Clinical trial NCT00983619
Conditions: B-cell Malignancies Cancer
Keywords: Cancer
Sponsor: MedImmune LLC
Start date: 2010-04-16; Completion date: 2019-03-21
Enrollment: 136 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this study is to determine the maximum tolerated dose of this drug (MEDI-551) in participants with advanced B-cell malignancies. Expansion to occur at maximum tolerated dose (MTD), or if not reached, at optimal biologic dose (OBD).

Detailed description:
To determine the MTD or OBD of MEDI-551 in participants with relapsed or refractory advanced B-cell malignancies.

Arms: arm 1: Participants will receive intravenous (IV) infusion of MEDI 551 0.5 mg/kg once every week in 4-week cycles until complete response, disease progression, toxicity, or another reason for treatment discontinuation will be observed. arm 2: Participants will receive IV infusion of MEDI 551 1 mg/kg once every week in 4-week cycles until complete response, disease progression, toxicity, or another reason for treatment discontinuation will be observed. arm 3: Participants will receive IV infusion of MEDI 551 2 mg/kg on Days 1 and 8 of Cycle 1 (loading doses) and then once every 28 days at the start of each subsequent cycle until complete response, disease progression, toxicity, or another reason for treatment discontinuation will be observed. arm 4: Participants will receive IV infusion of MEDI 551 4 mg/kg on Days 1 and 8 of Cycle 1 (loading doses) and then once every 28 days at the start of each subsequent cycle until complete response, disease progression, toxicity, or another reason for treatment discontinuation will be observed. arm 5: Participants will receive IV infusion of MEDI 551 8 mg/kg on Days 1 and 8 of Cycle 1 (loading doses) and then once every 28 days at the start of each subsequent cycle until complete response, disease progression, toxicity, or another reason for treatment discontinuation will be observed. arm 6: Participants will receive IV infusion of MEDI 551 12 mg/kg on Days 1 and 8 of Cycle 1 (loading doses) and then once every 28 days at the start of each subsequent cycle until complete response, disease progression, toxicity, or another reason for treatment discontinuation will be observed. arm 7: Participants will receive IV infusion of MEDI- 551 6 mg/kg weekly for 4 weeks during Cycle 1 (Days 1, 8, 15, and 22) and thereafter from Cycle 2 on Day 1 of each 28-day cycle until complete response, disease progression, toxicity, or another reason for treatment discontinuation will be observed. arm 8: Participants will receive IV infusion of MEDI- 551 12 mg/kg weekly for 4 weeks during Cycle 1 (Days 1, 8, 15, and 22) and thereafter from Cycle 2 on Day 1 of each 28-day cycle until complete response, disease progression, toxicity, or another reason for treatment discontinuation will be observed. arm 9: Participants will receive IV infusion of MEDI- 551 24 mg/kg weekly for 4 weeks during Cycle 1 (over 2 days on Day 1 and Day 2, and on Days 8, 15, and 22) and thereafter from Cycle 2, on Day 1 of each 28-day cycle until complete response, disease progression, toxicity, or another reason for treatment discontinuation will be observed. arm 10: Participants will receive IV infusion of MEDI- 551 8 mg/kg on Days 2 and 8 during Cycle 1 and on Day 1 during Cycle 2 (28-day cycle) in combination with rituximab 375 mg/m\^2 on Days 1, 8, 15, and 22. From Cycle 3 onwards, only MEDI- 551 8 mg/kg will be administered on Day 1 of each 28-day cycle. The treatment will be continued until the participants experiences unacceptable toxicity, disease progression, reaches complete response or withdraws consent. arm 11: Participants will receive IV infusion of MEDI- 551 12 mg/kg on Days 2 and 8 during Cycle 1 and on Day 1 during Cycle 2 (28-day cycle) in combination with rituximab 375 mg/m\^2 on Days 1, 8, 15, and 22. From Cycle 3 onwards, only MEDI- 551 8 mg/kg will be administered on Day 1 of each 28-day cycle. The treatment will be continued until the participants experiences unacceptable toxicity, disease progression, reaches complete response or withdraws consent. arm 12: Participants will receive IV infusion of MEDI-551 12 mg/kg on Days 1 and 8 of Cycle 1 and thereafter Day 1 of 28- day cycles from Cycle 2 onwards. Treatment will be continued until the participants experiences unacceptable toxicity, disease progression, reaches CR or withdraws consent.
Interventions: intervention 1: MEDI-551 intervention 2: Rituximab
Intervention descriptions: intervention 1: MEDI-551 will be administered intravenously (IV) once every week in 4-week cycles until complete response, disease progression, toxicity, or another reason for treatment discontinuation will be observed. intervention 2: Rituximab will be administered IV on Days 1, 8, 15, and 22 (28- day cycle). The treatment will be continued until the participants experiences unacceptable toxicity, disease progression, reaches complete response or withdraws consent.

Protocol documents:
Prot_001.pdf: 
MedImmune
Protocol MI-CP204
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eAn Open-label, Phase 1/2 Study of MEDI-551, a Humanized 
Monoclonal Antibody Directed Against CD19, in Adult Subjects 
With Relapsed or Refractory Advanced B-cell Malignancies
Sponsor Protocol Number: MI-CP204
Application Number:
IND-101933
EudraCT Number:
2009-016378-34
Investigational Product:
MEDI-551
Sponsor:
MedImmune, LLC, a wholly owned subsidiary of AstraZeneca
One MedImmune Way
Gaithersburg, MD 20878, USA
Primary Medical Monitor:
MedImmune
Phone: 
Fax: 
Secondary Medical 
Monitor: 
MedImmune
Phone:
;   Fax:
Study Monitor:
MedImmune
Protocol, Date: 
Original Protocol, 01Apr2009
Version 2.0, 28May2009
Version 3.0, 06Nov2009
Version 4.0, 27Jan2010
Version 5.0, 23Sep2010
Version 6.0, 18Jul2011
Version 7.0, 24Oct2011
Version 8.0, 02May2012
Version 9.0, 15Jul2013
Version 10.0, 07Oct2013
Version 11.0, 21Mar2014
Administrative Change 1, 30Jun2014
Version 12.0, 27Jan2015
Version 13.0, 01Jun2017


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TABLE OF CONTENTS
1
INTRODUCTION.........................................................................................................21
1.1
Disease Background ...........................................................................................21
1.2
Description of MEDI-551...................................................................................22
1.3
Nonclinical Experience with MEDI-551............................................................23
1.4
Clinical Experience with MEDI-551..................................................................24
1.5
Rationale for Study.............................................................................................28
1.6
Risk-benefit Summary........................................................................................33
2
STUDY OBJECTIVES.................................................................................................34
2.1
Primary Objectives .............................................................................................34
2.2
Secondary Objectives .........................................................................................35
2.3
Exploratory Objectives .......................................................................................36
3
STUDY DESIGN..........................................................................................................37
3.1
Overview of Study Design..................................................................................37
3.2
Estimated Study Duration...................................................................................45
4
STUDY PROCEDURES...............................................................................................45
4.1
Subject Participation and Identification..............................................................45
4.2
Subject Selection.................................................................................................46
4.2.1Inclusion Criteria ........................................................................................46
4.2.2Exclusion Criteria .......................................................................................49
4.3
Study Entry and Treatment Assignment.............................................................50
4.4
Blinding ..............................................................................................................51
4.5
Study Treatment..................................................................................................51
4.5.1Investigational Product (MEDI-551)..........................................................51
4.5.1.1
Investigational Product Inspection............................................52
4.5.1.2
Reporting Product Complaints..................................................52
4.5.2Treatment Regimens...................................................................................53
4.5.2.1
Dose Modification for Toxicity Management ..........................55
4.5.3Investigational Product Preparation and Administration............................61
4.5.4Concomitant Medications...........................................................................64
4.5.5Dose Escalation...........................................................................................65
4.5.6Dose-limiting Toxicities .............................................................................67
4.6
Monitoring Subject Compliance.........................................................................69
4.7
Subject Status......................................................................................................69
4.8
Study Completion ...............................................................................................70
5
ASSESSMENT OF EFFICACY AND CLINICAL PHARMACOLOGY...................70
5.1
Efficacy and Clinical Pharmacology Parameters................................................70
5.2
Schedule of Study Procedures ............................................................................71


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5.2.1Schedule of Study Procedures - All Subjects Approved for Version 
13.0 of the Protocol...................................................................72
5.3
Description of Study Procedures ........................................................................73
5.3.1Medical History and Physical Examination, ECG, Weight, and Vital
Signs..........................................................................................73
5.3.2Clinical Laboratory Tests............................................................................73
5.3.3T/B-cell and Immunoglobulin Levels.........................................................75
5.3.4Pharmacokinetic Evaluation and Methods .................................................75
5.3.5Immunogenicity Evaluation and Methods..................................................75
5.3.6Disease Evaluation and Methods................................................................75
5.3.7Estimate of Blood Volume Collection........................................................76
6
ASSESSMENT OF SAFETY .......................................................................................76
6.1
Safety Parameters ...............................................................................................76
6.1.1Adverse Events ...........................................................................................76
6.1.2Serious Adverse Events ..............................................................................76
6.1.3Other Events of Special Interest .................................................................77
6.1.3.1
Hepatic Function Abnormality .................................................77
6.1.3.2
Infusion Reactions ....................................................................77
6.2
Assessment and Recording of Safety Parameters...............................................78
6.2.1Assessment of Severity...............................................................................78
6.2.2Assessment of Relationship........................................................................79
6.2.3Recording of Adverse Events .....................................................................80
6.2.4Recording of Serious Adverse Events ........................................................80
6.2.5Recording of Other Events of Special Interest ...........................................81
6.3
Reporting Requirements for Safety Parameters..................................................81
6.3.1Study Reporting Period for Adverse Events...............................................81
6.3.2Study Reporting Period for Serious Adverse Events..................................82
6.3.3Notification of Sponsor of Serious Adverse Events...................................82
6.3.4Notification of Institutional Review Board or Independent Ethics 
Committee of Serious Adverse Events .....................................83
6.3.5Other Events Requiring Immediate Reporting ...........................................83
6.3.5.1
Pregnancy and Overdose ..........................................................83
6.3.5.2
Other Protocol-specific Events .................................................84
6.3.5.3
Hepatic Function Abnormality .................................................84
6.3.5.4
Hepatitis Reactivation...............................................................84
6.3.5.5
Infusion-related Reactions ........................................................84
6.3.5.6
Progressive Multifocal Leukoencephalopathy..........................85
6.4
Safety Management During the Study................................................................85


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6.4.1Interruption or Permanent Discontinuation of Study Dosing in 
Individual Subjects ...................................................................86
6.4.2Study Stopping Criteria ..............................................................................87
6.4.3Monitoring of Dose Administration ...........................................................88
7
STATISTICAL CONSIDERATIONS..........................................................................89
7.1
General Considerations.......................................................................................89
7.2
Analysis Populations...........................................................................................90
7.3
Endpoints ............................................................................................................90
7.3.1Primary Endpoints ......................................................................................90
7.3.2Secondary Endpoints ..................................................................................91
7.3.3Exploratory Endpoints................................................................................91
7.4
Assessments........................................................................................................92
7.4.1MTD or OBD/Highest Protocol-defined Dose...........................................92
7.4.2Safety Assessments.....................................................................................92
7.4.3Efficacy Assessments .................................................................................92
7.4.4Pharmacokinetic Assessment......................................................................93
7.4.5Assessment of Effect on Circulating Lymphocyte Populations .................93
7.4.6Immunogenicity Assessment......................................................................94
7.5
Sample Size and Power Calculations..................................................................94
8
DIRECT ACCESS TO SOURCE DATA AND DOCUMENTS..................................96
9
QUALITY CONTROL AND QUALITY ASSURANCE............................................96
9.1
Data Collection ...................................................................................................96
9.2
Study Monitoring................................................................................................97
9.3
Audit and Inspection of the Study ......................................................................97
10
ETHICS.........................................................................................................................98
10.1
Regulatory Considerations..................................................................................98
10.2
Institutional Review Board or Independent Ethics Committee ..........................98
10.3
Informed Consent ...............................................................................................99
11
DATA HANDLING AND RECORD KEEPING.......................................................101
12
FINANCING AND INSURANCE .............................................................................101
13
PUBLICATION POLICY...........................................................................................101
14
REFERENCES............................................................................................................102
15
SUMMARY OF PROTOCOL AMENDMENTS AND ADMINISTRATIVE 
CHANGES TO THE PROTOCOL .....................................................................108


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LIST OF IN-TEXT TABLES
Table 4.2.1-1
Recommended Methods of Contraception...........................................49
Table 4.5.2.1-1
MEDI-551 Dose Modifications for Arm A .........................................56
Table 4.5.2.1-2
MEDI-551 Dose Modifications for Nonhematologic and Hematologic 
Toxicity in Arms B, C, and D..............................................................59
Table 5.2.1-1
Schedule of Evaluations.......................................................................72
Table 7.5-1
True Underlying DLT Rate at a Given Dose Level.............................94
LIST OF IN-TEXT FIGURES
Figure 3.1-1
Flow Diagram for Dose Escalation in Arm A .....................................39
Figure 3.1-2
Flow Diagram for Dose Escalation and Expansion in Arm B.............42
Figure 3.1-3
Flow Diagram for Dose Escalation and Expansion in Arm C.............44
Figure 3.1-4
Flow Diagram for Treatment in Arm D...............................................45
LIST OF APPENDICES
Appendix 1
Signatures...........................................................................................139
Appendix 2
Rituximab Prescribing Information ...................................................141


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List of Abbreviations
Abbreviation
Definition
ADA
anti-drug antibody
ADCC
antibody-dependent cellular cytotoxicity
AE
adverse event
AIDS
acquired immune deficiency syndrome
AJCC
American Joint Committee on Cancer
ALL
acute lymphocytic leukemia
ALT
alanine aminotransferase
AST
aspartate aminotransferase
AUC
area under the concentration curve
AUC∞
area under the concentration-time curve from time 0 to infinity
AUCt
area under the concentration-time curve from time 0 to last measurable 
concentration
βhCG
beta human chorionic gonadotropin
BAFF
B-cell activating factor
BCR
B-cell receptor
BM
bone marrow
CD
cluster of differentiation
CHO
Chinese hamster ovary (cell line)
CI
confidence interval
CLL
chronic lymphocytic leukemia
CR
complete response
CRF
case report form
CT
computed tomography
DHAP
dexamethasone-cytarabine-cisplatin
DLBCL
diffuse large B-cell lymphoma
DLT
dose-limiting toxicity
DMC
Data Monitoring Committee
DNA
deoxyribonucleic acid
EC90
90% effective concentration
ECG
electrocardiogram 
EOT 
end of treatment
EU
European Union
FcγR
crystalline fragment gamma receptor
FDA
Food and Drug Administration
FDG-PET
fluorodeoxyglucose-positron emission tomography
FL
follicular lymphoma
GCP
Good Clinical Practices
GGT
gamma glutamyl transferase
HAHA
human anti-human antibodies


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Abbreviation
Definition
hCG
human chorionic gonadotropin
HIPAA
Health Insurance Portability and Accountability Act
HIV
human immunodeficiency virus
HSC
hematopoietic stem cell
huCD19
human CD19
ICE
ifosfamide-carboplatin-etoposide
ICH
International Council for Harmonisation
IEC
Independent Ethics Committee
Ig
immunoglobulin 
IM
immunogenicity
IRB
Institutional Review Board
IRR
infusion-related reaction and infusion reaction
IV
intravenous(ly)
IVRS
interactive voice response system
Kd
dissociation constant
MAb
monoclonal antibody
MCL
mantle cell lymphoma
MEDI-551
a humanized monoclonal antibody directed against CD19
MedDRA
Medical Dictionary for Regulatory Activities
miRNA
micro ribonucleic acid
MM
multiple myeloma
MRD
minimal residual disease
mRNA
messenger ribonucleic acid
MTD
maximum tolerated dose
NaCl
sodium chloride
NCI CTCAE V4.03
National Cancer Institute Common Terminology Criteria for Adverse Events 
Version 4.03
NHL
non-Hodgkin lymphoma
NK
natural killer
NMO
neuromyelitis optica
OBD
optimal biologic dose
OR
objective response
ORR
objective response rate
OS
overall survival
PD
progressive disease
PET
positron emission tomography
PFS
progression-free survival
PK
Pharmacokinetic
PR
partial response
QTc
corrected QT interval
RNA
ribonucleic acid


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Abbreviation
Definition
SAE
serious adverse event
SC
subcutaneous
SCT
stem cell transplant(ation)
SD
stable disease
SID
subject identification
SMC
Safety Monitoring Committee
SPEP
serum protein electrophoresis
SLL
small lymphocytic lymphoma
t½
terminal phase half-life
Tg
transgenic
TTR
time to response
ULN
upper limit of normal
UPEP
urine protein electrophoresis
US
United States
WBC
white blood cell
WHO
World Health Organization


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Study Abstract
TITLE
An Open-label, Phase 1/2 Study of MEDI-551, a Humanized Monoclonal Antibody Directed Against CD19, 
in Adult Subjects With Relapsed or Refractory Advanced B-cell Malignancies
OBJECTIVES
Primary Objectives:
Arm A (MEDI-551 monotherapy in advanced B-cell malignancies)
•
To determine the maximum tolerated dose (MTD) or optimal biologic dose (OBD) of MEDI-551 in 
subjects with relapsed or refractory advanced B-cell malignancies (chronic lymphocytic leukemia [CLL], 
including small lymphocytic lymphoma [SLL], diffuse large B-cell lymphoma [DLBCL], and follicular 
lymphoma [FL])
•
To determine the preliminary safety profile of MEDI-551
Arm B (MEDI-551 monotherapy in CLL)
Dose Escalation
•
To determine the MTD or highest protocol-defined dose of MEDI-551 in the absence of exceeding the 
MTD in subjects with relapsed or rituximab-refractory CLL (defined as those with less than a partial 
response [PR] or progression within 6 months after completing therapy with rituximab)
Dose Expansion
•
To evaluate further the safety and tolerability of MEDI-551 at the dose selected in the dose-escalation 
phase in subjects with relapsed or rituximab-refractory CLL
•
To evaluate the clinical activity of MEDI-551 at the dose selected in the dose-escalation phase in subjects 
with relapsed or rituximab-refractory CLL
Arm C (MEDI-551 combined with rituximab in aggressive lymphoma)
Dose Escalation
•
To determine the safety and tolerability of MEDI-551 in combination with rituximab at the MTD or the 
highest protocol-defined dose in the absence of exceeding the MTD in subjects with aggressive 
lymphomas
Dose Expansion
•
To evaluate further the safety and tolerability of MEDI-551 at the dose selected in the dose-escalation 
phase in combination with rituximab in subjects with aggressive lymphomas
•
To evaluate the clinical activity of MEDI-551 at the dose selected in the dose-escalation phase in 
combination with rituximab in relapsed and rituximab-refractory population (defined as those with less 
than a PR or progression within 6 months after completing therapy with rituximab)
Arm D (MEDI-551 monotherapy in any anti-CD20-refractory aggressive lymphoma)
•
To evaluate the clinical activity of MEDI-551 in subjects with any anti-CD20-refractory aggressive 
lymphomas (defined as any subject with less than a PR to any prior anti-CD20-based therapy or 
progression within 6 months after completing therapy with any anti-CD20-based regimen, including 
maintenance rituximab)
Secondary Objectives:
Arm A
•
To determine the preliminary efficacy profile of MEDI-551 in subjects with advanced B-cell malignancies 
(CLL [including SLL], DLBCL, and FL)
•
To determine the pharmacokinetics (PK) of MEDI-551 in subjects with advanced B-cell malignancies
•
To determine the effect of treatment with MEDI-551 on circulating lymphocyte populations and 
immunoglobulin (Ig) levels, including time to recovery after treatment


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•
To determine the immunogenicity (IM) of MEDI-551 in subjects with advanced B-cell malignancies
Arm B
•
To evaluate the PK and IM of MEDI-551 at doses studied in subjects with relapsed or rituximab-
refractory CLL
•
To evaluate the effect of therapy on the B-lymphocyte level in peripheral blood, including time to 
recovery of B-lymphocyte level
Arm C
•
To evaluate the PK and IM of MEDI-551 when administered in combination with rituximab in subjects 
with aggressive lymphomas
•
To evaluate the effect of therapy on the B-lymphocyte level in peripheral blood, including time to 
recovery of B-lymphocyte level
Arm D
•
To determine the safety and tolerability of MEDI-551 in subjects with any anti-CD20-refractory 
aggressive lymphomas
•
To evaluate the PK and IM of MEDI-551
•
To evaluate the effect of therapy on the B-lymphocyte level in peripheral blood, including time to 
recovery of B-lymphocyte level
Exploratory Objective:
Arm B
•


