# Presentation: 862910

## Ibritumomab Tiuxetan (ZevalinTM)  Radioimmunotherapy of Non-Hodgkin’s Lymphoma

**Oncology Drug Advisory Committee Meeting****September 11, 2001**

- ODAC Presentation

## Opening remarks 
Leslie L. Shelly, Ph.D. - Associate Director, Regulatory Affairs*
Scientific and medical summary of Zevalin 
Christine A. White, M.D. - Vice President, Medical Affairs*
Discussion 
Christine A. White, M.D. - Vice President, Medical Affairs*
Pratik Multani, M.D. - Director, Medical Affairs*
Bryan Leigh, M.D. - Director, Oncology*

**Leslie L. Shelly, Ph.D. - Associate Director, Regulatory Affairs***
**Scientific and medical summary of Zevalin **
**Christine A. White, M.D. - Vice President, Medical Affairs***
**Discussion **
**Christine A. White, M.D. - Vice President, Medical Affairs***
**Pratik Multani, M.D. - Director, Medical Affairs***
**Bryan Leigh, M.D. - Director, Oncology***

**Presentation Agenda**

***IDEC Pharmaceuticals, San Diego, CA**

## Treatment of patients with relapsed or refractory, low-grade, follicular, or CD20+ transformed B-cell non-Hodgkin’s lymphoma (NHL) and treatment of patients with rituximab-refractory follicular NHL

**Zevalin****TM ****(ibritumomab tiuxetan):****Proposed Indication **

- ODAC Presentation

## Non-Hodgkin’s Lymphoma

**Most NHL are of B cell origin and express CD20 **
**Ranks 5th in cancer incidence and mortality**
**Incidence:  54,900/year**
**Prevalence:  300,000 cases**
**65% low-grade or follicular**
**Transformation increases over time**
**Median age at diagnosis:  60 years**
**Median survival**
**Low-grade or follicular:  6.2 years**
**From transformation:  7 to 22 months**

## Zevalin Regimen

**Rituximab (250 mg/m****2****)**

**Followed by**
**111****In Zevalin**
**5 mCi (1.6 mg)**

**Rituximab (250 mg/m****2****)**

**Followed by**
**90****Y Zevalin**
**(0.4 or 0.3 mCi/kg;****max dose 32 mCi)**

**Imaging dose**

**Therapeutic dose**

**1**

**2**

**3**

**4**

**5**

**6**

**7**

**Day**

**8**

**Scans**

**2 - 24 hours**

**48 - 72 hours**

**90 - 120 hours****(optional)**

## IDEC

**111 ****Indium Isotope Supplier**

**IDEC**

**90 ****Yttrium Isotope Supplier**

**Distributor**

**NUCLEAR PHARMACY**

**111 ****In Kit**

**Single Point Distribution System**

**90****Y Kit**

## Clinical Basis for BLA

**Clinical Basis for BLA**

- ODAC Presentation

## Phase III Randomized Trial (106-04)
Primary endpoint:  ORR 
Designed with 80% power to detect a difference in ORR
TTP  to be clinically equivalent to control (within 1.5 months)
Phase III Rituximab-Refractory Trial (106-06)
Fast Track:  June 5, 2000

**Primary endpoint:  ORR **
**Designed with 80% power to detect a ****difference in ORR**
**TTP  to be clinically equivalent to control ****(within 1.5 months)**
**Phase III Rituximab-Refractory Trial (106-06)**
**Fast Track:  June 5, 2000**

**FDA Agreements **

- ODAC Presentation

## Clinically significant activity 
Acceptable toxicity 

**Acceptable toxicity **

**Zevalin****TM ****(ibritumomab tiuxetan):****Summary **

- ODAC Presentation

**Zevalin represents a clinically meaningful advance in therapy**

## IDEC Investigators

**Thomas Witzig, ****M.D.****Mayo Clinic**
**Sandra Horning, ****M.D.****Stanford University****ECOG Lymphoma Chair**
**Myron Czuczman, ****M.D.****Roswell Park Cancer Center**

**Gregory A. Wiseman, ****M.D.****Mayo Clinic**
**Andrew Raubitschek,**** M.D.****City of Hope**** **
**Albert LoBuglio, ****M.D.****University of Alabama, ****Birmingham**** **

- ODAC Presentation

## IDEC Investigators (cont.)

**Leo Gordon, ****M.D.****Northwestern University**
_**LEXCOR**_**Donald Klippenstein, ****M.D.****Roswell Park Cancer Center**
_**Dosimetry**_**Michael Stabin, ****Ph.D., C.H.P.****Oak Ridge Institute for Science and Education**

