CC39/11-1 ZOMETA ® in Prostate Cancer and Solid Tumors Other Than Prostate Cancer and Breast Cancer: Placebo-Controlled Trials Matthew Smith, MD, PhD Massachusetts

CC39/11-1

ZOMETA® in Prostate Cancer and

Solid Tumors Other Than Prostate Cancer and Breast Cancer:

Placebo-Controlled Trials Matthew Smith, MD, PhD

Massachusetts General Hospital Harvard Medical SchoolBoston, Massachusetts

Prof. Robert Coleman, MD, FRCPCancer Research Centre

Weston Park HospitalSheffield, England

C

CC39/11-2

Placebo-Controlled Trials Study Objective

Demonstrate that ZOMETA® is superior to placebo for the treatment of bone metastases

C

CC39/11-3

Placebo-Controlled Trials Study Endpoints (1)

Primary endpoint– Proportion (%) of patients experiencing any

skeletal-related event (SRE) not including hypercalcemia of malignancy (HCM)

C

CC39/11-4

Placebo-Controlled Trials 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

C

CC39/11-5

Placebo-Controlled Trials 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

Change of antineoplastic therapy for bone pain in prostate cancer

Hypercalcemia of malignancy (HCM)

C

CC39/11-6

Placebo-Controlled Trials 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§

C

§Skeletal events occurring within 21 days counted as a single occurrence.

CC39/11-7

Clinical Trials History

Original study design– ZOMETA® (8 mg or 4 mg) versus placebo

infused over 5 min every 3 wk for 9 (–PC/BC) or 15 mo (prostate cancer)

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 placebo

C

CC39/11-8

Clinical Trial History Amendment/Patient Accrual Timeline

29

6/98 12/98 6/99 6/00 12/0012/99

Accrual

1/01

Treatment and follow-up

275275

578578

368368Prostate cancer

N = 643

195195N = 773

Solid tumors –PB/BC

Renal Renal amendment 1amendment 1(5 (5 15 min 15 min

Infusion)Infusion)

Renal Renal amendment 2amendment 2(8 mg (8 mg 4 mg 4 mg

Dose)Dose)

CC39/11-9

ZOMETA® in Prostate Cancer:

Placebo-Controlled Trial (039)

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CC39/11-10

Prostate Cancer Trial Design (1)

Prostate carcinomaProstate carcinoma– Documented bone metastasesDocumented bone metastases

Rising PSARising PSA Baseline serum testosterone within the castrate Baseline serum testosterone within the castrate

range (range ( 50 ng/dL) 50 ng/dL) No strong opiate analgesicsNo strong opiate analgesics Serum creatinine 3.0 mg/dL (265 µmol/L) ECOG performance status 0, 1, 2 Appropriate antineoplastic therapy at

study entry

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CC39/11-11

Prostate Cancer Trial Design (2)

StratificationStratification– Presence or absence of any distant metastases Presence or absence of any distant metastases

at initial diagnosis of cancerat initial diagnosis of cancer Patients received oral vitamin D 400 IU and

calcium 500 mg Dose and dosing regimen

– ZOMETA® 4 mg, 8/4 mg, and placebo– 5-min amended to 15-min infusion– Every 3 wk

15-mo follow-up15-mo follow-up

C

CC39/11-12

Prostate Cancer Demographics and Prognostic Factors

ZOMETA® ZOMETA4 mg 8/4 mg Placebo

Demographic factor N = 214 N = 221 N = 208

Mean age, yr 71.8 71.2 72.2

Gender, % male 100.0 100.0 100.0

Race,Caucasian,% 83.2 84.2 82.7Black, % 11.2 8.3 9.1

Performance status

ECOG 0 - 1, % 92.1 91.3 91.3

Mean FACT-G score 81.0 81.4 82.2

No metastases atdiagnosis, n 115 134 116

Metastases at diagnosis, n 99 87 92

Baseline PSA, median 82 89 61

31

CC39/11-13

Prostate Cancer Patient Disposition

ZOMETA® ZOMETADisposition 4 mg 8/4 mg Placebo

8IS

E

T2

-3,

4

Intent-to-treat, N 214 221 208

Completed studytherapy (15 mo)