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STUDY DESIGN
This is a Phase 1/2, multicenter, international, open-label, dose-escalation and expanded cohort study to 
evaluate the safety, tolerability, and potential antitumor activity of MEDI-551 as single agent or in 
combination with rituximab in adult subjects with advanced B- cell malignancies. The study design of Arm A 
comprises a dose-escalation phase followed by a dose-expansion phase in subjects with advanced B-cell 
malignancies receiving single-agent MEDI-551. This study arm included participants from 21 investigational 
sites in the United States (US), Canada, and European Union (EU). As of Version 10.0 of the protocol, the 
study design also includes dose escalation and expansion in subjects with CLL receiving single-agent 
MEDI-551 (Arm B), and dose escalation and expansion in subjects with aggressive lymphoma receiving 
MEDI-551 combined with rituximab (Arm C). As of Version 11.0 of the protocol, the study design also 
includes subjects with any anti-CD20-refractory aggressive lymphoma receiving single-agent MEDI-551 
(Arm D). Arms B, C, and D were to include participants from 20 investigational sites in the US and 10 to 
15 sites in the EU.  
Enrollment in the study was closed as of 30Sep2015. As of 19Jan2017, 9 subjects remain on treatment; all 
have completed at least 1 year of treatment. All subjects who are currently receiving MEDI-551 treatment 
may continue to receive MEDI-551 until disease progression, unacceptable toxicity, complete response (CR),
withdrawal of consent, or another reason to discontinue therapy intervenes.  Subjects who achieve CR
(complete response) may receive 2 additional cycles at the same dose prior to EOT (End of Treatment). A 
simplified schedule of evaluations focused on safety will be used. Safety follow-up assessments will be 
conducted at the EOT Visit (defined as the last day of the last cycle of investigational product administration)
as well as at the 90-Day Post Last Dose Visit, which will serve as the End of Study Visit. Long-term follow-up 
for progression-free survival and overall survival will not be performed following implementation of Version 
13.0.  
Arm A
Enrollment in the dose-escalation and expansion phases of Arm A is complete. Protocol Version 4.0 was 
amended to make the study population for dose-escalation inclusive of subjects with FL, multiple myeloma 
(MM), CLL, or DLBCL. Dose escalation in Arm A began in subjects with FL or MM per protocol 
Versions 1.0 through 4.0. Subjects were enrolled into the first 2 cohorts under these versions of the protocol. 
Starting with Version 5.0 of the protocol, enrollment in dose-escalation Cohorts 3 and higher was open to 
subjects with the following advanced B-cell malignancies: FL, MM, CLL, or DLBCL. Subjects in Cohorts 1 
and 2 continued to follow the protocol Version 4.0 dose schedule of 0.5 mg/kg (Cohort 1) or 1 mg/kg (Cohort 
2) MEDI-551 administered intravenously (IV) once every week in 4-week cycles. Subjects enrolled in Cohorts 
3 and higher received 2, 4, 8, or 12 mg/kg MEDI-551 (Cohorts 3 to 6, respectively) IV once per week on Days 
1 and 8 of Cycle 1 (loading doses) and then once every 28 days at the start of each subsequent cycle. As per 
Cohorts 1 and 2, dosing in Cohorts 3 and higher followed a standard 3+3 dose-escalation scheme. Subjects in 
Arm A were not to receive a MEDI-551 dose greater than 12 mg/kg. No intrasubject dose escalation was 
allowed.
A total of approximately 18 to 36 evaluable subjects were required for the dose-escalation phase; 26 were 
enrolled. Subjects were considered evaluable if they received at least 1 full cycle (4 doses for Cohorts 1 and 2; 
2 doses for Cohorts 3 to 6) of MEDI-551 and completed the safety follow-up through the dose-limiting 
toxicity (DLT) evaluation period, or experienced any DLT. Non-evaluable subjects were to be replaced in the 
same dose cohort. Dose escalation continued until the MTD (if ≤ 12 mg/kg), the 12-mg/kg maximum dose, or 
a lower dose (optimum biological dose or the OBD) was reached.
Following determination of the MTD or OBD, approximately 60 subjects total, 20 subjects each with FL,
CLL, or DLBCL, were to be enrolled in the expansion phase of Arm A to determine the preliminary efficacy 
profile of MEDI-551 in the treatment of advanced B-cell malignancies. A total of 69 subjects (24 CLL, 
21 DLBCL, 23 FL, and 1 MM) were enrolled. Under previous versions of the protocol, the expansion phase 
was to also include 20 subjects with MM. Enrollment of subjects with MM into the expansion phase was 
discontinued based on data from this study and recent nonclinical studies suggesting a lack of activity in the 
advanced/refractory MM setting. As of Version 8.0 of the protocol (and following enrollment of 
1 MM subject), subjects with MM were not to be enrolled. Subjects in the expansion phase were treated on 
Days 1 and 8 of Cycle 1 (loading doses) and then once every 28 days at the start of each subsequent cycle at 
the maximum dose tested in the dose-escalation phase, 12 mg/kg or OBD as determined in the dose escalation 
phase. 


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A preplanned interim safety analysis, as defined in the statistical analysis plan, was undertaken after reaching 
the maximum dose in the escalation phase to examine treatment effects on key safety endpoints. The analysis 
was performed and the protocol was amended (Version 7.0) to include the results of the analysis. An MTD or 
OBD was not identified in the dose-escalation phase of Arm A, so the maximum dose of 12 mg/kg was used 
for the expansion phase of this arm. Different dose levels or dosing schedules could be evaluated in the 
expansion phase if all available safety, PK, pharmacodynamic, and efficacy data suggested that evaluation of 
different dose levels, dosing schedules and/or duration of treatment would be beneficial. 
All subjects who are currently receiving MEDI-551 treatment may continue to receive MEDI-551 until disease 
progression, unacceptable toxicity, CR, withdrawal of consent, or another reason to discontinue therapy 
intervenes.  Subjects who achieve CR may receive 2 additional cycles at the same dose prior to EOT.   Once
Version 13.0 is in effect, re-treatment will not be available for subjects who achieve a CR and subsequently 
relapse while off treatment. Prior to Version 13.0, the US Food and Drug Administration was to be consulted 
concerning the possibility of additional treatment with MEDI-551 for subjects within the US and US subjects 
enrolled in Arm A could have been retreated at the 12-mg/kg dose at the discretion of the investigator and after 
discussion with the sponsor. Non-US subjects in Arm A were not to be retreated with MEDI-551 on 
subsequent relapse. 
Safety follow-up assessments will be conducted at the EOT Visit (defined as the last day of the last cycle of 
investigational product administration) as well as at the 90-Day Post Last Dose Visit (defined as 90 days after 
the last dose of MEDI-55), which will serve as the End of Study Visit. In addition, prior to implementation of 
Version 13.0, all subjects were followed for disease evaluation every 3 months after the 90-Day Post Last 
Dose Visit until disease progression, death, initiation of alternative therapy, withdrawal of consent, or end of 
study and for survival every 3 months until death, withdrawal of consent, or end of the study. Once Version 
13.0 is in effect, all subjects who have completed treatment and safety follow-up will be considered to have 
completed the study.
Arm B
Enrollment in Arm B is complete. Based on evaluation of the PK data in CLL subjects (n = 26) from Arm A, 
there appeared to be lack of full exposure and numerically lower response rate compared to non-CLL subjects 
using the monthly dosing regimen at the highest dose evaluated (ie, 12 mg/kg). This arm of the study 
evaluated further dose escalation in CLL subjects utilizing a new schema, designed to saturate the potential B-
cell sink, achieve full exposure, and maximize clinical activity, by employing weekly dosing of MEDI-551 for 
4 weeks during Cycle 1 and then monthly dosing on Day 1 of each subsequent 28-day cycle to determine the 
MTD or the highest protocol-defined dose in the absence of exceeding the MTD, which would be evaluated
subsequently in a dose-expansion phase. To further minimize infusion-related reactions at higher dose levels, 
for the 24 and 48 mg/kg dose levels of MEDI-551, the initial weekly doses were to be administered over 2 
days on Day 1 and Day 2 in Cycle 1. Subsequent doses at the 24 and 48 mg/kg dose levels were to be 
administered in an identical fashion to lower dose levels (ie, weekly on Days 8, 15, and 22 in Cycle 1 and then 
on Day 1 of each 28-day cycle in Cycle 2 and beyond). Note that the 48 mg/kg cohort was not enrolled.
  Using a standard 3+3 design, 3 to 6 subjects with CLL were to be enrolled per cohort, starting at a dose of 
6 mg/kg and escalating to 3 additional dose levels (12, 24, and 48 mg/kg) in the dose-escalation phase of this 
arm.  If 0 of 3 or ≤1 of 6 subjects treated at the previous dose level experienced a DLT, dose escalation could
continue. The MTD was defined as the dose at which no more than 1 of 6 subjects experienced a DLT during 
Cycle 1. No intra-subject dose escalation was allowed. Subjects were considered evaluable for a DLT if they 
completed the first cycle of therapy or discontinued therapy during Cycle 1 due to a DLT. Nonevaluable 
subjects would be replaced in the same dose cohort. A total of up to 24 subjects were to be enrolled in the 
dose-escalation portion of this arm. Dose escalation was permitted after all investigators reviewed the 
available data and unanimously agreed during a data review meeting to proceed with enrollment into the next 
cohort. The outcome from this meeting was documented in writing and shared with all participating sites.
Once an MTD was identified or the maximum planned dose not exceeding the MTD was reached, additional 
CLL subjects were to be enrolled at the selected dose in the dose-expansion phase to ensure a total of 
26 efficacy evaluable subjects were available for analysis after completing one post-treatment disease 
evaluation. The dose-expansion phase was to include subjects treated at the MTD or maximum planned dose 
enrolled in the dose-escalation phase of this arm. 
Based on emerging PK and pharmacodynamic data, a dose of 12 mg/kg, administered weekly during Cycle 1 
and then monthly in subsequent cycles, was determined to be sufficient to saturate the B-cell sink and achieve 


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full exposure.  A single subject was enrolled in the 24 mg/kg cohort; at the sponsor’s discretion and not due to 
any safety issues, no further dose-escalation was conducted and Arm B dose-expansion was not conducted.  
The MTD was not reached.
Arm C
Enrollment in Arm C is complete. Given the high unmet medical need in patients with multiply relapsed 
aggressive lymphoma, the synergistic activity observed in preclinical studies with MEDI-551 and rituximab, 
as well as the promising clinical activity seen with other dual monoclonal antibody (MAb) combinations in 
patients with B-cell malignancies, this arm of the study evaluated the safety and efficacy of MEDI-551 in 
combination with rituximab in subjects with aggressive lymphoma (relapsed or refractory DLBCL, Grade 3b 
FL, FL transforming to DLBCL and mantle cell lymphoma [MCL]). Using a standard 3+3 design, 3 to 6 
subjects with aggressive non-Hodgkin lymphoma (NHL) were enrolled per cohort in the dose-escalation 
portion of this arm, starting at a MEDI-551 dose of 8 mg/kg and escalating to 12 mg/kg. This population 
received 8 mg/kg of MEDI-551 on Days 2 and 8 of Cycle 1 and Day 1 of Cycle 2, and beyond in 28-day 
cycles along with weekly rituximab for 8 weeks beginning on Day 1 of Cycle 1. Dose escalation continued to 
12 mg/kg if 0 of 3 or ≤1 of 6 subjects treated at the lower dose experienced a DLT. The MTD was defined as 
the dose at which no more than 1 of 6 subjects experienced a DLT. No intrasubject dose escalation was
allowed. Subjects were considered evaluable for a DLT if they completed the first cycle of therapy or 
discontinued therapy during Cycle 1 due to a DLT. Nonevaluable subjects were to be replaced in the same 
dose cohort. A total of up to 12 subjects were to be enrolled in the dose-escalation portion of this arm of the 
study. Dose escalation was permitted after all investigators reviewed the available data during a data review 
meeting and unanimously agreed to proceed with enrollment into the next cohort. The outcome from this 
meeting was documented in writing and shared with all participating sites. 
Once an MTD was identified or the maximum planned dose not exceeding the MTD was reached, additional 
subjects would be enrolled and treated at the selected dose of MEDI-551 in combination with rituximab in the 
dose-expansion portion of this arm to ensure a total sample size of 26 efficacy evaluable subjects were
available for analysis after completing one post-treatment disease evaluation. The 26 subjects were to include 
subjects treated at the selected dose during the dose-escalation portion of this arm. 
The maximum planned dose of 12 mg/kg was evaluated and MTD was not reached. Further enrollment was 
halted at the sponsor’s discretion (and not due to any safety issues) after enrollment of 19 subjects (3 in the 8 
mg/kg MEDI-551 cohort and 16 subjects who received 12 mg/kg MEDI-551).  Of the 19 subjects there were 
only 7 responders, and there was approximately a 13% probability of meeting the protocol-specified target 
response rate of 50%.  
Subjects in Arm C were stratified by their responsiveness to any prior anti-CD20-based therapy with the 
option of ensuring a minimum number of 7 subjects who were refractory to any anti-CD20-based therapies 
were enrolled if clinical data from Arm D or emerging preclinical data suggested that the combination of anti-
CD20 and anti-CD19 therapies improve response in this subpopulation.
Arm D
Enrollment in Arm D is complete. Given the high unmet medical need in patients with refractory aggressive 
lymphoma and in light of preservation of CD19 expression on the surface of these malignant cells, MEDI-551 
may represent a salvage therapy option for anti-CD20-refractory patients. With evidence of clinical activity 
and safety of MEDI-551 established in an unselected relapsed refractory lymphoma population (Arm A), Arm 
D was added to investigate MEDI-551 in the anti-CD20-refractory population. Arm D evaluated the efficacy 
of MEDI-551 in subjects with any anti-CD20-refractory aggressive lymphoma (refractory DLBCL, 
Grade 3b FL, FL transforming to DLBCL, and MCL).
Since the safety and tolerability of the 12-mg/kg dose of MEDI-551 had been verified in Arm A, 
approximately 26 subjects with any anti-CD20-refractory disease were to be enrolled and treated with single-
agent MEDI-551 at the dose and schedule used in the expansion cohort of Arm A (ie, 12 mg/kg of MEDI-551 
on Days 1 and 8 of Cycle 1, and on Day 1 of Cycle 2 and beyond in 28-day cycles). 
Further enrollment was halted at the sponsor’s discretion (and not due to any safety issues) after enrollment of 
16 subjects.  Of the 16 subjects there were only 3 responders, and there was approximately a 1% probability of 
meeting the protocol-specified target response rate of 50%.  


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SUBJECT POPULATION
The subjects in this study are adults with relapsed or refractory B-cell malignancies: CLL, including SLL, 
DLBCL, FL, MCL, and transformed indolent lymphoma. 


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SUMMARY OF ELIGIBILITY CRITERIA
Select Inclusion Criteria
•
Men or women at least 18 years of age or older at time of study entry
•
Diagnosis 
◦
Arm A: CLL (including SLL), DLBCL, or FL; SLL, DLBCL, and FL must be histologically 
confirmed
◦
Arm B: Histologically-confirmed SLL or previous confirmation of B-cell CLL with a characteristic 
immunophenotype by flow cytometry
◦
Arm C: Histologically-confirmed aggressive B-cell DLBCL, including FL transforming to DLBCL, 
transformed indolent lymphoma, MCL, or Grade 3b FL, according to the World Health Organization
(WHO)/American Joint Committee on Cancer (AJCC) criteria
◦
Arm D: Histologically confirmed anti-CD20-refractory (defined as any subject with less than a PR to 
any prior anti-CD20-based therapy or progression within 6 months after completing therapy with any 
anti-CD20-based regimen, including maintenance rituximab) aggressive B-cell DLBCL, including FL 
transforming to DLBCL, transformed indolent lymphoma, MCL, or Grade 3b FL according to the 
WHO/AJCC criteria
•
Evaluable/measurable disease
◦
Non-CLL B-cell malignancies (Arms A, C, and D):
•
Histologically-confirmed B-cell NHL (FL or DLBCL), transformed indolent lymphoma, and 
MCL: Measurable disease defined as ≥ 1 lesion ≥20 mm in 1 dimension or ≥15 mm in 
2 dimensions as measured by conventional or high resolution (spiral) computed 
tomography (CT). For Arms C and D: disease evaluable by the International Working Group 
criteria (Cheson et al, 2007).
•
Baseline positron emission tomography (PET) or PET/CT scans must show positive lesions 
compatible with CT-defined anatomical tumor sites (only applicable for FL, DLBCL, MCL, 
transformed indolent lymphoma, and FL transforming to DLBCL)
◦
CLL (Arms A and B):
•
Confirmed B-cell CLL/SLL with a characteristic immunophenotype by flow cytometry, and 
symptomatic disease requiring treatment
•
CT scans showing involvement of ≥ 1 clearly demarcated lesions measuring ≥ 1.5 cm
•
Prior therapy
◦
Arm A
•
Histologically-confirmed B-cell NHL (FL or DLBCL): Relapsed from or refractory to ≥ 1 prior 
regimen containing rituximab, either alone or in combination, and not be a candidate for 
hematopoietic stem cell transplant at (SCT) or bone marrow (BM) transplant
•
B-cell CLL: Relapsed from or refractory to ≥ 2 prior lines of treatment, at least one of which 
must have contained rituximab 
◦
Arm B: Relapsed from or refractory to ≥ 2 prior chemotherapy regimens with ≥ 1 regimen containing 
rituximab
◦
Arm C: Relapsed from or refractory to ≥ 2 prior chemotherapy regimens with ≥ 1 regimen containing 
rituximab or failed 1 prior rituximab-containing regimen and unable to tolerate additional multiagent 
chemotherapy
◦
Arm D: Refractory to ≥ 1 regimen containing any anti-CD20-based therapy, including salvage 
regimens and maintenance rituximab. Refractory subjects are defined as any subject with less than a 
PR to any prior anti-CD20-based therapies or progressed within 6 months after completing therapy 
with any anti-CD20-based regimens, including maintenance rituximab. These subjects must not be 
eligible for hematopoietic SCT or BM transplant
•
Prior radiation therapy is allowed provided exposure does not exceed an area of 25% of marrow space and 
occurred ≥6 weeks prior to the first dose of MEDI-551 (Arm A only)
•
Karnofsky performance status ≥ 70
•
Life expectancy of ≥ 12 weeks