- ODAC Presentation

**Larry Cripe,**** M.D.****Indiana University Cancer Center**
_**Radioincorporation**_**Michael Zimmer, ****Ph.D.****Northwestern University **
_**	**_

## Opening remarks 
Leslie L. Shelly, Ph.D. - Associate Director, Regulatory Affairs*
Scientific and medical summary of Zevalin 
Christine A. White, M.D. - Vice President, Medical Affairs*
Discussion 
Christine A. White, M.D. - Vice President, Medical Affairs*
Pratik Multani, M.D. - Director, Medical Affairs*
Bryan Leigh, M.D. - Director, Oncology*

**Leslie L. Shelly, Ph.D. - Associate Director, Regulatory Affairs***
**Scientific and medical summary of Zevalin **
**Christine A. White, M.D. - Vice President, Medical Affairs***
**Discussion **
**Christine A. White, M.D. - Vice President, Medical Affairs***
**Pratik Multani, M.D. - Director, Medical Affairs***
**Bryan Leigh, M.D. - Director, Oncology***

**Presentation Agenda**

***IDEC Pharmaceuticals, San Diego, CA**

## Ibritumomab Tiuxetan (ZevalinTM) Radioimmunotherapy of Non-Hodgkin’s Lymphoma

**Christine A. White, M.D.  ****Vice President, Medical Affairs ****IDEC Pharmaceuticals Corporation**
**Oncology Drug Advisory Committee Meeting****September 11, 2001**

- ODAC Presentation

## Background 
Phase I/II conclusions
Imaging and dosimetry
Phase III randomized trial
Phase III rituximab-refractory trial
Efficacy in transformed/nonfollicular low-grade
Integrated safety summary
Conclusions

***Background***** **
**Phase I/II conclusions**
**Imaging and dosimetry**
**Phase III randomized trial**
**Phase III rituximab-refractory trial**
**Efficacy in transformed/nonfollicular low-grade**
**Integrated safety summary**
**Conclusions**

- ODAC Presentation

**Presentation Outline**

## Response Rate and Duration Decrease with Successive Courses of Alkylator-Based Therapies

**100**

**80**

**60**

**40**

**20**

**Years**

**1**

**2**

**3**

**4**

**1st Rx**

**2nd Rx**

**3rd Rx**

**4th Rx**

**1**

**  ****70**

**  ****2**

**  ****59**

**  ****3**

**  ****59**

**  ****4**

**  ****44**

**  ****5**

**  ****39**

**Response**

** ****Rate (%)**

**Rx**

**Source:  Gallagher et al.  J Clin Oncol 1986;4(10):1470-80**

**Response Rate and Duration Decrease with Successive Courses of Alkylator-Based Therapies**

- ODAC Presentation

## Treatment of Relapsed or Refractory LG/F/T NHL

**Typically multiple cycles per course of therapy**

- ODAC Presentation

## Toxicities of Commonly Used Regimens

**Treatment**

**Toxicities of Commonly Used Regimens**

**Agent**

**(# of Studies)**

**Neutropenia**

**Grade 4**

**Thrombocytopenia**

**Grade 4**

**Infection**

**Grade 3 & 4**

**Related**

**Deaths**

**Fludarabine (5)**

**5 -**

**59%**

**0 - 3%**

**1 - 14%**

**3 - 5%**

**Cladribine (5)**

**13 - 36%**

**4 - 13%**

**8 - **

**40%**

**3 - **

**23%**

**ESHAP (1)**

**50%**

**NA**

**30%**

**16%**

**DHAP (1)**

**53%**

**39%**

**31%**

**17%**

**ICE (1)**

**13%**

**15%**

**14%**

**NA**

**CHOP (6)**

**16 - 39%**

**2 - 12%**

**3 - 33%**

**Grade 3 and 4 neurotoxicity in up to 10%; renal/hepatic toxicity in up to 21%**

- ODAC Presentation

## No conventional chemotherapy regimen is curative
No regimen has been shown to be superior with regard to survival
Patients need additional treatment options
In the absence of cure or survival benefit, treatments that induce remission and prolong time off therapy are valuable

**No regimen has been shown to be superior with regard to survival**
**Patients need additional treatment options**
**In the absence of cure or survival benefit, treatments that induce remission and prolong time off therapy are valuable**

**Treatment of ****Relapsed or Refractory LG/F/T NHL**

- ODAC Presentation

## Rationale for Radioimmunotherapy in NHL

**NHL is inherently sensitive to radiation**
**RT can be curative in limited stage NHL but can not be applied to advanced stage disease**
**RIT antibodies target radiation to tumor**
**RIT can kill both bound and neighboring tumor cells, overcoming the problem of access in bulky or poorly vascularized tumors**

