# Presentation: 673862

## BLA #125019ZEVALINTM Kit 

**Philippe Bishop, MD FDA/CBER**
**September 11, 2001**

## Presentation Outline

**Regulatory History**
**Study Results**
**Efficacy**
**Safety**
**Dosimetry & Biodistribution**
**Summary**
**Committee Questions**

## BLA #125019 Regulatory History

## ZEVALINTM BLA Contents

**Results of 5 clinical studies were submitted in support of the proposed biologic license application**

## Proposed Indication 

**Treatment of patients with relapsed or refractory low-grade, follicular or CD20+ transformed B-cell NHL, and for the treatment of patients with RITUXAN****®****-refractory follicular NHL. **

**Notes:**
The sponsor has submitted the results obtained in 348 subjects enrolled in five clinical studies [two efficacy studies, one phase 2 and one phase 1 trial, and preliminary information on an ongoing expanded access trial], in support of the proposed following indication: 

## Regulatory History

**106-98**

**12-9-99**

**106-06**

**7-7-98**

**106-05**

**5-20-98**

**106-04**

**2-24-98**

**106-03**

**6-13-96**

**IND Submission**

**11-24-92**

**Date**

## Regulatory History

| Date | Milestone |
| --- | --- |
| 6-5-00 | Fast Track Granted |
| 11-1-00 | BLA Received |
| 12-29-0 | Filing Action |
| 5-3-01 | FDA Review Letter |
| 7-9-01 | IDEC Complete Response |
| 9-11-01 | ODAC |
| 1-8-02 | Action Date |

**Regulatory History**

## Efficacy

## ZEVALINTM Therapy Development

**1 major controlled efficacy study**
**AND**
**1 supportive trial in the refractory setting**

**Notes:**
On September 30 1997 the FDA met with IDEC to discuss regulatory standards that could serve as basis for product registration.

## Active control: rituximab
Stratification by histology 
(IWF A/Follicular/Transformed)
1o efficacy endpoint: superior ORR (LEXCOR)

**Stratification by histology **
**(IWF A/Follicular/Transformed)**
**1****o**** efficacy endpoint: superior ORR (LEXCOR)**

**Efficacy Study****Trial 106-04 **

## 106-04 Primary Efficacy Analysis

|  | ZEVALINTM
N=73
% | Rituximab
N=70
% | p-value* |
| --- | --- | --- | --- |
| ORR#
(95% CI) | 73%
(62, 82) | 47%
(35, 60) | 0.002 |

**#****Protocol Defined Response Criteria/LEXCOR Evaluation**
*******Cochran-Mantel-Haenszel test stratified by histology type**

## 106-04 Subgroup AnalysisORR

| Histology Type | ZEVALINTM
N/Total (%) | Rituximab
N/Total (%) |
| --- | --- | --- |
| IWF A | 6/9 (67) | 3/8 (38) |
| Follicular | 42/55 (76) | 27/58 (47) |
| Transformed | 5/9 (56) | 3/4 (75) |

**106-04 Subgroup Analysis****ORR**

## 106-04 Duration of Response (DR)

*******K-M estimated medians (months)**

|  | ZEVALINTM
N=53 | Rituximab
N=33 |
| --- | --- | --- |
| Median*
Range
95% CI
Censored | 14.2
1-29+
9.4, --
25/53 (47%) | 12.1
2-25
8, 25
14/33 (42%) |

**Notes:**
Duration of response is defined as the interval from onset of response to disease progression.

## 106-04 Subgroup AnalysisDuration of Response

| Histology Type |  | ZEVALINTM | Rituximab |
| --- | --- | --- | --- |
| IWF A | N
Median (mos)
Range
Censored | 6
9.8
(5.0-20.5)
17% | 3
--
(8.0-14.5+)
67% |
| Follicular | N
Median (mos)
Range
Censored | 42
18.5
(1.7-28.9+)
52% | 27
12.1
(2.7-24.5)
41% |
| Transformed | N
Median (mos)
Range
Censored | 5
6.8
(0.9,20.3+)
40% | 3
11.7
(2.1-17+)
33% |

## Non-randomized trial in rituximab-refractory follicular B-cell NHL
1o efficacy endpoint: ORR (LEXCOR)

**1****o**** efficacy endpoint: ORR (LEXCOR)**

**Supportive Study****Trial 106-06 **

## Trial 106-06 

**In this patient population an ORR ****≥**** 35% and a DR comparable to prior rituximab was considered acceptable evidence of activity**

