 (0.4%)     0 (0.0%)       0 (0.0%)
  -------------------------------- ------------ -------------- ------------

### 5.4.2 Demographics and Disease Characteristics

Baseline demographics in patients with lung cancer or other solid tumors
were comparable for all three treatment groups, with the population
being predominantly male and Caucasian. The treatment groups were also
comparable with respect to baseline disease specific characteristics and
prognostic factors.

###### Table 5-27. Demographic characteristics by treatment group, Study 011 (ITT population)

  ------------------------------- ------------- ------------- -------------
                                  **Zometa 4    **Zometa 8/4  **Placebo**
                                  mg**          mg**          

  **Demographic variable**        **(N=257)**   **(N=266)**   **(N=250)**

  Age (years)                                                 

  Mean ± S.D.                     62.2 ± 10.58  60.8 ± 10.44  62.3 ± 10.82

  Range                           25 - 88       28 - 84       25 - 86

  Sex n (%)                                                   

  Male                            160 (62.3%)   186 (69.9%)   162 (64.8%)

  Female                          97 (37.7%)    80 (30.1%)    88 (35.2%)

  Race n (%) patients                                         

  Caucasian                       229(89.1%)    238(89.5%)    226(90.4%)

  Black                           15(5.8%)      15(5.6%)      12(4.8%)

  Other                           13(5.1%)      13(4.9%)      12(4.8%)

  Weight (kg)                                                 

  Mean ± S.D.                     72.7 ± 15.18  74.3 ± 16.91  71.6 ± 15.99

  Range                           41 - 141      33 - 136      33 - 152
  ------------------------------- ------------- ------------- -------------

The treatment groups were comparable for disease characteristics.
Approximately half of all patents had lung cancer and between 65 and 72%
of patients had experienced a prior SRE.

###### Table 5-28. Baseline disease characteristics in patients with lung cancer or other solid tumors (011)

  -------------------------------- ------------- ------------- -------------
                                   **Zometa 4    **Zometa 8/4  **Placebo**
                                   mg**          mg**          

  **Disease specific variables**   **(N=257)**   **(N=266)**   **(N=250)**

  Cancer type (n, %)                                           

  Lung                             126 (49.0%)   134 (50.4%)   126 (50.4%)

  Renal cell carcinoma             27 (10.5%)    28 (10.5%)    19 (7.6%)

  Cancer unknown primary           15 (5.8%)     14 (5.3%)     14 (5.6%)

  Head and neck                    6 (2.3%)      7 (2.6%)      4 (1.6%)

  Thyroid                          2 (0.8%)      5 (1.9%)      4 (1.6%)

  Other                            81 (31.5%)    78 (29.3%)    83 (33.2%)

  Metastases other than bone to    12 (4.7%)\    12 (4.5%)\    11 (4.5%)\
  visit 2\                         17 (6.7%)\    14 (5.3%)\    16(6.5%)\
  Lung\                            14 (5.5%)\    8 (3.0%)\     4 (1.6%)\
  Liver\                           7 (2.8%)      9 (3.4%)      5 (2.0%)
  Brain\                                                       
  Pleura                                                       

  Time since bone metastases\      4.7 ± 7.65\   4.9 ± 7.89\   5.0 ± 9.47\
  Mean ± S.D.\                     1.6           1.8           1.8
  Median                                                       

  Prior chemotherapy (n (%))       209 (81.3%)   212 (79.7%)   199 (79.6%)

  Prior SRE n (%) patients         167 (65.0%)   180 (67.7%)   180 (72.0%)

  Bone alkaline phosphatase\       276.1 ±       212.1 ±       242.2 ±
  Mean ± S.D.\                     457.2\        210.5\        284.9\
  Median                           168.5         149.0         162.0

  \* Small cell lung cancer                                    
  patients are included in                                     
  category noted as "other")                                   
  -------------------------------- ------------- ------------- -------------

### 5.4.3 Primary efficacy analysis

The proportion of patients with lung cancer or other solid tumors
experiencing at least one SRE was smaller for both Zometa dose groups
than those treated with placebo for the overall ITT population and both
tumor type strata. This difference was statistically significant for the
Zometa 8/4 mg group at 9 months for the overall ITT population. There
was no statistically significant difference between the Zometa treatment
groups.

###### Table 5-29. Proportion of patients with lung cancer or other solid tumors having any SRE (011)

+----------------+-----------+--------------------+-------------------+
|                |           | **95% C.I. and     |                   |
|                |           | P-value for the    |                   |
|                |           | difference**       |                   |
+----------------+-----------+--------------------+-------------------+
|                | **Pro     | **Zometa 4 mg**    | **Zometa 8/4 mg** |
|                | portion** |                    |                   |
+----------------+-----------+--------------------+-------------------+
| Lung cancer    |           |                    |                   |
+----------------+-----------+--------------------+-------------------+
| > Placebo      | 59/130    | (-15.6%, 8.4%),    | (-23.3%, 0.1%),   |
|                | (45%)     | p=0.557            | p=0.053           |
+----------------+-----------+--------------------+-------------------+
| > Zometa 4 mg  | 56/134    | \-                 | (-19.5%, 3.5%),   |
|                | (42%)     |                    | p=0.175           |
+----------------+-----------+--------------------+-------------------+
| > Zometa 8/4   | 47/139    | \-                 | \-                |
| > mg           | (34%)     |                    |                   |
+----------------+-----------+--------------------+-------------------+
| Other solid    |           |                    |                   |
| tumors         |           |                    |                   |
+----------------+-----------+--------------------+-------------------+
| > Placebo      | 52/120    | (-22.2%, 2.2%),    | (-20.1%, 4.3%),   |
|                | (43%)     | p=0.110            | p=0.205           |
+----------------+-----------+--------------------+-------------------+
| > Zometa 4 mg  | 41/123    | \-                 | (-9.7%, 13.9%),   |
|                | (33%)     |                    | p=0.727           |
+----------------+-----------+--------------------+-------------------+
| > Zometa 8/4   | 45/127    | \-                 | \-                |
| > mg           | (35%)     |                    |                   |
+----------------+-----------+--------------------+-------------------+
| Total          |           |                    |                   |
+----------------+-----------+--------------------+-------------------+
| > Placebo      | 111/250   | (-15.2%, 1.9%),    | (-18.2%,-1.4%),   |
|                | (44%)     | p=0.127            | p=0.023           |
+----------------+-----------+--------------------+-------------------+
| > Zometa 4 mg  | 97/257    | \-                 | (-11.4%, 5.1%),   |
|                | (38%)     |                    | p=0.452           |
+----------------+-----------+--------------------+-------------------+
| > Zometa 8/4   | 92/266    | \-                 | \-                |
| > mg           | (35%)     |                    |                   |
+----------------+-----------+--------------------+-------------------+
| Confidence     |           |                    |                   |
| interval for   |           |                    |                   |
| the difference |           |                    |                   |
| (treatment     |           |                    |                   |
| labeled in the |           |                    |                   |
| column minus   |           |                    |                   |
| row ) of       |           |                    |                   |
| percent of     |           |                    |                   |
| patients with  |           |                    |                   |
| events.        |           |                    |                   |
| Stratified     |           |                    |                   |
| Cochran-M      |           |                    |                   |
| antel-Haenszel |           |                    |                   |
| test for the   |           |                    |                   |
| proportion was |           |                    |                   |
| used for       |           |                    |                   |
| between        |           |                    |                   |
| treatment      |           |                    |                   |
| group          |           |                    |                   |
| comparisons.   |           |                    |                   |
+----------------+-----------+--------------------+-------------------+

### Secondary skeletal endpoint analyses

Proportion of patients having any SRE, including hypercalcemia

Unlike the studies in breast cancer/multiple myeloma or prostate cancer,
inclusion of hypercalcemia of malignancy as an SRE had a substantial
effect on the outcome of the analysis of the proportion of patients
having SREs. The proportions of patients with SREs including HCM were
significantly lower in both the Zometa 4 mg and 8/4 mg groups than for
placebo. This positive outcome represents the real clinical relevance of
Zometa treatment in this population, since HCM is an important SRE for
these patients.

Proportion of patients with individual SREs

The proportion of patients experiencing each specific SRE was lower for
both Zometa groups than for placebo, except for surgery to bone. The
difference versus placebo achieved statistical significance for
hypercalcemia in both Zometa groups, and for pathologic fractures and
vertebral fractures for the 8/4 mg group.

####### Figure 5-6. Individual SREs in patients with lung cancer or other solid tumors

Time to first SRE

Median time to first occurrence of an SRE was longer for patients
treated with Zometa than placebo. The difference versus placebo was
statistically significant for both Zometa groups.

###### Table 5-30. Time to first SRE in patients with lung cancer and other solid tumors (011)

  ------------------------- ------------- ------------- ------------- ------------- ------------- -------------
                            **Excluding                               **Including                 
                            HCM**                                     HCM**                       

                            **Zometa 4    **Zometa\     **\           **Zometa\     **Zometa\     **\
                            mg**          8/4 mg**      Placebo**     4 mg**        8/4 mg**      Placebo**

                            **(N=257)**   **(N=266)**   **(N=250)**   **(N=257)**   **(N=266)**   **(N=250)**

  Time to first SRE (days)                                                                        

  Median^1^                 230           219           163           230           219           155

  Event rate^1^             52.7%         52.9%         63.2%         52.7%         53.1%         65.7%

  P value^2^ vs placebo     0.023         0.034         \-            0.007         0.013         \-

  P value^2^ vs Zometa 4 mg \-            0.969         \-            \-            0.913         \-

  ^1^ Median and event rate                                                                       
  were derived from KM                                                                            
  estimate. Event rates                                                                           
  were calculated at day                                                                          
  252 for study 011.\                                                                             
  ^2^ Stratified                                                                                  
  Cochran-Mantel-Haenszel                                                                         
  test with modified ridit                                                                        
  score was used for the                                                                          
  between treatment group                                                                         
  comparisons.                                                                                    
  ------------------------- ------------- ------------- ------------- ------------- ------------- -------------

The mean SMR of any SRE (excluding HCM) was statistically significantly
lower for the Zometa 8/4 mg group than the placebo group. For any SRE
including HCM, mean SMR was statistically significantly lower for both
Zometa treatment groups than the placebo group.