## Critical Factors for Successful RIT

**Target antigen**
**Antibody selectivity**
**Choice of isotope**
**Stability of antibody-isotope linkage**

## Zevalin (ibritumomab tiuxetan)
Ibritumomab (murine parent of rituximab)
Binds CD20
Tiuxetan 
Stable retention of 90Y 

**Expressed only on****B-lineage cells**
**Important for cell ****cycle initiation ****and differentiation**
**Does not shed or ****modulate**** **

**Zevalin (ibritumomab tiuxetan)**
**Ibritumomab (murine parent of rituximab)**
**Binds CD20**
**Tiuxetan **
**Stable retention ****of ****90****Y**** **

**CD20**
**antigen**

**B cell**

**90****Y Zevalin**

**90****Y**

**Tiuxetan**

**Ibritumomab**

- ODAC Presentation

## Choice of Isotope

**Choice of Isotope**

**90****Y**

**90****Y**

**90****Y**

**90****Y**

**90****Y**

**90****Y**

- ODAC Presentation

## Background 
Phase I/II conclusions
Imaging and dosimetry
Phase III randomized trial
Phase III rituximab-refractory trial
Efficacy in transformed/nonfollicular low-grade
Integrated safety summary
Conclusions

**Background **
***Phase I/II conclusions***
**Imaging and dosimetry**
**Phase III randomized trial**
**Phase III rituximab-refractory trial**
**Efficacy in transformed/nonfollicular low-grade**
**Integrated safety summary**
**Conclusions**

- ODAC Presentation

**Presentation Outline**

## Zevalin Phase I and I/II Conclusions

**Unlabeled pretreatment rituximab improves Zevalin biodistribution**
**MTD:  0.4 mCi/kg (0.3 mCi/kg for patients with mild thrombocytopenia), max 32 mCi **
**Toxicity primarily hematologic and reversible**
**Correlated with mCi/kg dose**
**Clinical variables (baseline platelets, % marrow NHL involvement) more predictive of toxicity than dosimetry**
**Clinical parameters adequate for dosing**

## ORR:  82% in low-grade NHL	42% in intermediate-grade NHL	
Median TTP (responders):
0.4 mCi/kg:  			15.4 months
0.4 mCi/kg CR pts:		28.3 - 37.2+ months

**Median TTP (responders):**
**0.4 mCi/kg:  ****	****	****	****15.4 months**
**0.4 mCi/kg CR pts:****	****	****28.3 - 37.2+ months**

**Zevalin Phase I/II Study ****(N = 51)**

## Background
Phase I/II conclusions
Imaging and dosimetry
Phase III randomized trial
Phase III rituximab-refractory trial
Efficacy in transformed/nonfollicular low-grade
Integrated safety summary
Conclusions

**Background**
**Phase I/II conclusions**
***Imaging and dosimetry***
**Phase III randomized trial**
**Phase III rituximab-refractory trial**
**Efficacy in transformed/nonfollicular low-grade**
**Integrated safety summary**
**Conclusions**

- ODAC Presentation

**Presentation Outline**

## 111In-Labeled Zevalin Imaging

**111****In-Labeled Zevalin Imaging**

**Abdominal CT**** **

**Abdominal SPECT**

**4 hours**

**66 hours**

**139 hours**

- ODAC Presentation

## Imaging and Dosimetry

**Tumors imaged in all LG/F/T patients**
**Radiation absorbed dose to normal organs acceptable in all patients **
**Minimal urinary excretion, 7% over 7 days**
**No correlation between hematologic toxicity and dosimetry or PK parameters**

## Median 90Y Radiation Absorbed Dose

**Median ****90****Y Radiation Absorbed Dose**

**1480**

**0**

**200**

**400**

**600**

**800**

**1000**

**1200**

**1400**

**1600**

***All spleen and liver doses were adjusted for organ mass**
**†****10 men for sex-specific organs**** ****‡****Adrenals, brain, breasts, gallbladder wall, muscle, pancreas, skin, thymus, stomach**

- ODAC Presentation

**Tumor**

**cGy**

**2000**

## Background
Phase I/II conclusions
Imaging and dosimetry
Phase III randomized trial
Phase III rituximab-refractory trial
Efficacy in transformed/nonfollicular low-grade
Integrated safety summary
Conclusions

**Background**
**Phase I/II conclusions**
**Imaging and dosimetry**
***Phase III randomized trial***
**Phase III rituximab-refractory trial**
**Efficacy in transformed/nonfollicular low-grade**
**Integrated safety summary**
**Conclusions**

- ODAC Presentation

**Presentation Outline**

## Representative Population

- ODAC Presentation

**Representative Population**

**Similar to 1850 patients from 7 literature reports**

***Dana et al., 1993; Johnson et al., 1995; Bastion et al., 1997; Armitage and Weisenburger, 1998; ****Lopéz-Guillermo et al., 1998; McLaughlin et al., 1998; Rosenberg et al., 1982**

