CP-1 Osteonecrosis of the Jaw (ONJ) and Bisphosphonates Oncologic Drugs Advisory Committee March 4,...

CP-1

Osteonecrosis of the Jaw (ONJ)and

Bisphosphonates

Osteonecrosis of the Jaw (ONJ)and

Bisphosphonates

Oncologic Drugs Advisory CommitteeMarch 4, 2005

Novartis Pharmaceuticals

Oncologic Drugs Advisory CommitteeMarch 4, 2005

Novartis Pharmaceuticals

CP-2

Novartis PresentationNovartis Presentation

ONJ Reported in Bisphosphonate-Treated Patients — An Overview

D. Young, MDNovartis Pharmaceuticals Corp

Clinical Benefit of Bisphosphonates in Cancer Patients With Metastatic Bone Disease

J. Berenson, MDInstitute for Myeloma & Bone Cancer

Research

ONJ Reported in Bisphosphonate-Treated Patients — An Overview

D. Young, MDNovartis Pharmaceuticals Corp

Clinical Benefit of Bisphosphonates in Cancer Patients With Metastatic Bone Disease

J. Berenson, MDInstitute for Myeloma & Bone Cancer

Research

CP-3

External Advisors*External Advisors*

James Berenson, MD Medical & Scientific DirectorInstitute for Myeloma and Bone Cancer Research

Ana Hoff, MD Assistant ProfessorDepartment of EndocrinologyUniversity of Texas, MD Anderson Cancer Center

Regina Landesberg, DMD, PhD Assistant ProfessorDepartment of Oral/Maxillofacial SurgeryColumbia University

Lloyd Fisher, PhD Professor EmeritusBiostatistics DepartmentUniversity of Washington

Salvatore Ruggiero, DMD, MD Chief, Division of Oral & Maxillofacial SurgeryLong Island Jewish Medical Center

* The views expressed by these individuals are their own and not necessarily those of Novartis Oncology.

CP-4

Summary of Presentation (1)Summary of Presentation (1)

Zometa® and Aredia® are important medications that reduce complications of bone metastases in patients with solid tumors and multiple myeloma

Novartis has actively examined issue of ONJ since first spontaneous reports received in Dec 2002

– ONJ remains poorly understood

– Frequency estimates variable; however, ONJ appears to be an infrequent occurrence

– Insufficient evidence to support difference between Zometa and Aredia






CP-5

Summary of Presentation (2)Summary of Presentation (2)

Novartis is committed to

– Ensuring patient safety

– Enhancing understanding of ONJ through additional clinical investigation

– Continuing dissemination of evolving information and guidance to health-care providers and patients

Balance of benefit-risk for Zometa® and Aredia® remains favorable






CP-6

1. Jemal A, et al. CA Cancer J Clin. (2005)2. Coleman RE. Cancer Treat Rev. (2001)3. DeVita VT, et al. Cancer Principles & Practice of Oncology. Lippincott Williams & Wilkins. NY (2005) 4. Shoup M, et al. J Am Coll Surg. (2003)

Annual estimatenew cases - US,

x10001

Incidence of bone metastases,

% 2

Median survival, months2-4

Myeloma 16 70 - 95 50 - 67Renal 36 20 - 25 8 - 21Melanoma 60 14 - 45 5 - 31Bladder 63 40 9 - 20Thyroid 26 60 49Lung 173 30 - 40 17 - 33Breast 213 65 - 75 18 - 24Prostate 232 65 - 75 16 - 24

Metastatic Bone Disease is an Important Clinical Problem in Cancer PatientsMetastatic Bone Disease is an Important Clinical Problem in Cancer Patients

CP-7

Zometa® and Aredia® in Metastatic Bone DiseaseZometa® and Aredia® in Metastatic Bone Disease

Effective in the prevention of complications of bone metastases in breast cancer and multiple myeloma

Zometa is effective in prostate cancer, whereas Aredia is not. Unlike Aredia, Zometa was tested and showed efficacy in other tumor types such as lung, renal, colorectal, and bladder cancer

Benefit-risk profile is well established, with known, manageable renal adverse events

Recommended in ASCO guidelines for the management of multiple myeloma and metastatic breast cancer patients with bone lesions*, †

Effective in the prevention of complications of bone metastases in breast cancer and multiple myeloma

Zometa is effective in prostate cancer, whereas Aredia is not. Unlike Aredia, Zometa was tested and showed efficacy in other tumor types such as lung, renal, colorectal, and bladder cancer

Benefit-risk profile is well established, with known, manageable renal adverse events

Recommended in ASCO guidelines for the management of multiple myeloma and metastatic breast cancer patients with bone lesions*, †

* Hillner, et al. J Clin Oncol. 2003;21:4042-4057. † Berenson, et al. J Clin Oncol. 2002;20:3719-3736.