###### Table 5-31. Skeletal morbidity rate of any SRE in patients with lung cancer and other solid tumors (011)

  ----------------- ------------- ------------- ------------- ------------- ------------- -------------
                    **Excluding                               **Including                 
                    HCM**                                     HCM**                       

                    **Zometa 4    **Zometa\     **\           **Zometa\     **Zometa\     **\
                    mg**          8/4 mg**      Placebo**     4 mg**        8/4 mg**      Placebo**

                    **(N=257)**   **(N=266)**   **(N=250)**   **(N=257)**   **(N=266)**   **(N=250)**

  Skeletal                                                                                
  morbidity rate                                                                          

  Mean              2.24          1.55          2.52          2.24          1.59          2.73

  SD                9.12          3.80          5.12          9.12          3.84          5.29

  P value^1^ vs     0.069         0.005         \-            0.017         0.001         \-
  placebo                                                                                 

  P value^1^ vs     \-            0.309         \-            \-            0.372         \-
  Zometa 4 mg                                                                             

  ^1^ Stratified                                                                          
  Cox regression                                                                          
  with factor                                                                             
  treatment group                                                                         
  was used for the                                                                        
  between treatment                                                                       
  group                                                                                   
  comparisons.                                                                            
  ----------------- ------------- ------------- ------------- ------------- ------------- -------------

###### Table 5-32. Proportion of patients with lung cancer or other solid tumors having any SRE (+HCM)

+----------------+-----------+--------------------+-------------------+
|                |           | **95% C.I. and     |                   |
|                |           | P-value for the    |                   |
|                |           | difference**       |                   |
+----------------+-----------+--------------------+-------------------+
|                | **Pro     | **Zometa 4 mg**    | **Zometa 8/4 mg** |
|                | portion** |                    |                   |
+----------------+-----------+--------------------+-------------------+
| Lung cancer    |           |                    |                   |
+----------------+-----------+--------------------+-------------------+
| > Placebo      | 62/130    | (-17.9%, 6.1%),    | (-24.9%,-1.4%),   |
|                | (48%)     | p=0.336            | p=0.029           |
+----------------+-----------+--------------------+-------------------+
| > Zometa 4 mg  | 56/134    | \-                 | (-18.8%, 4.3%),   |
|                | (42%)     |                    | p=0.218           |
+----------------+-----------+--------------------+-------------------+
| > Zometa 8/4   | 48/139    | \-                 | \-                |
| > mg           | (35%)     |                    |                   |
+----------------+-----------+--------------------+-------------------+
| Other solid    |           |                    |                   |
| tumors         |           |                    |                   |
+----------------+-----------+--------------------+-------------------+
| > Placebo      | 55/120    | (-24.8%, -0.2%),   | (-22.6%, 1.8%),   |
|                | (46%)     | p=0.047            | p=0.097           |
+----------------+-----------+--------------------+-------------------+
| > Zometa 4 mg  | 41/123    | \-                 | (-9.7%, 13.9%),   |
|                | (33%)     |                    | p=0.727           |
+----------------+-----------+--------------------+-------------------+
| > Zometa 8/4   | 45/127    | \-                 | \-                |
| > mg           | (35%)     |                    |                   |
+----------------+-----------+--------------------+-------------------+
| Total          |           |                    |                   |
+----------------+-----------+--------------------+-------------------+
| > Placebo      | 117/250   | (-17.7%, -0.5%),   | (-20.3%,-3.4%),   |
|                | (47%)     | p=0.039            | p=0.006           |
+----------------+-----------+--------------------+-------------------+
| > Zometa 4 mg  | 97/257    | \-                 | (-11.0%, 5.5%),   |
|                | (38%)     |                    | p=0.508           |
+----------------+-----------+--------------------+-------------------+
| > Zometa 8/4   | 93/266    | \-                 | \-                |
| > mg           | (35%)     |                    |                   |
+----------------+-----------+--------------------+-------------------+
| Confidence     |           |                    |                   |
| interval for   |           |                    |                   |
| the difference |           |                    |                   |
| (treatment     |           |                    |                   |
| labeled in the |           |                    |                   |
| column minus   |           |                    |                   |
| row ) of       |           |                    |                   |
| percent of     |           |                    |                   |
| patients with  |           |                    |                   |
| events.        |           |                    |                   |
| Stratified     |           |                    |                   |
| Cochran-M      |           |                    |                   |
| antel-Haenszel |           |                    |                   |
| test for the   |           |                    |                   |
| proportion was |           |                    |                   |
| used for       |           |                    |                   |
| between        |           |                    |                   |
| treatment      |           |                    |                   |
| group          |           |                    |                   |
| comparisons.   |           |                    |                   |
+----------------+-----------+--------------------+-------------------+

Multiple events analysis

For SREs excluding HCM, there was a statistically significant difference
between the Zometa 4 mg group and the placebo group in the time to
multiple occurrences of the event in favor of the Zometa 4 mg group for
all strata together (p=0.017). The difference between the Zometa 4 mg
group and the placebo group in the lung cancer patients was approaching
statistical significance (p=0.061) in favor of Zometa 4 mg as well.
Overall, the effect of Zometa 4 mg versus placebo on the recurrence of
SRE were comparable in both lung cancer patients and other solid tumors
patients.

###### Table 5-33. Multiple-event analysis of time to SRE up to Month 9 in patients with lung cancer and other solid tumors (011)

  ------------ ----------- ------------ ----------- -- ----------- ------------ -----------
               **Zometa 4                              **Zometa                 
               mg v.s.**                               8/4 mg                   
                                                       v.s.**                   

               **Hazard    **95% CI for **\            **Hazard    **95% CI for **\
               ratio\***   Hazard       P-value**      ratio\***   Hazard       P-value**
                           ratio**                                 ratio**      

  **Lung                                                                        
  cancer**                                                                      

  Placebo      0.729       (0.524,      0.061          0.530       (0.377,      \<0.001
                           1.015)                                  0.745)       

  Zometa 4 mg  \-                       \-             0.719       (0.512,      0.057
                                                                   1.010)       

  **Other                                                                       
  solid                                                                         
  tumors**                                                                      

  Placebo      0.737       (0.493,      0.136          0.886       (0.605,      0.534
                           1.101)                                  1.298)       

  Zometa 4 mg  \-                       \-             1.210       (0.806,      0.358
                                                                   1.816)       

  **Total**                                                                     

  Placebo      0.732       (0.567,      0.017          0.687       (0.531,      0.004
                           0.946)                                  0.890)       

  Zometa 4 mg                                          0.929       (0.713,      0.586
                                                                   1.210)       
  ------------ ----------- ------------ ----------- -- ----------- ------------ -----------

\* Hazard ratio is the ratio of column versus row. Hazard ratios and
p-values are from Anderson-Gill approach for time to multiple events

P-value and the 95% C.I. are computed using the robust variance estimate

### 5.4.5 Analyses of Other Endpoints

#### Pain

The change from baseline in mean BPI pain score was not significantly
different between treatment groups. There was a small increase in
overall BPI composite scores in each group, but the increase was lower
in the Zometa 4 mg group than the other groups. For patients with pain
at baseline a slight decrease was seen for the Zometa 4 mg group.

#### Analgesics

The mean analgesic score increased from baseline to Month 9 for all
treatment groups, but the changes from baseline showed no statistically
significant differences between treatments at Month 9.

#### ECOG performance status

Mean ECOG score increased from baseline to Month 9 for all three
treatment groups. There was no statistically significant difference
between any treatment groups in the change from baseline in ECOG score.

#### Time to Progression

Median time to progression of bone lesions and time to progression of
disease were longer in the Zometa groups than the placebo group. This
difference was statistically significant for the 8/4 mg group.

###### Table 5-34. Time to progression of disease in patients with lung cancer and other solid tumors (011)

  -------------------------- -------------- -------------- -------------- --
                             **Zometa 4     **Zometa 8/4   **Placebo**    
                             mg**           mg**                          

                             **(N =257)**   **(N =266)**   **(N =250)**   

  Time to progression, bone                                               
  lesions                                                                 

  Median^1^\                 145.0\         238.0\         109.0\         
  Event rate^1^\             62.8%\         50.8%\         64.1%\         
  P-value^2^ vs placebo\     0.34\          0.009\         -\             
  P-value^2^ vs Zometa 4 mg  -              0.065          -              

  Time to disease                                                         
  progression                                                             

  Median^1^\                 89.0\          91.0\          84.0\          
  Event rate^1^\             86.4%\         81.4%\         90.1%\         
  P-value^2^ vs placebo\     0.117\         0.010\         -\             
  P-value^2^ vs Zometa 4 mg  -              0.269          -              

  ^1^ Median and event rate                                               
  were derived from KM                                                    
  estimate. Event rates were                                              
  calculated at day 252.\                                                 
  ^2^ Stratified Cox                                                      
  regression with factor                                                  
  treatment group was used                                                
  for the between treatment                                               
  group comparisons.                                                      
  -------------------------- -------------- -------------- -------------- --

#### Best bone lesion response

More patients in the Zometa groups than in the placebo group had partial
response.

###### Table 5-35. Frequency distribution of best bone lesion response (011)

  ------------------- ----------------- ----------------- -----------------
                      **Zometa 4 mg**   **Zometa 8/4 mg** **Placebo**

  **n (%) patients**  **(N =257)**      **(N =266)**      **(N =250)**

  Complete response\  0\                0\                0\
  Partial response\   21 (8%)\          27 (10%)\         11 (4%)\
  Stable disease\     55 (21%)\         51 (19%)\         49 (20%)\
  Progression\        86 (33%)\         75 (28%)\         90 (36%)\
  Unknown             95 (37%)          113 (42%)         100 (40%)
  ------------------- ----------------- ----------------- -----------------

  ---------------------- ------- ------- -------- -------- -------- --------
                                                                    

                                                                    

                                                                    

                                                                    

                                                                    

                                                                    

                                                                    

                                                                    

                                                                    
  ---------------------- ------- ------- -------- -------- -------- --------

#### Survival

The following survival analysis has been updated to include all data
available from the ongoing extensions up to October 26, 2001. Median
survival is provided in Table 5-36 and Kaplan-Meier curve of survival is
provided in Figure 5-7 below.

###### Table 5-36. Summary of median survival (days) by stratum and treatment group

  -------------------------------------------------------------------------
                            **Zometa**\     **Zometa**\     **Placebo**
                            **4 mg**        **8/4 mg**      
  ------------------------- --------------- --------------- ---------------
  **Stratum**                                               

  Lung cancer               199.5           181.0           155.0

  Other solid tumors        212.0           213.0           192.0

  Total                     202.5           189.0           183.0
  -------------------------------------------------------------------------

####### Figure 5-7. Kaplan-Meier curve for survival by treatment group

![](media/image13.wmf){width="4.819444444444445in"
height="3.720138888888889in"}

## 5.4.7 Efficacy Summary (other solid tumors)

The primary efficacy variable was compared between the mg Zometa
treatment group and placebo using a stratified Cochran-Mantel-Haenszel
test with modified ridit scores.