## Phase III Randomized Controlled Study

**Mayo Clinic****	****	****	****Northwestern Univ****MD Anderson****UCLA****Roswell Park****Harvard/Beth Israel****Cleveland Clinic****Washington Univ ****Jewish Hospital Kenwood, OH****Fox Chase Cancer Center****	****Mountain States Tumor Institute****Univ of Florida****Greenville Hospital, SC****Univ of Alabama**

**Henry Ford Cancer Center****Johns Hopkins Univ****Kansas Univ****Sutter Cancer Center****St. Vincent’s Hospital****Greenbaum Cancer Center, MD****City of Hope****Sharp/Sidney Kimmel Cancer Center****NYU****Georgetown Univ****Western Penn Cancer Institute****New York Hospital****Kaiser Permanente, CA**

- ODAC Presentation

## Study Design

**Zevalin regimen****Day 1:  ****Rituximab (250 mg/m****2****)**** **
**	****111****In Zevalin (5 mCi)**
**Day 7, 8, or 9:  ****	****Rituximab (250 mg/m****2****)**** **
**	****90****Y Zevalin (0.4 mCi/kg; ****	****	****	****max 32 mCi****)**

**Rituximab control****(375 mg/m****2**** weekly x 4)**

**R****A****N****D****O**
**M****I****Z****A****T****I****O****N**

**STRATIFIED ****by histology: ****IWF A, ****follicular, or****transformed**

## Prospectively-Defined Efficacy Endpoints

**Designed with 80% power to detect a difference of ****25% in ORR (alpha = 0.05)**
**Determined by independent LEXCOR panel blinded to treatment arm and investigator-assessed response**
**Secondary:  DR, TTP, time to next therapy, CR, CCR, PR, QOL**

**Prospectively-Defined ****Efficacy Endpoints**

## Inclusion
Bidimensionally measurable disease
< 25% marrow involvement by biopsy
WHO performance status < 2
ANC > 1,500/mm3, platelets > 150,000/mm3
Exclusion
Prior myeloablative therapy or RIT
Prior radiation to > 25% of active marrow
Prior anti-CD20 therapy
Total bilirubin or creatinine > 2.0 mg/dL
ALC > 5,000/mm3

**Bidimensionally measurable disease**
**<** **25% marrow involvement by biopsy**
**WHO performance status **_**<**_** 2**
**ANC **_**>**_** 1,500/mm****3****, platelets **_**>**_** 150,000/mm****3**
**Exclusion**
**Prior myeloablative therapy or RIT**
**Prior radiation to > 25% of active marrow**
**Prior anti-CD20 therapy**
**Total bilirubin or creatinine > 2.0 mg/dL**
**ALC > 5,000/mm****3**

**Enrollment Criteria****	**** **

## Demographics/Disease Status

**Well-balanced**
**No statistically significant differences in:**

**Age**
**Sex**
**Race**
**Stage**
**Histology**
**No. of prior regimens**

**Response to last therapy**
**Marrow involvement**
**Splenomegaly**
**Bulky disease**
**IPI risk group**
**Chemoresistance**

## Demographics/Disease Status

**Demographics/Disease Status**

- ODAC Presentation

## Disease Status (cont.)

- ODAC Presentation

***Resistance defined as no response or TTP < 6 months**

## Response Assessment Protocol-Defined Response Criteria

**Response Assessment**** ****Protocol-Defined Response Criteria**

**0**

**10**

**20**

**30**

**40**

**50**

**60**

**70**

**80**

**90**

**100**

**Zevalin**

**Rituximab**

**Response Rate (%)**

**73%**

**47%**

**52%**

**31%**

**4%**

**3%**

**11%**

**18%**

**Response**

**p-value**

**ORR**

**0.002**

**CR**

**0.326**

**(N = 73)**

**(N = 70)**

- ODAC Presentation

## Response by Histology

**Protocol-Defined Response Criteria**

- ODAC Presentation

***p-values generated by Fisher’s exact two-tailed test****†****Included SLL, MALT, lymphoplasmacytic, and monocytoid B**

## Response in Chemoresistant Patients

**Protocol-Defined Response Criteria**

- ODAC Presentation

**Resistant to last chemotherapy; resistance defined as no response or TTP < 6 months**
***p-value generated by Fisher’s exact two-tailed test**