CP-8

Osteonecrosis (ON): BackgroundOsteonecrosis (ON): Background

Etiology and pathogenesis not well understood

– Impaired blood supply leading to ischemia proposed as pathologic process preceding ON*

Most commonly seen in hip†

Multiple risk factors suspected, including cancer and cancer treatments

Bisphosphonates used to treat ON with some success‡

Etiology and pathogenesis not well understood

– Impaired blood supply leading to ischemia proposed as pathologic process preceding ON*

Most commonly seen in hip†

Multiple risk factors suspected, including cancer and cancer treatments

Bisphosphonates used to treat ON with some success‡

(NS10-02) Zometa Core presentation ONJ (CO).ppt

* Glueck et al (1997). In: Urbaniak JR and Jones JP, eds. Osteonecrosis, AAOS, 105-116 † Assouline-Dayan et al (2002). Semin Arthritis Rheum; 32:94-124.‡ Agarwala S et al. Rheumatology (Oxford). 2002.

* Glueck et al (1997). In: Urbaniak JR and Jones JP, eds. Osteonecrosis, AAOS, 105-116 † Assouline-Dayan et al (2002). Semin Arthritis Rheum; 32:94-124.‡ Agarwala S et al. Rheumatology (Oxford). 2002.

CP-9

Osteonecrosis of the Jaw (ONJ)Osteonecrosis of the Jaw (ONJ)

Involves portion of jaw bone (maxilla or mandible)– No consensus on diagnostic criteria for ONJ

Incidence unknown

Pathogenesis not understood– Similar risk factors to ON suggested

Risk factors specific to jaw bones may play a role– Exposure to external environment through teeth – Risk of trauma from repeated dental procedures

Involves portion of jaw bone (maxilla or mandible)– No consensus on diagnostic criteria for ONJ

Incidence unknown

Pathogenesis not understood– Similar risk factors to ON suggested

Risk factors specific to jaw bones may play a role– Exposure to external environment through teeth – Risk of trauma from repeated dental procedures

(NS3-19) July15,2004FDAONImeetingslides.doc

CP-10

ONJ in Cancer Patients ONJ in Cancer Patients

Awareness was limited, now growing

ONJ incidence in cancer patients unknown

Few literature reports before 20031-3

– Most often reported - osteoradionecrosis (ORN) following head and neck radiation

• Reported incidence of 8.2%4

Novartis received first spontaneous report of ONJ in IV BP-treated cancer patient in Dec 2002

Awareness was limited, now growing

ONJ incidence in cancer patients unknown

Few literature reports before 20031-3

– Most often reported - osteoradionecrosis (ORN) following head and neck radiation

• Reported incidence of 8.2%4

Novartis received first spontaneous report of ONJ in IV BP-treated cancer patient in Dec 2002

1. Winer et al. J Am Dent Assoc. (1972)2. Schwartz. Head Neck Surg. (1982)3. Sung et al. Spec Care Dent. (2002)4. Reuther et al. Oral Max Surgery. (2003)

(NS10-04) Zometa Core presentation ONJ (CO).ppt - Slide 4

CP-11

Review of Available Data on ONJReview of Available Data on ONJ

Clinical trials

Spontaneous reports to Novartis

Literature

MD Anderson Cancer Center study

Clinical trials


Literature


CP-12

Limitations in Existing DatasetsAvailable Datasets Limitations in Existing DatasetsAvailable Datasets

Controlled clinical trials– Most meaningful, quality assured, source verified, reliable– Lack of awareness of ONJ, follow-up to be updated

Spontaneous reports (Novartis database)– Incomplete case data– Diagnostic, selection, and reporting biases

Literature– Reports: anecdotal, completeness of data unknown– Web survey: uncontrolled, anonymous, selection bias, QA,

and source verification

MDACC– Planned retrospective review– Ongoing, 25% completed

Controlled clinical trials– Most meaningful, quality assured, source verified, reliable– Lack of awareness of ONJ, follow-up to be updated

Spontaneous reports (Novartis database)– Incomplete case data– Diagnostic, selection, and reporting biases