n 81 62 65

% 37.9 28.1 31.3

CC39/11-14

Prostate Cancer Reasons for Early Discontinuation

Patients, %


Reason for discontinuation N = 214 N = 221 N = 208

8IS

E

T2

-3,

4

Total discontinued prematurely 62.1 71.9 68.7

Death 11.7 18.1 15.4

Adverse events 17.8 19.9 13.9

Withdrew consent 19.2 22.6 16.8

Unsatisfactory therapeutic effect 8.9 7.7 16.3

Protocol violation 0.5 0.0 0.0

Lost to follow-up 1.9 0.0 2.4

Other 2.4 3.7 3.8

CC39/11-15

Prostate Cancer Proportion (%) of Patients With an SRE

3338

44

0

10

20

30

40

50

ZOMETA® 4 mg ZOMETA 8/4 mg Placebo

Per

cen

t o

f p

atie

nts

N = 214 221 208

12

P = .021P = .222

ZOMETA 4 mg versus placebo remained significant when fractures were excluded

CC39/11-16

Why Was No Dose Effect Observed?Percent Change From Baseline N-telopeptide (039)

Maximum target inhibition was achieved in the ZOMETA 4 mg group

-80

-60

-40

-20

0

20

40

1 3 6 9 12 15 End ofstudyTime, mo

Me

dia

n c

han

ge

fro

m b

ase

line

, %

ZOMETA® 4 mg ZOMETA 8/4 mg Placebo

CS

R 0

39

T 9

-13

22

CC39/11-17Prostate Cancer Combined AnalysisProportion (%) of Patients With an SRE

36

44

0

10

20

30

40

50

ZOMETA® 4 mg + 8/4 mg Placebo

Per

cen

t o

f p

atie

nts

N = 435 208

12

P = .041

CC39/11-18

Prostate Cancer Components of SRE by Month 15

23

13

5 42

24

15

85

3

29

22

7 7

3

0

5

10

15

20

25

30

35

Radiation tobone

All fractures Change ofantineoplastic

therapy

Spinal cordcompression

Surgery to bone

Per

cen

t o

f p

atie

nts

ZOMETA® 4 mg

ZOMETA 8/4 mg

Placebo

8IS

E T

2-1

5;C

SR

03

9 T

9-4

N

214

221

208

CC39/11-19

Prostate Cancer Time to First SRE

01

1 P

TF

9.2

-1p

3;

CS

R 0

39

T9

-2:

CS

R 0

11

T9

-3

ZOMETA 4 mg 214 149 97 70 45ZOMETA 8/4 mg 221 132 77 46 34Placebo 208 128 78 43 31

15

0102030405060708090

100

0 60 120 180 240 300 360 420Time after start of study drug, days

Pe

rce

nt

wit

ho

ut

ev

en

t

Median time, days P-value

ZOMETA® 4 mg NR .011ZOMETA 8/4 mg 363 .491Placebo 321

CC39/11-20

Prostate Cancer Mean SMR*

ZOMETA 8/4 mgZOMETA® 4 mg Placebo

0.0

0.5

1.0

1.5

2.0

2.5

3.0

3.5

Me

an

SM

R/y

r

N = 214 221 208

P = .143

P = .006

* +HCM P < .05 for ZOMETA 4 mg versus placebo

C

0.81.06

1.49

CC39/11-21Prostate CancerAndersen-Gill Multiple Event Analysis Time to SRE up to Month 15

ZOMETA® 4 mg ZOMETA 8/4 mg

Hazard 95% CI for Hazard 95% CI forratio hazard ratio ratio hazard ratio

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

CC39/11-22Prostate Cancer (039)Proportion of Patients With an SRE in Patients With Different Types of Bone Lesions

