# Presentation: 527184

## Efficacy and Safety of Combidex (NDA 21-115)

**FDA Oncology Advisory Committee**
**March 3, 2005**

**Zili Li, MD, MPH**
**Division of Medical Imaging and Radiopharmaceutical Drug Products, FDA**

## FDA Reviewers

**Chemistry:**** David Place and Eldon Leutzinger**
**Pharmacology:**** Tushar Kokate and Adebayo Laniyonu**
**Clinical Pharmacology:**** Alfredo Sancho and Young-Moon Choi**
**Statistical:**** Mahboob Sobhan and Mike Welch**
**Medical:**** Robert Yaes, Melanie Blank, Barbara Stinson and Zili Li**
**Project Management:**** James Moore, Thuy Nguyen and Pat Stewart**
**Internal Consultants:**** Charles Lee, Ann Corken Mackey, Janos Bacsanyi **
**	****                                     ****and Kathy Robie-Suh**

## Combidex

**Drug Class:**** An Iron-based MR Contrast Agent**
**Proposed Clinical Dose:**** 2.6 mg Fe/Kg**
**Methods of Administration:**
**Diluted in 100 ml/slow infusion**
**Diluted in 50 ml/slow infusion **
**Undiluted/direct bolus injection**

## Sponsor Proposed Indication

**	****“****Combidex can assist in the differentiation of metastatic and non-metastatic lymph nodes in patients with confirmed primary cancer who are at risk for lymph node metastases.”**** **

**Is this an MR contrast agent for all cancers?**

## Efficacy and Safety Studies

**      ****Efficacy:**** **
**US Phase 3 study (n=152)**
**Three European Phase 3 studies (n=181)**
**New England Journal Of Medicine (NEJM) study (n=80)**

**      ****Safety:**** **
**Multiple Phase 1, 2 & 3 clinical studies (n=2061)**

## NEJM Study – A pooled subgroup analysis of prostate cancer patients from two ongoing clinical studies

## Efficacy and Safety Conclusions (FDA vs. Sponsor)

**      ****Efficacy:**** **
**Sponsor:**** Combidex offers high sensitivity AND high specificity**
**FDA: ****Generalizibility and validity of study findings are still issues**

**      ****Safety:**
**Sponsor:**** No death or life-threatening AEs were associated with dilution and slow infusion**
**FDA:**** Dilution and slow infusion are not entirely risk free**

## Issues to Be Discussed

**Efficacy Issues**
**Study sample size**
**Representation of different tumor types**
**Study inclusion/exclusion criteria**
**Development and use of Combidex Imaging Guidelines**
**Safety Issues**
**Hypersensitivity reactions**
**Comparison with iodinated contrast agents**
**Risk/Benefit Ratio**
**Sponsor’s risk management program**
**Need to define the conditions of use**

## Issue #1: Small Number of Patients Included In the Primary Analysis

|      | US Study | European Studies (N=181) |  |  |
| --- | --- | --- | --- | --- |
|  | 38804-10
(Multiple 
Cancer types) | 3-2-A
(Head & neck) | 3-7-A
(Pelvis) | 3-10-A
(Breast) |
| Number of Patients Received Combidex | 152 | 90 | 56 | 35 |
| Included in Primary Analysis (n) (%)    
    Blinded Reader #1
    Blinded Reader #2 | 

97 (64%)
99 (65%) | 

37 (41%)
36 (40%) | 

11 (20%)
9 (16%) | 

--
-- |

## Issue #2: Inadequate Representation of Tumor Types 

| Top 10 Tumor Types 
In the US* | Distribution of 
New Cancer 
Cases in the US | Total Number of Patients 
in Primary Analysis |  |
| --- | --- | --- | --- |
|  |  | US Study | European Studies |
| 1. Prostate Cancer | 232,090 (17%) | 5 | 5 |
| 2. Breast Cancer | 212,930 (16%) | 20 | -- |
| 3. Lung Cancer | 172,570 (13%) | 25 | -- |
| 4. Colon & Rectal Cancer | 145,290 (11%) | 2 | -- |
| 5. Bladder Cancer | 63,210 (5%) | 4 | 6 |
| 6. Melanoma | 59,580 (4%) | 0 | -- |
| 7. Uterus/Cervix | 51,250 (4%) | 6 | -- |
| 8. Head & Neck | 39,250 (3%) | 27 | 37 |
| 9. Kidney Cancer | 36,160 (3%) | 2 | -- |
| 10. Pancreatic Cancer | 32,180 (2%) | 1 | -- |
| All other sites | 328,400 (25%) | 7 | -- |
| Total | 1,372,910 (100%) | 99 | 48 |