Literature– Reports: anecdotal, completeness of data unknown– Web survey: uncontrolled, anonymous, selection bias, QA,

and source verification

MDACC– Planned retrospective review– Ongoing, 25% completed

CP-13


Clinical trials


Literature


Clinical trials


Literature


CP-14

Screening for Potential ONJ CasesNovartis DatabasesScreening for Potential ONJ CasesNovartis Databases

Lack of clear definition poses a challenge No current MedDRA term Novartis used a wide net of 18 MedDRA terms:

Bone debridementBone debridement Jaw lesion excisionJaw lesion excision

Jaw operationJaw operation MandibulectomyMandibulectomy

Maxillofacial operationMaxillofacial operation Oral surgeryOral surgery

Aseptic necrosis boneAseptic necrosis bone Bone infarctionBone infarction

NecrosisNecrosis Osteomyelitis acuteOsteomyelitis acute

Osteomyelitis chronicOsteomyelitis chronic Osteomyelitis drainageOsteomyelitis drainage

OsteomyelitisOsteomyelitis OsteonecrosisOsteonecrosis

Primary sequestrumPrimary sequestrum Secondary sequestrumSecondary sequestrum

SequestrectomySequestrectomy Tertiary sequestrumTertiary sequestrum Screening results medically reviewed to identify ONJ

CP-15

Novartis Current “Case Definition”Novartis Current “Case Definition”

Any case or report suggestive of the following to maxillofacial area was considered “ONJ”– Osteonecrosis– Osteomyelitis– Exposed bone– Bone necrosis– Sequestrum– Impaired healing post-dental procedure

Any case or report suggestive of the following to maxillofacial area was considered “ONJ”– Osteonecrosis– Osteomyelitis– Exposed bone– Bone necrosis– Sequestrum– Impaired healing post-dental procedure

CP-16

Pivotal Trials: Study Design and Follow-up (1)Pivotal Trials: Study Design and Follow-up (1)

Trial Patient population Treatment, mg NFollow-up

Median, moCum dose

Median, mg ONJP12 MM A 90 205 18 1485 1, MM

Placebo 187 15 0

P18 BC-hormonal A 90 182 17 1440

Placebo 190 15 0

P19 BC-Chemotherapy A 90 185 13 1440

Placebo 197 10 0

007 MM and BC Z 0.4/8 62 10 4

Z 2/8 62 10 20

Z 4/8 59 10 40 1, MM

Z/A* 30 40 N/A 1, MM

A 90 75 10 N/A

036 HCM Z 4 46 1 4

Z 8 51 1 8

A 90 52 1 90

037 HCM Z 4 40 1 4

Z 8 47 1 8 1, H&N

A 90 51 1 90

25

*Dose of Zometa® is variable, Aredia® dose 90 mg.N/A = Not available; Z = Zometa; A = Aredia.

CP-17

Pivotal Trials: Study Design and Follow-up (2)Pivotal Trials: Study Design and Follow-up (2)

Trial Patient population Treatment, mg NFollow-up

Median, moCum dose

Median, mg ONJ

010 BC and MM Z 4 563 14 56 1, MM

Z 8/4 524 13 104

A 90 556 13 1,260

011 Lung cancer and other solid tumors (-BC/PC)

Z 4 254 6 24

Z 8/4 265 5 40

Placebo 247 5 0

039 HRPC with bone metastases

Z 4 214 13 58

Z 8/4 218 10 96

Placebo 208 10 0

704 HRPC without bone metastases

Z 4 49 16 54

Z 8/4 152 24 110 1, PC

Placebo 197 24 0

Open label phase

115 13 36

1501 BC Z 4 114 13 52

Placebo 113 13 0

25

Z = Zometa®; A = Aredia®.

CP-18

Pivotal Trials: ONJ Cases* Pivotal Trials: ONJ Cases*

TreatmentNumber of

patientsNumber

of ONJ cases Tumor type

Aredia® 90 mg 1334 2† MMMM

Zometa® (total) 2730

4 mg 1284 1 MM

8 mg 219 1 H & N

8 + 4 mg 1227 2 PCMM

Placebo 1347 0

(NS4-13) Zometa Briefing Document January 2005.doc Table 4-4

* Trials included in search: Zometa trial: 007, 010, 011, 039, 704, 036, 037 and 1501Aredia: P12, P18, P19

†Includes 1 patient who received Zometa 0.4 mg ×10

* Trials included in search: Zometa trial: 007, 010, 011, 039, 704, 036, 037 and 1501Aredia: P12, P18, P19