## Response by Tumor BulkProtocol-Defined Response Criteria	

- ODAC Presentation

## Response Assessment International Workshop Response Criteria

**0**

**10**

**20**

**30**

**40**

**50**

**60**

**70**

**80**

**90**

**100**

**Zevalin**

**Rituximab**

**Response Rate (%)**

**80%**

**56%**

**45%**

**16%**

**4%**

**4%**

**36%**

**30%**

**Response**

**p-value**

**ORR**

**0.002**

**CR**

**0.040**

**(N = 73)**

**(N = 70)**

- ODAC Presentation

## Duration of Response and TTP (months)

**Duration of Response and TTP ****(months)**

**Based on Kaplan-Meier estimation****Median observation time:  22 months**

- ODAC Presentation

## Duration of Response by Histology

***p-value generated by Log-rank test**

- ODAC Presentation

## TTP:  All Patients 

**C**

**C**

**C**

**C**

**C**

**C**

**C**

**C**

**C**

**C**

**C**

**C**

**C**

**C**

**C**

**C**

**C**

**C**

**C**

**C**

**C**

**C**

**C**

**C**

**C**

**C**

**C**

**C**

**C**

**C**

**C**

**C**

**TTP:  All Patients **

**0**

**10**

**20**

**30**

**40**

**50**

**60**

**70**

**80**

**90**

**100**

**C**

**C**

**C**

**C**

**C**

**C**

**C**

**C**

**Progression Free (%)**

**Months**

**C**

**C**

**C**

**C**

**C**

**C**

**C**

**Kaplan-Meier Analysis****C = censored**

**Zevalin (N = 73)**

**Rituximab (N = 70)**

- ODAC Presentation

**p = 0.173****Log-rank test**

## Time to Next Therapy All Patients

**C**

**C**

**C**

**C**

**C**

**C**

**C**

**C**

**C**

**C**

**C**

**C**

**C**

**C**

**C**

**C**

**C**

**C**

**C**

**C**

**C**

**C**

**C**

**C**

**C**

**C**

**C**

**C**

**C**

**C**

**C**

**Months**

**0**

**10**

**20**

**30**

**40**

**50**

**60**

**70**

**80**

**90**

**100**

**0**

**2**

**4**

**6**

**8**

**10**

**12**

**14**

**16**

**18**

**20**

**22**

**24**

**26**

**28**

**30**

**32**

**34**

**C**

**C**

**C**

**C**

**C**

**C**

**C**

**C**

**C**

**C**

**C**

**C**

**C**

**C**

**C**

**C**

**C**

**C**

**C**

**C**

**C**

**C**

**C**

**C**

**C**

**C**

**C**

**C**

**C**

**C**

**C**

**C**

**C**

**C**

**C**

**C**

**C**

**C**

**C**

**C**

**C**

**Patients Without Therapy (%)**

**p = 0.084****Log-rank test**

**Kaplan-Meier Analysis****C = censored**

**Zevalin (N = 73)**

**Rituximab (N = 70)**

- ODAC Presentation

## TTP:  Follicular Patients

**Kaplan-Meier Analysis****C = censored**

**C**

**C**

**C**

**C**

**C**

**C**

**C**

**C**

**C**

**C**

**C**

**C**

**C**

**C**

**C**

**C**

**C**

**Months**

**0**

**3**

**6**

**9**

**12**

**15**

**18**

**21**

**24**

**27**

**30**

**C**

**C**

**C**

**C**

**C**

**C**

**C**

**C**

**C**

**C**

**C**

**C**

**C**

**C**

**C**

**C**

**C**

**C**

**C**

**C**

**C**

**C**

**Progression Free (%)**

**33**

**C**

**p = 0.062****Log-rank test**

**36**

**Zevalin (N = 55)**

**Rituximab (N = 58)**

- ODAC Presentation

## Time to Next TherapyFollicular Patients

**C**

**C**

**C**

**C**

**C**

**C**

**C**

**C**

**C**

**C**

**C**

**C**

**C**

**C**

**C**

**C**

**C**

**C**

**C**

**C**

**C**

**C**

**C**

**C**

**C**

**C**

**C**

**C**

**C**

**C**

**C**

**C**

**C**

**C**

**C**

**C**

**C**

**C**

**C**

**C**

**C**

**C**

**C**

**C**

**C**

**C**

**C**

**C**

**C**

**C**

**C**

**C**

**C**

**C**

**C**

**C**

**C**

**C**

**C**

**C**

**C**

** ****Patients Without Therapy (%)**

**Months**

**Time to Next Therapy****Follicular Patients**

**p = 0.058****Log-rank test**

**Kaplan-Meier Analysis****C = censored**

**Zevalin (N = 55)**

**Rituximab (N = 58)**

- ODAC Presentation

## TTP:  CR/CCR Patients 

**Kaplan-Meier Analysis****C = censored**

**C**

**0**

**10**

**20**

**30**

**40**

**50**

**60**

**70**

**80**

**90**

**100**

**Months**

**C**

**C**

**C**

**C**

**C**

**C**

**C**

**C**

**C**

**C**

**C**

**C**

**C**

**C**

**Progression Free (%)**

**p = 0.144****Log-rank test**

**Zevalin (N = 15)**

**Rituximab (N = 11)**

- ODAC Presentation

## Phase III Randomized Summary

**Primary**
**Significantly higher ORR as determined by independent, blinded LEXCOR panel**
**Secondary**
**Overall TTP comparable**
**Trend toward longer TTP in follicular and CR/CCR patients **
**Trend toward longer time to next therapy in all patients **
**Median TTP in responders:  15.4 months**