19

3933

5044

35

52 51

40

0

10

20

30

40

50

60

70

Lytic Other Blastic

Pe

rce

nt

wit

h S

RE

ZOMETA® 4 mgZOMETA 8/4 mgPlacebo

57

N = 26 26 59 63 129 15621 39 124

CC39/11-23

Prostate Cancer Disease-Related Endpoints

Median time, days

ZOMETA® ZOMETA P-value, 4 mg 8/4 mg Placebo ZOMETA 4 mg

Endpoint N = 214 N = 221 N = 208 vs placebo

Time to progressionof bone lesion, days 92 89 87 .275

Time to progressionof disease, days 84 84 84 .771

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CC39/11-24

Prostate Cancer Quality-of-Life Endpoints

Change from baseline, mean SD

ZOMETA® ZOMETA 4 mg 8/4 mg Placebo

Endpoint (15 mo) N = 214 N = 221 N = 208

Brief pain inventory score§ 0.6 2.27 0.3 2.18 0.9 2.23

Analgesic score§ 1.0 1.33 0.9 1.40 1.1 1.49

Performance status (ECOG)§ 0.9 1.10 1.0 1.16 1.0 1.28

FACT-G total score|| –7.4 17.7 –7.4 15.4 –8.3 17.4

§Increased score = decline.||Increased score = improvement.

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CC39/11-25

Prostate Cancer Efficacy Summary

ZOMETA decreases skeletal complications in men with prostate cancer and bone metastases

C

Time to MultipleProportion first SRE Mean skeletal event analysis

with SRE, % (hazard ratio) morbidity rate hazard ratio

ZOMETA® 4 mg 33 0.669 0.80 0.643N = 214P-value .021 .011 .006 .004

ZOMETA 8/4 mg 38 0.901 1.06 0.847N = 221P-value .222 .491 .143 .247

Placebo 44 1.49N = 208 — —

CC39/11-26

ZOMETA® in Prostate Cancer:

Placebo-Controlled Trial (039)

Safety

C

CC39/11-27Primary Cause of Death During theTrial or Within 28 Days After Study Drug Termination§

Patients, n (%)


Cause of death N = 214 N = 218 N = 208

8

Neoplasms benign/malignant 15 (7.0) 18 (8.3) 14 (6.7)Respiratory/thoracic/mediastinal 3 (1.4) 2 (0.9) 5 (2.4)Cardiac 5 (2.3) 5 (2.3) 8 (3.8)General disorders/administration site 5 (2.3) 1 (0.5) 2 (1.0)Infections/infestations 2 (0.9) 2 (0.9) 4 (1.9)Renal/urinary 0 (0.0) 4 (1.8) 0 (0.0)

ISS

T5

-12

§6 mo additional data.

CC39/11-28

Prostate Cancer Survival – All Patients§

0102030405060708090

100

0 120 240 360 480 600 720 840 960

Time after start of study drug, days

Pe

rce

nt

su

rviv

ing

ZOMETA 4 mg 214 194 162 141 114 95 53 21 10ZOMETA 8/4 mg 218 197 166 121 91 75 42 12 5Placebo 208 190 148 119 94 75 37 17 4

Median time, days

ZOMETA® 4 mg 563 P = .087ZOMETA 8/4 mg 418 P = .765Placebo 469

03

9E

PT

F 1

0.5

-1p

335


CC39/11-29

Safety-evaluable patients, n (%)

ZOMETA® 4 mg ZOMETA 8/4 mg PlaceboPreferred term N = 214 N = 218 N = 208

Bone pain 108 (50.5) 133 (61.0) 127 (61.1)Nausea 77 (36.0) 115 (52.8) 77 (37.0)Constipation 72 (33.6) 85 (39.0) 72 (34.6)Fatigue 70 (32.7) 67 (37.0) 53 (25.5)Anemia NOS 57 (26.6) 60 (27.5) 37 (17.8)Myalgia 53 (24.8) 53 (24.3) 37 (17.8)Vomiting NOS 46 (21.5) 64 (29.4) 43 (20.7)Weakness 45 (21.0) 50 (22.9) 40 (19.2)Anorexia 43 (20.1) 55 (25.2) 36 (17.3)Pyrexia 43 (20.1) 48 (22.0) 27 (13.0)Edema lower limb 41 (19.2) 48 (22.0) 27 (13.0)Dizziness (except vertigo) 38 (17.8) 22 (10.1) 24 (11.5)Diarrhea NOS 36 (16.8) 35 (16.1) 32 (15.4)Weight decreased 36 (16.8) 38 (17.4) 26 (12.5)