†Includes 1 patient who received Zometa 0.4 mg ×10

CP-19

ONJ Cases in Pivotal Trials (1)ONJ Cases in Pivotal Trials (1)

Case

Diagnosis/siteYear Drug, mg TTE Risk factors

CTC grade/outcome

1. MM ASN/Mandible

1999

Z 0.4

A 90

28 mo Tooth abscess, HZV, Candida, steroids, chemo

Grade 2-3

Mandibular fracture

2. MM OM/Jaw

1992

A 90 14 mo Poor dentition, steroids,chemo

Grade 2

Unknown

3. MM OM/Jaw

2001

Z 4 22 mo Dental infection, chemo, steroids

Grade 1

Continued

MM = Multiple myeloma; H&N = Head and neck cancer; PC = Prostate cancer.

OM = Osteomyelitis, ON = Osteonecrosis, ASN = aseptic necrosis



CP-20

ONJ Cases in Pivotal Trials (2)ONJ Cases in Pivotal Trials (2)

Case

Diagnosis/siteYear Drug, mg TTE Risk factors

CTC grade/outcome

4. H&N ON/Maxilla

1999

Z 8 13 days Chemo Grade 2

Continued

5. PC OM/Jaw

2002

Z 8/4 27 mo Dental abscess, tooth extraction

Grade 2

Unknown

6. MM OM/Mandible

1998

Z 4/8 18 mo Jaw infection, steroids, chemo

Grade 2 - 3

R. mand. excision





CP-21

ONJ Cases: Other TrialsONJ Cases: Other Trials

Completed trials: no ONJ cases as of Jan 2005*– 23 trials in Zometa® program (N = 3428)

– Zometa 3217– Aredia 125– Placebo 86

– 26 trials in Aredia® program (N = 1401)– Aredia 1214– Placebo 187

Ongoing trials: 4 ONJ cases reported– > 10,000 patients enrolled

Completed trials: no ONJ cases as of Jan 2005*– 23 trials in Zometa® program (N = 3428)

– Zometa 3217– Aredia 125– Placebo 86

– 26 trials in Aredia® program (N = 1401)– Aredia 1214– Placebo 187

Ongoing trials: 4 ONJ cases reported– > 10,000 patients enrolled

*Except for 1 case of osteomyelitis of the jaw (OMJ) that existed prior to study entry.

CP-22

ONJ Cases in Ongoing Zometa® Trials*ONJ Cases in Ongoing Zometa® Trials*


Zometa trial Patients, N

ONJcases, n Diagnosis

Infusions prior to event, n

Tumor type Risk factor

2408† 1036 1 Osteonecrosis 4 BC Dental infection, extraction, chemo, steroids

DE07 309 1** Osteomyelitis 9 PC Pre-existing OM of jaw

KR02 40 1 Osteomyelitis 12 BC Chronic dental infection

DE01 101 1 Osteonecrosis 15 MM Spontaneous tooth loss, tooth extraction, dental abscess

† This study is not sponsored by Novartis.* All studies use Zometa 4 mg.** Patient had pre-existing osteomyelitis of the jaw at study entry.

CP-23


Clinical trials


Literature


Clinical trials


Literature


CP-24(NS4-8) Zometa Briefing Document January 2005.doc Table 4-2

Spontaneous Reports Of ONJ*Zometa® or Aredia®†Spontaneous Reports Of ONJ*Zometa® or Aredia®†

As of 07 Dec 04

Total 610‡

Total patients exposed

Drug ArediaZometaBoth

119248243

1.9 million1 million

Countries USNon-US

440170

Indication Multiple myeloma Breast Other

218125267

* Includes reportable cases from the literature.† The number of reported cases from generic pamidronate is unknown.‡ 91% of patients diagnosed with ONJ and 28% diagnosed with osteomyelitis.

As of 22 Feb 2005, total reports = 875

CP-25

Spontaneous Reports Of ONJReported Risk FactorsSpontaneous Reports Of ONJReported Risk Factors

Reported risk factors Reports, n (%)

At least 1 risk factor in addition to cancer 450 (74)

Corticosteroids† 230 (38)

Chemotherapy† 315 (52)

Hormonal therapy 63 (10)

Radiotherapy to head and neck 28 (5)

Anemia 89 (15)

Thalidomide 89 (15)

Transplant 57 (9)

Other‡ 263 (43)

† In 188 (31%) reports the patients had received both corticosteroids and chemotherapy.‡ Broad criteria used, including all conditions and medications with potential impact on bone metabolism.