**Phase III Randomized Summary**

- ODAC Presentation

## Background
Phase I/II conclusions
Imaging and dosimetry
Phase III randomized trial
Phase III rituximab-refractory trial
Efficacy in transformed/nonfollicular low-grade
Integrated safety summary
Conclusions

**Background**
**Phase I/II conclusions**
**Imaging and dosimetry**
**Phase III randomized trial**
***Phase III rituximab-refractory trial***
**Efficacy in transformed/nonfollicular low-grade**
**Integrated safety summary**
**Conclusions**

- ODAC Presentation

**Presentation Outline**

## Phase III Nonrandomized Controlled Study in Rituximab-Refractory Follicular NHL

**Mayo Clinic****Johns Hopkins Univ****Northwestern Univ****UCLA****Indiana Univ****Roswell Park****Sharp/Sidney Kimmel Cancer Center****Univ of Florida****Kansas Univ**

**Western Penn Cancer Institute****Harvard/Beth Israel****Washington Univ****Henry Ford Cancer Center****Sutter Cancer Center, CA****Univ of Miami****Radiation Therapy Assoc., FL****Kaiser Permanente, CA**

- ODAC Presentation

## Outpatient Treatment
*Day 1:  Rituximab (250 mg/m2) 	111In Zevalin (5 mCi)
 Day 7, 8, or 9:  	Rituximab (250 mg/m2)	90Y Zevalin (0.4 mCi/kg; max 32 mCi)

**Outpatient Treatment**
***Day 1:  ****Rituximab (250 mg/m****2****)**** ****	****111****In Zevalin (5 mCi)**
** ****Day 7, 8, or 9:  ****	****Rituximab (250 mg/m****2****)****	****90****Y Zevalin (0.4 mCi/kg; max 32 mCi)**

***29 patients did not receive ****111****In Zevalin imaging or dosimetry**

## Efficacy Objectives

**Response evaluated by independent LEXCOR panel**
**Secondary:  DR, TTP, time to next therapy, CR, CCR, PR, and comparison of ORR and DR with prior rituximab and last chemo**

**Efficacy Objectives**

## Demographics/Disease Status

- ODAC Presentation

***Resistance defined as no response or TTP < 6 months**

## Response Assessment ITT Follicular Patients (N = 54)

**Response Assessment ****ITT Follicular Patients (N = 54)**

- ODAC Presentation

## Duration of Response and TTP (months)

**Duration of Response and TTP ****(months)**

**Based on Kaplan-Meier estimation**

- ODAC Presentation

## Zevalin vs Prior Therapy Analysis

**Favors if:**
**Responded to one therapy but not the other**
**Responded to both but DR at least 3 months longer**
**Neutral if:**
**Did not respond to either therapy, or**
**Responded to both therapies but DR within 3 months**

- ODAC Presentation

## Zevalin vs Prior Rituximab or Last Chemotherapy (N = 54)

***Chemotherapy = patients’ 3rd regimen (median); Zevalin = patients’ 5th regimen (median)**

- ODAC Presentation

## Rituximab-Refractory Summary 

**Primary**
**Significant ORR in heavily pretreated, bulky, rituximab-refractory population **
**Secondary**
**Zevalin vs. prior rituximab:  statistically improved efficacy**
**Zevalin vs. last chemo:  no difference, better than expected**
**Median TTP in responders:  9.1 months**

**Rituximab-Refractory Summary **

- ODAC Presentation

## Background
Phase I/II conclusions
Imaging and dosimetry
Phase III randomized trial
Phase III rituximab-refractory trial
Efficacy in transformed/nonfollicular low-grade
Integrated safety summary
Conclusions

**Background**
**Phase I/II conclusions**
**Imaging and dosimetry**
**Phase III randomized trial**
**Phase III rituximab-refractory trial**
***Efficacy in transformed/nonfollicular low-grade***
**Integrated safety summary**
**Conclusions**