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•
Adequate hematological function defined as: 
◦
Arm A (except for CLL subjects with significant BM involvement by biopsy): hemoglobin ≥ 9 g/dL 
(≥ 8 g/dL for subjects who are transfusion dependent), absolute neutrophil count ≥1500/mm3, and 
platelet count ≥ 75,000/mm3
◦
Arms B, C, and D must meet the following criteria: hemoglobin ≥8 mg/dL, absolute neutrophil count 
≥ 1000/mm3, and platelet count ≥75,000/mm3. In the event of significant BM involvement, these 
hematologic criteria will not be required for enrollment eligibility
•
Adequate organ function defined as: 
◦
Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2 × institutional upper limit 
of normal (ULN); bilirubin ≤ 1.5 × ULN except in the case of subjects with documented Gilbert’s 
disease, ≤ 2.5 × ULN; serum creatinine ≤ 1.5 mg/dL or a calculated creatinine clearance of 
≥60 mL/min as determined by the Cockcroft-Gault equation
Select Exclusion Criteria
•
Any available standard line of therapy known to be life-prolonging or life-saving
•
Any concurrent chemotherapy, radiotherapy, immunotherapy, biologic, or hormonal therapy for treatment 
of cancer
•
Receipt of any chemotherapy or small molecule targeted therapy (such as imatinib or other tyrosine kinase 
inhibitors, and including any experimental therapies) or radiation therapy within 28 days or 5 half-lives, 
whichever is shorter, prior to the first dose of MEDI-551
•
Receipt of any biological or immunological-based therapies (including experimental therapies) for 
leukemia, lymphoma, or myeloma (including, but not limited to, MAb therapy such as rituximab, or 
cancer vaccine therapies) within 28 days or 5 half-lives, whichever is shorter, prior to the first dose of 
MEDI-551
•
Previous therapy directed against CD19, such as MAbs or MAb conjugates
•
Live or attenuated vaccines (other than experimental cancer vaccine therapy) within 28 days prior to 
receiving the first dose of MEDI-551
•
Evidence of significant active infection requiring antimicrobial, antifungal, antiparasitic, or antiviral 
therapy or for which other supportive care is given
•
Autologous SCT within 12 weeks prior to study entry (Arms A and D only)
•
Prior allogeneic SCT or organ transplant (Arms A and D only)
•
Human immunodeficiency virus (HIV) positive serology or AIDS
•
Active hepatitis B as defined by seropositivity for hepatitis B surface antigen (HBsAg) or positive 
hepatitis B core antibody. Subjects with hepatitis C antibody will be eligible provided that they do not 
have elevated liver transaminases or other evidence of active hepatitis.
•
Ongoing ≥ Grade 2 toxicities from previous cancer therapies unless specifically allowed in the 
Inclusion/Exclusion criteria
•
Use of immunosuppressive medication other than steroids within 28 days before the first dose of 
MEDI-551
•
Documented current central nervous system involvement by leukemia or lymphoma
•
Pregnancy or lactation
•
Previous medical history, or evidence, of an intercurrent illness that at the discretion of the principal 
investigator may compromise the safety of the subject in the study
•
Clinically significant abnormality on electrocardiogram (ECG). The corrected QT interval (QTc, 
Fridericia) must be < 470 milliseconds for men and < 490 milliseconds for women (Must be confirmed by 
at least 2 additional 12-lead ECGs at least 2 minutes apart such that average manually over-read QTcF 
based on 3 ECGs exceeds stated thresholds)
TREATMENT
Subjects in Arms A, B, and C were treated in one of two phases: dose escalation or cohort expansion. Subjects 
in Arm D were treated at the dose and schedule used in the expansion cohort of Arm A.
Arm A


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Subjects enrolled in the dose-escalation phase of Arm A were treated with 1 of 6 doses (0.5, 1, 2, 4, 8, or 
12 mg/kg) of MEDI-551. Dose escalation began in subjects with FL or MM per protocol Versions 1.0 through 
4.0. Under these versions of the protocol, subjects were enrolled into the first 2 cohorts. Starting with 
Version 5.0 of the protocol, enrollment in Cohorts 3 and higher was open to subjects with FL, MM, CLL or 
DLBCL. Subjects in Cohorts 1 and 2 received 0.5 or 1 mg/kg MEDI-551, respectively, IV once every week in 
4-week cycles. Subjects enrolled in Cohorts 3 to 6 received 2, 4, 8, or 12 mg/kg MEDI-551, respectively, IV 
once per week on Days 1 and 8 during Cycle 1 (loading doses) and then once every 28 days at the start of each 
subsequent cycle. Subjects who do not experience a DLT or do not otherwise become ineligible to receive 
MEDI-551 continue to receive MEDI-551 until CR, disease progression, toxicity, or another reason for 
treatment discontinuation is observed. Subjects who achieve a CR could receive an additional 2 cycles of 
MEDI-551 at the same dose prior to EOT. 
Following determination of the MTD or OBD or completion of dose escalation to 12 mg/kg, approximately 
80 subjects total, 20 subjects each with FL, MM, CLL, or DLBCL, were to be enrolled in the expansion phase 
of Arm A. As of Version 8.0 of the protocol, and following enrollment of 1 MM subject, enrollment of 
additional MM subjects was discontinued. Twenty subjects each with FL, CLL (including SLL), or DLBCL 
were to be enrolled in the expansion phase. A total of 69 subjects (24 CLL, 21 DLBCL, 23 FL, and 1 MM)
were enrolled. Subjects enrolled in the expansion phase were required to have evaluable disease as described 
in the inclusion criteria. Subjects in the expansion phase were treated with MEDI-551 on Days 1 and 8 of 
Cycle 1 (loading doses) and then once every 28 days at the start of each subsequent cycle unless evaluation of 
different schedule(s) was needed as described above. Subjects who did not complete 2 cycles of treatment for 
reasons other than toxicity to MEDI-551, disease progression, or death due to disease were to be replaced until 
a total of 20 subjects in each cohort were evaluable. 
Arm B
During the dose-escalation phase of Arm B, MEDI-551 was administered IV at 6 mg/kg weekly for 4 weeks 
during Cycle 1. For Cycle 2 and beyond, MEDI-551 6 mg/kg was administered on Day 1 of each 28-day cycle. 
Subsequent sequential cohorts were to evaluate doses of 12, 24, and 48 mg/kg administered weekly for 
4 weeks during Cycle 1 and then on Day 1 of each 28-day cycle starting with Cycle 2 and beyond. 
To further minimize infusion-related reactions at higher dose levels in Arm B, for the 24 and 48 mg/kg dose 
levels of MEDI-551, the initial weekly doses were to be administered over 2 days on Day 1 and Day 2 in 
Cycle 1. Additionally, mandatory premedication against IRR was required on both Day 1 and Day 2 of Cycle 
1. 
1. At the 24 mg/kg dose level, MEDI-551 was administered as follows:
a. On Day 1, 12 mg/kg as an infusion over a minimum of 81 minutes
b. On Day 2, 12 mg/kg as an infusion over a minimum of 60 minutes
2. At the 48 mg/kg dose level MEDI-551 was to be administered as follows:
a. On Day 1, 12 mg/kg as an infusion over a minimum of 81 minutes 
b. On Day 2, 36 mg/kg as an infusion over a minimum of 60 minutes (or over a minimum of 90 minutes 
  if the subject experienced an infusion reaction on Day 1)
Subsequent doses at the 24 and 48 mg/kg dose levels were to be administered in an identical fashion to lower 
dose levels (ie, weekly on Days 8, 15, and 22 in Cycle 1 and then on Day 1 of each 28-day cycle in Cycle 2 
and beyond).
During the dose-expansion phase of Arm B, the MTD or highest protocol-defined dose not exceeding the 
MTD was to be administered IV weekly for 4 weeks during Cycle 1 and then on Day 1 of each 28-day cycle 
starting with Cycle 2 and beyond.
Treatment may continue until the subject experiences unacceptable toxicity, progression of disease, reaches 
CR (2 additional cycles may be given prior to EOT) or withdraws consent.
Arm C
During the dose-escalation phase of Arm C, MEDI-551 was administered IV at 8 mg/kg on Days 2 and 8 in 
combination with rituximab 375 mg/m2 administered IV on Days 1, 8, 15, and 22 of Cycle 1 (28-day cycle). In 
Cycle 2, MEDI-551 was administered at 8 mg/kg on Day 1 and rituximab 375 mg/m2 was administered on 


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Days 1, 8, 15, and 22. In Cycle 3 and beyond, only MEDI-551 8 mg/kg was administered on Day 1 of each 
28-day cycle. As the MTD was not exceeded at 8 mg/kg, the MEDI-551 dose was escalated to 12 mg/kg 
administered in combination with a fixed dose of rituximab on the same schedule as noted above.
During the dose-expansion phase of Arm C, the selected MEDI-551 dose was administered IV on Days 2 and 
8 in combination with rituximab 375 mg/m2 administered IV on Days 1, 8, 15, and 22 of Cycle 1 (28-day 
cycle). In Cycle 2, the selected dose of MEDI-551 was administered on Day 1 and rituximab 375 mg/m2 was
administered on Days 1, 8, 15, and 22. In Cycle 3 and beyond, only MEDI-551 (at the MTD or highest 
protocol-defined not exceeding the MTD) was administered on Day 1 of each 28-day cycle.
Treatment may continue until the subject experiences unacceptable toxicity, disease progression, reaches CR 
(2 additional cycles may be given prior to EOT) or withdraws consent.
Arm D
MEDI-551 was administered IV at 12 mg/kg on Days 1 and 8 of Cycle 1 and on Day 1 of Cycle 2 and beyond 
in 28-day cycles. Treatment may continue until the subject experiences unacceptable toxicity, disease 
progression, reaches CR (2 additional cycles may be given prior to EOT) or withdraws consent.


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ASSESSMENT OF ENDPOINTS
The primary endpoints of each study arm are as follows: Arm A—MTD defined as the highest dose where 
≤1 out of 6 subjects experience a DLT during the DLT evaluation period or OBD, and safety of MEDI-551 in 
relapsed or refractory advanced B-cell malignancies; Arms B and C—MTD defined as the highest dose where 
≤ 1 out of 6 subjects experience a DLT during Cycle 1 or highest protocol-specified dose not exceeding MTD: 
DLTs , safety and tolerability, and clinical activity/efficacy of MEDI-551 as single agent in CLL or combined 
with rituximab in aggressive lymphomas; and Arm D—clinical activity/efficacy of single-agent MEDI-551 in 
any anti-CD20-refractory aggressive lymphomas. MTD or OBD/highest protocol-specified dose evaluation 
was based on the evaluable population for DLT during Cycle 1. The number and percentage of subjects with a 
DLT will be presented by dose level, and as a group overall. Safety endpoints include assessment of adverse 
events, serious adverse events, clinical laboratory evaluations, vital signs, physical examinations, and ECGs 
from the first administration of MEDI-551 through 60 days post-EOT (approximately 90 days after the last 
dose of MEDI-551). These assessments will be summarized for all subjects who received any MEDI-551. 
Clinical activity/efficacy will be assessed using CR, duration of CR, objective response, disease control, time 
to response, duration of objective response, duration of disease control, progression-free survival, and overall 
survival.
The secondary endpoints of each study arm are as follows: Arm A—clinical activity/efficacy, PK, and IM of 
MEDI-551 and effect of MEDI-551 on Ig levels and circulating B-lymphocyte populations; Arms B and C—
PK and IM of MEDI-551 as single agent or combined with rituximab, and effect of MEDI-551 on lymphocyte 
populations, including time to recovery of lymphocyte levels; and Arm D—safety and tolerability, PK and IM 
of single-agent MEDI-551, and effect of MEDI-551 on lymphocyte populations, including time to recovery of 
lymphocyte levels. Efficacy in Arm A will be assessed as described above for Arms B, C, and D. Safety in 
Arm D will be assessed as described above for Arms A, B, and C. The PK parameters of MEDI-551 will be 
estimated using non-compartmental analysis. A population PK analysis may also be performed to obtain 
additional PK parameters. Anti-MEDI-551 antibodies will be assessed and summarized descriptively by dose 
cohort for each arm. 
Exploratory endpoints of the study arms include the 
 
 
 
 
 
 
 
 
 
 
 


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SAMPLE SIZE AND POWER CALCULATIONS 
Arm A
For the dose-escalation phase, a minimum of 18 evaluable subjects (3 subjects each in Dose Cohort 1 through 
6) or up to approximately 36 evaluable subjects (3+3 subjects per dose cohort) were required to determine the 
MTD. A subject was considered evaluable for assessment of DLT if the subject received at least one full cycle 
(4 doses for Cohorts 1 and 2; 2 doses for Cohorts 3 to 6) of MEDI-551 and completed the safety follow-up 
through the DLT evaluation period (ie, the first 28-day cycle), or the subject experienced a DLT. Any non-
evaluable subject was to be replaced in the same dose cohort. 
A total of 26 subjects were enrolled in Arm A dose-escalation.
For the dose-expansion phase, approximately 20 subjects were to be entered into each of 3 arms to determine 
the preliminary efficacy profile of MEDI-551 in the treatment of advanced CLL (including SLL), DLBCL, and 
FL. The primary objective of the dose-expansion phase was to determine the preliminary efficacy profile of 
MEDI-551 in subjects with the advanced B-cell malignancies: CLL (including SLL), DLBCL, and FL. The 
sample size estimation was based on the CR rate and exact binomial test. A total of 20 subjects per arm were 
required to have approximately 80% power for testing the null hypotheses of 5% CR rate against the 
alternative of 20% CR rate at a 1-sided significance level of 0.1.
A total of 69 subjects (24 CLL, 21 DLBCL, 23 FL, and 1 MM) were enrolled in Arm A dose-expansion.
Arms B and C
Dose escalation: There were 4 planned dose levels (6, 12, 24, and 48 mg/kg) for MEDI-551 in the Arm B 
dose-escalation phase and 2 planned dose levels (8 and 12 mg/kg) for the Arm C dose-escalation phase. Using 
a standard 3+3 design, approximately 24 to 36 subjects were to be enrolled during the dose-escalation phase in 
Arms B and C depending on the observed safety profile and total number of dose levels evaluated.
A total of 7 subjects were enrolled in Arm B dose-escalation, including 1 at a dose of 24 mg/kg.  The dose 
escalation continued in Arm C as planned (8 mg/kg and 12 mg/kg) based on emerging PK and 
pharmacodynamic data that suggested a dose of 12 mg/kg, administered weekly during Cycle 1 and then 
monthly in subsequent cycles, was determined to be sufficient to saturate the B-cell sink and achieve full 
exposure.  At the sponsor’s discretion and not due to any safety issues, no further dose-escalation was 
conducted.  The MTD was not reached and dose expansion was not conducted in Arm B.  
Dose expansion: A sample size of 26 subjects was planned for each dose-expansion cohort in Arms B and C. 
Given an expected response rate of 50% for both cohorts, this would provide 80% power at a significance 
level of 0.20 (2-sided) to exclude the historical response rate of 30%, and associated 80% confidence intervals 
for the response rate would have a precision of ± 13%. The 30% historical response rate was selected for both 
Arms B and C expansion cohorts based on the following reported data:
•
In relapsed CLL patients, objective response rates between 15% and 30% were reported for rituximab 
monotherapy (O’Brien et al, 2001; Mavromatis and Cheson, 2003).
•
In DLBCL patients with 2 prior lines of therapy, response rates were only about 30% with single-agent 
rituximab (Coiffier et al, 1998; Wang et al, 2013; Churpek et al, 2013).
A total of 19 subjects were enrolled in Arm C.  Of these 19 subjects there were only 7 responders, and there 
was about a 13% probability of meeting the protocol-specified target response rate of 50%; further enrollment 
to Arm C was therefore halted at the sponsor’s discretion.  The MTD was not reached and enrollment in Arm 
C was discontinued prior to dose expansion at the sponsor’s discretion and not due to any safety issues.
Arm D
A sample size of approximately 26 subjects was planned for Arm D. Given an expected response rate of 50% 
for this cohort, this would provide 80% power at a significance level of 0.20 (2-sided) to exclude the historical 
response rate of 30% (Zinzani et al, 2013; Witzig et al, 2011), and associated 80% confidence intervals for the 
response rate would have a precision of ± 13%. 
A total of 16 subjects were enrolled in Arm D.  Of these 16 subjects there were only 3 responders, and there 
was about a 1% probability of meeting the protocol-specified target response rate of 50%; further enrollment 
was therefore halted at the sponsor’s discretion and not due to any safety issues.


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1
INTRODUCTION
1.1
Disease Background
CD19 Function and Expression
Cluster of differentiation (CD) 19 is a B-cell-restricted transmembrane protein member of the 
immunoglobulin (Ig) superfamily encoded by the CD19 gene (Cooper et al, 2004). This cell 
surface antigen is first expressed by early pre-B cells from the time of heavy chain 
rearrangement and is down-regulated during terminal differentiation into plasma 
cells (Nadler et al, 1983). CD19 is a component of the B-cell receptor (BCR) 
complex and controls the signaling threshold for B-cell development and humoral immunity
(Sato et al, 1995; Sato et al, 1997). Knockout mice lacking CD19 do not show defective 
B-cell development within the bone marrow (BM), but have reduced B-cell numbers in 
peripheral lymphoid organs and reduced serum Ig levels (Engel et al, 1995). Conversely, 
mice overexpressing CD19 within the B-cell compartment have a defect in early B-cell 
development in the BM, an increased response of B cells to mitogens, and elevated levels of 
serum Igs (Engel et al, 1995). CD19 is not expressed on hematopoietic stem cells or B cells 
before the pro-B-cell stage (Nadler et al, 1983; Loken et al, 1987).
Expression of CD19 in B-cell leukemias and lymphomas is widespread. CD19 is expressed 
in chronic lymphocytic leukemia (CLL), acute lymphocytic leukemia (ALL), and B-cell 
non-Hodgkin lymphoma (NHL) (Uckun et al, 1988; D’Arena et al, 2000; Ginaldi et al, 1998; 
Anderson et al, 1984). Histologically, the vast majority of NHL subtypes are 
derived from B cells and express common B-cell antigens such as CD19, CD20, and CD22 
(Armitage and Weisenburger, 1998; The International Non-Hodgkin’s Lymphoma 
Prognostic Factors Project, 1993; Harris et al, 1994; Masir et al, 2006). Compared to CD20, 
which is also expressed in multiple B-cell malignancies, CD19 is expressed at lower levels, 
but on a broader range of B cells; CD19 expression occurs earlier during B-cell 
development and continues for longer than does CD20 expression (Cooper et al 2004; 
D’Arena et al, 2000). In multiple myeloma (MM), CD19 is not expressed on malignant 
plasma cells, but an increasing population of CD19-positive cells appears following 
chemotherapy (Rasmussen et al, 2002; Bergsagel et al, 1995; Kiel et al, 1999). It is thought 
that this CD19-positive population represents a stem cell population that is resistant to 
available chemotherapies (Huff and Matsui, 2008).


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Treatment of B-cell Malignancies
Treatment of B-cell CLL and NHL, the largest groups of hematologic malignancies, relies 
primarily on a combination of chemotherapy and biotherapy based on the monoclonal 
antibody (MAb) rituximab, directed against CD20 (Robak, 2007). While many patients 
achieve long-lasting remissions with this combination in both CLL and NHL, patients whose 
disease progresses after treatment with rituximab and/or commonly used chemotherapies 
have few effective options (Robak, 2007; Coiffier, Sep2005; Coiffier, Mar2005). With each 
subsequent treatment, the duration of remission usually becomes shorter and, eventually, 
most CLL and NHL patients die from their disease (Hennessy et al, 2004). Once patients 
become refractory to rituximab (ie, achieve less than partial response [PR] or relapse within 
6 months of rituximab therapy), limited biologic agents are available as adjunctive treatment 
to chemotherapy. While treatment with ofatumumab, an anti-CD20 MAb, has resulted in an 
objective response rate (ORR) of approximately 58% in CLL patients, there are currently no 
approved agents for NHL patients (Wierda et al, 2010). Furthermore, it is unclear whether 
ofatumumab offers similar activity in CLL patients considered to be rituximab refractory. 
Therefore, an unmet medical need exists for patients who have relapsed or refractory NHL or 
CLL that is no longer responsive to rituximab or chemotherapy. The broad expression profile 
of CD19 on B-cell malignancies, including ALL, CLL, and NHL, makes this an attractive 
target both for patients in whom therapy with rituximab has failed and as a potential first-line 
treatment (Uckun et al, 1988). In MM, patients who are not candidates for a stem cell 
transplant (SCT) can achieve durable remissions with first-line chemotherapeutic regimens 
(San Miguel et al, 2008), but nearly all patients will eventually relapse and require 
subsequent therapy (Richardson et al, 2003). As with other B-cell malignancies, 
in MM, subsequent lines of therapy have a lower effectiveness and shorter duration 
(Richardson et al, 2003). Multiple myeloma patients who have received multiple lines of 
therapy likely have higher percentages of CD19-expressing cells (Matsui et al, 2008) and, 
because this may represent a stem cell population that is resistant to available 
chemotherapies, these patients have an unmet medical need.
1.2
Description of MEDI-551
The following sections provide a brief description of MEDI-551. Refer to the current 
Investigator’s Brochure for details.
MEDI-551 Pharmacology
MEDI-551 is a humanized IgG1 kappa MAb directed against human CD19 (huCD19). 
Affinity maturation of the parental humanized antibody 3649 resulted in antibody 16C4, 


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which has superior binding characteristics. MEDI-551 is generated by expression of MAb 
16C4 in a fucosyltransferase-deficient Chinese hamster ovary (CHO) producer cell line 
(BioWa Potelligent® Technology) generating a homogeneously afucosylated antibody with 
enhanced antibody-dependent cellular cytotoxicity (ADCC). MEDI-551 shows potent in vitro 
ADCC against multiple B-cell leukemia and lymphoma cell lines, as well as patient-derived 
CLL and ALL cells. MEDI-551 efficiently depletes blood and tissue B cells in huCD19 
transgenic (Tg) mice and has antitumor activity in severe combined immunodeficiency 
mouse models of human B-cell leukemia, lymphoma, and MM. MEDI-551 does not bind 
CD20, and thus activity of MEDI-551 should be independent of activity of rituximab or other 
CD20-targeted therapies. MEDI-551 is expected to selectively target B cells, with antitumor 
activity in a variety of B-cell-derived malignancies.
1.3
Nonclinical Experience with MEDI-551
MEDI-551 Toxicology
A pharmacologically relevant Tg animal model, huCD19 Tg mouse, was developed and used 
to evaluate the potential toxicity of MEDI-551 in animals. Because MEDI-551 binds neither 
rodent nor non-human primate CD19, these standard toxicology models were not considered 
pharmacologically relevant, and the Tg model was used instead.
The Tg model expresses huCD19 in a murine C57BL6 genetic background under the control 
of human regulatory elements, resulting in huCD19 expression that is restricted to B-lineage 
cells as it is in humans (Zhou et al, 1994; Yazawa et al, 2005). MEDI-551 binds to and 
depletes huCD19+ B cells in these huCD19 Tg mice with a similar affinity and by the same 
mechanism of action as is expected in humans. Nonclinical toxicology studies with this 
model demonstrated that there were no adverse effects after either a single dose (up to 
50 mg/kg), 5 weekly doses (up to 36.6 mg/kg), or 13 or 26 weekly doses (up to 30 mg/kg). 
The only findings in these toxicology studies were related to the pharmacologic action of 
B-cell depletion. The time to recovery of B cells appears to be dose dependent. An additional 
study to investigate subcutaneous (SC) dosing (13 weekly SC or intravenous [IV] doses up to 
30 mg/kg) was recently conducted and an increased incidence of background 
bronchioloalveolar adenomas (benign) was noted in the 30-mg/kg IV group at the recovery 
necropsy. Given that this finding is isolated to this study and was not observed in the longer 
26-week chronic toxicity study at the same dose, the relevance to overall risk assessment for 
patients is unknown. In addition, MEDI-551 was evaluated in an embryofetal development 
study in huCD19 Tg mice. The only adverse findings in the study were treatment-related 
reduction in fertility index and the number of mice that were pregnant or in cohabitation. 