Includes 3 patients with herpes virus infection of the maxillofacial area.

(NS9-12) Zometa Mar 4, 05 ODAC Meeting Briefing Appx 3.doc

CP-26

Spontaneous Reports Of ONJReported Dental EventsSpontaneous Reports Of ONJReported Dental Events

At least 50% of cases (n = 303) reported dental events preceding the diagnosis of ONJ

At least 50% of cases (n = 303) reported dental events preceding the diagnosis of ONJ

(NS9-11) Zometa Mar 4, 05 ODAC Meeting Briefing Appx 3.doc

Dental events n (%)

Prior extraction 252 (83)

Dental problems, procedures (other than extraction)

26 (9)

Other (eg, tooth abscess, trauma) 16 (5)

Denture trauma 9 (3)

CP-27

Spontaneous Reports Of ONJReported OutcomesSpontaneous Reports Of ONJReported Outcomes

Outcome

Bisphosphonates

Continued Discontinued Total‡

Recovered/Improved§ 13 32 45

No change 21 86 107

Deteriorated 7 10 17

Unknown 9 46 55

Total 50 174 224

‡ 224/610 reports assessable for outcome analysis. § Also includes recovered with sequelae.

CP-28

Spontaneous Reports: Time to Onset of ONJSpontaneous Reports: Time to Onset of ONJ

Direct comparison of time to onset between Zometa® & Aredia® is not feasible

– No common definition of ONJ

– Aredia available since 1991, Zometa since 2001

– Utilization of Aredia has declined significantly since 2001 (including generic introduction)

– Recent awareness could have accelerated diagnosis of ONJ

– Concurrent therapy has changed significantly over time with contribution unknown

Direct comparison of time to onset between Zometa® & Aredia® is not feasible

– No common definition of ONJ

– Aredia available since 1991, Zometa since 2001

– Utilization of Aredia has declined significantly since 2001 (including generic introduction)

– Recent awareness could have accelerated diagnosis of ONJ

– Concurrent therapy has changed significantly over time with contribution unknown

CP-29


Clinical trials


Literature


Clinical trials


Literature



Literature Reports of ONJLiterature Reports of ONJ

AuthorONJ patients reported, n Journal Methodology

de Almeida, de Araujo, and Pire

5 Rev Bras Oncologia Clinica (Brazil), 2004

Case report

Bagan 10 J Oral Pathol Med, 2004 Case report, manuscript

Durie 62 Blood, 2004 Abstract, anonymous Web-based survey

Thakkar 14 Blood, 2004 Case reports, abstract

Van Poznack 6 San Antonio Breast Cancer Symposium, 2004

Clinical database review, abstract

Ruggiero et al. 63 J Oral Maxillofac Surg, 2004

Case reports

Marx 36 J Oral MaxillofacSurg, 2003

Letter to the editor case reports

CP-31

Literature Report of ONJ: Ruggiero et al. 2004*Literature Report of ONJ: Ruggiero et al. 2004*

63 cases between Feb 01- Nov 03

– MM (28), BC (20), prostate (3), other (5), no cancer (7)

– Pamidronate (57%), zoledronic acid (31%), oral BP (12%)

– 71% female

– Mandible (63%), maxilla (37%)

– Typical presentation: pain, non-healing extraction socket, exposed bone

– Other treatments: chemotherapy

– Previous dental procedure: 86%

– Majority required surgical removal of involved bone

63 cases between Feb 01- Nov 03

– MM (28), BC (20), prostate (3), other (5), no cancer (7)

– Pamidronate (57%), zoledronic acid (31%), oral BP (12%)

– 71% female

– Mandible (63%), maxilla (37%)

– Typical presentation: pain, non-healing extraction socket, exposed bone

– Other treatments: chemotherapy

– Previous dental procedure: 86%

– Majority required surgical removal of involved bone

* Ruggiero SL, et al. J Oral Maxillofac Surg; 2004; 62 (5):527 - 534.

CP-32

Literature Report of ONJ: Durie et al. 2004*Literature Report of ONJ: Durie et al. 2004*

Web-based patient survey

Key issues– Data reliability/quality

• Anonymous responders• Unable to assure data quality

Potential bias & analyses considerations– Patients with an event, more motivated to respond– Patients with more recent event, may be more likely to

respond

Kaplan-Meier & logistic regression must be interpreted with caution– Not adjusted for time as confounding factor– Impact of approval / launch / usage time

• Aredia® approved since 1991 & Zometa® since 2001

Web-based patient survey

Key issues– Data reliability/quality

• Anonymous responders• Unable to assure data quality

Potential bias & analyses considerations– Patients with an event, more motivated to respond– Patients with more recent event, may be more likely to

respond

Kaplan-Meier & logistic regression must be interpreted with caution– Not adjusted for time as confounding factor– Impact of approval / launch / usage time

• Aredia® approved since 1991 & Zometa® since 2001

* Durie et al. Blood 2004;104:Abstract 756.