- ODAC Presentation

**Presentation Outline**

## 3 patients (20%) in ongoing remission at 11+, 22+, and 37+ months

**Transformed Histology**

**3 patients (20%) in ongoing remission at ****11+, 22+, and 37+ months**

## 2 patients (13.7%) in ongoing remission at 12+ months

**Nonfollicular Low-Grade Histology**

**2 patients (13.7%) in ongoing remission at ****12+ months**

## Background
Phase I/II conclusions
Imaging and dosimetry
Phase III randomized trial
Phase III rituximab-refractory trial
Efficacy in transformed/nonfollicular low-grade
Integrated safety summary
Conclusions

**Background**
**Phase I/II conclusions**
**Imaging and dosimetry**
**Phase III randomized trial**
**Phase III rituximab-refractory trial**
**Efficacy in transformed/nonfollicular low-grade**
***Integrated safety summary***
**Conclusions**

- ODAC Presentation

**Presentation Outline**

## Integrated Safety

**Nonhematologic AEs primarily Grade 1 or 2**
**Not associated with hair loss, severe mucositis, persistent nausea and vomiting common with chemotherapy**
**Low incidence of serious infection**
**Low incidence of HAMA/HACA**

**Integrated Safety**

## Integrated Safety (N = 349):  Most Frequent Nonhematologic Adverse Events

**Integrated Safety ****(N = 349)****:  Most Frequent Nonhematologic Adverse Events**

**Incidence > 5%; probably or possibly related to study drug or relationship unknown****No difference in AEs between patients < 65 years of age and patients **_**>**_** 65**

**35.2**

**24.6**

**20.9**

**13.2**

**8.9**

**8.9**

**7.7**

**7.7**

**7.4**

**7.4**

**6.6**

**6.0**

**5.7**

**5.4**

**Grade 1**
**Grade 2**
**Grade 3**
**Grade 4**

**Patients (%)**

- ODAC Presentation

**7.2**

## Phase III Nonhematologic AEs (N = 143)

**1**

**1**

**Phase III Nonhematologic AEs ****(N = 143)**

- ODAC Presentation

**Patients (%)**

**Incidence **_**>**_** 15%**

**1**

**1**

**Grades 3 and 4**

**50**

**40**

**30**

**20**

**10**

**0**

**10**

**20**

**30**

**40**

**50**

**Grades 1 and 2**

**44**

**41**

**4**

**43**

**19**

**25**

**29**

**19**

**14**

**19**

**17**

**19**

**11**

**19**

**7**

**18**

**16**

**16**

**15**

**7**

**7**

**7**

**15**

**15**

**11**

**16**

**8**

**16**

## Median Blood Counts (N = 349)

**0**

**4**

**8**

**12**

**16**

**Study Week**

**0**

**2**

**4**

**6**

**8**

**10**

**12**

**14**

**0**

**50**

**100**

**150**

**200**

**250**

**300**

**350**

**400**

**450**

**ANC**

**Hemoglobin**

**Platelets**

**ANC (10****3****/mm****3****)         Hemoglobin (g/dL)**

**Platelets (10****3****/mm****3****)**

**Median Blood Counts (N = 349)**

- ODAC Presentation

## Absolute Neutrophil Counts (N = 349)

**Absolute Neutrophil Counts ****(N = 349)**

- ODAC Presentation

**  ****16 (5%) recovered to ANC > 1000/mm****3  ****after wk 13**

**Nadir Week 9**

## Platelet Counts (N = 349)

**Platelet Counts ****(N = 349)**

**9 (3%) recovered to platelets > 50,000/mm****3 **** after wk 13 **

**Nadir Week 7**

- ODAC Presentation

## Duration of Hematologic Toxicity

- ODAC Presentation

**Last Date****in Grade 2**

**Duration**

**First Date****in Grade 3**

**Last Date****in Grade 3**

**First Date****in Grade 2**

**Grade 2**

**Grade 3**

## Hematologic Toxicity: 0.4 mCi/kg dose (maximum 32 mCi)

**Hematologic Toxicity: ****0.4 mCi/kg dose (maximum 32 mCi)**

***ANC < 1000 cells/mm****3****, platelets < 50,000/mm****3****, and hemoglobin < 8.0 g/dL;****No difference in hematologic toxicity between patients < 65 years of age and patients **_**>**_** 65**

- ODAC Presentation

## Hematologic Toxicity: 0.3 mCi/kg dose (maximum 32 mCi) 

**Hematologic Toxicity: ****0.3 mCi/kg dose (maximum 32 mCi) **

***ANC < 1000 cells/mm****3****, platelets < 50,000/mm****3****, and hemoglobin < 8.0 g/dL**

- ODAC Presentation

## Integrated Safety:  Hematologic Toxicity

**% marrow involvement**
**Number of prior therapies/purine analogs**
**Hematopoietic support  **
**Growth factors ****	****	****	****18% of patients**
**G-CSF****	****	****	****	****13%**
**Erythropoietin****	****	**** ****	****  8%**
**Red blood cell transfusion  ****	****20% **
**Platelet transfusion  ****	****	****22%**
**Grade 3 - 5 bleeding events****	****  2%**