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Importantly, MEDI-551 had no impact on embryofetal development. Treatment with 
MEDI-551 resulted in expected pharmacologic depletion of total B lymphocytes in 
peripheral blood of adult mice. In fetal livers, the site of B-cell development in mice, there 
was a dramatic difference in huCD19+ B cells between progeny of dosed mice and vehicle-
treated mice. Overall, the results suggest that MEDI-551 crosses the placenta and depletes 
B cells. An additional study to evaluate the recovery of B cells in infants from treated mice, 
as well as an assessment of immune function in these infants, will be performed at a future 
date.
Maximum Dose Selection
Nonclinical studies were conducted with normal donor peripheral blood mononuclear cells to 
predict the 90% effective concentration (EC90) for ADCC. Other studies were conducted to 
assess the binding affinity (dissociation constant [Kd]) of MEDI-551 to CD19-expressing 
cells. Serum MEDI-551 concentrations were simulated for the planned doses and compared 
to the determined EC90 for ADCC and Kd. It was determined that a dose beyond 12 mg/kg 
MEDI-551 is unlikely to result in added pharmacologic activity and clinical benefit. At 
12 mg/kg, MEDI-551 levels in subjects are projected to be far in excess of the in vitro EC90
and Kd for binding to the target (CD19).
Review of pharmacokinetic (PK) results for each histology enrolled in Arm A suggested that 
unlike follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL) subjects, CLL 
subjects had limited exposure due to a large B-cell sink even at the highest dose tested (12 
mg/kg). Lack of saturation of the B-cell sink may have limited the clinical activity of MEDI-
551 noted in CLL subjects. Consequently, Arm B will explore higher doses of MEDI-551 
and a more frequent dosing schedule to determine if saturation of the B-cell sink may be 
maximized.
1.4
Clinical Experience with MEDI-551
The clinical development of MEDI-551 is ongoing in subjects with B-cell malignancies, 
systemic scleroderma, relapsing/remitting multiple sclerosis, and neuromyelitis optica 
(NMO) and NMO spectrum disorders. There are 5 clinical studies of MEDI-551, including 
MI-CP204, in subjects with B-cell malignancies; these studies are described below, based on 
a data cutoff date of 31Mar2015.
In the current Phase 1/2 study, MI-CP204, enrollment in the dose-escalation and expansion 
phases in adult subjects with relapsed and refractory advanced B-cell malignancies (CLL, 
DLBCL, FL, or MM) has been completed (enrollment of MM subjects was discontinued 


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after the start of the dose-expansion phase due to lack of activity based on nonclinical and 
preliminary clinical data). Subjects in the dose-escalation phase received MEDI-551 at doses 
of 0.5, 1, 2, 4, 8, or 12 mg/kg (3 to 6 subjects per dose cohort), or 12 mg/kg (a total of 
75 subjects in the combined dose-escalation and dose-expansion portions of this arm of the 
study received 12 mg/kg). Two dose-limiting toxicities (DLTs) were reported as infusion-
related reactions; one occurred at the 4 mg/kg cohort and the other at 12 mg/kg dose level. 
The protocol was amended to add 3 arms to the study: Arm B applies dose escalation to 
determine the maximum tolerated dose (MTD) or maximum dose that will saturate the B-cell 
sink in subjects with CLL; Arm C combines rituximab and MEDI-551 in treating subjects
with aggressive lymphomas; and Arm D assesses the activity of MEDI-551 monotherapy in 
subjects with anti-CD20- refractory aggressive lymphomas. The protocol was further 
amended to include mandatory steroid prophylaxis and graded infusions consistent with 
Studies CD-ON-MEDI-551-1019 and CD-ON-MEDI-551-1088 (see below). A total of 111 
subjects have been treated with MEDI-551 in MI-CP204. The most commonly reported 
adverse events (AE) (> 20% of subjects) were infusion-related reaction, fatigue, cough, and 
nausea. The most commonly reported related AEs (in ≥ 5% of subjects in the overall study 
population) were infusion-related reaction, nausea, neutropenia, fatigue, and vomiting. 
Deaths were reported for 27 of 111 (24.3%) subjects in MI-CP204. Progressive disease (PD) 
was the most common cause.  All 27 deaths were considered unrelated to MEDI-551. 
Twenty-eight subjects (25.2%) in MI-CP204 experienced serious adverse events (SAEs); 
SAEs were noted in every dose cohort except the 2 dose cohorts in Arm B (6 mg/kg or 12 
mg/kg every week for 4 weeks, then every 4 weeks, N = 6 for the combined cohorts). In 
Study MI-CP204, mean serum MEDI-551 PK concentration-time profiles following IV
administration declined in a bi-exponential manner, with an initial rapid distribution followed 
by a slower elimination phase. In general, MEDI-551 PK was dose proportional between 
0.5 and 12 mg/kg following the first dose. Thirty of 111 subjects (27.0 %) in MI-CP204 
experienced objective response (OR), defined as complete response (CR) or partial response 
(PR). Three subjects, 2 subjects who achieved CR and 1 subject who achieved a very good 
PR, were retreated following relapse.
Study D2850C00001, sponsored by AstraZeneca Japan, is a Phase 1, open-label, dose-
escalation study of MEDI-551 in adult Japanese subjects with advanced B-cell malignancies. 
Twenty subjects were enrolled and have received doses of 2, 4, 8, or 12 mg/kg. The AEs 
most commonly reported (in ≥15% of subjects) were infusion-related reaction (IRR), 
hypertriglyceridemia, white blood cell (WBC) count decreased, leukopenia, nasopharyngitis,
lymphocyte count decreased, neutrophil count decreased, and rash. Following Cohort 1,
premedication with non-steroidal agents and antihistamines was permitted. After Grade 3
infusion-related reactions occurred in Cohort 2, premedication with steroids was also


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permitted if a subject had experienced infusion reactions with other drugs, had rapid bulky
tumor growth, high cytokine levels, and/or CLL. Two DLTs of infusion-related reaction 
occurred at the 12 mg/kg dose; hence the MTD was determined to be 8 mg/kg in this
population.
Two Phase 2 clinical studies are evaluating MEDI-551 for the treatment of B-cell
malignancies. Study CD-ON-MEDI-551-1019, which is closed to enrollment but still
ongoing, is a Phase 2, multicenter, international, randomized, 3-arm, active-control, open 
label study evaluating the antitumor activity, safety, tolerability, immunogenicity (IM),
pharmacokinetics (PK), and pharmacodynamics of MEDI-551 when used in combination
with bendamustine versus rituximab in combination with bendamustine in adult subjects with 
progressive CLL (also known as relapsed or refractory CLL). A total of 150 subjects have
been treated with one of 3 regimens: MEDI-551 2 mg/kg, MEDI-551 4 mg/kg, or rituximab,
each in combination with bendamustine. A total of 90 subjects have been treated with
MEDI-551. The most common AEs reported in the combined MEDI-551 groups (in > 20%
of subjects) were infusion-related reaction, nausea, fatigue, neutropenia, pyrexia, cough, and
constipation. The most common AEs (in ≥ 10%) of subjects in the combined MEDI-551
groups judged related to MEDI-551 were infusion-related reaction, nausea, neutropenia,
fatigue, chills, and vomiting. Deaths were reported for 18 of 90 subjects (20.0%) who
received MEDI-551 in CD-ON-MEDI-551-1019 (6 of 33 subjects [18.2%] in the 2 mg/kg
group and 12 of 57 subjects [21.1%] in the 4 mg/kg group) and in 6 of 60 subjects (10.0%) in
the rituximab + bendamustine group. All except for 1 of the deaths (4 mg/kg MEDI-551 +
bendamustine group) were considered not related to study drug. Thirty-five of 90 subjects
(38.9%) in the combined MEDI-551 groups and 19 of 60 subjects (31.7%) in the rituximab
group experienced SAEs. The SAE of infusion-related reaction occurred more frequently in
the combined MEDI-551 groups (10 of 90 subjects [11.1%]) than in the rituximab group 
(1 of 60 subjects [1.7%]). Febrile neutropenia occurred more frequently in the rituximab 
group (7 of 47 subjects [11.7%]) than in the combined MEDI-551 groups (2 of 90 subjects 
[2.2%]).
The CD-ON-MEDI-551-1019 study protocol was amended in May 2013 to mitigate the risk 
of infusion-related reactions by requiring premedication with steroids, antihistamines, and 
antipyretics before the initial MEDI-551 dose; using a reduced infusion rate during the initial 
administration of MEDI-551; and moving the first MEDI-551 dose to Day 2 of Cycle 1.
Study CD-ON-MEDI-551-1088 is a Phase 2 study of MEDI-551 when used in combination 
with ifosfamide-carboplatin-etoposide (ICE) or dexamethasone-cytarabine-cisplatin (DHAP) 
versus rituximab in combination with ICE or DHAP in adult subjects with relapsed or 


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refractory DLBCL. Subjects were initially assigned to one of three regimens: MEDI-551 
2 mg/kg, MEDI-551 4 mg/kg, or rituximab, each in combination with ICE or DHAP.
Enrollment was stopped in November 2012 following 2 deaths in subjects in the 4 mg/kg arm
of MEDI-551. These events were evaluated by the sponsor’s internal safety review 
committee and a Data Monitoring Committee. The safety review and data monitoring 
committees concluded that the role of MEDI-551 in these events was unclear and advised
that enrollment at a higher dose of MEDI-551 may be reopened only after more safety 
information on the MEDI-551 2 mg/kg dose in combination with chemotherapy was 
obtained. As a result of the review and recommendations of these groups, the protocol was 
amended. The study was re-opened for enrollment in the 4 mg/kg arm in December 2012 
after review of the safety data for the MEDI-551 2 mg/kg combination arm by the safety 
review committee. A total of 119 subjects in CD-ON-MEDI-551-1088 have received at least 
1 dose of study treatment, including 71 subjects in the combined MEDI-551 groups. Adverse 
events reported for > 20% of subjects in the combined MEDI-551 groups were anemia, 
thrombocytopenia, nausea, fatigue, neutropenia, constipation, vomiting, asthenia, and 
diarrhea. The most common AEs judged related to MEDI-551 (in > 10% of subjects in the
combined MEDI-551 groups) were anemia, thrombocytopenia, nausea, neutropenia, fatigue, 
and leukopenia. Deaths were reported for 9 of 71 subjects (12.7%) receiving MEDI-551 (7 of 
48 subjects [14.6%] in the 2 mg/kg group and 2 of 23 subjects [8.7%] in the 4 mg/kg group) 
and 8 of 48 subjects (16.7%) receiving rituximab in CD-ON-MEDI-551-1088. Two deaths in 
the MEDI-551 group and 1 death in the rituximab group were considered to be related to 
investigational product. Thirty of 71 subjects (42.3%) in the combined MEDI-551 groups and 
20 of 48 subjects (41.7%) in the rituximab group experienced SAEs in CD-ON-MEDI-551-
1088.
A Phase 1b/2, multicenter, open-label study of MEDI0680 (AMP-514), a MAb directed 
against human programmed cell death 1, in combination with MEDI-551, D2852C00004, is 
evaluating the safety, tolerability, clinical activity, MTD, PK, and anti-drug antibodies 
(ADAs) in subjects with relapsed and refractory aggressive B-cell lymphoma. Subjects 
receive MEDI-551 at 12 mg/kg (with possible dose de-escalation to 8 mg/kg) and MEDI0680 
(AMP-514) at 2.5 or 10 mg/kg. A total of 8 subjects have been enrolled. Adverse events 
reported by more than 1 subject were fatigue, constipation, diarrhea, nausea, vomiting, 
peripheral edema, paresthesia, and rash. Two subjects, both in the MEDI-551 12 mg/kg + 
MEDI0680 (AMP-514) 2.5 mg/kg dose group died. Both deaths were attributed to 
progressive disease and neither death was considered to be related to either study drug. 
Serious adverse events were reported for 2 subjects in the MEDI-551 12 mg/kg + MEDI0680 
(AMP-514) 2.5 mg/kg group. One subject suffered Grade 3 hydronephrosis from which he 


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recovered. The verbatim language for the second subject’s SAE (not yet coded) was 
hospitalization and disease progression.
One externally-sponsored scientific research study (J1340) initiated by a collaborator at 
Johns Hopkins University is ongoing. Fifteen subjects with MM have been enrolled; no 
significant safety concerns have been reported.  The accrual is completed but the study is 
ongoing.  
1.5
Rationale for Study
Patients with B-cell leukemia or lymphoma who have received rituximab either alone or in 
combination with chemotherapy have no available therapies after progression while on 
rituximab or treatment with approved or standard of care chemotherapies. For these patients, 
there are no curative therapies available. For patients with advanced MM, there are similarly 
no curative therapies, and CD19 expression on malignant cells appears to increase with 
increasing lines of therapy. Targeting CD19 is an attractive alternative in patients with 
rituximab-refractory B-cell leukemia or lymphoma and in advanced MM. 
This Phase 1/2 study has 4 treatment arms. The objective of Arm A was to determine the 
MTD or optimal biologic dose (OBD; one of which will be further tested as the 
recommended Phase 2 dose) and preliminary safety profile of MEDI-551 in subjects with 
advanced B-cell malignancies (CLL, DLBCL, FL, and MM). The study design employed in 
Arm A was used in earlier versions of the protocol and will be continued in Version 10.0 of 
the protocol. Subjects received MEDI-551 at doses ranging from 0.5 to 12 mg/kg delivered 
either weekly (Cohorts 1 and 2) or monthly (Cohorts 3 to 6, and expansion). Based on 
nonclinical studies and preliminary clinical data from this study suggesting a lack of activity 
in the advanced/refractory MM setting, MM subjects were excluded from enrollment as of 
Version 8.0 of the protocol.
A second arm (Arm B) was added because PK data from the ongoing Phase 1/2 study 
demonstrated a lack of full exposure (ie, the dose of antibody is insufficient to saturate the 
B-cell antigens) in CLL subjects treated with the current monthly dosing regimen and at 
doses tested. Therefore, as of Version 10.0 of the protocol, Arm B investigated a new 
dosing schema and higher doses of MEDI-551 in CLL subjects to determine if full exposure 
could be achieved and clinical activity maximized. A third arm (Arm C) was added to the 
Phase 1/2 study to investigate the safety, tolerability, and clinical activity of MEDI-551 in 
combination with rituximab in subjects with aggressive lymphomas. The rationale for this 
combination was based on nonclinical data suggesting synergistic activity with rituximab and 
a PK-maximized dose of MEDI-551. As of Version 11.0 of the protocol, a fourth arm (Arm 


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D) was added to this study to evaluate the clinical activity of MEDI-551 monotherapy in 
subjects with any anti-CD20-refractory aggressive lymphoma. The rationale for this arm was
based on data from Arm A, demonstrating the activity of single-agent MEDI-551 in a heavily 
pretreated relapsed refractory patient population that had received prior rituximab. Detailed 
justification for these study arms is provided below.
Rationale for Arm B
Clinical and PK data from Arm A of the Phase 1/2 study suggest that the lack of full 
exposure in CLL subjects compared with FL and DLBCL subjects may have resulted in 
reduced clinical activity in CLL (response: 19% CLL [n = 26] vs 29% FL [n = 34] and 23% 
DLBCL [n = 26]). The number of circulating malignant B cells is much higher in CLL 
patients than in those with other B-cell malignancies. Therefore, to maximize tumor cell 
killing, the dose of antibody should be sufficient to saturate the B-cell antigens (B-cell sink). 
Subjects with CLL treated with MEDI-551 at the 12-mg/kg dose demonstrate lower plasma 
concentrations of MEDI-551 than other subjects treated at that dose (mean minimum 
observed concentration at steady state is 89.5 ± 45.7 μg/mL for CLL and 134 ± 40.6 μg/mL 
for non-CLL), suggesting that the B-cell sink may not be saturated at the 12-mg/kg dose. 
Moreover, studies of rituximab have reported markedly lower rituximab 
concentrations/exposure and a low response rate (13%) in patients with SLL or CLL 
compared to patients with FL (60%) treated at the same dose of 375 mg/m2 weekly for 
4 weeks (McLaughlin et al, 1998). A greater response rate (50%) was seen in CLL patients 
given rituximab at 375 mg/m2 three times weekly for 4 weeks (Byrd et al, 2001), suggesting 
that dose intensity established via frequent dosing may also improve response rates. 
Additionally, dose intensity with higher doses of the MAb may be effective in improving 
responses as suggested by a response rate of 75% in patients receiving a rituximab dose of 
2250 mg/m2 weekly for 4 weeks (O’Brien et al, 2001). These data suggest that higher 
response rates with MEDI-551 may be achieved with increased dose density by using higher 
doses and/or more frequent dosing. Therefore, additional dose escalation with MEDI-551 
was warranted in CLL subjects to determine the MTD or the effective dose that may 
overcome the B-cell sink.
Arm B of this study was added to investigate further dose escalation using a dosing regimen 
that may maximize saturation of the B-cell sink in CLL subjects. In Arm B, CLL subjects 
received MEDI-551 weekly for the first 4 weeks followed by monthly infusions to ensure 
rapid saturation of the B-cell sink. The maximum MEDI-551 dose that subjects had 
previously received in a 1-month period was 24 mg/kg for those treated in the 12-mg/kg dose 
cohort using the earlier dosing schema (ie, loading dose on Days 1 and 8 of the first month, 