CP-33


Clinical trials


Literature


Clinical trials


Literature


CP-34

MD Anderson Cancer Center Study Objectives and MethodsMD Anderson Cancer Center Study Objectives and Methods

Principal Investigator: Ana Hoff, MD Objectives†

– Identify ONJ cases in cancer patients treated with IV BPs to estimate frequency

– Identify risk factors associated with ONJ Methods

– Retrospective chart review in past 10 yr• All IV BP users (N = 4032)• Identify patients with ONJ and ON of other sites

963 charts reviewed by Jan 12, 2005 Issue: Non random chart review

– Charts sorted by pharmacy records based on number of BP infusions (highest to lowest)

– 7 charts reviewed out of sequence because ONJ was suspected

Principal Investigator: Ana Hoff, MD Objectives†

– Identify ONJ cases in cancer patients treated with IV BPs to estimate frequency

– Identify risk factors associated with ONJ Methods

– Retrospective chart review in past 10 yr• All IV BP users (N = 4032)• Identify patients with ONJ and ON of other sites

963 charts reviewed by Jan 12, 2005 Issue: Non random chart review

– Charts sorted by pharmacy records based on number of BP infusions (highest to lowest)

– 7 charts reviewed out of sequence because ONJ was suspected

† Amendment to expand the review to non-bisphosphonate users being considered.

(NS10-11) Zometa Core presentation ONJ (CO).ppt

CP-35

MD Anderson Cancer Center StudyInterim Data: ONJ Cases by Tumor TypeMD Anderson Cancer Center StudyInterim Data: ONJ Cases by Tumor Type


Tumor type Patients (N) ONJ cases (n)Breast cancer 631 11Multiple myeloma 148 6Renal cell carcinoma 32 –Prostate cancer 18 –Lung cancer 17 –Lymphoma 13 –Others 89 1*Noncancer 15 –Total 963 18

* Thyroid cancer


Time from first BP to ONJ, mo

Median (range) 30 (4 – 57)*

Bisphosphonate received, n

Aredia® only 4

Zometa® only 3

Alendronate then Zometa 1

Aredia then Zometa 10

MD Anderson Cancer Center Interim Data: 18 Cases MD Anderson Cancer Center Interim Data: 18 Cases

* 4 months on Aredia. 57 months on Aredia followed by Zometa.

CP-37

ONJ in Cancer Patients Treated With BPsFrequency EstimatesONJ in Cancer Patients Treated With BPsFrequency Estimates

Database Frequency estimate Assessment

Spontaneous reports 875 of 2.9 million (0.03%)

Likely under-estimate

Controlled clinical trials 6 of 4056 pts (0.15%) Follow-up needs to be updated

MDACC 18 cases of 963 charts (1.9%)

Review not complete

Web-based survey (Durie)

75 of 1203 (6.2%) of respondents reported ONJ

Likely over-estimate

CP-38

ONJ in Cancer Patients Treated With BPs: Open QuestionsONJ in Cancer Patients Treated With BPs: Open Questions

– Natural history– Clear case definition• Diagnostic criteria• Staging system• Severity measures

– Time to onset – Risk factors– Prevention measures– Treatment algorithm – Causality

– Natural history– Clear case definition• Diagnostic criteria• Staging system• Severity measures

– Time to onset – Risk factors– Prevention measures– Treatment algorithm – Causality

(NS3-19) July15,2004FDAONImeetingslides.doc

CP-39

Novartis Initiatives Novartis Initiatives

CP-40

2002 2003 2004 2005

Novartis Initiatives—Completed ActivitiesNovartis Initiatives—Completed Activities12/02

First ONJ report

to Novartis

9/03 – 11/03 Zometa® PI update/ Aredia® PI update

(NS21-5)

12/03 Ad. board #1 (understand

ONJ)

3/04 Ad. board #2

(generate guidelines;

“white paper”)1/03

Initiate f/u &data collection

on cases

2Q-3Q Oncologist & dental surgeon visited to

collect data

6/04 Distribution

of the “white paper”

at ASCO

9/04 Distribution of“Dear Doctor”

letter

2/05 ASCOburst(FDA)

