# Presentation: 829180

## Osteonecrosis of the Jaw (ONJ)and Bisphosphonates

**Oncologic Drugs Advisory Committee****March 4, 2005**
**Novartis Pharmaceuticals**

## Novartis Presentation

**ONJ Reported in Bisphosphonate-Treated Patients — An Overview**
**	****	****D. Young, MD****	****Novartis Pharmaceuticals Corp**
**Clinical Benefit of Bisphosphonates in Cancer Patients With Metastatic Bone Disease**
**	****	****J. Berenson, MD****	****Institute for Myeloma & Bone Cancer Research**

## External Advisors*

| James Berenson, MD | Medical & Scientific DirectorInstitute for Myeloma and Bone Cancer Research |
| --- | --- |
| Ana Hoff, MD | Assistant ProfessorDepartment of EndocrinologyUniversity of Texas, MD Anderson Cancer Center |
| Regina Landesberg, DMD, PhD | Assistant ProfessorDepartment of Oral/Maxillofacial SurgeryColumbia University |
| Lloyd Fisher, PhD | Professor EmeritusBiostatistics DepartmentUniversity of Washington |
| Salvatore Ruggiero, DMD, MD | Chief, Division of Oral & Maxillofacial SurgeryLong Island Jewish Medical Center |

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

## 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**

## 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 **

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

**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 ****e****stimate**
**new cases - US****,****x1000****1**

**Incidence of **
**bone metastases,**
**% ****2**

**Median**** s****urviva****l****, **
**m****onths****2-4**

** **

**Myeloma**

** ****16**

**70 - 95**

**50 - 67**

**Renal**

** ****36**

**20 - 25**

**8 - 21**

**Melanoma**

** ****60**

**14 - 45**

**5 - 31**

**Bladder**

** ****63**** **

**40**

**9**** - 20**

**Thyroid**

** ****26**

**60**

**49**

**Lung**

** ****173**

**30 - 40**

**17**** - 33**

**Breast**

** ****213**

**65 - 75**

**1****8**** - 24**

**Prostate**

** ****232**

**65 - 75**

**1****6**** - 24**

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

## Zometa® 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*****, †**

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

## Osteonecrosis (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****‡**

**(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.**

## 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 **

**(NS3-19) July15,2004FDAONImeetingslides.doc**

## ONJ in Cancer Patients 

**Awareness was limited, now growing**
**ONJ incidence in cancer patients unknown**
**Few literature reports before 2003****1-3**
**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**

## Review of Available Data on ONJ

**Clinical trials**
**Spontaneous reports to Novartis **
**Literature**
**MD Anderson Cancer Center study**

## Limitations in Existing DatasetsAvailable 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**

## Review of Available Data on ONJ

**Clinical trials**
**Spontaneous reports to Novartis **
**Literature**
**MD Anderson Cancer Center study**

## Screening for Potential ONJ CasesNovartis Databases

| Lack of clear definition poses a challenge |  |
| --- | --- |
| No current MedDRA term |  |
| Novartis used a wide net of 18 MedDRA terms: |  |
| 	Bone debridement | Jaw lesion excision |
| 	Jaw operation | Mandibulectomy |
| 	Maxillofacial operation | Oral surgery |
| 	Aseptic necrosis bone | Bone infarction |
| 	Necrosis | Osteomyelitis acute |
| 	Osteomyelitis chronic | Osteomyelitis drainage |
| 	Osteomyelitis | Osteonecrosis |
| 	Primary sequestrum | Secondary sequestrum |
| 	Sequestrectomy | Tertiary sequestrum |
| Screening results medically reviewed to identify ONJ  |  |

## 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**

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

| Trial | Patient population | Treatment, mg  | N | Follow-upMedian, mo | Cum doseMedian, mg | ONJ |
| --- | --- | --- | --- | --- | --- | --- |
| P12 | 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.**

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

| Trial | Patient population | Treatment, mg  | N | Follow-upMedian, mo | Cum 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****®****.**