Prostate Cancer Incidence of Adverse Events ( 15%)Regardless of Study Drug Relationship

NOS = Not otherwise specified.

CS

R 0

39

T1

0-2

C

CC39/11-30Prostate CancerNCI Grade 3/4 HematologyElectrolyte and Mineral Changes

Anemia – Incidence < 10% for all treatment groups with

a higher incidence in the ZOMETA® 8/4-mg treatment group

– Higher use of red blood cells and erythropoietin in the ZOMETA treatment groups

Electrolyte and mineral adverse events– Incidence of hypocalcemia < 2% for all

treatment groups – Higher incidence of hypophosphatemia and

hypermagnesemia in the ZOMETA treatment groups

8V

ol 1

66

IS

S P

TT

5.1

-5

CC39/11-31

Patients Enrolling After the 15-min Amendment NCI Grade 3/4 Serum Creatinine Changes§

Patients, n (%)N = 257


N = 92 N = 87 N = 78

Grade 3 5 (5.4) 2 (2.3) 1 (1.3)

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

C


CC39/11-32Prostate CancerKaplan-Meier Estimates of First Serum Creatinine Increase§

0

20

40

60

80

100

n Hazard ratio P-value ZOMETA® 4 mg 112 2.033 .048

ZOMETA 8/4 mg|| 121 4.016 .001Placebo 121

01

0E

1 P

TF

10

.6-2

p1

35

0

20

40

60

80

100

0 120 240 360 480 600


n Hazard ratio P-value ZOMETA 4 mg 92 1.107 .802

ZOMETA 8/4 mg¶ 87 1.655 .199Placebo 78

§6 mo additional data.||53% of patients received only 8 mg.¶23% of patients received only 8 mg.

Percent ofpatients withoutincrease(randomizedprior to 15-mininfusionamendment)

Percent ofpatients withoutincrease(randomizedafter 15-mininfusionamendment)

CC39/11-33

Prostate Cancer Safety Summary

Adverse events commonly associated with bisphosphonates (fever, myalgias, anemias, hypophosphatemia, hypermagnesemia) were reported more frequently in the ZOMETA® treatment groups than in the placebo group

The risk of renal deterioration was similar between ZOMETA 4 mg (15-min infusion) and placebo

C

CC39/11-34

Prostate Cancer Overall Summary

ZOMETA® decreases skeletal complications in men with prostate cancer and bone metastases

C

CC39/11-35

ZOMETA® in Solid Tumors Other Than Prostate

Cancer and Breast Cancer (–PC/BC):Placebo-Controlled Trial (011)

Prof. Robert Coleman, MD, FRCPCancer Research Centre

Weston Park HospitalSheffield, England

C

CC39/11-36

Solid Tumors –PC/BC Trial Design (1)

Solid tumors other than prostate and Solid tumors other than prostate and breast cancer (–PC/BC)breast cancer (–PC/BC) 1 bone metastasis1 bone metastasis

Appropriate antineoplastic therapy at study entry

Serum creatinine 3.0 mg/dL (265 µmol/L)

ECOG performance status 0, 1, 2

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CC39/11-37

Solid Tumors –PC/BC Trial Design (2)

StratificationStratification– Non-small cell lung cancerNon-small cell lung cancer– Other solid tumors (renal, small cell lung, Other solid tumors (renal, small cell lung,

cancer of unknown primary, bladder, colorectal, cancer of unknown primary, bladder, colorectal, head and neck, etc.)head and neck, etc.)