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followed by monthly dosing). Safety data were available for the maximum dose. Doses of 4, 
8, and 12 mg/kg per month had been established as safe in this patient population. Therefore, 
dose escalation in Arm B was started at 6 mg/kg per week for 4 weeks followed by 6 mg/kg 
on Day 1 of every 28-day cycle from Cycle 2 and beyond, so that a maximum dose of 
24 mg/kg per month would not be exceeded in the first dose cohort tested. Weekly doses of 
12, 24, and 48 mg/kg were to be assessed in sequential dose-escalation cohorts based on the 
new dosing regimen. Dose escalation was allowed to continue until the MTD is defined or 
the highest protocol-defined dose not exceeding the MTD was reached. A 48-mg/kg 
maximum dose was proposed based on a review of rituximab data, which suggest that 
complete saturation of the B-cell sink in CLL occurs with approximately 4 to 5 g of the 
MAb. The maximum dose of MEDI-551 suggested corresponds to this antibody level.
Rationale for Arm C
B-cell markers including CD20 and CD19 are expressed in various B-cell malignancies and 
have served as targets for B-cell-directed therapies. The density of CD19 expression on the 
surface of B-cells is lower than that of CD20; however, prior therapy with 
CD20-targeted agents has been shown to reduce the percentage of CD20 expression on cells 
(Chu et al, 2002). Therefore, using agents that target both CD19 and CD20 simultaneously 
may maximize tumor cell killing by ensuring that malignant cells with low levels of either 
CD19 or CD20 are effectively eliminated. This hypothesis is supported by nonclinical data of 
MEDI-551 in combination with rituximab in the treatment of lymphoma cell lines, including 
rituximab-resistant lines, showing a 5 times greater increase in the percentage of tumor cell 
killing compared with either agent alone.
Arm A of the ongoing Phase 1/2 study has successfully determined a MEDI-551 dose and 
dosing schema that permits full exposure and maximizes the clinical activity of MEDI-551 in 
non-CLL NHL subjects. Therefore, based on nonclinical evidence showing that MEDI-551 
and rituximab may act synergistically, Arm C was added to investigate the combination of 
these 2 agents in the treatment of subjects with aggressive B-cell lymphoma. The addition of 
this dual-antibody arm to the protocol was warranted to further explore the activity of 
MEDI-551 in NHL. Evaluation of MEDI-551 combined with rituximab may facilitate future 
studies utilizing this combination either alone or in combination with chemotherapy.
While the majority of patients with aggressive B-cell malignancies will be cured, at least 
30% of those with DLBCL will relapse after first-line therapy, and a cure is still unattainable 
for patients with mantle cell lymphoma (MCL) or high-grade FL. For MCL, lenalidomide 
has been approved as a treatment option after second relapse, but there are no approved 


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therapies for patients with high-grade FL after second relapse. For those patients able to 
undergo allogeneic transplant, cure may be possible but the transplant process (regardless of 
disease course or treatment response) is associated with 30% mortality. Therefore, new
therapies with better toxicity profiles than traditional cytotoxic chemotherapy are needed for 
this patient population. Furthermore, in an aging population where the median age of 
diagnosis of lymphoma is 65 years, chemotherapy-free regimens are attractive as they 
minimize organ toxicities, myelosuppression, and infection risk inherent to conventional 
chemotherapy regimens. Nevertheless, these non-traditional chemotherapeutic agents may 
have other toxicities that complicate treatment in this elderly population. This older 
population and multiply relapsed patients often have multiple medical comorbidities resulting 
from cumulative toxicity from prior chemotherapy that prevent repeat multiagent 
chemotherapy administration. In addition, dual-antibody combinations have already been 
successfully and safely used in the management of patients with B-cell malignancies as 
demonstrated by high response rates with the combination of rituximab and epratuzumab 
with (96%) or without (67%) chemotherapy (Micallef et al, 2011; Leonard et al, 2005). 
Given the high unmet medical need in patients with multiply relapsed aggressive lymphoma, 
the synergistic activity observed in nonclinical studies with MEDI-551 and rituximab, as well 
as the promising clinical activity seen with other dual MAb combinations in patients with B-
cell malignancies, evaluation of the combination of rituximab and MEDI-551 was warranted 
in patients with multiply relapsed aggressive lymphoma in the current study.
Rituximab monotherapy in a multiply relapsed population has resulted in responses ranging 
from 15% to 30% (Coiffier et al, 1998; Wang et al, 2013) and other therapies (including 
chemotherapy options) being developed in this population have demonstrated response rates 
of approximately 30% (Wang et al, 2013; Churpek et al, 2013). At present, single-agent 
MEDI-551 has demonstrated an ORR of approximately 23%. Consequently, a dual-antibody 
combination that achieves a response rate ≥ 50% would warrant further investigation.
Unlike the CLL population, PK data suggest that a 12-mg/kg dose of MEDI-551, 
administered once every 28 days, offers adequate exposure to malignant B cells in DLBCL 
and FL and, therefore, further dose escalation is not warranted in this patient population. 
Based on the hypothesis that dual-antibody therapy may be more effective at eliminating 
malignant B cells, a dose-escalation cohort of aggressive lymphoma subjects was initially 
treated with a MEDI-551 dose of 8 mg/kg, one dose below the maximum dose tested along 
with a standard dose of rituximab (375 mg/m2). Dose escalation of MEDI-551 continued to 
12 mg/kg. Once an MTD had been achieved or safety of the maximum proposed dose had
been established, an expansion cohort was enrolled to confirm the activity of this dose of 
MEDI-551 in combination with rituximab. 


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Rationale for Arm D
The literature indicates that subjects who have received CD20-targeted agents such as 
rituximab develop resistance via several mechanisms, including “shaving” of CD20 off the 
surface of malignant cells upon repeated exposure to rituximab. Data from both cell lines and 
patient samples indicate a loss of CD20 with recurrent exposure to CD20-targeted agents 
(Tsai et al, 2012; Martin et al, 2008; Hagberg et al, 2006). Loss of CD20 may contribute to 
rituximab resistance in patients who become refractory to rituximab therapy following 
repeated exposure (ie, achieving less than a PR with rituximab-based regimens or 
progression within 6 months of having completed rituximab-based therapy). The percentage 
of patients considered refractory to rituximab is unknown. Nevertheless, data from the 
CORAL study suggested that approximately 20% of patients will develop rituximab 
resistance (Hagberg et al, 2006; Gisselbrecht et al, 2010). That study reported response rates 
of 50% in those who received rituximab as first-line therapy and 70% response rates in those
with no prior rituximab exposure. Furthermore, Gisselbrectht and colleagues reported 3-year 
event-free survival rates of 21% versus 47% in those with and without prior rituximab 
exposure (Gisselbrecht et al, 2010). However, despite a loss of CD20 after rituximab 
exposure, CD19 expression remains on the surface of malignant B cells, offering a potential 
target to salvage rituximab-refractory patients (Chu et al, 2002).
At present, there are no approved therapies for patients with aggressive lymphoma who are 
refractory to rituximab or any anti-CD20-based therapies and thus, this is a population with 
high unmet need. Lymphoma therapies generally incorporate a MAb in combination with 
either a cytotoxic regimen, an immunomodulatory molecule, or small targeted molecule. Due 
to a lack of approved non-CD20-targeted treatment options for aggressive lymphoma, 
retreatment with rituximab has continued, resulting in the administration of a regimen that 
appears to have reduced efficacy. CD19 expression, therefore, offers a promising target for 
treatment with CD19-targeted therapies such as MEDI-551.
MEDI-551 has demonstrated activity in the current study (Arm A) in a heavily pretreated 
patient population, all of whom received prior rituximab. Subjects in Arm A, with multiply 
relapsed aggressive lymphomas including DLBCL and high-grade FL, had received a median 
of 5 prior lines of therapy and demonstrated response rates of 23% with a preliminary 
duration of response of approximately 5 months. Based on the rationale above, it was 
possible that an even better response rate may have been seen in subjects refractory to any 
anti-CD20-based therapies, including rituximab.


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To evaluate the clinical activity of MEDI-551 in the refractory population, Arm D was 
added, to enroll adult subjects with any anti-CD20-refractory aggressive lymphoma 
(refractory DLBCL, Grade 3b FL, FL transforming to DLBCL, and MCL). The same dose 
used in the expansion cohort of Arm A, 12 mg/kg, was tested in Arm D. This dose and 
schedule of MEDI-551 provided adequate exposure and was well tolerated based on data 
from Arm A. A total of approximately 26 refractory subjects were to be enrolled and treated 
with MEDI-551 at 12 mg/kg given IV on Days 1 and 8 of Cycle 1 and then on Day 1 of 
every subsequent 28-day cycle with continuation of dosing until unacceptable toxicity, 
disease progression, or withdrawal of consent.
1.6
Risk-benefit Summary
MEDI-551 may offer a benefit to patients with CD19-expressing hematologic malignancies 
who have failed standard therapies. Nonclinical and clinical data support the antitumor 
activity of MEDI-551 in a variety of B-cell malignancies. Specifically, MEDI-551 showed 
response rates of 19% in CLL, 29% in FL, and 23% in DLBCL subjects who had received a 
median of 5 prior lines of therapy. Currently, infusion reactions are an identified risk of 
MEDI-551 treatment. Potential risks, based on the mechanism of action of MEDI-551, and 
data from nonclinical safety and pharmacology studies and published literature on relevant or 
similar therapies (primarily rituximab) include the following: acute hypersensitivity 
reactions, tumor lysis syndrome, IM-related reactions, immunosuppression with increased 
risk of infection, and adverse reproductive effects. There are, however, no clinical or 
nonclinical data to suggest that the toxicity profile of MEDI-551 will compare unfavorably to 
rituximab. Clinical data suggest the toxicities observed are consistent with the toxicity profile 
of other MAbs and B-cell-depleting agents.
The proposed Phase 1/2 trial will characterize both the safety and antitumor activity of 
MEDI-551 in B-cell malignancies, with the goal of more fully elucidating its risk-benefit 
profile. The exclusion criteria, safety monitoring, starting dose, dose-escalation scheme, and 
stopping criteria will minimize the risks for subjects participating in the monotherapy and 
combination therapy arms of the study.
The combination of rituximab and MEDI-551 has the potential for additive toxicities 
including acute hypersensitivity reactions, tumor lysis syndrome, IM-related reactions, 
immunosuppression with increased risk of infection, and potential adverse reproductive 
effects. The dosing schema for MEDI-551 and rituximab has been altered to minimize the 
risk of infusion-related AEs by separating MEDI-551 and rituximab dose administration on 
Day 1 of Cycle 1. Additional changes to the administration of MEDI-551, including change 
in the infusion rate and additional steroid premedication together with administration of an 


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anti-pyretic and H2-blocker, have been mandated to further minimize this risk. To further 
reduce the risk of additive toxicities, the dose-escalation schema in the combination arm 
(Arm C) starts with a 33.3% lower dose of MEDI-551 (ie, 8 mg/kg) than the maximum dose 
demonstrated as safe (ie, 12 mg/kg) in the single-agent treatment of subjects with B-cell 
malignancies. Finally, DLT criteria and dose-modification schemas have been adjusted to 
address the potential for increased hematologic and non-hematologic toxicities. Additional 
follow-up has been implemented to further ensure the safety of subjects (Section 6.3).
Based on the observed pharmacologic activity and mechanism of action of MEDI-551, as 
well as the considerable clinical experience with marketed products such as rituximab, which 
has a similar mechanism of action, the risk-benefit profile is considered acceptable for the 
single-agent arms (Arms A, B, and D) of the clinical study. In addition, with the safety 
provisions listed above and the knowledge that B-cell-targeted MAbs have been successfully 
and safely combined to treat this population, the risk-benefit profile is considered acceptable 
for the dual-antibody arm (Arm C) of this study.
2
STUDY OBJECTIVES
2.1
Primary Objectives
The primary objectives of this study are listed by study arm.
Arm A
1. To determine the MTD or OBD of MEDI-551 in subjects with relapsed or refractory 
advanced B-cell malignancies (CLL, including SLL, DLBCL, and FL)
2. To determine the preliminary safety profile of MEDI-551
Arm B
Dose escalation
1. To determine the MTD or highest protocol-defined dose of MEDI-551 in the absence of 
exceeding the MTD in subjects with relapsed or rituximab-refractory CLL (defined as 
those with less than a PR or progression within 6 months after completing therapy with 
rituximab)
Dose expansion
1. To evaluate further the safety and tolerability of MEDI-551 at the dose selected in the 
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2. To evaluate the clinical activity of MEDI-551 at the dose selected in the dose-escalation 
phase in subjects with relapsed or rituximab-refractory CLL
Arm C
Dose escalation
1. To determine the safety and tolerability of MEDI-551 in combination with rituximab at 
the MTD or the highest protocol-defined dose in the absence of exceeding the MTD in 
subjects with aggressive lymphomas
Dose expansion
1. To evaluate further the safety and tolerability of MEDI-551 at the dose selected in the 
dose-escalation phase in subjects with aggressive lymphomas
2. To evaluate the clinical activity of MEDI-551 at the dose selected in the dose-escalation 
phase in combination with rituximab in relapsed and rituximab-refractory population 
(defined as those with less than a PR or progression within 6 months after completing 
therapy with rituximab)
Arm D
1. To evaluate the clinical activity of MEDI-551 in subjects with any anti-CD20-refractory 
aggressive lymphomas (defined as any subject with less than a PR to any prior 
anti-CD20-based therapy or progression within 6 months after completing therapy with 
any anti-CD20-based regimen, including maintenance rituximab)
2.2
Secondary Objectives
The secondary objectives of this study are listed by study arm.
Arm A
1. To determine the preliminary efficacy profile of MEDI-551 in subjects with advanced 
B-cell malignancies (CLL [including SLL], DLBCL, and FL)
2. To determine the PK of MEDI-551 in subjects with advanced B-cell malignancies
3. To determine the effect of treatment with MEDI-551 on circulating lymphocyte 
populations and Ig levels, including time to recovery after treatment
4. To determine the IM of MEDI-551 in subjects with advanced B-cell malignancies


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Arm B
1. To evaluate the PK and IM of MEDI-551 at doses studied in subjects with relapsed or 
rituximab-refractory CLL
2. To evaluate the effect of therapy on the B-lymphocyte level in peripheral blood, 
including time to recovery of B-lymphocyte level
Arm C
1. To evaluate the PK and IM of MEDI-551 when administered in combination with 
rituximab in subjects with aggressive lymphomas
2. To evaluate the effect of therapy on the B-lymphocyte level in peripheral blood, 
including time to recovery of B-lymphocyte level
Arm D
1. To determine the safety and tolerability of MEDI-551 in subjects with any anti-CD20-
refractory aggressive lymphomas
2. To evaluate the PK and IM of MEDI-551
3. To evaluate the effect of therapy on the B-lymphocyte level in peripheral blood, 
including time to recovery of B-lymphocyte level
2.3
Exploratory Objectives
The exploratory objectives of this study are listed by study arm.
Arm A
1.
 
Arm B
1.
 
2.
 
3.
 


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Arm C
1.
 
2.
Arm D
1.
 
 
2.
3
STUDY DESIGN
3.1
Overview of Study Design
This is a Phase 1/2, multicenter, international, open-label, dose-escalation and expanded 
cohort study to evaluate the safety, tolerability, and potential antitumor activity of MEDI-551 
as single agent or in combination with rituximab in adult subjects with advanced B-cell 
malignancies. The study design of Arm A comprised a dose-escalation phase followed by a 
dose-expansion phase in subjects with advanced B-cell malignancies receiving single-agent 
MEDI-551. 
As of Version 10.0 of the protocol, the study design also includes dose escalation and 
expansion in subjects with CLL receiving single-agent MEDI-551 (Arm B), and dose 
escalation and expansion in subjects with aggressive lymphoma receiving MEDI-551 
combined with rituximab (Arm C). As of Version 11.0 of the protocol, the study design also 
includes subjects with any anti-CD20-refractory aggressive lymphoma receiving single-agent 
MEDI-551 (Arm D). 
This study included participants from 21 investigational sites in the United States (US), 
Canada, and European Union (EU).
Enrollment in the study was closed as of 30Sep2015.  As of 19Jan2017, 9 subjects remain on 
treatment; all have completed at least 1 year of treatment.  All subjects who are currently 
receiving MEDI-551 treatment may continue to receive MEDI-551 until disease progression, 
unacceptable toxicity, CR, withdrawal of consent, or another reason to discontinue therapy 
intervenes.  Subjects who achieve CR may receive 2 additional cycles at the same dose prior 
to EOT Visit. A simplified schedule of evaluations focused on safety will be used. Safety 
follow-up assessments will be conducted at the EOT Visit (defined as the last day of the last 


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cycle of investigational product administration) as well as at the 90-Day Post Last Dose Visit
(defined as 90 days after the last dose of study medication), which will serve as the End of 
Study Visit. Long-term follow-up for PFS and OS will not be performed following 
implementation of Version 13.0.  
Arm A
Enrollment in the dose-escalation and dose-expansion phases of Arm A is complete. Protocol 
Version 4.0 was amended to make the study population for dose-escalation inclusive of 
subjects with FL, MM, CLL, or DLBCL. Dose escalation in Arm A began in subjects with 
FL or MM per protocol Versions 1.0 through 4.0. Under these versions of the protocol, 
subjects were enrolled into the first 2 cohorts. Starting with Version 5.0 of the protocol, 
enrollment in dose-escalation Cohorts 3 and higher was open to subjects with the following 
advanced B-cell malignancies: FL, MM, CLL, or DLBCL. Subjects in Cohorts 1 and 2 
continued to follow the protocol Version 4.0 dose schedule of 0.5 mg/kg (Cohort 1) or 
1 mg/kg (Cohort 2) MEDI-551 administered IV once every week in 4-week cycles. Subjects 
enrolled in Cohorts 3 and higher received 2, 4, 8, or 12 mg/kg MEDI-551 (Cohorts 3 to 6, 
respectively) IV once per week on Days 1 and 8 of Cycle 1 (loading doses) and then once 
every 28 days at the start of each subsequent cycle. Rules for dose escalation are provided in 
Section 4.5.5. As per Cohorts 1 and 2, dosing in Cohorts 3 and higher followed a standard 
3+3 dose-escalation scheme. No intrasubject dose escalation was allowed. The dose cohorts 
for the dose-escalation phase in Arm A are shown in Figure 3.1-1.


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Figure 3.1-1
Flow Diagram for Dose Escalation in Arm A
CLL = chronic lymphocytic leukemia; DLBCL = diffuse large B-cell lymphoma; FL = follicular lymphoma; 
MM = multiple myeloma.
Note: Subjects in Cohorts 1 and 2 were treated as per Version 4.0 of the protocol. Subjects in Cohorts 3 and 
beyond were as per Version 5.0 and subsequent versions of the protocol.
Subjects continued to receive MEDI-551 until disease progression, toxicity, or another 
reason to discontinue therapy intervened. All subjects (US and non-US) who achieved a CR 
could have received an additional 2 cycles of MEDI-551 at the same dose. Rules for dose 
escalation are described in Section 4.5.5. A total of approximately 18 to 36 evaluable 
subjects were required for the dose-escalation phase; 26 were enrolled. Subjects were 
considered evaluable if they received at least one full cycle (4 doses for Cohorts 1 and 2; 
2 doses for Cohorts 3 to 6) of MEDI-551 and completed the safety follow-up through the 


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DLT evaluation period as defined in Section 4.5.6, or experienced any DLT. Non-evaluable 
subjects were replaced in the same dose cohort. Dose escalation continued until the MTD (if 
≤12 mg/kg), the 12-mg/kg maximum dose, or a lower dose (the OBD) as determined by a 
combination of safety, PK, pharmacodynamic, and response data was reached.
Following determination of the MTD or OBD, approximately 80 subjects total, 20 subjects 
each with FL, MM, CLL, or DLBCL, were to be enrolled in the dose-expansion phase of 
Arm A to determine the preliminary efficacy profile of MEDI-551 in the treatment of 
advanced B-cell malignancies. As of Version 8.0 of the protocol, enrollment of MM subjects 
in the expansion phase was discontinued based on data from this study and recent nonclinical 
studies suggesting a lack of activity in the advanced/refractory MM setting. Twenty subjects 
each with FL, CLL (including SLL), or DLBCL were enrolled in the dose-expansion phase 
for a total of approximately 60 evaluable subjects.  A total of 69 subjects (24 CLL, 
21 DLBCL, 23 FL, and 1 MM) were enrolled.
Subjects in the dose-expansion phase of Arm A were treated on Days 1 and 8 of Cycle 1 
(loading doses) and then once every 28 days at the start of each subsequent cycle at the 
MTD, maximum dose of 12 mg/kg, or OBD as determined in the dose-escalation phase. 
A preplanned interim safety analysis, as defined in the statistical analysis plan, was 
undertaken when the maximum dose was reached to examine treatment effects on key safety 
endpoints. As of Version 7.0 of the protocol, the dose-escalation phase of Arm A had been 
completed. No MTD or OBD was identified during the dose-escalation phase; therefore the 
expansion phase of Arm A proceeded using the previously selected maximum dose of 
12 mg/kg. The preplanned interim safety analysis was conducted at the completion of the 
dose-escalation phase. No significant safety findings were noted and no changes were made 
to the protocol as a result of these findings.
If evaluation of available safety, PK, pharmacodynamic, and efficacy data suggest that 
increased safety and/or efficacy is possible with a longer dosing interval, an extended interval 
may be evaluated. Subjects who achieved a CR may receive an additional 2 cycles of 
MEDI-551 at the same dose. Once Version 13.0 is in effect, re-treatment will not be available
for subjects who achieve a CR and subsequently relapse while off treatment. Prior to Version 
13.0, the US FDA was to be consulted concerning the possibility of additional treatment with 
MEDI-551 for subjects within the US, and US subjects enrolled in Arm A could have been
retreated at the 12-mg/kg dose at the discretion of the investigator and after discussion with 
the sponsor. Non-US subjects in Arm A were not to be retreated with MEDI-551 on 
subsequent relapse. 