For time to the first SRE (-HCM) and each type of SRE, survival analysis
methods, including Kaplan-Meier product-limit estimates of the "survival
functions", and the Cox regression stratified with the stratum were used
to assess the effectiveness of Zometa 4 mg in prolonging the time to the
first event.

For skeletal morbidity rate of SRE (-HCM), SRE (+HCM), and each type of
SREs, stratified Cochran-Mantel-Haenzsel with modified ridit scores were
used to assess the difference between the Zometa 4 mg and the placebo.

Zometa 4 mg given as a 15-minute infusion every 3 weeks in addition to
standard antineoplastic therapy was significantly more effective than
placebo in treatment of bone metastases in patients solid tumors other
than prostate and breast cancer (see Table 5-37).

Proportion of patients having any SRE excluding HCM, up to Month 9. Both
Zometa treatment arms had a lower proportion of SREs (-HCM) than the
placebo group. The difference between the Zometa 4 mg group and the
placebo group was not statistically significant. The difference between
the Zometa 8/4 mg group and the placebo group was statistically
significant

Proportion of patients with any SRE including HCM: the Zometa 4 mg group
had a statistically significantly lower proportion than the placebo: 38%
versus 47%, respectively, p=0.039.

Time to the first SRE (excluding HCM): the Zometa 4 mg treatment delayed
the time to first SRE by 67 days as compared to placebo, p=0.023.

The hazard ratio for SRE recurrent rates favored Zometa 4 mg over
placebo.

###### Table 5-37. Summary of analysis of skeletal related events in Study 011 (Lung cancer and other solid tumors)

  ------------- -------------- -------------- -------------- ------------------
                **\            **Time to      **\            **SRE Recurrence
                \              First SRE      \              (Anderson-Gill)\
                Proportion     (Event Rate)\  Skeletal       (Hazard ratio)**
                with SRE**     Day 252)**     Morbidity      
                                              Rate**         

  Zometa 4 mg   97/257 (38%)   52.7%\*        2.24           0.732\*

  Zometa 8/4 mg 92/266         52.9%\*\*      1.55\*\*       0.687\*\*
                (35%)\*\*                                    

  Placebo       111/250 (44%)  63.2%-         2.52           \-
  ------------- -------------- -------------- -------------- ------------------

\*P\<0.05 Zometa 4mg vs. Placebo\
\*\*P\<0.05 Zometa 8/4mg vs. Placebo

# 12 Phase III Studies -- Safety

All safety data in this section is taken from the 120 day safety update
and therefore reflects updated pooled data from phase II and phase III
data plus extension patients up to August 15, 2001, except for survival,
which includes all data up to October 26, 2001, and creatinine data,
which includes all data up to October 24,2001.

## 6.1 Adverse Events

### 6.1.1 Overall Incidence in Phase II/III bone metastases studies

The adverse events (AEs) occurring during the studies were generally of
a type and frequency expected in patients with cancer and bone
metastases undergoing antineoplastic therapy. Most AEs occurred at a
similar rate across treatment groups. Exceptions were nausea, fatigue,
vomiting, pyrexia, diarrhea, myalgia, cough, arthralgia, back pain,
depression and headache which occurred more frequently in the Zometa 4
mg, Zometa 8/4 mg, and Aredia groups than in the placebo group. These
types of AEs can generally be managed clinically and are usually not
serious in nature. Except for pyrexia and fatigue, the difference in
proportions of patients with any particular AE in the Zometa 4 mg group
and the placebo group did not exceed 10%. Pyrexia, myalgia, and
gastrointestinal side effects have been previously reported with
bisphosphonate therapy. Fatigue and cough, as well as headache, were
most common in the Aredia group and least common in the placebo group,
with intermediate frequencies in the Zometa 4 mg and 8/4 mg groups.
Since the Aredia and placebo groups include patients with different
tumor types and different antineoplastic therapies, a disease rather
than a drug relationship is likely for events showing this type of
frequency distribution.

###### Table 6-1. No. (%) of patients with most frequent adverse events (≥ 15%) -- Phase II/III studies

  ------------------------------------------------------------------------------
                       **Zometa   **Zometa 4 **Zometa   **Aredia   **Placebo**
                       \< 4 mg**  mg**       8/4 mg**   90 mg**    
  -------------------- ---------- ---------- ---------- ---------- -------------
                       **n (%)**  **n (%)**  **n (%)**  **n (%)**  **n (%)**

  **Patients studied**                                             

  Total no. of         145 (100)  1099 (100) 1007 (100) 631 (100)  455 (100)
  patients studied                                                 

  Total no. of         145 (100)  1083       998 (99.1) 623 (98.7) 445 (97.8)
  patients with an AE             (98.5)                           

  **Adverse events\                                                
  (preferred term)**                                               

  Bone pain            75 (51.7)  603 (54.9) 566 (56.2) 360 (57.1) 282 (62.0)

  Nausea               62 (42.8)  513 (46.7) 499 (49.6) 301 (47.7) 171 (37.6)

  Fatigue              37 (25.5)  433 (39.4) 368 (36.5) 273 (43.3) 129 (28.4)

  Vomiting NOS         36 (24.8)  362 (32.9) 333 (33.1) 207 (32.8) 121 (26.6)

  Pyrexia              40 (27.6)  346 (31.5) 321 (31.9) 187 (29.6) 88 (19.3)

  Anaemia NOS          31 (21.4)  368 (33.5) 337 (33.5) 197 (31.2) 128 (28.1)

  Constipation         27 (18.6)  344 (31.3) 315 (31.3) 182 (28.8) 173 (38.0)

  Dyspnoea NOS         17 (11.7)  298 (27.1) 269 (26.7) 172 (27.3) 106 (23.3)

  Diarrhoea NOS        29 (20.0)  268 (24.4) 255 (25.3) 185 (29.3) 83 (18.2)

  Myalgia              35 (24.1)  252 (22.9) 232 (23.0) 168 (26.6) 74 (16.3)

  Weakness             20 (13.8)  262 (23.8) 230 (22.8) 126 (20.0) 114 (25.1)

  Anorexia             13 (9.0)   247 (22.5) 219 (21.7) 93 (14.7)  104 (22.9)

  Cough                23 (15.9)  239 (21.7) 195 (19.4) 150 (23.8) 64 (14.1)

  Oedema lower limb    22 (15.2)  232 (21.1) 205 (20.4) 133 (21.1) 84 (18.5)

  Arthralgia           23 (15.9)  238 (21.7) 207 (20.6) 149 (23.6) 70 (15.4)

  Headache             29 (20.0)  218 (19.8) 196 (19.5) 170 (26.9) 50 (11.0)

  Malignant neoplasm   19 (13.1)  217 (19.7) 194 (19.3) 102 (16.2) 88 (19.3)
  aggravated                                                       

  Dizziness (exc       4 (2.8)    185 (16.8) 134 (13.3) 104 (16.5) 58 (12.7)
  vertigo)                                                         

  Insomnia NEC         25 (17.2)  179 (16.3) 158 (15.7) 130 (20.6) 72 (15.8)

  Weight decreased     5 (3.4)    171 (15.6) 163 (16.2) 55 (8.7)   62 (13.6)

  Back pain            14 (9.7)   168 (15.3) 157 (15.6) 113 (17.9) 40 (8.8)

  Depression NEC       11 (7.6)   156 (14.2) 131 (13.0) 105 (16.6) 47 (10.3)

  Pain in limb         12 (8.3)   156 (14.2) 122 (12.1) 95 (15.1)  51 (11.2)

  Upper respiratory    19 (13.1)  110 (10.0) 70 (7.0)   96 (15.2)  30 (6.6)
  tract infection NOS                                              
  ------------------------------------------------------------------------------

NOS: Not otherwise specified NEC: Not elsewhere classified

### 6.1.2 Grade 3 and 4 Adverse Events

Grade 3 and 4 AEs reported in ≥ 5% (grade 3 and 4 combined) of patients
in any treatment group are presented below. The incidence of any grade 3
and 4 AEs and the incidence of each type of grade 3 and 4 AE were
generally similar across treatment groups. An exception was grade 3 and
4 bone pain, which was experienced more frequently by patients in the
placebo group than in the bisphosphonate groups. Grade 3 and 4
neutropenia and thrombocytopenia AEs were slightly more common in the
bisphosphonate groups than in the placebo group.

###### Table 6-2. No. (%) of patients with grade 3 or 4 AEs (≥ 5%) -- Phase II/III studies

  -------------------------------------------------------------------------------
                       **Zometa\   **Zometa\   **Zometa   **Aredia\   **\
                       \< 4 mg**   4 mg**      8/4 mg**   90 mg**     Placebo**
  -------------------- ----------- ----------- ---------- ----------- -----------
                       **n (%)**   **n (%)**   **n (%)**  **n (%)**   **n (%)**

  **Patients studied**                                                

  Total no. of         145 (100)   1099 (100)  1007 (100) 631 (100)   455 (100)
  patients studied                                                    

  No. with grade 3 AEs 46 (31.7)   417 (37.9)  377 (37.4) 242 (38.4)  185 (40.7)

  No. with grade 4 AEs 31 (21.4)   396 (36.0)  377 (37.4) 210 (33.3)  169 (37.1)

  **AE (preferred                                                     
  term)**                                                             

  Anaemia                                                             

  Grade 3              9 (6.2)     114 (10.4)  86 (8.5)   55 (8.7)    37 (8.1)

  Grade 4              3 (2.1)     26 (2.4)    18 (1.8)   17 (2.7)    5 (1.1)

  Neutropenia                                                         

  Grade 3              5 (3.4)     49 (4.5)    45 (4.5)   32 (5.1)    11 (2.4)

  Grade 4              5 (3.4)     27 (2.5)    33 (3.3)   28 (4.4)    9 (2.0)

  Thrombocytopenia                                                    

  Grade 3              1 (0.7)     38 (3.5)    38 (3.8)   18 (2.9)    7 (1.5)

  Grade 4              7 (4.8)     18 (1.6)    16 (1.6)   12 (2.2)    0 (0.0)

  Nausea                                                              

  Grade 3              5 (3.4)     75 (6.8)    59 (5.9)   35 (5.5)    18 (4.0)

  Grade 4              0 (0.0)     7 (0.6)     11 (1.1)   4 (0.6)     4 (0.9)

  Vomiting                                                            

  Grade 3              4 (2.8)     62 (5.6)    52 (5.2)   29 (4.6)    20 (4.4)

  Grade 4              1 (0.7)     8 (0.7)     11 (1.1)   6 (1.0)     5 (1.1)