## 106-06 Primary Efficacy Analysis

|  | All Subjects
N=54 | Follicular Subjects
N=52 |
| --- | --- | --- |
| ORR*
95% CI | 59%
45, 82 | 58%
43, 71 |

*******Protocol Defined Response Criteria/LEXCOR Evaluation**

## 106-06 Duration of Response*

******* Protocol defined analysis**
**# ****K-M estimated medians (months)**

|  | ZEVALINTM
N=32 | Rituximab
N=17 |
| --- | --- | --- |
| Median#
Range
95% CI
Censored | 7.7
2-25+
6-9
31% | 4.0
1-7
3-6
0% |

**Notes:**
Duration of response is defined as the interval from onset of response to disease progression.

## ZEVALIN vs. Prior Rituximab Therapy Analysis

**DR for ZEVALINTM therapy compared to the prior rituximab therapy **
**Each subject used as their own control **
_**Favors ZEVALINTM**_** if duration of response to ZEVALINTM is at least 1 month longer**
_**Favors rituximab**_** if duration of response to rituximab is at least 1 month longer**

## 106-06Duration of Response

**37**

**20**

**Neither**

**9**

**5**

**Favors Rituximab**

**54**

**29**

**Favors ZEVALIN****TM**

**%**

**N**

**DR for ZEVALINTM therapy compared to the prior rituximab therapy **
**Each subject used as their own control**

**Notes:**
Duration of response is defined as the interval from onset of response to disease progression.
.  In this analysis, the length of the duration of response was categorized as longer for ZEVALIN, equivalent, or longer for RITUXAN.  If the duration of response for ZEVALINTM therapy was longer than DR to RITUXAN by more than 1 month, then the ZEVALINTM therapy was considered beneficial (i.e., in favor of ZEVALIN).  If this difference was ≤1 month, then the responses were called equivalent.  If the duration of response to prior RITUXAN was longer than DR to ZEVALIN therapy by more than 1 months then ZEVALINTM therapy was considered not beneficial to patients (i.e., in favor of rituximab).

Using this algorithm, the following table provides a summary of the results for the exploratory analysis for confirmed responses:

## EfficacyFDA Assessment

**ZEVALINTM therapy has demonstrable and durable anti-tumor activity (ORR) in follicular subjects.**
**Limited data in IWF A and transformed subjects preclude definitive conclusions.**

## Safety

## Hematologic ToxicityWithin First 90 Days (N=392)

|  | Grade 3-4
N (%) | Grade 4
N (%) | Median Duration
Grade 3-4
(range) |
| --- | --- | --- | --- |
| ANC | 214 (55) | 118 (30) | 25 days
(2-190+) |
| PLT | 224 (57) | 39 (10) | 27 days
(7-167+) |

## Grade 3-4 ANCN=214/392 (55%)

## Immunologic Effects

**All subjects had B-cell depletion**
**Median time to baseline recovery = 6 months**
**Transient IgM decline**
**IgG and IgA remained normal**

## Infections

**114/358 (32%) had a total of 183 events**
**28/358 (8%) had Grade 3-4 events**

**Notes:**
The majority of infections were not subcategorized in the CRF (n=68).  Among those that were subcategorized, bacterial infection occurred in 48 subjects, viral infections in 17, and mucco-cutaneous fungal in 13 subjects. 

23 of 348 subjects (7%) were hospitalized with infection or febrile neutropenia 
6 subjects had febrile neutropenia
4 subjects had urinary tract infections
4 subjects had sepsis (3 foreign-body related)
4 subjects had pneumonia
3 subjects had cellulitis or abscess
2 subjects had gastroenteritis or diarrhea 

## Grade 3-4 PLTN=224/392 (57%)

## Study 106-05: Grades 3-4 PLTN=26/30 (87%)

## Incidence of Bleeding

**62 (18%) subjects had at least 1 bleeding event**
**7 subjects had a total of 12 Grade 3-5 events**
**2 intracranial bleed ******** Death**
**1 vaginal bleed**
**1 ecchymosis**
**4 GI bleed**
**1 hematemesis**
**3 melena**