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Arm B
Enrollment in Arm B is complete. Based on evaluation of the PK data in CLL subjects 
(n = 26) from Arm A, there appeared to be lack of full exposure and numerically lower
response rate compared to non-CLL subjects using the current monthly dosing regimen at the 
highest dose evaluated (ie, 12 mg/kg). This arm of the study evaluated further dose escalation 
in CLL subjects utilizing a new schema, designed to saturate the potential B-cell sink, 
achieve full exposure, and maximize clinical activity, by employing weekly dosing of MEDI-
551 for 4 weeks during Cycle 1 and then monthly dosing on Day 1 of each subsequent 
28-day cycle to determine the MTD or the highest protocol-defined dose in the absence of 
exceeding the MTD, which would be evaluated in a dose-expansion phase. To further 
minimize infusion-related reactions at higher dose levels, for the 24 and 48 mg/kg dose levels 
of MEDI-551, the initial weekly doses were to be administered over 2 days on Day 1 and 
Day 2 in Cycle 1. Subsequent doses at the 24 and 48 mg/kg dose levels were to be 
administered in an identical fashion to lower dose levels (ie, weekly on Days 8, 15, and 22 in 
Cycle 1 and then on Day 1 of each 28-day cycle in Cycle 2 and beyond). Note that the 
48 mg/kg cohort was not enrolled. A flow diagram for Arm B is provided in Figure 3.1-2.
Using a standard 3+3 design, 3 to 6 subjects with CLL were to be enrolled per cohort, 
starting at a dose of 6 mg/kg and escalating to 3 additional dose levels (12, 24, and 48 mg/kg) 
in the dose-escalation phase of this arm. Treatment may continue until the subject
experiences unacceptable toxicity, disease progression, achieves CR (2 additional cycles at 
the same dose may be given prior to EOT) or withdraws consent. If 0 of 3 or ≤1 of 6 subjects 
treated at the previous dose level experienced a DLT, dose escalation could continue. The 
MTD was defined as the dose at which no more than 1 of 6 subjects experienced a DLT 
during Cycle 1. No intrasubject dose escalation was allowed. Subjects were considered 
evaluable for a DLT if they completed their first cycle of therapy or discontinued therapy 
during Cycle 1 due to a DLT. Nonevaluable subjects were to be replaced in the same dose 
cohort. A total of up to 24 subjects were to be enrolled in the dose-escalation portion of this 
arm. Dose escalation was permitted after all investigators reviewed the available data after a 
data review meeting and unanimously agreed to proceed with enrollment into the next cohort. 
The outcome from this meeting was documented in writing and shared with all participating 
sites.
Once an MTD was identified or the maximum planned dose not exceeding the MTD was 
reached, additional CLL subjects were to be enrolled at the selected dose in the 
dose-expansion phase to ensure a total of 26 efficacy evaluable subjects were available for 
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included subjects treated at the MTD or maximum planned dose enrolled in the 
dose-escalation phase of this arm. Treatment may continue until the subject experiences 
unacceptable toxicity, disease progression, withdraws consent, or achieves CR (2 additional 
cycles at the same dose may be given prior to EOT).
Figure 3.1-2
Flow Diagram for Dose Escalation and Expansion in Arm B
MTD = maximum tolerated dose.
* Note: For the 24 and 48 mg/kg cohorts, the initial weekly doses were administered over 2 days on Day 1 and 
Day 2 in Cycle 1. Subsequent doses for the 24 and 48 mg/kg cohorts were to be administered weekly on Days 8, 
15, and 22 in Cycle 1 and then on Day 1 of each 28-day cycle in Cycle 2 and beyond. Note that the 48 mg/kg 
cohort was not enrolled.
Arm C
Enrollment in Arm C is complete. Given the high unmet medical need in patients with 
multiply relapsed aggressive lymphoma, the synergistic activity observed in preclinical 
studies with MEDI-551 and rituximab, as well as the promising clinical activity seen with 
other dual MAb combinations in patients with B-cell malignancies, this arm of the study 
evaluated the safety and efficacy of MEDI-551 in combination with rituximab in subjects 
with aggressive lymphoma (relapsed or refractory DLBCL, Grade 3b FL, FL transforming to 


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DLBCL and MCL) in dose-escalation and dose-expansion cohorts. A flow diagram for Arm 
C is provided in Figure 3.1-3.
Using a standard 3+3 design, 3 to 6 subjects with aggressive NHL were enrolled per cohort 
in the dose-escalation portion of this arm, starting at a MEDI-551 dose of 8 mg/kg and 
escalating to 12 mg/kg. Subjects in this arm received weekly rituximab for 8 weeks 
beginning on Day 1 of Cycle 1 along with MEDI-551 8 mg/kg on Days 2 and 8 of Cycle 1, 
and on Day 1 of Cycle 2 and beyond in 28-day cycles. Dose escalation continued to 
12 mg/kg as 0 of 3 or ≤ 1 of 6 subjects treated at the lower dose experienced a DLT. The 
MTD was defined as the dose at which no more than 1 of 6 subjects experienced a DLT. No 
intrasubject dose escalation was allowed. Subjects were considered evaluable for a DLT if 
they completed their first cycle of therapy or discontinued therapy during Cycle 1 due to a 
DLT. Nonevaluable subjects were to be replaced in the same dose cohort. A total of up to 
12 subjects were to be enrolled in the dose-escalation portion of this arm of the study. Dose 
escalation was permitted after all investigators reviewed the available data during a data 
review meeting and unanimously agreed to proceed with enrollment into the next cohort. The 
outcome from this meeting was documented in writing and shared with all participating sites.
Once an MTD was identified or the maximum planned dose not exceeding the MTD was
reached, additional subjects were to be enrolled and treated at the selected dose of MEDI-551 
in combination with rituximab in the dose-expansion portion of this arm to ensure a total 
sample size of 26 efficacy evaluable subjects were available for analysis after completing one 
post-treatment disease evaluation. The 26 subjects were to include subjects treated at the 
selected dose during the dose-escalation portion of this arm. Treatment may continue until 
the subject experiences unacceptable toxicity, disease progression, withdraws consent, or 
achieves a CR (2 additional cycles of MEDI-551 at the same dose may be administered 
before EOT). A total of 19 subjects were enrolled in Arm C.
Subjects in Arm C were stratified based on their responsiveness to any prior anti-
CD20-based therapy with the option of ensuring a minimum number of 7 subjects who are 
refractory to any prior anti-CD20-based therapy are enrolled if clinical data from Arm D or 
emerging preclinical data suggest that the combination of anti-CD20 and anti-CD19 therapies 
improve response in this subpopulation.


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Figure 3.1-3
Flow Diagram for Dose Escalation and Expansion in Arm C
MTD = maximum tolerated dose.
Arm D
Enrollment in Arm D is complete. Given the high unmet medical need in patients with 
refractory aggressive lymphoma and in light of preservation of CD19 expression on the 
surface of these malignant cells, MEDI-551 may represent a salvage therapy option for anti-
CD20-refractory patients. Evidence of clinical activity and safety of MEDI-551 in an 
unselected patient population (Arm A) supported investigating MEDI-551 in the
anti-CD20-refractory population. Arm D evaluated the clinical activity of MEDI-551 in 
subjects with any anti-CD20-refractory aggressive lymphoma (refractory DLBCL, Grade 3b 
FL, FL transforming to DLBCL, and MCL). A flow diagram for Arm D is provided in 
Figure 3.1-4.
Since the safety and tolerability of the 12-mg/kg dose of MEDI-551 has been verified in 
Arm A, approximately 26 subjects with any anti-CD20-refractory disease were to be enrolled 
and treated with single-agent MEDI-551 at the dose and schedule used in the expansion 
cohort of Arm A (ie, 12 mg/kg of MEDI-551 on Days 1 and 8 of Cycle 1, and on Day 1 of 
Cycle 2 and beyond in 28-day cycles). A total of 16 subjects were enrolled in Arm D.
Treatment may continue until the subject experiences unacceptable toxicity, disease 


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progression, withdraws consent, or achieves a CR (2 additional cycles of MEDI-551 at the 
same dose may be administered before EOT).
MEDI-551 
12 mg/kg
Cycle Study Day
1  8
1 
≤28 Days
28 Days
28 Days
Cycle 1
Cycles 2+
MEDI-551
Screening period of  ≤28 days
Subjects will receive MEDI-551 until disease progression, 
unacceptable toxicity, or consent withdrawal
Safety follow-up period (through 90 days post last dose)
Long-term follow-up every 3 months for disease 
evaluation and survival until the end of study
Treatment
Figure 3.1-4
Flow Diagram for Treatment in Arm D
The endpoints to be measured in this study are described in Section 7.3.
3.2
Estimated Study Duration
The duration of investigational product treatment will be determined by disease response and 
safety. Safety follow-up assessments will be conducted through approximately 90 days after 
the last dose of investigational product, which is equivalent to approximately 60 days post-
EOT Visit. The estimated study duration is approximately 8 to 10 years from the time the 
first subject is enrolled in the study. Study completion is defined as the date of the last 
protocol-specified visit for the last subject in the study.
4
STUDY PROCEDURES
4.1
Subject Participation and Identification
Study participation begins once written informed consent is obtained (see Section 10.3 for 
details). Once informed consent is obtained, a subject identification (SID) number will be 
assigned by a central system (eg, an interactive voice response system [IVRS]), and the 
screening evaluations may begin to assess study eligibility (inclusion/exclusion) criteria. The 


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SID number will be used to identify the subject during the screening process and throughout 
study participation, if applicable.
A master log will be maintained of all consented subjects and will document all screening 
failures (ie, subjects who are consented but do not meet study eligibility criteria).
4.2
Subject Selection
The subjects enrolled in this study were adults with relapsed or refractory B-cell 
malignancies: CLL (including SLL), DLBCL, FL (as of protocol Version 8.0), MCL (as of 
protocol Version 10.0), and transformed indolent lymphoma (as of protocol Version 11.0).
The investigator (physician) or qualified designee was to discuss the study with a subject/the 
legal representative of a subject who is considered a potential candidate for the study and 
provide the subject/legal representative with the study-specific informed consent form 
approved by the Institutional Review Board (IRB)/Independent Ethics Committee (IEC). The 
investigator or designee was to address any questions and/or concerns that the subject/legal 
representative may have and, if there is continued interest, was to secure written informed 
consent for participation in the study. Written informed consent and any locally required 
authorization (eg, Health Insurance Portability and Accountability Act [HIPAA] 
authorization in the US, European Union [EU] Data Privacy Directive authorization in the 
EU), and written informed assent was to be obtained prior to conducting any protocol-related 
procedures, including screening evaluations or medication washouts. See Section 10.3 for 
additional details concerning informed consent.
4.2.1
Inclusion Criteria
Subjects must meet all of the following criteria:
1. Men or women at least 18 years of age or older at time of study entry
2. Written informed consent and HIPAA authorization (applies to covered entities in the 
USA only) obtained from the subject/legal representative prior to performing any 
protocol-related procedures, including screening evaluations
3. Diagnosis 
◦
Arm A: CLL (including SLL), DLBCL, or FL; SLL, DLBCL, and FL must be 
histologically confirmed
◦
Arm B: Histologically confirmed SLL or previous confirmation of B-cell CLL with a 
characteristic immunophenotype by flow cytometry
◦
Arm C: Histologically confirmed aggressive B-cell DLBCL, including FL 
transforming to DLBCL, transformed indolent lymphoma, MCL, or Grade 3b FL, 


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according to the World Health Organization (WHO)/American Joint Committee on 
Cancer (AJCC) criteria
◦
Arm D: Histologically confirmed anti-CD20-refractory (defined as any subject with 
less than a PR to any prior anti-CD20-based therapy or progression within 6 months 
after completing therapy with any anti-CD20-based regimen, including maintenance 
rituximab) aggressive B-cell DLBCL, including FL transforming to DLBCL, 
transformed indolent lymphoma, MCL, or Grade 3b FL, according to the 
WHO/AJCC criteria
4. Optional: Willing to provide a fresh tumor sample if a sufficient quantity of archival
tumor sample is not available (Arms B, C, and D). 
5. Evaluable/measurable disease
◦
Non-CLL B-cell malignancies (Arms A, C, and D):
▪
Histologically confirmed B-cell NHL (FL or DLBCL), transformed indolent 
lymphoma, and MCL: Measurable disease defined as ≥ 1 lesion ≥20 mm in one 
dimension or ≥15 mm in 2 dimensions as measured by conventional or high-
resolution (spiral) computed tomography (CT). For Arms C and D: disease 
evaluable by the International Working Group criteria (Cheson et al, 2007)
▪
Baseline PET or PET/CT scans must show positive lesions compatible with CT-
defined anatomical tumor sites (only applicable for FL, DLBCL, MCL, 
transformed indolent lymphoma, and FL transforming to DLBCL)
◦
CLL (Arms A and B): 
▪
Confirmed B-cell CLL/SLL with a characteristic immunophenotype by flow 
cytometry, and symptomatic disease requiring treatment
▪
CT scans showing involvement of ≥ 1clearly demarcated lesions measuring 
≥1.5 cm 
6. Prior therapy
◦
Arm A:
▪
Histologically confirmed B-cell NHL (FL or DLBCL): Relapsed from or 
refractory to ≥ 1 prior regimen containing rituximab, either alone or in 
combination, and not be a candidate for hematopoietic SCT or BM transplant
▪
B-cell CLL: Relapsed from or refractory to ≥ 2 prior lines of treatment, ≥ 1 of 
which must have contained rituximab
◦
Arm B: Relapsed from or refractory to ≥ 2 prior chemotherapy regimens with 
≥1 regimen containing rituximab
◦
Arm C: Relapsed from or refractory to ≥ 2 prior chemotherapy regimens with 
≥1 regimen containing rituximab or failed 1 prior rituximab-containing regimen and 
unable to tolerate additional multiagent chemotherapy
◦
Arm D: Refractory to ≥ 1 regimen containing any anti-CD20-based therapy, including 
salvage regimens and maintenance rituximab. Refractory subjects are defined as any 
subject with less than a PR to any prior anti-CD20-based therapies or progressed 
within 6 months after completing therapy with any anti-CD20-based regimens, 
including maintenance rituximab. These subjects must not be eligible for 
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7. Prior radiation therapy is allowed provided exposure does not exceed an area of 25% of 
marrow space and occurred ≥ 6 weeks prior to the first dose of MEDI-551 (Arm A only)
8. Karnofsky performance status ≥ 70
9. Life expectancy of ≥ 12 weeks
10. Adequate hematologic function 
Arm A (except for CLL subjects with significant BM involvement by biopsy) must meet 
the following criteria:
◦
Hemoglobin ≥ 9 g/dL, (≥ 8 g/dL for subjects who are transfusion dependent)
◦
Absolute neutrophil count ≥ 1500/mm3
◦
Platelet count ≥ 75,000/mm3
Arms B, C, and D must meet the following criteria:
◦
Hemoglobin ≥ 8 g/dL
◦
Absolute neutrophil count ≥ 1000/mm3
◦
Platelet count ≥ 75,000/mm3
◦
In the event of significant BM involvement, the above hematologic criteria will not be 
required for enrollment eligibility
11. Adequate organ function defined as follows:
◦
Aspartate aminotransferase (AST) and alanine aminotransferase 
(ALT) ≤2 × institutional upper limit of normal (ULN)
◦
Bilirubin ≤ 1.5 × ULN except for subjects with documented Gilbert’s disease, 
≤2.5 × ULN;
◦
Serum creatinine ≤ 1.5 mg/dL or a calculated creatinine clearance of ≥60 mL/min as 
determined by the Cockcroft-Gault equation1
12. Female subjects of childbearing potential who are sexually active with a nonsterilized 
male partner must use highly effective contraception from screening and must agree to 
continue using such precautions for at least 180 days after the last dose of investigational 
product. Depending on the investigational product received, this period may be longer. 
Cessation of birth control after this point should be discussed with a responsible 
physician
◦
Females of childbearing potential are defined as those who are not surgically sterile 
(ie, bilateral tubal ligation, bilateral oophorectomy, or complete hysterectomy) or 
those who are postmenopausal (defined as 12 months with no menses without an 
alternative medical cause or follicle-stimulating hormone/luteinizing hormone levels 
consistent with a menopausal state)
◦
A highly effective method of contraception is defined as one that results in a low 
failure rate (ie, less than 1% per year) when used consistently and correctly. 
Acceptable methods of contraception are described in Table 4.2.1-1. Sustained 
abstinence is an acceptable practice; however, periodic abstinence, the rhythm 
method, and the withdrawal method are not acceptable methods of contraception
                                                
1 Cockcroft-Gault equation: (140 - age) × weight in kg / (serum creatinine × 72). Multiply by 0.85 for females.


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13. Non-sterilized males who are sexually active with a female partner of childbearing 
potential must use a highly effective method of contraception (Table 4.2.1-1) from at 
least Day 1 through 90 days after the last dose of investigational product
14. Negative serum beta human chorionic gonadotropin (βhCG) test (for women of 
childbearing potential only)
15. Females or female partners not of childbearing potential must have been surgically 
sterilized or postmenopausal (as defined above in inclusion criterion #12). Sterilized 
males must be at least 1 year post vasectomy
Table 4.2.1-1
Recommended Methods of Contraception
Barrier Methods
Intrauterine Devices
Hormonal Contraceptives
Male condom plus spermicide
Cap (plus spermicidal cream or 
jelly) plus male condom
Diaphragm (plus spermicidal 
cream or jelly) plus male condom
Copper T
Progesterone T plus condom or 
spermicide
Implants
Hormone shot/injection
Combined pill
Minipill
Patch
4.2.2
Exclusion Criteria
Any of the following would exclude the subject from participation in the study:
1. Any available standard line of therapy known to be life-prolonging or life-saving
2. Any concurrent chemotherapy, radiotherapy, immunotherapy, biologic or hormonal 
therapy for treatment of cancer
3. History of allergy or reaction to any component of the MEDI-551 formulation
4. Receipt of any chemotherapy or small molecule targeted therapy (such as imatinib or 
other tyrosine kinase inhibitors, and including any experimental therapies) or radiation 
therapy within 28 days or 5 half-lives, whichever is shorter, prior to the first dose of 
MEDI-551
5. Receipt of any biological or immunological-based therapies (including experimental 
therapies) for leukemia, lymphoma, or myeloma (including, but not limited to, MAb 
therapy such as rituximab, or cancer vaccine therapies) within 28 days or 5 half-lives, 
whichever is shorter, prior to the first dose of MEDI-551 
6. Previous therapy directed against CD19, such as MAbs or MAb conjugates
7. Live or attenuated vaccines (other than experimental cancer vaccine therapy) within 
28 days prior to receiving the first dose of MEDI-551
8. Evidence of significant active infection requiring antimicrobial, antifungal, antiparasitic, 
or antiviral therapy or for which other supportive care is given
9. Autologous SCT within 12 weeks prior to study entry (Arms A and D only)
10. Prior allogeneic SCT or organ transplant (Arms A and D only)
11. Human immunodeficiency virus (HIV) positive serology or AIDS
12. Active hepatitis B as defined by seropositivity for hepatitis B surface antigen or positive 
hepatitis B core antibody. Subjects with hepatitis C antibody will be eligible provided 