  Weakness                                                            

  Grade 3              6 (4.1)     63 (5.7)    61 (6.1)   21 (3.3)    35 (7.7)

  Grade 4              0 (0.0)     11 (1.0)    7 (0.7)    6 (1.0)     7 (1.5)

  Fatigue                                                             

  Grade 3              9 (6.2)     64 (5.8)    51 (5.1)   27 (4.3)    19 (4.2)

  Grade 4              0 (0.0)     9 (0.8)     1 (0.1)    3 (0.5)     0 (0.0)

  Pneumonia                                                           

  Grade 3              4 (2.8)     33 (3.0)    33 (3.3)   26 (4.1)    14 (3.1)

  Grade 4              2 (1.4)     21 (1.9)    21 (2.1)   12 (1.9)    10 (2.2)

  Dehydration                                                         

  Grade 3              1 (0.7)     51 (4.6)    49 (4.9)   22 (3.5)    12 (2.6)

  Grade 4              0 (0.0)     14 (1.3)    12 (1.2)   2 (0.3)     8 (1.8)

  Bone pain                                                           

  Grade 3              22 (15.2)   170 (15.5)  179 (17.8) 90 (14.3)   120 (26.4)

  Grade 4              4 (2.8)     20 (1.8)    20 (2.0)   12 (1.9)    20 (4.4)

  Malignant neoplasm                                                  
  aggravated                                                          

  Grade 3              5 (3.4)     72 (6.6)    56 (5.6)   31 (4.9)    30 (6.6)

  Grade 4              10 (6.9)    93 (8.5)    89 (8.8)   33 (5.2)    42 (9.2)

  Dyspnoea                                                            

  Grade 3              3 (2.1)     79 (7.2)    79 (7.8)   40 (6.3)    34 (7.5)

  Grade 4              1 (0.7)     23 (2.1)    19 (1.9)   14 (2.2)    11 (2.4)
  -------------------------------------------------------------------------------

###  Serious Adverse Events

The most frequently (≥ 5% in any treatment group) reported SAEs are
summarized below. The types of SAEs observed were similar in nature to
the most frequently reported AEs (regardless of severity) overall,
except that progression of cancer (preferred term: malignant neoplasm
aggravated) was the most common serious event.

Only a small proportion of SAEs were suspected to be drug-related. The
proportion of patients with SAEs suspected to be study-drug related was
highest (5.0%) in the Zometa 8/4 mg group, primarily due to the higher
incidence of acute renal failure suspected to be drug-related (1.7%) in
this group.

###### Table 6-3. No (%) of patients with SAEs (≥ 5%) -- Phase II/III Studies

  ---------------------- ------------- ------------- ------------- ------------- -----------
                         **Zometa**\   **Zometa**\   **Zometa**\   **Aredia**\   **\
                         **\< 4 mg**   **4 mg**      **8/4 mg**    **90 mg**     Placebo**

                         **n (%)**     **n (%)**     **n (%)**     **n (%)**     **n (%)**

  **Patients studied**                                                           

  Total no. of patients  145 (100)     1099 (100)    1007 (100)    631 (100)     455 (100)

  Total no. of patients  59 (40.7)     652 (59.3)    624 (62.0)    340 (53.9)    293 (64.4)
  with any SAE                                                                   

  **Serious adverse                                                              
  events (preferred                                                              
  term)**                                                                        

  Malignant neoplasm\    10 (6.9)      141 (12.8)    122 (12.1)    52 (8.2)      58 (12.7)
  aggravated                                                                     

  Pyrexia                8 (5.5)       78 (7.1)      66 (6.6)      48 (7.6)      17 (3.7)

  Anaemia NOS            7 (4.8)       74 (6.7)      43 (4.3)      25 (4.0)      18 (4.0)

  Dehydration            3 (2.1)       72 (6.6)      64 (6.4)      24 (3.8)      25 (5.5)

  Bone pain              7 (4.8)       68 (6.2)      69 (6.9)      35 (5.5)      62 (13.6)

  Dyspnoea NOS           5 (3.4)       69 (6.3)      62 (6.2)      42 (6.7)      32 (7.0)

  Nausea                 2 (1.4)       58 (5.3)      54 (5.4)      22 (3.5)      20 (4.4)

  Pneumonia NOS          7 (4.8)       57 (5.2)      59 (5.9)      38 (6.0)      27 (5.9)

  Vomiting               2 (1.4)       57 (5.2)      58 (5.8)      29 (4.6)      22 (4.8)

  Weakness               2 (1.4)       49 (4.5)      41 (4.1)      17 (2.7)      30 (6.6)
  ---------------------- ------------- ------------- ------------- ------------- -----------

Preferred terms are sorted in descending frequency, as reported in the
Zometa 4 mg column.

## 6.2 NCI Grade 3 and 4 Laboratory Abnormalities

The tables below summarize grade 3 and 4 abnormalities for selected
chemistry tests other than creatinine and for hematology tests. Few
patients had grade 3 or 4 hypomagnesemia (N = 8) or hypernatremia (N =
4), so these tests are not included.

###### Table 6-4. No. (%) of patients with grade 3 or 4 serum chemistry values -- Phase II/III studies

  ---------------------------------------------------------------------------------------
                      **Zometa**\   **Zometa**\   **Zometa**\   **Aredia**\   **\
                      **\< 4 mg**   **4 mg**      **8/4 mg**    **90 mg**     Placebo**
  ------------------- ------------- ------------- ------------- ------------- -----------
                      **n (%)**     **n (%)**     **n (%)**     **n (%)**     **n (%)**

  **Chemistry test**                                                          

  Hypophosphatemia    N=144         N=1041        N=945         N=611         N=415

  Grade 3             16 (11.1)     124 (11.9)    167 (17.7)    47 (7.7)      14 (3.4)

  Grade 4             1 (0.7)       6 (0.6)       5 (0.5)       0 (0.0)       1 (0.2)

  Hyperphosphatemia   N=144         N=1041        N=945         N=611         N=415

  Grade 3             8 (5.6)       11 (1.1)      7 (0.7)       16 (2.6)      3 (0.7)

  Grade 4             3 (2.1)       15 (1.4)      5 (0.5)       15 (2.5)      1 (0.2)

  Hypocalcemia        N=144         N=1041        N=946         N=610         N=415

  Grade 3             0 (0.0)       7 (0.7)       10 (1.1)      5 (0.8)       0 (0.0)

  Grade 4             1 (0.7)       7 (0.7)       1 (0.1)       3 (0.5)       1 (0.2)

  Hypercalcemia       N=144         N=1041        N=946         N=610         N=415

  Grade 3             1 (0.7)       4 (0.4)       5 (0.5)       5 (0.8)       4 (1.0)

  Grade 4             2 (1.4)       1 (0.1)       3 (0.3)       5 (0.8)       1 (0.2)

  Hyponatremia        N=144         N=1039        N=946         N=610         N=415

  Grade 3             6 (4.2)       74 (7.1)      54 (5.7)      32 (5.2)      22 (5.3)

  Grade 4             0 (0.0)       2 (0.2)       3 (0.3)       1 (0.2)       1 (0.2)

  Hypokalemia         N=144         N=1037        N=945         N=610         N=415

  Grade 3             3 (2.1)       51 (4.9)      71 (7.5)      25 (4.1)      10 (2.4)

  Grade 4             1 (0.7)       8 (0.8)       15 (1.6)      4 (0.7)       2 (0.5)

  Hyperkalemia        N=144         N=1037        N=945         N=610         N=415

  Grade 3             10 (6.9)      33 (3.2)      18 (1.9)      18 (3.0)      8 (1.9)

  Grade 4             5 (3.5)       33 (3.2)      12 (1.3)      14 (2.3)      9 (2.2)

  Hypermagnesemia     N=144         N=1039        N=945         N=609         N=415

  Grade 3             1 (0.7)       20 (1.9)      20 (2.1)      3 (0.5)       8 (1.9)

  Grade 4             0 (0.0)       0 (0.0)       2 (0.2)       0 (0.0)       2 (0.5)

  Alkaline            N=144         N=1033        N=935         N=609         N=414
  phosphatase                                                                 

  Grade 3             15 (10.4)     91 (8.8)      102 (10.9)    32 (5.3)      67 (16.2)

  Grade 4             1 (0.7)       3 (0.3)       4 (0.4)       0 (0.0)       6 (1.5)

  SGOT                N=144         N=1040        N=946         N=611         N=415

  Grade 3             14 (9.7)      58 (5.6)      51 (5.4)      31 (5.1)      18 (4.3)

  Grade 4             1 (0.7)       3 (0.3)       2 (0.2)       5 (0.8)       2 (0.5)

  SGPT                N=144         N=1041        N=946         N=611         N=415

  Grade 3             13 (9.0)      35 (3.4)      27 (2.9)      34 (5.6)      5 (1.2)

  Grade 4             0 (0.0)       3 (0.3)       1 (0.1)       0 (0.0)       1 (0.2)

  Total bilirubin     N=144         N=1039        N=946         N=611         N=414

  Grade 3             5 (3.5)       7 (0.7)       5 (0.5)       9 (1.5)       4 (1.0)

  Grade 4             1 (0.7)       0 (0.0)       1 (0.1)       3 (0.5)       2 (0.5)
  ---------------------------------------------------------------------------------------

###### Table 6-5. No. (%) of patients with grade 3 or 4 hematology laboratory abnormalities -- Phase II/III bone metastases studies

  --------------------------------------------------------------------------------
                        **Zometa\   **Zometa\   **Zometa   **Aredia\   **\
                        \<4 mg**    4 mg**      8/4 mg**   90 mg**     Placebo**
  --------------------- ----------- ----------- ---------- ----------- -----------
  **Hematology test**   **n (%)**   **n (%)**   **n (%)**  **n (%)**   **n (%)**

  Hemoglobin            N=143       N=1022      N=931      N=601       N=408

  Grade 3               11 (7.7)    64 (6.3)    52 (5.6)   32 (5.3)    14 (3.4)

  Grade 4               5 (3.5)     13 (1.3)    13 (1.4)   8 (1.3)     2 (0.5)

  WBC Count             N=143       N=1021      N=925      N=600       N=408

  Grade 3               21 (14.7)   79 (7.7)    60 (6.5)   59 (9.8)    20 (4.9)

  Grade 4               5 (3.5)     14 (1.4)    8 (0.9)    13 (2.2)    0 (0.0)

  Absolute neutrophil   N=137       N=995       N=906      N=580       N=399
  count                                                                

  Grade 3               18 (13.1)   74 (7.4)    51 (5.6)   56 (9.7)    18 (4.5)

