Novartis Pharmaceuticals Corporation

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Appendix 4:
ONJ in Clinical Studies

 

 

Zometa® (zoledronic acid) Injection

and

Aredia® (pamidronate disodium) Injection

Submitted:  February 1, 2005

 

 

Oncologic Drugs Advisory Committee Meeting

March 4, 2005

 

 

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Table 1 -  Pivotal bone metastases studies included in the search for terms related to ONJ using MedDRA terms

Phase I
Study No.

Indication

No. patients

Study duration

Zol
0.4/8 mg

Zol
2/8 mg

Zol
4/8 mg

Zol/Aredia
90 mg

Aredia
90 mg

CZOL4460007+E1)

BCa, MM

288

9mo/21mo

62

62

59

30

75

 

Phase III randomized
Study No.

Indication

No. patients

Study duration

Treatment Groups (No. patients)

Zol
4 mg

Zol 8mg/
4 mg

Aredia
90 mg

Placebo

ZOMETA studies

 

 

 

 

 

 

 

CZOL4460010+E

MM, BCa

1648

25 mo

564

526

558

NA

CZOL4460011+E

Solid tumors (except BCa+PCa)

773

21 mo

257

266

NA

250

CZOL4460039+E

PCa

643

24 mo

214

221

NA

208

CZOL4460704

PCa

405

38.7 mo2)

49

155

NA

201

Total Zometa studies

 

3,469

 

1,084

1,168

558

659

 

 

 

 

 

 

 

 

AREDIA studies

 

 

 

 

 

 

 

CARD233AP12

MM

392

21 mo

NA

NA

203

189

CARD233AP18

BCa

371

24 mo

NA

NA

182

189

CARD233AP19

BCa

382

24 mo

NA

NA

185

197

Total Aredia studies

 

1,145

 

 

 

570

575

TOTAL (Z+A Phase III)

 

4,614

 

1,084

1,168

1,128

1,234

1) After the 9 month core study patients who entered the extension study were switched from lower Zometa doses to 8 mg Zometa or Aredia.  Patients in the Aredia group continued to receive Aredia.

2) Study was terminated earlier.  The maximum duration on study was 38.7 months.

Table 2 – Pivotal Zometa hypercalcemia studies included in the search for terms related to ONJ using MedDRA

Phase I
Study No.

Indication

No. patients

Study duration

Zol
0.002 mg/kg

Zol
0.005 mg/kg

Zol
0.01 mg/kg

Zol
0.02 mg/kg

Zol
0.04 mg/kg

CHJC11)

Cancer

33

5 weeks

3

3

4

5

18

 

Phase II
Study No.

Indication

No. patients

Study duration

Zol
4 mg

Zol
8 mg

Aredia
90 mg

CZOL4460362)

Cancer

144

Max. 3 mo

46

48

50

CZOL4460372)

Cancer

138

Max. 3 mo

40

47

51

Total Phase 2

 

282

 

84

95

101

1)Single infusion
2)Hypercalcemia of malignancy (HCM) study: patients received a single dose of Zometa 4 mg or 8 mg or Aredia.  Patients with HCM that was refractory or had relapsed after the first dose received a second infusion of Zometa 8 mg

Table 3 – Non-pivotal bone metastases studies included in the search for terms related to ONJ using MedDRA

Phase I –III
Study No.

Indication

No. patients

Study duration

Zol
≤ 2 mg

Zol
4 mg

Zol
8/4 mg

Zol
8 mg

Zol
16 mg

Are
90 mg

Placebo

CZOL44600011)

M. Paget

16

14 d

16

NA

NA

NA

NA

NA

NA

CZOL44600021)

M. Paget

175

3 mo

140

NA

NA

NA

NA

NA

35

CZOL4460003+E

Cancer

59

3mo/48mo

45

7

NA

7

NA

NA

NA

CZOL4460035+E

NSCLC, PCa

42

2mo/ max. 31.6 mo

16

8

NA

82)

103)

NA

NA

CZOL4460503+E

Cancer

36

1 mo/~3 y

NA

12

NA

12

12

NA

NA

CZOL4460506+E

Cancer

19

3 mo/2 yrs

NA

19

NA

NA

NA

NA

NA

CZOL4460510

MM, PCa

20

6 mo/1 y

Core: 1x4 mg, 2x8mg, 2x12 mg, 1x4mg sequentially

Extention: 4 mg (investigator may decide to give 8 or 12 mg)

NA

NA

CZOL4460705

PCa

106

12 mo

NA

55

NA

NA

NA

NA

51

CZOL446IA03

MM, BCa

240

15-20 weeks

NA

NA

115

NA

NA

125

NA

Total

 

713

 

217

1014)

1154)

274)

224)

125

86

 

Phase IV
Single Arm
Study No.