*** Source Data: American Cancer Society. Cancer Facts and Figures 2005. Atlanta: American Cancer Society; 2005. **

## Why Many Cancer Patients Were Not Included in the Primary Analysis

**All lymph nodes visualized by the site investigators**

**Matched to Pathology**

**Nodes Included in Primary Analysis**

**Visualized by blinded readers**

## Number of Lymph Nodes Included in the Primary Analysis

| (N = number of patients) | US Study | European Studies (N=181) |  |  |
| --- | --- | --- | --- | --- |
|  | 38804-10
(N=152) | 3-2-A
(N=90) | 3-7-A
(N=56) | 3-10-A
(N=35) |
| Nodes Visualized by Site Investigators on MR images (n) | 371 | 834 | 333 | 234 |
| Nodes Matched to Pathology Results (n) (%) | 276 (74%) | 86 (10%) | 65 (20%) | 144 (62%) |
| Nodes Included in the Primary Analysis (n) (%)
     Reader 1
     Reader 2 | 

167 (45%)
154 (42%) | 

47 (6%)
46 (6%) | 

11 (3%)
11 (3%) | 

--
-- |

## Variation in Sensitivity of Combidex by Tumor Type

| Primary Tumor Sites | US Study |  |  | European Studies |  |  |
| --- | --- | --- | --- | --- | --- | --- |
|  | NO. of
Cancer 
Positive
Nodes | Point 
Estimate | Lower 
Bound of 
95% CI | NO. of
Cancer 
Positive
Nodes | Point 
Estimate | Lower 
Bound of 
95% CI |
| Head & Neck | 29 | 86% | 67% | 39 | 95% | 82% |
| Lung | 9 | 100% | 66% | -- | -- | -- |
| Breast | 25 | 76% | 55% | -- | -- | -- |
| Abdomen & Pelvis | 21 | 81% | 58% | 6 | 100% | 55% |
| Total  | 84 | 83% | 73% | 45 | 89% | 76% |

## Variation in Specificity of Combidex by Tumor Type

| Primary Tumor Sites | US Study |  |  | European Studies |  |  |
| --- | --- | --- | --- | --- | --- | --- |
|  | NO. of Cancer Negative Nodes | Point 
Estimate | Lower 
Bound of 
95% CI | NO. of Cancer Negative Nodes | Point 
Estimate | Lower 
Bound of 
95% CI |
| Head & Neck | 34 | 91% | 75% | 7 | 86% | 42% |
| Lung | 18 | 44% | 21% | -- | -- | -- |
| Breast | 34 | 71% | 52% | -- | -- | -- |
| Abdomen & Pelvis | 13 | 62% | 32% | 6 | 100% | 55% |
| Total  | 99 | 72% | 62% | 13 | 92% | 64% |

## Issue #3: Impact of Study Inclusion/Exclusion Criteria

**Excluded if received **
**chemotherapy in the past 6 months**
**radiation treatment in the past 6 months**

## Issue #4: Independence of Combidex Imaging Guidelines Development

**Original Statement:**
**“****To finalize the Guidelines, the Sponsor looked at the histology results for the images that [consultant] had reviewed to correlate her descriptions and drawings to diagnoses of metastatic and non-metastatic nodes”**
**Revised Statements (February 14, 2005): **
**“****The guidelines and visual diagrams were developed with the Phase II images”**
**“****Images from 16 patients in the Phase III study were reviewed by [consultant]”**
**“****No pathologic information regarding the nodes was provided to [consultant]”**

## Correlation Between European Guidelines and Combidex Imaging Guidelines

**      ****European Guidelines: **
**	**

**      ****Combidex Imaging Guidelines **
**	**

## Combidex-Induced Hypersensitivity Reactions

**Hypersensitivity-Related Death**
**70 year-old male with history of allergy to contrast**
**Received undiluted bolus injection**
**Reaction began 1-2 minutes post injection**
**911 was called**
**Patient was pronounced dead in ER 35 minutes post-dosing**
**Autopsy revealed no evidence of MI or PE**
**Cause of Death: Combidex-induced anaphylactic shock**

## The Size of Safety Database: Patient Exposure by Dose and Administration

| Dose (mg Fe/kg) | Method of Administration |  |  | Total |
| --- | --- | --- | --- | --- |
|  | Direct Bolus Injection | 50 mL dilution/
slow infusion | 100 mL dilution/
slow infusion |  |
| 0.3 – 1.7 | 129 | 38 | 324 | 491 |
| 2.6 | 2 | 326 | 1236 | 1564 |
| 3.4 | -- | -- |  6 | 6 |
| Total | 131 | 364 | 1566 | 2061 |