  Grade 4               11 (8.0)    38 (3.8)    27 (3.0)   24 (4.1)    10 (2.5)

  Absolute lymphocyte   N=143       N=1015      N=922      N=591       N=406
  ct.                                                                  

  Grade 3               48 (33.6)   262 (25.8)  233 (25.3) 179 (30.3)  93 (22.9)

  Grade 4               0 (0.0)     0 (0.0)     0 (0.0)    0 (0.0)     0 (0.0)

  Platelet count        N=143       N=1015      N=925      N=600       N=408

  Grade 3               16 (11.2)   53 (5.2)    31 (3.4)   29 (4.8)    9 (2.2)

  Grade 4               1 (0.7)     2 (0.2)     2 (0.2)    1 (0.2)     0 (0.0)
  --------------------------------------------------------------------------------

## Renal Effects

### 6.3.1 Renal Adverse Events in Phase II/III Bone Metastases Studies

Renal AEs overall and renal impairment, acute renal failure, increased
blood creatinine, hematuria, and oliguria increased with increasing dose
of Zometa, and occurred more frequently in the Zometa 8/4 mg group than
in the Aredia or placebo groups. The placebo group also had a high
(25.7%) incidence of renal and urinary AEs overall, and certain renal
AEs (urinary frequency, hematuria, urinary retention, obstructive
uropathy, hematuria present, urinary tract disorder, and difficulty in
micturition) occurred in a greater proportion of placebo patients than
other patients. Because the placebo group contains a disproportionate
percentage (45.7%) of patients with prostate cancer, these AEs are
likely to be disease-related. The frequency of renal adverse events is
presented for two groups of patients, those who received at least one
5-minute infusion (pre-15 minute infusion amendment) and those who were
randomized after the amendment.

###### Table 6-6. No. (%) of patients with AEs (≥ 1%) of the renal and urinary system -- pre-15-minute infusion amendment

  ---------------------------------------------------------------------------------
                          **Zometa\   **Zometa\   **Zometa   **Aredia   **\
                          \< 4 mg**   4 mg**      8/4 mg**   90 mg**    Placebo**
  ----------------------- ----------- ----------- ---------- ---------- -----------
                          **n (%)**   **n (%)**   **n (%)**  **n (%)**  **n (%)**

  **Patients studied**                                                  

  Total no. of patients   145 (100)   535 (100)   437 (100)  358 (100)  187 (100)
  studied                                                               

  Total no. of patients   10 (6.9)    120 (22.4)  129 (29.5) 49 (13.7)  48 (25.7)
  with a renal or urinary                                               
  AE                                                                    

  **Adverse events                                                      
  (preferred term)**                                                    

  Urinary frequency       0 (0.0)     23 (4.3)    21 (4.8)   6 (1.7)    10 (5.3)

  Renal impairment NOS    1 (0.7)     20 (3.7)    22 (5.0)   5 (1.4)    5 (2.7)

  Renal failure acute     2 (1.4)     19 (3.6)    24 (5.5)   10 (2.8)   4 (2.1)

  Blood creatinine        0 (0.0)     21 (3.9)    23 (5.3)   14 (3.9)   3 (1.6)
  increased                                                             

  Haematuria              0 (0.0)     19 (3.6)    27 (6.2)   5 (1.4)    14 (7.5)

  Urinary retention       0 (0.0)     11 (2.1)    23 (5.3)   3 (0.8)    14 (7.5)

  Hydronephrosis          0 (0.0)     9 (1.7)     8 (1.8)    6 (1.7)    3 (1.6)

  Oliguria                0 (0.0)     6 (1.1)     9 (2.1)    2 (0.6)    0 (0.0)

  Renal failure NOS       1 (0.7)     6 (1.1)     4 (0.9)    1 (0.3)    1 (0.5)

  Renal failure chronic   1 (0.7)     6 (1.1)     3 (0.7)    0 (0.0)    1 (0.5)

  Calculus renal NOS      1 (0.7)     5 (0.9)     5 (1.1)    0 (0.0)    0 (0.0)

  Obstructive uropathy    2 (1.4)     6 (1.1)     6 (1.4)    1 (0.3)    6 (3.2)

  Haematuria present      0 (0.0)     3 (0.6)     7 (1.6)    1 (0.3)    5 (2.7)

  Urinary tract disorder  0 (0.0)     4 (0.7)     0 (0.0)    0 (0.0)    3 (1.6)
  NOS                                                                   

  Difficulty in           0 (0.0)     2 (0.4)     2 (0.5)    1 (0.3)    3 (1.6)
  micturition                                                           

  Pyelonephritis NOS      3 (2.1)     2 (0.4)     0 (0.0)    2 (0.6)    1 (0.5)
  ---------------------------------------------------------------------------------

Post-15-minute infusion amendment, the overall incidence of renal or
urinary AEs decreased in the Zometa 8/4 mg compared with the incidence
pre-15-minute infusion. Renal impairment, increased blood creatinine,
and acute renal failure were slightly more common in the Zometa 4 mg
group than in the Aredia or placebo groups.

###### Table 6-7. No. (%) of patients with AEs (≥ 1%) of the renal and urinary system -- post-15-minute infusion patients

  --------------------------------------------------------------------------
                            **Zometa\    **Zometa    **Aredia    **\
                            4 mg**       8/4 mg**    90 mg**     Placebo**
  ------------------------- ------------ ----------- ----------- -----------
                            **n (%)**    **n (%)**   **n (%)**   **n (%)**

  **Patients studied**                                           

  Total no. of patients     564 (100)    570 (100)   273 (100)   268 (100)
  studied                                                        

  Total no. of patients     108 (19.1)   120 (21.1)  43 (15.8)   52 (19.4)
  with a renal or urinary                                        
  AE                                                             

  **Adverse events                                               
  (preferred term)**                                             

  Haematuria                30 (5.3)     22 (3.9)    7 (2.6)     18 (6.7)

  Renal impairment NOS      18 (3.2)     19 (3.3)    6 (2.2)     5 (1.9)

  Urinary frequency         18 (3.2)     15 (2.6)    5 (1.8)     7 (2.6)

  Blood creatinine          19 (3.4)     26 (4.6)    7 (2.6)     5 (1.9)
  increased                                                      

  Urinary retention         13 (2.3)     21 (3.7)    3 (1.1)     12 (4.5)

  Renal failure acute       13 (2.3)     25 (4.4)    2 (0.7)     3 (1.1)

  Haematuria present        6 (1.1)      5 (0.9)     0 (0.0)     2 (0.7)

  Urinary tract disorder    5 (0.9)      3 (0.5)     3 (1.1)     1 (0.4)
  NOS                                                            

  Hydronephrosis            5 (0.9)      11 (1.9)    0 (0.0)     3 (1.1)

  Oliguria                  2 (0.4)      6 (1.1)     1 (0.4)     2 (0.7)

  Hyperuricaemia            1 (0.2)      1 (0.2)     7 (2.6)     3 (1.1)

  Obstructive uropathy      4 (0.7)      7 (1.2)     3 (1.1)     1 (0.4)

  Renal failure NOS         4 (0.7)      4 (0.7)     3 (1.1)     2 (0.7)

  Difficulty in micturition 0 (0.0)      2 (0.4)     0 (0.0)     5 (1.9)

  Micturition urgency       3 (0.5)      1 (0.2)     3 (1.1)     3 (1.1)
  --------------------------------------------------------------------------

NOS: not otherwise specified

### Grade 3 and 4 Creatinine Values

For creatinine values only, all available results, including those from
the extension studies \[007E, 010E, 011E, 039 (phase 2)\] up to October
24, 2001 and those performed by local laboratories at other times than
specified in the protocol, are included. The frequency of post-baseline
grade 3 or 4 creatinine values in the Zometa 4 mg post-15 minute
infusion amendment population was similar to both the Aredia and placebo
groups who received the 15 minutes infusion.

###### Table 6-8. No. (%) of patients with grade 3 or 4 serum creatinine values pre- and post-15-minute infusion amendment -- Phase II/III bone metastases studies

  --------------------------------------------------------------------------------------
                     **Zometa**\   **Zometa**\   **Zometa**\   **Aredia**\   **\
                     **\< 4 mg**   **4 mg**      **8/4 mg**    **90 mg**     Placebo**
  ------------------ ------------- ------------- ------------- ------------- -----------
                     **n (%)**     **n (%)**     **n (%)**     **n (%)**     **n (%)**

  **Pre-15-minute                                                            
  infusion                                                                   
  amendment**                                                                

  No. of patients    144           513           416           344           175

  Baseline                                                                   

  Grade 3            0 (0.0)       0 (0.0)       1 (0.24)      0 (0.0)       0 (0.0)

  Grade 4            0 (0.0)       0 (0.0)       0 (0.0)       0 (0.0)       0 (0.0)

  Post-baseline                                                              

  Grade 3            2 (1.39)      9 (1.75)      5 (1.20)      4 (1.16)      2 (1.14)

  Grade 4            0 (0.0)       1 (0.19)      2 (0.48)      0 (0.0)       0 (0.0)

  **Post-15-minute                                                           
  infusion                                                                   
  amendment**                                                                

  No. of patients    0             529           531           268           241

  Baseline                                                                   

  Grade 3            \-            0 (0.0)       0 (0.0)       0 (0.0)       0 (0.0)

  Grade 4            \-            0 (0.0)       0 (0.0)       0 (0.0)       0 (0.0)

  Post-baseline                                                              

  Grade 3            \-            7 (1.32)      10 (1.88)     4 (1.49)      4 (1.66)

  Grade 4            \-            2 (0.38)      1 (0.19)      1 (0.37)      0 (0.0)
  --------------------------------------------------------------------------------------

### 6.3.5 Renal Function Deterioration -- Advisory Board Criteria

In another analysis of renal function, the following criteria determined
by the Renal Advisory Board were used to define post-baseline renal
function deterioration:

-   For patients with a baseline serum creatinine \< 1.4 mg/dL, an
    increase of 0.5 mg/dL above baseline, or

```{=html}
<!-- -->
```
-   For patients with a baseline serum creatinine ≥ 1.4 mg/dL, an
    increase of 1.0 mg/dL above baseline, or

-   Any doubling of the baseline serum creatinine.

As shown in the tables below, a dose relationship was observed with
respect to the Zometa 4 mg and 8/4 mg groups both pre- and
post-15-minute infusion. In both groups most of the increase was in the
patients with normal renal function at baseline. Both the Aredia and
placebo groups showed an increase in the number of patients experiencing
renal function deterioration in the post-15 minute group, and in both
groups the increase was in patients with a normal serum creatinine at
baseline. Post 15-minute infusion patients in the Zometa 8/4 mg group
continued to have the highest incidence of renal function deterioration
(17.5%). Patients in the Zometa 4 mg group had a slightly higher
incidence of such events than patients in the Aredia group (11.7% versus
9.3%).