Patients received oral vitamin D 400 IU and calcium 500 mg

Dose and dosing regimen– ZOMETA® 4 mg, 8/4 mg, and placebo– 5-min amended to 15-min infusion– Every 3 wk

9-mo follow-up9-mo follow-up

C

CC39/11-38

Solid Tumors –PC/BC Demographics and Prognostic Factors


Demographic factor N = 257 N = 266 N = 250

Mean age, yr 62.2 60.8 62.3

Gender, % male 62.3 69.9 64.8

Race

Caucasian, % 89.1 89.5 90.4Black, % 5.9 5.7 4.9

Performance status

ECOG 0 - 1, % 83.1 82.3 87.0

Mean FACT-G score 70.1 69.3 70.8

NSCLC, n 134 139 130

Other solid tumors, n 123 127 120

31

CC39/11-39

Solid Tumors –PC/BC Patient Disposition

8IS

E

T2

-3,

4

ZOMETA® ZOMETA

Disposition 4 mg 8/4 mg Placebo

Intent-to-treat, N 257 266 250

Completed studytherapy (9 mo)

n 68 65 63

% 26.5 24.4 25.2

CC39/11-40

Solid Tumors –PC/BC Reasons for Early Discontinuation

Patients, %


Reason for discontinuation N = 257 N = 266 N = 250

8IS

E

T2

-3,

4

Total discontinued prematurely 73.5 75.6 74.8

Death 25.7 28.2 26.4

Adverse events 19.1 24.4 20.8

Withdrew consent 17.9 13.5 16.8

Unsatisfactory therapeutic effect 7.0 5.3 8.0

Protocol violation 1.6 0.0 0.0

Lost to follow-up 0.8 1.5 0.0

Other 1.6 2.7 2.8

CC39/11-41Solid Tumors –PC/BC Proportion (%) of Patients With an SRETime to First SRE

3835

44

0

10

20

30

40

50

Pe

rce

nt

of

pa

tie

nts

ZOMETA® 4 mgZOMETA 8/4 mgPlacebo

N = 257 N = 266 N = 250

12

P = .127

P = .023

0

10

20

30

40

50

60

70

80

90

100

0 30 60 90 120 150 180 210 240Time after start of study drug, days

Pe

rce

nt

wit

ho

ut

ev

en

t Median time, days P-value

ZOMETA 4 mg 230 .023ZOMETA 8/4 mg 219 .034Placebo 163

ZOMETA 4 mg 257 107 62

468/4 mg 266 99 56

40Placebo 250 81 48

36

CC39/11-42

Solid Tumors –PC/BC Components of SRE by Month 9

27

16

4 3

26

12

53

32

21

4 4

0

5

10

15

20

25

30

35

Radiation tobone

All fractures Surgery to bone Spinal cordcompression

Per

cen

t o

f p

atie

nts

ZOMETA® 4 mg

ZOMETA 8/4 mg

Placebo

8IS

E T

2-1

5;

CS

R 0

11

T9

-7

N

257

266

250

CC39/11-43

Solid Tumors –PC/BC Mean SMR*

ZOMETA 8/4 mgZOMETA® 4 mg Placebo

0.0

0.5

1.0

1.5

2.0

2.5

3.0

3.5

N = 257 266 250

P = .005

P = .069

Mea

n S

MR

/yr

* + HCM P < .05 for ZOMETA 4 mg and 8/4 mg versus placebo.

