**Review of Biologics License Application**

**for**

**IDEC Pharmaceutical ZEVALIN™ Kit**

**BLA# 125019**

[Sponsor 1](#sponsor)

[Product 1](#product)

[Proposed indication 1](#proposed-indication)

[Review Committee 1](#review-committee)

[EXECUTIVE SUMMARY 3](#executive-summary)

[General Product Description 7](#general-product-description)

[Product Nomenclature: 8](#product-nomenclature)

[Zevalin™ Therapy Preclinical Development Summary
10](#zevalin-therapy-preclinical-development-summary)

[In vitro Preclinical Studies 10](#in-vitro-preclinical-studies)

[In vivo Preclinical Studies 12](#in-vivo-preclinical-studies)

[Zevalin™ Therapy Clinical Development Program
14](#zevalin-therapy-clinical-development-program)

[Non-Hodgkin's Lymphomas 14](#non-hodgkins-lymphomas)

[General 14](#general)

[Epidemiology 14](#epidemiology)

[Classification 14](#classification)

[Natural History 16](#natural-history)

[Prognostic Indicators 17](#prognostic-indicators)

[Therapy 18](#therapy)

[First Line Treatment 18](#first-line-treatment)

[Second Line Treatment 19](#second-line-treatment)

[Zevalin™ Clinical Trials Summary (BB-IND# 4850)
22](#zevalin-clinical-trials-summary-bb-ind-4850)

[General Overview 22](#general-overview)

[Regulatory History 23](#regulatory-history)

[Eligibility Criteria Overview 24](#eligibility-criteria-overview)

[Trial Summary Tables 25](#trial-summary-tables)

[Bioresearch Monitoring Inspection Results
34](#bioresearch-monitoring-inspection-results)

[Inspectional Findings 34](#inspectional-findings)

[Northwestern University / Dr. Gordon
34](#northwestern-university-dr.-gordon)

[Sidney Kimmel Cancer Center / Dr. Saleh
34](#sidney-kimmel-cancer-center-dr.-saleh)

[Inspectional Summary Statement 34](#inspectional-summary-statement)

[Financial disclosure 35](#financial-disclosure)

[Phase I/II TRIALS 37](#phase-iii-trials)

[Study 106-03 37](#study-106-03)

[Protocol History 37](#protocol-history)

[Study Design, Objectives, and Treatment Plan
37](#study-design-objectives-and-treatment-plan)

[Study Results 38](#study-results)

[Disposition 38](#disposition)

[Protocol Modifications 39](#protocol-modifications)

[Activity Results 40](#activity-results)

[Safety Evaluation 40](#safety-evaluation)

[Human Anti-Chimeric Antibody (HACA) Response:
43](#human-anti-chimeric-antibody-haca-response)

[Deaths within Study Day 100 44](#deaths-within-study-day-100)

[Conclusions 44](#conclusions)

[Study 106-05 46](#study-106-05)

[Protocol History 46](#protocol-history-1)

[Study Design, Objectives, and Treatment Plan
46](#study-design-objectives-and-treatment-plan-1)

[Patient Populations /Study Results
46](#patient-populations-study-results)

[Protocol Violations: 46](#protocol-violations)

[Demographics 47](#demographics)

[Activity Results 47](#activity-results-1)

[Safety Evaluation 48](#safety-evaluation-1)

[Human Anti-Chimeric Antibody (HACA) Response:
53](#human-anti-chimeric-antibody-haca-response-1)

[Deaths within Study Day 100 53](#deaths-within-study-day-100-1)

[Conclusions 53](#conclusions-1)

[Study 106-98 54](#study-106-98)

[Protocol History 54](#protocol-history-2)

[Study Design, Objectives, and Treatment Plan
54](#study-design-objectives-and-treatment-plan-2)

[Study Results 55](#study-results-1)

[Safety Evaluation 55](#safety-evaluation-2)

[Deaths within Study Day 100 60](#deaths-within-study-day-100-2)

[Conclusions 61](#conclusions-2)

[Phase III Studies 63](#phase-iii-studies)

[Study 106-04 63](#study-106-04)

[Protocol History 63](#protocol-history-3)

[Study Design, Objectives, and Treatment Plan
64](#study-design-objectives-and-treatment-plan-3)

[Objectives: 64](#objectives)

[Inclusion Criteria 65](#inclusion-criteria)

[Exclusion Criteria 65](#exclusion-criteria)

[Treatment Plan 66](#treatment-plan)

[Results 66](#results)

[Protocol Violations 66](#protocol-violations-1)

[Study Population & Disease Characteristics
67](#study-population-disease-characteristics)

[Risk Assessment 68](#risk-assessment)

[Prior Therapy 68](#prior-therapy)

[Subject Disposition 69](#subject-disposition)

[Primary Efficacy Analysis 69](#primary-efficacy-analysis)

[Exploratory Analyses of the Primary Endpoint.
71](#exploratory-analyses-of-the-primary-endpoint.)

[Secondary Endpoints 72](#secondary-endpoints)

[Exploratory Analysis 74](#exploratory-analysis)

[Safety---Adverse Events 76](#safetyadverse-events)

[Immunologic Reconstitution 82](#immunologic-reconstitution)

[Deaths within Study Day 100 83](#deaths-within-study-day-100-3)

[Conclusions 84](#conclusions-3)

[Study 106-06 85](#study-106-06)

[Protocol History 85](#protocol-history-4)

[Study Design, Objectives, Eligibility, and Treatment Plan
86](#study-design-objectives-eligibility-and-treatment-plan)

[Design 86](#design)

[Objectives: 86](#objectives-1)

[Inclusion Criteria 87](#inclusion-criteria-1)

[Exclusion Criteria 87](#exclusion-criteria-1)

[Treatment Plan 88](#treatment-plan-1)

[Study Results 88](#study-results-2)

[Subject Disposition 88](#subject-disposition-1)

[Protocol Violations 88](#protocol-violations-2)

[Study Population & Disease Characteristics
90](#study-population-disease-characteristics-1)

[Risk Assessment 91](#risk-assessment-1)

[Prior Therapy 91](#prior-therapy-1)

[Study Results---Primary Efficacy Analysis
92](#study-resultsprimary-efficacy-analysis)

[Exploratory Analyses of the Primary Endpoint
93](#exploratory-analyses-of-the-primary-endpoint)

[Secondary Analyses 93](#secondary-analyses)

[Safety \-- Adverse Events 96](#safety----adverse-events)

[Immunologic Reconstitution 100](#immunologic-reconstitution-1)

[Deaths within Study Day 100 101](#deaths-within-study-day-100-4)

[Conclusions 101](#conclusions-4)

[Introduction 104](#introduction)

[At Risk - Worst Case Assessments
104](#at-risk---worst-case-assessments)

[Assessment Of Adjacent Structures At Risk.
104](#assessment-of-adjacent-structures-at-risk.)

[Alteration in Biodistribution of the Radiolabeled Antibody.
104](#alteration-in-biodistribution-of-the-radiolabeled-antibody.)

[Obstructed Route of Renal/Urinary Tract Clearance Pathway.
105](#obstructed-route-of-renalurinary-tract-clearance-pathway.)

[Design of the Biodistribution Imaging and Organ Dosimetry
105](#design-of-the-biodistribution-imaging-and-organ-dosimetry)

[Whole Body Biodistribution Imaging
105](#whole-body-biodistribution-imaging)

[Time Points Evaluated 105](#time-points-evaluated)

[Subject Population 105](#subject-population)

[Electronic Submission 106](#electronic-submission)

[Biodistribution Imaging Findings
106](#biodistribution-imaging-findings)

[Biodistribution Imaging -- Normal Organs
106](#biodistribution-imaging-normal-organs)

[Liver and Spleen 106](#liver-and-spleen)

[Bone Marrow 106](#bone-marrow)

[Testes 107](#testes)

[Kidney, Urinary Bladder 107](#kidney-urinary-bladder)

[Bowel 107](#bowel)

[Large Bowel 107](#large-bowel)

[Small Bowel 107](#small-bowel)

[Heart, Large Vascular Structures 108](#heart-large-vascular-structures)

[Lung Fields 108](#lung-fields)

[Biodistribution Imaging -- Tumor Sites
108](#biodistribution-imaging-tumor-sites)

[Biodistribution Review Comments 108](#biodistribution-review-comments)

[Normal Organ Dosimetry 109](#normal-organ-dosimetry)

[Organs To Be Evaluated By Time Activity Curves
109](#organs-to-be-evaluated-by-time-activity-curves)

[Subject Population and Regions of Interest
109](#subject-population-and-regions-of-interest)

[Route of Excretion 110](#route-of-excretion)

[Image Quantification 110](#image-quantification)

[IDEC methodology for Image Quantification
111](#idec-methodology-for-image-quantification)

[CBER Review Comment: 112](#cber-review-comment)

[CBER Evaluation of Image Quantification
113](#cber-evaluation-of-image-quantification)

[Patient 106-04-003-215 113](#patient-106-04-003-215)

[Patient 106-04-007-250 114](#patient-106-04-007-250)

[Patient 106-04-001-116 115](#patient-106-04-001-116)

[CBER Review Comment 115](#cber-review-comment-1)

[Kinetic Modeling 116](#kinetic-modeling)

[Mathematical Models Used By IDEC To Estimate Organ Residence Times
116](#mathematical-models-used-by-idec-to-estimate-organ-residence-times)

[Organ Residence Times 116](#organ-residence-times)

[Urine Residence Times 116](#urine-residence-times)

[CBER Review Comment 116](#cber-review-comment-2)

[Red Marrow Residence Times 116](#red-marrow-residence-times)

[Remainder Of Body Residence Times
117](#remainder-of-body-residence-times)

[Conservation Of Activity 117](#conservation-of-activity)

[Dosimetry Methods 117](#dosimetry-methods)

[Dosimetry Results 117](#dosimetry-results)

[Y-90-2B8 Dosimetry 118](#y-90-2b8-dosimetry)

[In-111-2B8 Dosimetry 118](#in-111-2b8-dosimetry)

[Selected Tumor Dosimetry 119](#selected-tumor-dosimetry)

[CBER Review Comment 122](#cber-review-comment-3)

[CBER's Evaluation of Dosimetry for 15 Selected Tumors.
122](#cbers-evaluation-of-dosimetry-for-15-selected-tumors.)

[CBER Review Comment 122](#cber-review-comment-4)

[Absorbed Radiation Dose Depth Profiles For Surrounding Tissues From
Theoretical Tumor Models
123](#absorbed-radiation-dose-depth-profiles-for-surrounding-tissues-from-theoretical-tumor-models)

[Tumor Adjacent to Pericardium or Bowel Wall
123](#tumor-adjacent-to-pericardium-or-bowel-wall)

[Tumor Surrounding Small Cylindrical Structure (nerve or artery)
124](#tumor-surrounding-small-cylindrical-structure-nerve-or-artery)

[Tumor Adjacent to Pulmonary Artery
125](#tumor-adjacent-to-pulmonary-artery)

[CBER Review Comment 126](#cber-review-comment-5)

[Radiation Absorbed Doses to Adjacent Structures from a Reported Tumor
126](#radiation-absorbed-doses-to-adjacent-structures-from-a-reported-tumor)

[CBER Review Comment 128](#cber-review-comment-6)

[Dosimetry Assuming Altered Biodistribution (Model = Large Colloid Type)
129](#dosimetry-assuming-altered-biodistribution-model-large-colloid-type)

[CBER Review Comment 129](#cber-review-comment-7)

[Dosimetry for Renal Obstruction 130](#dosimetry-for-renal-obstruction)

[External Beam Radiation Therapy - Radiation Tolerance Doses\*
130](#external-beam-radiation-therapy---radiation-tolerance-doses)

[CBER Review Comment 130](#cber-review-comment-8)

[OVERALL SUMMARY 133](#overall-summary)

[General 133](#general-1)

[SUMMARY OF EFFICACY DATA 134](#summary-of-efficacy-data)

[Primary Efficacy Endpoints 134](#primary-efficacy-endpoints)

[SUMMARY OF SAFETY DATA 135](#summary-of-safety-data)

[Non Hematologic Adverse Events 135](#non-hematologic-adverse-events-4)

[Non-Hematologic AEs by NCI CTC Grade
135](#non-hematologic-aes-by-nci-ctc-grade)

[Incidence of Non-cytopenic AEs 136](#incidence-of-non-cytopenic-aes)

[NCI CTC Grade 3 and 4 Adverse Events Exclusing cytopenia
136](#nci-ctc-grade-3-and-4-adverse-events-exclusing-cytopenia)

[Safety of IDEC-In2B8 (N = 348) 138](#safety-of-idec-in2b8-n-348)

[Abdominal AE 139](#abdominal-ae)

[Hospitalization 139](#hospitalization)

[Immune Reconstitution 139](#immune-reconstitution)

[HAMA and HACA 139](#hama-and-haca)

[Infections 139](#infections)

[Secondary Malignancy and Myelodysplasia
140](#secondary-malignancy-and-myelodysplasia)

[Hematologic Toxicity 141](#hematologic-toxicity)

[Neutropenia 141](#neutropenia)

[Use of hematopoeitic growth factors
142](#use-of-hematopoeitic-growth-factors)

[Thrombocytopenia 142](#thrombocytopenia)

[Use of hematopoeitic growth factors
142](#use-of-hematopoeitic-growth-factors-1)

[Anemia 142](#anemia)

[Use of hematopoeitic growth factors
142](#use-of-hematopoeitic-growth-factors-2)

[Hematologic Toxicity and Delayed Hematologic Recovery
143](#hematologic-toxicity-and-delayed-hematologic-recovery)

[Prior Therapy 143](#prior-therapy-2)

[Prior Fludarabine Therapy 143](#prior-fludarabine-therapy)

[Bone Marrow Involvement 143](#bone-marrow-involvement)

[Geriatric Use: 144](#geriatric-use)

[Pediatric Use: 144](#pediatric-use)

[Deaths 144](#deaths)

[Non Lymphoma Related Causes Of Death
144](#non-lymphoma-related-causes-of-death)

[SUMMARY OF Dosimetry DATA 144](#summary-of-dosimetry-data)

[Biodistribution Imaging 144](#biodistribution-imaging)

[Normal Organ Dosimetry 145](#normal-organ-dosimetry-1)

[Tumor Dosimetry 145](#tumor-dosimetry)

[Radiation Absorbed Dose Estimates for "Worst Case Scenarios"
146](#radiation-absorbed-dose-estimates-for-worst-case-scenarios)

[REFERENCES 148](#references)

# Sponsor

IDEC Pharmaceuticals Corporation

3030 Callan Road, San Diego, California 92121

\(858\) 431-8500

# Product

ZEVALIN™ Kit for the preparation of

indium (^111^In) ibritumomab tiuxetan

and

yttrium (^90^Y) ibritumomab tiuxetan

to be used in combination with Rituxan^®^ (rituximab)

# Proposed indication

ZEVALIN™ is indicated for the treatment of patients with relapsed or
refractory low-grade, follicular or CD20 + transformed B-cell
non-Hodgkin\'s lymphoma, and for the treatment of patients with
RITUXAN-refractory follicular non-Hodgkin's lymphoma.

# Review Committee

Product/Committee Chair: Marjorie Shapiro, Ph.D.

Clinical Reviewers: Philippe C. Bishop, MD

George Mills, MD

Biostatisticians: Satish C. Misra, Ph.D.

Clinical Toxicology and Pharmacology: David Green, Ph.D.

RPM: Mike Noska

Compliance/BIMO: Mary Andrich

DMA/CMC: Leon Epps

DMPQ/CMC Kevin O'Brien

DMPQ/CMC Deborah Trout

EXECUTIVE SUMMARY

# EXECUTIVE SUMMARY

The Zevalin^TM^ Kit contains the materials for final manufacture
Zevalin^TM^ therapy. The treatment program consists of sequential
administrations of unlabeled chimeric anti-CD20 antibody (rituximab) and
radiolabeled murine anti-CD20 antibody (ibritumomab). Ibritumomab is the
parent murine anti-CD20 antibody from which rituximab was generated.

Rituximab is administered immediately prior to the radiolabeled
ibritumomab in order to saturate the CD20 receptors on normal
lymphocytes in the circulation and to enhance tumor targeting by the
radiolabeled antibody. The clinical development program required
administration of the 111-In-ibritumomab tiuxetan in order to allow
confirmation of tumor targeting, to allow identification and
characterization of normal organ biodistribution, altered
biodistribution, and to generate data to permit biodistribution risk
assessment (eg: proximity and risk of injury to normal tissue adjacent
to tumor site) and dosimetric assessment.

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:

"Treatment of patients with relapsed or refractory low-grade follicular
or CD20+ transformed B-cell non-Hodgkin's lymphoma, and for the
treatment of RITUXAN-refractory follicular non-Hodgkin's lymphoma"

Anti-tumor activity, as measured by durable objective tumor responses,
was documented in both efficacy studies.

-   106-04 Randomized, multicenter trial of Zevalin^TM^ therapy vs.
    RITUXAN

  ---------------------------- -------------------- ---------------------
  Outcome                      Zevalin (n=73)       Rituxan (n=70)

  ORR                          73%                  47%

  Resp. Duration (mos)         14.2                 12.1

  CR                           20%                  9%

  Time to Progr. (mos)         11.2                 10.1
  ---------------------------- -------------------- ---------------------

-   106-06- Single-arm trial of Zevalin^TM^ in chemotherapy-refractory
    and RITUXAN-refractory patients

    -   58% overall response rate in follicular NHL

    -   4% CR rate in follicular NHL

    -   Duration of response (responders) 7.7+ months

The toxicity profile of Zevalin^TM^ therapy is dominated by cytopenias,
which occurred at a high frequency (55-57% Grade 3 and 4 neutropenia and
thrombocytopenia) and last approximately 3-4 weeks. In exploratory
analyses, extent of prior therapy, prior fludarabine use, extent of
malignant infiltration of the marrow, and pretreatment cytopenias, were
all associated with greater risk of prolonged cytopenias. Severe
non-hematologic toxicities occurred in less than 10% of subjects. The
most serious adverse events included infections (predominantly bacterial
in origin), allergic reactions (bronchospasm and angioedema), hemorrhage
while thrombocytopenic (resulting in two deaths) and myeloid
malignancies and dyscrasias (3 patients with AML and 2 with MDS). The
most common non-hematologic toxicities that appear to be related to
Zevalin^TM^ therapy (as compared to incidence in the RITUXAN arm of
106-04) were gastrointestinal symptoms (nausea, vomiting, abdominal
pain, diarrhea), which occurred at grade 1-2 severity in 57% of Zevalin
subjects vs. 34% of RITUXAN subjects. Other adverse effects that
occurred at a higher rate in the Zevalin arm included infection,
increased cough, dyspnea, dizziness, arthralgia, anorexia, anxiety, and
ecchymosis.

Tumor targeting was documented in the majority of patients, although not
necessarily at all known sites of disease. In those without evidence of
tumor targeting, anti-tumor activity was observed. Since the numbers
were small, and to show distribution to normal lymphocytes, most notably
gastrointestinal uptake in lymphoid aggregates (Peyer's patches) and the
spleen, as well as unexpected uptake in testes.

Areas for the Committee to consider:

1.  The anti-tumor activity observed is clinically significant but also
    associated with significant toxicity, which in a small proportion of
    subjects may be associated with serious morbidity and/or preclude
    the ability to deliver adequate dose intensity of salvage therapy.
    The benefits of this active agent are clearly acceptable in the
    setting of chemotherapy and RITUXAN- refractory patients, however
    the benefits in patients who have not failed RITUXAN may not
    outweigh the higher toxicity for all such subjects. The Agency seeks
    the Committee's comments on the proposed indication for patients who
    are relapsed or refractory but have not received prior RITUXAN.

2.  Zevalin^TM^ therapy has demonstrated anti-tumor activity in a
    heavily pretreated population. The experience in subjects with
    low-grade, non-follicular lymphoma and with low-grade lymphoma that
    has undergone transformation is very limited. The clinical behavior
    and level of CD20 expression in these two entities may be
    sufficiently different from that of low-grade follicular NHL to
    allow extrapolation of the clinical results. The Agency believes
    that the data are insufficient to determine the net benefit in these
    settings and that additional studies with adequate experience in
    these subpopulations should be undertaken.

3.  Low grade NHLs are extremely rare in the pediatric population. In
    the past, the Committee has advised that studies in pediatric
    patients should not be required (under the Pediatric Rule) because
    the disease (follicular NHL) does not occur with sufficient
    frequency in children. The Agency seeks the Committee's advice
    regarding the waiver of studies in pediatric patients.

4.  The ibritumomab antibody is a foreign protein; both this product and
    other murine or partially murine (chimeric) proteins generate immune
    responses in human subjects. Based on clinical experience with other
    murine proteins, the development of an immune response will alter
    both the safety profile and reduce the efficacy of the product,
    through altered biodistribution and clearance of the product.

-   One subject was reported by the investigator to have altered
    biodistribution in the study population. However, the number of
    subjects studied for biodistribution (182 patients) is insufficient
    to rule out an altered biodistribution that may occur at rate ≤ 5%.

-   The population studied in these trials was carefully screened, in
    that patients with prior exposure to murine antibodies or evidence
    of human anti-murine antibodies (HAMA) were excluded. As novel
    murine or partially murine agents enter the clinical trials and
    ultimately approved for marketing, it is expected that the potential
    for prior exposure to a murine protein and the potential of
    acquiring an immune response will increase. The safety and efficacy
    profile observed in the current Zevalin^TM^ therapy trials is
    unlikely to be applicable to a population exposed to other murine
    proteins. Limitation of Zevalin^TM^ therapy to subjects with no
    prior exposure to murine proteins is impractical and possibly
    unnecessary, however no other screening test has been adequately
    evaluated to identify patients at increased risk of altered
    biodistribution.

-   An additional function of pre-treatment imaging and biodistribution
    studies would be to identify areas of uptake adjacent to normal
    tissues that may be damaged by targeted radiotherapy. In such
    subjects, adequate counseling regarding potential risks and, in some
    instances, more targeted assessment for radiation-related toxicity
    could be undertaken.

Given these concerns, the Agency seeks advice on additional
post-marketing studies to better assess the utility of pre-treatment
imaging in optimizing the safety and effectiveness of Zevalin^TM^
therapy.

GENERAL PRODUCT DESCRIPTION

# General Product Description

ZEVALIN™ (ibritumomab tiuxetan) is the immunoconjugate prepared by a
stable thiourea covalent bond between the monoclonal antibody
ibritumomab and the linker-chelator tiuxetan
\[\[N-\[2-bis(carboxymethyl)amino\]-3-(p-isothiocyanatophenyl)-
propyl\]-\[N-\[2-bis(carboxymethyl)amino\]-2-(methyl)-ethyl\]\]glycine.
This linker-chelator provides a high affinity, conformationally
restricted chelation site for ^111^ In or ^90^ Y.

![](media/image1.png){width="4.6875in" height="2.3645833333333335in"}

Ibritumomab is produced by genetically modified Chinese hamster ovary
(CHO cells) cells grown in suspension culture in a nutrient medium.

## Product Nomenclature:

[Zevalin™ Therapy:]{.underline} one infusion of 250 mg/m^2^ rituximab
immediately preceding a fixed dose of 5.0 mCi (1.6 mg total antibody
dose) of ^111^In Ibritumomab Tiuxetan injected as a slow 10 minute IV
push; followed seven days later by a second infusion of 250 mg/m^2^ of
rituximab prior to 0.4 mCi/kg (1.6 mg total antibody dose) of ^90^Y
Ibritumomab Tiuxetan slow IV 10 minutes push.

[Zevalin™ Kit]{.underline}: components necessary for the final
manufacturing of the 2 radionucleotide labeled antibodies ^111^In
Ibritumomab Tiuxetan and ^90^Y Ibritumomab Tiuxetan.

[Zevalin™ Antibody:]{.underline} Ibritumomab tiuxetan

[Ibritumomab tiuxetan:]{.underline} drug product also known as
IDEC-2B8-MX-DTPA consisting of the murine antibody (IDEC-2B8) directed
against CD20 fused with the radioisotope linker (MX-DTPA).

[^111^In Ibritumomab Tiuxetan]{.underline}: (synonyms: In2B8,
IDEC-In2B8, ^111^In-2B8-MX-DTPA); Indium labeled murine antibody
(IDEC-2B8) directed against CD20 fused with the radioisotope linker
(MX-DTPA).

[^90^Y Ibritumomab Tiuxetan]{.underline}: (synonyms: Y2B8, IDEC-Y2B8,
^90^Y-2B8-MX-DTPA); yttrium labeled murine antibody (IDEC-2B8) fused
with the radioisotope linker (MX-DTPA).

[Rituximab:]{.underline} (synonyms: Rituxan™, IDEC-C2B8); genetically
engineered chimeric murine/human monoclonal antibody directed against
the CD20.

Preclinical Development

# Zevalin™ Therapy Preclinical Development Summary

## In vitro Preclinical Studies

Several in vitro studies were performed with radiolabeled
IDEC-2B8-MX-DTPA, IDEC-2B8-MX-DTPA, and native IDEC-2B8 antibody. The
results demonstrated:

1.  Comparability of IDEC-2B8-MX-DTPA and radiolabeled IDEC-2B8-MX-DTPA
    manufactured by Covance and IDEC using IDEC-2B8 produced by CHO
    cells (comparable radioincorporation, binding, and stability both in
    the clinical formulation and in human serum) \[ IDEC Studies IV0039,
    AN0019, IV0026C, IV0026B, IV0040, IV0041, IV0026A\].

2.  Optimization of radiolabeling using IDEC-2B8-MX-DTPA with
    yttrium-\[90\] or indium-\[111\] and retention of apparent affinity
    of IDEC-2B8 before and after conjugation with MX-DTPA. \[IDEC
    Studies AN0019, IV0026C\].

3.  Radiolabeled antibody bound specifically to the CD20 antigen with
    apparent affinity values ranging from 14 - 18 X 10 -9 M (versus 3.5
    -- 6.0 X 10 -9 M for the unconjugated, CHO-expressed IDEC-2B8
    antibody) \[IDEC Studies AS0028A, IV0026C, AN0019\]

4.  CHO-expressed IDEC-2B8 antibody antigen binding in vitro induced
    cellular apoptosis but did not affect complement-dependent cell
    cytotoxicity (CDC) and only weakly mediated antibody-dependent cell
    cytocoxicity (ADCC) \[IDEC Studies IV0052\]

5.  IDEC-2B8 and IDEC-2B8-MX-DTPA reacted with antigen with a very
    restricted pattern of distribution consistent with CD20. The
    antibodies did not bind to normal human tissues with the exception
    of lymphoid tissues. Reactivity was observed in lymphatic follicles
    of the lamina propria (Peyer's Patches) of the large intestine.
    Strong immunoreactivity was observed in germinal centers of the
    white pulp of the spleen. In addition, aggregates or scattered
    lymphocytes present in the stroma of various organs including
    bladder, lung, and uterus were immunoreactive with IDEC-2B8-MX-DTPA.
    \[IDEC Studies IH0031\].

+-------------+--------------------------------------------------------+
| > **IDEC    | > **Study Title (GLP Status)**                         |
| > \#**      |                                                        |
| >           |                                                        |
| > **Date**  |                                                        |
+=============+========================================================+
| > IV0039    | > Comparison of 2B8-MX-DTPA Manufactured by Covance    |
| >           | > and IDEC after Radiolabeling with ^111^In or ^90^Y:  |
| > Nov 4,    | > Radioincorporation and Binding (non-GLP)             |
| > 1997      |                                                        |
+-------------+--------------------------------------------------------+
| > AN 0019   | > Determination of the Apparent Affinity Constants of  |
| >           | > Unconjugated IDEC-2B8 and Conjugated                 |
| > Sept 20,  | > IDEC-2B8-MX-DTPA                                     |
| > 2000      |                                                        |
+-------------+--------------------------------------------------------+
| > IV0026C   | > Preclinical Development Summary of CHO-Derived 2B8   |
| >           | > and 2B8-MX-DTPA (non-GLP)                            |
| > Dec 23,   |                                                        |
| > 1996      |                                                        |
+-------------+--------------------------------------------------------+
| > IV0026B   | > In Vitro Stability of Clinically-Formulated CHO-     |
| >           | > Derived Y2B8 and In2B8 Prepared Using the            |
| > Dec 23,   | > Radiolabeling Kit Protocols (non-GLP)                |
| > 1996      |                                                        |
+-------------+--------------------------------------------------------+
| > IV0040    | > In Vitro Stability of Clinically-Formulated Y2B8     |
| >           | > Prepared from 2B8-MX-DTPA Manufactured by Covance    |
| > Nov 4,    | > (non-GLP)                                            |
| > 1997      |                                                        |
+-------------+--------------------------------------------------------+
| > IV0041    | > In Vitro Stability in Human Serum of Y2B8 Prepared   |
| >           | > from 2B8-MX-DTPA Manufactured by Covance (non-GLP)   |
| > Nov 4,    |                                                        |
| > 1997      |                                                        |
+-------------+--------------------------------------------------------+
| > IV0026A   | > In Vitro Stability in Human Serum of CHO- Derived    |
| >           | > Y2B8 and In2B8 Prepared Using the Radiolabeling Kit  |
| > Dec 23,   | > Protocols (non-GLP)                                  |
| > 1996      |                                                        |
+-------------+--------------------------------------------------------+
| > AS0028A   | > Preclinical Development of Murine Monoclonal         |
| >           | > Anti-CD20 Antibody 2B8 and Conjugate 2B8- MX-DTPA    |
| > Nov 5,    | > (non-GLP)                                            |
| > 1992      |                                                        |
+-------------+--------------------------------------------------------+
| > IV0052    | > In Vitro Evaluation of IDEC-2B8 for Induction of     |
| >           | > Apoptosis in B Lymphoma Cells (non-GLP)              |
| > Apr 14,   |                                                        |
| > 2000      |                                                        |
+-------------+--------------------------------------------------------+
| > IH0031    | > Cross-Reactivity Analysis of CHO-Cell Produced       |
| > (IMPATH   | > 2B8-MX-DTPA Conjugated Antibody Against Human        |
| > Study     | > Tissues (GLP)                                        |
| > IDC16),   |                                                        |
| >           |                                                        |
| > Feb 10,   |                                                        |
| > 1997      |                                                        |
+-------------+--------------------------------------------------------+

## In vivo Preclinical Studies

Pharmacology/toxicology studies were performed in monkeys, the most
similar animal model to humans and an animal model in which monoclonal
antibodies to human CD20 are cross-reactive. Biodistribution, dosimetry,
and PK studies were performed in rodent models. The results
demonstrated:

1.  IDEC-2B8 and ^89^Y-IDEC-2B8-MX-DTPA were tolerated in monkeys at all
    doses administered \[IDEC Study 3D56\].

2.  Dosimetry studies suggested that irradiation to non-target tissues
    would be within acceptable limits in humans (dose estimates based on
    murine biodistribution studies) \[IDEC Study AS0079\]

3.  ^111^In-IDEC-2B8-MX-DTPA preferentially localized to tumor in murine
    xenograft animal model \[IDEC Study AS0080\]

4.  Reduction of tumor growth in murine xenograft animal model with
    ^90^Y-IDEC-2B8-MX \[IDEC Study AS0044B\]

5.  Half-lives of IDEC-2B8 and IDEC-2B8-MX-DTPA were 7 to 11 days in
    rodents, 0.7 to 4.5 days in monkeys, depending on rituximab
    depletion of B cells bearing CD20 and the development of monkey
    anti-IDEC-2B8-MX-DTPA antibodies \[IDEC Study AS0172; AS0147\].

+-------------+--------------------------------------------------------+
| > **IDEC    | > **Study Title**                                      |
| > \#**      |                                                        |
| >           |                                                        |
| > **Date**  |                                                        |
+=============+========================================================+
| > 3D56      | > Pathology/Toxicology study of CHO cell produced      |
| >           | > non-radioactive \[^89^Y\]-2B8-MX-DTPA and C2B8       |
| > February  | > antibodies in cynomolgus monkeys.                    |
| > 20 1997   |                                                        |
+-------------+--------------------------------------------------------+
| > AS 0079   | > Biodistribution and Excretion Study of \[^90^Y\]-2B8 |
| >           | > Antibody in BALB/c Mice                              |
| > February  |                                                        |
| > 18, 2000  |                                                        |
+-------------+--------------------------------------------------------+
| > AS0080.   | > Biodistribution and Excretion Study of 111           |
| >           | > In-2B8-MX-DTPA in Daudi Tumor-Bearing Nu/Nu Mice     |
| > February  |                                                        |
| > 25, 2000  |                                                        |
+-------------+--------------------------------------------------------+
| > AS0044B   | > Evaluation of Y2B8 and C2B8 in Combination Therapy   |
| >           | > Using Tumor-Bearing Mice                             |
| > September |                                                        |
| > 22, 1993  |                                                        |
+-------------+--------------------------------------------------------+
| > AS0172    | > Comparative Rat Pharmacokinetics of Two 2B8-MX       |
| >           | > Conjugate Lots                                       |
| > May 31,   |                                                        |
| > 2000      |                                                        |
+-------------+--------------------------------------------------------+
| > AS0147    | > Comparative Pharmacokinetic Analysis of Two          |
| >           | > IDEC-2B8-MX-DTPA Lots In Rats                        |
| > October,  |                                                        |
| > 1997      |                                                        |
+-------------+--------------------------------------------------------+

Clinical Development

# Zevalin™ Therapy Clinical Development Program

ZEVALIN™ therapy clinical development has focused on the treatment of
patients with relapsed or refractory low-grade, follicular or CD20 +
transformed B-cell non-Hodgkin\'s lymphoma, and for the treatment of
patients with RITUXAN-refractory follicular non-Hodgkin's lymphoma.

There is no previous clinical experience with Zevalin therapy outside of
the clinical studies provided in the license application materials.

## Non-Hodgkin's Lymphomas

### General

Non-Hodgkin's lymphomas (NHLs) encompass several unique malignant
lymphoid disease entities that vary in clinical behavior, morphologic
appearance, immunologic, and molecular phenotype. The various types
represent neoplastic lymphoid cells arrested at different stages of
normal differentiation. Based on their natural history, NHLs can be
clinically classified as indolent, aggressive, and highly aggressive.

### Epidemiology

NHLs are the fifth most common cause of cancer in the United States,
with an estimated incidence of 63,600 cases in 2001[^1]. Follicular
center cell lymphomas are the second most common subtype, comprising
approximately 40% of all non-Hodgkin's lymphomas. Since 1950, the
incidence of NHL has steadily increased at approximately 4% per year.

### Classification

Several histologic classifications of NHLs exist. Commonly used systems
are the 1982 International Working Formulation (IWF)[^2] and the 1994
Revised European-American (REAL) classifications[^3]. These
classification systems group lymphoid neoplasms according to clinical
behavior (low grade/indolent, intermediate grade/aggressive, or high
grade/very aggressive). Historically, this grouping often served as a
basis for choosing a first line therapy.

More recently, the World Health Organization (WHO) proposed a new
classification system[^4]. Unlike the IWF and REAL classifications, the
WHO committee felt that grouping lymphoid neoplasms according to
clinical behavior was neither necessary nor desirable[^5]. The committee
recognized that specific disease entities could be defined by a
combination of morphology, immunology, genetic features, and clinical
features. Each entity had distinct clinical behavior and outcome
predictable by applicable prognostic factors (e.g.; the international
Prognostic Index) and related to the type of initial therapy
administered. The committee concluded that each lymphoma type needed to
be treated as distinct entities. Therefore, rather than depending on
clinical grouping (i.e.; low grade/indolent, etc.), the committee
emphasized that clinical decisions should be based on the specific
lymphoid neoplasm.

### Natural History

The median age prevalence of indolent lymphoma is in the sixth decade.
B-cell indolent (low-risk group) NHL is not curable with standard
treatment. First line therapy is commonly associated with a high rate of
clinical response followed by relapse. Subsequent remissions may occur
but at a progressively lower rate and with progressively shorter
durations with a median progression-free survival (PFS) frequently less
than 6 months[^6] using traditional chemotherapeutic regimens. However,
recent studies suggest that treatment using unconjugated monoclonal
antibodies directed against CD20 antigen may yield a prolonged median
PFS greater than 6 months[^7] in relapsed or refractory indolent NHL
populations.

Over time, indolent NHL may transform to aggressive (intermediate risk)
or very aggressive (high-risk) lymphomas that have a more aggressive
clinical course. The incidence of transformation ranges from 40% to 70%
and is associated with disease progression and known adverse prognostic
factors[^8]. In general, transformation has a poor prognosis and
frequently results in a rapidly fatal outcome. However, some patients
can have complete responses to salvage chemotherapy regimens and achieve
durable complete remissions[^9]. Overall survival following
transformation is poor with an estimated median survival ranging from 7
to 22 months.

### Prognostic Indicators

The most valuable and widely used prognostic indicator system for NHL is
the International Prognostic Index (IPI)[^10]. The IPI is a prognostic
index that was developed to predict outcome in patients with aggressive
NHL, based on patients' clinical characteristics before treatment.
However, the IPI has been shown to apply to indolent (low-risk)
lymphoma[^11].

**IPI Score and Clinical Outcome**

**(Follicle Center Cell NHL)**

  -------------- --------- -------------- ------------- ------------------
  **IPI**        **CR      **5-yr FFS     **5-yr OS     **Median OS (mo)**
                 (%)**     (%)**          (%)**         

  **Low**        92        75             85            160

  **Low-Int**    81        64             69            108

  **High-Int**   77        38             28            35

  **High**       0         0              0             12
  -------------- --------- -------------- ------------- ------------------

Cytogenetics, gene rearrangement, and oncoproteins are important
molecular markers of histologic subtype and mechanisms of
lymphomagenesis. BCL2 oncogene (t14;18) overexpression is characteristic
of follicular center cell NHLs. However, the use of biomarkers to
predict clinical outcome in indolent NHL is investigational and need to
be validated in prospective trials.

### Therapy

#### First Line Treatment

![](media/image2.wmf){width="4.365277777777778in"
height="2.3854166666666665in"}

Localized indolent lymphoma at initial presentation is unusual and
represents less than 5% of the population. Patients with early-stage
indolent lymphomas are potentially curable with radiation therapy (46%
to 68% 10-year DFS)[^12]^,^ [^13]^,^ [^14]. The addition of chemotherapy
to radiotherapy as primary treatment has not convincingly prolonged
remission duration or survival.

The majority of patients with indolent NHL present with advanced
disease. For the majority of patients, selection of initial treatment is
based on the clinical situation, prognostic indicators, physician bias,
and patient choice. There is no single standard initial therapy for
indolent NHL.

In general, alkylating agents are useful palliative treatment options
that can result in improved well-being for most patients, often for long
periods. Although commonly used, combinations of chemotherapy have not
convincingly resulted in longer or greater number remissions. There is
no proof that initial combination chemotherapy will prolong survival in
comparison with single drugs. The addition of interferon to initial
combination chemotherapy may increase the response rate, significantly
prolong remission duration, but prolonged survival has not been
unequivocally proven. In the absence of disease-related symptoms,
treatment can safely be deferred without adversely impacting survival.

Distinguishing follicular lymphoma into those with predominantly small
cells (follicule small, grade I), those with an intermediate number of
small and large cells (follicule center, mixed small/large grade II),
and those with more large cells (Follicule center, large grade III) is
difficult[^15]. However studies that have assessed the clinical behavior
or these lymphomas have shown that patients with follicular large cell
lymphoma have a shorter remission duration and overall survival than
patients with the other subtypes. For these patients, the incorporation
of an anthracycline into the initial treatment regimen appears to
improve outcome[^16].

Overall response rates to therapy for low-grade lymphomas at the later
stages (Stage III or IV) are between 80% to 90% with different
chemotherapeutic regimens. The rate of complete response to initial
therapy ranges from 23% to 83% in various studies. The median duration
of response for therapy is 2 years for most studies. Less than 10% of
patients remain in remission for more than 5 years. However, median
survival exceeds 9 years in many series. The choice for either (a) a
conservative approach or (b) an aggressive approach exists because there
is still no evidence that one is more effective than the other in terms
of overall survival.

#### Second Line Treatment

Patients with relapsed indolent lymphoma may repeatedly respond to
alkylating agents or combinations containing an alkylating agent,
although the proportion responding decreases with each relapse. Patients
relapsing after or who are refractory to treatment with alkylating
agents often respond to treatment with combinations containing an
anthracycline. Responses are also often seen in patients treated with
purine analogues alone or in combination with other drugs. High dose
chemotherapy followed by autologous or allogeneic reestablishment of
bone marrow function can induce long-term remissions but it is not
proven whether they are more frequent or of longer duration than with
conventionally dosed therapy. The impact of the novel treatment
strategies including high-dose therapy on overall survival is still
uncertain. Rituximab can induce remissions in chemoresistant patients.

Rituxan is the only FDA approved agent indicated for use in relapsed or
refractory low grade or follicular B NHL. Marketing approval was based
on 3 single arm trials with a total of 242 registered participants. The
ORR was 48% (6% CR and 42% PR). Notable was a time to treatment response
of 50 days and duration of response of 10-12 months. The toxicity
profile was acceptable and serious adverse events were uncommon (\<5%).

**IND Clinical Trials Summary**

## ***Zevalin™ Clinical Trials Summary (BB-IND# 4850)***

### General Overview

Five clinical trials constitute the basis for registration. Clinical
trials exploring IDEC-Y2B8 treatment in patients with B-cell NHL began
in 1993 and are currently ongoing under IDEC's BB-IND#4850.

Zevalin™ therapy efficacy studies were conducted in 2 pivotal trials:
Study 106-04 and Study 106-06. Both studies included subjects with
histologically confirmed, relapsed or refractory low-grade or follicular
(IWF A-D) or transformed from low-grade to intermediate-grade histology
(IWF E-G) B-cell NHL, requiring treatment as determined by an increase
in overall tumor size, the presence of B symptoms and/or the presence of
masses that are causing ongoing clinical symptomatology.

Zevalin™ therapy safety experience arises from 5 studies submitted in
the license application: the 2 pivotal trials (106-04 and 106-06) and 3
supportive studies (106-03, 106-05, and 106-98). To date, safety data on
419 subjects has been provided for consideration. Of these, 349 were
treated with IDEC-Y2B8, 70 were treated with rituximab as a control
therapy. Of the 349 subjects treated with IDEC-Y2B8, 182 received 2
doses of radiolabeled ibritumomab tiuxetan (a Study Day 1 dose of
IDEC-In2B8 followed by imaging and a Study Day 8 dose of IDEC-Y2B8).