###### Table 6-9. No. (%) of patients with notable serum creatinine values pre- and post-15-minute infusion amendment -- Phase II/III bone metastases studies

  ------------------ ----------- ---------- ---------- ----------- -----------
                     **Zometa \< **Zometa 4 **Zometa   **\         **\
                     4 mg**      mg**       8/4 mg**   Aredia 90   Placebo**
                                                       mg**        

  **Baseline serum   **n (%)**   **n (%)**  **n (%)**  **n (%)**   **n (%)**
  creatinine**                                                     

  **Pre-15-minute                                                  
  infusion                                                         
  amendment**                                                      

  **Normal**                                                       

  No of patients     134         456        363        326         149

  No. with renal     22 (16.4)   67 (14.7)  81 (22.3)  25 (7.7)    14 (9.4)
  function                                                         
  deterioration                                                    

  **Abnormal**                                                     

  No of patients     10          57         53         18          26

  No. with renal     4 (40.0)    17 (29.8)  17 (32.1)  1 (5.6)     1 (3.8)
  function                                                         
  deterioration                                                    

  **Total**                                                        

  No of patients     144         513        416        344         175

  No. with renal     26 (18.1)   84 (16.4)  98 (23.6)  26 (7.6)    15 (8.6)
  function                                                         
  deterioration                                                    

  **Post-15-minute                                                 
  infusion                                                         
  amendment**                                                      

  **Normal**                                                       

  No of patients     N/A         482        470        246         211

  No. with renal     N/A         55 (11.4)  80 (17.0)  23 (9.3)    18 (8.5)
  function                                                         
  deterioration                                                    

  **Abnormal**                                                     

  No of patients     N/A         47         61         22          30

  No. with renal     N/A         7 (14.9)   13 (21.3)  2 (9.1)     3 (10.0)
  function                                                         
  deterioration                                                    

  **Total**                                                        

  No of patients     N/A         529        531        268         241

  No. with renal     N/A         62 (11.7)  93 (17.5)  25 (9.3)    21 (8.7)
  function                                                         
  deterioration                                                    
  ------------------ ----------- ---------- ---------- ----------- -----------

Note: Patients receiving \< 4 mg Zometa only received 5-minute infusions
and are therefore not included in the post-15-minute infusion analysis.

### 6.3.6 Time to Creatinine Increase

Time to the first renal function deterioration was analyzed in the Phase
III studies using Cox regression with stratum as the stratified variable
and treatment group as the factor.

Risk ratios for time to the first renal function deterioration analysis
were calculated in each study. A risk ratio of 1 indicated no difference
between 2 treatment groups and a risk ratio greater than 1 indicated a
higher risk for the test group versus the reference group.

In Study 010, for patients who were randomized after the 15-minute
infusion Amendment date, the risk ratio was 0.984 up to month 13 between
the Zometa 4 mg group and the pamidronate 90 mg group. The risk ratio
calculated up to month 19 is 1.012. This indicates that the risk to the
first renal function deterioration has remained comparable for patients
in the Zometa 4 mg and pamidronate 90 mg groups.

In Study 011, for patients who were randomized after the 15-minute
infusion Amendment date, the risk ratio was 1.571 up to month 9 between
the Zometa 4 mg group and the placebo group, indicating that the risk of
renal function deterioration was higher for the Zometa 4 mg group,
although the p-value was not statistically significant. The risk ratio
calculated up to month 15 between the Zometa 4 mg group and the placebo
group was 1.587, and the p- value remained not statistically
significant. Therefore, the risk of renal deterioration in the 4 mg
group is unchanged.

In Study 039, for patients who were randomized after the 15-minute
infusion amendment date, the risk ratio was 1.066 up to month 15 between
the Zometa 4 mg group and the placebo group, indicating that the risk to
the first renal function deterioration was comparable for the patients
in these two groups. The risk ratio up to month 21 between the same two
groups was 1.107, indicating that the risk to first renal function
deterioration remains comparable between them.

The Kaplan-Meier curves (pre and post 15 minute amendment) for the
breast cancer/multiple myeloma (010), other solid tumors (011), and
prostate studies are shown below:

####### Figure 6-1. Kaplan-Meier curve for time to the first renal function deterioration by treatment group for the pre 15-minute infusion Amendment patients (Protocol 010, Safety evaluable patients)

![](media/image14.wmf){width="4.511805555555555in"
height="3.482638888888889in"}

####### Figure 6-2. Kaplan-Meier curve for time to the first renal function deterioration by treatment group for the post 15-minute infusion Amendment patients (Protocol 010, Safety evaluable patients)

![](media/image15.wmf){width="4.623611111111111in" height="3.5625in"}

####### Figure 6-3. Kaplan-Meier curve for time to the first renal function deterioration by treatment group for the pre 15-minute infusion Amendment patients (Protocol 011, Safety evaluable patients)

![](media/image16.wmf){width="4.331944444444445in"
height="3.3340277777777776in"}

[]{#__RefHeading___Toc533676768 .anchor}Figure 6-4. Kaplan-Meier curve
for time to the first renal function deterioration by treatment group
for the post 15-minute infusion Amendment patients (Protocol 011, Safety
evaluable patients)

![](media/image17.wmf){width="4.271527777777778in"
height="3.303472222222222in"}

####### Figure 6-5. Kaplan-Meier curve for time to the first renal function deterioration by treatment group for the pre 15-minute infusion Amendment patients (Protocol 039, Safety evaluable patients)

![](media/image18.wmf){width="4.695833333333334in"
height="3.6215277777777777in"}

####### Figure 6-6. Kaplan-Meier curve for time to the first renal function deterioration by treatment group for the post 15-minute infusion Amendment patients (Protocol 039, Safety evaluable patients)

![](media/image19.wmf){width="4.875694444444444in"
height="3.745138888888889in"}

## 6.4 Deaths

### 6.4.1 Primary Cause of Death

The proportion of patients who died was highest (29.7%) in the placebo
group. The Zometa \< 4 mg group and the Aredia group had the lowest
proportions of patients who died (9.7% and 16.6%, respectively). These
were the only two treatment groups that only had patients with breast
cancer and multiple myeloma. The proportions of patients who died in the
Zometa 4 mg (22.7%) and 8/4 mg (24.0%) groups fell between the
proportions in the Aredia and placebo groups. This pattern reflects the
differences in tumor types in the different treatment groups.

The primary causes of death are presented by body system and treatment
group in the following table.

###### Table 6-11. Primary causes of death (by body system) in Phase II/III studies

<table style="width:100%;">
<colgroup>
<col style="width: 31%" />
<col style="width: 0%" />
<col style="width: 14%" />
<col style="width: 0%" />
<col style="width: 12%" />
<col style="width: 0%" />
<col style="width: 15%" />
<col style="width: 0%" />
<col style="width: 14%" />
<col style="width: 0%" />
<col style="width: 12%" />
</colgroup>
<thead>
<tr class="header">
<th></th>
<th colspan="2"><strong>Zol</strong><br />
<strong>&lt; 4 mg</strong></th>
<th colspan="2"><strong>Zol</strong><br />
<strong>4 mg</strong></th>
<th colspan="2"><strong>Zol</strong><br />
<strong>8/4 mg</strong></th>
<th colspan="2"><strong>Aredia</strong><br />
<strong>90 mg</strong></th>
<th colspan="2"><strong><br />
Placebo</strong></th>
</tr>
</thead>
<tbody>
<tr class="odd">
<td colspan="2"></td>
<td colspan="2"><strong>n (%)</strong></td>
<td colspan="2"><strong>n (%)</strong></td>
<td colspan="2"><strong>n (%)</strong></td>
<td colspan="2"><strong>n (%)</strong></td>
<td><strong>n (%)</strong></td>
</tr>
<tr class="even">
<td colspan="2"><strong>Patients studied</strong></td>
<td colspan="2"></td>
<td colspan="2"></td>
<td colspan="2"></td>
<td colspan="2"></td>
<td></td>
</tr>
<tr class="odd">
<td colspan="2">Total no. of patients studied</td>
<td colspan="2">145 (100)</td>
<td colspan="2">1099 (100)</td>
<td colspan="2">1007 (100)</td>
<td colspan="2">631 (100)</td>
<td>455 (100)</td>
</tr>
<tr class="even">
<td colspan="2">No. of patients who died<sup>a</sup></td>
<td colspan="2">14 (9.7)</td>
<td colspan="2">250 (22.7)</td>
<td colspan="2">242 (24.0)</td>
<td colspan="2">105 (16.6)</td>
<td>135 (29.7)</td>
</tr>
<tr class="odd">
<td colspan="2"><strong>Body system</strong></td>
<td colspan="2"></td>
<td colspan="2"></td>
<td colspan="2"></td>
<td colspan="2"></td>
<td></td>
</tr>
<tr class="even">
<td colspan="2">Incomplete code<sup>b</sup></td>
<td colspan="2">0 (0.0)</td>
<td colspan="2">54 (4.9)</td>
<td colspan="2">47 (4.7)</td>
<td colspan="2">14 (2.2)</td>
<td>20 (4.4)</td>
</tr>
<tr class="odd">
<td colspan="2">Blood/lymphatic</td>
<td colspan="2">0 (0.0)</td>
<td colspan="2">0 (0.0)</td>
<td colspan="2">1 (0.1)</td>
<td colspan="2">0 (0.0)</td>
<td>0 (0.0)</td>
</tr>
<tr class="even">
<td colspan="2">Cardiac</td>
<td colspan="2">1 (0.7)</td>
<td colspan="2">20 (1.8)</td>
<td colspan="2">20 (2.0)</td>
<td colspan="2">9 (1.4)</td>
<td>11 (2.4)</td>
</tr>
<tr class="odd">
<td colspan="2">Gastrointestinal</td>
<td colspan="2">0 (0.0)</td>
<td colspan="2">2 (0.2)</td>
<td colspan="2">4 (0.4)</td>
<td colspan="2">1 (0.2)</td>
<td>2 (0.4)</td>
</tr>
<tr class="even">
<td colspan="2">General disorders/administration site</td>
<td colspan="2">1 (0.7)</td>
<td colspan="2">11 (1.0)</td>
<td colspan="2">7 (0.7)</td>
<td colspan="2">5 (0.8)</td>
<td>6 (1.3)</td>
</tr>
<tr class="odd">
<td colspan="2">Hepatobiliary</td>
<td colspan="2">0 (0.0)</td>
<td colspan="2">3 (0.3)</td>
<td colspan="2">2 (0.2)</td>
<td colspan="2">0 (0.0)</td>
<td>0 (0.0)</td>
</tr>
<tr class="even">
<td colspan="2">Infections/infestations</td>
<td colspan="2">2 (1.4)</td>
<td colspan="2">21 (1.9)</td>
<td colspan="2">16 (1.6)</td>
<td colspan="2">12 (1.9)</td>
<td>8 (1.8)</td>
</tr>
<tr class="odd">
<td colspan="2">Injury/poisoning</td>
<td colspan="2">0 (0.0)</td>
<td colspan="2">0 (0.0)</td>
<td colspan="2">1 (0.1)</td>
<td colspan="2">0 (0.0)</td>
<td>1 (0.2)</td>
</tr>
<tr class="even">
<td colspan="2">Metabolism/nutrition</td>
<td colspan="2">0 (0.0)</td>
<td colspan="2">0 (0.0)</td>
<td colspan="2">2 (0.2)</td>
<td colspan="2">0 (0.0)</td>
<td>1 (0.2)</td>
</tr>
<tr class="odd">
<td colspan="2"><p>Musculoskeletal/</p>
<p>connective tissue/bone</p></td>
<td colspan="2">0 (0.0)</td>
<td colspan="2">1 (0.1)</td>
<td colspan="2">0 (0.0)</td>
<td colspan="2">0 (0.0)</td>
<td>0 (0.0)</td>
</tr>
<tr class="even">
<td colspan="2">Neoplasms benign/malignant</td>
<td colspan="2">9 (6.2)</td>
<td colspan="2">106 (9.6)</td>
<td colspan="2">101 (10.0)</td>
<td colspan="2">48 (7.6)</td>
<td>66 (14.5)</td>
</tr>
<tr class="odd">
<td colspan="2">Nervous system</td>
<td colspan="2">1 (0.7)</td>
<td colspan="2">3 (0.3)</td>
<td colspan="2">6 (0.6)</td>
<td colspan="2">5 (0.8)</td>
<td>1 (0.2)</td>
</tr>
<tr class="even">
<td colspan="2">Psychiatric</td>
<td colspan="2">0 (0.0)</td>
<td colspan="2">0 (0.0)</td>
<td colspan="2">2 (0.2)</td>
<td colspan="2">0 (0.0)</td>
<td>1 (0.2)</td>
</tr>
<tr class="odd">
<td colspan="2">Renal/urinary</td>
<td colspan="2">0 (0.0)</td>
<td colspan="2">1 (0.1)</td>
<td colspan="2">10 (1.0)</td>
<td colspan="2">0 (0.0)</td>
<td>0 (0.0)</td>
</tr>
<tr class="even">
<td colspan="2">Respiratory/thoracic/<br />
mediastinal</td>
<td colspan="2">0 (0.0)</td>
<td colspan="2">23 (2.1)</td>
<td colspan="2">18 (1.8)</td>
<td colspan="2">9 (1.4)</td>
<td>13 (2.9)</td>
</tr>
<tr class="odd">
<td colspan="2">Vascular</td>
<td colspan="2">0 (0.0)</td>
<td colspan="2">5 (0.5)</td>
<td colspan="2">5 (0.5)</td>
<td colspan="2">2 (0.3)</td>
<td>5 (1.1)</td>
</tr>
</tbody>
</table>