C

2.24

1.55

2.52

CC39/11-44Solid Tumors –PC/BC Andersen-Gill Multiple Event Analysis Time to SRE up to Month 9

ZOMETA® 4 mg ZOMETA 8/4 mg

Hazard 95% CI for Hazard 95% CI forStratum ratio hazard ratio ratio hazard ratio

NSCLC Placebo 0.729 (0.524, 1.015) 0.530 (0.377, 0.745)Other solid tumors Placebo 0.737 (0.493, 1.101) 0.886 (0.605, 1.298)

Total Placebo 0.732 (0.567, 0.946) 0.687 (0.531, 0.890)

C

CC39/11-45Other Solid Tumors (011)Proportion of Patients With an SRE in Patients With Different Types of Bone Lesions

4337

26

39

3229

52

3835

0

10

20

30

40

50

60

70

Lytic Other Blastic

Pe

rce

nt

wit

h S

RE

ZOMETA® 4 mg

ZOMETA 8/4 mgPlacebo

57

N = 111 119 104 82 42 51128 96 40

CC39/11-46

Solid Tumors –PC/BC Disease-Related Endpoints

Median time, days

ZOMETA® ZOMETA P-value, 4 mg 8/4 mg Placebo ZOMETA 4 mg

Endpoint N = 257 N = 266 N = 250 vs placebo

Time to progressionof bone lesion, days 145 238 109 .34

Time to progressionof disease, days 89 91 84 .117

C

CC39/11-47

Solid Tumors –PC/BC Quality-of-Life Endpoints

Change from baseline, mean SD


Endpoint (9 mo) N = 257 N = 266 N = 250

Brief pain inventory score§ 0.1 2.36 0.3 2.08 0.3 2.34

Analgesic score§ 0.3 1.20 0.3 1.18 0.3 1.08

Performance status (ECOG)§ 0.9 1.22 1.0 1.25 1.1 1.18

FACT-G total score|| –4.7 15.7 –2.8 16.7 –4.9 16.8

§Increased score = decline.||Increased score = improvement.

C

CC39/11-48

Solid Tumors –PC/BC Efficacy Summary

ZOMETA is the first bisphosphonate to demonstrate efficacy in decreasing skeletal complications in a broad range of solid tumors

C

Time to MultipleProportion first SRE Mean skeletal event analysis

with SRE. % (hazard ratio) morbidity rate hazard ratio

ZOMETA® 4 mg 38 0.728 2.24 0.732N = 257P-value .127 .023 .069 .017

ZOMETA 8/4 mg 35 0.741 1.55 0.687N = 266P-value .023 .034 .005 .004

Placebo 44 2.52 —N = 250

CC39/11-49

ZOMETA® in Solid Tumors Other Than Prostate

Cancer and Breast Cancer (–PC/BC):Placebo-Controlled Trial (011)

Safety

C

CC39/11-50Primary Cause of Death During theTrial or Within 28 Days After Study Drug Termination§

Patients, n (%)


Cause of death N = 254 N = 265 N = 247

8

Neoplasms benign/malignant 33 (13.0) 43 (16.2) 52 (21.1)Respiratory/thoracic/mediastinal 15 (5.9) 10 (3.8) 8 (3.2)Cardiac 8 (3.1) 9 (3.4) 3 (1.2)General disorders/administration site 3 (1.2) 5 (1.9) 4 (1.6)Infections/infestations 6 (2.4) 6 (2.3) 4 (1.6)Renal/urinary 1 (0.4) 2 (0.8) 0 (0.0)Hepato-biliary disorders 0 (0.0) 1 (0.4) 0 (0.0)

ISS

T5

-12


CC39/11-51

Solid Tumors –PC/BC Survival – All Patients§

0102030405060708090

100

0 120 240 360 480 600


Pe

rce

nt

su

rviv

ing

ZOMETA 4 mg 254 173 102 65 36 17ZOMETA 8/4 mg 265 177 107 73 38 13Placebo 247 155 92 62 31 18

Median time, days

ZOMETA® 4 mg 203 P = .947ZOMETA 8/4 mg 189 P = .471Placebo 183

01

1E

1 P

TF

10

.5-1

p3

35


CC39/11-52

Safety-evaluable patients, n (%)