### Regulatory History

  ------------------- ---------------------------------------------------
  **Date**            **Milestone**

  24-NOV-1992         IND Original Submission

  13-JUN-1996         Trial 106-03 Initiated

  30 Sep 1997         106-04 Phase 3 Meeting

  24-FEB-1998         Trial 106-04 Initiated

  20-MAY-1998         Trial 106-05 Initiated

  7-JUL-1998          Trial 106-06 Initiated

  17-NOV-1998         106-06 Phase 3 Meeting

  23-MAR-1999         Pre-PLA Meeting

  9-DEC-1999          Trial 106-98 Initiated

  05-JUN-2000         Fast Track Designation Granted

  18-JUL-2000         Pre-BLA Meeting

  01-NOV-2000         Application Received

  29-DEC-2000         Filing Action

  03-MAY-2001         First Action-Complete Response (CR) Letter

  10-JUL-2001         Complete Response To CR Letter Received

  11-SEP-2001         ODAC Presentation
  ------------------- ---------------------------------------------------

### Eligibility Criteria Overview

+-----------------------+----+----+-----+------------+--------------+
|                       | ** | ** | *   | **106-06** | **106-98**   |
|                       | 10 | 10 | *10 |            |              |
|                       | 6- | 6- | 6-0 |            |              |
|                       | 03 | 04 | 5** |            |              |
|                       | ** | ** |     |            |              |
+-----------------------+----+----+-----+------------+--------------+
| > N (Total = 426)     | 58 | 1  | 30  | 57         | 183 (still   |
|                       |    | 43 |     |            | accruing)    |
+-----------------------+----+----+-----+------------+--------------+
| > **INCLUSION         |    |    |     |            |              |
| > CRITERIA**          |    |    |     |            |              |
+-----------------------+----+----+-----+------------+--------------+
| > Previous treatment  | ≥  | ≥  | ≥ 1 | Rituxan    | Open Access  |
| > (tx)                | 1  | 1  |     | failures   |              |
+-----------------------+----+----+-----+------------+--------------+
| > IWF Histology       | A  | A  | A - | B - D      | A-G          |
|                       |  - |  - | G   |            |              |
|                       | G  | G  |     |            |              |
+-----------------------+----+----+-----+------------+--------------+
| > \< 25% BM           | X  | X  | X   | X          | X            |
| > involvement         |    |    |     |            |              |
+-----------------------+----+----+-----+------------+--------------+
| > ANC ≥ 1,500         | X  | X  | X   | X          | X            |
+-----------------------+----+----+-----+------------+--------------+
| > Platelet Count      | ≥  | ≥  | 1   | ≥ 150      | ≥ 100        |
|                       | 1  | 1  | 00- |            |              |
|                       | 00 | 50 | 149 |            |              |
+-----------------------+----+----+-----+------------+--------------+
| > **EXCLUSION         |    |    |     |            |              |
| > CRITERIA**          |    |    |     |            |              |
+-----------------------+----+----+-----+------------+--------------+
| > Prior ABMT or PBSC  | X  | X  | X   | X          | X            |
+-----------------------+----+----+-----+------------+--------------+
| > Prior               | X  | X  | X   | X          | X            |
| > radioimmunotherapy  |    |    |     |            |              |
+-----------------------+----+----+-----+------------+--------------+
| > XRT to \> 25% BM    | X  | X  | X   | X          | X            |
+-----------------------+----+----+-----+------------+--------------+

### Trial Summary Tables

+----+------------+------+-----+---+---+---------------+---------------+
| *  | **Title**  | **   | **D | * | * | **Study       | **Results**   |
| *S |            | Date | ate | * | * | Objectives**  |               |
| tu |            | S    | St  | R | ( |               |               |
| dy |            | tudy | udy | C | n |               |               |
| ** |            | Ini  | Cl  | T | ) |               |               |
|    |            | tiat | ose | * | * |               |               |
|    |            | ed** | d** | * | * |               |               |
+====+============+======+=====+===+===+===============+===============+
| 10 | Phase I    | June | Aug | N | 1 | 1)  Safety    | 1)            |
| 6- | Trial:     | 8,   | ust | o | 7 |     and       |   Correlation |
| 01 | Treatment  | 1993 | 23, |   |   |     tolerance |     was shown |
|    | of B-Cell  |      | 1   |   |   |     of        |     between   |
|    | Lymphoma   |      | 996 |   |   |     IDEC-Y2B8 |               |
|    | with 90    |      |     |   |   |     in        |    increasing |
|    | Y-Labeled  |      |     |   |   |     patients  |               |
|    | Pan B      |      |     |   |   |     with      |   hematologic |
|    | Monoclonal |      |     |   |   |     B-cell    |     toxicity  |
|    | Antibody   |      |     |   |   |     lymphoma, |     and       |
|    | with       |      |     |   |   |               |     treatment |
|    | Peripheral |      |     |   |   | 2)  MTD of    |     doses.    |
|    | Stem Cell  |      |     |   |   |     IDEC-Y2B8 |               |
|    | or         |      |     |   |   |               | 2)  The       |
|    | Autologous |      |     |   |   |    peripheral |               |
|    | Bone       |      |     |   |   |     stem      | dose-limiting |
|    | Marrow     |      |     |   |   |     cells     |               |
|    | Trans      |      |     |   |   |     (PSC) or  |    toxicities |
|    | plantation |      |     |   |   |     bone      |     were      |
|    |            |      |     |   |   |     marrow    |     thro      |
|    |            |      |     |   |   |     (BM)      | mbocytopenia, |
|    |            |      |     |   |   |               |               |
|    |            |      |     |   |   |    reinfusion |   leukopenia, |
|    |            |      |     |   |   |     are used  |     and       |
|    |            |      |     |   |   |     for       |               |
|    |            |      |     |   |   |     rescue    |  neutropenia. |
|    |            |      |     |   |   |     from      |               |
|    |            |      |     |   |   |     marrow    | 3)  A Y2B8    |
|    |            |      |     |   |   |     toxicity, |     dose of ≤ |
|    |            |      |     |   |   |               |     0.5       |
|    |            |      |     |   |   | 3)  Measure   |     mCi/kg    |
|    |            |      |     |   |   |     the       |     did not   |
|    |            |      |     |   |   |     bio       |     require   |
|    |            |      |     |   |   | distribution, |               |
|    |            |      |     |   |   |     phar      |    peripheral |
|    |            |      |     |   |   | macokinetics, |     stem cell |
|    |            |      |     |   |   |               |     or bone   |
|    |            |      |     |   |   |    dosimetry, |     marrow    |
|    |            |      |     |   |   |               |     support.  |
|    |            |      |     |   |   |    clearance, |               |
|    |            |      |     |   |   |     and tumor | 4)  Subject   |
|    |            |      |     |   |   |     uptake of |     104 had   |
|    |            |      |     |   |   |     indium-\[ |     confirmed |
|    |            |      |     |   |   | 111\]-labeled |     positive  |
|    |            |      |     |   |   |     anti-CD20 |     HAMA.     |
|    |            |      |     |   |   |               |               |
|    |            |      |     |   |   |    monoclonal | 5)  Subject   |
|    |            |      |     |   |   |     antibody  |     116 had   |
|    |            |      |     |   |   |               |               |
|    |            |      |     |   |   | (IDEC-In2B8), |   unconfirmed |
|    |            |      |     |   |   |               |     positive  |
|    |            |      |     |   |   | 4)  Compare   |     HAMA      |
|    |            |      |     |   |   |     the       |               |
|    |            |      |     |   |   |     delivered | 6)  Subject   |
|    |            |      |     |   |   |     dose to   |     109       |
|    |            |      |     |   |   |     the       |     initially |
|    |            |      |     |   |   |     measured  |     reported  |
|    |            |      |     |   |   |     effects   |     to have a |
|    |            |      |     |   |   |     in order  |     positive  |
|    |            |      |     |   |   |     to define |     HAMA by   |
|    |            |      |     |   |   |     which     |     the       |
|    |            |      |     |   |   |               |               |
|    |            |      |     |   |   |    dosimetric |  investigator |
|    |            |      |     |   |   |               |     had       |
|    |            |      |     |   |   |  measurements |     negative  |
|    |            |      |     |   |   |     on        |     HAMA upon |
|    |            |      |     |   |   |               |     retesting |
|    |            |      |     |   |   |    individual |     but was   |
|    |            |      |     |   |   |     patients  |     removed   |
|    |            |      |     |   |   |     help to   |     from      |
|    |            |      |     |   |   |     predict   |     study due |
|    |            |      |     |   |   |     toxicity  |     to        |
|    |            |      |     |   |   |     and       |               |
|    |            |      |     |   |   |     response, |   unfavorable |
|    |            |      |     |   |   |     and       |     bi        |
|    |            |      |     |   |   |               | odistribution |
|    |            |      |     |   |   | 5)  Determine |     (liver to |
|    |            |      |     |   |   |     the       |     whole     |
|    |            |      |     |   |   |     frequency |     body      |
|    |            |      |     |   |   |     of        |     ratio was |
|    |            |      |     |   |   |               |     \> 8:1.   |
|    |            |      |     |   |   |   development |     Please    |
|    |            |      |     |   |   |     human     |     note that |
|    |            |      |     |   |   |               |     the liver |
|    |            |      |     |   |   |   anti-murine |     dose was  |
|    |            |      |     |   |   |     antibody  |     estimated |
|    |            |      |     |   |   |     (HAMA).   |     to be     |
|    |            |      |     |   |   |               |     900cGy).  |
+----+------------+------+-----+---+---+---------------+---------------+
| 10 | A Phase    | S    | Ma  | n | 1 | 1)  Evaluate  | This study    |
| 6- | I/II       | epte | rch | o |   |     the       | was           |
| 02 | Clinical   | mber | 22, |   |   |     safety of | discontinued  |
|    | Trial of   | 28,  | 1   |   |   |     IDEC-Y2B8 | due to        |
|    | Yt         | 1993 | 994 |   |   |     given in  | a             |
|    | trium-\[90 |      |     |   |   |     repeated  | dministrative |
|    | \]-Labeled |      |     |   |   |     low doses | reasons       |
|    | IDEC-2B8   |      |     |   |   |     to        |               |
|    | Given      |      |     |   |   |     patients  | Conclusions   |
|    | Every Six  |      |     |   |   |     with      | cannot be     |
|    | to Eight   |      |     |   |   |     relapsed  | made due to   |
|    | Weeks to   |      |     |   |   |     or        | limited       |
|    | Patients   |      |     |   |   |               | enrollment.   |
|    | with       |      |     |   |   |    refractory |               |
|    | B-cell     |      |     |   |   |     NHL       |               |
|    | Lymphoma   |      |     |   |   |     following |               |
|    |            |      |     |   |   |               |               |
|    |            |      |     |   |   |  conventional |               |
|    |            |      |     |   |   |     therapy,  |               |
|    |            |      |     |   |   |               |               |
|    |            |      |     |   |   | 2)  Determine |               |
|    |            |      |     |   |   |     if        |               |
|    |            |      |     |   |   |               |               |
|    |            |      |     |   |   |    IDEC-In2B8 |               |
|    |            |      |     |   |   |     can       |               |
|    |            |      |     |   |   |     target    |               |
|    |            |      |     |   |   |     tumor     |               |
|    |            |      |     |   |   |     sites,    |               |
|    |            |      |     |   |   |               |               |
|    |            |      |     |   |   | 3)  Establish |               |
|    |            |      |     |   |   |     the       |               |
|    |            |      |     |   |   |     bio       |               |
|    |            |      |     |   |   | distribution, |               |
|    |            |      |     |   |   |     phar      |               |
|    |            |      |     |   |   | macokinetics, |               |
|    |            |      |     |   |   |               |               |
|    |            |      |     |   |   |    dosimetric |               |
|    |            |      |     |   |   |               |               |
|    |            |      |     |   |   |   parameters, |               |
|    |            |      |     |   |   |               |               |
|    |            |      |     |   |   |    clearance, |               |
|    |            |      |     |   |   |     and tumor |               |
|    |            |      |     |   |   |     uptake of |               |
|    |            |      |     |   |   |               |               |
|    |            |      |     |   |   |  radiolabeled |               |
|    |            |      |     |   |   |     IDEC-2B8  |               |
|    |            |      |     |   |   |     antibody, |               |
|    |            |      |     |   |   |               |               |
|    |            |      |     |   |   | 4)  Assess    |               |
|    |            |      |     |   |   |     the       |               |
|    |            |      |     |   |   |     percent   |               |
|    |            |      |     |   |   |     injected  |               |
|    |            |      |     |   |   |     dose/gram |               |
|    |            |      |     |   |   |     IDEC-Y2B8 |               |
|    |            |      |     |   |   |     in tumor  |               |
|    |            |      |     |   |   |     by repeat |               |
|    |            |      |     |   |   |     biopsy,   |               |
|    |            |      |     |   |   |               |               |
|    |            |      |     |   |   | 5)  Estimate  |               |
|    |            |      |     |   |   |     the       |               |
|    |            |      |     |   |   |     frequency |               |
|    |            |      |     |   |   |     for the   |               |
|    |            |      |     |   |   |               |               |
|    |            |      |     |   |   |   development |               |
|    |            |      |     |   |   |     of HAMA   |               |
|    |            |      |     |   |   |               |               |
|    |            |      |     |   |   | 6)  Estimate  |               |
|    |            |      |     |   |   |     radiation |               |
|    |            |      |     |   |   |     dose      |               |
|    |            |      |     |   |   |     delivered |               |
|    |            |      |     |   |   |     to the    |               |
|    |            |      |     |   |   |     tumor and |               |
|    |            |      |     |   |   |     normal    |               |
|    |            |      |     |   |   |     organs by |               |
|    |            |      |     |   |   |               |               |
|    |            |      |     |   |   |    dosimetry, |               |
|    |            |      |     |   |   |               |               |
|    |            |      |     |   |   | 7)  Assess    |               |
|    |            |      |     |   |   |               |               |
|    |            |      |     |   |   |   preliminary |               |
|    |            |      |     |   |   |     clinical  |               |
|    |            |      |     |   |   |     activity  |               |
|    |            |      |     |   |   |     in an     |               |
|    |            |      |     |   |   |     early     |               |
|    |            |      |     |   |   |     Phase II  |               |
|    |            |      |     |   |   |     trial.    |               |
+----+------------+------+-----+---+---+---------------+---------------+
| 10 | A Phase    | June | Sep | N | 5 | 1)  Evaluate  | 1)  Adverse   |
| 6- | I/II       | 13,  | tem | o | 8 |     the       |     events    |
| 03 | Clinical   | 1996 | ber |   |   |     safety    |     were      |
|    | Trial to   |      | 11, |   |   |     and       |     primarily |
|    | Evaluate   |      | 1   |   |   |     clinical  |               |
|    | the Safety |      | 998 |   |   |     activity  |  hematologic, |
|    | and        |      |     |   |   |     of Y2B8   |               |
|    | Clinical   |      |     |   |   |     in        | 2)  Grade 4   |
|    | Activity   |      |     |   |   |     relapsed  |               |
|    | of         |      |     |   |   |     or        |   hematologic |
|    | IDEC-Y2B8  |      |     |   |   |               |     toxicity  |
|    | Ad         |      |     |   |   |    refractory |     was       |
|    | ministered |      |     |   |   |     B-cell    |     related   |
|    | to         |      |     |   |   |     NHL       |     to        |
|    | Patients   |      |     |   |   |               |     thr       |
|    | with       |      |     |   |   | 2)  Evaluate  | ombocytopenia |
|    | B-Cell     |      |     |   |   |     the       |     and bone  |
|    | Lymphoma   |      |     |   |   |     safety    |     marrow    |
|    |            |      |     |   |   |     and       |               |
|    |            |      |     |   |   |     activity  |   involvement |
|    |            |      |     |   |   |     of        |     with      |
|    |            |      |     |   |   |     Rituximab |     lymphoma  |
|    |            |      |     |   |   |     when used |     at        |
|    |            |      |     |   |   |     in        |     baseline. |
|    |            |      |     |   |   |               |               |
|    |            |      |     |   |   |   conjunction | 3)  2% of     |
|    |            |      |     |   |   |     with Y2B8 |     patients  |
|    |            |      |     |   |   |               |     developed |
|    |            |      |     |   |   | 3)  Study the |     p         |
|    |            |      |     |   |   |     IDECIn2B8 | ost-treatment |
|    |            |      |     |   |   |     targeting |               |
|    |            |      |     |   |   |     of tumor  |    HACA/HAMA. |
|    |            |      |     |   |   |     sites and |               |
|    |            |      |     |   |   |     the       | 4             |
|    |            |      |     |   |   |     bio       | )  Dosimetric |
|    |            |      |     |   |   | distribution, |               |
|    |            |      |     |   |   |     phar      |    parameters |
|    |            |      |     |   |   | macokinetics, |     were not  |
|    |            |      |     |   |   |               |     able to   |
|    |            |      |     |   |   |    dosimetric |     predict   |
|    |            |      |     |   |   |               |     which     |
|    |            |      |     |   |   |   parameters, |     patients  |
|    |            |      |     |   |   |               |     were at   |
|    |            |      |     |   |   |    clearance, |     higher    |
|    |            |      |     |   |   |     and tumor |     risk for  |
|    |            |      |     |   |   |     uptake of |               |
|    |            |      |     |   |   |               |   hematologic |
|    |            |      |     |   |   |    IDEC-In2B8 |     toxicity. |
|    |            |      |     |   |   |     by        |               |
|    |            |      |     |   |   |               |               |
|    |            |      |     |   |   |  radioimaging |               |
|    |            |      |     |   |   |               |               |
|    |            |      |     |   |   |    techniques |               |
|    |            |      |     |   |   |     when      |               |
|    |            |      |     |   |   |     Rituximab |               |
|    |            |      |     |   |   |     is given  |               |
|    |            |      |     |   |   |     prior to  |               |
|    |            |      |     |   |   |               |               |
|    |            |      |     |   |   |    IDEC-In2B8 |               |
|    |            |      |     |   |   |               |               |
|    |            |      |     |   |   | 4)  Estimate  |               |
|    |            |      |     |   |   |     the       |               |
|    |            |      |     |   |   |     IDECY2B8  |               |
|    |            |      |     |   |   |     radiation |               |
|    |            |      |     |   |   |     dose      |               |
|    |            |      |     |   |   |     delivered |               |
|    |            |      |     |   |   |     to normal |               |
|    |            |      |     |   |   |     organs    |               |
|    |            |      |     |   |   |     and to    |               |
|    |            |      |     |   |   |     tumors,   |               |
|    |            |      |     |   |   |     using     |               |
|    |            |      |     |   |   |               |               |
|    |            |      |     |   |   |    dosimetry. |               |
+----+------------+------+-----+---+---+---------------+---------------+
| 10 | A          | Febr | J   | Y | 1 | 1)  To        | 1)  Zevalin™  |
| 6- | R          | uary | uly | e | 4 |     compare   |     therapy   |
| 04 | andomized, | 24,  | 28, | s | 3 |     the       |     has a     |
|    | Phase III  | 1998 | 2   |   |   |     efficacy  |     superior  |
|    | Mu         |      | 000 |   |   |     of        |     overall   |
|    | lticenter, |      |     |   |   |     Zevalin™  |     response  |
|    | Controlled |      |     |   |   |     therapy   |     rate (73% |
|    | Trial to   |      |     |   |   |     in        |     vs. 47%,  |
|    | Evaluate   |      |     |   |   |     relapsed  |     p=0.002)  |
|    | the        |      |     |   |   |     or        |     in        |
|    | Efficacy   |      |     |   |   |               |     patients  |
|    | and Safety |      |     |   |   |   refractory, |     with      |
|    | of         |      |     |   |   |     low-grade |     relapsed  |
|    | IDEC-Y2B8  |      |     |   |   |     or        |     or        |
|    | Radioimm   |      |     |   |   |               |               |
|    | unotherapy |      |     |   |   |    follicular |   refractory, |
|    | Compared   |      |     |   |   |     NHL with  |               |
|    | to         |      |     |   |   |     that of   |    low-grade, |
|    | Ri         |      |     |   |   |     rituximab |               |
|    | tuxanImm |      |     |   |   |               |    follicular |
|    | unotherapy |      |     |   |   |   monotherapy |     B-cell    |
|    | of         |      |     |   |   |               |     NHL.      |
|    | Relapsed   |      |     |   |   | 2)  To        |               |
|    | or         |      |     |   |   |               | 2)  Zevalin™  |
|    | Refractory |      |     |   |   |  characterize |     group     |
|    | Low-Grade  |      |     |   |   |     the       |     time to   |
|    | or         |      |     |   |   |     safety of |               |
|    | Follicular |      |     |   |   |     Zevalin™  |   progression |
|    | B-Cell     |      |     |   |   |     therapy   |     (all      |
|    | Non        |      |     |   |   |     compared  |     subjects) |
|    | -Hodgkin's |      |     |   |   |     with the  |     and       |
|    | Lymphoma   |      |     |   |   |     safety of |     duration  |
|    | III        |      |     |   |   |     rituximab |     of        |
|    |            |      |     |   |   |               |     response  |
|    |            |      |     |   |   |   monotherapy |               |
|    |            |      |     |   |   |               |   (responders |
|    |            |      |     |   |   | 3)  To        |     only)     |
|    |            |      |     |   |   |     estimate  |     were not  |
|    |            |      |     |   |   |     IDEC-Y2B8 |               |
|    |            |      |     |   |   |     radiation | statistically |
|    |            |      |     |   |   |     absorbed  |     different |
|    |            |      |     |   |   |     doses     |     to the    |
|    |            |      |     |   |   |     delivered |     rituximab |
|    |            |      |     |   |   |     to the    |     group.    |
|    |            |      |     |   |   |     tumor and |               |
|    |            |      |     |   |   |     to normal | 3)            |
|    |            |      |     |   |   |     organs    |   Hematologic |
|    |            |      |     |   |   |               |     toxicity  |
|    |            |      |     |   |   | 4)  To        |     is common |
|    |            |      |     |   |   |               |     with      |
|    |            |      |     |   |   |   demonstrate |     Zevalin™  |
|    |            |      |     |   |   |     the       |     therapy   |
|    |            |      |     |   |   |     clinical  |     and       |
|    |            |      |     |   |   |     utility   |               |
|    |            |      |     |   |   |     of        |    represents |
|    |            |      |     |   |   |     baseline  |     a         |
|    |            |      |     |   |   |     platelet  |               |
|    |            |      |     |   |   |     counts as |   significant |
|    |            |      |     |   |   |     a         |     clinical  |
|    |            |      |     |   |   |     surrogate |               |
|    |            |      |     |   |   |     predictor |   limitation. |
|    |            |      |     |   |   |     of        |               |
|    |            |      |     |   |   |     IDEC-Y2B8 | 4)  Median    |
|    |            |      |     |   |   |     safety.   |     duration  |
|    |            |      |     |   |   |               |     of Grade  |
|    |            |      |     |   |   |               |     ≥ 3       |
|    |            |      |     |   |   |               |               |
|    |            |      |     |   |   |               |   neutropenia |
|    |            |      |     |   |   |               |     within 90 |
|    |            |      |     |   |   |               |     days of   |
|    |            |      |     |   |   |               |     Zevalin™  |
|    |            |      |     |   |   |               |     therapy   |
|    |            |      |     |   |   |               |     was 27    |
|    |            |      |     |   |   |               |     days for  |
|    |            |      |     |   |   |               |     56% of    |
|    |            |      |     |   |   |               |     subjects. |
|    |            |      |     |   |   |               |               |
|    |            |      |     |   |   |               | 5)  Median    |
|    |            |      |     |   |   |               |     duration  |
|    |            |      |     |   |   |               |     of Grade  |
|    |            |      |     |   |   |               |     ≥ 3       |
|    |            |      |     |   |   |               |     thr       |
|    |            |      |     |   |   |               | ombocytopenia |
|    |            |      |     |   |   |               |     within 90 |
|    |            |      |     |   |   |               |     days of   |
|    |            |      |     |   |   |               |     Zevalin™  |
|    |            |      |     |   |   |               |     therapy   |
|    |            |      |     |   |   |               |     was 23    |
|    |            |      |     |   |   |               |     days for  |
|    |            |      |     |   |   |               |     60% of    |
|    |            |      |     |   |   |               |     subjects  |
+----+------------+------+-----+---+---+---------------+---------------+
| 10 | A Phase    | May  | J   | N | 3 | 1             | 1)  IDEC-Y2B8 |
| 6- | II,        | 20,  | une | o | 0 | )  determine |     given at  |
| 05 | O          | 1998 | 20, |   |   |     the       |     0.3       |
|    | pen-Label, |      | 2   |   |   |     safety    |     mCi/kg is |
|    | Mu         |      | 000 |   |   |     and       |     usually   |
|    | lti-Center |      |     |   |   |     efficacy  |     tolerated |
|    | Trial to   |      |     |   |   |     of a      |     in        |
|    | Evaluate   |      |     |   |   |     reduced   |     subjects  |
|    | the Safety |      |     |   |   |     dose (0.3 |     with mild |
|    | and        |      |     |   |   |     mCi/kg)   |     thr       |
|    | Efficacy   |      |     |   |   |     of        | ombocytopenia |
|    | of         |      |     |   |   |     IDEC-Y2B8 |     but may   |
|    | IDEC-Y2B8  |      |     |   |   |     therapy   |     result in |
|    | Radioimm   |      |     |   |   |     in        |     prolonged |
|    | unotherapy |      |     |   |   |     relapsed  |     or        |
|    | of         |      |     |   |   |     or        |               |
|    | Relapsed   |      |     |   |   |               |    refractory |
|    | or         |      |     |   |   |   refractory, |               |
|    | Refractory |      |     |   |   |               |   hematologic |
|    | Low-Grade  |      |     |   |   |    low-grade, |     toxicity. |
|    | or         |      |     |   |   |               |               |
|    | Follicular |      |     |   |   |   follicular, | 2)  Zevalin™  |
|    | B-Cell     |      |     |   |   |     or        |     therapy   |
|    | Non        |      |     |   |   |               |     has       |
|    | -Hodgkin's |      |     |   |   |   transformed |     clinical  |
|    | Lymphoma   |      |     |   |   |     NHL       |     activity  |
|    | in         |      |     |   |   |     subjects  |     in mildly |
|    | Patients   |      |     |   |   |     who have  |     thr       |
|    | with Mild  |      |     |   |   |     mild      | ombocytopenic |
|    | Thromb     |      |     |   |   |     thr       |     subjects  |
|    | ocytopenia |      |     |   |   | ombocytopenia |               |
|    |            |      |     |   |   |               | 3)  Clinical  |
|    |            |      |     |   |   | 2)            |     selection |
|    |            |      |     |   |   |  characterize |     criteria  |
|    |            |      |     |   |   |     the       |     including |
|    |            |      |     |   |   |     safety of |     baseline  |
|    |            |      |     |   |   |     Zevalin™  |     platelet  |
|    |            |      |     |   |   |     therapy   |     count,    |
|    |            |      |     |   |   |               |     bone      |
|    |            |      |     |   |   | 3)  To        |     marrow    |
|    |            |      |     |   |   |     estimate  |               |
|    |            |      |     |   |   |     IDEC-Y2B8 |  involvement, |
|    |            |      |     |   |   |     radiation |     and       |
|    |            |      |     |   |   |     absorbed  |     i         |
|    |            |      |     |   |   |     doses     | ndividualized |
|    |            |      |     |   |   |     delivered |     dosing    |
|    |            |      |     |   |   |     to the    |     based on  |
|    |            |      |     |   |   |     tumor and |     patient   |
|    |            |      |     |   |   |     to normal |     weight    |
|    |            |      |     |   |   |     organs    |     resulted  |
|    |            |      |     |   |   |               |     in        |
|    |            |      |     |   |   | 4)  To        |               |
|    |            |      |     |   |   |               |    acceptable |
|    |            |      |     |   |   |   demonstrate |     toxicity  |
|    |            |      |     |   |   |     the       |     profile   |
|    |            |      |     |   |   |     clinical  |     for       |
|    |            |      |     |   |   |     utility   |     subjects  |
|    |            |      |     |   |   |     of        |     treated   |
|    |            |      |     |   |   |     baseline  |     with      |
|    |            |      |     |   |   |     platelet  |     Zevalin   |
|    |            |      |     |   |   |     counts as |     therapy.. |
|    |            |      |     |   |   |     a         |               |
|    |            |      |     |   |   |     surrogate | 4)  Median    |
|    |            |      |     |   |   |     predictor |     duration  |
|    |            |      |     |   |   |     of        |     of Grade  |
|    |            |      |     |   |   |     IDEC-Y2B8 |     ≥ 3       |
|    |            |      |     |   |   |     safety.   |               |
|    |            |      |     |   |   |               |   neutropenia |
|    |            |      |     |   |   |               |     within 90 |
|    |            |      |     |   |   |               |     days of   |
|    |            |      |     |   |   |               |     Zevalin™  |
|    |            |      |     |   |   |               |     therapy   |
|    |            |      |     |   |   |               |     was 29    |
|    |            |      |     |   |   |               |     days for  |
|    |            |      |     |   |   |               |     87% of    |
|    |            |      |     |   |   |               |     subjects. |
|    |            |      |     |   |   |               |               |
|    |            |      |     |   |   |               | 5)  Median    |
|    |            |      |     |   |   |               |     duration  |
|    |            |      |     |   |   |               |     of Grade  |
|    |            |      |     |   |   |               |     ≥ 3       |
|    |            |      |     |   |   |               |     thr       |
|    |            |      |     |   |   |               | ombocytopenia |
|    |            |      |     |   |   |               |     within 90 |
|    |            |      |     |   |   |               |     days of   |
|    |            |      |     |   |   |               |     Zevalin™  |
|    |            |      |     |   |   |               |     therapy   |
|    |            |      |     |   |   |               |     was 30    |
|    |            |      |     |   |   |               |     days for  |
|    |            |      |     |   |   |               |     87% of    |
|    |            |      |     |   |   |               |     subjects. |
+----+------------+------+-----+---+---+---------------+---------------+
| 10 | A Phase    | July | J   | N | 5 | 1)  Determine | 1)  Zevalin™  |
| 6- | III,       | 7,   | une | o | 7 |     the       |     therapy   |
| 06 | O          | 1998 | 30, |   |   |     efficacy  |     has       |
|    | pen-Label, |      | 2   |   |   |     of        |     clinical  |
|    | Non        |      | 000 |   |   |     Zevalin™  |     activity  |
|    | randomized |      |     |   |   |     therapy   |     in        |
|    | C          |      |     |   |   |     in        |     patients  |
|    | ontrolled, |      |     |   |   |     relapsed  |     with      |
|    | M          |      |     |   |   |     or        |     relapsed  |
|    | ulticenter |      |     |   |   |               |     or        |
|    | Trial to   |      |     |   |   |   refractory, |               |
|    | Evaluate   |      |     |   |   |               |   refractory, |
|    | the        |      |     |   |   |    follicular |               |
|    | Efficacy   |      |     |   |   |     (IWF B,   |    follicular |
|    | and Safety |      |     |   |   |     C, D;     |     B-cell    |
|    | of         |      |     |   |   |     also      |     NHL who   |
|    | IDEC-Y2B8  |      |     |   |   |     defined   |     are also  |
|    | Radioimm   |      |     |   |   |     as REAL   |               |
|    | unotherapy |      |     |   |   |     c         |    refractory |
|    | in         |      |     |   |   | lassification |     to        |
|    | Patients   |      |     |   |   |               |     rituximab |
|    | with       |      |     |   |   |    Follicular |     therapy.  |
|    | B-Cell     |      |     |   |   |     center    |               |
|    | Non        |      |     |   |   |     grade I,  | 2)  The       |
|    | -Hodgkin's |      |     |   |   |     II,       |     LEXCOR    |
|    | Lymphoma   |      |     |   |   |     and III)  |     protocol  |
|    | Who Are    |      |     |   |   |     B-cell    |     defined   |
|    | Refractory |      |     |   |   |     NHL       |     overall   |
|    | to Prior   |      |     |   |   |     subjects  |     response  |
|    | Rituximab  |      |     |   |   |     whose     |     rate to   |
|    | Therapy    |      |     |   |   |     disease   |     Zevalin™  |
|    |            |      |     |   |   |     was       |     therapy   |
|    |            |      |     |   |   |               |     was 59%   |
|    |            |      |     |   |   |    refractory |               |
|    |            |      |     |   |   |     to        | 3)  Time to   |
|    |            |      |     |   |   |     previous  |               |
|    |            |      |     |   |   |     treatment |   progression |
|    |            |      |     |   |   |     with      |     for all   |
|    |            |      |     |   |   |               |     subjects  |
|    |            |      |     |   |   |    rituximab, |     was 6.8   |
|    |            |      |     |   |   |               |     months    |
|    |            |      |     |   |   | 2)  Determine |               |
|    |            |      |     |   |   |     the       | 4)  Duration  |
|    |            |      |     |   |   |     overall   |     of        |
|    |            |      |     |   |   |     response  |     response  |
|    |            |      |     |   |   |     rate      |     (CR and   |
|    |            |      |     |   |   |     (ORR) to  |     PR) to    |
|    |            |      |     |   |   |     Zevalin™  |     Zevalin™  |
|    |            |      |     |   |   |     therapy   |     therapy   |
|    |            |      |     |   |   |     in        |     was 7.7   |
|    |            |      |     |   |   |               |     months    |
|    |            |      |     |   |   |    follicular |               |
|    |            |      |     |   |   |     NHL       | 5)  Median    |
|    |            |      |     |   |   |     patients, |     duration  |
|    |            |      |     |   |   |     and       |     of Grade  |
|    |            |      |     |   |   |               |     ≥ 3       |
|    |            |      |     |   |   | 3)            |               |
|    |            |      |     |   |   |  Characterize |   neutropenia |
|    |            |      |     |   |   |     the       |     within 90 |
|    |            |      |     |   |   |     safety    |     days of   |
|    |            |      |     |   |   |     profile   |     Zevalin™  |
|    |            |      |     |   |   |     of        |     therapy   |
|    |            |      |     |   |   |     Zevalin™  |     was 22    |
|    |            |      |     |   |   |     Therapy   |     days for  |
|    |            |      |     |   |   |               |     68% of    |
|    |            |      |     |   |   |               |     subjects. |
|    |            |      |     |   |   |               |               |
|    |            |      |     |   |   |               | 6)  Median    |
|    |            |      |     |   |   |               |     duration  |
|    |            |      |     |   |   |               |     of Grade  |
|    |            |      |     |   |   |               |     ≥ 3       |
|    |            |      |     |   |   |               |     thr       |
|    |            |      |     |   |   |               | ombocytopenia |
|    |            |      |     |   |   |               |     within 90 |
|    |            |      |     |   |   |               |     days of   |
|    |            |      |     |   |   |               |     Zevalin™  |
|    |            |      |     |   |   |               |     therapy   |
|    |            |      |     |   |   |               |     was 24    |
|    |            |      |     |   |   |               |     days for  |
|    |            |      |     |   |   |               |     75% of    |
|    |            |      |     |   |   |               |     subjects  |
+----+------------+------+-----+---+---+---------------+---------------+
| 10 | A          | Dece | o   | N | 1 | 1)  To        | 1.  The study |
| 6- | Mu         | mber | ngo | o | 8 |     provide   |     is        |
| 98 | lticenter, | 9,   | ing |   | 2 |     Zevalin™  |     ongoing   |
|    | Open-Label | 1999 |     |   |   |     therapy   |     and will  |
|    | Trial to   |      |     |   |   |     to        |     be        |
|    | Evaluate   |      |     |   |   |     patients  |     analyzed  |
|    | the        |      |     |   |   |     with      |     following |
|    | Efficacy   |      |     |   |   |     relapsed  |               |
|    | and Safety |      |     |   |   |     or        |    completion |
|    | of         |      |     |   |   |               |               |
|    | IDEC-Y2B8  |      |     |   |   |    refractory | 2.  The       |
|    | Radioimm   |      |     |   |   |     low-grade |     120-day   |
|    | unotherapy |      |     |   |   |     or        |     update    |
|    | of         |      |     |   |   |               |     will      |
|    | Relapsed   |      |     |   |   |    follicular |     include   |
|    | or         |      |     |   |   |     or        |     safety    |
|    | Refractory |      |     |   |   |               |     analyses  |
|    | Low-Grade  |      |     |   |   |   transformed |     of all    |
|    | or         |      |     |   |   |     B-cell    |     patients  |
|    | Follicular |      |     |   |   |     NHL       |               |
|    | or         |      |     |   |   |               |    completing |
|    | T          |      |     |   |   | 2)  To add to |     the       |
|    | ransformed |      |     |   |   |     the       |     13-week   |
|    | B-Cell     |      |     |   |   |     overall   |     treatment |
|    | Non        |      |     |   |   |     efficacy  |     period,   |
|    | -Hodgkin's |      |     |   |   |     and       |     and an    |
|    | Lymphoma   |      |     |   |   |     safety    |     interim   |
|    |            |      |     |   |   |               |     safety    |
|    |            |      |     |   |   |    experience |     analysis  |
|    |            |      |     |   |   |     in this   |     of all    |
|    |            |      |     |   |   |               |     patients  |
|    |            |      |     |   |   |    indication |               |
|    |            |      |     |   |   |               | participating |
|    |            |      |     |   |   | 3)  To        |     in the    |
|    |            |      |     |   |   |     compare,  |     90Y       |
|    |            |      |     |   |   |     in a      |     pha       |
|    |            |      |     |   |   |     selected  | rmacokinetics |
|    |            |      |     |   |   |     subset of |               |
|    |            |      |     |   |   |     patients, |    comparison |
|    |            |      |     |   |   |     the       |     study.    |
|    |            |      |     |   |   |     bi        |               |
|    |            |      |     |   |   | odistribution | 3.  Median    |
|    |            |      |     |   |   |     of        |     duration  |
|    |            |      |     |   |   |     IDEC-Y2B8 |     of Grade  |
|    |            |      |     |   |   |     prepared  |     ≥ 3       |
|    |            |      |     |   |   |     with 90Y  |               |
|    |            |      |     |   |   |               |   neutropenia |
|    |            |      |     |   |   | radionuclides |     within 90 |
|    |            |      |     |   |   |     from two  |     days of   |
|    |            |      |     |   |   |     different |     Zevalin™  |
|    |            |      |     |   |   |     suppliers |     therapy   |
|    |            |      |     |   |   |               |     was 22    |
|    |            |      |     |   |   |               |     days for  |
|    |            |      |     |   |   |               |     43% of    |
|    |            |      |     |   |   |               |     subjects  |
|    |            |      |     |   |   |               |               |
|    |            |      |     |   |   |               | 4.  Median    |
|    |            |      |     |   |   |               |     duration  |
|    |            |      |     |   |   |               |     of Grade  |
|    |            |      |     |   |   |               |     ≥ 3       |
|    |            |      |     |   |   |               |     thr       |
|    |            |      |     |   |   |               | ombocytopenia |
|    |            |      |     |   |   |               |     within 90 |
|    |            |      |     |   |   |               |     days of   |
|    |            |      |     |   |   |               |     Zevalin™  |
|    |            |      |     |   |   |               |     therapy   |
|    |            |      |     |   |   |               |     was 28    |
|    |            |      |     |   |   |               |     days for  |
|    |            |      |     |   |   |               |     44% of    |
|    |            |      |     |   |   |               |     subjects  |
+----+------------+------+-----+---+---+---------------+---------------+

Inspections and Financial Disclosures

## Bioresearch Monitoring Inspection Results

Inspections of three clinical investigators were performed in support of
the subject BLA. The inspections were conducted in with CPGM with
7348.811, the Inspection Program for Clinical Investigators.

Specific questions concerning the studies were included. Data audits
were performed at the following three sites:

+-------------+-------------+-------------+-------------+-------------+
| **Site**    | **          | **Invest    | **Form      | **Class     |
|             | Protocols** | igator(s)** | 483**       | ification** |
+-------------+-------------+-------------+-------------+-------------+
| Mayo Clinic | 106-03      | Witzig,     | No          | NAI         |
|             |             | Wiseman     |             |             |
|             | 106-04      |             |             |             |
+-------------+-------------+-------------+-------------+-------------+
| N           | 106-03      | Gordon      | No          | NAI         |
| orthwestern |             |             |             |             |
| University  | 106-04      |             |             |             |
+-------------+-------------+-------------+-------------+-------------+
| Sidney      | 106-03      | Saleh       | Yes         | VAI         |
| Kimmel      |             |             |             |             |
| Cancer      | 106-04      |             |             |             |
| Center      |             |             |             |             |
+-------------+-------------+-------------+-------------+-------------+

### Inspectional Findings

A Form FDA 483 was issued to Dr. Saleh.

Inspection of the sites revealed the following

#### Northwestern University / Dr. Gordon

Three subjects were given doses of IDEC-Y2B8 that were higher than
specified by Protocol 106-03. The doses were calculated at 0.4 mCi/kg in
the Nuclear Medicine Department without taking into account the maximum
dose of 32 mCi in the protocol.

#### Sidney Kimmel Cancer Center / Dr. Saleh 

Although all subjects signed consent forms at enrollment, versions that
were revised while on study were missing for 2 subjects. Another
subject, who was enrolled on 6/97, did not sign an 8/97 version of the
consent form until 1/99.

### Inspectional Summary Statement

The results of bioresearch monitoring inspections of five clinical sites
indicate that the deviations made by the clinical investigators are not
substantive, with the exceptions noted, and that the submitted data can
be considered reliable and accurate.

## Financial disclosure

Under 21 CFR 54, an applicant is required to certify all investigators
and consultants have disclosed any financial arrangements that could
influence the study outcome.

Investigators and consultants were asked to provide information
pertaining to:

1.  Any financial arrangement between the sponsor and the individual
    that could influence the outcome of the study

2.  Any significant payments of other sorts (eg: grants, honoraria,
    retainer fees, equipment, etc) made on or after February 2, 1999

3.  Any proprietary interest held in the product tested

4.  Any individual, spousal, or dependent children equity interest
    exceeding a value of \$50,000.

The sponsor collected retroactive financial disclosure information
retroactive to Frebruary 2, 1999 from 34 of 36 principle investigators,
4 of 5 co-principle investigators, and 343 of 386 sub-investigators. In
addition, information was collected for 12 of 13 consultants who had
participated in the Lymphoma Expects Confirmation of Response assessment
(LEXCOR) or dosimetry assessment. The sponsor has provided documentation
that substantiates multiple attempts at getting the required information
from those investigators who failed to provide financial disclosures.

The sponsor has certified that :

1.  1 former PI, 2 sub-investigators and their institutions, and 1
    consultant had significant equity interest that required disclosure.

2.  None of the clinical investigators or consultants held any
    proprietary interests in Zevalin

**FDA Conclusion**:

Study results from sites involving investigators who had disclosed
significant equity interest were similar to other study sites and did
not significantly impact or alter the efficacy results.