^a^ The number of deaths includes all deaths recorded at study
completion or with a death date within 28 days after study termination.

^b^ No MedDRA code of patients who died after completion of study.

# 7. Summary of Safety

The safety characteristics of Zometa may be summarized as follows:

-   Zometa 4 mg given as an intravenous 15-minute repeated infusion
    every 3-4 weeks was well-tolerated in a broad target population of
    cancer patients with bone metastases.

-   The most commonly occurring adverse events and serious adverse
    events in these studies, such as bone pain, nausea, fatigue, and
    progression of cancer, were not unexpected in patients with
    metastatic cancer, many of whom were receiving antineoplastic
    therapy.

-   A dose relationship was observed for adverse events of the renal and
    urinary system and for renal function deterioration (based on
    creatinine analysis), with doses of 8 mg or higher having a higher
    incidence of such events.

-   The incidence of creatinine elevations and more serious degrees of
    renal function impairment was similar for Zometa 4 mg over 15
    minutes and pamidronate 90 mg over 2 hours and thus monitoring of
    renal functions should be similar for the two compounds.

-   A minimum infusion time of 15 minutes and minimum infusate volume of
    100 mL is recommended for the 4 mg dose, as faster infusion rates
    and more concentrated drug administration may increase the risk for
    renal function deterioration.

-   The risk of hypophosphatemia, hypokalemia, and hypocalcemia are also
    dose-related. At a dose of 4 mg, however, the incidence of these
    electrolyte abnormalities is very low.

-   Zometa, like other bisphosphonates, may be associated with the
    occurrence of an acute phase reaction with symptoms such as fever,
    chills, myalgias, and arthralgias.

-   The incidence of eye abnormalities and injection site reactions
    appeared to be lower with Zometa than with Aredia.

# 8. Summary of Effectiveness

The Zometa study program in patients with malignant bone lesions was
extensive in scope, enrolling over 3000 patients with multiple myeloma
or with bone metastases from a broad range of cancer types. These
studies have provided consistent evidence of Zometa effectiveness in
delaying or reducing the occurrence of skeletal-related morbid events,
in all tumor types studied. In breast cancer and multiple myeloma,
Zometa was shown to be effective in comparison to pamidronate (the
bisphosphonate currently approved for this use). In studies in patients
with prostate cancer or solid tumors other than prostate or breast
cancer, where previous bisphosphonates have not been shown to be
effective, Zometa was shown to be superior to placebo in delaying or
reducing the incidence of skeletal-related morbid events. The study data
indicate that both 4 mg and 8 mg doses of Zometa are effective, but
there is no evidence of any significant advantage in clinical
effectiveness for the higher dose, indicating that maximal effectiveness
is provided at the lower dose. Evidence of effectiveness is seen in
prostate cancer, where osteoblastic bone lesions are more common, as
well as in other malignancies where osteolytic lesions predominate. This
is believed to be due to the fact that osteoclast activation, with
excessive pathological bone resorption, is a central feature of all
malignant bone lesions; and Zometa is highly potent in blocking the
osteoclast activation associated with malignant bone lesions.

The consistency of the clinical effectiveness data is illustrated in the
following tables, which briefly recapitulate the findings of analyses of
Skeletal Related Events, the primary study endpoint. As noted
previously, the primary analysis for each of the phase III studies
compared the proportion of patients in each study arm who had an SRE
over the course of their study participation. Additional analyses
examined time to first SRE; rate of SREs over time (the Skeletal
Morbidity Rate); and Multiple Event analyses, using Anderson-Gill
methodology to evaluate SRE recurrence in patients in each study arm.

###### Table 8-1. Proportion of patients with one or more SREs (Phase III trials, primary analyses)

  ----------------- ----------------- ----------------- -----------------
                    **Study 010**     **Study 039**     **Study 011**

                    **Breast Cancer   **\               **\
                    or Myeloma**      Prostate Cancer** Other Solid
                                                        Tumors**

  Zometa 4 mg       248/561 (44%)     71/214 (33%)\*    97/257 (38%)

  Zometa 8/4 mg     242/524 (46%)     85/221 (38%)      92/266 (35%)\*

  Aredia            257/555 (46%)                       

  Placebo                             92/208 (44%)      111/250 (44%)
  ----------------- ----------------- ----------------- -----------------

\*P \< 0.05, compared to placebo

###### Table 8-2. Median Time to first SRE (Phase III trials)

  ----------------- ----------------- ----------------- -----------------
                    **Study 010**     **Study 039**     **Study 011**

                    **Breast Cancer   **\               **\
                    or Myeloma**      Prostate Cancer** Other Solid
                                                        Tumors**

  Zometa 4 mg       373               Not reached\      230\*
                                      (\> 420)\*        

  Zometa 8/4 mg     353               363               219\*

  Aredia            363                                 

  Placebo                             321               163
  ----------------- ----------------- ----------------- -----------------

\*P \< 0.05, compared to placebo

###### Table 8-3. Skeletal Morbidity Rate (rate of SREs over time, Phase III studies)

  ----------------- ----------------- ----------------- -----------------
                    **Study 010**     **Study 039**     **Study 011**

                    **Breast Cancer   **\               **\
                    or Myeloma**      Prostate Cancer** Other Solid
                                                        Tumors**

  Zometa 4 mg       1.09 ± 2.66       0.80 ± 1.703\*    3.08 ± 21.1

  Zometa 8/4 mg     1.10 ± 1.99       1.06 ± 2.193      1.96 ± 6.02

  Aredia            1.50 ± 5.45                         

  Placebo                             1.49 ± 3.336      2.74 ± 5.79
  ----------------- ----------------- ----------------- -----------------

\*P \< 0.05; 21-day window analyses

###### Table 8-4. Risk ratios compared to control, Multiple Event Analyses of SREs (Phase III studies)

  ----------------- ----------------- ----------------- -----------------
                    **Study 010**     **Study 039**     **Study 011**

                    **Breast Cancer   **\               **\
                    or Myeloma**      Prostate Cancer** Other Solid
                                                        Tumors**

  Zometa 4 mg       0.885             0.643\*           0.732\*

  Zometa 8/4 mg     0.910             0.847             0.687\*

  Aredia (control)  \-                                  

  Placebo (control)                   \-                \-
  ----------------- ----------------- ----------------- -----------------

\*P \< 0.05; 21-day window analyses

The above tables demonstrate the consistency of the effectiveness
findings, across these large controlled trials and across the different
analyses of Skeletal Related Events. The Multiple Event (Anderson-Gill)
analyses are of interest because they consider all SRE data (not just
the first event) as well as all available information on SRE-free
intervals in study participants, and thus may provide an especially
sensitive measure of the clinical impact of treatment. These analyses
provide substantial support for the effectiveness of Zometa in reducing
SRE risk in the placebo-controlled studies in prostate cancer and other
solid tumors, and show some suggestion of reduced risk compared to
pamidronate in the active-controlled study in breast cancer and multiple
myeloma. The data are consistent with the thesis that the increased
potency of Zometa may translate to greater, more broad-spectrum activity
(compared to other bisphosphonates) in the treatment of patients with
malignant bone lesions. Zometa thus can provide an important benefit to
a broad range of patients living with malignant bone lesions, reducing
the frequency with which these lesions cause clinical and functional
problems such as pain, disability, or loss of independence.