**Integrated Safety:  ****Hematologic Toxicity**

## Incidence of Infection/Febrile Neutropenia

- ODAC Presentation

**Integrated Safety (N = 349)****	****29%****	****5%****	****7%**

## Immunology

**Median B cells:  recover to normal by Month 6  **
**Median T cells:  remain normal **
**Median IgG and IgA:  remain normal**
**Median IgM:  transient decline, recovery by Month 6**
**HAMA:  1.4%**
**HACA:  0.5%**

## MDS/AML

**MDS/AML**

**5 cases out of 349 patients (1.4%)**

***1% blasts in peripheral blood at Week 4 after Zevalin**
**†****Exact prior therapy dates not available; regimens included:  chlorambucil, CHOP, ProMACE-CytaBOM, FAMP **

## Integrated Safety:  MDS/AML

**Annualized Rate for Time to ****Development of MDS or AML**

**Literature:  4% - 8% incidence of MDS in 1100 NHL patients without ****high-dose therapy; 1% - 1.5% per year, from 2 - 9 years**

## Mortality (N = 349)

**70 deaths to date**
**56 secondary to NHL**
**2 subsequent chemo induced neutropenic sepsis**
**5 MDS/AML**
**2 intracranial hemorrhage**
**5 due to unrelated or pre-existing illness**

## Unrelated Deaths

- ODAC Presentation

## Subsequent Chemotherapy

***First subsequent chemotherapy****†****Includes ESHAP, DHAP, ICE, ProMACE-CytaBOM, CHOP-Bleo, and fludarabine-containing ****combinations, and autologous and allogeneic transplantations **

**Subsequent Chemotherapy**

**N = 139; response assessment available for N = 40**

## Subsequent Bone Marrow Transplantation

**10 patients received transplants after Zevalin**
**9 autologous**
**Stem cells collected prior to Zevalin (N = 3)**
**Stem cells collected after Zevalin (N = 6)**
**1 allogeneic**
**2 additional patients had stem cells collected after Zevalin**

## Background
Phase I/II  conclusions
Imaging and dosimetry
Phase III randomized trial
Phase III rituximab-refractory trial
Efficacy in transformed/nonfollicular low-grade
Integrated safety summary
Conclusions

**Background**
**Phase I/II  conclusions**
**Imaging and dosimetry**
**Phase III randomized trial**
**Phase III rituximab-refractory trial**
**Efficacy in transformed/nonfollicular low-grade**
**Integrated safety summary**
***Conclusions***

**Presentation Outline**

- ODAC Presentation

## Summary

**Zevalin represents a new class of targeted therapy**
**Well-tolerated, outpatient therapy completed in 8 days**
**AEs primarily hematologic**
**Severity related to baseline platelet count and % bone marrow involvement**
**Nonhematologic AEs predominantly Grade 1 and 2**
**Low incidence of severe infection**
**< 1% treatment related mortality**
**Incidence of HAMA/HACA:  < 2% **
**Rare cases of MDS; within expected rate**

## Summary (cont.)

**Clinical benefit established**
**ORR statistically higher than rituximab control in randomized Phase III study**
**Trend towards longer TTP in follicular and CR/CCR patients; longer TTNT in all patients**
**Significant activity in heavily pretreated, bulky, rituximab-refractory population**
**Median TTP in responders:  15.4 months in Phase I/II and randomized Phase III studies**

## Conclusion

**Zevalin therapy represents a clinically meaningful advance for patients with relapsed or refractory, low-grade, follicular, or CD20+ transformed B-cell NHL and rituximab-refractory NHL**

## Opening remarks 
Leslie L. Shelly, Ph.D. - Associate Director, Regulatory Affairs*
Scientific and medical summary of Zevalin 
Christine A. White, M.D. - Vice President, Medical Affairs*
Discussion 
Christine A. White, M.D. - Vice President, Medical Affairs*
Pratik Multani, M.D. - Director, Medical Affairs*
Bryan Leigh, M.D. - Director, Oncology*

**Leslie L. Shelly, Ph.D. - Associate Director, Regulatory Affairs***
**Scientific and medical summary of Zevalin **
**Christine A. White, M.D. - Vice President, Medical Affairs***
**Discussion **
**Christine A. White, M.D. - Vice President, Medical Affairs***
**Pratik Multani, M.D. - Director, Medical Affairs***
**Bryan Leigh, M.D. - Director, Oncology***

**Presentation Agenda**

***IDEC Pharmaceuticals, San Diego, CA**

## Slide 89