Phase I/II Trials

## Phase I/II TRIALS

Studies 106-03, 106-05, and 106-98

### Study 106-03

#### Protocol History

+----------+------------+----------------------------------------------+
| **Date** | **M        | Comments                                     |
|          | ilestone** |                                              |
+----------+------------+----------------------------------------------+
| 22-      | Protocol   |                                              |
| DEC-1995 | Submitted  |                                              |
+----------+------------+----------------------------------------------+
| 8-       | Protocol   | 1.  Imaging study time points changed        |
| MAR-1996 | Amendment  |                                              |
|          | #1         | 2.  PK and selected laboratory assessment    |
|          |            |     specifications modified                  |
+----------+------------+----------------------------------------------+
| 13-      | Trial      |                                              |
| JUN-1996 | Initiated  |                                              |
+----------+------------+----------------------------------------------+
| 14-      | Protocol   | 1.  Administrative changes                   |
| JUN-1996 | Amendment  |                                              |
|          | #2         | 2.  Dosimetry and PK analysis time point     |
|          |            |     modified                                 |
|          |            |                                              |
|          |            | 3.  Laboratory and BM sampling time points   |
|          |            |     amended                                  |
|          |            |                                              |
|          |            | 4.  Optional SPECT imaging allowed           |
|          |            |                                              |
|          |            | 5.  Response criteria definition modified    |
|          |            |                                              |
|          |            | 6.  Y2B8 Dose specification for subjects \<  |
|          |            |     50 Kg                                    |
+----------+------------+----------------------------------------------+
| 5-       | Protocol   | 1.  Gamma-camera imaging requirements        |
| JUN-1997 | amendment  |     modified                                 |
|          | #3         |                                              |
|          |            | 2.  Parallel analysis for group 3 to assess  |
|          |            |     the need or adequacy of dosimetry is     |
|          |            |     further defined                          |
|          |            |                                              |
|          |            | 3.  Lexcor panel included                    |
|          |            |                                              |
|          |            | 4.  Administrative changes                   |
+----------+------------+----------------------------------------------+
| 4-       | Protocol   | 1.  Groups 2 and 3 patients stratified by    |
| AUG-1997 | Amendment  |     baseline platelet counts to receive 0.3  |
|          | #4         |     or 0.4 mCi/kg IDEC-Y2B8                  |
|          |            |                                              |
|          |            | 2.  Efficacy analyses by histology and by    |
|          |            |     dose subgroups defined                   |
|          |            |                                              |
|          |            | 3.  Accrual to Group 3 increased             |
|          |            |                                              |
|          |            | 4.  Study drug handling clarification        |
+----------+------------+----------------------------------------------+

#### Study Design, Objectives, and Treatment Plan

This was an open-label, single-arm, multicenter, Phase I/II clinical
activity and safety study of IDEC-Y2B8 in patients with advanced,
refractory or relapsed NHL. Patients with low- or intermediate-grade or
mantle cell NHL who had relapsed disease or had failed primary
conventional therapy and required treatment were eligible to participate
in this study.

The study was comprised of three groups.

-   **Group 1** included subjects enrolled to determine the optimum dose
    of rituximab to be used as an unlabelled antibody prior to
    IDEC-In2B8 and IDEC-Y2B8 administration

-   **Group 2** studies determine the optimum dose ^90^Y as a component
    of IDEC-Y2B8.

-   **Group 3** subjects were treated with the optimal Rituximab,
    IDEC-In2B8 and IDEC-Y2B8 doses determined from Group 1 and 2 safety
    and imaging results.

    All doses of Rituximab were to be determined based on body surface
    area and

were to be given prior to IDEC-In2B8 (5 mCi), and IDEC-Y2B8. The dose of
IDEC-Y2B8 was calculated based upon the patient's weight during the
Baseline evaluation. Subjects were treated with IDEC-Y2B8 only if the
dosimetry MIRDOSE projected organ exposure was \<2000 rad for normal
organs and \<300 rad for bone marrow.

+------+------------+-----------------------------------+------------+
| > *  | > **N**    | > **Treatment**                   | > **O      |
| *Gro |            |                                   | bjective** |
| up** |            |                                   |            |
+------+------------+-----------------------------------+------------+
| > 1  | > 6-9      | > Day 0, 7: 100 or 250 mg/m^2^    | > Optimize |
|      | >          | > Rituximab and 5 mCi IDEC-In2B8  | >          |
|      | >          | >                                 |  Rituximab |
|      |  (n=3/dose | > WK 2,3,4,5: 375 mg/m^2^         | > Dose     |
|      | > level)   | > Rituximab                       |            |
+------+------------+-----------------------------------+------------+
| > 2  | 15-18      | > Day 0: Optimum dose of          | > Optimize |
|      |            | > Rituximab and IDEC-In2B8        | >          |
|      | >          | >                                 |  IDEC-Y2B8 |
|      |  (n=5/dose | > Day 7-10: Following receipt of  | > Dose     |
|      | > level)   | > dosimetry data:                 |            |
|      |            | >                                 |            |
|      |            | > Optimum dose of Rituximab and   |            |
|      |            | > 0.2, 0.3, or 0.4 mCi/kg         |            |
|      |            | > IDEC-Y2B8                       |            |
+------+------------+-----------------------------------+------------+
| > 3  | > 20-35    | > Day 0: Optimum dose of          | > Phase II |
|      |            | > Rituximab and 5 mCi IDEC-In2B8  | > R        |
|      |            | >                                 | ecommended |
|      |            | > Day 7-10: Following receipt of  | > Dose     |
|      |            | > dosimetry data: Optimum dose of |            |
|      |            | > Rituximab and optimum dose      |            |
|      |            | > (mCi/kg) IDEC-Y2B8              |            |
+------+------------+-----------------------------------+------------+

#### Study Results

##### Disposition

Fifty-eight subjects were enrolled in Study 106-03

-   7 were enrolled in Group 1,

> 6 were treated with rituximab and IDEC-In-2B8
>
> 1 subject did not receive study drug for personal reasons.

-   51 were enrolled in Groups 2 and 3

> 50 participants received any dose of IDEC-Y2B8.
>
> 1 Subject enrolled at the 0.3 mCi/kg never received IDEC-Y2B8 and was
> treated with four infusions of Rituximab based on the on
> site-specific, imaged --based, bone marrow dosimetry although the
> estimated marrow radiation dose was acceptable on blood-derived and
> sacral image-derived MIRDOSE3 dosimetry performed by the central
> dosimetry analysis.
>
> 12 did not complete the treatment period (defined as the time between
> the first infusion and 12 weeks after the last infusion)

-   1 subject (0.2 mCi/kg) died because of disease progression, and

-   1 subject receiving 0.2 mCi/kg, 2 receiving 0.3 mCi/kg, and 8
    receiving 0.4 mCi/kg IDEC-Y2B8 did not complete the treatment period
    due to disease progression.

##### Protocol Modifications

1.  1 Subject had an initial kidney dose estimated at 2187 rads that
    exceeded the protocol defined maximum allowable dose (2000 rad
    limit). However, SPECT scanning indicated that the high values were
    due to tumor involvement in the retroperitoneal area rather than to
    the overlying kidney. Based on these observations, an exception to
    the protocol was approved to allow administration of IDEC-Y2B8 for
    this subject.

+-----------------------------------+----------------------------------+
| **Demographics (n=51 subjects     |                                  |
| included in Groups 2 and 3)**     |                                  |
+-----------------------------------+----------------------------------+
| Median age                        | 60 years (range 24-82 years)     |
+-----------------------------------+----------------------------------+
| Sex                               | 71% male; 29% female             |
+-----------------------------------+----------------------------------+
| Race                              | 96% Caucasian                    |
+-----------------------------------+----------------------------------+
| Median time from initial Dx       | 3.8 years (range 0.7-33.1 years) |
+-----------------------------------+----------------------------------+
| Prior anthracyclines              | 92%                              |
+-----------------------------------+----------------------------------+
| Resistant to prior therapy^\*^    | 20%                              |
+-----------------------------------+----------------------------------+
| Extranodal sites                  |                                  |
+-----------------------------------+----------------------------------+
| > 0-1                             | 57%                              |
+-----------------------------------+----------------------------------+
| > \>1                             | 27%                              |
+-----------------------------------+----------------------------------+
| > Unknown                         | 16%                              |
+-----------------------------------+----------------------------------+
| ^\*^ Resistance is defined as     |                                  |
| non-responders or progressed      |                                  |
| within 6 months                   |                                  |
+-----------------------------------+----------------------------------+

+------------+-----------------------------------------------+--------+
|            | **IWF Histology (Type)**                      | **%**  |
|            |                                               |        |
|            | **N = 51**                                    |        |
+------------+-----------------------------------------------+--------+
| > Low      | A                                             | 6      |
| > Grade    |                                               |        |
+------------+-----------------------------------------------+--------+
|            | B                                             | 27     |
+------------+-----------------------------------------------+--------+
|            | C                                             | 33     |
+------------+-----------------------------------------------+--------+
| > In       | D                                             | 4      |
| termediate |                                               |        |
| > Grade    |                                               |        |
+------------+-----------------------------------------------+--------+
|            | E                                             | 0      |
+------------+-----------------------------------------------+--------+
|            | F                                             | 6      |
+------------+-----------------------------------------------+--------+
|            | G                                             | 18     |
+------------+-----------------------------------------------+--------+
|            | Mantle                                        | 6      |
+------------+-----------------------------------------------+--------+

##### Activity Results

Among 51 subjects registered in groups 2 and 3, 34 (67%) had a response
(13 CR + 21 PR) to Zevalin therapy. Twenty-eight of 34 (82%) of subjects
with low-grade NHL (IWF A, B, and C) had a response (9 CR + 19 PR) to
Zevalin therapy.

Subjects resistant to any prior chemotherapy had a 50% response rate,
which was not statistically different from the response rate in
chemo-sensitive patients.

##### Safety Evaluation

The dataset includes the 50 subjects who received Zevalin therapy from
Groups 2 and 3. All adverse events (AEs) were reported through 12 weeks
following treatment with IDEC-Y2B8. AEs considered serious events and/or
events related to the study treatment were to be reported through one
year following the treatment period.

###### Adverse Events -- Overall Assessment

All 50 subjects experienced at least 1 adverse event.

A total of 528 AEs were reported for all subjects. Fifty-three percent
were Grade 1, 23% Grade 2, 14% Grade 3, and 10% Grade 4 by NCI CTC Grade
criteria.

-   Subjects were monitored for infections for one year following their
    first infusion

> 22 infections were reported in 14 subjects during the treatment
> period;

-   7 subjects had Grade 1,

-   4 had Grade 2,

-   1 had Grade 3,

-   2 had Grade 4 infections.

```{=html}
<!-- -->
```
-   Of the three subjects with Grade 3 and 4 infections,

    -   1 subject in the 0.4-mCi/kg dose group had Grade 3 pneumonia;

    -   1 subject in the 0.3-mCi/kg dose group had Grade 3 pneumonia
        concurrent with a Grade 4 bacterial infection;

    -   1 subject in the 0.4-mCi/kg dose group had Grade 4 clostridial
        sepsis (secondary to a gastro-splenic lymphomatous fistula.)

        **Frequency of Common AEs by Subject**

**(n=50 subjects)**

  ---------------------------------------------- ------------------------
  **AE (all grades)**                            **% of subjects (n=50)**

  Leukopenia                                     88%

  Thrombocytopenia                               88%

  Neutropenia                                    74%

  Anemia                                         58%

  Asthenia                                       34%

  Chills                                         34%

  Fever                                          30%

  Nausea                                         28%
  ---------------------------------------------- ------------------------

###### Hematologic Adverse Events

For all hematologic adverse events, duration of Grade ≥ 3 toxicity is
defined as end date minus start date, where end date and start date are
defined relative to the nadir lab value. A patient's end date is defined
as the 1^st^ lab test date after the nadir visit when the patient's lab
test is above the Grade ≥ 3 toxicity limit. A patient's start date is
defined as the most recent lab test date prior to the nadir visit when
the patient's lab test is above the Grade ≥ 3 toxicity limit.

Patients not recovered from Grade ≥ 3 toxicity were censored by one of
two rules. If a patient had received next anti-cancer therapy, that
patient was censored to the date of the most recent lab test prior to
receiving next anti-cancer therapy. If the patient had not received next
anti-cancer therapy, that patient was censored to the date of the most
recent lab test.

####### ANC

23 of 50 subjects (46 %) who received any dose of Y2B8 had Grade 3 or 4
ANC within 90 days of initial therapy.

One subject never recovered to Grade ≤ 2 ANC with 64 days of laboratory
follow-up. The subject experienced progressive lymphoma on Study Day 56
and received CHOP-Bleomycin chemotherapy beginning Study Day 57. Weekly
laboratory data through Study Day 64 were included in the original
submission.

**Median duration of grade 3-4 neutropenia was 26 days** (Range 6-173
days).

![](media/image3.wmf){width="5.992361111111111in"
height="3.6368055555555556in"}

####### Platelets

27 of 50 subjects (54 %) who received any dose of Y2B8 had Grade 3 or 4
PLT within 90 days of initial therapy.

Two subjects did not resolve their thrombocytopenic episode:

-   One subject never recovered to Grade ≤ 2 PLT with 33 days of
    laboratory follow-up. The subject expired on Study Day 36 with
    progressive disease.

```{=html}
<!-- -->
```
-   One Subject never recovered to Grade ≤ 2 PLT with 37 days of
    laboratory follow-up. The patient experienced progressive lymphoma
    on Study Day 32 and received etoposide/dexamethasone chemotherapy
    beginning Study Day 32. Laboratory data through Study Day 37 were
    included in the original submission.

    **Median duration of grade 3-4 thrombocytopenia was 29 days** (Range
    1-67 days).

![](media/image4.wmf){width="5.995833333333334in" height="4.1in"}

####### Baseline Bone Marrow Involvement and Hematologic Toxicity

An exploratory analysis was conducted to determine whether a
relationship existed between degree of bone marrow involvement and
hematologic toxicity following treatment with IDEC-Y2B8.

Patients were sorted into groups based on bone marrow involvement:

1.  0% bone marrow involvement: N = 25

2.  0.1% to 5.0% bone marrow involvement: N = 4

3.  5.1% to \< 20% bone marrow involvement: N = 11

4.  ≥ 20% bone marrow involvement: N = 6

The prevalence of hematologic toxicity was then determined. The
incidence of platelet nadir of \< 25,000 cells/ µL was greater with
increasing bone marrow involvement (8%; 25%; 46%; 100%). The incidence
of Grade 4 neutropenia was greater with increasing bone marrow
involvement (4%; 25%; 46%; 100%). The incidence of Grade 4 anemia did
not appear to vary with increasing bone marrow involvement (0%; 25%; 0%;
50%).

##### Human Anti-Chimeric Antibody (HACA) Response:

46 subjects were assayed at Baseline and at follow up for HACA/HAMA
response

-   1 developed positive HAMA and HACA titers post-treatment

This subject had no detectable HACA or HAMA titer on Study Days --19 and
42, but on Study Day 64, the subject had a HACA titer of 1232 ng/mL and
a HAMA titer of 13.6 µg/mL. On Study Day 92, the subject had a HACA
titer of 1058 ng/mL and a HAMA of 13.6 µg/mL.

-   1 had a positive HACA at baseline and negative value post Zevalin
    therapy.

> This Subject was tested on Study Day --13 and had a positive HACA
> titer of 121 ng/mL. The subject was tested again on Study Days 36, 64,
> 92, 206, and 303, and no HACA titer was detected on any of those days.

##### Deaths within Study Day 100

3 subjects died before study day 100:

1.  Subject 106-03-XXX-XXX entered Study 106-03 on XXXXXXXXXX and
    received 0.2 mCi/kg dose Y2B8 on XXXXXXXXXX. On XXXXXXXXXX, Study
    Day 23, the subject was admitted to the hospital for further
    evaluation and treatment of profound weakness, abdominal pain,
    nausea, vomiting, and dehydration. Abdominal CT scan confirmed
    significant disease progression in the abdomen. The subject
    continued to deteriorate and end of life palliative care was
    instituted. The subject expired on XXXXXXXXXX (Study Day 36). The
    official cause of death was listed as a cardiopulmonary arrest
    secondary to progressive malignant lymphoma. No autopsy was
    performed.

2.  Subject 106-03-XXX-XXX entered Study 106-03 on XXXXXXXXXXX and
    received 0.4 mCi / kg dose IDEC-Y2B8 on XXXXXXXXXX. On XXXXXXXXXX
    (Study Day 36), a staging CT that revealed worsening of large right
    retroperitoneal lymphadenopathy with involvement of the right crus
    of the diaphragm and a mass involving the aorto-caval region
    displacing the right kidney laterally, surrounding and encasing the
    inferior vena cava. The mass encased the aorta and crossed the
    midline to the left. As a result of this disease progression, the
    subject discontinued the study on Study Day 36. During the
    procedure, a pulmonary embolus of the left descending pulmonary
    artery was discovered and this resulted in hospitalized and heparin
    and warfarin therapy. The subject was discharged on XXXXXXXXXX
    (Study Day 45). The subject continued to deteriorate and began
    receiving hospice care at home in early October. He expired on
    XXXXXXXXXX (Study Day 86). No autopsy was performed.

3.  Subject 106-03-XXX-XXX was enrolled in Group 1 of Study 106-03 and
    therefore did not receive Zevalin. The patient died on Study Day 17
    of progressive lymphoma. Laboratory data for Study Days 7 and 14
    were included in the original submission.

### Conclusions

1.  Based on Group 1 data, the 250 mg/m^2^ Rituximab dose was chosen to
    be given prior to IDEC-In2B8 and IDEC-Y2B8 in Groups 2 and 3 for the
    following reasons:

-   No difference in tumor or normal organ dosimetry was seen between
    the first and second images in both dosing groups;

-   There is potential for enhanced clinical response from the higher
    dose of Rituximab.

2.  The most frequently reported adverse events were hematologic and
    constitutional symptoms. Within 90 days of Zevalin™ therapy, a
    median of 26 days duration was observed for Grade ≥3 neutropenia in
    46% of subjects and a median of 29 days duration was observed for
    Grade ≥ 3 thrombocytopenia in 54% of subjects.

3.  Grade 4 hematologic toxicity was related to thrombocytopenia and
    bone marrow involvement with lymphoma at baseline and dosimetric
    parameters were not able to predict which patients were at higher
    risk for hematologic toxicity.

4.  2% (1/51) of patients developed post-treatment HACA/HAMA.

### Study 106-05

#### Protocol History

+-------------+------------------+-------------------------------------+
| **Date**    | **Milestone**    | Comments                            |
+-------------+------------------+-------------------------------------+
| 12-MAY-1998 | Protocol         |                                     |
|             | Submitted        |                                     |
+-------------+------------------+-------------------------------------+
| 20-MAY-1998 | Trial Initiated  |                                     |
+-------------+------------------+-------------------------------------+
| 06-AUG-1998 | Protocol         | 3 subjects previously enrolled      |
|             | Amendment        |                                     |
|             |                  | 1.  Revision of the study design    |
|             |                  |                                     |
|             |                  | 2.  Number of participating sites   |
|             |                  |     increased                       |
|             |                  |                                     |
|             |                  | 3.  Changes to the inclusion        |
|             |                  |     criteria,                       |
|             |                  |                                     |
|             |                  | 4.  Clarification of dosimetry      |
|             |                  |     measurements,                   |
|             |                  |                                     |
|             |                  | 5.  Administrative changes          |
+-------------+------------------+-------------------------------------+
| 26-FEB-1999 | Protocol         | 1.  Binding assay requirements      |
|             | Amendment        |     removed                         |
+-------------+------------------+-------------------------------------+

#### Study Design, Objectives, and Treatment Plan

This was an open-label, single-arm, multicenter, Phase II study of 0.3
mCi/kg of IDEC-Y2B8 in mildly thrombocytopenic patients with advanced,
relapsed or refractory, low-grade, follicular, or transformed B-cell NHL
who failed primary conventional chemotherapy. Subjects had to have
platelet levels \>100,000 and \< 150,000.

The principle objective was to determine the safety and activity of a
reduced dose (0.3 mCi/kg) of IDEC-Y2B8 therapy in the setting of mild
thrombocytopenia and to determine if baseline platelet count provides
adequate information for choosing a safe and effective dose of
IDEC-Y2B8, in this defined patient population.

Rituximab (250 mg/m^2^) was to be given prior to IDEC-In2B8 (5 mCi), and
IDEC-Y2B8.

Dosimetry studies were performed

#### Patient Populations /Study Results

30 subjects were enrolled in Study 106-05 and all received both
rituximab infusions and the IDEC-In2B8 and IDEC-Y2B8 injections.

##### Protocol Violations:

-   2 subjects had bone marrow involvement \> 25% at baseline, based on
    a review of bone marrow pathology

-   Subject 106-05-XXX-XXX received In2B8 1 day after rituximab
    infusion.

-   2 subjects received Y2B8 more than 7 days after In2B8.

-   2 subjects received doses of Y2B8 that were greater than ± 10% of
    the intended dose. The total dose administered to both was at the
    limit of the protocol defined maximum dose of 32 mCi.

-   Subject 106-05-XXX-XXX received a total Y2B8 dose of 34.2 that was
    greater than the protocol-defined maximum dose of 32 mCi.

-   Subject 106-05-XXX-XXX was underdosed with Y2B8 and received 0.26
    mCi/Kg actual dose (16.46 mCi total dose)

##### Demographics

+-------------------------------------+--------------------------------+
| **Demographics (N=30 subjects)**    |                                |
+-------------------------------------+--------------------------------+
| Median age                          | 61 years                       |
+-------------------------------------+--------------------------------+
| Range                               | 22-85 years                    |
+-------------------------------------+--------------------------------+
| Sex                                 | 60% male; 40% female           |
+-------------------------------------+--------------------------------+
| Race                                | 97% Caucasian                  |
+-------------------------------------+--------------------------------+
| Resistant to prior therapy          | 63.3%                          |
+-------------------------------------+--------------------------------+
| Extranodal sites                    | 80%                            |
|                                     |                                |
| > 0-1                               | 20%                            |
| >                                   |                                |
| > \>1                               |                                |
+-------------------------------------+--------------------------------+
| IPI Risk Group                      | 33%                            |
|                                     |                                |
| > Low                               | 33%                            |
| >                                   |                                |
| > Low-Intermediate                  | 20%                            |
| >                                   |                                |
| > High-Intermediate                 | 7%                             |
| >                                   |                                |
| > High                              | 7%                             |
| >                                   |                                |
| > Unknown                           |                                |
+-------------------------------------+--------------------------------+
| Histology                           | 7%                             |
|                                     |                                |
| > IWF A                             | 83%                            |
| >                                   |                                |
| > Follicular                        | 10%                            |
| >                                   |                                |
| > Transformed                       |                                |
+-------------------------------------+--------------------------------+
| Bone Marrow Involvement             | 33%                            |
|                                     |                                |
| > 0%                                | 40%                            |
| >                                   |                                |
| > 5-20%                             | 27%                            |
| >                                   |                                |
| > \> 20%                            |                                |
+-------------------------------------+--------------------------------+

##### Activity Results

The assessment of Zevalin therapy activity analysis includes all 30
subjects enrolled in the study. For these subjects, the overall response
rate (ORR) as assessed by the principle investigator was 67% (10 CR + 10
PR). TTP was 9.3+ months (n=30). Duration of response was 11.8+ months
(range 3.6-17.4+ months with 45% of subjects censored).

##### Safety Evaluation

The safety analysis includes all 30 subjects enrolled in the study. All
AEs regardless of the relationship to the study drug occurring during
the treatment period (first treatment of the study drug until 12 weeks
following IDEC-Y2B8 administration), were recorded on an appropriate
source document at the clinical site and on the applicable case report
form (CRF). Following this time, AEs were to be recorded on the CRF if
the investigator attributed the event to the study drug(s). AEs
occurring after the initiation of other anticancer therapy were not to
be followed, unless the therapy was initiated and the AE occured within
30 days following the last study drug infusion or the investigator felts
the event was related to the study drug.

###### Non-Hematologic Adverse Events

29 of 30 subjects (97% of study participants) experienced a total of 295
non-hematologic Grade ≥ 1 non-hematologic AEs. Sixty-six percent of
non-hematologic AEs were Grade 1, 29% Grade 3, 4% Grade 3, and 1 % Grade
4 by NCI CTC Grade criteria.

Clinically significant AEs included the following:

-   3 subjects had Grade 1 AEs associated with a sensation of swelling
    of the throat and tongue (classified as angioedema)

-   1 subject had Grade 1 edema of the face

-   4 subjects had respiratory system AEs classified as bronchospasm (3
    Grade 1 and 1 Grade 2) occurring on a treatment day

-   1 subject was diagnosed with AML on Study Day 281. The patient
    developed progressive pancytopenia and rare blasts in the peripheral
    blood approximately one month after Zevalin therapy. Bilateral bone
    marrow aspirates and biopsies were performed approximately three
    months following rituximab treatment, which showed a marrow with 70%
    cellularity, decreased megakaryocytes, and extensive infiltration by
    immature myeloblasts. There was also paratrabecular infiltration by
    lymphoma cells. The peripheral blood smear showed a normocytic,
    normochromic anemia, leukopenia with neutropenia, markedly decreased
    platelets, and rare blasts. Cytogenetic studies on the bone marrow
    revealed a t(9;11), typically associated with AML-M5. The final
    diagnosis was acute myelogenous leukemia (AML), consistent with
    therapy-related AML. It was the opinion of the investigator and the
    sponsor that the AML could be related to prior exposure to alkylator
    therapy, as evidenced by the mild thrombocytopenia prior to study
    entry. Nevertheless, a relationship to Zevalin therapy could not be
    ruled out.

####### Non-Hematologic AEs Summary Table

**Frequency of Non-Hematologic AEs**

**by Subject (n=30 subjects)**

  --------------------------------------------- -------------------------
  **AE (all grades**                            **% of subjects**

  Asthenia                                      57

  Nausea                                        40

  Chills                                        37

  Fever                                         33

  Vomiting                                      30

  Headache                                      27

  Increased Cough                               23

  Pruritus                                      23

  Abdominal Pain                                20

  Irritation Throat                             17

  Dizziness                                     17

  Dyspnea                                       17

  Myalgia                                       13

  Peripheral Edema                              10

  Angioedema                                    10

  Infection                                     7
  --------------------------------------------- -------------------------

###### Hematologic Adverse Events

For all hematologic adverse events, duration of Grade ≥ 3 toxicity is
defined as end date minus start date, where end date and start date are
defined relative to the nadir lab value. A patient's end date is defined
as the 1^st^ lab test date after the nadir visit when the patient's lab
test is above the Grade ≥ 3 toxicity limit. A patient's start date is
defined as the most recent lab test date prior to the nadir visit when
the patient's lab test is above the Grade ≥ 3 toxicity limit.

Patients not recovered from Grade ≥ 3 toxicity were censored by one of
two rules. If a patient had received next anti-cancer therapy, that
patient was censored to the date of the most recent lab test prior to
receiving next anti-cancer therapy. If the patient had not received next
anti-cancer therapy, that patient was censored to the date of the most
recent lab test.

####### Baseline Bone Marrow Involvement and Hematologic Toxicity

An exploratory analysis was conducted to determine whether a
relationship existed between degree of bone marrow involvement and
hematologic toxicity following treatment with IDEC-Y2B8.

Patients were sorted into groups based on bone marrow involvement:

5.  0% bone marrow involvement: N = 10

6.  0.1% to 5.0% bone marrow involvement: N = 0

7.  5.1% to \< 20% bone marrow involvement: N = 12

8.  20% bone marrow involvement: N = 8

The prevalence of hematologic toxicity was then determined. The
incidence of Grade 4 platelet nadir was greater with increasing bone
marrow involvement (10%; 0%; 38%). The incidence of Grade 4 neutropenia
was greater with increasing bone marrow involvement (10.%; 33%; 63%).
The incidence of Grade 4 anemia did not appear to vary with increasing
bone marrow involvement (10%; 0%; 0%).

####### ANC

26 of 30 subjects (87 %) who received any dose of Y2B8 had Grade 3 or 4
ANC within 90 days of initial therapy.

**Median duration of grade 3-4 neutropenia was 29 days** (Range 3-78
days)

####### ![](media/image5.wmf){width="5.992361111111111in" height="3.7895833333333333in"}Platelets

26 of 30 subjects (87 %) who received any dose of Y2B8 had Grade 3 or 4
thrombocytopenia within 90 days of initial therapy.

SAEs and not evidence of platelet recovery:

-   Subject 106-05-XXX-XXX never recovered to Grade ≤ 2 PLT with 139
    days of laboratory follow-up. This subject received additional
    therapy for disease progression beginning on Study Day 132.

-   Subject 106-05-XXX-XXX is a 67-year-old female with B-cell NHL
    (IWF-A) who was hospitalized with thrombocytopenia (Grade 4), on
    Study Day 37. Laboratory tests revealed the following: WBC 1000
    cells/mm3, platelets 9000 cells/mm3, and Hgb 9.5 g/dL. She received
    platelet and RBC transfusions, and was discharged on Study Day 38.
    The patient was readmitted on Study Day 54 with low laboratory
    values: platelets 3,000 cells/mm3, WBC 2100 cells/mm3, and Hgb 9.6
    g/dL, and was discharged the next day. The patient required platelet
    and RBC transfusions over a one-month period; G-CSF, and epoetin
    over a two-month period; and oprelvekin (IL-11) for two weeks due to
    prolonged myelosuppression. At baseline, bone marrow biopsy revealed
    diffuse infiltration by small monoclonal B-cells; however, the
    percent bone marrow involvement was reported to be less than 25%,
    making the patient eligible for the study. Because of the prolonged
    thrombocytopenia and the description of diffuse infiltration of
    monoclonal B-cells on the biopsy report, the original bone marrow
    biopsy was reviewed once again. On repeat microscopic differential
    count of the baseline bone marrow aspirate, 37% of the cellular
    elements were considered malignant lymphocytes. According to
    protocol the subject would have been ineligible for the study. The
    extended thrombocytopenia was classified as probably related to
    treatment by the PI and/or sponsor.

-   Patient 106-05-XXX-XXX is a 78-year-old female with follicular NHL
    who was admitted to the hospital with bruising, thrombocytopenia
    (Grade 4), leukopenia (Grade 3), and anemia (Grade 2) on Study
    Day 54. Laboratory tests revealed the following: WBC 1400 cells/mm3,
    platelets 17,000 cells/mm3, and Hgb 8.6 g/dL. The patient received
    platelet and RBC transfusions and was discharged the next day. On
    Study Day 67, the patient's laboratory tests showed improvement: WBC
    8000 cells/mm3, platelets 59,000 cells/mm3, and Hgb 14.4 g/dL. The
    events were classified as probably related to the study treatment.

-   Patient 106-05-XXX-XXX is a 45-year-old female with NHL who had a
    history of hemolytic anemia. She was admitted to the hospital with
    thrombocytopenia (Grade 3) on Study Day 46. Laboratory tests prior
    to admission on Study Day 44 revealed the following: WBC 2400
    cells/mm3, platelets 10,000 cells/mm3, and Hgb 7.0 g/dL. She
    received platelet and RBC transfusions and was discharged the next
    day. Discharge laboratory test results on Study Day 47 were the
    following: WBC 1300 cells/mm3, platelets 26,000 cells/mm3, and Hgb
    7.1 g/dL. Follow-up results on Study Day 50 were the following: WBC
    1700 cells/mm3, platelets 19,000 cells/mm3, Hgb 9.4 g/dL, and ANC
    1200 cells/mm3. The event was classified as probably related to the
    study drug. The patient was readmitted on Study Day 70 for abdominal
    pain (Grade 3) and thigh pain. Laboratory tests on admission
    revealed the following: WBC 700 cells/mm3, platelets 17,000
    cells/mm3, Hgb 7.9 g/dL. She was found to be neutropenic and to have
    hemolytic anemia (Grade 3) and was treated with IV antibiotics. The
    patient experienced a vancomycin allergic reaction (Grade 2). The
    patient began prednisone therapy, which she continued after
    discharge on Study Day 74. The neutropenia was classified as
    possibly related to the study treatment.

    **Median duration of grade 3-4 thrombocytopenia was 30 days** (Range
    14-106+ days)

![](media/image6.wmf){width="6.0in" height="4.1in"}

##### Human Anti-Chimeric Antibody (HACA) Response:

All 30 patients were tested and no patient developed a detectable
HACA/HAMA level following treatment.

##### Deaths within Study Day 100

No deaths were reported to have occurred within Study Day 100.

### Conclusions

1.  A Y2B8 dose of 0.3 mCi/kg Y2B8 administered to mildly
    thrombocytopenic low-grade, follicular, or transformed B-cell NHL
    population is feasible but resulted in prolonged or refractory Grade
    ≥ 3 neutropenia and/or thrombocytopenia in the majority of study
    participants.

2.  Most frequently reported adverse events were hematologic. A median
    of 29 and 30 days duration was observed for Grade ≥3 neutropenia and
    thrombocytopenia in 87% of subjects within 90 days of Zevalin™
    therapy.

3.  No HAMA/HACA reactions were observed.

4.  One case of MDS was observed

### Study 106-98

#### Protocol History

+----------+--------+--------------------------------------------------+
| **Date** | *      | **Comments**                                     |
|          | *Miles |                                                  |
|          | tone** |                                                  |
+==========+========+==================================================+
| S        | Pr     |                                                  |
| eptember | otocol |                                                  |
| 1, 1999  | Sub    |                                                  |
|          | mitted |                                                  |
+----------+--------+--------------------------------------------------+
| November | Ame    | 1.  To allow the treatment of mildly             |
| 10, 1999 | ndment |     thrombocytopenic patients (baseline platelet |
|          | #1     |     counts from 100,000/mm^3^ to 149,000/mm^3^)  |
|          |        |     with reduced-dose IDEC-Y2B8 (0.3 mCi/kg).    |
|          |        |                                                  |
|          |        | 2.  To add the REAL classification of NHL        |
|          |        |                                                  |
|          |        | 3.  To note that in Phase I/II trials that       |
|          |        |     maximum allowable dosimetry estimated        |
|          |        |     absorbed radiation doses to the spleen could |
|          |        |     be greater than 2000cGy for patients with    |
|          |        |     splenic involvement by NHL                   |
|          |        |                                                  |
|          |        | 4.  To amend the schedule for Evaluation of      |
|          |        |     Response and recommend that it be performed  |
|          |        |     every 3 months for the first year            |
|          |        |                                                  |
|          |        | 5.  To correct the criteria for complete         |
|          |        |     response from "no decrease in performance    |
|          |        |     status" to "no worsening in performance      |
|          |        |     status"                                      |
+----------+--------+--------------------------------------------------+
| December | Pr     |                                                  |
| 9, 1999  | otocol |                                                  |
|          | ini    |                                                  |
|          | tiated |                                                  |
+----------+--------+--------------------------------------------------+
| February | Ame    | 1.  To obtain pharmacokinetic samples from       |
| 25, 2000 | ndment |     selected patients at predetermined sites on  |
|          | #2     |     35 subjects. In mid 2000, IDEC began using   |
|          |        |     an additional supplier of ^90^Yttrium for    |
|          |        |     the preparation of the IDEC-Y2B8.            |
+----------+--------+--------------------------------------------------+
| March 6, | Ame    | 1.  Indium Imaging reinstated                    |
| 2001     | ndment |                                                  |
|          | #3     |                                                  |
+----------+--------+--------------------------------------------------+

#### Study Design, Objectives, and Treatment Plan

This study is a single arm open access trial that is currently on going.

The study is designed with the following objectives:

1.  To provide treatment to patients with relapsed or refractory
    low-grade or follicular or Transformed B-cell NHL who were
    ineligible for other IDEC-Y2B8 protocols

2.  To add to the overall efficacy and safety experience in this
    indication

3.  To compare, in a selected subset of patients, the biodistribution of
    IDEC-Y2B8 prepared with ^90^Y radionuclides from two different
    suppliers

Candidates must have histologically confirmed, relapsed or refractory
low-grade or follicular or transformed B-cell NHL requiring treatment;
subjects refractory to rituximab and those ineligible for other
IDEC-Y2B8 protocols are included. Proof of CD20+ B cells is required in
IWF A or transformed NHL patients.

The majority of subjects accrued to date have received the following
regimen:

-   An initial IV infusion of 250 mg/m Rituxan followed 1 week later by

-   An IV infusion of 250 mg/m^2^ Rituxan and an IV injection of
    IDEC-Y2B8.

A minority of subjects received:

-   An initial IV infusion of 250 mg/m Rituxan and an IV injection of
    IDEC-In2B8, followed 1 week later by

-   An IV infusion of 250 mg/m^2^ Rituxan and an IV injection of
    IDEC-Y2B8.

Subjects with baseline platelet counts 100,000 -- 149,000 cells/mm^3^
received 0.3 mCi ^90^Y/kg, and those with ≥ 150,000 cells/mm^3^ received
0.4 mCi ^90^Y/kg. The exact dose is based on body weight at baseline
(maximum dose was not to exceed 32 mCi of ^90^Y).

#### Study Results

The primary data derived from this study pertains to the safety of
Zevalin™ therapy in relapsed or refractory low-grade or follicular or
transformed B-cell NHL.

A total of 182 subjects from study 106-98 were included in the Zevalin
BLA. This figure represents the total number of subjects at all points
of follow-up, who were enrolled on study 106-98 at the time the database
snapshot was taken.

Of these 182 subjects:

-   138 subjects had passed the 13 weeks follow-up time point at which
    time, investigators were required to submit all adverse event data.
    For the purpose of the BLA, 13 weeks of follow-up was defined as
    having received the Day 1 infusion on or before September 30, 2000.

-   Additional safety information on 10 subjects who had not yet
    completed 13 weeks of clinical follow-up was provided. Information
    pertaining to these 10 subjects may be incomplete. FDA included
    these subjects in the overall safety analysis. The sponsor omitted
    these subjects from their overall safety analysis.

-   A total of 148 subjects is included in FDA'a non-hematologic adverse
    event safety analysis;

-   182 subjects were included in FDA'a hematologic adverse event safety
    analysis.

##### Safety Evaluation

AEs were recorded using the NCI Clinical Cooperative Groups toxicity
criteria and the Cancer Treatment Evaluation Program. Laboratory tests
were conducted at each clinical site at monthly intervals for 3 months.

###### Non-Hematologic Adverse Events

124 of 148 subjects (84%) experienced non-hematologic AEs. 601
non-hematologic adverse events were reported over for the entire period
of follow-up. Fifty-seven percent of AEs were Grade 1, 29% Grade 2, 11%
Grade 3 and 3% Grade 4 by NCI CTC Grade Criteria.

Subjects with clinically significant AEs.

-   2 subjects had AEs associated with a sensation of swelling of the
    throat and tongue classified as angioedema (1 Grade 1 and 1 Grade 2)

-   4 subjects had Grade 1 respiratory system AEs classified as
    bronchospasm occurring on a treatment day

-   1 subject had carcinoma of the skin

-   1 subject had Grade 3 colitis

-   6 had diarrhea (2 Grade 1; 3 Grade 2; 1 Grade 3)

-   1 had Grade 2 bloody diarrhea that was also documented pre-study

-   3 had Grade 2 herpes zoster

-   3 had myasthenia (1 Grade 1; 1 Grade 2; and 1 Grade 3)

-   2 had Grade 3 sepsis

-   Subject 106-98-XXX-XXX was hospitalized with Grade 2 axillary lymph
    node necrosis 64 days post-IDEC-Y2B8 treatment. The event was
    considered by the investigator and sponsor as unrelated to study
    treatment and secondary to disease progression.

    **Frequency of Common**

**Non-Hematologic AEs by Subject**

**(n=148 subjects)**

  -------------------------------------------- --------------------------
  **AE (all grades)**                          **% of subjects**

  Asthenia                                     32

  Nausea                                       20

  Chills                                       16

  Dyspnea                                      14

  Abdominal Pain                               9
  -------------------------------------------- --------------------------

**Frequency of Notable**

**Non-Hematologic AEs by Subjects**

(n=148 subjects)

  --------------------------------------------- -------------------------
  **AE**                                        **%**

  Rash                                          7

  Dizziness                                     6

  Fever                                         6

  Increased Cough                               5

  Irritation Throat                             5

  Abdominal Enlargement                         5

  Febrile neutropenia                           5

  Vomiting                                      4

  Allergic reaction                             4

  Myalgia                                       4

  Angioedema                                    3
  --------------------------------------------- -------------------------

###### Hematologic Adverse Events

For all hematologic adverse events, duration of Grade ≥ 3 toxicity is
defined as end date minus start date, where end date and start date are
defined relative to the nadir lab value. A patient's end date is defined
as the 1^st^ lab test date after the nadir visit when the patient's lab
test is above the Grade ≥ 3 toxicity limit. A patient's start date is
defined as the most recent lab test date prior to the nadir visit when
the patient's lab test is above the Grade ≥ 3 toxicity limit.

Patients not recovered from Grade ≥ 3 toxicity were censored by one of
two rules. If a patient had received next anti-cancer therapy, that
patient was censored to the date of the most recent lab test prior to
receiving next anti-cancer therapy. If the patient had not received next
anti-cancer therapy, that patient was censored to the date of the most
recent lab test.

####### ANC

79 of 182 subjects (43%) who received any dose of Y2B8 had Grade 3 or 4
ANC within 90 days of initial therapy.

4 Subjects failed to have documented neutropenic recovery.

-   Subject 106-98-XXX-XXX never recovered ANC with 36 days of
    follow-up. On Study Day 20, a clinical evaluation determined that
    the subject had progressive disease. Radiation therapy was
    instituted on Study Day 21. The subject died on Study Day 48.

-   Subject 106-98-XXX-XXX never recovered ANC with 175 days of
    follow-up

-   Subject 106-98-XXX-XXX never recovered ANC with 22 days of
    follow-up. The subject died of progressive disease on Study Day 37.

-   Subject 106-98-XXX-XXX never recovered ANC with 100 days of
    follow-up. The subject had progressive disease and went on hospice
    care. No additional data were provided.

    **Median duration of grade 3-4 neutropenia was 22 days** (Range
    1-176+ days)

![](media/image7.wmf){width="5.992361111111111in"
height="3.6368055555555556in"}

####### Platelets

80 of 182 subjects (44%) who received any dose of Y2B8 had Grade 3 or 4
thrombocytopenia within 90 days of initial therapy

12 subjects failed to have documented paletelet recovery.

-   Subject 106-98-XXX-XXX never recovered PLT with 41 days of
    follow-up. This subject had progressive disease on Study Day 20,
    began radiation therapy on Study Day 21 and died of NHL on Study Day
    48.

-   Subject 106-98-XXX-XXX never recovered PLT with 210 days of
    follow-up

-   Subject 106-98-XXX-XXX never recovered PLT with 33 days of
    follow-up. This subject was reported to have had disease progression
    on Study Day 26 and to have died on Study Day 35.

-   Subject 106-98-XXX-XXX never recovered PLT with 34 days of
    follow-up. Progressive disease was documented on study day 35.
    Additional chemotherapy was initiated on Study Day 48.

-   Subject 106-98-XXX-XXX never recovered PLT with 57 days of
    follow-up. This subject had documented disease progression on Study
    Day 37. Additional therapy was initiated on Day 44.

-   Subject 106-98-XXX-XXX never recovered PLT with 41 days of
    follow-up. Progressive disease was documented on Study Day 41 and
    radiation therapy begun on Study Day 44. The subject expired on
    Study Day 101.

-   Subject 106-98-XXX-XXX never recovered PLT with 234 days of
    follow-up. This subject had a baseline hypocellular bone marrow and
    history of failed prior stem cell collection.

-   Subject 106-98-XXX-XXX never recovered PLT with 37 days of follow-up
    The subject expired on Study Day 37.

-   Subject 106-98-XXX-XXX never recovered PLT with 44 days of
    follow-up. The subject expired on Study Day 74.

-   Subject 106-98-XXX-XXX never recovered PLT with 112 days of
    follow-up. The subject had progressive disease documented on Study
    Day 58 and additional chemotherapy was initiated on Study Day 66.
    The subject died of NHL on Study day 119.

-   Subject 106-98-XXX-XXX never recovered PLT with 42 days of
    follow-up. The subject had progressive disease on Study Day 32 and
    died on Study Day 44.