5/04 Patient

initiative/Generation of education

materials

4/04initiate MDACC study

8/04 Zometa and Aredia

labels revised

3/04Updated PIs

with additionalONJ info

4/04IC

changes made

CP-41

Recommended Management of ONJAdvisory Panel – March 24, 2004 (1)Recommended Management of ONJAdvisory Panel – March 24, 2004 (1)

Diagnosis– Typical symptoms: pain, soft-tissue swelling and

infection, loose teeth, and exposed bone– Imaging (eg, panoramic and tomographic), biopsy, and

cultures may be helpful Treatment

– Nonsurgical approach preferred: minimal debridement, cover exposed bone, protective stint

– Antibiotics, antifungal and antiviral agents, oral rinses– Close follow-up, and cessation of BP therapy may be

considered. Risk of SRE needs to be considered when stopping BP therapy

Diagnosis– Typical symptoms: pain, soft-tissue swelling and

infection, loose teeth, and exposed bone– Imaging (eg, panoramic and tomographic), biopsy, and

cultures may be helpful Treatment

– Nonsurgical approach preferred: minimal debridement, cover exposed bone, protective stint

– Antibiotics, antifungal and antiviral agents, oral rinses– Close follow-up, and cessation of BP therapy may be

considered. Risk of SRE needs to be considered when stopping BP therapy

CP-42

Recommended Management of ONJAdvisory Panel – March 24, 2004 (2)Recommended Management of ONJAdvisory Panel – March 24, 2004 (2)

Prevention

– Avoid elective jaw procedures

– Routine dental exams including panoramic radiograph

– Tooth extraction prior to BP therapy if possible

– Preventive dentistry prior to chemotherapy

– Patient education regarding importance of good hygiene

– Oncologist to perform visual inspection of oral cavity prior to BP therapy and at each follow-up visit

– Cessation of BP therapy may be considered if oral surgery required, risk of SRE needs to be considered when stopping BP therapy

Prevention

– Avoid elective jaw procedures

– Routine dental exams including panoramic radiograph

– Tooth extraction prior to BP therapy if possible

– Preventive dentistry prior to chemotherapy

– Patient education regarding importance of good hygiene

– Oncologist to perform visual inspection of oral cavity prior to BP therapy and at each follow-up visit

– Cessation of BP therapy may be considered if oral surgery required, risk of SRE needs to be considered when stopping BP therapy

CP-43

Patient Outreach With Advocacy GroupsPatient Outreach With Advocacy Groups

Meeting held May 2004– 9 patient advocacy groups attended

representing multiple tumor types (breast, myeloma, prostate, lung, and kidney)

Additional follow-up with 14 groups (Dec 2004/early 2005)

Planned activity: post ODAC briefing teleconference with patient advocacy groups

Meeting held May 2004– 9 patient advocacy groups attended

representing multiple tumor types (breast, myeloma, prostate, lung, and kidney)

Additional follow-up with 14 groups (Dec 2004/early 2005)

Planned activity: post ODAC briefing teleconference with patient advocacy groups

(NS22-17) Patient Advocacy ONJ.ppt slide 1

CP-44

Patient BrochurePatient Brochure

Definition, signs, and symptoms of ONJ

Routine dental hygiene for patients with cancer

Dental care recommendations to patients with cancer

Urge patients to communicate with physicians and dentists regarding adverse events

Definition, signs, and symptoms of ONJ

Routine dental hygiene for patients with cancer

Dental care recommendations to patients with cancer

Urge patients to communicate with physicians and dentists regarding adverse events

(NS21-1) “Taking Care of Yourself While Living With Cancer: Dental Health and Osteonecrosis of the Jaw” Novartis Patient Information Brochure. 2004.

Taking Care of YourselfWhile Living With Cancer

Dental Health andOsteonecrosis of the Jaw

CP-45

Clinical Investigations – Actions PlannedClinical Investigations – Actions Planned

Develop case definition and severity scale with expert panel

Obtain follow up data on patients from pivotal trials for ONJ

Develop CRF to capture data regarding ONJ in ongoing studies

Implement new studies that include prospective monitoring for ONJ

Develop case definition and severity scale with expert panel

Obtain follow up data on patients from pivotal trials for ONJ

Develop CRF to capture data regarding ONJ in ongoing studies

Implement new studies that include prospective monitoring for ONJ

CP-46

Clinical Investigation – New StudiesClinical Investigation – New Studies

Retrospective chart review for ONJ in MM patients (initiate 2Q 2005)