It is important to note that hypercalcemia of malignancy (HCM) was not
included in the composite Skeletal Related Event endpoint. However, HCM
is associated with a range of unpleasant and potentially dangerous
symptoms, and often requires emergent hospitalization for treatment.
Zometa is approved for the treatment of HCM; the current Zometa clinical
study program has provided evidence that Zometa can also reduce the
incidence of (i.e., prevent) HCM. Incorporation of HCM events together
with SREs in analyses of these clinical studies provides further
evidence of the substantial value of Zometa in these patient
populations.

Finally, Zometa has the advantage that it can be administered as a
15-minute infusion, reducing the time patients must spend in health care
settings (compared to the 2-4 hour infusion required for pamidronate and
other bisphosphonates).

In conclusion, based on this consistent pattern of efficacy in the broad
range of tumor types included in these phase III pivotal trials,
treatment with Zometa 4 mg as a 15-minute intravenous infusion every 3-4
weeks can be recommended for cancer patients with multiple myeloma or
with cancer metastatic to bone (regardless of tumor type).

# 9. Benefit-Risk Assessment

Bone metastases are associated with considerable morbidity (including
pain and disability) and have a severe impact on the daily lives of
patients with terminal malignant disease and a limited life expectancy.
Zometa provides an effective treatment for osteolytic and osteoblastic
bone metastases originating from a wide range of primary tumors,
reducing the incidence of skeletal-related events (including fractures
and hypercalcemia) and delaying the occurrence of such events. Of
particular note, Zometa is the first bisphosphonate with demonstrated,
statistically significant efficacy in reducing skeletal morbidity due to
bone metastases in prostate cancer.

In a comparative study in patients with breast cancer or multiple
myeloma, Zometa was shown to be of equivalent efficacy to pamidronate,
the current standard of care for patients with bone metastases due to
these cancers. Zometa, however, has the advantage that it can be
administered as a 15-minute infusion rather than the 2-4 hour infusion
required with pamidronate and other bisphosphonates.

The safety profile of 4 mg Zometa given as a 15-minute infusion,
established in a development program with over 2500 patients with bone
metastases who were treated with Zometa, appears to be very similar to
that of 90 mg pamidronate given as a 2-hour infusion, and is generally
typical of an intravenous bisphosphonate.

In conclusion, any risks of treatment with Zometa, when used as
indicated in the product insert (PI), are far outweighed by the risks of
skeletal morbidity resulting from untreated bone metastases, and by the
benefits that treatment offers in reducing the incidence of SREs and
delaying their occurrence. Zometa has the potential to play an important
role in the management of osteolytic and osteoblastic bone metastases
associated with a wide range of primary tumors. The proposed product
labeling (PI) reflects the efficacy and safety profile of Zometa as
demonstrated in the clinical development program. Approved Zometa
labeling should therefore be modified to allow for the safe use of this
effective product in the treatment of bone metastases associated with
breast cancer, prostate cancer and other solid tumors, and osteolytic
lesions of multiple myeloma in conjunction with standard antineoplastic
therapy.

# 10. Overall Conclusion

The 4 mg dose of Zometa was consistently superior to placebo in the
pivotal Phase III studies, and was equivalent to pamidronate in patients
with breast cancer or multiple myeloma. The incidence of SREs (the
primary efficacy variable in these studies) was statistically
significantly lower than with placebo. The efficacy of Zometa was
apparent across the range of primary tumor types studied (breast cancer,
multiple myeloma, lung, prostate and other solid tumors). It is
particularly notable that efficacy was clearly demonstrated in prostate
cancer (in Study 039), in terms of fewer SREs and a considerable
extension of the time to first SRE. Statistically significant efficacy
in the treatment (other than pain relief) of bone metastases in prostate
cancer has not previously been demonstrated with any other
bisphosphonate, including pamidronate. This benefit was apparent after
only 3 months of treatment. In the protocol-defined primary efficacy
analysis (incidence of SREs excluding HCM) in study 011, the difference
between Zometa 4 mg and placebo was not statistically significant.
However, the difference was statistically significant for the incidence
of SREs including HCM (a clinically important and potentially
life-threatening complication), and in other secondary analyses,
including the time to first SRE, and skeletal morbidity rates. Zometa 4
mg was able to delay the first SRE by a median of over 2 months compared
with placebo, an important finding in a patient population with a life
expectancy of 6 months or less. The efficacy of Zometa 4 mg in this
study was clear despite the fact that many patients received only 4
doses.

The safety profile of Zometa as demonstrated in the clinical development
program appeared similar to that of pamidronate. The overall safety
profile indicates only one clinically significant safety risk, that of
renal function deterioration with doses of 8 mg or higher. However, a
dose of 4 mg given over 15 minutes every 3 to 4 weeks, the recommended
dose and regimen for treatment of patients with cancer and bone
metastases, has an acceptable risk profile with regard to effects on
renal function.

# 11. References

1\. Lipton A, Small E, Saad F, et al. The new bisphosphonate, Zometa
(zoledronci acid) decreases skeletal complications in both lytic and
blastic lesions: a comparision to pamidronate (abstract 34. Cancer
Invest 2001:20(1):45-47.

2\. NDA 21-223 Zometa (Zoledronic acid) in the treatment of
hypercalcemia of malignancy, Approval date: 20-Aug --01.

3\. EU TIH authorization number -- EU/1/01/176/001-003: TIH approval
20-Mar-01.

4\. Mundy GR, Raisz LG, Cooper RE, et al. Evidence for the secretion of
an osteoclast stimulating factor in myeloma. N Engl J Med 1974; 291:
1041-1046.

5\. Valentin - Opran A, Charmon SA, Meunier PJ, et al. Quantitative
histology of myeloma-induced bone changes. Br J Haematol 1982; 52:
601-610.

6\. Taube T, Elomaa I, Blomqvist C, et al. Histomorphometric evidence
for osteoclast-mediated bone resorption in metastatic breast cancer.
Bone 1994; 15: 161-166.

7\. Mundy GR, Ibbotson KJ, D'Souza SM. Tumor products and the
hypercalcemia of malignancy. J Clin Invest 1985; 76: 391-394.

8\. Garrett JR, Durie BGM, Nedwin GE, et al. Production of lymphotoxin,
a bone resorbing cytokine, by cultured human myeloma cells. N Engl J Med
1987; 317: 526-532.

9\. Gozzolino F, Torcia M, Aldinacci DL, et al. Production of
interleukin-1 by bone marrow myeloma cells. Blood 1989; 74: 380-387.

10\. Vargas SJ, Gillespie MT, Powell GJ, et al. Localization of
parathyroid hormone-related protein mRNA expression in breast cancer and
metastatic lesions by in situ hybridization. J Bone Miner Res 1992; 7:
971-979.

11\. Lipton A, Costa L, Ali S, Demers L. Use of bone turnover for
monitoring bone metastases and response to therapy. Seminars in Oncology
2001;28 (4) Supp 11;54-59.

12\. Ralston SH, Patel U, Fraser WD, et al. Comparison of three
intravenous bisphosphonates in cancer-associated hypercalcemia. Lancet
1989; 2:1180-1182.

13\. Thiebaud D, Jaeger PH, Jacquet AF, Burckhardt P. Dose-response in
the treatment of hypercalcemia of malignancy by a single infusion of the
bisphosphonate AHPrBP. J Clin Oncol 1988: 6: 762-786.

14\. Body JJ, Borkowski A, Cleeren A, Bijvoet OLM. Treatment of
malignancy-associated hypercalcemia with intravenous
aminohydroxypropylidene diphosphonate. J Clin Oncol 1986; 4: 1177-1183.

15\. Gucalp R, Ritch P, Wiernick PH, et al. Comparative study of
pamidronate disodium and etidronate disodium in the treatment of
cancer-related hypercalcemia. J Clin Oncol 1992; 10: 134-142.

16\. Nussbaum SR, Younger J, Vandepol CJ, et al. Single-dose intravenous
therapy with pamidronate for the treatment of hypercalcemia of
malignancy: Comparison of 30-, 60-, and 90-mg dosages. Am J Med 1993;
297-304.

17\. Berenson JR, Lichtenstein A, Porter L, et al. Efficacy of
pamidronate in reducing skeletal events in patients with advanced
multiple myeloma. N Engl J Med 1996; 334: 488-493.

18\. Hortobagyi GN, Theriault RL, Porter L, et al. Efficacy of
pamidronate in reducing skeletal complications in patients with breast
cancer and lytic bone metastases. N Engl J Med 1996; 335: 1785-1791.

19\. Bounameaux HM, Schifferli J, Montani JP et al. Renal failure
associated with intravenous disphosphonates. Lancet, 1983; I: 471.

20\. Mian M, Beghe F, Caprio A, et al. Tolerability and safety of
clodronate therapy in bone diseases. Int J Clin Pharmacol Res. 1991;
11(2): 107-14.

21\. Hortobagyi GN, Theriault RL, Lipton A et al. Long-term prevention
of skeletal complications of metastatic breast cancer with pamidronate.
Protocol 19 Aredia Breast Cancer Study Group. J Clin Oncol. 1998; 16(6):
2038-44.

##  ATTACHMENT 1: COMPOSITION OF DATA SAFETY MONITORING BOARD (DSMB)

Dr Tim Eisen

Senior Lecturer in Medical Oncology

University College London

Department of Oncology

91 Riding House Street

London W1P 8BT

Dr. Steve Johnston (Breast Cancer)

Senior Lecturer & Honorary Consultant Medical Oncologist

The Royal Marsden NHS Trust

Dept of Medicine (1st floor Mulbery Hse)

Fulham Rd

London SW3 6JJ

Professor John Whitehead

Medical and Pharmaceutical Statistics Research Unit

The University of Reading

PO Box 240

Earley Gate

Reading, RG6-GFN,

UK

## ATTACHMENT 2: COMPOSITION OF RENAL ADVISORY BOARD (RAB)

Raimund Hirschberg, MD

Harbor-UCLA Medical Center, Box 406

1000 West Carson St

Torrance, CA 90509

William Bennett, MD

Legacy Good Samaritan Hospital

1040 NW 22nd Avenue, Suite 430

Portland, Oregon 97210

Prof. Claudio Ponticelli

Div. di Nefrologia e Dialisi

Padiglione CROFF

Ospedale Policlinico

Via Commenda, 15

20122 MILANO - ITALY

A. Ross Morton, MD

Renal Unit, Davies 2

Kingston General Hospital

Kingston, ON

K7L 2V7

## ATTACHMENT 3:

##  PROPOSED ZOMETA LABELING (including HCM)

###