-   Subject 106-98-XXX-XXX never recovered PLT with 106 days of
    follow-up. The subject had progressive disease on Study Day 100 and
    subsequently received palliative care. No additional laboratory data
    was available.

Subjects with clinically significant AEs:

-   4 subjects had hematochezia (1 Grade 2 and 3 Grade 3)

-   1 subjects had intracranial bleed

-   1 subjects had Grade 1 heme per rectum

-   4 subjects had Grade 1 epitaxis

-   2 subjects had Grade 1 vaginal bleeding

-   1 subjects had Grade 3 hematemesis

-   2 subjects had hematuria (1 Grade 1 and 1 Grade 2)

-   4 subjects had melena (2 Grade 1 and 2 Grade 3)

    **Median duration of grade 3-4 thrombocytopenia was 28 days** (Range
    1-182+ days)

    ![](media/image8.wmf){width="5.992361111111111in"
    height="3.6368055555555556in"}

##### Deaths within Study Day 100

106-98- XXX-XXX (day 74)

Subject 106-98- XXX-XXX is a 62-year-old Hispanic male with a history of
idiopathic pulmonary fibrosis for which he was taking prednisone,
furosemide, zolpidem, potassium chloride, hydrocodone, lisinopril, and
escalating doses of azathioprine. The patient was diagnosed with IWF D
NHL in XXXXXXXXXX and had previously received CHOP and
etoposide/cyclophosphamide/procarbazine/prednisone. He received
IDEC-Y2B8 (0.3 mCi/kg) on XXXXXXXXXX. On Day 74 he was admitted to the
hospital with respiratory failure, placed on a respirator, and died. The
event (respiratory failure) was considered related to the patient's
underlying disease by the investigator and sponsor. There were no
comments pertaining to whether or not an autopsy was obtained.

106-98- XXX-XXX (day 84)

Subject 106-98- XXX-XXX is a 72-year-old Caucasian male with a history
of chronic obstructive pulmonary disease (COPD), congestive heart
failure, and coronary artery disease (CAD). He was diagnosed with IWF A
NHL in XXXXXXXXXX and received IDEC-Y2B8 (0.3 mCi/kg) on XXXXXXXXXX
(Study Day 8). The patient was taking metoprolol, lisinopril, prazosin,
paroxetine, aspirin, lasix, fentanyl, oxycodine, and sinvastatin for
heart condition and died in his sleep on Study Day 85. Unresolved AEs at
time of death were Grade 1 asthenia and chronic pain; the cause of death
was cardiac arrest secondary to CAD. This event was considered not
related to study treatment. There were no comments pertaining to whether
or not an autopsy was obtained.

106-98- XXX-XXX (day 13)

Subject 106-98- XXX-XXX is a 65-year-old Caucasian female with a history
of COPD, hypercalcemia, and a 50-pack year history of smoking. She was
diagnosed with IWF B in XXXXXXXXXX and previously received fludarabine,
DHAD, CNOP, solumedrol, and rituximab before being treated with
IDEC-Y2B8 (0.3 mCi/kg) in XXXXXXXXXX. She received the rituximab
infusion on XXXXXXXXXX (Study Day 1) and was admitted to the hospital
with dyspnea, and pulmonary edema, and hypercalcemia. Her condition
improved with treatment, and she received the second rituximab infusion
and IDEC-Y2B8 injection in the hospital as scheduled on Study Day 8 and
was discharged. At the time of the second infusion, patient was using
oxygen via nasal canula at 10 L. Patient was readmitted to the hospital
on Study Day 11 (XXXXXXXXXX) with gastrointestinal bleed that resolved.
She received prophylactic IV ranitidine. Chest X-ray revealed severe
lymphomatous involvement; basic panel was BUN of 51 mg/dL, creatinine of
1.6 mg/dL, calcium of 12.5 mg/dL, bicarbonate of 19 mmol/L; WBC count
was 4000 cells/mm3, platelets were 77,000 cells/mm3, and hemoglobin was
8.6 g/dL. Patient was given saline diuresis to lower calcium. Her
pulmonary status worsened, and she received oxygen, progressing from 15
L to 100% nonrebreather oxygen. Patient developed recurrent fevers and
received ceftriaxone and morphine. Patient became comatose on Study Day
12 (XXXXXXXXXX) and died of respiratory failure on Study Day 13
(XXXXXXXXXX). Cause of death was listed as respiratory failure secondary
to recurrent B-cell lymphoma. This event was considered not related to
study treatment, but related to the patient's pre-existing pulmonary
condition and underlying disease. There were no comments pertaining to
whether or not an autopsy was obtained.

### Conclusions

1.  Study continues to be open to accrual and definitive conclusions
    cannot be made at this time.

2.  Safety data extends the overall Zevalin™ experience.

3.  Most frequently reported adverse events were hematologic.

-   Grade ≥ 3 neutropenia was observed in 43% of subjects with a median
    duration of 22 days.

-   Grade ≥ 3 thrombocytopenia was observed in 44% of subjects with a
    median duration of 28 days.

    Phase III Studies

## Phase III Studies 

Studies 106-04 and 106-06

The effectiveness of Zevalin™ rests primarily on the results of two
Phase III studies: Study 106-04, a randomized, multicenter
active-control study and Study 106-06, an uncontrolled, supportive
trial.

### Study 106-04

#### Protocol History

+---------+--------+---------------------------------------------------+
| *       | *      | **Comments**                                      |
| *Date** | *Miles |                                                   |
|         | tone** |                                                   |
+=========+========+===================================================+
| D       | Pr     |                                                   |
| ecember | otocol |                                                   |
| 8, 1997 | Sub    |                                                   |
|         | mitted |                                                   |
+---------+--------+---------------------------------------------------+
| F       | Pr     |                                                   |
| ebruary | otocol |                                                   |
| 24,     | ini    |                                                   |
| 1998    | tiated |                                                   |
+---------+--------+---------------------------------------------------+
| March   | Ame    | 1.  Inclusion of an interim analysis.             |
| 13,     | ndment |                                                   |
| 1998.   | #1     | 2.  Dosimetry no longer be necessary for a        |
|         |        |     defined low-risk population.                  |
|         |        |                                                   |
|         |        | 3.  To include an analysis for bcl-2 from         |
|         |        |     peripheral blood, if positive at baseline, at |
|         |        |     Months 6, 9, and 12.                          |
|         |        |                                                   |
|         |        | 4.  To define the exclusion criteria of           |
|         |        |     concurrent systemic corticosteroid therapy.   |
|         |        |                                                   |
|         |        | 5.  To clarify that the inclusion criteria total  |
|         |        |     lymphocyte count \< 5,000/mm^3^ is applicable |
|         |        |     to only those patients with small lymphocytic |
|         |        |     lymphoma - Working Class Formulation Type A.  |
|         |        |                                                   |
|         |        | 6.  To omit the requirement for a baseline HACA   |
|         |        |     analysis.                                     |
|         |        |                                                   |
|         |        | 7.  To clarify that patient will remain on study  |
|         |        |     following disease progression for follow up   |
|         |        |     of the patient's first anti-cancer therapy    |
|         |        |     following study treatment and survival        |
|         |        |     status.                                       |
|         |        |                                                   |
|         |        | 8.  To clarify that the number of participating   |
|         |        |     clinical sites will be approximately 30.      |
+---------+--------+---------------------------------------------------+
| June 2, | Ame    | 1.  To include patients whose tumor histology has |
| 1998.   | ndment |     transformed.                                  |
|         | #2     |                                                   |
|         |        | 2.  To add a third stratification subgroup for    |
|         |        |     transformed patients.                         |
+---------+--------+---------------------------------------------------+
| October | Ame    | 1.  To revise the bidimensional lesion            |
| 9,      | ndment |     measurement requirement to allow patients     |
| 1998.   | #3     |     with measurable disease between 2 - 3 cm to   |
|         |        |     be enrolled.                                  |
|         |        |                                                   |
|         |        | 2.  To allow screening evaluations to be done     |
|         |        |     within the time specified prior to the date   |
|         |        |     of patient registration instead of prior to   |
|         |        |     the initial study treatment.                  |
|         |        |                                                   |
|         |        | 3.  To require the LEXCOR to review all patients, |
|         |        |     not just responders, enrolled in the study.   |
|         |        |                                                   |
|         |        | 4.  To include a bcl-2 analysis at two additional |
|         |        |     time points, if positive at baseline.         |
|         |        |                                                   |
|         |        | 5.  To revise Appendix K to clarify dosimetry     |
|         |        |     procedures and include a section describing   |
|         |        |     the role and the activities of the Central    |
|         |        |     Data Processing center at the Mayo Clinic.    |
+---------+--------+---------------------------------------------------+
| F       | Ame    | 1.  To remove the binding assay requirement       |
| ebruary | ndment |     (radiolabeling immunoreactivity QC) from      |
| 26,     | #4     |     ongoing IDEC-Y2B8 clinical trials.            |
| 1999.   |        |                                                   |
+---------+--------+---------------------------------------------------+

#### Study Design, Objectives, and Treatment Plan

![](media/image9.wmf){width="2.7708333333333335in"
height="1.4395833333333334in"}This Phase III, prospective, two-arm,
randomized, controlled, open-labeled, multicenter study was designed to
compare Zevalin™ therapy with rituximab in subjects with relapsed or
refractory low-grade or follicular NHL (IWF types A, follicular, or
transformed).

##### Objectives:

1.  To compare the efficacy of Zevalin™ therapy (rituximab infusion
    followed by ^121^In labeled murine antibody 2B8 and a second
    rituximab infusion followed by ^90^Y labeled murine antibody 2B8) in
    relapsed or refractory, low-grade or follicular NHL with that of
    rituximab alone.

-   The protocol defined overall response rate (ORR) as determined by an
    independent panel of radiology and oncology experts in lymphoma
    (LEXCOR) who were blinded to the treatment received and the
    Investigator's assessment of response is the primary efficacy
    variable. The sample size was chosen to yield at least 80% power
    given an 0.05 alpha level and a 25% higher overall response rate in
    the IDEC-Y2B8 group. Patients were stratified by histology and
    randomly assigned to either the IDEC-Y2B8 or rituximab group.

```{=html}
<!-- -->
```
-   Duration of response and time to progression are secondary efficacy
    variables. (NOTE: The study was not designed or powered to
    demonstrate a difference in TTP and DR for Zevalin therapy compared
    with rituximab treatment (FDA agreement, September 30, 1997).
    Instead the protocol statistical section prospectively defined the
    TTP and DR objectives stating "the target median TTP for Zevalin
    therapy group will be at least similar to that of the rituximab
    group.")

-   Additional analyses include complete, clinical complete and partial
    response rate, time to next anti-cancer treatment, and quality of
    life

> 2\. To characterize the safety of IDEC-Y2B8 and IDEC-In2B8 when
> administered in conjunction with rituximab (Zevalin™ therapy) compared
> with the safety of rituximab alone.
>
> 3\. To study dosimetry of IDEC-In2B8 preceded by rituximab as a
> predictor of IDEC-Y2B8 radiation dose delivered to the tumor and to
> normal organs.
>
> 4\. To eliminate the necessity for dosimetry by demonstrating that
> baseline platelet counts provide adequate information for predicting
> safety of IDEC-Y2B8 administration in this defined population.

##### Inclusion Criteria

1.  Histologically confirmed, relapsed or refractory low-grade or
    follicular (IWF A-D)

> **or**

2.  Transformed from low-grade to intermediate-grade histology (IWF E-G)
    B-cell NHL requiring treatment (­ tumor size, B symptoms, and/or
    symptomatic masses)

3.  Bi-dimensionally measurable disease

4.  CD20+ B-cell population in LN or BM

5.  \< 25% BM involvement

6.  No anti-cancer therapy for three weeks (six weeks if nitrosourea or
    Mitomycin C) prior to study initiation, and fully recovered from all
    toxicities associated with prior surgery, radiation treatments,
    chemotherapy, or immunotherapy.

7.  Age ≥ 18 years

8.  Expected survival ≥ 3 months

9.  Pre-study WHO performance status of 0, 1, or 2

10. Acceptable hematologic status within two weeks prior to initial
    treatment, including:

-   Absolute neutrophil count ≥ 1,500/mm^3^.

```{=html}
<!-- -->
```
-   Total lymphocyte count ≤ 5,000/mm^3^ for patients with small
    lymphocytic lymphoma (Working Class Formulation Type A)

```{=html}
<!-- -->
```
-   Platelet counts ≥ 150,000/mm^3^.

##### Exclusion Criteria

11. Histologies falling outside of the designated Working Formulation,
    e.g., mantle cell/zone and subjects with chronic lymphocytic
    leukemia (CLL)

12. Prior myeloablative therapies with autologous bone marrow
    transplantation (ABMT) or peripheral blood stem cell (PBSC) rescue

13. Prior radioimmunotherapy

14. Presence of CNS lymphoma

15. Presence of HAMA

16. Prior anti-CD20 therapy, including IDEC-Y2B8 and rituximab

17. HIV or AIDS-related lymphoma

18. Abnormal liver function: total bilirubin \> 2.0 mg/dL

```{=html}
<!-- -->
```
1.  Abnormal renal function: serum creatinine \> 2.0 mg/dL

2.  Prior external beam radiation therapy to \> 25% of active bone
    marrow (involved field or regional)

```{=html}
<!-- -->
```
19. Use of G-CSF or GM-CSF therapy within two weeks prior to treatment

20. Serious nonmalignant disease or infection

21. Major surgery, other than diagnostic surgery, within four weeks

22. Another primary malignancy (other than squamous or basal cell
    carcinoma of the skin or in situ carcinoma of the cervix) for which
    the patient has not been disease-free for at least five years

23. Concurrent systemic corticosteroid therapy: (1) ≥ 40 mg prednisone
    as a single dose (or equivalent) **or** (2) ≤ 40 mg prednisone (or
    equivalent) for more than six doses (to allow for pre-medication of
    CT allergy dye and treatment of possible first rituximab infusion
    reactions)

##### Treatment Plan

###### Zevalin™ Arm

Subjects randomized to the Zevalin™ treatment group received one
infusion of 250 mg/m^2^ rituximab prior to a fixed dose of 5.0 mCi (1.6
mg total antibody dose) of IDEC-In2B8, which was injected as a slow IV
push over 10 minutes. Dosimetry and biodistribution studies were then
performed prior to administering a second infusion of 250 mg/m^2^ of
rituximab followed by 0.4 mCi/kg (1.6 mg total antibody dose) of
IDEC-Y2B8 slow IV push over 10 minutes the following week.

For subjects whose body weight exceeded 80 kg, a maximum dose of 32 mCi
of ^90^Y was to be administered.

###### Rituximab Arm

Subjects randomized to the rituximab group received an infusion of 375
mg/m^2^ rituximab once weekly times four.

#### ![](media/image10.wmf){width="3.5208333333333335in" height="2.1875in"}Results

The ITT dataset for safety and for efficacy included all 143 patients
enrolled.

[Zevalin™ Group]{.underline}: 73 subjects who received two infusions of
250 mg/m rituximab, one injection of 5.0 mCi of IDEC-In2B8, and one
injection of 0.4 mCi/kg IDEC-Y2B8.

[Rituximab Group]{.underline}: 70 subjects who received a course of
rituximab, which consisted of four infusions of 375mg/m^2^ rituximab
(once weekly x 4).

##### Protocol Violations

###### Zevalin™ Group

1.  Subject 106-04-023-277 was permitted to continue prescribed oral
    Prednisone 10 mg daily, a stable regimen which began approximately
    two years prior to enrollment.

2.  Subject 106-04-018-312 refused follow up after Week 4 visit and the
    patient was taken off the study. Weekly laboratory data through
    Study Day 63 were included in the original submission. Additional
    laboratory data for Study Day 171, the day prior to initiation of
    subsequent anticancer therapy (chlorambucil and prednisone), were
    obtained and documented hematologic recovery.

3.  Administration of yttrium treatment was delayed beyond one week in
    11 subjects.

###### Rituximab Group

1.  ANC in Patient 106-04-XXX-XXX was below the 1500 cells/mm^3^ minimum
    (1265 cells/mm^3^).

2.  In Patient 106-04-XXX-XXX, five infusions of rituximab were
    administered because the first infusion was interrupted for
    alleviation of infusion-related events.

3.  CT scans for confirmation of response were done \< 28 days for
    Subjects 106-04- XXX-XXX (21 days) and 106-04- XXX-XXX (27 days)

4.  Subject 106-04- XXX-XXX full sets of CT scans for confirmation of
    response were not performed at Week 8, Week 12, or Month 6. A full
    set was done at Month 9.

##### Study Population & Disease Characteristics

Differences between the Zevalin™ and Rituximab group were not
significant.

+------------------------+--------------------+------------------------+
|                        | **Y2B8**           | **Rituxan**            |
|                        |                    |                        |
|                        | **(N = 73)**       | **(N = 70)**           |
|                        |                    |                        |
|                        | **%**              | **%**                  |
+========================+====================+========================+
| Stratified Histology   |                    |                        |
| Type                   |                    |                        |
+------------------------+--------------------+------------------------+
| A                      | 12                 | 11                     |
+------------------------+--------------------+------------------------+
| Follicular             | 78                 | 80                     |
+------------------------+--------------------+------------------------+
| Transformed            | 10                 | 9                      |
+------------------------+--------------------+------------------------+
| Disease Stage at Study |                    |                        |
| Entry                  |                    |                        |
+------------------------+--------------------+------------------------+
| I/II                   | 11                 | 9                      |
+------------------------+--------------------+------------------------+
| III/IV                 | 89                 | 91                     |
+------------------------+--------------------+------------------------+
| Tumor bulk             |                    |                        |
+------------------------+--------------------+------------------------+
| \< 5 cm                | 55                 | 55                     |
+------------------------+--------------------+------------------------+
| 5 - \< 7 cm            | 25                 | 19                     |
+------------------------+--------------------+------------------------+
| 7 - \< 10 cm           | 12                 | 19                     |
+------------------------+--------------------+------------------------+
| ≥ 10 cm                | 8                  | 7                      |
+------------------------+--------------------+------------------------+
| Extranodal Disease (#  |                    |                        |
| sites)                 |                    |                        |
+------------------------+--------------------+------------------------+
| 0, 1                   | 82                 | 87                     |
+------------------------+--------------------+------------------------+
| ≥ 2                    | 18                 | 13                     |
+------------------------+--------------------+------------------------+
| Bone Marrow            |                    |                        |
| Involvement            |                    |                        |
+------------------------+--------------------+------------------------+
| 0%                     | 58                 | 66                     |
+------------------------+--------------------+------------------------+
| 0.1 - 5%               | 4                  | 7                      |
+------------------------+--------------------+------------------------+
| 5 - 20%                | 27                 | 21                     |
+------------------------+--------------------+------------------------+
| ≥ 20%                  | 11                 | 6                      |
+------------------------+--------------------+------------------------+
| Splenomegaly           |                    |                        |
+------------------------+--------------------+------------------------+
| Yes                    | 10                 | 4                      |
+------------------------+--------------------+------------------------+
| No                     | 90                 | 96                     |
+------------------------+--------------------+------------------------+

##### Risk Assessment

Prognostic indicators and risk assessment were not different for the
study groups.

**IPI Risk Group**

+--------------------------------+------------------+------------------+
|                                | **Y2B8**         | **Rituxan**      |
|                                |                  |                  |
|                                | **(N = 73)**     | **(N = 70)**     |
+================================+==================+==================+
|                                | **%**            | **%**            |
+--------------------------------+------------------+------------------+
| > Low                          | > 34             | > 46             |
+--------------------------------+------------------+------------------+
| > Low/Intermediate             | > 52             | > 33             |
+--------------------------------+------------------+------------------+
| > Intermediate/High            | > 7              | > 10             |
+--------------------------------+------------------+------------------+
| > High                         | > 4              | > 3              |
+--------------------------------+------------------+------------------+
| > Unknown                      | > 3              | > 8              |
+--------------------------------+------------------+------------------+

##### Prior Therapy

No differences in the number or type of prior therapy were seen between
the two study groups.

**Number of Prior Regimens**

+------------------------+-------------------+------------------------+
|                        | **Y2B8**          | **Rituxan**            |
+========================+===================+========================+
|                        | **N**             | **N**                  |
+------------------------+-------------------+------------------------+
| > Median               | > 2               | > 2                    |
+------------------------+-------------------+------------------------+
| > Range                | > 1-6             | > 1-5                  |
+------------------------+-------------------+------------------------+

+------------------------------------+----------------+---------------+
|                                    | **Y2B8**       | **Rituxan**   |
|                                    |                |               |
|                                    | **(N = 73)**   | **(N = 70)**  |
|                                    |                |               |
|                                    | **%**          | **%**         |
+====================================+================+===============+
| Type of Prior Regimen              |                |               |
+------------------------------------+----------------+---------------+
| > Alkylator +/- Prednisone         | > 29           | > 27          |
+------------------------------------+----------------+---------------+
| > Purine Analogs                   | > 10           | > 21          |
+------------------------------------+----------------+---------------+
| > Steroids                         | > 19           | > 21          |
+------------------------------------+----------------+---------------+
| > CVP or COP                       | > 37           | > 27          |
+------------------------------------+----------------+---------------+
| > CHOP                             | > 41           | > 49          |
+------------------------------------+----------------+---------------+
| > Other Aggressive                 | > 25           | > 43          |
+------------------------------------+----------------+---------------+
| Prior Radiotherapy                 |                |               |
+------------------------------------+----------------+---------------+
| > Yes                              | > 29           | > 21          |
+------------------------------------+----------------+---------------+
| > No                               | > 71           | > 79          |
+------------------------------------+----------------+---------------+

##### Subject Disposition

+---------------------------------+--------+--------+--------+---+--------+
|                                 | **     |        | **Rit  |   |        |
|                                 | Y2B8** |        | uxan** |   |        |
|                                 |        |        |        |   |        |
|                                 | **N =  |        | **N =  |   |        |
|                                 | 73**   |        | 70**   |   |        |
+---------------------------------+--------+--------+--------+---+--------+
| > **Disposition**               | **N**  | *      | **N**  | * |        |
|                                 |        | *(%)** |        | * |        |
|                                 |        |        |        | ( |        |
|                                 |        |        |        | % |        |
|                                 |        |        |        | ) |        |
|                                 |        |        |        | * |        |
|                                 |        |        |        | * |        |
+---------------------------------+--------+--------+--------+---+--------+
| > On-Going Patient              | 27     | \(37\) | 23     |   | \(33\) |
+---------------------------------+--------+--------+--------+---+--------+
| > Off Study Patient             | 46     | \(63\) | 47     |   | \(67\) |
+---------------------------------+--------+--------+--------+---+--------+
| > Complete Treatment Period     | 38     | \(83\) | 34     |   | \(72\) |
+---------------------------------+--------+--------+--------+---+--------+
| > Not Complete Treatment Period | 8      | \(17\) | 13     |   | \(28\) |
+---------------------------------+--------+--------+--------+---+--------+
| > **Reason For Off Study**      |        |        |        |   |        |
+---------------------------------+--------+--------+--------+---+--------+
| > Progressed                    | 45     | \(98\) | 42     |   | \(89\) |
+---------------------------------+--------+--------+--------+---+--------+
| > Death                         | 0      | \(0\)  | 1      |   | \(2\)  |
+---------------------------------+--------+--------+--------+---+--------+
| > Other Therapy                 | 1      | \(2\)  | 4      |   | \(9\)  |
+---------------------------------+--------+--------+--------+---+--------+

##### Primary Efficacy Analysis

The primary efficacy variable for study 106-04 is the protocol defined
overall response rate as determined by an independent review panel
(LEXCOR). Subjects were stratified by histology at registration. Per
agreement with FDA, the Cochran-Mantel-Haenszel test by pathology report
histology type would be used to assess ORR. In addition, Zevalin therapy
needed to show superior ORR with similar or longer DR to the rituximab
control group to be considered successful.

An interim analysis was to be performed when efficacy data for the first
90 patients became available. The purpose of the interim analysis was to
confirm that the primary analysis had a minimum of 80% power given an
alpha level of 0.05. Power calculations were based on baseline
assumptions of a 50% ORR for the rituximab treatment arm and 75% to 80%
ORR for the Zevalin treatment arm. If, based on interim results, the
study was declared underpowered, the sample size could be adjusted.
Otherwise, a minimum of 140 patients was to be enrolled in the study to
provide enough patients for safety assessment. The two-stage group
sequential stopping rules based on the O'Brien-Flemming method was to be
used. The levels of significance for the interim and final analysis were
to be 0.005 and 0.048, respectively.

###### Overall Response (ITT -- All Subjects) 

(CR+CCR+PR) Rate and Complete Response (CR)

+------------------+------------+-----------+-------------+---------+
|                  | **I        | **Ri      | **U         | **Adj   |
|                  | DEC-Y2B8** | tuximab** | nadjusted** | usted** |
|                  |            |           |             |         |
|                  | **(N=73)** | *         | **exact     | *       |
|                  |            | *(N=70)** | p-value**   | *p-valu |
|                  | **%**      |           |             | e^\*^** |
|                  |            | **%**     |             |         |
+------------------+------------+-----------+-------------+---------+
| ORR              |            |           |             |         |
+------------------+------------+-----------+-------------+---------+
| LEXCOR           | 73         | 47        | 0.002       | 0.002   |
| (PDRC)^\#^       |            |           |             |         |
|                  | (62, 82)   | (35, 60)  |             |         |
| 95% CI           |            |           |             |         |
+------------------+------------+-----------+-------------+---------+
| LEXCOR           | 80         | 56        | 0.004       | 0.002   |
| (IWRC)^\$^       |            |           |             |         |
|                  | (68, 88)   | (43, 68)  |             |         |
| 95% CI           |            |           |             |         |
+------------------+------------+-----------+-------------+---------+
| Investigator     | 82         | 54        | \<0.001     | \<0.001 |
|                  |            |           |             |         |
| 95% CI           | (72, 90)   | (42, 66)  |             |         |
+------------------+------------+-----------+-------------+---------+
| **CR rate**      |            |           |             |         |
+------------------+------------+-----------+-------------+---------+
| LEXCOR           | 18         | 11        | 0.348       | 0.326   |
| (PDRC)^\#^       |            |           |             |         |
|                  | (10, 29)   | (5, 21)   |             |         |
| 95% CI           |            |           |             |         |
+------------------+------------+-----------+-------------+---------+
| LEXCOR           | 30         | 16        | 0.048       | 0.040   |
| (IWRC)^\$^       |            |           |             |         |
|                  | (20, 42)   | (8, 26)   |             |         |
| 95% CI           |            |           |             |         |
+------------------+------------+-----------+-------------+---------+
| Investigator     | 36         | 20        | 0.042       | 0.033   |
|                  |            |           |             |         |
| 95% CI           | (25, 48)   | (11, 33)  |             |         |
+------------------+------------+-----------+-------------+---------+

^\*^ Adjusted p-values generated by Cochran-Mantel-Haenszel test by
pathology report histology type

^\#^ PDRC: Protocol Defined Response Criteria

^\$^ IWRC: International Workshop Response Criteria

##### Exploratory Analyses of the Primary Endpoint.

###### LEXCOR Response Assessment by Histology

+------------+----------------+---------------------+-----------------+
| > **       | **Histology    | **Zevalin™          | **Rituximab**   |
| Response** | Type**         | Therapy**           |                 |
|            |                |                     | **(n=70)**      |
|            |                | **(N=73)**          |                 |
|            |                |                     | **Resp/Total    |
|            |                | **Resp/Total (%)**  | (%)**           |
+------------+----------------+---------------------+-----------------+
| > ORR      | A              | 6/9 (67)            | 3/8 (38)        |
+------------+----------------+---------------------+-----------------+
|            | Follicular     | 42/55 (76)          | 27/58 (47)      |
+------------+----------------+---------------------+-----------------+
|            | Transformed    | 5/9 (56)            | 3/4 (75)        |
+------------+----------------+---------------------+-----------------+
| > CR       | A              | 1/9 (11)            | 1/8 (13)        |
+------------+----------------+---------------------+-----------------+
|            | Follicular     | 11/55 (20)          | 5/58 (9)        |
+------------+----------------+---------------------+-----------------+
|            | Transformed    | 1/9 (11)            | 2/4 (50)        |
+------------+----------------+---------------------+-----------------+

###### Overall Response (Follicular Patients)

Overall Response Rate and Complete Response (CR)

+----------------+-----------------+---------------+------------------+
|                | **IDEC-Y2B8**   | **Rituximab** | **Unadjusted**   |
|                |                 |               |                  |
|                | **(N=55)**      | **(N=58)**    | **exact          |
|                |                 |               | p-value**        |
|                | **%**           | **%**         |                  |
+----------------+-----------------+---------------+------------------+
| ORR            |                 |               |                  |
+----------------+-----------------+---------------+------------------+
| LEXCOR         | 76              | 47            | 0.002            |
|                |                 |               |                  |
| 95% CI         | (63, 87)        | (33, 60)      |                  |
+----------------+-----------------+---------------+------------------+
| Investigator   | 87              | 57            | \<0.001          |
|                |                 |               |                  |
| 95% CI         | (76, 95)        | (43, 70)      |                  |
+----------------+-----------------+---------------+------------------+
| **CR rate**    |                 |               |                  |
+----------------+-----------------+---------------+------------------+
| LEXCOR         | 20              | 9             | 0.107            |
|                |                 |               |                  |
| 95% CI         | (10, 33)        | (3, 19)       |                  |
+----------------+-----------------+---------------+------------------+
| Investigator   | 40              | 19            | 0.022            |
|                |                 |               |                  |
| 95% CI         | (27, 54)        | (10, 31)      |                  |
+----------------+-----------------+---------------+------------------+

###### Agreement Rate Between LEXCOR and Investigators 

There is no significant disconcordance between the two groups in the
determination of overall response rates. However, there is a significant
disconcordance in determination of CR rate to Zevalin by investigators
as compared to LEXCOR. This was not observed for CR rate to Rituxan.

Overall Response (CR + CCR + PR)

+---------+---------------------------+-------+------+-------+------+
| ###     | ######### LEXCOR          |       |      |       |      |
| ######  |                           |       |      |       |      |
+---------+---------------------------+-------+------+-------+------+
| > **    |                           | Y2B8  |      | Ri    |      |
| INVESTI |                           |       |      | tuxan |      |
| GATOR** |                           |       |      |       |      |
+---------+---------------------------+-------+------+-------+------+
|         |                           | Yes   | No   | Yes   | No   |
+---------+---------------------------+-------+------+-------+------+
|         | Yes                       | 50    | 10   | 31    | 7    |
+---------+---------------------------+-------+------+-------+------+
|         | No                        | 3     | 10   | 2     | 30   |
+---------+---------------------------+-------+------+-------+------+
|         | Concordance Rate          | 82%   |      | 87%   |      |
+---------+---------------------------+-------+------+-------+------+

**Complete Response**

+--------+---------------------------+-------+------+--------+-------+
| ####   | ######### LEXCOR          |       |      |        |       |
| #####  |                           |       |      |        |       |
+--------+---------------------------+-------+------+--------+-------+
| > **IN |                           | Y2B8  |      | R      |       |
| VESTIG |                           |       |      | ituxan |       |
| ATOR** |                           |       |      |        |       |
+--------+---------------------------+-------+------+--------+-------+
|        |                           | Yes   | No   | Yes    | No    |
+--------+---------------------------+-------+------+--------+-------+
|        | Yes                       | 12    | 14   | 7      | 7     |
+--------+---------------------------+-------+------+--------+-------+
|        | No                        | 1     | 46   | 1      | 55    |
+--------+---------------------------+-------+------+--------+-------+
|        | Concordance Rate          | 80%   |      | 89%    |       |
+--------+---------------------------+-------+------+--------+-------+

##### Secondary Endpoints

Secondary efficacy variables supporting the primary analysis were
prospectively defined and included duration of response and time to
progression.

However, the study was not designed or powered to demonstrate a
difference in TTP for Zevalin therapy compared with rituximab. Instead
the protocol statistical section prospectively defined a TTP and DR
objective using a Logrank test, stating that "The target median TTP and
response duration time for IDEC-Y2B8 group will be either equivalent or
better than that of the Rituxan group. Based on the current clinical
experience, a median TTP of 7.5 months was expected for all patients in
the rituximab group.

###### Duration of Response and Time to Progression

+----------------------------+--------------+------------+-----------+
| **Treatment**              | **Variable** | **I        | **Ri      |
|                            |              | DEC-Y2B8** | tuximab** |
|                            |              |            |           |
|                            |              | **(n =     | **(n =    |
|                            |              | 73)**      | 70)**     |
+============================+==============+============+===========+
| Time to Progression        | N            | 73         | 70        |
| (months)                   |              |            |           |
|                            | Median (K-M) | 11.2       | 10.1      |
| All Patients (n=143)       |              |            |           |
|                            | 95% CI       | (7.8 --    | (6.8 --   |
|                            |              | 15.4)      | 12.9)     |
|                            | Range        |            |           |
|                            |              | (0.8 --    | (0.7 --   |
|                            | Total        | 31.5+)     | 26.1)     |
|                            | Censored     |            |           |
|                            |              | 27 (37%)   | 20 (29%)  |
|                            | Total Failed |            |           |
|                            |              | 46         | 50        |
|                            | Total        |            |           |
|                            | Missing      | 0          | 0         |
+----------------------------+--------------+------------+-----------+
| Duration of Response       | N            | 53         | 33        |
| (months)                   |              |            |           |
|                            | Median (K-M) | 14.2       | 12.1      |
| (n=86)                     |              |            |           |
|                            | 95% CI       | (9.4, ..)  | (8.0,     |
|                            |              |            | 24.5)     |
|                            | Range        | (0.9 --    |           |
|                            |              | 28.9+)     | (2.1 --   |
|                            | Total        |            | 24.5)     |
|                            | Censored     | 25 (47%)   |           |
|                            |              |            | 14 (42%)  |
|                            | Total Failed | 28         |           |
|                            |              |            | 19        |
|                            | Total        | 20         |           |
|                            | Missing      |            | 37        |
+----------------------------+--------------+------------+-----------+

Time to Progression from the first infusion (treatment) to disease
progression in months

For patients whose disease did not progress, the interval from the first
infusion to the last contact with no evidence of disease progression is
computed (censored at this point).

Duration of Response from onset of response to disease progression in
months

TTP Kaplan-Meier Analysis

![](media/image1.wmf)

##### Exploratory Analysis

###### Duration of Response by Histology

+-------------------+-----------------+---------------+---------------+
| > **Histology     |                 | > **Zevalin** | >             |
| > Type**          |                 | >             | **Rituximab** |
|                   |                 | > **(N =      | >             |
|                   |                 | > 53)**       | > **(N =      |
|                   |                 |               | > 33)**       |
+-------------------+-----------------+---------------+---------------+
| > A               | > N             | > 6           | > 3           |
|                   | >               | >             | >             |
|                   | > Median (mos)  | > 9.8         | > NA          |
|                   | >               | >             | >             |
|                   | > Range         | > (5.0, 20.5) | > (8.0,       |
|                   | >               | >             | > 14.5+)      |
|                   | > 95% CI        | > (7.1, 20.5) | >             |
|                   | >               | >             | > (8.0, NA)   |
|                   | > \% Censored   | > 17%         | >             |
|                   |                 |               | > 67%         |
+-------------------+-----------------+---------------+---------------+
| > Follicular      | > N             | > 42          | > 27          |
|                   | >               | >             | >             |
|                   | > Median (mos)  | > 18.5+       | > 12.1+       |
|                   | >               | >             | >             |
|                   | > Range         | > (1.7,       | > (2.7, 24.5) |
|                   | >               | > 28.9+)      | >             |
|                   | > 95% CI        | >             | > (7.9, 24.5) |
|                   | >               | > (10.0, NA)  | >             |
|                   | > \% Censored   | >             | > 41%         |
|                   |                 | > 52%         |               |
+-------------------+-----------------+---------------+---------------+
| > Transformed     | > N             | > 5           | > 3           |
|                   | >               | >             | >             |
|                   | > Median(mos)   | > 6.8         | > 11.7        |
|                   | >               | >             | >             |
|                   | > Range         | > (0.9,       | > (2.1,       |
|                   | >               | > 20.3+)      | > 17.0+)      |
|                   | > 95% CI        | >             | >             |
|                   | >               | > (0.9, NA)   | > (2.1, NA)   |
|                   | > \% Censored   | >             | >             |
|                   |                 | > 40%         | > 33%         |
+-------------------+-----------------+---------------+---------------+

###### Overall Response Rates in Subjects with Bulky Disease

+-------------------------------+------------------+-------------------+
| > **Bulky Disease Category**  | > **Zevalin**    | > **Rituximab**   |
|                               | >                | >                 |
|                               | > **N/Total      | > **N/Total (%)** |
|                               | > (%)**          |                   |
+-------------------------------+------------------+-------------------+
| > \< 5 cm                     | > 31/40 (78)     | > 19/39 (49)      |
+-------------------------------+------------------+-------------------+
| > ≥ 5 cm                      | > 22/33 (67)     | > 14/31 (45)      |
+-------------------------------+------------------+-------------------+

###### Quality of Life: FACT-G Analysis

Functional Assessment of Cancer Therapy-General (FACT-G) scores for two
separate patient populations (all patients and patients classified as
responders) were performed. The paired t-test was performed for within
treatment comparisons in each patient population (the total score at
baseline and total score at 12-weeks post-treatment). The general linear
model, with the total scores at 12-weeks post-treatment as the dependent
variable, evaluated treatment differences, where total score at baseline
and prognostic factors were included as covariates.

The FACT-G survey is validated instrument that captures the major areas
of a patient's evaluation of cancer's impact on his or her life. Domains
included in the self-administered questionnaire were: physical,
social/family, relationship with doctor, emotional, and functional
well-being. Scores indicate the level of impact that cancer has on a
patient's quality of life; an increase in score equates an increase in
QOL.

FACT-G overall score was available at baseline and 12 weeks
post-treatment for 45 Zevalin therapy subjects (62%) and 36 rituximab
subjects(51%). The baseline mean overall FACT-G score was 87 in Zevalin
therapy group and 91 in rituximab group. The mean overall FACT-G score
at 12 weeks post-treatment was improved: 93.3 in Zevalin therapy group
and 93 in rituximab group. The change in score from baseline to 12 weeks
post-treatment was statistically significant in the IDEC-Y2B8 treatment
group (p = 0.001), but not in the rituximab treatment group (p = 0.185).

Below is a summary of the FACT-G scores for paired t-test:

  --------------------------------------------------- ---------- -------------
                                                      **IDEC     **Rituxan**
                                                      Y2B8**     

  Enrolled                                            73         70

  Completed the FACT-G Survey at Baseline & 12 weeks  45 (62%)   36 (51%)
  post-treatment                                                 

  Mean FACT-G Score at the Baseline for completed     86.9       90.7
  surveys (n=45, 36)                                             

  Post treatment (Week 12) Mean Score                 93.9       93.4

  Change from baseline                                6.4        2.7

  95% Confidence interval on difference               (3.0, 9.8) (-1.2, 6.6)
  --------------------------------------------------- ---------- -------------

####### Quality of Life Conclusions: 

This was a tertiary endpoint in the protocol. The protocol stated that
QOL would be assessed at baseline, week 4, week 8 and week 12. The week
8 assessment in the Rituxan arm was missing by design. There was no
hypothesis pre-specified in the protocol regarding analyses of QOL.
There were significant limitations in interpretation of the QOL data,
e.g., modest sample size, lack of pre-specified analytic plan, missing
information, informative dropouts, biased baseline values (they were
obtained after treatment was administered), no adjustment for endpoint
multiplicity adjustments.

##### Safety---Adverse Events

###### Non Hematologic Adverse Events 

####### Safety Evaluation \-- Y2B8 DATA

73 of 73 subjects (100%) experienced a total of 663 non-hematologic AEs
for the entire period of follow-up.

+--------------------+--------------------+---------------------------+
| **Frequency of     |                    |                           |
| Non-Hematologic    |                    |                           |
| AEs by**           |                    |                           |
|                    |                    |                           |
| **NCI CTC Grades** |                    |                           |
+--------------------+--------------------+---------------------------+
| **Grade**          | **Zevalin**        | **Rituximab**             |
|                    |                    |                           |
|                    | **N= 663**         | **N=449**                 |
|                    |                    |                           |
|                    | **%**              | **%**                     |
+--------------------+--------------------+---------------------------+
| 1                  | 61                 | 71                        |
+--------------------+--------------------+---------------------------+
| 2                  | 32                 | 22                        |
+--------------------+--------------------+---------------------------+
| 3                  | 6                  | 5                         |
+--------------------+--------------------+---------------------------+
| 4                  | 1                  | 2                         |
+--------------------+--------------------+---------------------------+

Clinically significant AE:

-   1 had allergic Grade 3 reaction

-   6 subjects had AEs associated with a sensation of swelling of the
    throat and tongue classified as angioedema (3 Grade 1 and 3 Grade 2)

-   4 subjects had respiratory system AEs classified as bronchospasm
    occurring on a treatment day (1 Grade 1 and 3 Grade 2)

-   1 subject had Grade 2 colitis

-   7 had diarrhea (5 Grade 1 and 1 each for Grade 2 and 3)

-   1 had Grade 2 gastroenteritis

-   3 had GI disease (2 Grade 1 irritable bowel and gastroesophageal
    reflux, and 1 Grade 2 gastroesophageal reflux)

-   1 had Grade 4 intestinal obstruction

-   1 had Grade 2 herpes zoster

-   2 had myasthenia (1 Grade 1 and 1 Grade 2)

-   3 had Grade 2 urticaria

-   8 had Grade 1 pruritis

####### Safety Evaluation \-- Rituxan™ DATA

68 of 70 subjects (97%) experienced a total of 449 non-hematologic AEs
for the entire period of follow-up.

Clinically significant AEs:

-   2 had allergic reaction (1 Grade 1 and 1 Grade 2)

-   11 subjects (8 Grade 1 and 4 Grade 2; one subject had 2 events) had
    AEs associated with a sensation of swelling of the throat and tongue
    (classified as angioedema)

-   3 subjects (1 Grade 1 and 2 Grade 2) had respiratory system AEs
    occurring on a treatment day (classified as bronchospasm)

-   6 had Grade 1 diarrhea

-   1 had Grade 1 gastroenteritis

-   1 had Grade 1 gastritis

-   1 had Grade 3 GI disease

-   2 had herpes zoster (1 Grade 1 and 1 Grade 2)

-   1 had Grade 1 myasthenia

-   0 had sepsis

-   3 had urticaria

-   13 had pruritus (11 Grade 1, 3 Grade 2; 1 Grade 3; 2 subjects had 2
    events each).