## Pivotal Trials: ONJ Cases*  

| Treatment | Number of patients | Numberof ONJ cases | Tumor type |
| --- | --- | --- | --- |
| Aredia® 90 mg | 1334 | 2† | MMMM |
| Zometa® (total) | 2730 |  |  |
| 	4 mg | 1284 | 1 | MM |
| 	8 mg | 219 | 1 | H & N |
| 	8 + 4 mg | 1227 | 2 | PCMM |
| 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 1501****Aredia: P12, P18, P19**
**†****Includes 1 patient who received Zometa 0.4 mg ×10**** **

## ONJ Cases in Pivotal Trials (1)

| Case | Diagnosis/siteYear | 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**

## ONJ Cases in Pivotal Trials (2)

| Case | Diagnosis/siteYear | 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  |  |

**MM = Multiple myeloma; H&N = Head and neck cancer; PC = Prostate cancer. **
**OM = Osteomyelitis, ON = Osteonecrosis, ASN = aseptic necrosis**

## ONJ 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 **

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

## ONJ Cases in Ongoing Zometa® Trials*

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

| Zometa 
trial | Patients, N | ONJcases, 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.**

## Review of Available Data on ONJ

**Clinical trials**
**Spontaneous reports to Novartis **
**Literature**
**MD Anderson Cancer Center study**

## 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 | ArediaZometaBoth | 119248243 | 1.9 million1 million |
| Countries | USNon-US | 440170 |  |
| Indication | Multiple myeloma Breast Other | 218125267 |  |

******* 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**

## Spontaneous Reports Of ONJReported 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**

## Spontaneous Reports Of ONJReported Dental Events

**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) |

## Spontaneous Reports Of ONJReported 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.**

## Spontaneous 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**

## Review of Available Data on ONJ

**Clinical trials**
**Spontaneous reports to Novartis**** **
**Literature**
**MD Anderson Cancer Center study**

## Literature Reports of ONJ

**Literature Reports of ONJ**

| Author | ONJ 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 Maxillofac
Surg, 2003 | Letter to the editor case reports |

## 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**

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

## 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**

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

## Review of Available Data on ONJ

**Clinical trials**
**Spontaneous reports to Novartis **
**Literature**
**MD Anderson Cancer Center study**

## MD 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**

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

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

## MD Anderson Cancer Center StudyInterim Data: ONJ Cases by Tumor Type

**(NS4-16) Zometa Briefing Document January 2005.doc Table 4-7**

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

**  **

*** Thyroid cancer**

## MD Anderson Cancer Center Interim Data: 18 Cases 

| 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 **

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

## ONJ in Cancer Patients Treated With BPsFrequency 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 |

## ONJ 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**

**(NS3-19) July15,2004FDAONImeetingslides.doc**

## Novartis Initiatives 

## Novartis Initiatives—Completed Activities

**Novartis Initiatives—Completed Activities**

**(NS21-5)**

## Recommended Management of ONJAdvisory 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**

## Recommended Management of ONJAdvisory 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**

## Patient 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**

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

## Patient 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**

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

## Clinical 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**

## Clinical 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) **

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

** **

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

**Breast cancer/myeloma**
**+ bone metastasis**
**Zometa**** ****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 analysis**
**for efficacy and safety***

**0**

*** Primary efficacy endpoint: Time to first SRE**

**Randomization 2:2:1**

**+ Rescue: Zometa 4 mg q wk after first SRE**

**+ Rescue: Zometa 4 mg q wk after first SRE**

## SWOG 0307: Study Design

**Randomized phase III trial; NSABP 34 replacement trial**
**Stage I, II, and III breast cancer on standard adjuvant therapy ****(n = 6000)**

**R**
**A**
**N**
**D**
**O**
**M**
**I ZE**

**Zometa****®***** 4 mg IV**
**q 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**

## SWOG 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**

## ONJ 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**

##  Conclusions 

## Conclusions (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**

## Conclusions (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 **