## Risk and Severity of Hypersensitivity Reactions

| Type of Hypersensitivity Reactions | Risk of Hypersensitivity Reactions by Method of Administration |  |  |
| --- | --- | --- | --- |
|  | At all doses and methods of administration
(N=2061)  | At proposed dose and administration
(N=1236) | At direct bolus injection
(n=131) |
| All Hypersensitivity Reactions | 111 (5.4%) | 66 (5.3%) | 8 (6.1%) |
| Death | 1 (0.04%) | 0 | 1 (0.7%) |
| Serious non-fatal adverse event | 6 (0.3%) | 2 (0.16%) | 3 (2.3%) |
| Hypersensitivity reaction involving at least two body systems | 20 (1.0%) | 13 (1.1%) | 3 (2.3%) |
| Treated with antihistamine | 48 (2.8%) | 27 (2.4%) | 3 (2.3%) |
| Treated with steroids | 21 (1.0%) | 19 (1.5%) | 0 |

## Presenting Symptoms of Hypersensitivity Reactions

| Presenting Symptoms (not mutually exclusive) | Distribution of Presenting Symptoms by Method of Administration |  |  |
| --- | --- | --- | --- |
|  | At all doses and methods of administration
(N=111)  | At proposed dose and administration
(N=66) | At direct bolus injection
(N=8) |
| Rash, urticaria or pruritus | 95 (86%) | 56 (85%) | 5 (63%) |
| Dyspnea with vasodilation, hypotension or syncope | 14 (13%) | 10 (15%) | 2 (25%) |
| Facial, laryngeal or generalized edema | 9 (8%) | 5 (8%) | 2 (25%) |

## Comparison with Iodinated Contrast Agents 

|     Hypersensitivity Reactions in the Clinical Trials | Three Iodinated 
Contrast Agents | Combidex
 |
| --- | --- | --- |
| Death | 0/4545 | 1/2061   (All)
0/1236   (Infusion) |
| Serious non-fatal | 0/4545 | 6/2061   (All)
2/1236   (Infusion) |
| Uriticaria
Rash
Pruritus | 0.3 to 0.8%
0.6%
0.1 to 1.6% | 2.2%
2.8%
2.4% |

## Improving the Risk/Benefit Ratio 

**Risk**
**Benefit**** **

## Sponsor’s Risk Management Program

**Use of Dilution and Slow Infusion**
**Labeling (Warnings & Precautions)**
**Physician Education**
**Target launch to academic centers and monitor first 1,000 patients**

## FDA: To Enhance the Benefit to the Patients

**Need to better understand Combidex performance by tumor type and nodal size**
**Need to define the conditions of use**

## Sensitivity and Specificity by Size (US Study Only) 

| Size of Lymph Nodes | Readers | Sensitivity | Specificity |
| --- | --- | --- | --- |
| < 10 mm | Reader 1 
Reader 2  | 69%
66% | 81%
78% |
| > 10 mm | Reader 1 
Reader 2  | 93%
98% | 56%
71% |

## Prevalence of Histologically Positive Nodes by Nodal Size

| Nodal Size from Pathology | US Study
38804-10 | European Studies |  |  |
| --- | --- | --- | --- | --- |
|  |  | 3-2-A | 3-7-A | 3-10-A |
| < 10 mm | 33/329
(10%) | -- | 46/696
(7%) | 99/466
(21%) |
| > 10 mm | 56/167
(34%) | 85/129
(66%) | 17/87
(20%) | 26/50
(52%) |

## Predictive Values of a Positive or Negative Combidex Test 

| Lymph Nodes: Size < 10 mm
Sensitivity 68%, Specificity 80% |  |  | Lymph Nodes: Size > 10 mm
Sensitivity 95%, Specificity 64% |  |  |
| --- | --- | --- | --- | --- | --- |
| Prevalence | PPV | NPV | Prevalence | PPV | NPV |
| 1% | 3% | 99% | 25% | 47% | 98% |
| 10% | 27% | 96% | 50% | 73% | 93% |
| 25% | 53% | 88% | 75% | 89% | 81% |
| 50% | 77% | 71% | 90% | 96% | 59% |

## To Define the Conditions of Use

**Uses that may not be helpful**
**Patient with a low risk for metastasis**
**Patients with a lymph node (> 10 mm) visualized from non-contrast MR imaging**
**Substitute for pathology confirmation**
**Surveillance for tumor recurrences in treated patients**

**   ****Key question: How will Combidex results be benefit to patients ?**
**Prostate Cancer**
**Bladder Cancer**
**Breast Cancer**
**Head & Neck Cancer**