-   1 had a gastrointestinal carcinoma

-   1 had a carcinoma of the skin

-   1 had 2 events associated with edema of the face (1 Grade 1 and 1
    Grade 2)

+------------------------------+-------------------+-------------------+
| Frequency of Common and      |                   |                   |
| Notable Non-Hematologic AEs  |                   |                   |
| by Subject                   |                   |                   |
+------------------------------+-------------------+-------------------+
| **AE (all grades)**          | **Zevlin**        | **Rituximab**     |
|                              |                   |                   |
|                              | **N=73 subjects** | **N=70 subjects** |
|                              |                   |                   |
|                              | **%**             | **%**             |
+------------------------------+-------------------+-------------------+
| Asthenia                     | 51                | 44                |
+------------------------------+-------------------+-------------------+
| **Nausea**                   | **44**            | **21**            |
+------------------------------+-------------------+-------------------+
| Chills                       | 26                | 29                |
+------------------------------+-------------------+-------------------+
| **Infection**                | **25**            | **10**            |
+------------------------------+-------------------+-------------------+
| Pain                         | 22                | 17                |
+------------------------------+-------------------+-------------------+
| **Abdominal Pain**           | **21**            | **13**            |
+------------------------------+-------------------+-------------------+
| Fever                        | 21                | 19                |
+------------------------------+-------------------+-------------------+
| **Vomiting**                 | **19**            | **7**             |
+------------------------------+-------------------+-------------------+
| Headache                     | 18                | 24                |
+------------------------------+-------------------+-------------------+
| Irritation Throat            | 18                | 16                |
+------------------------------+-------------------+-------------------+
| **Increased Cough**          | **16**            | **9**             |
+------------------------------+-------------------+-------------------+
| **Dizziness**                | **15**            | **7**             |
+------------------------------+-------------------+-------------------+
| **Dyspnea**                  | **15**            | **9**             |
+------------------------------+-------------------+-------------------+
| **Peripheral edema**         | **15**            | **3**             |
+------------------------------+-------------------+-------------------+
| Rash                         | 15                | 14                |
+------------------------------+-------------------+-------------------+
| **Arthralgia**               | **14**            | **7**             |
+------------------------------+-------------------+-------------------+
| **Anorexia**                 | **11**            | **3**             |
+------------------------------+-------------------+-------------------+
| **Anxiety**                  | **11**            | **4**             |
+------------------------------+-------------------+-------------------+
| Hypotension                  | 11                | 10                |
+------------------------------+-------------------+-------------------+
| Myalgia                      | 11                | 14                |
+------------------------------+-------------------+-------------------+
| **Pruritus**                 | **11**            | **19**            |
+------------------------------+-------------------+-------------------+
| Diarrhea                     | 10                | 9                 |
+------------------------------+-------------------+-------------------+
| **Ecchymosis**               | **10**            | **1**             |
+------------------------------+-------------------+-------------------+
| **Angioedema**               | **8**             | **16**            |
+------------------------------+-------------------+-------------------+
| Flushing                     | 8                 | 6                 |
+------------------------------+-------------------+-------------------+
| Abdominal Enlargement        | 5                 | 3                 |
+------------------------------+-------------------+-------------------+
| Allergic reaction            | 1                 | 3                 |
+------------------------------+-------------------+-------------------+

####### Comparative Analysis of Non-Hematologic AEs: 

######## Gastrointestinal AE

-   A two fold increase in adverse events related to the bowel (grades
    1-2 nausea, vomiting, and abdominal pain) was noted in the Zevalin™
    arm as compared to the control arm (58% versus 34%)

+--------------+----------------------------+--------------------------+
| GI           |                            |                          |
| toxicity^1^  |                            |                          |
+--------------+----------------------------+--------------------------+
|              | **Zevalin**                | **Rituxan**              |
|              |                            |                          |
|              | **AEs = 131 events**       | **AEs = 63 events**      |
|              |                            |                          |
|              | **(73 Subjects)**          | **(70 Subjects)**        |
|              |                            |                          |
|              | **%**                      | **%**                    |
+--------------+----------------------------+--------------------------+
| Grade 1      | 63                         | 73                       |
+--------------+----------------------------+--------------------------+
| Grade 2      | 32                         | 19                       |
+--------------+----------------------------+--------------------------+
| Grade 3      | 3                          | 5                        |
+--------------+----------------------------+--------------------------+
| Grade 4      | 2                          | 3                        |
+--------------+----------------------------+--------------------------+

^1^ Includes all IDECBODY "DIG" and COSTAR "PAIN ABDO"

######## Human Anti-Murine Antibody (HAMA) Response:

> 2 subjects had a detectable HAMA prior to Zevalin™ therapy

-   Subject 106-04- XXX-XXX had a HAMA value of 12.6 μg/mL on Study Day
    --14. This subject was admitted to the hospital on Study Day 9 with
    a fever of 104^o^F (Grade 2), nausea (Grade 2), diarrhea (Grade 2),
    weakness (Grade 2), myalgia (Grade 2), dehydration (Grade 3),
    hypotension (Grade 2), and tachycardia (Grade 2). Laboratory tests
    on admission revealed the following: total bilirubin level of 4.9
    mg/dL, alkaline phosphatase level of 952 U/mL, and lipase level of
    1096 U/mL. All events were related to an obstructed biliary stent.
    The subject had a Grade 4 cholangitis and Grade 3 sepsis which were
    reported as a serious adverse events and not related to Zevalin™
    therapy.

-   Sbject 106-04- XXX-XXX had a HAMA value of 14.7 μg/mL on Study Day
    -13 and experienced no Grade 3 or 4 AEs.

> 1 subject had a detectable HAMA following Zevalin™ therapy:

-   Subject 106-04- XXX-XXX had a HAMA assay of 13.2 μg/mL on Study Day
    39; this patient had no Grade 3 or 4 AEs.

######## Human Anti-Chimeric Antibody (HACA) Response:

> 1 subject developed a detectable HACA following rituximab therapy.

-   Patient 106-04- XXX-XXX had a HACA assay value of 169 mg/mL on Study
    Day 102 and did not experience any Grade 3 or 4 AEs.

###### Hematologic Adverse Events

For all hematologic adverse events, duration of Grade ≥ 3 toxicity is
defined as end date minus start date, where end date and start date are
defined relative to the nadir lab value. A patient's end date is defined
as the 1^st^ lab test date after the nadir visit when the patient's lab
test is above the Grade ≥ 3 toxicity limit. A patient's start date is
defined as the most recent lab test date prior to the nadir visit when
the patient's lab test is above the Grade ≥ 3 toxicity limit.

Patients not recovered from Grade ≥ 3 toxicity were censored by one of
two rules. If a patient had received next anti-cancer therapy, that
patient was censored to the date of the most recent lab test prior to
receiving next anti-cancer therapy. If the patient had not received next
anti-cancer therapy, that patient was censored to the date of the most
recent lab test.

####### ANC -- Y2B8 Group

41 of 73 subjects (56%) in the Y2B8 arm had Grade 3 or 4 ANC within 90
days of initial therapy

![](media/image2.wmf){width="5.992361111111111in"
height="3.6368055555555556in"}**Median duration of grade 3-4 neutropenia
was 27 days** (Range 5-65 days)

####### ANC -- Rituximab Group

0 of 70 subjects (0%) randomized to receive Rituxan™ had Grade 3 or 4
ANC within 90 days of initial therapy

####### Platelets -- Y2B8 Group

44 of 73 subjects (60%) randomized to receive Y2B8 had Grade 3 or 4
thrombocytopenia within 90 days of initial therapy

**Median duration of grade 3-thrombocytopenia was 23 days** (Range 1-43
days)

2 subjects failed to have documented platelet recovery:

-   106-04- XXX-XXX never recovered PLT with a 36 day follow-up period.
    Progressive disease was documented on Study Day 25 and additional
    therapy instituted on Study 37. The subject expired on Study Day 60.

-   106-04- XXX-XXX never recovered PLT with a 39 day follow-up period.
    Progressive disease was documented on Study Day 36 and additional
    anti-lymphoma therapy initiated on that day. Additional laboratory
    data was not available. The subject expired on Study Day 94.

Subjects with clinically significant AEs:

-   2 subjects had Grade 1 heme per rectum

-   1 subject had Grade 1 retinal hemorrhage

-   3 subjects had epitaxis

-   3 (2 Grade 1 and 1 Grade 2) had petechia

![](media/image3.wmf){width="6.0in" height="4.1in"}

####### Platelets -- Rituximab Group

0 of 70 subjects (0 %) randomized to receive Rituxan™ had Grade 3 or 4
thrombocytopenia within 90 days of initial therapy

Subjects with clinically significant AEs.

-   1 had Grade 3 GI heme

-   1 had Grade 2 vaginal heme

-   1 had Grade 1 hematuria

-   1 had Grade 1epitaxis

##### Immunologic Reconstitution

###### Quantitative B-cells 

The median absolute B-cell count declined in both treatment groups after
treatment onset.

####### Zevalin™ Therapy group

Baseline data were available for 70 subjects (96%).

-   Baseline median cell count was 83.5 cells/µL for CD19+.(normal
    range: 32 - 341 cells/µL)

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```
-   Four weeks post-therapy the median value decreased to zero and began
    to recover by post-treatment Month 6 (median count 17.5 cells/µL).

-   By Study Month 12, the median cell count was 170 cells/µL (range 62
    to 1273 cells/µL).

####### Rituximab group

Baseline Data were available at for 69 patients (99%).

-   Baseline median cell count at was 73.0 cells/µL for CD19+.

-   Four weeks post-therapy, the median value decreased to zero and
    began to recover by post-treatment Month 9 (median count 25.0
    cells/µL).

###### Quantitative Serum Immunoglobulins

In the Zevalin™ and rituximab treatment groups, median IgG, IgM, and IgA
levels remained within normal limits during treatment and follow up.

Within the Zevalin™ treatment group:

-   No subjects experienced Grade 3 IgG serum levels

-   8 subjects experienced Grade 3 IgM serum levels

-   2 subjects experienced Grade 3 IgA serum levels

Within the rituximab treatment group:

-   2 subjects experienced Grade 3 IgG serum levels

-   4 subjects experienced Grade 3 IgM serum levels

-   1 subject experienced Grade 3 IgA serum levels

##### Deaths within Study Day 100

Patient 106-04- XXX-XXX is a 40-year-old male with transformed
non-Hodgkins lymphoma, XXXXXXXXXX. The subject was randomized to the
Zevalin™ treatment arm and received 31.5 mCi of Y2B8 (0.4 mCi / kg) on
XXXXXXXXXX. Chest and Abominal/Pelvic CT scans done on Study Day 26
(XXXXXXXXXX) revealed progression of disease. On Study Day 37
(XXXXXXXXXX) dexamethasone/methotrexate was started. He died of
progressive lymphoma on Study Day 60 (XXXXXXXXXX). No autopsy was
performed.

Patient 106-04- XXX-XXX is a 70-year-old female with transformed
non-Hodgkins lymphoma, XXXXXXXXXX. The subject was randomized to the
rituximab arm and received 4 weekly rituximab administrations beginning
on XXXXXXXXXX. On Study Day 22 (02-Jul-199), the day of the fourth
rituximab infusion, the subject was admitted with complaints of
anorexia, abdominal pain, and increasing bilateral leg edema. She also
had elevated liver function tests and jaundice. Chest and
Abominal/Pelvic CT scans revealed extensive progression of disease in
the chest and abdomen. She was discharged on Study Day 24 (XXXXXXXXXX)
with hospice care. She died of progressive lymphoma on Study Day 37
(1XXXXXXXXXX). No autopsy was performed.

Patient 106-04- XXX-XXX is a 60-year-old male with transformed NHL. The
patient was diagnosed with follicular small cleaved cell NHL in
XXXXXXXXXX. The histology was diagnosed as transformed in XXXXXXXXXX.
The subject was randomized to the Zevalin™ arm and received 32 mCi
IDEC-Y2B8 on XXXXXXXX. CT scans on Study Day 36 (XXXXXXXXXX) showed
progression of disease within the abdomen. The patient received no
further therapy and died on Study Day 94 (XXXXXXXXXX). No autopsy was
performed.

### Conclusions

1.  The primary objective of superior overall response rate (ORR;
    complete response \[CR\] + clinical complete response \[CCR\] +
    partial response \[PR\]) in the intent-to-treat (ITT) population.
    was achieved.

-   Zevalin™ therapy was statistically superior to rituximab therapy
    (ORR = 73% vs 47%, p-value = 0.002)

2.  The Kaplan Meier estimated median duration of response (DR) for
    Zevalin™ treated subjects is numerically but not statistically
    longer than that for rituximab subjects

-   In the ITT population, the median DR to Zevalin™ therapy was 14.2+
    months (range 0.9 to 28.9+ month)

-   In the ITT population, the median DR to Rituximab therapy was 12.1+
    months (range 2.1 to 24.5+ months).

3.  The Kaplan Meier estimated time to disease progression (TTP) is
    clinically equivalent between the Zevalin™ and rituximab groups.

-   In the ITT population, the median TTP was 11.2+ months for Zevalin™
    therapy (range 0.8 to 31.5+ month)

-   In the ITT population, the median TTP was 10.1+ months (range 0.7 to
    26.1+ months) for Rituximab therapy.

4.  Impact on QOL cannot be assessed.

5.  Hematologic toxicity is common with Zevalin™ therapy and represents
    a significant clinical limitation.

-   Median duration of Grade ≥ 3 neutropenia within 90 days of Zevalin™
    therapy was 27 days for 56% of subjects.

-   Median duration of Grade ≥ 3 thrombocytopenia within 90 days of
    Zevalin™ therapy was 23 days for 60% of subjects.

### Study 106-06

#### Protocol History

+----------+----------+-----------------------------------------------+
| **Date** | **Mil    | Comments                                      |
|          | estone** |                                               |
+==========+==========+===============================================+
| June 11, | Protocol |                                               |
| 1998     | S        |                                               |
|          | ubmitted |                                               |
+----------+----------+-----------------------------------------------+
| July 7,  | Protocol |                                               |
| 1998     | I        |                                               |
|          | nitiated |                                               |
+----------+----------+-----------------------------------------------+
| S        | A        | 1.  To change from a Phase II study to a      |
| eptember | mendment |     single arm Phase III study in a           |
| 21,      | #1       |     refractory population.                    |
| 1998.    |          |                                               |
|          |          | 2.  To establish a target ORR of 35% in       |
|          |          |     rituximab refractory follicular NHL (N    |
|          |          |     = 50) as clinically significant.          |
|          |          |                                               |
|          |          | 3.  To define and expand the subjects         |
|          |          |     included in the study as the following:   |
|          |          |                                               |
|          |          |     -   Subjects with follicular B-cell NHL   |
|          |          |         previously treated with rituximab at  |
|          |          |         375 mg/m^2^ q wk X 4 in whom the most |
|          |          |         recent rituximab treatment did not    |
|          |          |         result in an objective response (CR   |
|          |          |         or PR) or who progressed within 6     |
|          |          |         months of the first rituximab         |
|          |          |         infusion.                             |
|          |          |                                               |
|          |          |     -   Subjects with either small lymphocyte |
|          |          |         B-cell NHL (IWF A) or transformed     |
|          |          |         B-cell NHL who were treated on the    |
|          |          |         rituximab arm of IDEC Study 106-04    |
|          |          |         and did not achieve a CR or PR and    |
|          |          |         now have documented disease           |
|          |          |         progression requiring treatment.      |
|          |          |                                               |
|          |          | 4.  To utilize a nonrandomized reference      |
|          |          |     group of rituximab non-responders treated |
|          |          |     with subsequent systemic therapy for      |
|          |          |     comparative analysis of ORR and duration  |
|          |          |     of response (DR).                         |
|          |          |                                               |
|          |          | 5.  To change the total number of subjects    |
|          |          |     treated with IDEC-Y2B8 to approximately   |
|          |          |     60 in order to achieve 50 evaluable       |
|          |          |     follicular NHL subjects.                  |
|          |          |                                               |
|          |          | 6.  To add a minimum requirement of at least  |
|          |          |     one lesion measuring 2.0 cm in a single   |
|          |          |     dimension in the measurable disease       |
|          |          |     section of inclusion criteria.            |
|          |          |                                               |
|          |          | 7.  To add *bcl*-2 analysis in peripheral     |
|          |          |     blood and bone marrow by PCR method.      |
|          |          |                                               |
|          |          | 8.  To add lymph node biopsy or fine needle   |
|          |          |     aspirate demonstrating histologic         |
|          |          |     confirmation of LG/F NHL within 6 months  |
|          |          |     of the first study treatment.             |
|          |          |                                               |
|          |          | 9.  To add a FACT-G questionnaire (quality of |
|          |          |     life).                                    |
|          |          |                                               |
|          |          | 10. To add LEXCOR                             |
|          |          |                                               |
|          |          | 11. To add the collection of the best         |
|          |          |     response to other anticancer therapy in   |
|          |          |     long-term follow-up survival.             |
+----------+----------+-----------------------------------------------+
| February | A        | 14 subjects had been enrolled in this study   |
| 26,      | mendment |                                               |
| 1999.    | #2       | 1.  Remove the binding assay requirement from |
|          |          |     ongoing IDEC-Y2B8 clinical trials.        |
+----------+----------+-----------------------------------------------+
| March    | A        | 17 subjects had been enrolled in this study.  |
| 16,      | mendment |                                               |
| 1999.    | #3       | 1.  To remove IDEC-In2B8 administration and   |
|          |          |     dosimetry as a study requirement.         |
|          |          |                                               |
|          |          | 2.  To modify the statistics section to       |
|          |          |     include a comparison of the ORR and DR    |
|          |          |     for follicular NHL subjects in this trial |
|          |          |     with the following:                       |
|          |          |                                               |
|          |          | -   ORR and DR from these subjects' most      |
|          |          |     recent rituximab therapy.                 |
|          |          |                                               |
|          |          | -   ORR and DR from these subjects' last      |
|          |          |     chemotherapy.                             |
|          |          |                                               |
|          |          | 3.  To remove the requirement for CD20        |
|          |          |     positive assessment for subjects with     |
|          |          |     follicular NHL.                           |
|          |          |                                               |
|          |          | 4.  To add a comparison of REAL               |
|          |          |     Classification and International Working  |
|          |          |     Formulations of NHL.                      |
+----------+----------+-----------------------------------------------+

#### Study Design, Objectives, Eligibility, and Treatment Plan

##### Design

This Phase III open-label, single arm, multi-center study was designed
to evaluate ORR and DR in subjects with advanced follicular B-cell
non-Hodgkin's lymphoma (NHL), who were refractory to rituximab therapy.

##### Objectives:

The **primary objectives** of this study were the following:

1.  Determine the efficacy of Zevalin™ therapy in relapsed or
    refractory, follicular (IWF B, C, D; also defined as REAL
    classification Follicular center grade I, II, and III) B-cell NHL
    patients whose disease was refractory to previous treatment with
    rituximab.

2.  Characterize the safety of Zevalin™ as a therapeutic regimen.

The **secondary objectives** of this study were the following:

1.  Determine the duration of response (DR) and time to progression
    (TTP).

2.  Determine complete response (CR), clinical complete response (CCR),
    and partial response (PR) rates, time to next anticancer treatment,
    and quality of life.

3.  Compare the ORR and DR of follicular NHL patients in this trial with
    the following:

4.  ORR and DR from these patients' most recent rituximab therapy

5.  ORR and DR from these patients' last chemotherapy

6.  Compare the ORR and DR of follicular NHL patients in this trial with
    that of a Reference Group.

7.  Compare serious adverse events (SAEs) of follicular NHL patients in
    this trial with those of a Reference Group.

##### Inclusion Criteria

1.  Follicular NHL subjects who were previously treated with rituximab
    375 mg/m^2^ times four and

    -   Whose most recent treatment did not result in a PR or CR as
        documented by baseline and post-treatment ct scans and who now
        have disease progression, or who had progression of disease
        within 6 months of first rituximab infusion, or

    -   Who were enrolled in IDEC study 106-04, randomized to the
        rituximab arm, did not achieve a PR or CR, and now have
        documented disease progression requiring treatment.

2.  Bidimensionally measurable disease meeting a minimum requirement of
    at least one lesion measuring 2.0 cm in a single dimension

3.  No anticancer therapy for 3 weeks prior to study initiation (6 weeks
    if patient treated with nitrosourea or Mitomycin C), and fully
    recovered from all toxicities associated with prior surgery,
    radiation treatments, chemotherapy, or immunotherapy.

4.  18 years of age or older

5.  Expected survival ≥ 3 months

6.  WHO performance status of 0, 1, or 2

7.  Acceptable hematologic status within 2 weeks prior to initial
    treatment, including:

-   Absolute neutrophil count ≥ 1,500 cells/mm^3^

-   Total lymphocyte count \< 5,000 cells/mm^3^ for patients with small
    lymphocytic lymphoma (IWF A)

-   Platelet count ≥ 150,000 cells/mm^3^.

8.  Less than 25% bone marrow involvement with lymphoma

9.  CD20 positive B-cell population in lymph nodes or bone marrow in
    transformed or IWF A subjects

##### Exclusion Criteria

1.  Treatment with prior myeloablative therapies with autologous bone
    marrow transplantation (ABMT) or peripheral blood stem cell (PBMC)
    support

2.  Prior radioimmunotherapy, including IDEC-Y2b8

3.  Presence of CNS lymphoma

4.  Presence of chronic lymphocytic leukemia (CLL)

5.  Presence of HIV or AIDS-related lymphoma

6.  Presence of small lymphocytic lymphoma (IWF A) with a total
    lymphocyte count \> 5,000 cells/mm^3^

7.  Pleural or peritoneal invasion and/or effusion with positive
    cytology for lymphoma

8.  Abnormal liver function: total bilirubin \> 2.0 mg/dl

9.  Abnormal renal function: serum creatinine \> 2.0 mg/dl

10. Prior external-beam radiation therapy to \> 25% of active bone
    marrow (involved field or regional)

11. Treatment with G-CSF or GM-CSF within 2 weeks of IDEC-Y2B8 treatment

12. Serious nonmalignant disease, active infection.

13. Major surgery, other than diagnostic surgery, within 4 weeks of
    treatment

14. Another primary malignancy (other than squamous or basal cell
    carcinoma of the skin or in situ carcinoma of the cervix) for which
    the patient has not been disease-free for at least 5 years

15. Presence of HAMA/HACA (result required prior to study entry)

16. Concurrent systemic corticosteroid therapy: a single dose ≥ 40 mg of
    prednisone (or equivalent) or ≤ 40 mg prednisone (or equivalent) for
    more than six doses

##### Treatment Plan

Subjects received one infusion of 250 mg/m^2^ rituximab prior to a fixed
dose of 5.0 mCi (1.6 mg total antibody dose) of IDEC-In2B8, which was
injected as a slow IV push over 10 minutes. Seven days later, a second
infusion of 250 mg/m^2^ of rituximab followed by 0.4 mCi/kg (1.6 mg
total antibody dose) of IDEC-Y2B8 slow IV push over 10 minutes the
following week was administered.

For subjects whose body weight exceeded 80 kg, a maximum dose of 32 mCi
of ^90^Y was to be administered.

#### Study Results

##### Subject Disposition

57 subjects were enrolled in the study

-   57 received two rituximab infusions and the IDEC-Y2B8 dose.

-   28 patients received the injection of IDEC-In2B8. The remaining 29
    patients were enrolled after the protocol was amended to remove
    dosimetry, and thus did not receive the injection of IDEC-In2B8.

13 of 57 subjects (23%) were previously treated in Study 106-04.

##### Protocol Violations

1.  Subjects 106-06- XXX-XXX and 106-06- XXX-XXX had a TTP longer than 6
    months following their last rituximab therapy (8 and 7 months,
    respectively). These subjects were not included in the ITT efficacy
    analysis.

2.  Subject 106-06- XXX-XXX had a prior rituximab regimen other than 375
    mg/m^2^ once weekly times four. The regimen consisted of 375 mg/m^2^
    of rituximab once weekly times four and then once monthly times
    seven.

3.  Subject 106-06- XXX-XXX was enrolled with a platelet count of
    147,000 cells/mm^3^ (\< 150,000 cells/mm^3^)

4.  Five subjects received an IDEC-Y2B8 dose that exceeded the intended
    dose of 0.4 mCi/kg or the maximum dose of 32 mCi:

-   Subject 106-06- XXX-XXX received 32.95 mCi.

-   Subject 106-06- XXX-XXX received 0.48 mCi/kg.

-   Subject 106-06- XXX-XXX received 34.4 mCi.

-   Subject 106-06- XXX-XXX received 32.8 mCi.

-   Subject 106-06- XXX-XXX received 35 mCi.

5.  Two subjects had a delay between the first treatment day and the
    second treatment day:

-   Subject 106-06- XXX-XXX had a 10 days interval

-   Subject 106-06- XXX-XXX had 14 days interval

6.  Two subjects had a confirmation of response efficacy evaluation less
    than 28 days from the onset of response:

-   Subject 106-06- XXX-XXX had a confirmation of response evaluation at
    26 days.

-   Subject 106-06- XXX-XXX had a confirmation of response evaluation at
    27 days

7.  Subject 106-06- XXX-XXX received 15 to 20 mg of prednisone during
    the treatment period for a pre-existing granuloma annulare
    (prohibited concomitant medication during the treatment period).

8.  Infusion data for the first rituximab infusion of Subject 106-06-
    XXX-XXX was lost at the site. However, the administration of the
    first rituximab infusion was confirmed by the site.

9.  Subject 106-06- XXX-XXX had a platelet count of 119,000 cells/mm^3^
    at study entry, below the required level of ≥ 150,000 cells/mm^3^.
    This patient was treated in the rituximab arm of Study 106-04 and,
    with FDA permission, was treated in Study 106-06 at a reduced dose
    (0.3 mCi/kg).

10. Subject 106-06- XXX-XXX was enrolled in the study with IWF A
    histology type, bulky disease, ascites, and a positive HACA response
    of 44.70 ng/mL.

11. Subject 106-06- XXX-XXX baseline CT scans were performed 34 days
    prior to study entry.

12. Subject 106-06- XXX-XXX baseline CT scans were performed 32 days
    prior to study entry.

##### Study Population & Disease Characteristics

Demographics and Disease Characteristics (n=57)

+------------------------------------------+---------------------------+
| > **Age (years)**                        |                           |
+------------------------------------------+---------------------------+
| > Mean                                   | > 54.4                    |
+------------------------------------------+---------------------------+
| > Std                                    | > 10.4                    |
+------------------------------------------+---------------------------+
| > Median                                 | > 54.0                    |
+------------------------------------------+---------------------------+
| > Range                                  | > 34.0 - 73.0             |
+------------------------------------------+---------------------------+
| > **Gender (%)**                         |                           |
+------------------------------------------+---------------------------+
| > Female                                 | > 51                      |
+------------------------------------------+---------------------------+
| > Male                                   | > 49                      |
+------------------------------------------+---------------------------+
| > **Ethnicity (%)**                      |                           |
+------------------------------------------+---------------------------+
| > Caucasian                              | > 95                      |
+------------------------------------------+---------------------------+
| > African-American                       | > 2                       |
+------------------------------------------+---------------------------+
| > Other                                  | > 3                       |
+------------------------------------------+---------------------------+
| **Stratified Histology Type (%)**        |                           |
+------------------------------------------+---------------------------+
| A                                        | > 4                       |
+------------------------------------------+---------------------------+
| Follicular                               | > 95                      |
+------------------------------------------+---------------------------+
| Transformed                              | > 2                       |
+------------------------------------------+---------------------------+
| **Disease Stage at Study Entry (%)**     |                           |
+------------------------------------------+---------------------------+
| I/II                                     | > 7                       |
+------------------------------------------+---------------------------+
| III/IV                                   | > 90                      |
+------------------------------------------+---------------------------+
| Unknown                                  | > 3                       |
+------------------------------------------+---------------------------+
| **Tumor bulk (%)**                       |                           |
+------------------------------------------+---------------------------+
| \< 5 cm                                  | > 26                      |
+------------------------------------------+---------------------------+
| 5 - \< 7 cm                              | > 30                      |
+------------------------------------------+---------------------------+
| 7 - \< 10 cm                             | > 25                      |
+------------------------------------------+---------------------------+
| ≥ 10 cm                                  | > 19                      |
+------------------------------------------+---------------------------+
| **Bone Marrow Involvement (%)**          |                           |
+------------------------------------------+---------------------------+
| > 0%                                     | > 68                      |
+------------------------------------------+---------------------------+
| > 0.1 - 5%                               | > 5                       |
+------------------------------------------+---------------------------+
| > 5 - 20%                                | > 21                      |
+------------------------------------------+---------------------------+
| > ≥ 20%                                  | > 5                       |
+------------------------------------------+---------------------------+
| **Splenomegaly (%)**                     |                           |
+------------------------------------------+---------------------------+
| > Yes                                    | > 12                      |
+------------------------------------------+---------------------------+
| > No                                     | > 88                      |
+------------------------------------------+---------------------------+

##### Risk Assessment

**IPI Risk Group (N=57)**

+--------------------------------------------------------+-------------+
|                                                        | **%**       |
+========================================================+=============+
| > Low                                                  | > 44        |
+--------------------------------------------------------+-------------+
| > Low/Intermediate                                     | > 21        |
+--------------------------------------------------------+-------------+
| > Intermediate/High                                    | > 12        |
+--------------------------------------------------------+-------------+
| > High                                                 | > 7         |
+--------------------------------------------------------+-------------+
| > Unknown                                              | > 16        |
+--------------------------------------------------------+-------------+

##### Prior Therapy

All subjects (n=57) had a median of 4 prior regimens (range 1-9) prior
to receiving Zevalin therapy. All subjects had prior rituximab therapy.

-   **Chemoresistance** was reported as follows

> 20 subjects (36.4%) were resistant to all chemotherapy,
>
> 45 subjects (81.8%) were resistant to at least one chemotherapy
> regimen,
>
> 32 subjects (58.2%) were resistant to their first chemotherapy,
>
> 37 subjects (67.3%) were resistant to their last chemotherapy.

**Type of Prior Regimen**

(N=57 subjects)

+-------------------------------------------------+--------------------+
|                                                 | **%**              |
+=================================================+====================+
| > Rituximab                                     | > 100              |
+-------------------------------------------------+--------------------+
| > Alkylator +/- Prednisone                      | > 32               |
+-------------------------------------------------+--------------------+
| > Purine Analogs                                | > 23               |
+-------------------------------------------------+--------------------+
| > Steroids                                      | > 19               |
+-------------------------------------------------+--------------------+
| > CVP or COP                                    | > 39               |
+-------------------------------------------------+--------------------+
| > CHOP                                          | > 56               |
+-------------------------------------------------+--------------------+
| > Other bioimmunotherapy                        | > 7                |
+-------------------------------------------------+--------------------+
| > Other Aggressive                              | > 65               |
+-------------------------------------------------+--------------------+
| Prior Radiotherapy                              |                    |
+-------------------------------------------------+--------------------+
| > Yes                                           | > 30               |
+-------------------------------------------------+--------------------+
| > No                                            | > 70               |
+-------------------------------------------------+--------------------+

##### Study Results---Primary Efficacy Analysis

The data set for the 1^o^ efficacy was prospectively defined as the
LEXCOR evaluation of ORR (CR + CCR + PR) in follicular subjects only.
The 1^o^ efficacy variable was to be assessed using 95% confidence
intervals; and, if the ORR was at least 35%, Zevalin therapy would be
considered clinically effective.

-   Of the 57 patients enrolled in the study, 54 were follicular
    patients.

> 3 patients with non-follicular histologies were the following:
>
> Subject 106-06- XXX-XXX IWF A
>
> Subject 106-06- XXX-XXX IWF A
>
> Subject 106-06- XXX-XXX IWF G.

-   Of the 54 follicular patients enrolled,

> 2 were excluded from the efficacy analysis because their TTP after
> rituximab therapy was greater than 6 months, a protocol violation.
> However, excluding these subjects from the overall primary analysis
> did not affect the study conclusions. Therefore, all secondary and
> exploratory analyses presented are for the overall study population.

###### Overall Response

(CR+CCR+PR) Rate and Complete Response (CR)

+--------------+---------+-----------------+-------------+------------+
|              | **All   |                 | **Protocol  |            |
|              | Fol     |                 | Eligible    |            |
|              | licular |                 | Follicular  |            |
|              | Sub     |                 | Subjects    |            |
|              | jects** |                 | (N=52)**    |            |
|              |         |                 |             |            |
|              | **(     |                 |             |            |
|              | N=54)** |                 |             |            |
+--------------+---------+-----------------+-------------+------------+
|              | **%**   | **95% CI**      | **%**       | **95% CI** |
+--------------+---------+-----------------+-------------+------------+
| **ORR**      |         |                 |             |            |
+--------------+---------+-----------------+-------------+------------+
| LEXCOR       | 59      | (45, 82)        | 58          | (43, 71)   |
+--------------+---------+-----------------+-------------+------------+
| Investigator | 63      | (49, 76)        | 62          | (47, 75)   |
+--------------+---------+-----------------+-------------+------------+
| CR rate      |         |                 |             |            |
+--------------+---------+-----------------+-------------+------------+
| LEXCOR       | 4       | (1,13)          | 4           | (1,13)     |
+--------------+---------+-----------------+-------------+------------+
| Investigator | 19      | (9, 31)         | 17          | (8, 30)    |
+--------------+---------+-----------------+-------------+------------+

##### Exploratory Analyses of the Primary Endpoint

###### Agreement Rate Between LEXCOR and Investigators (N=54)

+----------+-------------------------------------+----------+---------+
| >        | ######### LEXCOR                    |          |         |
| **INVEST |                                     |          |         |
| IGATOR** |                                     |          |         |
+----------+-------------------------------------+----------+---------+
|          | Overall Response (CR + CCR + PR)    |          |         |
+----------+-------------------------------------+----------+---------+
|          |                                     | Yes      | No      |
+----------+-------------------------------------+----------+---------+
|          | Yes                                 | 28       | 6       |
+----------+-------------------------------------+----------+---------+
|          | No                                  | 4        | 16      |
+----------+-------------------------------------+----------+---------+
|          | Concordance Rate                    | 82%      |         |
+----------+-------------------------------------+----------+---------+
|          | Complete Response                   |          |         |
+----------+-------------------------------------+----------+---------+
|          | Yes                                 | 1        | 9       |
+----------+-------------------------------------+----------+---------+
|          | No                                  | 1        | 43      |
+----------+-------------------------------------+----------+---------+
|          | Concordance Rate                    | 82%      |         |
+----------+-------------------------------------+----------+---------+

##### Secondary Analyses

Secondary efficacy variables supporting the primary analysis include
time to progression (TTP) duration of response (DR), and comparison of
Zevalin therapy with previous rituximab therapy or previous
chemotherapy.

###### Time to Progression and Duration of Response

+------------------------+-----------+-------+---------+------------+
|                        | **ID      |       |         |            |
|                        | EC-Y2B8** |       |         |            |
+========================+===========+=======+=========+============+
|                        | Estimated | 95%   | Range   | Total      |
|                        |           | CI    |         | Censored   |
|                        | Median    |       |         |            |
|                        | (K-M)     |       |         |            |
+------------------------+-----------+-------+---------+------------+
| Time to Progression    | 6.8       | (6.1, | (1.1,   | 16 (30%)   |
| (months)^\*^           |           | 9.3)  | 25.9)   |            |
|                        |           |       |         |            |
| (N=54)                 |           |       |         |            |
+------------------------+-----------+-------+---------+------------+
| Duration of Response   | 7.7       | (5.5, | (2.3,   | 10 (31%)   |
| (months)^\#^           |           | 9.1)  | 24.9+)  |            |
|                        |           |       |         |            |
| (N=32)                 |           |       |         |            |
+------------------------+-----------+-------+---------+------------+

^\*^Time to Progression from the first infusion (treatment) to disease
progression in months

^\#^Duration of Response from onset of response to disease progression
in months

###### Duration of Response Relative to Prior NHL Therapy

The overall response rate to Zevalin™ therapy was compared to the last
prior rituximab therapy and the last prior chemotherapy regimen.

-   Median time interval from the start date of last prior therapy
    (regardless of whether it was rituximab or chemotherapy) to the
    start date of Zevalin™ treatment: 6.5 months.

###### Comparison of Zevalin Therapy to Previous Rituximab Therapy

-   54 Subjects with follicular NHL received prior rituximab therapy.

    **Duration of Response for Subjects with Follicular NHL**

As Compared to Prior Rituximab Therapy

+------------------------------+-------------------+-------------------+
|                              | > **IDEC-Y2B8**   | > **Last          |
|                              | >                 | > Rituximab**     |
|                              | > **N=32          | >                 |
|                              | > Responder**     | > **N=17          |
|                              |                   | > Responder**     |
+------------------------------+-------------------+-------------------+
| > Median DR (months) \[95%   | > 7.7+ \[5.5,     | > 4.0 \[3.00,     |
| > CI\]                       | > 9.1\]           | > 6.00\]          |
+------------------------------+-------------------+-------------------+
| > Range                      | > 2.3+ to 24.9+   | > 1 to 7          |
+------------------------------+-------------------+-------------------+
| > Censored (%)               | > 31              | > 0               |
+------------------------------+-------------------+-------------------+

**Response to Zevalin™ Therapy Compared with\
Response to Prior Rituximab Therapy**

+----+----------------+--------------+----------------+--------------+
|    | Zevalin™       |              |                |              |
|    | Therapy        |              |                |              |
+----+----------------+--------------+----------------+--------------+
| >  |                | Responder    | Non-responder  | Total        |
|  P |                |              |                |              |
| ri |                |              |                |              |
| or |                |              |                |              |
| >  |                |              |                |              |
| Ri |                |              |                |              |
| tu |                |              |                |              |
| xa |                |              |                |              |
| n™ |                |              |                |              |
| >  |                |              |                |              |
|  T |                |              |                |              |
| he |                |              |                |              |
| ra |                |              |                |              |
| py |                |              |                |              |
+----+----------------+--------------+----------------+--------------+
|    | Responder      | 13           | 4              | 17           |
+----+----------------+--------------+----------------+--------------+
|    | Non-responder  | 19           | 18             | 37           |
+----+----------------+--------------+----------------+--------------+
|    | Total          | 32           | 22             |              |
+----+----------------+--------------+----------------+--------------+

Duration of response for Zevalin™ therapy was compared to the prior
rituximab therapy using subjects as their own control. 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 Zevalin™ therapy was longer than DR to Rituxan by more than 1 month,
then the Zevalin™ 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 Zevalin™
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:

Zevalin™ Therapy Compared To Prior Rituximab Therapy

  ------------------------ ---------------------- -----------------------
  **Response Duration**    **\# Subjects**        **%**

  Favor Zevalin            29                     54

  Equivalent               20                     37

  Favor Rituxan            5                      9

  p-value using sign-rank                         
  test in favor of Zevalin                        
  ------------------------ ---------------------- -----------------------

Among the 32 subjects who achieved an objective response to Zevalin, 29
had a response that was longer in duration than their response to prior
rituximab. The proportion of subjects with a longer duration of response
to Zevalin was statistically significant (sign-rank test).

###### Comparison of Zevalin Therapy to Previous Chemotherapy

-   52 of 54 subjects with follicular NHL received prior chemotherapy .

-   1 of 52 subjects had missing data pertaining to duration of response
    to the prior chemotherapy. Hence for this analysis, the total
    population included 51 subjects.

-   Median time interval from the start date of last prior chemotherapy
    to the start date of Zevalin™ treatment was 16 months.

    **Duration of Response for Subjects with Follicular NHL**

**As Compared to Prior Chemotherapy Regimen**

**(n=51 Subjects)**

+-----------------------------+------------------+---------------------+
|                             | > **IDEC-Y2B8**  | > **Last            |
|                             | >                | > Chemotherapy**    |
|                             | > **N=32         | >                   |
|                             | > Responder**    | > **N=34            |
|                             |                  | > Responder**       |
+-----------------------------+------------------+---------------------+
| > Median DR (months) \[95%  | > 7.7+ \[5.5,    | > 6.5 \[4.0, 10.0\] |
| > CI\]                      | > 9.1\]          |                     |
+-----------------------------+------------------+---------------------+
| > Range                     | > 2.3+ to 24.9+  | > 1 to 175          |
+-----------------------------+------------------+---------------------+
| > Censored (%)              | > 31             | > 0                 |
+-----------------------------+------------------+---------------------+

**Response to Zevalin™ Therapy Compared with\
Response to Prior Chemotherapy**

**(n=51 Subjects)**

+-----+-----------------+-------------+-----------------+------------+
|     | Zevalin™        |             |                 |            |
|     | Therapy         |             |                 |            |
+-----+-----------------+-------------+-----------------+------------+
| >   |                 | Responder   | Non-responder   | Total      |
|  Pr |                 |             |                 |            |
| ior |                 |             |                 |            |
| >   |                 |             |                 |            |
| Che |                 |             |                 |            |
| mot |                 |             |                 |            |
| her |                 |             |                 |            |
| apy |                 |             |                 |            |
+-----+-----------------+-------------+-----------------+------------+
|     | Responder       | 22          | 12              | 34         |
+-----+-----------------+-------------+-----------------+------------+
|     | Non-responder   | 8           | 9               | 17         |
+-----+-----------------+-------------+-----------------+------------+
|     | Total           | 30          | 21              |            |
+-----+-----------------+-------------+-----------------+------------+

Duration of response for Zevalin™ therapy was compared to the DR of
prior chemotherapy using subjects as their own control. In this
analysis, the length of the duration of response was categorized as
longer for Zevalin, equivalent, of longer for chemotherapy. If the
duration of response for Zevalin™ therapy was longer than DR to
chemotherapy by more than 1 month, then the Zevalin™ 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 chemotherapy was longer than DR to Zevalin therapy
by more than 1 months then Zevalin™ therapy was considered not
beneficial to patients (i.e., in favor of previous chemotherapy).

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

**Zevalin™ therapy compared to last prior Chemotherapy**

N=51

  ---------------------------- ----------------------- -------------------
  **Response**                 **Frequency**           **%**

  Favor Zevalin                16                      31

  Equivalent                   15                      30

  Favor Chemo                  20                      39
  ---------------------------- ----------------------- -------------------

Among the 32 subjects who achieved an objective response to Zevalin, 16
had a response that was longer in duration than their response to prior
chemotherapy. The proportion of subjects with a longer duration of
response to Zevalin was not statistically significant (sign-rank test).

##### Safety \-- Adverse Events

###### Non Hematologic Adverse Events

56 of 57 subjects (98%) experienced a total of 447 non-hematologic AEs
for the entire period of follow-up. Sixty three percent were Grade 1,
30% Grade 2, 4% Grade 3, and 2% Grade 4 by the NCI CTC grade criteria.

Clinically Significant AEs:

-   1 subject had Grade 1 gastritis

-   2 subject had Grade 1 GI disturbance

-   1 subject had Grade 2 herpes simplex

-   1 subject had Grade 4 pneumonia

-   1 subject had Grade 4 sepsis

-   1 subject had Grade 1 edema of the face

-   1 subject had an AML

> This subject was diagnosed with acute myelogenous leukemia on Study
> Day 244.
>
> follicular small-cleaved cell NHL diagnosed in 1995. He was treated
> previously with multiple chemotherapeutic agents, followed by
> rituximab. By Week 9 of Zevalin™ therapy, his WBC dropped to 3600
> cells/mm^3^, and fell further to 1300 cells/ mm^3^ by Month 6. A bone
> marrow aspirate and biopsy was performed on Study Day 191, which
> showed a hypocellular marrow with markedly decreased megakaryocytes
> and a decreased myeloid to erythroid ratio. Myelopoiesis was
> morphologically unremarkable; however, and the peripheral blood smear
> did not show malignant immature forms. The patient's WBC continued to
> fall and was 900 cells/ mm^3^ by Study Day 233. Peripheral blood
> revealed leukopenia with circulating blasts. Another bone marrow
> aspirate and biopsy showed that the marrow was hypoplastic, with
> myeloid maturation arrest and an increased number of blasts. A
> diagnosis of myelodysplasia with excess blasts was made. Flow
> cytometry confirmed the presence of increased myeloid blasts
> consistent with acute myelogenous leukemia (AML) of the M1 subtype,
> according to the FAB classification. A repeat bone marrow on Study Day
> 280 revealed 33% blasts, consistent with AML of the M0 subtype.
> Peripheral blood counts on Study Day 280 revealed a WBC of 2000 cells/
> mm^3^, with 6% neutrophils, 1% bands, 22% lymphocytes, and 70% blasts.
> The investigator and the sponsor concur that the AML was related to
> the heavy exposure to prior alkylator therapy, as evidenced by the
> hypoplastic marrow prior to study entry and the occasional presence of
> blasts in the peripheral blood 28 days following therapy with Zevalin™
> therapy.