Prospective studies to include ONJ assessment

– Study 2352: MBC and MM (initiate 4Q 2005)

– SWOG 0307: Adjuvant BC (under discussion)

Prospective registry for ONJ or ONJ natural history study (2H 2005)

Retrospective chart review for ONJ in MM patients (initiate 2Q 2005)

Prospective studies to include ONJ assessment

– Study 2352: MBC and MM (initiate 4Q 2005)

– SWOG 0307: Adjuvant BC (under discussion)

Prospective registry for ONJ or ONJ natural history study (2H 2005)

CP-47

Phase III Randomized Trial With Zometa® Study 2352 DesignPhase III Randomized Trial With Zometa® Study 2352 Design

Breast cancer/myeloma

+ bone metastasisZometa pretreated:

12 mo

N = 3513

Arm 1, n = 1,405 Zometa 4 mg q 3-4 wk

Arm 2, n = 1,405 Zometa 4 mg q 3 mo

Arm 3, n = 703 Placebo q 4 wk

13-month analysisfor efficacy and safety*0

* Primary efficacy endpoint: Time to first SRE

Ran

do

miz

atio

n 2

:2:1

+ Rescue: Zometa 4 mg q wk after first SRE

+ Rescue: Zometa 4 mg q wk after first SRE

CP-48

SWOG 0307: Study DesignSWOG 0307: Study Design

Randomized phase III trial; NSABP 34 replacement trial

Stage I, II, and III breast cancer on standard adjuvant therapy (n = 6000)

Randomized phase III trial; NSABP 34 replacement trial

Stage I, II, and III breast cancer on standard adjuvant therapy (n = 6000)

RANDOMI ZE

Zometa®* 4 mg IVq mo x 6 mos, q 3 mos x 2.5 yrs

Clodronate* 1600 mg PO daily x 3 yrs

Ibandronate* 50 mg PO daily x 3 yrs

*Daily supplemental calcium (1000 to 1500 mg) and vitamin D (400 to 800 IU)

(NS22-2) Leo’s SWOG slides.ppt slide 2

CP-49

SWOG 0307: Osteonecrosis of the Jaw Surveillance PlanSWOG 0307: Osteonecrosis of the Jaw Surveillance Plan

Objective: Evaluation of risk factors for osteonecrosis of the jaw

Schedule: - Dental exams at baseline and end of study (completed by a dental health professional)

- Standard dental exams and care while on study

Required Exam: - Visual dental inspection and periodontal probing

- X-rays only to assess degree of periodontal involvement and endodontic problems

Documentation: - Completion of S0307 Dental Examination Form, Osteonecrotic Jaw Lesion Form, Treatment Summary Form, & Supplementary Follow-up Form

- Consultation with S0307 Jaw/Dental Health Coordinator for any patient diagnosed with osteonecrosis of the jaw (Dr. Mark Shubert, DDS, MDS)

Patient Information:

- Patients are requested to avoid dental procedures while on myelosuppressive chemotherapy

- Patients are expected to undergo standard dental exam and care while on study

- Osteonecrosis of the jaw was listed as one of the possible side effects of zoledronic acid in the S0307 Inform Consent Form

(NS22-3) Leo’s SWOG slides.ppt slide 3

CP-50

ONJ Monitoring in Clinical Trials: ProposalONJ Monitoring in Clinical Trials: Proposal

Physical examination of head & neck and oral cavity to– Rule out metastatic involvement– Detect

• Breach of the oral mucosa• Exposed bone

Imaging– Panoramic radiograph

Assessment frequency based on tumor type and stage of disease (minimum: baseline, q6 months)

Develop specific case report forms– Dental exam– ONJ assessment

Physical examination of head & neck and oral cavity to– Rule out metastatic involvement– Detect

• Breach of the oral mucosa• Exposed bone

Imaging– Panoramic radiograph

Assessment frequency based on tumor type and stage of disease (minimum: baseline, q6 months)

Develop specific case report forms– Dental exam– ONJ assessment

CP-51

Conclusions Conclusions

CP-52

Conclusions (1)Conclusions (1)











CP-53

Conclusions (2)Conclusions (2)











CP-1 Osteonecrosis of the Jaw (ONJ) and Bisphosphonates Oncologic Drugs Advisory Committee March 4,...

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Transcript of CP-1 Osteonecrosis of the Jaw (ONJ) and Bisphosphonates Oncologic Drugs Advisory Committee March 4,...