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CC10-2. Breast Cancer and Multiple Myeloma Trial Design (1). Double-blind, double-dummy StratificationDurie-Salmon Stage III multiple myeloma with ? 1 osteolytic lesionChemotherapyHormonal therapyAppropriate antineoplastic therapy at baseline and during the course of the trial ECOG performance
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1. ZOMETA® in Breast Cancer and Multiple Myeloma: Pamidronate-Controlled Trial (010) James Berenson, MDCedars-Sinai Medical CenterLos Angeles, California
2. CC10-2 Breast Cancer and Multiple MyelomaTrial Design (1) Double-blind, double-dummy
Stratification
Durie-Salmon Stage III multiple myeloma with? 1 osteolytic lesion
Chemotherapy
Hormonal therapy
Appropriate antineoplastic therapy at baseline and during the course of the trial
ECOG performance status 0, 1, 2
Serum creatinine ? 3.0 mg/dL (265 µmol/L)
3. CC10-3 Breast Cancer and Multiple MyelomaTrial Design (2) 12-mo dosing regimen
Pamidronate 90 mg every 3 to 4 wk/120-min infusion
ZOMETA® 4 mg and 8/4 mg every 3 to 4 wk/5-min amended to 15-min infusion
Study duration of 13 mo
Patients received oral vitamin D 400 IU and calcium 500 mg
4. CC10-4 Breast Cancer and Multiple MyelomaStudy Objectives Primary objective
Demonstrate the effectiveness of ZOMETA® through the noninferiority§ comparison to pamidronate for the treatment of bone metastases
Demonstrate safety profile of ZOMETA comparable to pamidronate
5. CC10-5 Breast Cancer and Multiple MyelomaStudy Endpoints (1) Primary endpoint
Proportion (%) of patients experiencing any skeletal-related event (SRE) not including hypercalcemia of malignancy (HCM)
6. CC10-6 Breast Cancer and Multiple Myeloma Study Endpoints (2) Secondary endpoints
Time to first SRE
Skeletal morbidity rate (SMR)
Andersen-Gill multiple event analysis
Time to first SRE, SMR, and proportion (%) of patients with any SRE (+HCM)
Pain/analgesic scores
Bone lesion response
Time to progression of disease
Safety (including survival)
Additional 6 mo of survival and serum creatinine data
7. CC10-7 Breast Cancer and Multiple Myeloma Skeletal-Related Events (SREs) Pathologic fractures
Spinal cord compression
Radiation for bone pain or to treat or prevent pathologic fractures or spinal cord compression
Surgery to bone
Hypercalcemia of malignancy (HCM)
8. CC10-8 Breast Cancer and Multiple Myeloma Preplanned SRE Analysis Proportion (%) of patients with an SRE
Number of patients with SRE divided by number of patients in each treatment group
Time to first SRE
Time from randomization to first SRE (days)
Skeletal morbidity rate (SMR)§
Number of SREs divided by time at risk on trial (yr)
Andersen-Gill multiple event analysis§
Time from randomization to each occurrence of the events
9. CC10-9 Clinical Trial History Original study design
ZOMETA® (4 mg or 8 mg) via 5-min infusion versus pamidronate 90 mg infused over 120 min every 3 to 4 wk for 12 mo
Renal amendment 1 (June 1999)
Infusion time for ZOMETA increased from 5 min to 15 min
Infusion volume increased from 50 mL to 100 mL
Renal amendment 2 (June 2000)
8 mg switched to 4 mg (8/4-mg group)
Renal function monitoring within 2 wk prior to each dose
Statistical amendment
Primary efficacy analysis based on ZOMETA 4 mg versus pamidronate 90 mg
10. CC10-10 Clinical Trial History Breast Cancer and Multiple Myeloma (010)
11. CC10-11 Breast Cancer and Multiple Myeloma Demographics and Prognostic Factors ZOMETA® ZOMETA Pam 4 mg 8/4 mg 90 mg
Demographic factor N = 561 N = 524 N = 555
Mean age, yr 59.7 58.9 58.8
Gender, % female 81.5 81.7 83.5
Race, % Caucasian 87.9 84.4 87.1
Performance status
ECOG 0 - 1, % 84.5 81.9 78.6
Breast cancer
Chemotherapy, n 178 172 181
Hormonal therapy, n 200 192 207
Multiple myeloma, n 183 160 167
12. CC10-12 Breast Cancer and Multiple Myeloma Patient Disposition
ZOMETA® ZOMETA Pam
Disposition 4 mg 8/4 mg 90 mg
Intent-to-treat, N 561 524 555
Completed studytherapy (13 mo)
n 353 313 337
% 62.9 59.7 60.7
13. CC10-13 Breast Cancer and Multiple Myeloma Reasons for Early Discontinuation Patients, %