ZOMETA® 4 mg ZOMETA 8/4 mg PlaceboPreferred term N = 254 N = 265 N = 247

Bone pain 129 (50.8) 130 (49.1) 145 (58.7)Nausea 116 (45.7) 106 (40.0) 83 (33.6)Anemia NOS 94 (37.0) 82 (30.9) 82 (33.2)Vomiting NOS 91 (35.8) 83 (31.3) 71 (28.7)Constipation 85 (33.5) 76 (28.7) 89 (36.0)Dyspnea NOS 83 (32.7) 90 (34.0) 65 (26.3)Fatigue 79 (31.1) 78 (29.4) 72 (29.1)Pyrexia 67 (26.4) 70 (26.4) 56 (22.7)Weakness 66 (26.0) 67 (25.3) 65 (26.3)Anorexia 58 (22.8) 60 (22.6) 62 (25.1)Edema lower limb 56 (22.0) 53 (20.0) 49 (19.8)Malignant neoplasm aggravated 54 (21.3) 67 (25.3) 56 (22.7)Cough 47 (18.5) 44 (16.6) 38 (15.4)Diarrhea NOS 43 (16.9) 48 (18.1) 44 (17.8)Headache NOS 42 (16.5) 36 (13.6) 26 (10.5)Insomnia NEC 42 (16.5) 38 (14.3) 30 (12.1)Dehydration 40 (15.7) 48 (18.1) 41 (16.6)

Solid Tumors –PC/BC Incidence of Adverse Events ( 15%)Regardless of Study Drug Relationship

NOS = Not otherwise specified. NEC = Not elsewhere classified.

C

CC39/11-53Solid Tumors –PC/BC NCI Grade 3/4 HematologyElectrolyte and Mineral Changes

Anemia – Incidence < 5% for all treatment groups, with a

slightly higher incidence in the ZOMETA® treatment groups

– Use of red blood cells and erythropoietin was similar for all treatment groups

Electrolyte and mineral adverse events– Incidence of hypocalcemia < 2% for all

treatment groups– Higher incidence of hypophosphatemia in the

ZOMETA treatment groups

8V

ol 1

66

IS

S P

TT

5.1

-5

CC39/11-54

Patients Enrolling After the 15-min Amendment NCI Grade 3/4 Serum Creatinine Changes§

Patients, n (%)

N = 509


N = 165 N = 181 N = 163

Grade 3 1 (0.6) 2 (1.1) 3 (1.8)

Grade 4 2 (1.2) 0 (0.0) 0 (0.0)

C


CC39/11-55Solid Tumors –PC/BC Kaplan-Meier Estimates of First Serum Creatinine Increase§

01

1E

1 P

TF

10

.6-2

p1

35

§6 mo additional data.||24% of patients received only 8-mg.¶51% of patients received only 8 mg.

0

20

40

60

80

100

n Hazard ratio P-valueZOMETA® 4 mg 61 3.836 .050ZOMETA 8/4 mg|| 55 2.883 .132Placebo 54

0

20

40

60

80

100

0 120 240 360


n Hazard ratio P-valueZOMETA 4 mg 165 1.587 .228ZOMETA 8/4 mg¶ 181 1.907 .079Placebo 163

Percent ofpatients(randomizedprior to 15-mininfusionamendment)

Percent ofpatients(randomizedafter 15-mininfusionamendment)

CC39/11-56

Solid Tumors –PC/BC Safety Summary

Adverse events commonly associated with bisphosphonates (hypophosphatemia, anemias) were reported more frequently in the ZOMETA® treatment groups

Risk of renal deterioration was moderately higher in the ZOMETA 4-mg treatment group(15-min infusion) than in the placebo group

C

CC39/11-57

Solid Tumors –PC/BC Overall Summary

ZOMETA® is the first bisphosphonate to demonstrate efficacy in decreasing skeletal complications in a broad range of solid tumors

ZOMETA (4 mg via 15-min infusion) has a safety profile similar to i.v. pamidronate 90 mg (historical)

C

Documents

CC39/11-1 ZOMETA ® in Prostate Cancer and Solid Tumors Other Than Prostate Cancer and Breast Cancer: Placebo-Controlled Trials Matthew Smith, MD, PhD Massachusetts