Frequency of Common and Notable

**Non-Hematologic AEs by Subject (N=57 Subjects)**

  -------------------------------------------------------- --------------
  **AE (all grades)**                                      **%**

  Asthenia                                                 77

  Nausea                                                   40

  Chills                                                   28

  Fever                                                    26

  Abdominal Pain                                           21

  Diarrhea                                                 19

  Headache                                                 19

  Dyspnea                                                  18

  Increased Cough                                          18

  Irritation Throat                                        18

  Pain                                                     16

  Anorexia                                                 14

  Vomiting                                                 14

  Ecchymosis                                               12

  Infection                                                12

  Myalgia                                                  11

  Arthralgia                                               9

  Dizziness                                                9

  Pruritus                                                 9

  Peripheral edema                                         7

  Abdominal Enlargement                                    5

  Hypotension                                              5

  Rash                                                     5

  Flushing                                                 4

  Allergic reaction                                        2

  Angioedema                                               2

  Anxiety                                                  2
  -------------------------------------------------------- --------------

###### Human Anti-Chimeric Antibody (HACA)Response:

No subject developed HACA during the study.

2/57 subject (3.5%) had a detectable HACA prior to treatment.

-   Subject 106-06- XXX-XXX had a HACA level of 30.6 ng/mL on Study Day
    --29 that was not detectable on Study Day --13. Following Zevalin™
    therapy a PR was achieved. The subject did not experience any Grade
    3 or 4 AEs, or any SAEs.

-   Subject 106-06- XXX-XXX had a HACA level of 44.7 ng/mL on Study Day
    --4, 159,500 ng/mL on Study Day 37, and 41,800 ng/mL on Study
    Day 78. Best response was SD. The subject did not experience any
    Grade 3 or 4 AEs, or any SAEs

###### Human Anti-Murine Antibody Response

1/57 (2%) subject developed a HAMA response during the study.

-   Subject 106-06- XXX-XXX, who previously received rituximab on IDEC
    Study 106-04, had a HAMA level of 29 μg/mL on Study Day 42 and 24.7
    μg/mL on Study Day 101. This patient achieved a CR, and did not
    experience any study-related AEs.

###### Hematologic Adverse Events

For all hematologic adverse events, duration of Grade ≥ 3 toxicity is
defined as end date minus start date, where end date and start date are
defined relative to the nadir lab value. A patient's end date is defined
as the 1^st^ lab test date after the nadir visit when the patient's lab
test is above the Grade ≥ 3 toxicity limit. A patient's start date is
defined as the most recent lab test date prior to the nadir visit when
the patient's lab test is above the Grade ≥ 3 toxicity limit.

Patients not recovered from Grade ≥ 3 toxicity were censored by one of
two rules. If a patient had received next anti-cancer therapy, that
patient was censored to the date of the most recent lab test prior to
receiving next anti-cancer therapy. If the patient had not received next
anti-cancer therapy, that patient was censored to the date of the most
recent lab test.

####### ANC

39 of 57 subjects (68%) treated with Y2B8 had Grade 3 or 4 ANC within 90
days of initial therapy

1 Subject failed to have documented ANC recovery.

-   106-06- XXX-XXX never recovered ANC with a 54-day follow-up period.

> The subject experienced progressive lymphoma on Study Day 36 and went
> on to hospice care. He died of lymphoma on Study Day 64. Additional
> laboratory data through Study Day 54 were collected.

**Median duration of grade 3-4 neutropenia was 22 days** (Range 8-64
days)

![](media/image4.wmf){width="5.992361111111111in"
height="3.6368055555555556in"}

####### Platelets

43 of 57 subjects (75%) treated with Y2B8 had Grade 3 or 4
thrombocytopenia within 90 days of initial therapy

2 subjects failed to have documented platelet recovery.

-   106-06- XXX-XXX never recovered PLT with a 37-day follow-up period.

> The subject experienced progressive lymphoma on Study Day 35 and
> received cyclophosphamide/doxorubicin/vincristine/dexamethasone/
> etoposide chemotherapy beginning Study Day 37. Weekly laboratory data
> through Study Day 35 were included in the original submission.

-   106-06- XXX-XXX never recovered PLT with a 54-day follow-up period.

> The subject experienced progressive lymphoma on Study Day 36 and went
> on to hospice care. He died of lymphoma on Study Day 64. Additional
> laboratory data through Study Day 54 were collected.
>
> Subjects with clinically significant AEs.

-   2 subjects had Grade 1 bleeding gums

-   2 had rectal bleeding (1 Grade 1 and 1 Grade 2)

-   2 had vaginal bleeding (1 Grade 1 and 1 Grade 3)

-   1 had subdural hematoma

-   4 had petichae (2 Grade 1 and 2 Grade 2)

    **Median duration of grade 3-4 thrombocytopenia was 24 days** (Range
    7-53 days)

![](media/image5.wmf){width="6.501388888888889in"
height="3.6680555555555556in"}

##### Immunologic Reconstitution

###### Quantitative B-cells 

The median absolute B-cell count declined after treatment onset.
Recovery started by 6 months post-treatment, and median counts returned
to the normal range by 9 months post-treatment.

###### Quantitative Serum Immunoglobulins

51 subjects had values tested at baseline

Mean IgG, IgM, and IgA levels remained within the normal range
throughout the treatment period and follow up.

-   2 subjects had a Grade 3 nadir (\< 275 mg/dL) in serum IgG level.

-   3 subjects had a Grade 3 nadir (\< 22.5 mg/dL) in serum IgM level.

-   3 subjects had a Grade 3 nadir (\< 30 mg/dL) in serum IgA level.

##### Deaths within Study Day 100

Subject 106-06- XXX-XXX is a 71-year-old male with large-cell NHL,
diagnosed in XXXXXXXXXX. The subject received Zevalin™ therapy on
XXXXXXXXXX. CT scans obtained on Study Day 36 (XXXXXXXXXX) showed
disease progression within the abdomen. A follow up CT scans done on
Study Day 54 (XXXXXXXXXX) demonstrated worsening disease. On Study Day
62, the subject had an ANC of 1000 cells/mm^3^, a Hct of 28%, and a
platelet count of 32,000/mm^3^, which was up from a nadir of
16,000/mm^3^. The subject received hospice care and died on Study Day 64
(XXXXXXXXXX). No autopsy was performed.

Subject106-06- XXX-XXX was a 69-year-old female with follicular NHL
diagnosed in XXXXXXXXXX, previously treated with total body irradiation,
CVP, etoposide/doxorubicin/ prednisone, chlorambucil, and rituximab. She
also had a history of deep vein thrombosis (DVT). The subject was taking
intermittent ibuprofen and warfarin (2.5 mg alternating with 5 mg)
because of a history of DVT. She received Zevalin™ therapy on
XXXXXXXXXXX. On Study Day 49 (XXXXXXXXXX), the subject fell at home and
struck her head, resulting in a headache (Grade 3). Two days later on
Study Day 51 (XXXXXXXXXX), she was hospitalized with confusion and was
found to have ecchymosis (Grade 3) and subdural hematomas. Platelet
count was 25,000 cells/mm^3^ and hemoglobin level was 7.5 g/dL. She
received platelet, RBC, and cryoprecipitate transfusions. While
hospitalized, she developed bilateral pulmonary infiltrates, pneumonia
(Grade 4), and adult respiratory distress syndrome (Grade 4) requiring
intubation. She also experienced bowel obstruction (Grade 3), uterine
bleeding (Grade 3), kidney failure (Grade 4), and liver failure (Grade
4). She developed signs of worsening sepsis (Grade 4) with high fevers
(Grade 3), tachycardia (Grade 2), hypotension (Grade 3), and progressive
skin mottling in her extremities. The subject subsequently developed
encephalopathy (Grade 3) complicated by seizure activity (Grade 3). She
died on Study Day 70 (XXXXXXXXXX). The event of thrombocytopenia was
considered probably related to the study drug by the principle
investigator and sponsor. An autopsy was not performed.

### Conclusions

1.  The primary ORR objective for Zevalin™ therapy was achieved.

-   The prospectively defined targeted ORR was 35% in subjects with
    follicular histology who were refractory to Rituxan.

-   Zevalin™ therapy induced responses (ORR: 59%) in relapsed or
    refractory, follicular (IWF B, C, D; also defined as REAL
    classification Follicular center grade I, II, and III) B-cell NHL
    subjects whose disease was refractory (TTP \< 6 months) to previous
    treatment with rituximab.

2.  Zevalin™ therapy resulted with a longer DR to that achieved with
    prior Rituxan (7.7 vs. 4.0 months).

3.  Median duration of Grade ≥ 3 neutropenia within 90 days of Zevalin™
    therapy was 22 days for 68% of subjects.

4.  Median duration of Grade ≥ 3 thrombocytopenia within 90 days of
    Zevalin™ therapy was 24 days for 75% of subjects

Biodistribution and Radiation Dosimetry

## Introduction

Prior to the administration of Y-90-2B8 therapy, the clinical sites
performed a biodistribution imaging study for each subject. The
biodistribution study, performed with In-111-2B8, resulted in whole body
images at five time points. Based on the biodistribution study, the
clinical sites determined the normal organ dosimetry for the subject. To
allow the therapeutic administration, the normal organ dosimetry
findings were required to be consistent with the eligibility criteria
(maximum allowable absorbed radiation dose to organs: 2,000 cGy for
normal organs and 300 cGy for red marrow).

To provide a standardized methodology for the normal organ dosimetry and
tumor dosimetry, the Mayo Clinic and the Oak Ridge Associated
Universities (ORAU) accomplished a central analysis of the normal organ
dosimetry from the controlled trials (106-03, 106-04, 106-05, and
106-06). The centralized analyses of the normal organ dosimetry results
for 179 patients, as well as the tumor dosimetry for 57 selected tumor
sites, were submitted to the BLA.

In the review of IDEC's submission of the biodistribution imaging,
normal organ dosimetry and tumor dosimetry, CBER has performed the
following:

-   A review of the imaging findings from the biodistribution imaging
    studies with In-111-2B8

-   Analyzed and recalculated the submitted normal organ dosimetry for
    Y-90-2B8

-   Analyzed and recalculated the submitted normal organ dosimetry for
    In-111-2B8

-   Analyzed and recalculated the submitted tumor dosimetry

### At Risk - Worst Case Assessments

In support of the biodistribution and dosimetry review, the following
three "worst case" analyses have been performed:

#### Assessment Of Adjacent Structures At Risk. 

The path-length of Yttrium-90 is 5 mm and the energy is 2.3 MeV. Normal
structures adjacent to tumor sites will have absorbed radiation from the
tumor sites. The dosimetry evaluations of selected tumor sites have
demonstrated one tumor site with an estimated radiation absorbed dose of
24, 254 cGy. Six radiation absorbed dose estimates have been analyzed
for the presence of such a tumor site in various anatomical locations.

#### Alteration in Biodistribution of the Radiolabeled Antibody. 

The presence of an immune response, e.g., HAMA, HACA, may alter the
biodistribution of a radiolabeled antibody. A large colloid model has
been utilized to estimate the normal organ dosimetry of Y-90-2B8 with an
altered biodistribution.

#### Obstructed Route of Renal/Urinary Tract Clearance Pathway. 

The stated route of clearance for Y-90-2B8 is renal/urinary tract. Based
on renal obstruction, the normal organ dosimetry has been estimated.

## Design of the Biodistribution Imaging and Organ Dosimetry 

The therapy radioisotope, Yttrium-90, is essentially a pure beta
emitter. Yttrium-90 is not an imaging agent for biodistribution imaging,
normal organ dosimetry and tumor dosimetry quantification. Indium-111 is
the surrogate diagnostic radiolabel for Y-90 and it is assumed that the
biodistribution of the therapeutic Y-90-2B8, and the diagnostic
In-111-2B8 are essentially identical.

### Whole Body Biodistribution Imaging

On day 0, subjects received 250 mg/m^2^ rituximab immediately followed
by 5 mCi ^111^In-2B8 for biodistribution imaging and dosimetry
evaluation.

The nuclear medicine camera acquired whole body images with a medium
energy collimator with photopeak settings at 172 and 247 keV and a 15%
window.

Serial anterior and posterior whole body images were collected at each
of five imaging time points in a 256 by 1024 matrix.

### Time Points Evaluated

The whole body biodistribution imaging time points were scheduled as the
follows:

1.  0.5 hours

2.  4 hours

3.  24 hours

4.  72 hours

5.  144 hours

### Subject Population

IDEC has submitted normal organ dosimetry findings for 179 patients to
the BLA. The submitted subjects are from four clinical trials.

Table: Normal Organ Dosimetry -- Subject Population

  ----------------------- ----------------------- -----------------------
  Clinical Trial          **Subjects Enrolled**   **Subjects Submitted
                                                  for Dosimetry
                                                  Evaluation**

  **106-03**              **58**                  **50**

  **106-04**              **73**                  **72**

  **106-05**              **30**                  **30**

  **106-06**              **57**                  **27**
  ----------------------- ----------------------- -----------------------

### Electronic Submission

The whole body biodistribution images were electronically archived and
submitted without data compression or data loss. The images have been
presented in an electronic dataset within a searchable, interactive
database. The supporting datasets have been submitted in SAS transport
files.

## Biodistribution Imaging Findings

### Biodistribution Imaging -- Normal Organs

In the biodistribution imaging, the normal organs are visualized by
having uptake of In-111-2B8 in the organ greater than the adjacent whole
body background activity.

The review findings of the biodistribution imaging for the visualized
organs are as follows:

#### Liver and Spleen 

> The imaging of the liver and spleen demonstrate an intense and uniform
> uptake pattern seen commonly with diagnostic ^111^In-radiolabeled
> antibodies. Excellent anatomical details are seen for both organs.

#### Bone Marrow

> The bone marrow compartment is well seen in the expected distribution
> of the red marrow in adults. In many patients there appears to be
> active uptake of the In-111-2B8 in the expected regions of the yellow
> marrow in adults. In multiple patients, the bone marrow imaging
> demonstrated patchy areas of increased localization, suggesting
> possible imaging of NHL bone marrow involvement.

#### Testes

> Imaging of the testes is remarkable for the intensity and the
> uniformity of the radiotracer localization (equivalent to the spleen).
> No asymmetry of the testes or focal localization to suggest imaging of
> occult, focal NHL was identified. Correlation with the pre-clinical
> human tissue binding studies notes no known normal tissues in the
> testes targeted by the 2B8 antibody. No follow up laboratory
> evaluation of testicular function has been performed in the controlled
> trials.

#### Kidney, Urinary Bladder

The kidneys and urinary bladder are well defined by In-111-2B8. The
urinary bladder is variable in its configuration and partially filled
with radiotracer, compatible with the urinary tract function as the
clearance pathway of the radiolabel. In occasional subjects, elevation
of the central region of the urinary bladder is seen, compatible with
prostatic enlargement.

#### Bowel

IDEC established an independent panel of Nuclear Medicine physicians to
assess the 179 biodistribution imaging studies for the presence of bowel
imaging. The independent panel found 174 of 179 biodistribution imaging
studies to be adequate for assessment of bowel imaging. The independent
panel described bowel imaging in 32% (55/174) of the biodistribution
imaging studies.

#### Large Bowel 

> Variable regions of the large bowel demonstrate well-defined
> localization of In-111-2B8 in subjects. The localization of In-111-2B8
> in the large bowel is commonly seen by 72 hours, and once seen,
> appears unchanging in its anatomical distribution through the last
> imaging time point. In many patients, the localization of the
> radiotracer defines both walls of the large bowel. This imaging of
> both walls of the large bowel suggests prominent localization in the
> bowel wall as compared to presence of the radiolabel in the bowel
> lumen. The imaging of the large bowel is compatible with In-111-2B8
> targeting normal sites of lymphoid aggregates in the bowel wall as
> well as sites of NHL. In addition, the imaging of the large bowel may
> represent the presence of an occult second clearance pathway in the
> bowel.

#### Small Bowel 

> Variable regions of the small bowel appear to be imaged in patients.
> The small bowel is less well defined by In-111-2B8 imaging as compared
> to the imaging of the large bowel. The imaging of the small bowel is
> commonly seen by 72 hours and once seen, appears unchanging through
> the last imaging time point.

#### Heart, Large Vascular Structures

> The cardiac chambers and major vascular structures demonstrate
> well-defined localization in the initial imaging with the expected
> loss of imaging by the 48 to 72 hours imaging. This imaging pattern is
> compatible with the infusion of In-111-2B8, and the expected clearance
> of the radiolabeled antibody from the vascular space.

#### Lung Fields

> The lung fields demonstrate a modest diffuse to somewhat irregular
> localization of the radiolabeled antibody as compared to the whole
> body background activity.

### Biodistribution Imaging -- Tumor Sites

Many imaged tumor sites are seen and have well-defined localization of
In-111-2B8. Many tumor sites are of greater imaging intensity in the
localization of In-111-2B8 as compared to the normal organs.

### Biodistribution Review Comments

In-111-2B8 whole body biodistribution imaging provides diagnostic
quality whole body images at the five time points. Excellent definition
of the liver, spleen, testes, bone marrow, kidneys, urinary bladder,
large bowel, heart and major vascular structures has been demonstrated
in the submitted whole body images from the controlled clinical trials.

The biodistribution imaging with In-111-2B8 provides supportive
information for the safe administration of Y-90-2B8 as follows:

> The biodistribution images confirm the presence of the expected
> pattern of In-111-2B8 in the normal organs. An alteration in the
> biodistribution in normal organs suggests the presence of one or more
> of the following conditions:

-   Immune response, e.g., HAMA, HACA.

-   Organ dysfunction, e.g., urinary tract obstruction.

-   Improper preparation of the In-111-2B8 imaging agent.

-   Presence of occult NHL.

> The biodistribution images establish the "normal structures at risk"
> due to the radiation absorbed dose exposures from adjacent tumor
> sites.

In addition, the performance of the biodistribution imaging allows the
following:

-   Quantitation of the radiation dose for those tumor sites, which are
    adjacent to "normal structures at risk."

-   Quantitation of the radiation absorbed dose to normal organs and
    tumor sites.

## Normal Organ Dosimetry

In the multiple controlled clinical trials supporting the BLA, IDEC has
utilized In-111-2B8 for biodistribution imaging, which is the basis for
the determination of the normal organ dosimetry for Y-90-2B8.

In-111-2B8 biodistribution whole body imaging at five time points was
completed for the controlled clinical trials (106-03, 106-04, 106-05,
and 106-06). From these whole body biodistribution images, the residence
times in the normal organs for the radiolabeled antibody,
^111^In/^90^Y-2B8, was determined by assigning regions of interest for
each visualized organ. Based on the residence times, the normal organ
dosimetry was estimated by the MIRDOSE software.

### Organs To Be Evaluated By Time Activity Curves

For the determination of dosimetry by the MIRDOSE software, all organs
visualized are considered to have greater concentration of the
radiolabeled antibody as compared to the whole body background activity.
These visualized organs are evaluated by regions of interest (ROIs) with
quantification of the radioactivity present in these organs at the
multiple time points. The determination of the radioactivity
localization in these organs by the ROIs for the multiple time points
produces the time-activity curves. By integration of the time activity
curves, the residence times are obtained, which are required for the
MIRDOSE software to estimate the normal organ dosimetry.

### Subject Population and Regions of Interest

For 15 patients randomly selected from the 179 patients submitted with
normal organ dosimetry, IDEC has evaluated the following listed
organs/tissues and total body activity:

1.  Total Body

2.  Blood

3.  Heart

4.  Lung

5.  Liver

6.  Small Intestine

7.  Large Intestine

8.  Spleen

9.  Testes

10. Kidneys

11. Sacrum (Bone Marrow)

### Route of Excretion

**IDEC assumed the only excretion route is through the urinary tract.
Therefore, IDEC has elected to estimate urinary excretion as equal to
100% of administered activity minus the whole body retained
radioactivity as determined by the whole body biodistribution imaging.
No assessment for gastrointestinal clearance was performed.**

**CBER Review Comment:**

CBER's review of the whole body biodistribution images demonstrates
localization of the radiotracer in both the small and large bowel in
patients. The biodistribution findings over multiple time points
suggests fixed localization to the bowel wall rather than a changing
pattern of activity to suggest clearance passage in the lumen.

**The pre-clinical human tissue binding studies establish that
^111^In/^90^Y-2B8 will localize in lymphoid aggregates in the bowel wall
as well as non-Hodgkin's lymphoma (NHL). Therefore, the source of this
activity in the bowel may be attributable to localization of In-111-2B8
in NHL and/or lymphoid aggregates in the bowel wall.**

**However, IDEC has not provided evaluations of stool collections to
establish the presence or absence of bowel clearance. Therefore, the
possible contribution of activity in the bowel lumen from a second route
of clearance in the bowel has not been ruled out. Thus, IDEC's dosimetry
study results are indeterminate to document all possible routes of
clearance.**

**If determined to be clinically significant, IDEC should perform future
dosimetry study evaluations for fecal clearance of the radiolabel to
determine if a second route of clearance is present.**

### Image Quantification

Image quantification determines the time activity curves for In-111-2B8
in the various organs/tissues for the dosimetry determination. This
section provides the following:

A review of the image quantification methods utilized by IDEC.

> CBER performed comparison studies for three patients based on IDEC's
> quantification methods.

#### IDEC methodology for Image Quantification 

-   On day 0, subjects received 250 mg/m^2^ rituximab immediately
    followed by 5 mCi ^111^In-2B8 for biodistribution and dosimetry
    evaluation.

-   Serial anterior and posterior whole body images were collected at
    each of 5 imaging time points in a 256 by 1024 matrix. Images were
    acquired using a medium energy collimator with the nuclear medicine
    camera photopeak settings of 172 and 247 keV with a 15% window.

-   Based on the whole body images, regions of interest (ROIs) were
    selected and drawn around specified organs/tissues, e.g., whole
    body, lungs, liver, spleen, kidneys, sacrum, upper large intestine
    (ULI), lower large intestine (LLI), small intestine (SI), heart, and
    testes.

-   Activity in each organ/tissue selected by a region of interest at
    each time point (activity is expressed as percent of
    \[administered\] injected activity) was determined by the following:

> Taking the geometric mean of the anterior and posterior counts in each
> organ ROI and dividing by the geometric mean of the whole body counts
> ROI.
>
> The use of the geometric mean is intended to account for attenuation
> by body structures of the radioactive emissions. To improve the
> precision of this process, consistent camera settings were assured
> through the use of a known activity standard with the imaging.
>
> As an example of the use of the geometric mean, the percent of the
> injected activity in liver at some time point x is found as follows:

Posterior counts in liver ROI at time x = 9,000

> Anterior counts in liver ROI at time x = 10,000
>
> Geometric mean of anterior and posterior liver ROI counts at time x. =
> 9487
>
> Where Geometric Mean (GM) of A and B is:
>
> $$\text{GM} = (A \cdot B)^{\frac{1}{2}}$$

Posterior whole body ROI counts at first image time = 1,000,000

> Anterior whole body ROI counts at first image time = 1,100,000
>
> Geometric mean of anterior and posterior whole body ROI counts at
> first image time. = 1,048,808
>
> Percent Injected activity in liver at time x = 9487 / 1,048,808 =
> 0.009 or 0.9%

This example assumes the whole body scan times were identical.

The baseline CT scan was used to determine patient-specific spleen and
liver mass corrected doses for the central dosimetry evaluations.

The initial estimates of radiation absorbed dose were made at the
clinical sites, prior to the administration of Y-90-2B8. Subsequently,
the Mayo Clinic and the Radiation Internal Dose Information Center, Oak
Ridge Institute of Science and Education (ORISE) performed centralized
dosimetric analyses of all patients.

##### CBER Review Comment: 

This methodology is assumed to yield reasonable results for most organs.
However, for regions such as lungs, which have a higher transmission
factor than soft tissue, the IDEC methodology is considered to likely
overestimate the activity. Thus the IDEC dosimetry estimates for lungs
are likely overestimates. For regions involving thick bone components,
such as sacrum (bone marrow), the IDEC methodology would likely result
in an underestimate of activity. For testes, with reduced overlying
tissue as compared to the adjacent abdominal region, the methodology may
result in an overestimation of the absorbed radiation dose.

#### CBER Evaluation of Image Quantification

In the image quantification evaluation, CBER emulated IDEC's regions of
interest for the organs and utilized the same methodology for image
quantification as that used by IDEC.

Planar image data from two patients (106-04-003-215 and 106-04-007-250)
were selected. CBER drew regions of interest around the liver, spleen,
kidneys, and lungs, which demonstrated visible uptake of In-111-2B8 as
compared to the whole body background activity.

##### Patient 106-04-003-215

Table: Percent-Injected Dose Results Comparison

IDEC results/CBER results

+-----+--------+----------+----------+----------+----------+----------+
| ### |        | **Time   |          |          |          |          |
| ### |        | Points   |          |          |          |          |
| ### |        | (        |          |          |          |          |
|  Or |        | hours)** |          |          |          |          |
| gan |        |          |          |          |          |          |
+-----+--------+----------+----------+----------+----------+----------+
|     |        | **0.5**  | **4**    | **24**   | **72**   | **142**  |
+-----+--------+----------+----------+----------+----------+----------+
| **R | *      | **97     | **94.    | **74.    | **43.    | **16.    |
| ATI | *Whole | .1/100** | 2/98.5** | 6/78.6** | 2/44.9** | 1/17.1** |
| O** | Body** |          |          |          |          |          |
|     |        |          |          |          |          |          |
| **  |        |          |          |          |          |          |
| IDE |        |          |          |          |          |          |
| C** |        |          |          |          |          |          |
|     |        |          |          |          |          |          |
| **  |        |          |          |          |          |          |
| /** |        |          |          |          |          |          |
|     |        |          |          |          |          |          |
| **  |        |          |          |          |          |          |
| CBE |        |          |          |          |          |          |
| R** |        |          |          |          |          |          |
+-----+--------+----------+----------+----------+----------+----------+
|     | **L    | **       | **11     | **9      | **5      | **2      |
|     | iver** | 11.6/9** | .6/9.6** | .5/6.5** | .7/4.4** | .3/1.8** |
+-----+--------+----------+----------+----------+----------+----------+
|     | **Sp   | **3      | **3      | **2      | **1      | **0      |
|     | leen** | .0/2.4** | .1/1.9** | .5/1.3** | .5/0.8** | .6/0.4** |
+-----+--------+----------+----------+----------+----------+----------+
|     | **Kid  | **0      | **0      | **0      | **0      | **0      |
|     | neys** | .3/1.8** | .3/1.2** | .3/1.0** | .1/0.4** | .1/0.2** |
+-----+--------+----------+----------+----------+----------+----------+
|     | **L    | **5      | **5      | **3      | **1      | **0      |
|     | ungs** | .5/3.5** | .3/3.9** | .9/1.9** | .9/1.1** | .7/0.6** |
+-----+--------+----------+----------+----------+----------+----------+

**Percent-injected dose results comparison**

Table: % Ratio Of IDEC Results To CBER Results

(IDEC value/CBER value)

+-----+--------+----------+----------+----------+----------+----------+
| **O |        | **Time   |          |          |          |          |
| rga |        | Points   |          |          |          |          |
| n** |        | (        |          |          |          |          |
|     |        | hours)** |          |          |          |          |
+-----+--------+----------+----------+----------+----------+----------+
|     |        | **0.5**  | **4**    | **24**   | **72**   | **142**  |
+-----+--------+----------+----------+----------+----------+----------+
| **R | *      | **0.97** | **0.96** | **0.95** | **0.96** | **0.95** |
| ATI | *Whole |          |          |          |          |          |
| O** | Body** |          |          |          |          |          |
|     |        |          |          |          |          |          |
| **  |        |          |          |          |          |          |
| IDE |        |          |          |          |          |          |
| C** |        |          |          |          |          |          |
|     |        |          |          |          |          |          |
| **  |        |          |          |          |          |          |
| /** |        |          |          |          |          |          |
|     |        |          |          |          |          |          |
| **  |        |          |          |          |          |          |
| CBE |        |          |          |          |          |          |
| R** |        |          |          |          |          |          |
+-----+--------+----------+----------+----------+----------+----------+
|     | **L    | **1.30** | **1.21** | **1.46** | **1.31** | **1.28** |
|     | iver** |          |          |          |          |          |
+-----+--------+----------+----------+----------+----------+----------+
|     | **Sp   | **1.24** | **1.61** | **1.94** | **1.75** | **1.44** |
|     | leen** |          |          |          |          |          |
+-----+--------+----------+----------+----------+----------+----------+
|     | **Kid  | **0.14** | **0.25** | **0.33** | **0.19** | **0.30** |
|     | neys** |          |          |          |          |          |
+-----+--------+----------+----------+----------+----------+----------+
|     | **L    | **1.60** | **1.36** | **1.99** | **1.72** | **1.15** |
|     | ungs** |          |          |          |          |          |
+-----+--------+----------+----------+----------+----------+----------+

##### Patient 106-04-007-250

Table: Percent-Injected Dose Results Comparison

IDEC results/CBER results

+-----+--------+----------+----------+----------+----------+----------+
| ### |        | **Time   |          |          |          |          |
| ### |        | Points   |          |          |          |          |
| ### |        | (        |          |          |          |          |
|  Or |        | hours)** |          |          |          |          |
| gan |        |          |          |          |          |          |
+-----+--------+----------+----------+----------+----------+----------+
|     |        | **0.5**  | **4**    | **24**   | **72**   | **142**  |
+-----+--------+----------+----------+----------+----------+----------+
| **R | *      | **       | *        | *        | *        | *        |
| ATI | *Whole | 99/100** | *93/97** | *76/75** | *42/44** | *20/21** |
| O** | Body** |          |          |          |          |          |
|     |        |          |          |          |          |          |
| **  |        |          |          |          |          |          |
| IDE |        |          |          |          |          |          |
| C** |        |          |          |          |          |          |
|     |        |          |          |          |          |          |
| **  |        |          |          |          |          |          |
| /** |        |          |          |          |          |          |
|     |        |          |          |          |          |          |
| **  |        |          |          |          |          |          |
| CBE |        |          |          |          |          |          |
| R** |        |          |          |          |          |          |
+-----+--------+----------+----------+----------+----------+----------+
|     | **L    | **15.    | **14.    | **13.    | **9      | **4      |
|     | iver** | 6/14.4** | 8/13.4** | 7/11.4** | .1/7.9** | .3/3.7** |
+-----+--------+----------+----------+----------+----------+----------+
|     | **Kid  | **1      | **1      | **1      | **0      | **0      |
|     | neys** | .3/1.9** | .1/1.9** | .1/2.3** | .6/0.9** | .3/0.5** |
+-----+--------+----------+----------+----------+----------+----------+
|     | **L    | **6      | **6      | **4      | **2      | **1      |
|     | ungs** | .3/5.6** | .3/4.8** | .7/3.9** | .2/1.5** | .1/0.5** |
+-----+--------+----------+----------+----------+----------+----------+

**Percent-Injected Dose Results Comparison**

Table: % Ratio Of IDEC Results To CBER Results

(IDEC value/CBER value)

+-----+--------+----------+----------+----------+----------+----------+
| ### |        | **Time   |          |          |          |          |
| ### |        | Points(  |          |          |          |          |
| ### |        | hours)** |          |          |          |          |
|  Or |        |          |          |          |          |          |
| gan |        |          |          |          |          |          |
+-----+--------+----------+----------+----------+----------+----------+
|     |        | **0.5**  | **4**    | **24**   | **72**   | **142**  |
+-----+--------+----------+----------+----------+----------+----------+
| **R | *      | **0.99** | **0.96** | **1.01** | **0.95** | **0.95** |
| ATI | *Whole |          |          |          |          |          |
| O** | Body** |          |          |          |          |          |
|     |        |          |          |          |          |          |
| **  |        |          |          |          |          |          |
| IDE |        |          |          |          |          |          |
| C** |        |          |          |          |          |          |
|     |        |          |          |          |          |          |
| **  |        |          |          |          |          |          |
| /** |        |          |          |          |          |          |
|     |        |          |          |          |          |          |
| **  |        |          |          |          |          |          |
| CBE |        |          |          |          |          |          |
| R** |        |          |          |          |          |          |
+-----+--------+----------+----------+----------+----------+----------+
|     | #      | **1.08** | **1.10** | **1.20** | **1.15** | **1.16** |
|     | ###### |          |          |          |          |          |
|     |  Liver |          |          |          |          |          |
+-----+--------+----------+----------+----------+----------+----------+
|     | **Kid  | **0.68** | **0.58** | **0.48** | **0.67** | **0.60** |
|     | neys** |          |          |          |          |          |
+-----+--------+----------+----------+----------+----------+----------+
|     | **L    | **1.13** | **1.31** | **1.21** | **1.47** | **2.20** |
|     | ungs** |          |          |          |          |          |
+-----+--------+----------+----------+----------+----------+----------+

IDEC submitted image quantification results for testes, small intestine,
upper large intestine, lower large intestine, sacrum (bone marrow), and
heart contents. In this evaluation, CBER emulated IDEC's regions of
interest for these organs and utilized the same methodology for image
quantification as that used by IDEC.

CBER's analysis of IDEC's methodology for image quantification notes
IDEC had not utilized background subtraction. IDEC's approach, as
compared to the use of background subtraction, will produce a
significant difference with reported higher estimated percent injected
doses to these organs. For comparison purposes, CBER has calculated the
percent injected doses in the organs/tissues without background
subtraction.

##### Patient 106-04-001-116

Table: Percent Injected Dose ([Without]{.underline} Background
Subtraction Applied)

IDEC results/CBER results.

+-----+--------+----------+----------+----------+----------+----------+
| *   |        | Time     |          |          |          |          |
| *Or |        | Points   |          |          |          |          |
| gan |        | (hours)  |          |          |          |          |
| s** |        |          |          |          |          |          |
+-----+--------+----------+----------+----------+----------+----------+
|     |        | **0.45** | **4.07** | **19.2** | **66.7** | *        |
|     |        |          |          |          |          | *163.7** |
+-----+--------+----------+----------+----------+----------+----------+
| **R | **H    | **8      | **7      | **6      | **3      | **2      |
| ATI | eart** | .6/8.3** | .4/7.3** | .2/6.6** | .7/4.9** | .6/3.2** |
| O** |        |          |          |          |          |          |
|     |        |          |          |          |          |          |
| **  |        |          |          |          |          |          |
| IDE |        |          |          |          |          |          |
| C** |        |          |          |          |          |          |
|     |        |          |          |          |          |          |
| **  |        |          |          |          |          |          |
| /** |        |          |          |          |          |          |
|     |        |          |          |          |          |          |
| **  |        |          |          |          |          |          |
| CBE |        |          |          |          |          |          |
| R** |        |          |          |          |          |          |
+-----+--------+----------+----------+----------+----------+----------+
|     | *      | **2      | **2      | **2      | **1      | **1      |
|     | *Small | .3/3.7** | .1/3.3** | .1/3.4** | .8/2.7** | .4/2.6** |
|     | Intes  |          |          |          |          |          |
|     | tine** |          |          |          |          |          |
|     |        |          |          |          |          |          |
|     | **     |          |          |          |          |          |
|     | (SI)** |          |          |          |          |          |
+-----+--------+----------+----------+----------+----------+----------+
|     | *      | **2      | **2      | **2      | **2      | **1      |
|     | *Upper | .7/3.1** | .5/2.7** | .7/2.6** | .3/2.1** | .7/1.7** |
|     | Large  |          |          |          |          |          |
|     | Int    |          |          |          |          |          |
|     | estine |          |          |          |          |          |
|     | (      |          |          |          |          |          |
|     | ULI)** |          |          |          |          |          |
+-----+--------+----------+----------+----------+----------+----------+
|     | *      | **2      | **2      | **2      | **1      | **1      |
|     | *Lower | .6/1.5** | .3/1.4** | .3/1.3** | .9/1.0** | .4/0.9** |
|     | Large  |          |          |          |          |          |
|     | Int    |          |          |          |          |          |
|     | estine |          |          |          |          |          |
|     | (      |          |          |          |          |          |
|     | LLI)** |          |          |          |          |          |
+-----+--------+----------+----------+----------+----------+----------+
|     | **Te   | **1      | **1      | **1      | **0      | **0      |
|     | stes** | .8/1.2** | .5/0.8** | .1/0.7** | .7/0.3** | .5/0.3** |
+-----+--------+----------+----------+----------+----------+----------+
|     | **     | **0      | **0      | **0      | **0      | **0      |
|     | Sacral | .8/0.7** | .7/0.7** | .6/0.8** | .3/0.6** | .1/0.5** |
|     | Ma     |          |          |          |          |          |
|     | rrow** |          |          |          |          |          |
+-----+--------+----------+----------+----------+----------+----------+

Table: % Ratio of Percent Injected Dose ([Without]{.underline}
Background Subtraction Applied)

Ratio of IDEC results to Reviewer results (IDEC value/Reviewer value)

+------+---------+---------+---------+---------+---------+---------+
| **   |         | **Time  |         |         |         |         |
| Orga |         | (h      |         |         |         |         |
| ns** |         | ours)** |         |         |         |         |
+------+---------+---------+---------+---------+---------+---------+
|      |         | *       | *       | *       | *       | **      |
|      |         | *0.45** | *4.07** | *19.2** | *66.7** | 163.7** |
+------+---------+---------+---------+---------+---------+---------+
| *    | **Heart | **1.0** | **1.0** | **0.9** | **0.8** | **0.8** |
| *RAT | Con     |         |         |         |         |         |
| IO** | tents** |         |         |         |         |         |
|      |         |         |         |         |         |         |
| **ID |         |         |         |         |         |         |
| EC** |         |         |         |         |         |         |
|      |         |         |         |         |         |         |
| *    |         |         |         |         |         |         |
| */** |         |         |         |         |         |         |
|      |         |         |         |         |         |         |
| **CB |         |         |         |         |         |         |
| ER** |         |         |         |         |         |         |
+------+---------+---------+---------+---------+---------+---------+
|      | **SI**  | **0.6** | **0.6** | **0.6** | **0.7** | **0.5** |
+------+---------+---------+---------+---------+---------+---------+
|      | **ULI** | **0.9** | **0.9** | **1.0** | **1.1** | **1.0** |
+------+---------+---------+---------+---------+---------+---------+
|      | **LLI** | **1.7** | **1.7** | **1.8** | **1.8** | **1.6** |
+------+---------+---------+---------+---------+---------+---------+
|      | **T     | **1.5** | **1.9** | **1.6** | **2.3** | **1.7** |
|      | estes** |         |         |         |         |         |
+------+---------+---------+---------+---------+---------+---------+
|      | *       | **1.1** | **1.0** | **0.7** | **0.5** | **0.2** |
|      | *Sacral |         |         |         |         |         |
|      | M       |         |         |         |         |         |
|      | arrow** |         |         |         |         |         |
+------+---------+---------+---------+---------+---------+---------+

##### CBER Review Comment

**Based on the results of two patients (106-04-003-215 and
106-04-007-250) the results of IDEC and CBER for whole body, liver,
spleen, lungs, and kidney are very similar and considered within
expected limitations of the assessment methodology.**

**For the 3rd patient (106-04-001-116), heart contents, SI, ULI, LLI,
sacral marrow, and testes results were compared. CBER performed the
evaluation without background subtraction and with IDEC's ROIs. CBER's
results were similar to IDEC's results.**

## Kinetic Modeling

This section describes the methods IDEC has utilized to determine the
organ/tissue residence times for the radiolabeled antibody from the time
activity source data obtained from the following:

1)  Whole body imaging

2)  Excreta sampling

3)  Blood sampling

### Mathematical Models Used By IDEC To Estimate Organ Residence Times

#### Organ Residence Times 

> All quantified organs/tissues (whole body, blood, liver, spleen, lung,
> kidneys) were determined by curve fitting the collected data with sums
> of exponentials and integrating the resulting functions.

#### Urine Residence Times 

> Urine residence times were found using the parameters of the whole
> body fits to determine the biological half-life (lives) of excretion.
> A 4.8 hours voiding bladder model was then applied to the integration
> process.

##### CBER Review Comment

> **If significant activity was removed from the body via the
> gastrointestinal tract, the bladder wall absorbed doses determined by
> IDEC are likely overestimates.)**

#### Red Marrow Residence Times 

> Red marrow residence times were determined using sacral marrow regions
> of interest. The blood data and the methodology described by Squoros
> \[J Nucl Med 1993;34:689-694\] has also been submitted to the BLA, but
> set aside in the final review of the normal organ dosimetry. The
> Squoros model involves curve fitting the blood data using sums of
> exponentials and assumes that bone marrow activity is proportional to
> blood activity.

**CBER Review Comment**

> **The Squoros methodology is appropriate for the estimation of bone
> marrow radiation exposure only when the administered radiolabeled
> agent has no specific localization in the bone marrow space and/or its
> elements. The radiolabeled anti-CD20 antibody (^111^In/^90^Y-2B8)
> targets both benign lymphoid tissues and NHL. The evaluated BLA
> subject population has normal lymphoid tissues and tumor, NHL, present
> in the bone marrow. Indeed, the inclusion criteria allowed patients
> with up to 25% bone marrow replacement by NHL, which is targeted by
> the radiolabeled antibody, ^111^In/^90^Y-2B8. Therefore, the Squoros
> methodology is an inappropriate bone marrow dosimetry model for
> ^111^In/^90^Y-2B8 in subjects with NHL.**

#### Remainder Of Body Residence Times 

Remainder of body residence times was determined by subtracting the
organ residence times from the whole body residence times. After the
last time point imaged, the time-activity curve was assumed to continue
to follow the mathematical fit that was determined using the data
collected. (sums of exponentials).

#### Conservation Of Activity

To insure the model accounts for 100% of the injected activity at all
times (that is, it conserves activity), the dosimetry model uses whole
body imaging with the determination of remainder of body residence times
by subtracting organ residence times from whole body residence times.

## Dosimetry Methods 

**Dosimetry Methods:** Dosimetry estimates were based on the following:

-   Residence times as described in the Kinetic Modeling section

-   MIRDOSE 3.1 software

```{=html}
<!-- -->
```
-   S-values Source: MIRDOSE 3.1 software

## Dosimetry Results

This section displays and compares IDEC's and CBER's results of the
MIRDOSE software estimation of the radiation absorbed doses using the
residence times described in the Kinetic Modeling section. The results
obtained by CBER in this section are based on the time-activity data
submitted to the BLA by IDEC. The differences are compatible with the
smaller sample (6 patients) used by CBER for the comparison.