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that they do not have elevated liver transaminases or other evidence of active hepatitis 
(Villadolid et al, 2010)
13. Ongoing ≥ Grade 2 toxicities from previous cancer therapies unless specifically allowed 
in the Inclusion/Exclusion criteria. Use of immunosuppressive medication other than 
steroids within 28 days before the first dose of MEDI-551
14. Use of systemic steroids within 7 days before the first dose of MEDI-551 (inhaled and 
topical corticosteroids are permitted). Subjects may take replacement doses of steroids 
(defined as ≤ 30 mg/day hydrocortisone or the equivalent) if on a stable dose for at least 
2 weeks prior to the first dose of MEDI-551. This does not include required steroid 
prophylaxis prior to the first infusion of MEDI-551
15. Documented current central nervous system involvement by leukemia or lymphoma
16. Pregnancy or lactation
17. Previous medical history, or evidence, of an intercurrent illness that at the discretion of 
the principal investigator may compromise the safety of the subject in the study
18. Clinically significant abnormality on electrocardiogram (ECG). The corrected QT 
interval (QTc, Fridericia) must be < 470 milliseconds for men and < 490 milliseconds for 
women (Must be confirmed by at least 2 additional 12-lead ECGs at least 2 minutes apart 
such that average manually over-read QTcF based on 3 ECGs exceeds stated thresholds)
19. Any physical, social, or psychiatric condition that would prevent effective cooperation or 
participation in the study
20. Concurrent enrollment in another clinical study, unless in a follow-up period or it is an 
observational study
21. Employees of the clinical study site who are directly involved with the conduct of the 
study, or immediate family members of such individuals. These subjects may be treated 
at another site participating in the study
22. History of other invasive malignancy within 5 years except for localized/in situ 
carcinomas.
4.3
Study Entry and Treatment Assignment
An IVRS was used to both document participation and to assign a dose cohort 
(dose-escalation phase) or treatment arm (expansion phase) to the subject. A subject was
considered entered into the study when the investigator notified the IVRS that the subject met 
eligibility criteria and the IVRS provided the assignment of investigational product.
The procedure for using IVRS was as follows:
•
Once the subject had signed the informed consent form, the investigator or designee 
contacted the IVRS and the IVRS provided the assignment of the SID number
•
After confirmation of eligibility, the investigator or designee contacted the IVRS and 
provided the SID number and subject’s baseline characteristic(s) used to verify that it is 
the same subject


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•
The IVRS assigned a dose cohort or treatment arm to the subject based on disease type
•
A confirmatory fax/email with this information was sent to the investigator/designee who 
dispensed the investigational product to the subject and recorded the appropriate 
information in the subject’s medical records and investigational product accountability 
log
Details for using IVRS were provided in the IVRS manual.
Investigational product (MEDI-551) must be administered after the dose cohort or treatment 
arm is assigned. If there is a delay in the administration of investigational product such that it 
will not be administered within the specified timeframe, the MedImmune study monitor 
and/or its designee must be notified immediately.
4.4
Blinding
This study was not blinded.
4.5
Study Treatment
4.5.1
Investigational Product (MEDI-551)
MEDI-551 is manufactured by MedImmune, LLC. Investigational product will be distributed 
to clinical sites using designated distribution centers. The sponsor will provide the 
investigators with adequate quantities of investigational product. Investigational product will 
be stored at 2°C to 8°C (36°F to 46°F) and must not be frozen. Investigational product will be 
supplied to the investigational product manager in vials with identical appearances. The 
clinical site staff will order investigational product from the investigational product manager 
using the site’s normal ordering procedures. The investigational product manager will 
prepare the investigational product. MEDI-551 is supplied as a sterile liquid solution at a 
dosage strength of 
 at MEDI-551 concentrations of 
.
Investigational product will be supplied as described below:


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:
The 
 Drug Products are supplied in vials with a nominal 
-
 
solution of MEDI-551 at a concentration of 
 MEDI-551, and 
contain a nominal 
 of MEDI-551. 
The Drug Product solution at the 
 strength contains 
 
 
.
: The 
 Drug Products are supplied in vials with a nominal 
 
solution of MEDI-551 at a concentration of 
, and contain a 
nominal 
 of MEDI-551.
The Drug Product solution at the 
 strength contains 
 
The investigator’s or site’s designated investigational product manager is required to 
maintain accurate investigational product accountability records. Upon completion of the 
study, copies of investigational product accountability records will be returned to the 
sponsor. All unused investigational product will be returned to a MedImmune-authorized 
depot or disposed of upon authorization by MedImmune.
4.5.1.1
Investigational Product Inspection
Each vial of investigational product selected for dose preparation should be inspected. 
MEDI-551 is supplied as 
), clear, colorless, liquid solutions
that are free from visible particles. If any defects in the investigational product are noted, the 
investigator and site monitor should be notified immediately (see Section 4.5.1.2).
4.5.1.2
Reporting Product Complaints
Any defects in the investigational product must be reported immediately to the MedImmune 
Product Complaint Department by the site with further notification to the site monitor. All 
defects will be communicated to MedImmune and investigated further with the Product 
Complaint Department. During the investigation of the product complaint, all investigational 
products must be stored at labeled conditions unless otherwise instructed.


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MedImmune contact information for reporting product complaints:
Email: productcomplaints@medimmune.com
Phone: +1-301-398-2105
            +1-877-MEDI-411 (+1-877-633-4411)
Fax:    +1-301-398-8800
Mail:   MedImmune, LLC
           Attn: Product Complaint Department
           One MedImmune Way,
           Gaithersburg, MD USA 20878
4.5.2
Treatment Regimens
Arm A
Subjects enrolled in the dose-escalation phase of Arm A were treated with 1 of 6 doses (0.5, 
1, 2, 4, 8, or 12 mg/kg) of MEDI-551. Subjects in Cohorts 1 and 2 received 0.5 or 1 mg/kg 
MEDI 551, respectively, IV once every week in 4-week cycles. Subjects enrolled in 
Cohorts 3, 4, 5, and 6 will receive 2, 4, 8, or 12 mg/kg MEDI-551, respectively, IV once per 
week on Days 1 and 8 of Cycle 1 (loading doses) and then once every 28 days at the start of 
each subsequent cycle. Subjects who did not experience a DLT or did not otherwise become 
ineligible to receive MEDI-551 may continue to receive MEDI-551 until CR, disease 
progression, toxicity, or another reason for treatment discontinuation is observed. Subjects 
who achieve a CR may receive an additional 2 cycles of MEDI-551 at the same dose. Once 
Version 13.0 is implemented, re-treatment will not be available for subjects who achieve a 
CR and subsequently relapse while off treatment.
Following determination of the MTD or OBD or completion of dose escalation to 12 mg/kg 
as described in Section 4.5.5, additional subjects with FL, CLL, or DLBCL were enrolled in 
the dose-expansion phase of Arm A. A total of 69 subjects (24 CLL, 21 DLBCL, 23 FL, and 
1 MM) were enrolled. One subject with MM was enrolled before the MM group was 
removed from the dose-expansion phase of the study. Enrollment of MM subjects was 
discontinued due to a lack of activity based on nonclinical and preliminary clinical data. 
Subjects in these dose-expansion cohorts were treated at a dose of 12 mg/kg in the absence of 
establishing a MTD. Different dose levels or dosing schedules may be evaluated if all 
available safety, PK, pharmacodynamic, and efficacy data suggest that evaluation of different 
dose levels, dosing schedules and/or duration of treatment would be beneficial. Subjects in 
the expansion phase were treated with MEDI-551 on Days 1 and 8 of Cycle 1 (loading doses) 
and then on Day 1 of every subsequent 28-day cycle unless evaluation of different 
schedule(s) was needed as described above. 


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Arm B
During the dose-escalation phase of Arm B, MEDI-551 was administered IV at 6 mg/kg 
weekly for 4 weeks during Cycle 1. For Cycle 2 and beyond, MEDI-551 6 mg/kg was
administered on Day 1 of each 28-day cycle. Subsequent sequential cohorts were to evaluate 
doses of 12, 24, and 48 mg/kg administered weekly for 4 weeks during Cycle 1 and then on 
Day 1 of each 28-day cycle starting with Cycle 2 and beyond. 
To further minimize infusion-related reactions at higher dose levels, for the 24 and 48 mg/kg
dose levels of MEDI-551, the initial weekly doses were to be administered over 2 days on 
Day 1 and Day 2 in Cycle 1. Additionally, as detailed in Section 4.5.3, mandatory 
premedication against IRR was required on both Day 1 and Day 2 of Cycle 1. 
1. At the 24 mg/kg dose level MEDI-551 was administered as follows:
a.
On Day 1, 12 mg/kg as an infusion over a minimum of 81 minutes as detailed in 
Section 4.5.3
b. On Day 2, 12 mg/kg as an infusion over a minimum of 60 minutes as detailed in 
Section 4.5.3  
2. At the 48 mg/kg dose level MEDI-551 was to be administered as follows:
a.
On Day 1, 12 mg/kg as an infusion over a minimum of 81 minutes as detailed in 
Section 4.5.3
b. On Day 2, 36 mg/kg as an infusion over a minimum of 60 minutes as detailed in 
Section 4.5.3
Subsequent doses at the 24 and 48 mg/kg dose levels was to be administered in an identical 
fashion to lower dose levels (ie, weekly on Days 8, 15, and 22 in Cycle 1 and then on Day 1 
of each 28-day cycle in Cycle 2 and beyond).
During the dose-expansion phase of Arm B, the selected MEDI-551 dose was to be 
administered IV weekly for 4 weeks during Cycle 1 and then on Day 1 of an every 28-day 
cycle starting with Cycle 2 and beyond.
Treatment may continue until the subject experiences unacceptable toxicity, disease 
progression, reaches CR (2 additional cycles may be given prior to EOT) or withdraws 
consent.
Arm C
During the dose-escalation phase of Arm C, MEDI-551 was administered IV at 8 mg/kg on 
Days 2 and 8 in combination with rituximab 375 mg/m2 administered IV on Days 1, 8, 15, 


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and 22 of Cycle 1 (28-day cycle). In Cycle 2, MEDI-551 was administered at 8 mg/kg on 
Day 1 and rituximab 375 mg/m2 was administered on Days 1, 8, 15, and 22. For Cycle 3 and 
beyond, only MEDI-551 8 mg/kg was administered on Day 1 of each 28-day cycle. As the 
MTD was not exceeded at 8 mg/kg, the MEDI-551 dose was escalated to 12 mg/kg 
administered in combination with a fixed dose of rituximab on the same schedule as noted 
above.
Treatment during the dose-escalation phase may continue until the subject experiences 
unacceptable toxicity, disease progression, reaches CR (2 additional cycles may be given
prior to EOT) or withdraws consent.
Arm D
MEDI-551 was be administered IV at 12 mg/kg on Days 1 and 8 of Cycle 1 and on Day 1 of 
Cycle 2 and beyond in 28-day cycles. Treatment may continue until the subject experiences 
unacceptable toxicity, disease progression, reaches CR (2 additional cycles may be given
prior to EOT) or withdraws consent.
4.5.2.1
Dose Modification for Toxicity Management
Arm A
In rare circumstances and under the authority of the Medical Monitor, subjects were retreated 
following a DLT as described in Section 6.4.1.
During the DLT period, dose modification was not permitted. However, a delay in therapy 
due to a reversible non-DLT toxicity was permitted as long as the total delay within the cycle
is ≤5 days total. Any toxicity leading to a delay > 5 days in duration during the DLT period 
was be considered a DLT.
Following the DLT period, subsequent cycles of MEDI-551 were delayed or modified based 
on hematologic and nonhematologic toxicities observed during each subsequent cycle of 
treatment as described in Table 4.5.2.1-1. Both hematologic and nonhematologic toxicities 
were graded according to the National Cancer Institute Common Terminology Criteria for 
Adverse Events Version 4.03 (NCI CTCAE V4.03; CTCAE, 2010).
The following AEs are exceptions to the dose modification and stopping rules described 
below in Table 4.5.2.1-1 and require NO modification of MEDI-551 dosing: lymphopenia 
(any grade) and hematologic abnormalities equal in severity to the subject’s baseline grade. 
Dose modification for Grade 2, 3, or 4 AEs will occur as described in Table 4.5.2.1-1. For 


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Grade 4 hematologic toxicity (other than lymphopenia), resolution to ≤Grade 2 or subject’s 
baseline is required to re-initiate treatment.
Adverse events for which a cause other than MEDI-551 can be clearly attributed (such as an 
accident) will not result in a dose delay or reduction.
Table 4.5.2.1-1
MEDI-551 Dose Modifications for Arm A 
Hematologic or 
Nonhematologic Toxicity
Dose Modification of MEDI-551
Grade ≤ 1
None
Grade 2 a
First Occurrence:
•
For AEs present before the next dose of MEDI-551 is to be given, delay the 
next dose of MEDI-551 for up to 7 days until resolution to ≤Grade 1 or 
baseline, and resume at current dose level.
•
Reduce the dose of MEDI-551 to 50% and restart therapy if AE does not 
resolve to ≤ Grade 1 or baseline within 7 days.
•
For Grade 2 infusion reaction, infusion rate may be decreased by 50% or 
interrupted for up to 4 hours and symptomatic care instituted as clinically 
indicated. Following interruption, infusion should be resumed at 50% of 
original rate for remainder of infusion.
•
For allergic reactions ≥ Grade 2 or any allergic reaction necessitating the use 
of pressors, permanently discontinue MEDI-551.
Second Occurrence:
•
For second occurrence of Grade 2 AE, delay for up to 7 days until resolution 
to ≤ Grade 1 or baseline and initiate next dose at 50% of current dose level. 
The exceptions are as follows:
◦
For Grade ≥ 2 allergic reactions, MEDI-551 is to be permanently
discontinued at the first occurrence.
◦
Grade 2 infusion reactions do not necessitate dose reduction.
•
Permanently discontinue MEDI-551 if AE does not resolve to ≤ Grade 1 or 
baseline within 7 days or if the dose has previously been reduced.


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Table 4.5.2.1-1
MEDI-551 Dose Modifications for Arm A 
Hematologic or 
Nonhematologic Toxicity
Dose Modification of MEDI-551
Grade 3 or 4 b, c
First Occurrence:
•
For AEs present before the next dose of MEDI-551 is to be given, delay next 
dose of MEDI-551 for up to 7 days until resolution to ≤Grade 1 or baseline, 
and resume at 50% of current dose level.
•
If next dose is delayed for > 7 days due to failure of toxicity to resolve to 
≤Grade 1 or baseline, discontinue MEDI-551.
•
For Grade 3 infusion reaction, infusion rate may be decreased by 50% or 
interrupted for up to 4 hours and symptomatic care instituted as clinically 
indicated; steroid prophylaxis must be employed for all subsequent doses of 
MEDI-551. Following interruption, infusion should be resumed at 50% of 
original rate for remainder of infusion. For Grade 3 infusion reaction that 
does not respond to medical therapy (including interruption of infusion for 
≤4 hours) or that occurs despite steroid prophylaxis, permanently 
discontinue MEDI-551.
•
For any Grade 4 infusion or allergic reaction that necessitates the use of 
systemic pressor agents, permanently discontinue MEDI-551.
Second Occurrence:
•
Permanently discontinue MEDI-551.
See Section 6.4.1 for additional details on dose interruption and study discontinuation criteria.
a
Hematologic abnormalities equal in severity to the subject’s baseline and lymphopenia (any grade) do not 
require dose modification. 
b
Except Grade 3 or 4 toxicities noted as exceptions to the DLT criteria (see Section 4.5.6).
c
For ≥Grade 3 hematologic toxicities other than lymphopenia, resolution to ≤ Grade 2 or subject’s baseline 
is required to re-initiate treatment. 
Arms B, C, and D
During the DLT period, dose modification was not permitted. However, a delay in therapy 
due to reversible non-DLT toxicity was permitted as long as the total delay within the cycle 
is ≤7 days total. Any toxicity leading to a delay > 7 days in duration during the DLT period 
was considered a DLT.
Following the DLT period, subsequent cycles of MEDI-551 could be delayed or modified 
based on hematologic and nonhematologic toxicities observed during each subsequent cycle 
of treatment as described in Table 4.5.2.1-2. Both hematologic and nonhematologic toxicities 
were graded according to the NCI CTCAE V4.03 (CTCAE, 2010).
The following AEs were exceptions to the dose modification and stopping rules described in 
Table 4.5.2.1-2 and required NO modification of MEDI-551 dosing: lymphopenia (any 
grade) or hypogammaglobulinemia. Dose modification for Grade 2, 3, or 4 AEs occurred as 
described in Table 4.5.2.1-2. Laboratory changes within a cycle did not require prompt dose 
modification or delay unless clinically indicated in the investigator’s opinion. Adverse events 


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for which a cause other than MEDI-551 could be clearly attributed (such as an accident) did
not result in a dose delay or reduction. If more than one dose reduction was needed for the 
same toxicity, the subject was required to permanently discontinue treatment.
For subjects in the dose-escalation portion of Arms B and C, if the start of Cycle 2 was
delayed for toxicity-related reasons beyond 7 days, the subject was considered to have had a 
DLT and was required to resume dosing at a dose level below which they were enrolled. If 
the subject was unable to recover from toxicity within 7 days despite the dose modification 
indicated in Table 4.5.2.1-2, they were required to permanently discontinue treatment. The 
start of Cycle 3 and beyond was allowed to be delayed by up to 7 days to permit resolution of 
toxicity or for logistical reasons. If a subject delayed 2 consecutive cycles by >7 days each, 
they were to be withdrawn from therapy even if delays are due to different toxicities. 
For all subjects in the dose-expansion portion of Arms B and C, and for all subjects enrolled 
in Arm D, any cycle could be delayed by 7 days to permit resolution of toxicity or for 
logistical reasons. For a given subject, a single cycle was allowed to be delayed by up to 
28 days to permit recovery from toxicity. Upon recovery of toxicity, dose modification was 
required to be performed according to the guidelines provided in Table 4.5.2.1-2. If a cycle 
was delayed by > 28 days, the subject was required to permanently discontinue treatment. If 
a subject had received 1 dose reduction and a subsequent cycle was delayed by > 7 days to 
permit recovery from toxicity, the subject was required to permanently discontinue treatment.
If 2 consecutive cycles were delayed by 7 days each, the subject was required to permanently 
discontinue therapy even if delays are due to different toxicities.