**5 subjects**

## Exploratory Analyses  Cytopenias Risk Factors

**Baseline BM involvement**
**Number of prior regimens**
**Prior fludarabine therapy**
**Baseline platelet level **

## Non Cytopenic AEsPer Patient Incidence (N=358)

| AE | All Grades (%) | Grade 3-4 (%) |
| --- | --- | --- |
| Asthenia | 52 | 3 |
| Nausea | 37 | <1 |
| Infections | 32 | 8 |
| Chills | 28 | <1 |
| Fever | 26 | 3 |
| Abdominal pain | 18 | 3 |
| Dyspnea | 16 | 2 |
| Headache | 16 | <1 |
| Increased cough | 15 | 0 |
| Pain | 15 | <1 |

## Common Non-Heme AEsStudy 106-04

## Notable AEs (All Grades)Study 106-04

## Secondary Malignanciesn=349

** ****3 AML**
** ****2 MDS**
** ****1 meningioma**
**Onset 8 to 34 months post ZEVALINTM therapy and 4 to 13 years following NHL diagnosis**

**Notes:**
On the rituximab arm there was1 subject with pancreatic adenoma.

## HAMA/HACA Response(N=211)

**5 subjects had positive HAMA titers**
**2 had positive baseline HAMA titers **
**3 developed titers post-treatment**
**3 subjects had positive HACA titers**
**2 had positive baseline HACA titers**
**1 developed titers post-treatment**

## Deaths

**70 of 349 (20%) subjects died**
**58 ******** PD**
**12 ******** other causes**
**2 intracranial hemorrhage**
**5 MDS/AML**
**3 pulmonary complications**
**1 cardiac arrest**
**1 pneumonia**

**Notes:**
1.2 to 39.9 months post 1st infusion
6 died within 3 months of therapy

## Safety FDA Assessment 

**ZEVALINTM therapy is characterized by a high incidence of cytopenias**
**Gr. 3-4 ANC 55%**
**Gr. 3-4 PLT 57%**
**median duration 3-4 weeks**

## Most serious AEs included
Hemorrhage  2 deaths
Myeloid malig.  5 deaths
Infections
Allergic reactions

**Hemorrhage ******** 2 deaths**
**Myeloid malig. ******** 5 deaths**
**Infections**
**Allergic reactions**

**Safety**** FDA Assessment **

## Dosimetry & Biodistribution

## Whole Body Biodistribution Imaging

**179 subjects assessed **
**Five imaging time points**
**Diagnostic quality imaging for multiple organs**
**Diagnostic quality imaging for known tumor sites**

## Normal Organ Dosimetry

**MIRDOSE 3.1 Software**
**Regions of Interest for Multiple Organs with Localization of Radiolabeled Antibody:**
**	****Heart, Lung, Liver, Small Intestine, Spleen, Testes, Kidneys, Bone Marrow (Sacrum)**

## Radiation Absorbed DoseNotable Organs

**70-106**

**90**

**Red marrow (Sacral ROI)**

**256-467**

**368**

**Lower large bowel**

**122-288**

**211**

**Upper large bowel**

**38-1184**

**950**

**Testes**

**349-880**

**547**

**Liver**

**781-2368**

**1350**

**Spleen**

**Range**

**Median dose (cGy) for 32 mCi**

**Organ**

## GI Toxicity (All Grades)

## “Worst Case” Scenarios

**Adjacent normal tissues **
**Alteration in the biodistribution **
**Obstruction of clearance route - renal obstruction**

**Notes:**
at risk for radiation injury from tumor sites 
of the radiolabeled antibody due to immune response

## Dosimetry-BiodistributionFDA Assessment

**Normal organ dosimetry supports the use of fixed-dose of ****90****Y-labeled ZEVALIN****TM****.**
**Biodistribution is necessary for assessment of normal organ and tumor site localization  **

## Dosimetry-BiodistributionFDA Assessment

**There are inadequate data to assess the safety of additive localized radiation effects from external beam radiation therapy and ZEVALIN****TM therapy.  **

## Conclusions

## Summary

**Durable anti-tumor activity (ORR) was documented in both efficacy studies**
**ZEVALINTM therapy is associated with significant hematologic toxicity in a majority of subjects and serious morbidity in a minority of  subjects.**

## Summary

**As compared to RITUXAN****®****, ZEVALIN****TM**** was associated with superior ORR, similar DR and TTP.**
**ZEVALIN****TM**** showed 58% ORR in RITUXAN****®**** refractory subjects.**

## Summary

**Data are limited in non-follicular subgroups.**
**Data in these subgroups is limited to subjects who have not received prior RITUXAN****®****.**

## Questions to the Committee