ZOMETA® ZOMETA Pam 4 mg 8/4 mg 90 mg Reason for discontinuation N = 561 N = 524 N = 555
Total discontinued prematurely 37.1 40.3 39.3
Death 10.7 10.7 11.5
Adverse events 10.2 13.4 9.2
Withdrew consent 8.4 8.6 10.1
Unsatisfactory therapeutic effect 3.2 3.4 4.0
Condition no longer required study drug 1.1 1.3 1.4
Protocol violation 1.1 0.8 0.7
Others 2.5 2.2 2.3
14. CC10-14 Breast Cancer and Multiple Myeloma Proportion (%) of Patients With an SRE
15. CC10-15 Noninferiority Margin for Study 010(Using Pamidronate 12, 18, and 19) % with SRE Placebo vs Pam 90 mg
Patients Placebo Pam Diff 95% CI margin
All 52.0 38.9 13.1 (7.3, 18.9) 3.65
16. CC10-16 Breast Cancer and Multiple Myeloma Components of SRE by Month 13
17. CC10-17 Breast Cancer and Multiple Myeloma Time to First SRE
18. CC10-18 Breast Cancer and Multiple Myeloma Mean SMR
19. CC10-19 Breast Cancer and Multiple MyelomaAndersen-Gill Multiple Event Analysis Time to SRE up to Month 13 ZOMETA® 4 mg ZOMETA 8/4 mg
Hazard 95% CI for Hazard 95% CI for ratio hazard ratio ratio hazard ratio
Pam 90 mg 0.885 (0.748, 1.047) 0.910 (0.768, 1.079)
ZOMETA 4 mg 1.025 (0.863, 1.218)
20. CC10-20 Breast Cancer (010)Proportion of Patients With an SRE Patients With Different Types of Bone Lesions
21. CC10-21 Breast Cancer and Multiple Myeloma Disease- and QOL-Related Endpoints Comparable disease and QOL-related measures were demonstrated for the ZOMETA® and pamidronate arms
Time to progression of bone metastases
Time to overall progression of disease
Pain and analgesic scores
ECOG performance status
Global quality of life
22. CC10-22 Breast Cancer and Multiple Myeloma Disease-Related Endpoints
23. CC10-23 Breast Cancer and Multiple Myeloma Quality-of-Life Endpoints
24. CC10-24 Breast Cancer and Multiple Myeloma Efficacy Summary ZOMETA demonstrated comparable efficacy to pamidronate (noninferiority) in preventing skeletal-related events
25. ZOMETA® in Breast Cancer and Multiple Myeloma:Pamidronate-Controlled Trial (010) Safety
26. CC10-26 Primary Cause of Death During theTrial or Within 28 Days After Study Drug Termination§ Patients, n (%)
ZOMETA® ZOMETA Pam
4 mg 8/4 mg 90 mgCause of death N = 563 N = 524 N = 556
27. CC10-27 Breast Cancer and Multiple Myeloma Survival – All Patients§
28. CC10-28 Breast Cancer and Multiple Myeloma Incidence of Adverse Events (? 15%)Regardless of Study Drug Relationship
29. CC10-29 Breast Cancer and Multiple MyelomaNCI Grade 3/4 HematologyElectrolyte and Mineral Changes Anemia
Incidence < 6% for all treatment groups
No differences between treatment groups
Use of red blood cells and erythropoietin was similar for all treatment groups
Electrolyte and mineral adverse events
Incidence < 10% in all treatment groups
Most common events in the ZOMETA® 4 mg treatment group were hypophosphatemia, hypokalemia, and hyperkalemia
30. CC10-30 Breast Cancer and Multiple MyelomaDefinition of Serum Creatinine Increase Serum creatinine normal (< 1.4 mg/dL) and an increase of 0.5 mg/dL
Serum creatinine abnormal (? 1.4 mg/dL) and an increase of 1.0 mg/dL
Doubling of serum creatinine baseline value
If serum creatinine was increased, dose was held
until within 10% of the baseline serum level
31. CC10-31 Breast Cancer and Multiple Myeloma Kaplan-Meier Estimates of First Serum Creatinine Increase§
32. CC10-32 Breast Cancer and Multiple MyelomaPatients Enrolling After the 15-min Amendment NCI Grade 3/4 Serum Creatinine Changes§ Patients, n (%) N = 803
ZOMETA® ZOMETA Pam 4 mg 8/4 mg 90 mg N = 272 N = 263 N = 268
Grade 3 1 (0.4) 6 (2.3) 4 (1.5)
Grade 4 0 (0.0) 1 (0.4) 1 (0.4)
33. CC10-33 Breast Cancer and Multiple Myeloma Safety Summary ZOMETA® (4 mg via 15-min infusion) has a safety profile, including renal effects, comparable to i.v. pamidronate (90 mg over 120 min) dosed every 3 to 4 weeks
34. CC10-34 Breast Cancer and Multiple Myeloma Overall Summary ZOMETA® 4 mg via 15-min infusion every 3 to 4 weeks demonstrated comparable safety and efficacy (noninferiority) to pamidronate 90 mg over 120 min in treating bone metastases in breast cancer and osteolytic lesions in multiple myeloma