### Y-90-2B8 Dosimetry

Table: Y-90-2B8 Normal Organs Absorbed Radiation Doses in cGy/mCi

+--------------+------------+-------+-------+-------+--------+-------+
| **Orga       | **Source   | **I   | **Ra  | *     | **R    | **I   |
| ns/Tissues** | of Data    | DEC** | nge** | *CBER | ange** | DEC/C |
|              | for        |       |       | cGy/  |        | BER** |
|              | D          | *     |       | mCi** |        |       |
|              | osimetry** | *cGy/ |       |       |        |       |
|              |            | mCi** |       |       |        |       |
+--------------+------------+-------+-------+-------+--------+-------+
| **Adrenals** | **Whole    | **    | **(   | **    | *      | **0   |
|              | Body ROI** | 1.0** | 0.1-1 | 1.1** | *(0.7- | .93** |
|              |            |       | .7)** |       | 1.3)** |       |
+--------------+------------+-------+-------+-------+--------+-------+
| **Brain**    | **Whole    | **    | **(   | **    | *      | **0   |
|              | Body ROI** | 1.0** | 0.1-1 | 1.1** | *(0.7- | .93** |
|              |            |       | .7)** |       | 1.3)** |       |
+--------------+------------+-------+-------+-------+--------+-------+
| **Breasts**  | **Whole    | **    | **(   | **    | *      | **0   |
|              | Body ROI** | 1.0** | 0.1-1 | 1.1** | *(0.7- | .93** |
|              |            |       | .7)** |       | 1.3)** |       |
+--------------+------------+-------+-------+-------+--------+-------+
| *            | **Whole    | **    | **(   | **    | *      | **0   |
| *Gallbladder | Body ROI** | 1.0** | 0.1-1 | 1.1** | *(0.7- | .93** |
| Wall**       |            |       | .7)** |       | 1.3)** |       |
+--------------+------------+-------+-------+-------+--------+-------+
| **Lower      | **Organ    | **1   | **(6  | **1   | **     | **1   |
| Large        | ROI**      | 1.5** | .8-18 | 1.5** | (8.0-1 | .00** |
| Intestine    |            |       | .3)** |       | 4.6)** |       |
| (LLI) Wall** |            |       |       |       |        |       |
+--------------+------------+-------+-------+-------+--------+-------+
| **Small      | **Organ    | **    | **(   | **    | *      | **1   |
| Intestine    | ROI**      | 4.3** | 2.4-6 | 4.1** | *(2.4- | .05** |
| (SI)**       |            |       | .3)** |       | 5.0)** |       |
+--------------+------------+-------+-------+-------+--------+-------+
| **Stomach**  | **Whole    | **    | **(   | **    | *      | **0   |
|              | Body ROI** | 1.0** | 0.1-1 | 1.1** | *(0.7- | .93** |
|              |            |       | .7)** |       | 1.3)** |       |
+--------------+------------+-------+-------+-------+--------+-------+
| **Upper      | **Organ    | **    | **(3  | **    | *      | **1   |
| Large        | ROI**      | 7.0** | .7-12 | 6.6** | *(3.8- | .06** |
| Intestine    |            |       | .1)** |       | 9.0)** |       |
| (ULI) Wall** |            |       |       |       |        |       |
+--------------+------------+-------+-------+-------+--------+-------+
| **Heart      | **Organ    | **    | **(5  | **    | **     | **1   |
| Wall**       | ROI**      | 9.6** | .5-11 | 8.9** | (5.6-1 | .08** |
|              |            |       | .9)** |       | 1.0)** |       |
+--------------+------------+-------+-------+-------+--------+-------+
| **Kidneys**  | **Organ    | **    | **(   | **    | *      | **1   |
|              | ROI**      | 0.4** | 0.0-0 | 0.2** | *(0.0- | .84** |
|              |            |       | .8)** |       | 0.8)** |       |
+--------------+------------+-------+-------+-------+--------+-------+
| **Liver**    | **Organ    | **2   | **(8  | **1   | **(    | **1   |
|              | ROI**      | 0.0** | .4-29 | 7.1** | 10.9-2 | .17** |
|              |            |       | .9)** |       | 7.5)** |       |
+--------------+------------+-------+-------+-------+--------+-------+
| **Lungs**    | **Organ    | **    | **(4  | **    | *      | **1   |
|              | ROI**      | 7.1** | .3-12 | 6.2** | *(4.5- | .13** |
|              |            |       | .4)** |       | 8.0)** |       |
+--------------+------------+-------+-------+-------+--------+-------+
| **Muscle**   | **Whole    | **    | **(   | **    | *      | **0   |
|              | Body ROI** | 1.0** | 0.1-1 | 1.1** | *(0.7- | .93** |
|              |            |       | .7)** |       | 1.3)** |       |
+--------------+------------+-------+-------+-------+--------+-------+
| **Ovaries**  | **Whole    | **    | **(   | **    | *      | **1   |
|              | Body ROI** | 1.4** | 1.3-1 | 1.1** | *(0.7- | .29** |
|              |            |       | .7)** |       | 1.3)** |       |
+--------------+------------+-------+-------+-------+--------+-------+
| **Pancreas** | **Whole    | **    | **(   | **    | *      | **0   |
|              | Body ROI** | 1.0** | 0.1-1 | 1.1** | *(0.7- | .93** |
|              |            |       | .7)** |       | 1.3)** |       |
+--------------+------------+-------+-------+-------+--------+-------+
| **Red        | **Sacrum   | **    | **(   | **    | *      | **1   |
| Marrow**     | ROI**      | 4.7** | 2.6-6 | 2.8** | *(2.2- | .69** |
|              |            |       | .8)** |       | 3.3)** |       |
+--------------+------------+-------+-------+-------+--------+-------+
| **Bone       | **Sacrum   | **    | **(   | **    | *      | **1   |
| Surfaces**   | ROI**      | 3.3** | 1.8-4 | 2.2** | *(1.8- | .50** |
|              |            |       | .3)** |       | 2.4)** |       |
+--------------+------------+-------+-------+-------+--------+-------+
| **Skin**     | **Whole    | **    | **(   | **    | *      | **0   |
|              | Body ROI** | 1.0** | 0.1-1 | 1.1** | *(0.7- | .93** |
|              |            |       | .7)** |       | 1.3)** |       |
+--------------+------------+-------+-------+-------+--------+-------+
| **Spleen**   | **Organ    | **3   | **(6  | **4   | **(    | **0   |
|              | ROI**      | 5.0** | .7-53 | 2.2** | 24.4-7 | .83** |
|              |            |       | .2)** |       | 4.0)** |       |
+--------------+------------+-------+-------+-------+--------+-------+
| **Testes**   | **Organ    | **3   | **(19 | **2   | *      | **1   |
|              | ROI**      | 3.1** | .9-42 | 9.7** | *(1.2- | .11** |
|              |            |       | .3)** |       | 37)7** |       |
+--------------+------------+-------+-------+-------+--------+-------+
| **Thymus**   | **Whole    | **    | **(   | **    | *      | **0   |
|              | Body ROI** | 1.0** | 0.1-1 | 1.1** | *(0.7- | .93** |
|              |            |       | .7)** |       | 1.3)** |       |
+--------------+------------+-------+-------+-------+--------+-------+
| **Thyroid**  | **Whole    | **    | **(   | **    | *      | **0   |
|              | Body ROI** | 1.0** | 0.1-1 | 1.1** | *(0.7- | .93** |
|              |            |       | .7)** |       | 1.3)** |       |
+--------------+------------+-------+-------+-------+--------+-------+
| **Urinary    | **Whole    | **    | **(   | **    | *      | **1   |
| Bladder      | Body ROI** | 3.9** | 2.6-7 | 3.2** | *(2.8- | .21** |
| Wall**       |            |       | .8)** |       | 3.5)** |       |
+--------------+------------+-------+-------+-------+--------+-------+
| **Uterus**   | **Whole    | **    | **(   | **    | *      | **1   |
|              | Body ROI** | 1.4** | 1.3-1 | 1.1** | *(0.7- | .29** |
|              |            |       | .7)** |       | 1.3)** |       |
+--------------+------------+-------+-------+-------+--------+-------+
| **Total      | **Whole    | **    | **(   | **    | *      | **1   |
| Body**       | Body ROI** | 1.9** | 0.7-2 | 1.9** | *(1.8- | .04** |
|              |            |       | .6)** |       | 2.0)** |       |
+--------------+------------+-------+-------+-------+--------+-------+

\* All excretion assumed to be urinary. Whole body fits were used to
determined excretion parameters.

### In-111-2B8 Dosimetry

Dosimetry for In-111 was determined by CBER for 6 patients and compared
to the results reported by IDEC. CBER's results were based on the
kinetic data as provided by IDEC. The absorbed doses found by CBER were
similar to those found by IDEC.

Table: In-111-2B8 Normal Organs Radiation Absorbed Doses in cGy/mCi

+--------------+-------------+-------+-------+--------+------+-------+
| **Orga       | **Source of | **I   | **Ra  | **CBER | *    | **I   |
| ns/Tissues** | Data for    | DEC** | nge** | cGy    | *Ran | DEC/C |
|              | Dosimetry** |       |       | /mCi** | ge** | BER** |
|              |             | *     |       |        |      |       |
|              |             | *cGy/ |       |        |      |       |
|              |             | mCi** |       |        |      |       |
+--------------+-------------+-------+-------+--------+------+-------+
| **Adrenals** | **Whole     | **    | **(   | *      | *    | **1   |
|              | Body ROI**  | 0.8** | 0.4-1 | *0.7** | *(0. | .06** |
|              |             |       | .0)** |        | 7-0. |       |
|              |             |       |       |        | 9)** |       |
+--------------+-------------+-------+-------+--------+------+-------+
| **Brain**    | **Whole     | **    | **(   | *      | *    | **0   |
|              | Body ROI**  | 0.2** | 0.0-0 | *0.2** | *(0. | .97** |
|              |             |       | .3)** |        | 2-0. |       |
|              |             |       |       |        | 3)** |       |
+--------------+-------------+-------+-------+--------+------+-------+
| **Breasts**  | **Whole     | **    | **(   | *      | *    | **1   |
|              | Body ROI**  | 0.3** | 0.1-0 | *0.3** | *(0. | .02** |
|              |             |       | .4)** |        | 3-0. |       |
|              |             |       |       |        | 3)** |       |
+--------------+-------------+-------+-------+--------+------+-------+
| *            | **Whole     | **    | **(   | *      | *    | **1   |
| *Gallbladder | Body ROI**  | 1.1** | 0.5-1 | *1.0** | *(0. | .07** |
| Wall**       |             |       | .4)** |        | 8-1. |       |
|              |             |       |       |        | 3)** |       |
+--------------+-------------+-------+-------+--------+------+-------+
| **LLI Wall** | **Organ     | **    | **    | *      | *    | **1   |
|              | ROI**       | 1.1** | 0.7-1 | *1.1** | *(0. | .03** |
|              |             |       | .8)** |        | 8-1. |       |
|              |             |       |       |        | 3)** |       |
+--------------+-------------+-------+-------+--------+------+-------+
| **Small      | **Organ     | **    | **(   | *      | *    | **1   |
| Intestine**  | ROI**       | 0.8** | 0.4-1 | *0.7** | *(0. | .05** |
|              |             |       | .1)** |        | 6-0. |       |
|              |             |       |       |        | 8)** |       |
+--------------+-------------+-------+-------+--------+------+-------+
| **Stomach**  | **Whole     | **    | **(   | *      | *    | **0   |
|              | Body ROI**  | 0.6** | 0.3-0 | *0.6** | *(0. | .99** |
|              |             |       | .8)** |        | 5-0. |       |
|              |             |       |       |        | 7)** |       |
+--------------+-------------+-------+-------+--------+------+-------+
| **ULI Wall** | **Organ     | **    | **(   | *      | *    | **1   |
|              | ROI**       | 1.0** | 0.7-1 | *1.0** | *(0. | .07** |
|              |             |       | .6)** |        | 8-1. |       |
|              |             |       |       |        | 2)** |       |
+--------------+-------------+-------+-------+--------+------+-------+
| **Heart      | **Organ     | **    | **(   | *      | *    | **1   |
| Wall**       | ROI**       | 1.4** | 0.9-1 | *1.3** | *(0. | .09** |
|              |             |       | .7)** |        | 9-1. |       |
|              |             |       |       |        | 5)** |       |
+--------------+-------------+-------+-------+--------+------+-------+
| **Kidneys**  | **Organ     | **    | **(   | *      | *    | **1   |
|              | ROI**       | 0.6** | 0.3-0 | *0.6** | *(0. | .05** |
|              |             |       | .7)** |        | 5-0. |       |
|              |             |       |       |        | 6)** |       |
+--------------+-------------+-------+-------+--------+------+-------+
| **Liver**    | **Organ     | **    | **(   | *      | *    | **1   |
|              | ROI**       | 2.7** | 1.2-4 | *2.4** | *(1. | .14** |
|              |             |       | .0)** |        | 6-3. |       |
|              |             |       |       |        | 7)** |       |
+--------------+-------------+-------+-------+--------+------+-------+
| **Lungs**    | **Organ     | **    | **(   | *      | *    | **1   |
|              | ROI**       | 0.9** | 0.5-1 | *0.8** | *(0. | .12** |
|              |             |       | .4)** |        | 8-0. |       |
|              |             |       |       |        | 9)** |       |
+--------------+-------------+-------+-------+--------+------+-------+
| **Muscle**   | **Whole     | **    | **(   | *      | *    | **1   |
|              | Body ROI**  | 0.4** | 0.1-0 | *0.4** | *(0. | .00** |
|              |             |       | .5)** |        | 3-0. |       |
|              |             |       |       |        | 4)** |       |
+--------------+-------------+-------+-------+--------+------+-------+
| **Ovaries**  | **Whole     | **    | **(   | *      | *    | **1   |
|              | Body ROI**  | 0.7** | 0.6-0 | *0.6** | *(0. | .35** |
|              |             |       | .8)** |        | 4-0. |       |
|              |             |       |       |        | 6)** |       |
+--------------+-------------+-------+-------+--------+------+-------+
| **Pancreas** | **Whole     | **    | **(   | *      | *    | **1   |
|              | Body ROI**  | 0.9** | 0.5-1 | *0.9** | *(0. | .00** |
|              |             |       | .1)** |        | 7-1. |       |
|              |             |       |       |        | 0)** |       |
+--------------+-------------+-------+-------+--------+------+-------+
| **Red        | **Sacrum    | **    | **(   | *      | *    | **1   |
| Marrow**     | ROI**       | 0.6** | 0.4-0 | *0.5** | *(0. | .29** |
|              |             |       | .8)** |        | 5-0. |       |
|              |             |       |       |        | 5)** |       |
+--------------+-------------+-------+-------+--------+------+-------+
| **Bone       | **Sacrum    | **    | **    | *      | *    | **1   |
| Surfaces**   | ROI**       | 0.7** | 0.3-0 | *0.6** | *(0. | .13** |
|              |             |       | .9)** |        | 5-0. |       |
|              |             |       |       |        | 6)** |       |
+--------------+-------------+-------+-------+--------+------+-------+
| **Skin**     | **Whole     | **    | **(   | *      | *    | **0   |
|              | Body ROI**  | 0.2** | 0.1-0 | *0.2** | *(0. | .97** |
|              |             |       | .3)** |        | 2-0. |       |
|              |             |       |       |        | 2)** |       |
+--------------+-------------+-------+-------+--------+------+-------+
| **Spleen**   | **Organ     | **    | **(   | *      | *    | **0   |
|              | ROI**       | 3.2** | 0.8-4 | *3.8** | *(2. | .84** |
|              |             |       | .6)** |        | 4-6. |       |
|              |             |       |       |        | 5)** |       |
+--------------+-------------+-------+-------+--------+------+-------+
| **Testes**   | **Organ     | **    | **(   | *      | *    | **1   |
|              | ROI**       | 2.3** | 1.4-3 | *2.0** | *(0. | .18** |
|              |             |       | .0)** |        | 3-2. |       |
|              |             |       |       |        | 6)** |       |
+--------------+-------------+-------+-------+--------+------+-------+
| **Thymus**   | **Whole     | **    | **(   | *      | *    | **1   |
|              | Body ROI**  | 0.5** | 0.3-0 | *0.5** | *(0. | .02** |
|              |             |       | .6)** |        | 4-0. |       |
|              |             |       |       |        | 5)** |       |
+--------------+-------------+-------+-------+--------+------+-------+
| **Thyroid**  | **Whole     | **    | **(   | *      | *    | **0   |
|              | Body ROI**  | 0.3** | 0.0-0 | *0.3** | *(0. | .92** |
|              |             |       | .4)** |        | 2-0. |       |
|              |             |       |       |        | 3)** |       |
+--------------+-------------+-------+-------+--------+------+-------+
| **Urine      | **Whole     | **    | **(   | *      | *    | **1   |
| Bladder      | Body ROI**  | 0.6** | 0.5-0 | *0.6** | *(0. | .09** |
| Wall**       |             |       | .8)** |        | 5-0. |       |
|              |             |       |       |        | 6)** |       |
+--------------+-------------+-------+-------+--------+------+-------+
| **Uterus**   | **Whole     | **    | **(   | *      | *    | **1   |
|              | Body ROI**  | 0.6** | 0.5-0 | *0.5** | *(0. | .28** |
|              |             |       | .7)** |        | 4-0. |       |
|              |             |       |       |        | 5)** |       |
+--------------+-------------+-------+-------+--------+------+-------+
| **Total      | **Whole     | **    | **(   | *      | *    | **1   |
| Body**       | Body ROI**  | 0.5** | 0.2-0 | *0.4** | *(0. | .03** |
|              |             |       | .6)** |        | 4-0. |       |
|              |             |       |       |        | 5)** |       |
+--------------+-------------+-------+-------+--------+------+-------+

### Selected Tumor Dosimetry 

The following tables (data reported in two consecutive tables due to
size/space limitation) display the tumor radiation absorbed doses as
determined by IDEC. The tumor dosimetry is listed in order of highest
absorbed dose to lowest absorbed dose for tumors. Following these tables
is a log-log scatter plot of absorbed dose vs. mass.

Table: Tumor Dosimetry Table with Tumor Mass and Location

  -------- ----------------- ------------------- -------------- ----------------------
           **Patient         **Tumor Location**  **Tumor Mass   **Tumor Dose (cGy)**
           Number**                              (grams)**      

  **1**    **10604020411**   **R. Lung**         **4.0**        **24274**

  **2**    **10604001252**   **Neck**            **2.1**        **23766**

  **3**    **10604001293**   **Abdomen**         **2.9**        **19200**

  **4**    **10604001204**   **Abdomen**         **10.2**       **11814**

  **5**    **10604001303**   **Neck**            **4.2**        **8696**

  **6**    **10603002305**   **L. Lumbar Spine** **3.5**        **6363**

  **7**    **10603008302**   **Neck**            **1.2**        **5073**

  **8**    **10604001106**   **Abdomen**         **4.3**        **3231**

  **9**    **10604002246**   **L. Neck**         **2.2**        **3136**

  **10**   **10604001279**   **Abdomen**         **20.9**       **2996**

  **11**   **10603009335**   **L. Neck**         **2.0**        **2993**

  **12**   **10604001300**   **Abdomen**         **49.1**       **2940**

  **13**   **10604014111**   **R. Inguinal**     **3.1**        **2893**

  **14**   **10603007212**   **L. Neck**         **19.6**       **2755**

  **15**   **10604001208**   **L. Chest**        **5.4**        **2688**

  **15**   **10604001208**   **Abdomen**         **26.8**       **2624**

  **17**   **10604007250**   **R. Axilla**       **1.9**        **2615**

  **18**   **10604023277**   **L.                **4.9**        **2608**
                             Submandibular**                    

  **19**   **10603002333**   **L. Groin**        **18.9**       **2462**

  **20**   **10604001279**   **Upper Chest**     **13.6**       **2352**

  **21**   **10603002333**   **R. Groin**        **14.1**       **2240**

  **22**   **10603002210**   **R. Lumbar Spine** **36.2**       **2179**

  **23**   **10603002210**   **L. Lumbar Spine** **38.2**       **2121**

  **24**   **10603009335**   **R. Neck**         **4.7**        **1989**

  **25**   **10604002101**   **L. Sub Axilla**   **5.7**        **1879**

  **26**   **10604002101**   **L. Internal       **2.7**        **1879**
                             Axilla**                           

  **27**   **10604011239**   **L.                **17.8**       **1736**
                             Supraclavicular**                  

  **28**   **10604001291**   **Abdomen**         **78.4**       **1528**

  **29**   **10604001210**   **Abdomen**         **8.3**        **1484**

  **30**   **10604001259**   **Pelvis**          **16.1**       **1468**

  **31**   **10603002205**   **R. Neck**         **5.0**        **1434**

  **32**   **10604003205**   **Chest**           **24.8**       **1338**

  **33**   **10603007212**   **L. Thoracic       **79.2**       **1331**
                             Spine**                            

  **34**   **10604001105**   **L. Neck**         **1.8**        **1309**

  **35**   **10604011268**   **L. Inguinal**     **1.8**        **1280**

  **36**   **10603002333**   **R. Neck**         **13.4**       **1253**

  **37**   **10604001279**   **L. Inguinal**     **32.8**       **980**

  **38**   **10603009335**   **R. Pelvis**       **40.7**       **955**

  **39**   **10604001202**   **R. Chest**        **8.9**        **947**
  -------- ----------------- ------------------- -------------- ----------------------

Table: Tumor Dosimetry Table with Tumor Mass and Location (continued)

  -------- ----------------- ---------------- ---------------- ------------------
           **Patient         **Tumor          **Tumor          **Tumor
           Number**          Location**       Mass(grams)**    Dose(cGy)**

  **40**   **10604001232**   **Pelvis**       **25.1**         **790**

  **41**   **10603009335**   **L. Pelvis**    **40.7**         **761**

  **42**   **10604001202**   **L. Chest**     **22.1**         **646**

  **43**   **10604001105**   **R. Neck**      **1.5**          **638**

  **44**   **10603002307**   **Pelvis**       **284.9**        **608**

  **45**   **10603002206**   **Abdomen**      **21.8**         **586**

  **46**   **10603002333**   **L. Neck**      **5.9**          **578**

  **47**   **10603002333**   **Upper          **33.5**         **575**
                             Abdomen**                         

  **48**   **10604031217**   **Mesenteric**   **69.6**         **448**

  **49**   **10604001303**   **Abdomen**      **24.3**         **416**

  **50**   **10604001232**   **R. Chest**     **80.8**         **379**

  **51**   **10604001300**   **Pelvis**       **198.7**        **357**

  **52**   **10604001230**   **Pelvis**       **227.6**        **336**

  **53**   **10604002267**   **L. Parotid**   **1.6**          **306**

  **54**   **10604029222**   **R. Axilla**    **13.4**         **306**

  **55**   **10604001202**   **L. Pelvis**    **18.7**         **237**

  **56**   **10604001407**   **Abdomen**      **302.5**        **192**

  **57**   **10604001116**   **Abdomen**      **317.0**        **61**
  -------- ----------------- ---------------- ---------------- ------------------

Tumor radiation absorbed dose estimates by both IDEC and CBER were
obtained using absorbed fractions that were based on the average beta
energy emission of Y-90, and the assumption that the tumors could be
modeled as spheres for radiation transport purposes.

Graph: Scatter Plot of Tumor Absorbed Dose vs. Mass

  -----------------------------------------------------------------------
  ![](media/image6.png)

  -----------------------------------------------------------------------

##### CBER Review Comment 

Review of IDEC's reported tumor dosimetry evaluations notes the tumor
mass appears inversely related to the absorbed radiation dose. This
trend suggests the possibility of a decreasing estimated radiation
exposure to the tumor site as the tumor mass increases in size. However,
the evaluated tumor sites are a minority of the imaged tumor sites and
may not be representative of the total population of the tumor sites.
Furthermore, these tumors were selected in a non-random, uncontrolled
manner without a prospectively designed protocol. Therefore, future
studies should be considered to evaluate the possible relationships
between tumor mass, estimated tumor radiation absorbed dose, and the
confirmed response by the tumor site.

#### CBER's Evaluation of Dosimetry for 15 Selected Tumors. 

**CBER has performed a re-evaluation of the absorbed radiation dose
estimates for 15 tumors. CBER's dosimetry data are based on the kinetic
data, and the tumor mass data provided by IDEC.**

+---+------------+------------+--------+---------+---------+----------+
| * |            | **Tumor**  | *      | **IDEC  | **CBER  | **CBE    |
| * |            |            | *Tumor | Dose**  | Dose    | R/IDEC** |
| P |            | **         | Mass** |         | cG      |          |
| a |            | Location** |        | **cG    | y/mCi** |          |
| t |            |            | **g    | y/mCi** |         |          |
| i |            |            | rams** |         |         |          |
| e |            |            |        |         |         |          |
| n |            |            |        |         |         |          |
| t |            |            |        |         |         |          |
| * |            |            |        |         |         |          |
| * |            |            |        |         |         |          |
|   |            |            |        |         |         |          |
| * |            |            |        |         |         |          |
| * |            |            |        |         |         |          |
| I |            |            |        |         |         |          |
| D |            |            |        |         |         |          |
| * |            |            |        |         |         |          |
| * |            |            |        |         |         |          |
+---+------------+------------+--------+---------+---------+----------+
| * | **106-04   | **Neck**   | *      | **749** | *       | **1.54** |
| * | -001-252** |            | *2.1** |         | *1150** |          |
| 1 |            |            |        |         |         |          |
| * |            |            |        |         |         |          |
| * |            |            |        |         |         |          |
+---+------------+------------+--------+---------+---------+----------+
| * | **106-04   | **R.       | **4**  | **778** | **815** | **1.05** |
| * | -020-411** | Lung**     |        |         |         |          |
| 2 |            |            |        |         |         |          |
| * |            |            |        |         |         |          |
| * |            |            |        |         |         |          |
+---+------------+------------+--------+---------+---------+----------+
| * | **106-04   | *          | **     | **107** | **158** | **1.48** |
| * | -001-279** | *Abdomen** | 20.9** |         |         |          |
| 3 |            |            |        |         |         |          |
| * |            |            |        |         |         |          |
| * |            |            |        |         |         |          |
+---+------------+------------+--------+---------+---------+----------+
| * | **106-04   | *          | *      | **136** | **142** | **1.05** |
| * | -001-106** | *Abdomen** | *4.3** |         |         |          |
| 4 |            |            |        |         |         |          |
| * |            |            |        |         |         |          |
| * |            |            |        |         |         |          |
+---+------------+------------+--------+---------+---------+----------+
| * | **106-04   | **L.       | **     | **80**  | **81**  | **1.01** |
| * | -011-239** | Supracl    | 17.8** |         |         |          |
| 5 |            | avicular** |        |         |         |          |
| * |            |            |        |         |         |          |
| * |            |            |        |         |         |          |
+---+------------+------------+--------+---------+---------+----------+
| * | **106-04   | *          | **     | **14**  | **63**  | **4.5**  |
| * | -001-303** | *Abdomen** | 24.3** |         |         |          |
| 6 |            |            |        |         |         |          |
| * |            |            |        |         |         |          |
| * |            |            |        |         |         |          |
+---+------------+------------+--------+---------+---------+----------+
| * | **106-04   | **Pelvis** | **     | **54**  | **63**  | **1.16** |
| * | -001-259** |            | 16.1** |         |         |          |
| 7 |            |            |        |         |         |          |
| * |            |            |        |         |         |          |
| * |            |            |        |         |         |          |
+---+------------+------------+--------+---------+---------+----------+
| * | **106-04   | **Chest**  | **     | **60**  | **53**  | **0.88** |
| * | -003-205** |            | 24.8** |         |         |          |
| 8 |            |            |        |         |         |          |
| * |            |            |        |         |         |          |
| * |            |            |        |         |         |          |
+---+------------+------------+--------+---------+---------+----------+
| * | **106-04   | *          | **     | **48**  | **50**  | **1.04** |
| * | -001-291** | *Abdomen** | 78.4** |         |         |          |
| 9 |            |            |        |         |         |          |
| * |            |            |        |         |         |          |
| * |            |            |        |         |         |          |
+---+------------+------------+--------+---------+---------+----------+
| * | **106-04   | **L.       | **     | **30**  | **30**  | **0.99** |
| * | -001-202** | Chest**    | 22.1** |         |         |          |
| 1 |            |            |        |         |         |          |
| 0 |            |            |        |         |         |          |
| * |            |            |        |         |         |          |
| * |            |            |        |         |         |          |
+---+------------+------------+--------+---------+---------+----------+
| * | **106-04   | **R.       | **     | **17**  | **16**  | **0.96** |
| * | -029-222** | Axilla**   | 13.4** |         |         |          |
| 1 |            |            |        |         |         |          |
| 1 |            |            |        |         |         |          |
| * |            |            |        |         |         |          |
| * |            |            |        |         |         |          |
+---+------------+------------+--------+---------+---------+----------+
| * | **106-04   | **Me       | **     | **14**  | **15**  | **1.06** |
| * | -031-217** | senteric** | 69.6** |         |         |          |
| 1 |            |            |        |         |         |          |
| 2 |            |            |        |         |         |          |
| * |            |            |        |         |         |          |
| * |            |            |        |         |         |          |
+---+------------+------------+--------+---------+---------+----------+
| * | **106-04   | **Pelvis** | **2    | **12**  | **13**  | **1.05** |
| * | -001-230** |            | 27.6** |         |         |          |
| 1 |            |            |        |         |         |          |
| 3 |            |            |        |         |         |          |
| * |            |            |        |         |         |          |
| * |            |            |        |         |         |          |
+---+------------+------------+--------+---------+---------+----------+
| * | **106-04   | **Pelvis** | **1    | **13**  | **13**  | **1.03** |
| * | -001-300** |            | 98.7** |         |         |          |
| 1 |            |            |        |         |         |          |
| 4 |            |            |        |         |         |          |
| * |            |            |        |         |         |          |
| * |            |            |        |         |         |          |
+---+------------+------------+--------+---------+---------+----------+
| * | **106-04   | *          | **3    | **6**   | **6**   | **1.07** |
| * | -001-407** | *Abdomen** | 02.5** |         |         |          |
| 1 |            |            |        |         |         |          |
| 5 |            |            |        |         |         |          |
| * |            |            |        |         |         |          |
| * |            |            |        |         |         |          |
+---+------------+------------+--------+---------+---------+----------+

##### CBER Review Comment 

**For 9 of the 15 tumors, CBER found results within 10% of the results
obtained by IDEC, and for 12 of the 15, within 20% of the result found
by IDEC. In summary, CBER's results are compatible with IDEC's
results.**

**Tumor radiation absorbed dose estimates by both IDEC and CBER were
obtained using absorbed fractions that were based on the average beta
energy emission of Y-90, and the assumption that the tumors could be
modeled as spheres for radiation transport purposes.** **Both of these
assumptions are considered conservative, and the assumptions are
expected to result in an overestimate of the actual radiation absorbed
dose to the tumors.**

### Absorbed Radiation Dose Depth Profiles For Surrounding Tissues From Theoretical Tumor Models

Given the radiation absorbed doses reported by IDEC in several tumors,
and the relatively long path length (5 mm) of the Y-90 beta emission,
there exists the possibility of significant absorbed radiation doses to
tissues immediately adjacent to the tumor sites.

This section describes the use of several geometric models and radiation
transport simulations to estimate radiation absorbed dose to structures
adjacent to theoretical tumors.

Three models were constructed, with two tumor sizes each, to investigate
various situations including tumor around the pulmonary artery, tumor
around a small cylinder such as a nerve, and tumor impinging on the
pericardium or bowel wall. These models are discussed in the following
text.

Depth absorbed dose profiles for all models were calculated for Y-90.
This calculation was performed by determining absorbed fractions using
Monte Carlo simulation of the radiation transport models. For each
simulation between 100 thousand and 20 million particle histories were
run. Full beta spectrums were generated for the simulations. Photon
emission simulations were run but contributed far less than 1% of the
absorbed dose in all cases. For the electron simulations, sufficient
numbers of histories were run such that the relative errors were less
than 10%. The MCNP (Monte Carlo N-Particle Transport Code System)
relative error criteria for generally reliable results is 10% or less.

###  Tumor Adjacent to Pericardium or Bowel Wall

This simulation was designed to model a hemispherical tumor located on
the bowel wall, on the surface of the pericardium, or any other soft
tissue structure. The tumor was modeled as a hemispherical source, and
the radiation absorbed dose was determined as a function of distance
away from the planar surface of the hemispherical tumor. The target
tissue of interest was subdivided using cutting planes such that a
depth-absorbed dose profile could be obtained. The first table lists the
depth absorbed dose in terms of percent of "tumor" absorbed dose into
the tissue of interest for a 5 gram hemispherical tumor model. The
second table lists the depth absorbed dose profile into the tissue of
interest for the 20 grams hemispherical tumor model.

Table: 5g Hemispherical Tumor Depth Absorbed Dose Profile for Tissue

  ----------------------------------- -----------------------------------
  **Depth (mm)**                      **Percent of Source Absorbed Dose**

  **Source ("tumor")**                **100.0%**

  **0.25**                            **51.4%**

  **0.75**                            **36.5%**

  **1.25**                            **26.4%**

  **1.75**                            **18.7%**

  **2.5**                             **11.6%**

  **3.5**                             **5.9%**

  **5.0**                             **1.7%**
  ----------------------------------- -----------------------------------

Table: 20g Hemispherical Tumor Depth Absorbed Dose Profile for Tissue

  ----------------------------------- -----------------------------------
  **Depth (mm)**                      **Percent of Source Absorbed Dose**

  **Source ("tumor")**                **100.0%**

  **0.25**                            **47.1%**

  **0.75**                            **32.9%**

  **1.5**                             **20.1%**

  **2.5**                             **10.3%**

  **3.5**                             **4.9%**

  **5.0**                             **1.6%**
  ----------------------------------- -----------------------------------

### Tumor Surrounding Small Cylindrical Structure (nerve or artery)

This simulation was designed to model a tumor wrapped around a small
cylindrical structure. In this model the small cylinder had a radius of
2 mm, which would represent a small artery or nerve. Tumors were modeled
as spherical sources. The cylindrical target shell was subdivided into
many thin shells such that a depth-absorbed dose could be obtained. The
model was configured so that the tumors completely encased the small
cylindrical target. Two sizes of tumors were modeled, 5 grams and 20
grams. The first table lists the depth absorbed dose profile in terms of
percent of the absorbed dose in the tumor as a function of depth into
the cylinder for the 5 grams model. The second table lists the depth
absorbed dose profile for the cylinder using a 20 grams tumor model.

Table: Encircling 5g Tumor Depth Absorbed Dose Profile for Small
Cylindrical Target

  ----------------------------------- -----------------------------------
  **Depth (mm)**                      **Percent Source Absorbed Dose**

  **Source ("tumor")**                **100.0%**

  **0.05**                            **85.3%**

  **0.15**                            **76.6%**

  **0.25**                            **76.5%**

  **0.35**                            **75.2%**

  **0.45**                            **74.2%**

  **0.55**                            **69.8%**

  **0.65**                            **64.6%**

  **0.75**                            **58.8%**

  **0.85**                            **60.0%**

  **0.95**                            **56.8%**

  **1.05**                            **51.0%**

  **1.15**                            **58.0%**

  **1.25**                            **56.8%**

  **1.35**                            **55.1%**
  ----------------------------------- -----------------------------------

Table: Encircling 20g Tumor Depth Absorbed Dose Profile for Small
Cylindrical Target

  ------------------------------ ----------------------------------------
  **Depth (mm)**                 **Percent Source Absorbed Dose**

  **Source ("tumor")**           **100.0%**

  **0.05**                       **74.8%**

  **0.15**                       **68.2%**

  **0.25**                       **66.5%**

  **0.35**                       **60.1%**

  **0.45**                       **57.7%**

  **0.55**                       **56.9%**

  **0.65**                       **58.8%**

  **0.75**                       **57.0%**

  **0.85**                       **54.7%**

  **0.95**                       **54.0%**

  **1.05**                       **52.9%**

  **1.15**                       **54.7%**

  **1.25**                       **60.5%**

  **1.35**                       **55.6%**
  ------------------------------ ----------------------------------------

### Tumor Adjacent to Pulmonary Artery

This simulation was designed to model a tumor that was wrapped around
the pulmonary artery. The model consisted of a spherical source
(representing tumor) with a cylinder running through the center to
represent the pulmonary artery. This cylinder was further sub-divided
into many cylindrical target shells such that the radiation absorbed
dose could be determined as a function of depth. The pulmonary artery
wall was modeled using the dimensions specified in ICRP 23. The model
was configured such that the tumors completely surrounded the artery.
Two sizes of tumors were modeled, 10 grams and 20 grams. The first table
lists the depth absorbed dose profile for the 10 gram tumor model in
terms of percent of the absorbed dose in the tumor as a function of
depth into the artery wall. The second table lists the depth absorbed
dose profile for the artery wall using a 20 gram tumor model.

Table: 10g Tumor Depth Absorbed Dose Profile for the Pulmonary Artery
Wall

  ------------------------------------ ----------------------------------
  **Depth (mm)**                       **Percent of Source Absorbed
                                       Dose**

  **Source ("tumor")**                 **100.0%**

  **0.05**                             **74.4%**

  **0.2**                              **64.8%**

  **0.45**                             **54.2%**

  **0.75**                             **45.1%**

  **1.1**                              **36.6%**
  ------------------------------------ ----------------------------------

Table: 20g Tumor Depth Absorbed Dose Profile for the Pulmonary Artery
Wall

  ------------------------------------ ----------------------------------
  **Depth (mm)**                       **Percent of Source Absorbed
                                       Dose**

  **Source ("tumor")**                 **100.0%**

  **0.05**                             **66.4%**

  **0.2**                              **57.8%**

  **0.45**                             **48.6%**

  **0.75**                             **39.9%**

  **1.1**                              **32.2%**
  ------------------------------------ ----------------------------------

##### CBER Review Comment

**The theoretical models demonstrate the potential for a significant
absorbed radiation dose to the surface of a normal structure from an
adjacent tumor site.**

### Radiation Absorbed Doses to Adjacent Structures from a Reported Tumor

IDEC reported a radiation absorbed dose of 24,274 cGy for a tumor site
in patient number 106-04-020-411. Given this reported radiation absorbed
dose for a tumor site, the relatively long path length (5 mm) of the
Y-90 beta emission, and the presented theoretical models, there exists
the possibility of significant radiation absorbed doses to tissues
immediately adjacent to such a reported tumor.

Assuming an equivalent tumor site radiation absorbed dose (24,274 cGy),
the radiation absorbed dose as a function of depth was determined for
the six "worst case" scenarios. These results are displayed in the
following six tables.

Table: Estimated Absorbed Dose To Pulmonary Artery From An Adjacent 10g
Tumor

  ------------------------------------ ----------------------------------
  **Depth (mm) Into Pulmonary Artery   **Absorbed Dose (cGy)**
  Wall**                               

  **Source ("tumor")**                 **24,274**

  **0.05**                             **18,057**

  **0.2**                              **15,738**

  **0.45**                             **13,154**

  **0.75**                             **10,957**

  **1.1**                              **8,883**
  ------------------------------------ ----------------------------------

Table: Estimated Absorbed Dose To Pulmonary Artery From An Adjacent 20g
Tumor

  ------------------------------------ ----------------------------------
  **Depth (mm) Into Pulmonary Artery   **Absorbed Dose (cGy)**
  Wall**                               

  **Source ("tumor")**                 **24,274**

  **0.05**                             **16,128**

  **0.2**                              **14,039**

  **0.45**                             **11,795**

  **0.75**                             **9,680**

  **1.1**                              **7,818**
  ------------------------------------ ----------------------------------

Table: Estimated Absorbed Dose To Tissue From An Adjacent Hemispherical
5g Tumor

  ------------------------------------ ----------------------------------
  **Depth (mm) into Adjacent Tissue**  **Absorbed Dose (cGy)**

  **Source ("tumor")**                 **24,274**

  **0.25**                             **12,477**

  **0.75**                             **8,865**

  **1.25**                             **6,422**

  **1.75**                             **4,549**

  **2.5**                              **2,811**

  **3.5**                              **1,440**

  **5.0**                              **426**
  ------------------------------------ ----------------------------------

Table: Estimated Absorbed Dose To Tissue From An Adjacent Hemispherical
20g Tumor

  ------------------------------------ ----------------------------------
  **Depth (mm) into Adjacent Tissue**  **Absorbed Dose (cGy)**

  **Source ("tumor")**                 **24,274**

  **0.25**                             **11,438**

  **0.75**                             **7,988**

  **1.5**                              **4,886**

  **2.5**                              **2,513**

  **3.5**                              **1,200**

  **5.0**                              **383**

  **7.0**                              **45**
  ------------------------------------ ----------------------------------

Table: Estimated Absorbed Dose To Small Cylinder From An Encircling 5g
Tumor

  ------------------------------------ ----------------------------------
  **Depth (mm) into Small Cylinder**   **Absorbed Dose (cGy)**

  **Source ("tumor")**                 **24,274**

  **0.05**                             **20,706**

  **0.15**                             **18,594**

  **0.25**                             **18,570**

  **0.35**                             **18,254**

  **0.45**                             **18,011**

  **0.55**                             **16,943**

  **0.65**                             **15,681**

  **0.75**                             **14,273**

  **0.85**                             **14,564**

  **0.95**                             **13,788**

  **1.05**                             **12,380**

  **1.15**                             **14,079**

  **1.25**                             **13,788**

  **1.35**                             **13,375**
  ------------------------------------ ----------------------------------

Table: Estimated Absorbed Dose To Small Cylinder From An Encircling 20g
Tumor

  ------------------------------------ ----------------------------------
  **Depth (mm) into Small Cylinder**   **Absorbed Dose (cGy)**

  **Source ("tumor")**                 **24,274**

  **0.05**                             **18,157**

  **0.15**                             **16,555**

  **0.25**                             **16,142**

  **0.35**                             **14,589**

  **0.45**                             **14,006**

  **0.55**                             **13,812**

  **0.65**                             **14,273**

  **0.75**                             **13,836**

  **0.85**                             **13,278**

  **0.95**                             **13,108**

  **1.05**                             **12,841**

  **1.15**                             **13,278**

  **1.25**                             **14,686**

  **1.35**                             **13,496**
  ------------------------------------ ----------------------------------

### CBER Review Comment

**Based on the reported estimated absorbed radiation dose in a tumor
site (24,274 cGy) and the presented theoretical models, there is a
potential risk of significant absorbed radiation in a normal structure
from an adjacent tumor site.**

###  Dosimetry Assuming Altered Biodistribution (Model = Large Colloid Type)

Dosimetry estimates for Y-90 were determined using a colloid type
distribution, based on the model described in ICRP-53 \[ICRP 1988\]. The
model assumes \"large\" colloids (100-1000 nm diameter), with
distributions of 70% in liver, and 10% each in spleen, red marrow, and
remaining tissue. It was further assumed that removal of activity was by
physical decay only.