Indication

Zometa 4 mg
No. of Patients

Study Duration

CZOL446EDE02

Cancer

604

36-48 weeks (follow-up until week 60)

CZOL446EIT01

BCa

312

48 weeks

CZOL446EAU05

PCa

184

36-48 weeks

CZOL446EAU07

MM

11

16 weeks

CZOL446GAU09

MM

2

12 months

CZOL446EGB01

BCa

101

9 months

CZOL446EIN01

Cancer

73

3 months

CZOL446EPH01

BCa, PCa, MM

70

6 months

CZOL446GFR02

BCa

102

12 months

CZOL446EUS24

PCa

257

12 months

Total

1,716

 

 

1)Zometa administered as single dose

2)After the 8-26 months 5 patients switched from 8 mg Zometa to 4 mg Zometa

3)2 patients from the 16 mg Zometa group switched to Aredia after 18 months

4)Patient numbers of study CZOL4460510 are not included due to non-uniform dose regimem

 

Table 4 – Osteonecrosis/osteomyelitis cases (related to jaw or with unknown location) reported in pivotal bone metastases and hypercalcemia trials

Center/

Subject

Indication

Treatment

Group

No. inf.1)

Date First Infusion

Diagnosis / Location

Start/end date

AE reporting/ study drug relationship

Possible risk factors2)

CZOL446G0007 (n=288)

609/2023

Multiple myeloma

Zol 0.4 mg/

Aredia 90 mg3)

28

(10+18)

4Nov1996

Aseptic necrosis bone / mandible

Mar 1999/

Data not available

Not serious / not suspected

Chemotherapy; cortico­steroids; candidal infection (4Dec1996); tooth abscess (12Aug1997)

627/2382

Multiple myeloma

Zol 4/8mg

17

(10+7)

24Oct1996

 

Osteomyelitis (tenderness) /

mandible4)

9Apr1998/

continued

Not serious / not suspected

Chemotherapy; cortico­steroids; 1 cm radiolucency at mandible seen on a radiograph of the skull (31Jul1997); jaw infection (start date unknown); osteoarthritis (medical history/ongoing)

CZOL446G0010 (n=1648)

2264/11160

Multiple myeloma

Zol 4 mg

28

10May1999

Osteomyelitis5) / Jaw

5Mar2001/ continued

Not serious / not suspected

Chemotherapy; cortico­steroids; ulcer mouth (Oct2000); cyst under chin (Apr2000); infection of the gum and teeth, lesions in the mandible (not related to myeloma, no exposed bone (5Mar2001)

2346/10594

Multiple myeloma

Zol 8/4 mg

12

(12+0)

27May1999

Osteonecrosis,bone necrosis / not specified6)

17Apr2000/

continued

Not serious / not suspected

Chemotherapy; cortico­steroids

2346/20593

Breast cancer

Zol 8/4 mg

22

(14+8)

14Jun1999

Osteoradio­necrosis / jaw

18Dec2000/

continued

Not serious / not suspected

Radiation (date unknown); tooth extraction (16Apr1999); mouth sores (Jul1999); periodontal disease (28Jan00); chemotherapy; cortico­steroids

CZOL446G0704 (n=398)

0521/0002

Prostate cancer

Zol 8/4 mg

20

(7+13)

29Dec1999

Osteomyelitis /

jaw

26Mar2002/

continuing

Not serious / not suspected

Dental abscess (8Nov2001), tooth extraction (date unknown); oral fistula (26Mar2002); arthritis (1994, active problem); hormone therapy

CARD233AP12 (n=392)

M6596P/6

MM

Aredia 90 mg

14

20Aug1991

Osteomyelitis /

jaw

21Oct1992/

ongoing

Not serious / not suspected

Chemotherapy; cortico­steroids; dentition poor (10Jul1992); denuded bone in posterior aspect of mandible (15Sep1992)

CARD233AP19 (n=380)

M7488U/101

BCa

Placebo

3

7Oct1992

Osteomyelitis / not specified

30Nov1992/29Dec1992

Not serious / not suspected

Chemotherapy; hormone therapy; sepsis (19Oct1992)

CZOL4460037 (Hypercalcemia)

M1694E/1303

SSC Head&Neck

Zometa 8 mg

1

16Jul1992

Osteonecrosis / Maxilla (cancer related)

28Jul1999/

ongoing

Not serious/ not suspected

Chemotherapy

1)Number of infusions received before diagnosis of osteomyelitis/necrosis

2)In medical history or as current condition

3)The patient received 10 infusions of Zometa 0.4 mg before switching to Aredia (18 infusions)

4)Excision of right mandibular bone and soft tissue mass (26.Apr.2001)

5)Term not identified in CRF

6)No adverse events indicating jaw involvement

Table 5 – ONJ cases reported in ongoing beone metastases studies

Center/

Subject

Indication

Treatment

No. inf.1)

Date First Infusion

Diagnosis / Location

Start/end date

AE reporting/ study drug relationship

Possible risk factors2)

CZOL446G2408 (ongoing, 1036 patients enrolled, 6Jan2005)

1/100055

Breast cancer

Zometa 4 mg

Max. 4

26Jan04

Osteonecrosis / jaw

May2004

Serious / suspected

Chemotherapy; corticosteroids; gingival infection (9Feb2004); dental extraction (16Feb2004)

CZOL446EDE07 (ongoing, 309 patients enrolled, 14Jan2005)

20/9

Prostate cancer

Zometa 4 mg

Max. 9

25Feb03

Osteomyelitis / jaw

Already present at study entry

Serious / not suspected

Preexisting osteomyelitis of the jaw

CZOL446EDEKR02 (ongoing, 40 patients enrolled Jan2005)

1/11

Breast cancer

Zometa 4 mg

Max. 4

25Jul03

Osteomyelitis / jaw

After 6Jan2004

Serious / not suspected

Chemotherapy; chronic gingivitis (6Jan2004); sequestrectomy (20Apr2004)

CZOL446EDE01 (ongoing, 101 patients enrolled, 14Jan2005)

?

Multiple myeloma

Zometa 4 mg

?

?

Osteonecrosis / jaw

?

Not serious / ?

?