Table: Colloid Distribution of Y-90-2B8 for the Maximum Allowable 32 mCi
Dose

+----------+-------+-------+----------+---------+---------+----------+
|          | **N   | **N   | *        | *       | Normal  | *        |
|          | ormal | ormal | *Altered | *Normal | Organ   | *Altered |
|          | Organ | Or    | Biodist  | Organ** | Do      | Biodist  |
|          | D     | gan** | ribution |         | simetry | ribution |
|          | osime |       | Dos      | Do      |         | Dos      |
|          | try** | **D   | imetry** | simetry | **CBER  | imetry** |
|          |       | osime |          |         | (cGy/32 |          |
|          | *     | try** | *        | *       | mCi)**  | *        |
|          | *IDEC |       | *Colloid | *IDEC** |         | *Colloid |
|          | (     | *     | Dist     |         |         | Dist     |
|          | cGy/m | *CBER | ribution | **      |         | ribution |
|          | Ci)** | (     | (cG      | (cGy/32 |         | (cGy/32  |
|          |       | cGy/m | y/mCi)** | mCi )** |         | mCi)**   |
|          |       | Ci)** |          |         |         |          |
+----------+-------+-------+----------+---------+---------+----------+
| **Ad     | **    | **    | **0.3**  | **33**  | **35**  | **9.6**  |
| renals** | 1.0** | 1.1** |          |         |         |          |
+----------+-------+-------+----------+---------+---------+----------+
| *        | **    | **    | **0.3**  | **33**  | **35**  | **9.6**  |
| *Brain** | 1.0** | 1.1** |          |         |         |          |
+----------+-------+-------+----------+---------+---------+----------+
| **B      | **    | **    | **0.3**  | **33**  | **35**  | **9.6**  |
| reasts** | 1.0** | 1.1** |          |         |         |          |
+----------+-------+-------+----------+---------+---------+----------+
| **Gal    | **    | **    | **0.3**  | **33**  | **35**  | **9.6**  |
| lbladder | 1.0** | 1.1** |          |         |         |          |
| Wall**   |       |       |          |         |         |          |
+----------+-------+-------+----------+---------+---------+----------+
| **LLI    | **1   | **1   | **0.3**  | **367** | **367** | **9.6**  |
| Wall**   | 1.5** | 1.5** |          |         |         |          |
+----------+-------+-------+----------+---------+---------+----------+
| **Small  | **    | **    | **0.3**  | **138** | **131** | **9.6**  |
| Int      | 4.3** | 4.1** |          |         |         |          |
| estine** |       |       |          |         |         |          |
+----------+-------+-------+----------+---------+---------+----------+
| **S      | **    | **    | **0.3**  | **33**  | **35**  | **9.6**  |
| tomach** | 1.0** | 1.1** |          |         |         |          |
+----------+-------+-------+----------+---------+---------+----------+
| **ULI    | **    | **    | **0.3**  | **224** | **211** | **9.6**  |
| Wall**   | 7.0** | 6.6** |          |         |         |          |
+----------+-------+-------+----------+---------+---------+----------+
| **Heart  | **    | **    | **0.3**  | **309** | **286** | **9.6**  |
| Wall**   | 9.6** | 8.9** |          |         |         |          |
+----------+-------+-------+----------+---------+---------+----------+
| **K      | **    | **    | **0.3**  | **12**  | **6**   | **9.6**  |
| idneys** | 0.4** | 0.2** |          |         |         |          |
+----------+-------+-------+----------+---------+---------+----------+
| *        | **2   | **1   | **67**   | **639** | **546** | **2144** |
| *Liver** | 0.0** | 7.1** |          |         |         |          |
+----------+-------+-------+----------+---------+---------+----------+
| *        | **    | **    | **0.3**  | **226** | **200** | **9.6**  |
| *Lungs** | 7.1** | 6.2** |          |         |         |          |
+----------+-------+-------+----------+---------+---------+----------+
| **       | **    | **    | **0.3**  | **33**  | **35**  | **9.6**  |
| Muscle** | 1.0** | 1.1** |          |         |         |          |
+----------+-------+-------+----------+---------+---------+----------+
| **O      | **    | **    | **0.3**  | **45**  | **35**  | **9.6**  |
| varies** | 1.4** | 1.1** |          |         |         |          |
+----------+-------+-------+----------+---------+---------+----------+
| **Pa     | **    | **    | **0.3**  | **33**  | **35**  | **9.6**  |
| ncreas** | 1.0** | 1.1** |          |         |         |          |
+----------+-------+-------+----------+---------+---------+----------+
| **Red    | **    | **    | **7.4**  | **152** | **89**  | *        |
| Marrow** | 4.7** | 2.8** |          |         |         | *236.8** |
+----------+-------+-------+----------+---------+---------+----------+
| **Bone   | **    | **    | **4.8**  | **105** | **70**  | *        |
| Sur      | 3.3** | 2.2** |          |         |         | *153.6** |
| faces†** |       |       |          |         |         |          |
+----------+-------+-------+----------+---------+---------+----------+
| **Skin** | **    | **    | **0.3**  | **33**  | **35**  | **9.6**  |
|          | 1.0** | 1.1** |          |         |         |          |
+----------+-------+-------+----------+---------+---------+----------+
| **       | **3   | **4   | **101**  | *       | *       | **3232** |
| Spleen** | 5.0** | 2.2** |          | *1120** | *1350** |          |
+----------+-------+-------+----------+---------+---------+----------+
| **       | **3   | **2   | **0.3**  | *       | **952** | **9.6**  |
| Testes** | 3.1** | 9.7** |          | *1060** |         |          |
+----------+-------+-------+----------+---------+---------+----------+
| **       | **    | **    | **0.3**  | **33**  | **35**  | **9.6**  |
| Thymus** | 1.0** | 1.1** |          |         |         |          |
+----------+-------+-------+----------+---------+---------+----------+
| **T      | **    | **    | **0.3**  | **33**  | **35**  | **9.6**  |
| hyroid** | 1.0** | 1.1** |          |         |         |          |
+----------+-------+-------+----------+---------+---------+----------+
| **Urine  | **    | **    | **0.3**  | **99**  | **102** | **9.6**  |
| Bladder  | 3.1** | 3.2** |          |         |         |          |
| Wall**   |       |       |          |         |         |          |
+----------+-------+-------+----------+---------+---------+----------+
| **       | **    | **    | **0.3**  | **48**  | **35**  | **9.6**  |
| Uterus** | 1.5** | 1.1** |          |         |         |          |
+----------+-------+-------+----------+---------+---------+----------+

† Absorbed dose due to activity assumed to be in red marrow as described
above.

### CBER Review Comment

The altered biodistribution scenario, as represented by the large
colloid model, estimated the radiation absorbed doses to the spleen at
3,232 cGy and to the liver at 2,144 cGy. These values exceed the
controlled trials prospectively designed maximum absorbed radiation
organ exposure of 2,000 cGy. The safety and efficacy of Y-90-2B8 has not
been studied in presence of normal organ radiation absorbed doses at
these levels.

### Dosimetry for Renal Obstruction

The stated clearance pathway for Y-90-2B8 is renal/urinary tract. Based
on the kinetic data collected, 7.3% of Y-90-2B8 will clear through
unobstructed kidneys following the administration of the maximum
allowable dose (32 mCi) of Y-90-2B8. For the "worst case" evaluation of
renal obstruction, this 7.3% will be transferred into the kidneys with a
46 hour biological half-time. For renal obstruction, once the activity
is in the kidneys, the activity is assumed to be retained with an
indefinite biological half-life. This will result in an absorbed dose to
kidneys of approximately 21 cGy/mCi, and with an administered activity
of 32 mCi, a total absorbed dose of 840 cGy.

## External Beam Radiation Therapy - Radiation Tolerance Doses\*

##### CBER Review Comment

**The following data are not considered to be directly applicable to
absorbed radiation doses from unsealed radiation therapy, e.g.,
radiolabeled monoclonal antibody therapy. This information is provided
for background reference only.**

The following table lists the radiation absorbed doses from external
radiation therapy required to produce the listed effects in the listed
organs. The primary source of these data is from external beam radiation
therapy applications.

TD 5/5 is the absorbed dose level required to produce the described
injury within 5 years in 5% of those so exposed. TD 50/5 is the absorbed
dose level required to produce the described injury within 5 years in
50% of those so exposed. The %-irradiated column describes the amount of
the organ that was exposed to the radiation.

Table: External Beam Radiation Therapy - Radiation Tolerance Doses\*

  -------------------- ---------------- -------------- -------------- --------------
  **Organ**            **Injury**       **TD 5/5       **TD 50/5      **%
                                        (cGy)**        (cGy)**        irradiated**

  **Gastrointestinal   **enteritis**    **500**        **1000**       **whole**
  Epithelial Cells**                                                  

  **Peripheral Nerve** **neuropathy**   **1500**       **2000**       **whole**

  **Heart**            **pericarditis   **4500**       **5500**       **60%**
                       and                                            
                       pancarditis**                                  

  **Heart**            **pericarditis   **7000**       **8000**       **25%**
                       and                                            
                       pancarditis**                                  

  **Intestine**        **ulcer,         **4500**       **5500**       **400 square
                       perforation,                                   cm**
                       hemorrhage**                                   

  **Intestine**        **ulcer,         **5000**       **6500**       **100 square
                       perforation,                                   cm**
                       hemorrhage**                                   

  **Large Arteries and **sclerosis**    **\>8000**     **\>10000**    **10 square
  Veins**                                                             cm**

  **Peripheral         **neuritis**     **6000**       **10000**      **10 cm**
  Nerves**                                                            

  **Small Intestine**  **Obstruction,   **5000**       **6000**       **1/3**
                       perforation,                                   
                       fistula**                                      

  **Small Intestine**  **Obstruction,   **none**       **none**       **2/3**
                       perforation,                                   
                       fistula**                                      

  **Small Intestine**  **Obstruction,   **4000**       **5500**       **3/3**
                       perforation,                                   
                       fistula**                                      
  -------------------- ---------------- -------------- -------------- --------------

\*Sources:

1.  Vaeth JM, Meyer JL (eds) Radiation Tolerance of Normal Tissues.
    23^rd^ Annual San Francisco Cancer Symposium. 1988.

2.  Bentel GC, Nelson CE, Noell KT. Treatment Planning and Dose
    Calculation in Radiation Oncology. 4^th^ Edition. Pergamon
    Press,1989.

3.  Emani B, Lyman J, et al. Tolerance of Normal Tissue to Therapeutic
    Irradiation. Int J Rad Onc Biol Phys. Vol 21:1;109-122. 1991

    OVERALL SUMMARY

# OVERALL SUMMARY

## General

Zevalin™ Therapy Clinical Studies

+----------------------+-------------------------------------+--------+
| **Data Set**         | **IDEC Studies**                    | **N**  |
+----------------------+-------------------------------------+--------+
| Overall-Efficacy     | Study 106-04                        | 143    |
| Analysis             |                                     |        |
|                      | IDEC-Y2B8 Subjects (N = 73)         |        |
| Relapsed or          |                                     |        |
| refractory, low      | Rituximab Subjects (N = 70)         |        |
| grade or follicular  |                                     |        |
| B-cell NHL           |                                     |        |
+----------------------+-------------------------------------+--------+
| Overall-Efficacy     | Study 106-06^&^                     | 54     |
| Analysis             |                                     |        |
|                      | (N = 54)                            |        |
| Relapsed or          |                                     |        |
| refractory,          |                                     |        |
| follicular B-cell    |                                     |        |
| NHL, refractory to   |                                     |        |
| rituximab therapy    |                                     |        |
+----------------------+-------------------------------------+--------+
| Overall Safety       | Integrated data from Studies        | 348    |
| Analysis             | 106-03^\#^, 106-04\*, 106-05,       |        |
|                      | 106-06^\$^, and data from 138       |        |
|                      | subjects in Study 106-98^@^         |        |
+----------------------+-------------------------------------+--------+
| Overall              | Integrated data from Studies        | 358    |
| Non-Hematologic      | 106-03^\#^, 106-04\*, 106-05,       |        |
| Adverse Event        | 106-06^\$^, and data from 148       |        |
| Analysis             | subjects in Study 106-98^@^         |        |
+----------------------+-------------------------------------+--------+
| Overall Hematologic  | Integrated data from Studies        | 392    |
| Adverse Event        | 106-03^\#^, 106-04\*, 106-05,       |        |
| Analysis             | 106-06^\$^, and data from 182       |        |
|                      | subjects in Study 106-98            |        |
+----------------------+-------------------------------------+--------+
| Safety Comparison of | IDEC-In2B8/IDEC-Y2B8 Subjects from  | 348    |
| Treatment with       | Studies 106-03, 106-04\*, 106-05,   |        |
| IDEC-Y2B8 alone      | and 106-06 (N = 182)                |        |
| versus IDEC-Y2B8     |                                     |        |
| with prior           | IDEC-Y2B8 Only Subjects from        |        |
| IDEC-In2B8           | Studies 106-06 and 106-98 (N = 167) |        |
+----------------------+-------------------------------------+--------+

^&^ Includes 54 of 57 subjects with follicular histology as was
prospectively defined for inclusion in the overall efficacy analysis.
The remaining 3 subjects had tumor histology other than follicle center
cell.

^\#^ Includes 50 of 51 ITT subjects treated with Zevalin™ therapy. 1
subject was enrolled but did not receive Zevalin™ therapy.

^\*^ Includes the 73 ITT subjects who were randomized to the Zevalin™
treatment group.

^\$^ Includes all 57 ITT subjects.

^@^ Includes 148 subjects for whom adverse event data was provided in
the June 2001 updated safety dataset. However, 10 subjects who were
included in the dataset had not yet completed 13 weeks of clinical
follow-up and information pertaining to these 10 subjects may be
incomplete. FDA included these subjects in the overall non-hematologic
adverse event analysis (the sponsor omitted these subjects from their
analysis), but only considered the 138 subjects who had completed 13
weeks of clinical follow-up for the overall safety analysis (same as the
sponsor).

## SUMMARY OF EFFICACY DATA

### Primary Efficacy Endpoints

The effectiveness of Zevalin™ rests primarily on the results of two
studies: Study 106-04, a randomized, multicenter active-control study
and Study 106-06, an uncontrolled, supportive trial.

FDA has confirmed the primary efficacy evaluation of higher overall
response rate in the Zevalin™ therapy arm as compared to the rituximab
arm in Study 106-04 and agrees with the sponsor's analysis. Zevalin™
therapy is effective and produced an ORR of 73% with a median of 14.2
months duration of response in subjects with relapsed or refractory, low
grade or follicular B-cell NHL. In comparison, rituximab yielded a 47%
ORR with a median duration of response of 12.1 months. The increased
overall response rate (Zevalin™ therapy activity) was observed for
subjects with IWF A and follicular histology but not for subjects with
transformed histology (5 of 9 Zevalin™ responder vs. 3 of 4 Rituxan™
responder).

We have confirmed the primary efficacy evaluation of overall response
rate and duration of response rate in Zevalin™ therapy treated subjects
with advanced, relapsed or refractory, follicular B-cell NHL who were
refractory to rituximab therapy. Zevalin™ therapy yielded a 59% ORR with
a median duration of response of 7.7 months.

Insufficient data was provided to assess overall response rates and
duration of response for subjects with transformed low grade NHL.

## SUMMARY OF SAFETY DATA

### Non Hematologic Adverse Events

-   The analyses of non-hematologic adverse events are based on results
    in 358 subjects from 5 clinical trials.

-   Other clinical safety summary analyses exclude 10 subjects enrolled
    in the 106-98 for whom some adverse events were reported but have
    not completed 13 weeks of clinical follow-up.

  -------------- ------- ------------------------------------------------
  Zevalin™       N=358   Trials
  Therapy Dose           
  Level                  

  0.4 mCi/kg     296     106-03 (N = 30), 106-04 (N = 73), 106-06 (N =
                         57), and 106-98 (N = 136)^\*^

  0.3 mCi/kg     58      106-03 (N = 16), 106-05 (N = 30), and 106-98 (N
                         = 12)^\*^

  0.2 mCi/kg     4       106-03, N= 4
  -------------- ------- ------------------------------------------------

^\*^ Includes 10 subjects who have not yet completed 13 weeks of
clinical follow-up

#### Non-Hematologic AEs by NCI CTC Grade

A total of 2414 non-hematologic adverse events have been reported to
date. Sixty-two percent were Grade 1, 29% Grade 2, 7% Grade 3, and 2 %
Grade 4 by NCI CTC Grade Criteria.

#### Incidence of Non-cytopenic AEs

Per Patient Incidence of Common and Notable

**Non-Hematologic AEs (N=358 Subjects)**

+-----------------------------------+----------------+----------------+
| **AE (COSTART)**                  | **all grades** | **Grade 3-4**  |
|                                   |                |                |
|                                   | **(%)**        | **(%)**        |
+-----------------------------------+----------------+----------------+
| Asthenia                          | 52             | 3              |
+-----------------------------------+----------------+----------------+
| Nausea                            | 37             | \< 1           |
+-----------------------------------+----------------+----------------+
| Chills                            | 28             | \< 1           |
+-----------------------------------+----------------+----------------+
| Fever                             | 26             | 3              |
+-----------------------------------+----------------+----------------+
| Infection                         | 19             | \< 1           |
+-----------------------------------+----------------+----------------+
| Abdominal Pain                    | 18             | 3              |
+-----------------------------------+----------------+----------------+
| Dyspnea                           | 16             | 2              |
+-----------------------------------+----------------+----------------+
| Headache                          | 16             | \< 1           |
+-----------------------------------+----------------+----------------+
| Increased Cough                   | 15             | 0              |
+-----------------------------------+----------------+----------------+
| Pain                              | 15             | \< 1           |
+-----------------------------------+----------------+----------------+
| Vomiting                          | 14             | 0              |
+-----------------------------------+----------------+----------------+
| Dizziness                         | 12             | \< 1           |
+-----------------------------------+----------------+----------------+
| Irritation Throat                 | 11             | 0              |
+-----------------------------------+----------------+----------------+
| Peripheral edema                  | 11             | \< 1           |
+-----------------------------------+----------------+----------------+
| Pruritus                          | 11             | \< 1           |
+-----------------------------------+----------------+----------------+
| Anorexia                          | 10             | 0              |
+-----------------------------------+----------------+----------------+
| Diarrhea                          | 10             | \< 1           |
+-----------------------------------+----------------+----------------+
| Rash                              | 10             | \< 1           |
+-----------------------------------+----------------+----------------+
| Arthralgia                        | 9              | \< 1           |
+-----------------------------------+----------------+----------------+
| Ecchymosis                        | 8              | \< 1           |
+-----------------------------------+----------------+----------------+
| Myalgia                           | 7              | \< 1           |
+-----------------------------------+----------------+----------------+
| Flushing                          | 6              | 0              |
+-----------------------------------+----------------+----------------+
| Hypotension                       | 6              | 1              |
+-----------------------------------+----------------+----------------+
| Abdominal Enlargement             | 5              | 0              |
+-----------------------------------+----------------+----------------+
| Angioedema                        | 5              | \< 1           |
+-----------------------------------+----------------+----------------+
| Anxiety                           | 4              | \< 1           |
+-----------------------------------+----------------+----------------+
| Allergic reaction                 | 2              | \< 1           |
+-----------------------------------+----------------+----------------+

#### NCI CTC Grade 3 and 4 Adverse Events Exclusing cytopenia

The following table lists all non-hematologic, Grade ≥ 3 adverse events.
More than one event may have occurred in a single individual and a
single event may have been coded using multiple COSTART terms (e.g.,
Liver Failure and SGOT increase).

**Number of Grade ≥ 3 AE Reports by Event Term (Alphabetica**l listing)

+----------------------------------+-----------+-----------+-----------+
| > COSTART Term                   | > Grade 3 | > Grade 4 | > Total   |
|                                  |           |           | > \#      |
+==================================+===========+===========+===========+
| > Abdominal Pain                 | > 11      | > 0       | > 11      |
+----------------------------------+-----------+-----------+-----------+
| > Acute Myelogenous Leukemia     | > 0       | > 3       | > 3       |
+----------------------------------+-----------+-----------+-----------+
| > Alkaline Phosphatase Increase  | > 2       | > 0       | > 2       |
+----------------------------------+-----------+-----------+-----------+
| > Allergic Reaction              | > 3       | > 1       | > 4       |
+----------------------------------+-----------+-----------+-----------+
| > Angioedema                     | > 1       | > 0       | > 1       |
+----------------------------------+-----------+-----------+-----------+
| > Anxiety                        | > 2       | > 0       | > 2       |
+----------------------------------+-----------+-----------+-----------+
| > Apnea                          | > 0       | > 3       | > 3       |
+----------------------------------+-----------+-----------+-----------+
| > Arrhythmia                     | > 2       | > 0       | > 2       |
+----------------------------------+-----------+-----------+-----------+
| > Arthralgia                     | > 1       | > 1       | > 2       |
+----------------------------------+-----------+-----------+-----------+
| > Arthritis                      | > 1       | > 0       | > 1       |
+----------------------------------+-----------+-----------+-----------+
| > Ascites                        | > 1       | > 1       | > 2       |
+----------------------------------+-----------+-----------+-----------+
| > Asthenia                       | > 8       | > 1       | > 9       |
+----------------------------------+-----------+-----------+-----------+
| > Atrial Fibrillation            | > 1       | > 0       | > 1       |
+----------------------------------+-----------+-----------+-----------+
| > Bilirubinemia                  | > 2       | > 0       | > 2       |
+----------------------------------+-----------+-----------+-----------+
| > Cachexia                       | > 1       | > 0       | > 1       |
+----------------------------------+-----------+-----------+-----------+
| > Cellulitis                     | > 1       | > 0       | > 1       |
+----------------------------------+-----------+-----------+-----------+
| > Chills                         | > 1       | > 0       | > 1       |
+----------------------------------+-----------+-----------+-----------+
| > Cholangitis                    | > 0       | > 1       | > 1       |
+----------------------------------+-----------+-----------+-----------+
| > Cholecystitis                  | > 1       | > 0       | > 1       |
+----------------------------------+-----------+-----------+-----------+
| > Colitis                        | > 1       | > 0       | > 1       |
+----------------------------------+-----------+-----------+-----------+
| > Constipation                   | > 2       | > 0       | > 2       |
+----------------------------------+-----------+-----------+-----------+
| > Convulsion                     | > 3       | > 0       | > 3       |
+----------------------------------+-----------+-----------+-----------+
| > Coronary Artery Disease        | > 1       | > 0       | > 1       |
+----------------------------------+-----------+-----------+-----------+
| > Deep Thrombophlebitis          | > 2       | > 0       | > 2       |
+----------------------------------+-----------+-----------+-----------+
| > Dehydration                    | > 4       | > 0       | > 4       |
+----------------------------------+-----------+-----------+-----------+
| > Depression                     | > 2       | > 0       | > 2       |
+----------------------------------+-----------+-----------+-----------+
| > Diarrhea                       | > 2       | > 0       | > 2       |
+----------------------------------+-----------+-----------+-----------+
| > Diplopia                       | > 1       | > 0       | > 1       |
+----------------------------------+-----------+-----------+-----------+
| > Dizziness                      | > 1       | > 0       | > 1       |
+----------------------------------+-----------+-----------+-----------+
| > Dyspnea                        | > 5       | > 2       | > 7       |
+----------------------------------+-----------+-----------+-----------+
| > Easy Bruisability              | > 1       | > 0       | > 1       |
+----------------------------------+-----------+-----------+-----------+
| > Ecchymosis                     | > 1       | > 0       | > 1       |
+----------------------------------+-----------+-----------+-----------+
| > Edema Lung                     | > 1       | > 0       | > 1       |
+----------------------------------+-----------+-----------+-----------+
| > Encephalopathy                 | > 1       | > 0       | > 1       |
+----------------------------------+-----------+-----------+-----------+
| > Febrile Neutropenia            | > 7       | > 2       | > 9       |
+----------------------------------+-----------+-----------+-----------+
| > Fever                          | > 2       | > 1       | > 3       |
+----------------------------------+-----------+-----------+-----------+
| > GI Heme                        | > 4       | > 0       | > 4       |
+----------------------------------+-----------+-----------+-----------+
| > Headache                       | > 2       | > 0       | > 2       |
+----------------------------------+-----------+-----------+-----------+
| > Heart Fail Right               | > 1       | > 0       | > 1       |
+----------------------------------+-----------+-----------+-----------+
| > Hematemesis                    | > 1       | > 0       | > 1       |
+----------------------------------+-----------+-----------+-----------+
| > Hepatitis                      | > 1       | > 0       | > 1       |
+----------------------------------+-----------+-----------+-----------+
| > Hypercalcemia                  | > 1       | > 1       | > 2       |
+----------------------------------+-----------+-----------+-----------+
| > Hyperglycemia                  | > 5       | > 0       | > 5       |
+----------------------------------+-----------+-----------+-----------+
| > Hyperuricemia                  | > 0       | > 1       | > 1       |
+----------------------------------+-----------+-----------+-----------+
| > Hyperventilation               | > 1       | > 0       | > 1       |
+----------------------------------+-----------+-----------+-----------+
| > Hypoproteinemia                | > 1       | > 0       | > 1       |
+----------------------------------+-----------+-----------+-----------+
| > Hypotension                    | > 2       | > 1       | > 3       |
+----------------------------------+-----------+-----------+-----------+
| > Hypoxia                        | > 3       | > 0       | > 3       |
+----------------------------------+-----------+-----------+-----------+
| > Infection                      | > 1       | > 0       | > 1       |
+----------------------------------+-----------+-----------+-----------+
| > Infection Bacterial            | > 0       | > 1       | > 1       |
+----------------------------------+-----------+-----------+-----------+
| > Insomnia                       | > 1       | > 0       | > 1       |
+----------------------------------+-----------+-----------+-----------+
| > Intestinal Obstruction         | > 0       | > 2       | > 2       |
+----------------------------------+-----------+-----------+-----------+
| > Intracranial Hemorrhage        | > 0       | > 1       | > 1       |
+----------------------------------+-----------+-----------+-----------+
| > Ischemia Myocardia             | > 1       | > 0       | > 1       |
+----------------------------------+-----------+-----------+-----------+
| > Jaundice                       | > 2       | > 0       | > 2       |
+----------------------------------+-----------+-----------+-----------+
| > Kidney Failure                 | > 0       | > 1       | > 1       |
+----------------------------------+-----------+-----------+-----------+
| > LDH Increase                   | > 2       | > 0       | > 2       |
+----------------------------------+-----------+-----------+-----------+
| > Liver Failure                  | > 0       | > 1       | > 1       |
+----------------------------------+-----------+-----------+-----------+
| > Malaise                        | > 2       | > 0       | > 2       |
+----------------------------------+-----------+-----------+-----------+
| > Melena                         | > 3       | > 0       | > 3       |
+----------------------------------+-----------+-----------+-----------+
| > Migraine                       | > 1       | > 0       | > 1       |
+----------------------------------+-----------+-----------+-----------+
| > Myalgia                        | > 1       | > 0       | > 1       |
+----------------------------------+-----------+-----------+-----------+
| > Myasthenia                     | > 1       | > 0       | > 1       |
+----------------------------------+-----------+-----------+-----------+
| > Nausea                         | > 2       | > 0       | > 2       |
+----------------------------------+-----------+-----------+-----------+
| > Neuritis                       | > 1       | > 0       | > 1       |
+----------------------------------+-----------+-----------+-----------+
| > Osteomyelitis                  | > 1       | > 0       | > 1       |
+----------------------------------+-----------+-----------+-----------+
| > Pain                           | > 3       | > 0       | > 3       |
+----------------------------------+-----------+-----------+-----------+
| > Pain Back                      | > 1       | > 0       | > 1       |
+----------------------------------+-----------+-----------+-----------+
| > Pain Eye                       | > 1       | > 0       | > 1       |
+----------------------------------+-----------+-----------+-----------+
| > Pain Neck                      | > 1       | > 0       | > 1       |
+----------------------------------+-----------+-----------+-----------+
| > Pain Tumor                     | > 3       | > 0       | > 3       |
+----------------------------------+-----------+-----------+-----------+
| > Pericarditis                   | > 1       | > 0       | > 1       |
+----------------------------------+-----------+-----------+-----------+
| > Peripheral Edema               | > 3       | > 0       | > 3       |
+----------------------------------+-----------+-----------+-----------+
| > Pleural Effusion               | > 2       | > 0       | > 2       |
+----------------------------------+-----------+-----------+-----------+
| > Pneumonia                      | > 6       | > 2       | > 8       |
+----------------------------------+-----------+-----------+-----------+
| > Prothrombin Increase           | > 1       | > 0       | > 1       |
+----------------------------------+-----------+-----------+-----------+
| > Pruritus                       | > 1       | > 0       | > 1       |
+----------------------------------+-----------+-----------+-----------+
| > Pulmonary Embolism             | > 0       | > 1       | > 1       |
+----------------------------------+-----------+-----------+-----------+
| > Rash                           | > 1       | > 0       | > 1       |
+----------------------------------+-----------+-----------+-----------+
| > Respiratory Disease            | > 1       | > 2       | > 3       |
+----------------------------------+-----------+-----------+-----------+
| > Sepsis                         | > 3       | > 3       | > 6       |
+----------------------------------+-----------+-----------+-----------+
| > SGOT Increase                  | > 1       | > 0       | > 1       |
+----------------------------------+-----------+-----------+-----------+
| > SGPT Inc                       | > 2       | > 0       | > 2       |
+----------------------------------+-----------+-----------+-----------+
| > Somnolence                     | > 1       | > 0       | > 1       |
+----------------------------------+-----------+-----------+-----------+
| > Subdural Hematoma              | > 0       | > 1       | > 1       |
+----------------------------------+-----------+-----------+-----------+
| > Supventricular Tachycardia     | > 2       | > 0       | > 2       |
+----------------------------------+-----------+-----------+-----------+
| > Tachycardia                    | > 1       | > 0       | > 1       |
+----------------------------------+-----------+-----------+-----------+
| > Urinary Tract Infection        | > 6       | > 0       | > 6       |
+----------------------------------+-----------+-----------+-----------+
| > Urine Frequency                | > 1       | > 0       | > 1       |
+----------------------------------+-----------+-----------+-----------+
| > Urticaria                      | > 1       | > 0       | > 1       |
+----------------------------------+-----------+-----------+-----------+
| > Vaginal Hemorrhage             | > 1       | > 0       | > 1       |
+----------------------------------+-----------+-----------+-----------+
| > Venacaval Pressure Increase    | > 1       | > 0       | > 1       |
+----------------------------------+-----------+-----------+-----------+
| > Total                          | > 162     | > 35      | > 197     |
+----------------------------------+-----------+-----------+-----------+

#### Safety of IDEC-In2B8 (N = 348)

-   IDEC-In2B8 administered 1 week prior to IDEC-Y2B8 is associated with
    an increase in overall frequency of AEs (all grades).

-   The incidence of all Grade 3 or 4 non hematologic and hematologic
    AEs were similar whether or not therapy included IDEC-In2B8

#### Abdominal AE 

The clinical observation of increased GI adverse events in patients
treated with the radiolabeled antibody and the imaging findings of
localization of the radiolabeled antibody in the bowel are compatible
with a second organ radiation toxicity involving the bowel.

-   The pre-clinical evaluation of the antibody's human tissue
    cross-reactivity established that the localization of IDEC-2B8
    occurs in the lymphoid aggregates present in the normal submucosa in
    the bowel.

-   Whole body biodistribution images from study participants
    demonstrates well-defined localization of the radiolabeled antibody
    in the bowel of many subjects.

-   Review of the adverse events with Zevalin™ therapy in the controlled
    clinical trial, 106-04, reveals a two fold increase in adverse
    events, (grades 1-2 nausea, vomiting, and abdominal pain) related to
    the bowel in the Zevalin™ arm as compared to the control arm (58%
    versus 34%).

#### Hospitalization

23 of 348 subjects (7%) were hospitalized with infection or febrile
neutropenia

-   6 subjects had febrile neutropenia

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-   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

#### Immune Reconstitution

-   All subjects experienced a depletion of B cells that reverted to
    baseline with a median of 6 months.

-   The median serum IgG and IgA concentrations remained within the
    normal range for all patients

-   A transient decline in serum IgM that returns to normal in 3 months
    despite a 6-month reversible

#### HAMA and HACA

-   3 of 211 subjects (1.4%) and 1/211 (0.5%) developed HAMA and or HACA
    antibody titers following Zevalin™ therapy.

-   2 subjects had pre-existing positive HAMA titers and 3 had
    pre-existing HACA titers. These subjects went on to receiving
    Zevalin™ therapy. None had unusual toxicity.

-   1 subject enrolled in IDEC 106-01 trial had a positive baseline HAMA
    titer at the study site. Upon re-testing, HAMA titers were found to
    be negative. However, the subject was removed from study due to
    unfavorable biodistribution.

#### Infections

Overall, 114 of 358 (32%) subjects developed a total of 183 infections.
Subjects may have had more than 1 type of infection in the course of
follow-up post Zevalin therapy. Of all reported events, 43% percent were
Grade 1, 35% Grade 2, 16% Grade 3, and 6% Grade 4 by NCI CTC Grade
Criteria.

-   28 of 358 (8%) subjects had Grade ≥ 3 infections.

    **Grade ≥ 3 Infections**

**by COSTART Preferred Term (n=41 AEs)**

+-------------------------------------------------------------+--------+
| > **AE**                                                    | **N**  |
+-------------------------------------------------------------+--------+
| > Febrile Neutropenia                                       | 9      |
+-------------------------------------------------------------+--------+
| > Pneumonia                                                 | 8      |
+-------------------------------------------------------------+--------+
| > Urinary Tract Infection                                   | 6      |
+-------------------------------------------------------------+--------+
| > Sepsis                                                    | 6      |
+-------------------------------------------------------------+--------+
| > Respiratory Infection                                     | 2      |
+-------------------------------------------------------------+--------+
| > Cellulitis                                                | 1      |
+-------------------------------------------------------------+--------+
| > Cholangitis                                               | 1      |
+-------------------------------------------------------------+--------+
| > Colitis                                                   | 1      |
+-------------------------------------------------------------+--------+
| > Diarrhea                                                  | 1      |
+-------------------------------------------------------------+--------+
| > Fever                                                     | 1      |
+-------------------------------------------------------------+--------+
| > Hepatitis                                                 | 1      |
+-------------------------------------------------------------+--------+
| > Infection (NOS)                                           | 1      |
+-------------------------------------------------------------+--------+
| > Bacterial Infection (NOS)                                 | 1      |
+-------------------------------------------------------------+--------+
| > Osteomyelitis                                             | 1      |
+-------------------------------------------------------------+--------+
| > Pericarditis                                              | 1      |
+-------------------------------------------------------------+--------+

-   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.

![](media/image7.wmf){width="4.25in" height="2.9055555555555554in"}

#### Secondary Malignancy and Myelodysplasia

Six of 348 subjects (1.7%) developed secondary malignancies following
treatment with Zevalin therapy

-   3 AML

-   2 MDS

-   1 meningioma

-   Onset 8-24 months post Zevalin™ and 4.4 to 11.5 years post NHL
    diagnosis.

### Hematologic Toxicity

The overall hematologic adverse event analyses included a total of 392
subjects for whom hematology data was available (Studies 106-03, 106-04,
106-05, 106-06, and 182 subjects in Study 106-98).

For all hematologic adverse events, duration of Grade ≥ 3 toxicity is
defined as end date minus start date, where end date and start date are
defined relative to the nadir lab value. A patient's end date is defined
as the 1^st^ lab test date after the nadir visit when the patient's lab
test is above the Grade ≥ 3 toxicity limit. A patient's start date is
defined as the most recent lab test date prior to the nadir visit when
the patient's lab test is above the Grade ≥ 3 toxicity limit.

Patients not recovered from Grade ≥ 3 toxicity were censored by one of
two rules. If a patient had received next anti-cancer therapy, that
patient was censored to the date of the most recent lab test prior to
receiving next anti-cancer therapy. If the patient had not received next
anti-cancer therapy, that patient was censored to the date of the most
recent lab test.

#### Neutropenia

-   214 of 392 (55%) subjects experienced Grade ≥ 3 neutropenia within
    90 days of Zevalin therapy.

-   For the 214 subjects with grade ≥ 3 neutropenia within 90 days of
    Zevalin therapy, the median duration was 25 days (range 2-190+
    days).

![](media/image8.wmf){width="6.0in" height="3.384027777777778in"}

##### Use of hematopoeitic growth factors

Among 211 patients for whom data were collected,

-   37 (17.5%) received filgrastim

-   22 (10.4%) received prophylactic antibiotics

#### Thrombocytopenia

-   224 of 392 (57%) subjects experienced Grade ≥ 3 thrombocytopenia
    within 90 days of Zevalin therapy.

-   For the 224 subjects with Grade ≥ 3 thrombocytopenia within 90 days
    of Zevalin therapy, the median duration was 27 days (range 7 to 167+
    days)

![](media/image9.wmf){width="5.996527777777778in"
height="3.3826388888888888in"}

##### Use of hematopoeitic growth factors

Of 211 patients for whom data were collected,

-   3 (1%) received oprelvekin

-   47 (22%) received platelet transfusions

#### Anemia 

46 of 349(13%) subjects had Grade 3 anemia

14 of 349 (4%) subjects had Grade 4 anemia

##### Use of hematopoeitic growth factors

Of 211 subjects for whom data were collected,

-   17 (8%) received erythropoietin

-   43 (20%) received red blood cell transfusions

#### Hematologic Toxicity and Delayed Hematologic Recovery

Exploratory analyses to assess risk factors predictive of hematologic
toxicity and delayed hematologic recovery were performed by the sponsor.

##### Prior Therapy

1.  23 subjects whose platelet counts did not recover to ≥ 100,000
    cells/mm^3^ were compared with 299 subjects whose platelet counts
    did recover. Non-recovered subjects received significantly more
    chemotherapy regimens than recovered subjects.

-   61% of non-recovered subjects received 4 or more prior chemotherapy
    regimens compared with 26% of recovered subjects.

-   Number of prior chemotherapy regimens was associated with a greater
    incidence of Grade 3 or 4 anemia, Grade 4 thrombocytopenia.

-   Number of prior chemotherapy regimens is not associated with a
    longer median duration of Grade ≥3 or Grade 4 neutropenia,
    thrombocytopenia, or anemia.

##### Prior Fludarabine Therapy

1.  Subjects treated with fludarabine had significantly lower platelet
    count and hemoglobin concentration at baseline.

2.  Fludarabine-treated subjects were more likely than patients not
    previously treated with fludarabine to develop Grade ≥3 neutropenia,
    thrombocytopenia, and anemia.

3.  Prior fludarabine treatment was associated with a significantly
    longer median duration of Grade 3 or 4 thrombocytopenia;

4.  Median duration of Grade 3 or 4 neutropenia and anemia was longer in
    fludarabine-treated patients; however, this difference was not
    significant

##### Bone Marrow Involvement

1.  The presence of bone marrow involvement at baseline was associated
    with a significantly greater incidence of:

-   Grade 4 neutropenia,

-   Grade 4 thrombocytopenia,

-   Grade 4 anemia

2.  The incidence of Grade 4 hematologic toxicity increased with
    increasing bone marrow involvement at baseline

## Geriatric Use: 

Of 211 patients treated with ZEVALIN™ in clinical studies, 33.6%
(71 patients) were age 65 years and over, and 9.0% (19 patients) were
age 75 years and over. The safety and effectiveness of ZEVALIN™ were
similar in elderly and younger adult patients. Other reported clinical
experience has not identified differences in response between elderly
and younger adults.

## Pediatric Use: 

There is no experience using Zevalin therapy in the pediatric
population. Indolent NHL is extremely rare in the pediatric population.

## Deaths

70 of 349 (20%) subjects have died.

58 of 70 (83%) deaths were reported to be secondary to disease
progression. 43 of the 58 subjects received additional anticancer
treatment following Zevalin.

### Non Lymphoma Related Causes Of Death

Among the 12 subjects who did not die of progressive disease, the cause
of death is listed as follows:

-   2 subjects with pancytopenia died of intracranial hemorrhage. Both
    had traumatic head injury; one was taking oral anti-coagulants. One
    died on Study Day 62, the other on Study Day 144.

-   5 subjects died of MDS/AML (41, 30, 19, 14, and 13 months post
    Zevalin therapy).

-   3 subjects died of pulmonary complications and/or respiratory
    failure in the setting of pre-existing pulmonary disease (COPD and
    idiopathic pulmonary fibrosis) on Study Day 12, 80, and 873.

-   1 subject died of cardiac arrest in the setting of pre-existing
    coronary artery disease on Study Day 471.

-   1 subject died of complications related to a pneumonia following
    additional chemotherapy for progressive disease on Study Day 71.

## SUMMARY OF Dosimetry DATA

### Biodistribution Imaging

CBER has reviewed the biodistribution imaging of In-111-2B8 performed at
five time points prior to the administration of Y-90-2B8.

CBER has found the In-111-2B8 whole body biodistribution imaging
provides diagnostic quality whole body images at the five time points.
Excellent definition of the liver, spleen, testes, bone marrow, kidneys,
urinary bladder, large bowel, heart and major vascular structures has
been demonstrated in the submitted whole body images from the controlled
clinical trials.

The biodistribution imaging with In-111-2B8 provides supportive
information for the safe administration of Y-90-2B8 as follows:

> The biodistribution images confirm the presence of the expected
> pattern of In-111-2B8 in the normal organs. An alteration in the
> biodistribution in normal organs suggests the presence of one or more
> of the following conditions:

-   Immune response, e.g., HAMA, HACA.

-   Organ dysfunction, e.g., urinary tract obstruction.

-   Improper preparation of the In-111-2B8 imaging agent.

-   Presence of occult NHL.

> The biodistribution images establish the "normal structures at risk"
> due to the radiation absorbed dose exposures from adjacent tumor
> sites.

In addition, the performance of the biodistribution imaging allows the
following:

-   Quantitation of the radiation dose for those tumor sites, which are
    adjacent to "normal structures at risk."

-   Quantitation of the radiation absorbed dose to normal organs and
    tumor sites.

### Normal Organ Dosimetry

FDA has confirmed that the normal organ dosimetry submitted by IDEC is
based on the appropriate MIRDOSE software and methodology for the
estimation of the radiation absorbed doses.

CBER's review supports the normal organ dosimetry results submitted by
IDEC. The normal organ dosimetry results are remarkable for the
radiation absorbed dose to the testes and the gastrointestinal tract.
The long term evaluation of these organs for the effects of the
radiation absorbed dose is indicated.

The gastrointestinal tract has not been evaluated as a route of
clearance for ^111^In/^90^Y-2B8.

### Tumor Dosimetry

CBER's review of the tumor dosimetry confirms 57 tumor sites have been
evaluated from 38 patients. The information from these tumor sites is
considered supportive to the BLA, but the 57 tumor sites cannot be
considered as necessarily representative of all tumor sites. Further
investigational studies should be performed to characterize the tumor
site uptake and the tumor site response to Y-90-2B8 therapy.

### Radiation Absorbed Dose Estimates for "Worst Case Scenarios"

CBER's review of theoretical models has established a potential risk for
radiation absorbed doses to normal structures in the following worst
case scenarios:

-   Normal structures adjacent to tumor sites with significant radiation
    absorbed doses.

-   An altered biodistribution (e.g., immune response due to HACA, HAMA)
    of Y-90-2B8.

-   Renal obstruction.

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