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Table 4.5.2.1-2
MEDI-551 Dose Modifications for Nonhematologic and 
Hematologic Toxicity in Arms B, C, and D
Toxicity Grade
Dose Modification of MEDI-551
Nonhematologic Toxicity
Grade ≤ 1
None
Grade 2
First Occurrence:
•
For Adverse Events (AEs) present before the next dose of MEDI-551 is to be given:
•
If resolution to ≤Grade 1 or baseline within 7 days, then resume at current dose level
a)
If resolution to ≤Grade 1 or baseline within 8-28 days, then resume dose at 
50% of current dose level
•
If resolution to ≤Grade 1 or baseline exceeds 28 days, then discontinue MEDI-551 
•
For Grade 2 infusion reaction, infusion rate may be decreased by 50% or interrupted 
for up to 4 hours and symptomatic care instituted as clinically indicated. Following 
interruption, infusion should be resumed at 50% of original rate for remainder of 
infusion.
•
For allergic reactions ≥ Grade 2 or any allergic reaction necessitating the use of 
pressors, permanently discontinue MEDI-551.
Second Occurrence:
•
For AEs present before the next dose of MEDI-551 is to be given:
a)
If resolution to ≤ Grade 1 or baseline within 7 days, then initiate next dose at 
50% of current dose level with the following exceptions:
i)
For ≥Grade 2 allergic reactions, MEDI-551 is to be permanently 
discontinued at the first occurrence
ii)
Grade 2 infusion reactions do not necessitate dose reduction
iii)
For Grade 2 AE that previously required dose reduction but resolves 
within 7 days on 2nd occurrence, resume at current dose level (ie, 50% 
of original dose)
b)
If resolution to ≤Grade 1 or baseline beyond 7 days, then permanently 
discontinue MEDI-551
c)
If resolution to ≤Grade 1 or baseline takes exactly 7 days in two consecutive 
cycles, then permanently discontinue MEDI-551
Third Occurrence:
•
For AEs present before the next dose of MEDI-551 is to be given, permanently 
discontinue MEDI -551


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Table 4.5.2.1-2
MEDI-551 Dose Modifications for Nonhematologic and 
Hematologic Toxicity in Arms B, C, and D
Toxicity Grade
Dose Modification of MEDI-551
Grade 3 or 4 a,b
First Occurrence:
•
For AEs present before the next dose of MEDI-551 is to be given, delay next dose of 
MEDI-551 for up to 7 days until resolution to ≤Grade 1 or baseline, and resume at 
50% of current dose level.
•
If next dose is delayed for > 7 days due to failure of toxicity to resolve to ≤Grade 1 or 
baseline, permanently discontinue MEDI-551.
•
For Grade 3 infusion reaction, infusion must be stopped for up to 4 hours until the 
subject recovers. An additional dose of steroids will be given and the infusion may
resume but the infusion rate must be decreased by 50% for remainder of infusion. For 
Grade 3 infusion reaction that does not respond to medical therapy (including 
interruption of infusion for ≤ 4 hours) or that occurs despite steroid prophylaxis, 
discontinue MEDI-551.
•
For any Grade 4 infusion or allergic reaction that necessitates the use of systemic 
pressor agents, permanently discontinue MEDI-551.
Second Occurrence:
•
For AEs present before the next dose of MEDI-551 is to be given, permanently 
discontinue MEDI-551.
Hematologic Toxicity c,d
Grade 1 or 2 
None
Grade 3 a,b
First Occurrence:
•
Delay dose by up to 7 days until resolution to ≤Grade 2 and resume at current dose 
level. If subject does not recover to ≤Grade 2 within that time, permanently 
discontinue MEDI-551.
Second Occurrence:
•
Delay dose by up to 7 days until resolution to ≤Grade 2 and decrease dose by 50%. If 
subject does not recover to ≤Grade 2 within that time, permanently discontinue 
MEDI-551.
Third Occurrence:
•
Permanently discontinue MEDI-551.
Grade 4 a,b
First Occurrence:
•
Delay dose by up to 7 days until resolution to ≤ Grade2 and decrease dose by 50%. If 
subject does not recover to ≤Grade 2 within that time, permanently discontinue 
MEDI-551.
Second Occurrence:
•
Permanently discontinue MEDI-551.
See Section 6.4.1 for additional details on dose interruption and study discontinuation criteria.
a
Except Grade 3 or 4 toxicities noted as exceptions to the Dose Limiting Toxicity (DLT) criteria (see 
Section 4.5.6).
b
Please note that for laboratory findings observed in the absence of clinical abnormality, repeat laboratory 
testing will be conducted to confirm significant laboratory findings before implementing dose modification.
c
For advanced B-cell malignancy dose escalation/expansion, hematologic abnormalities equal in severity to 
the subject’s baseline and lymphopenia (any grade) do not require dose modification. 
d
For subjects in Arms B, C, and D, lymphopenia or changes in lymphocyte counts will not be considered 
hematologic toxicities. Hematologic abnormalities equal in severity to the subject’s baseline grade will not 
warrant dose modification unless they recur after normalization or improvement in the counts to ≤ Grade 2. 
Thereafter, hematologic abnormalities will require dose modification or cessation of dosing as indicated in 


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Table 4.5.2.1-2
MEDI-551 Dose Modifications for Nonhematologic and 
Hematologic Toxicity in Arms B, C, and D
Toxicity Grade
Dose Modification of MEDI-551
this table.
4.5.3
Investigational Product Preparation and Administration
The day of receipt of the first dose of investigational product is considered Day 1. The 
weight used to calculate the dose will be the weight on Day 1 of each cycle. The weight at 
screening may be used for Cycle 1, Day 1 if the weight on Day 1 is within 10% of the 
screening weight. No change in dose should be made during a particular cycle unless a 
change in weight of greater than 10% is observed from the weight used to calculate the dose 
for that cycle. An equation for weight-based dose calculation is provided below.
Drug Volume (mL) = Dose (mg/kg) × Patient Weight (kg) ÷ Product Concentration (mg/mL)
The dose of investigational product for administration must be prepared by the investigators
or site’s designated investigational product manager using aseptic technique. The 
investigational product manager will select the appropriate number of vials of investigational 
product required to prepare the subject’s dose. Allow the vial(s) to come to room 
temperature.
To prepare investigational product for administration, the investigational product manager 
should remove the tab portion of the vial cap and clean the rubber stopper with 70% ethyl 
alcohol or equivalent. To avoid foaming, the vial should not be shaken. A vial should only be 
used one time to prepare a single dose.
Arm A
The dose of MEDI-551 must be prepared using aseptic technique. MEDI-551 must be diluted 
for IV administration in a PVC-, DEHP-, and latex-free infusion bag containing a total 
volume of 250 mL of 0.9% sodium chloride for injection. An amount of 0.9 % sodium 
chloride equal to the volume of MEDI-551 solution to be added should be removed from the 
infusion bag, and then the calculated amount of MEDI-551 should be added to the infusion 
bag. The prepared solution may be stored at room temperature prior to being administered to 
the subject. MEDI-551 must be administered within 8 hours after preparation. If the dose is 
not administered within 8 hours, a new dose must be prepared using a new vial, as the 
MEDI-551 product contains no bacteriostatic agents. 


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MEDI-551 will be administered as an IV infusion over 60 minutes (+ 15 minutes) using a 
0.2 micron filter. Subjects will be monitored during and after infusion with assessment of 
vital signs every 15 minutes during infusion, at the end of infusion, and 30 and 60 minutes 
after the infusion.
In the event of an IRR, the infusion of MEDI-551 may be decreased by 50% or interrupted 
until resolution of the event (up to 4 hours) and re-initiated at 50% of the initial rate until 
completion of the infusion. Acetaminophen and/or an antihistamine (eg, diphenhydramine) 
may be administered at the discretion of the investigator. If the infusion reaction is severe or 
prolonged, methylprednisolone 100 mg (or the equivalent) should be administered as well. 
For subsequent infusions in subjects who experience an infusion reaction and do not require 
discontinuation of MEDI-551 (see Section 6.4.1), acetaminophen and an antihistamine may 
be administered prior to initiation of the MEDI-551 infusion. If a subject experiences a Grade 
3 infusion reaction, all subsequent administration of MEDI-551 must be preceded by IV 
methylprednisolone 100 mg (or the equivalent) 30 minutes prior to initiation of MEDI-551 
infusion. Investigators may administer steroids during any cycle at their discretion as 
clinically indicated and per their institution’s guidelines.
Arms B, C, and D
The use of the 2 dosage strengths, 
, will be specified by the sponsor. 
Subjects who begin therapy with the 
 form will continue therapy with that 
dosage form. Subjects in cohorts of Arms B, C and D receiving MEDI-551 at dose levels of 
12 mg/kg or less will receive the 
dosage form. However, the 
 
(
) investigational product must be used for the 24 and 48 mg/kg cohorts of Arm 
B. The dose of MEDI-551 must be prepared using aseptic technique. MEDI-551 has been 
shown to be compatible with PVC-, DEHP-, and latex-free infusion bags containing a total 
volume of 250 mL of 0.9% sodium chloride for injection. An amount of 0.9 % sodium 
chloride equal to the volume of MEDI-551 solution to be added should be removed from the 
infusion bag, and then the calculated amount of MEDI-551 should be added to the infusion 
bag. The prepared solution may be stored at room temperature prior to being administered to 
the subject. MEDI-551 infusion must begin within 4 hours after preparation. If the infusion 
of the dose is not initiated within 4 hours, a new dose must be prepared using a new vial, as 
the MEDI-551 product contains no bacteriostatic agents. MEDI-551 will be administered by 
IV infusion using a 0.2-micron in-line filter.
All subjects must receive mandatory premedication consisting of a minimum dose of 60 mg 
of IV methylprednisolone (or its equivalent) as well as 500 to 650 mg oral acetaminophen (or 


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paracetamol equivalent) and 50 mg IV diphenhydramine (or its equivalent) before the start of 
the initial MEDI-551 infusion. The initial infusion of MEDI-551 will be administered a 
minimum of 30 to 60 minutes after administration of mandatory premedications (as described 
in this section) according to the following sequence of infusion rates, regardless of dosage 
form:
•
1 mL/minute for a minimum of 15 minutes, then
•
2 mL/minute for a minimum of 15 minutes, then
•
4 mL/minute to complete the infusion
The minimum infusion time will be 81 minutes. Subjects receiving doses ≥ 24 mg/kg in Arm 
B will receive the initial infusion over 2 days on Day 1 and Day 2 of Cycle 1. The Day 1 
infusion will be administered over a minimum of 81 minutes as described above. The Day 2 
infusion will be administered over a minimum of 60 minutes (+ 15 minutes at the 
investigator’s discretion). If the subject experiences an infusion reaction on Day 1, the Day 2 
infusion will be administered over a minimum of 90 minutes. Subjects will be monitored 
closely during the initial infusion of MEDI-551, with vital signs recorded every 5 minutes 
over the first 30 minutes of the infusion and then every 15 minutes for the remainder of the 
infusion duration. Additional details regarding vital signs monitoring during the initial 
infusion of MEDI-551 are provided in Section 6.4.3. For subsequent infusions, MEDI-551 
will be administered over 60 minutes (+ 15 minutes at the investigator’s discretion). Vital 
signs will be monitored as described in Section 6.4.3. The initial infusion of MEDI-551 will 
be administered on Day 1 of Cycle 1 for Arms B and D, and Day 2 of Cycle 1 for Arm C.
In the event of an IRR, the infusion of MEDI-551 may be interrupted until resolution of the 
event (up to 4 hours) and re-initiated at the 1-mL/minute rate. MEDI-551 infusion must be 
completed within 4 hours after the initial start of the infusion (NOTE: This is in addition to 
the 4 hours permitted from preparation of MEDI-551 solution to start of infusion). A new IP 
solution is required to be prepared if MEDI-551 infusion is not able to be completed within 
4 hours after the initial start of the infusion. The rate may be increased slowly (by 50% every 
15 minutes) until completion of the infusion. If the infusion reaction is severe or prolonged, 
methylprednisolone 100 mg (or the equivalent) may be administered in addition to 
acetaminophen (or institutional equivalent) and/or an antihistamine at the discretion of the 
investigator for management of the IRR (Simons, 2010; Sampson et al, 2006). In the event of 
a Grade 4 IRR, MEDI-551 should be permanently discontinued (see Section 4.5.2.1 and 
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If a subject experiences a Grade 3 IRR and does not require permanent discontinuation of 
MEDI-551 (see Section 4.5.2.1 and Section 4.5.6), all subsequent administration of MEDI-
551 must be preceded by IV methylprednisolone 100 mg (or the equivalent), oral 
acetaminophen 500 to 650 mg (or equivalent dose of paracetamol), and IV diphenhydramine 
(or its equivalent) 50 mg 30 to 60 minutes prior to initiation of MEDI-551 infusion. Subjects 
who only experience a Grade 1 or 2 IRR and do not require permanent discontinuation of 
MEDI-551 (see Section 4.5.2.1) may receive methylprednisolone (or the equivalent), 
acetaminophen (or paracetamol equivalent), and diphenhydramine 30 to 60 minutes prior to 
initiation of the MEDI-551 infusion at the investigator’s discretion.
As with any antibody, allergic reactions to dose administration are possible. Therefore, 
appropriate drugs and medical equipment to treat acute anaphylactic reactions must be 
immediately available, and study personnel must be trained to recognize and treat 
anaphylaxis.
For Arm C only: Rituximab will be administered per institutional guidelines (see Appendix 2
for rituximab prescribing information). All subjects must receive mandatory premedication 
consisting of a minimum dose of 60 mg IV methylprednisolone (or its equivalent) as well as 
500 to 650 mg oral acetaminophen (or paracetamol equivalent), and 50 mg IV 
diphenhydramine 30 to 60 minutes before the start of the initial rituximab infusion on Day 1 
of Cycle 1. The initial infusion of rituximab will be administered over a minimum of 30 to 
60 minutes after administration of mandatory premedications. On Day 2 of Cycle 1, 
MEDI-551 will be administered over a minimum of 81 minutes following mandatory 
premedications as indicated above under “Arms B, C, and D”.  On Day 8 of Cycle 1 and Day 
1 of Cycle 2, MEDI-551 should be administered first with rituximab administration a 
minimum of 30 minutes after completion of the MEDI-551 infusion.
4.5.4
Concomitant Medications
Subjects may receive medications as supportive care or to treat AEs as deemed necessary by 
the investigator or the subject’s physician. The use of pre-medication prior to administration 
of MEDI-551, in the absence of a previously documented reaction to MEDI-551, is permitted 
when it is clinically indicated or in accordance with institutional guidelines for administration 
of a MAb. Premedication with acetaminophen, diphenhydramine, and corticosteroids is 
mandatory before the first MEDI-551 infusion for Arms B, C, and D. The infusion rate 
should be reviewed and adjusted to minimize infusion reactions as detailed in Section 4.5.3. 
In addition, the following concomitant medications are allowed: 1) hematopoietic growth 
factors to treat anemia and cytopenias as per usual institutional practice following 
consultation with the Medical Monitor; 2) red cell and platelet transfusions in subjects who 


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are transfusion-dependent; 3) prophylactic intravenous Ig to prevent infections; 4) intrathecal 
prophylaxis with either methotrexate or cytarabine, if clinically indicated; and 5) 
prophylactic antibiotics. No transfusions are permitted during the DLT period for all dose-
escalation cohorts in Arms B and C. For subjects with large tumor burden or elevated LHD 
(ie, at high risk for tumor lysis syndrome), prophylaxis against tumor lysis syndrome may be 
given according to institutional guidelines prior to initiation of study treatment (eg,
hydration, urine alkalinization, administration of hypouricemic agent). Subjects’ hydration 
status should be assessed to reduce risks of infusion-related hypotension; laboratory 
abnormalities that could complicate management if tumor lysis syndrome were to develop
should be managed according to institutional standards.
All concomitant medications given to the subject from the time the subject signs the 
informed consent form through 90-Day Post Last Dose Visit will be recorded on the source 
document. 
4.5.5
Dose Escalation
Rules for dose escalation in Arms A, B, and C are described below. This section is not 
relevant to Arm D.
Arm A
1. The MTD was to be determined based on the assessment of DLT during the DLT period 
(see Section 4.5.6). Subjects were considered evaluable for assessment of DLT if they 
received at least 1 full cycle (4 doses for Cohorts 1 and 2; 2 doses for Cohorts 3 to 6) of 
MEDI-551 and completed the safety follow-up through the DLT evaluation period, or 
experienced any DLT. Non-evaluable subjects were to be replaced. Any MEDI-551 
treatment-related toxicity (regardless of grade) leading to an inability to receive a full 
cycle of MEDI-551 was to be considered a DLT.
2. Per protocol Version 4.0, dose escalation was initiated in 3 subjects with FL or MM 
treated at the 0.5 mg/kg dose, once a week for 4-week cycles. No DLTs were observed in 
the first 3 subjects during the DLT period; therefore, enrollment in the next higher dose 
cohort (Cohort 2) began. Subjects in Cohorts 1 and 2 continued to receive MEDI-551 
weekly in 4-week cycles.
3. If no DLTs are observed in Cohort 2, dose escalation into Cohort 3 will proceed with 
enrollment of subjects with advanced B-cell malignancies (CLL, DLBCL, FL, or MM). If 
a DLT is observed in Cohort 2, expansion and evaluation will occur per Rule 5 below. 
Three subjects will be treated at the Cohort 3 dose on Days 1 and 8 in the 1st cycle 
(loading doses) and then once every 28 days at the start of each subsequent cycle. If no 
DLTs are observed in the first 3 subjects during the DLT period, enrollment in the next 
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4. For the first two dose cohorts only, subject enrollment was staggered so that no fewer 
than 7 days (including the day of treatment of the first subject) separates treatment start 
dates for each subject. A staggered enrollment achieves an observation period between 
subjects such that an adequate safety evaluation, including the assessment for cytokine 
release syndrome and tumor lysis syndrome, could be performed prior to entry of 
additional subjects. If no Grade ≥2 cytokine release syndrome or tumor lysis syndrome 
was observed in the subjects in the first two cohorts during the first 7 days of treatment, 
enrollment and treatment of subjects in subsequent cohorts (Cohorts 3 and higher) was 
allowed to proceed concurrently.
5. If 1 of 3 subjects in a dose cohort experienced a DLT during the DLT period, that dose 
cohort was allowed be expanded to a total of 6 subjects. If 1 of 6 subjects experienced a 
DLT, dose escalation continued in the next higher dose cohort.
6. If ≥ 2 subjects in a dose cohort experienced a DLT during the DLT period, the MTD 
would have been exceeded and no further subjects would be enrolled into that dose 
cohort. If this occurred, the preceding dose cohort would be evaluated for the MTD and a 
total of 6 subjects would be treated at the preceding dose. If ≤ 1 of 6 subjects experienced
a DLT at the preceding dose, then this dose level would be the MTD.
7.
If the MTD is not reached, either the maximum dose of 12 mg/kg or a lower dose (OBD) 
as determined by PK, pharmacodynamic, biomarker, and safety data will be used for 
cohort expansion.
8. At the discretion of the sponsor, an intermediate dose could have been chosen for dose 
escalation. Situations that might have prompted selection of an intermediate dose
included unexpected toxicities that did not meet the definition of DLT or multiple similar 
toxicities in a cohort that did not meet the definition of a DLT. If an intermediate dose 
was chosen, subsequent dose escalation would be to the next predetermined dose 
provided all the criteria for dose escalation in Rules 2-6 above were met. Further dose 
escalation would be based on toxicities observed at each dose level, and would be 
allowed to proceed according to the original dosing schedule or would be allowed to
include additional intermediate dosing steps based on accumulated safety data.
Arms B and C
1. The MTD was to be determined based on the assessment of DLT during the DLT period 
(see Section 4.5.6). Subjects were considered evaluable for assessment of DLT if they 
completed Cycle 1 of MEDI-551 or discontinued MEDI-551 treatment during Cycle 1 
due to a DLT. Non-evaluable subjects were to be replaced. Any MEDI-551 treatment-
related toxicity (regardless of grade) leading to an inability to complete the first cycle of 
MEDI-551 was considered a DLT.
2. If 0 of 3 or < 1 of 6 subjects treated at the previous dose level experienced a DLT, dose 
escalation was allowed to continue.
3. If ≥ 2 of 6 subjects in a dose cohort experienced a DLT during the DLT period, the MTD 
would have been exceeded and no further subjects would be enrolled into that dose 
cohort. If this occurred, the preceding dose cohort would be evaluated for the MTD and a 
total of 6 subjects would be treated at the preceding dose. If ≤ 1 of 6 subjects experienced
a DLT at the preceding dose, then this dose level would be the MTD.


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4. If the MTD was not reached, the highest protocol-specified dose will be used for cohort 
expansion. The highest protocol-specified dose is 48 mg/kg for Arm B and 12 mg/kg for 
Arm C. 
A study-specific Dose Escalation Committee consisting of all study investigators and the 
sponsor’s medical monitor provided ongoing safety surveillance of the study, with regularly 
scheduled reviews of safety and other relevant data. This committee was responsible for 
dose-escalation decisions and making recommendations regarding further conduct of the 
study. The sponsor notified sites when enrollment into each dose cohort had been completed 
and when enrollment into the next dose cohort was permitted. Details of the composition and 
role of the Dose Escalation Committee are presented in Section 6.4.
4.5.6
Dose-limiting Toxicities
Dose-limiting toxicities for Arms A, B, and C are described below. This section is not 
relevant to Arm D.
Arm A
The period for evaluating DLTs was from the time of first administration of MEDI-551 
through the first 28-day cycle. Delays of ≤ 5 days within a cycle due to reversible non-DLT 
toxicities were allowed during the DLT period; in that case, the DLT period was no greater 
than 33 days. Subjects who did not receive 2 doses (subjects enrolled under protocol 
Version 5.0) or 4 doses (subjects enrolled under protocol Version 4.0) of MEDI-551 during 
this time for reasons other than toxicity were to be replaced with another subject at the same 
dose level. Grading of DLTs was according to the NCI CTCAE V4.03 (CTCAE, 2010).
A DLT was defined as:
•
A MEDI-551 treatment-related AE of any toxicity grade that led to an inability to receive 
a full cycle of MEDI-551 or 
•
Any Grade 3 or higher toxicity as described below that could not be reasonably ascribed 
to another cause, such as disease progression or accident.
During the DLT period, a delay in therapy due to a reversible non-DLT toxicity lasting 
≤5 days total was not considered a DLT as long as the subject received the full intended 
dose.
Nonhematologic DLTs were any Grade 3 or higher diagnosis or laboratory finding with the 
following exceptions:


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•
Grade 3 fever that lasts ≤ 24 hours with or without medical therapy and is not considered 
an SAE
•
Transient Grade 3 rigors or chills that responds to optimum medical therapy
•
Grade 3 tumor lysis syndrome that resolves to ≤ Grade 2 within 72 hours after initiation 
of treatment
•
Any Grade 3 or 4 electrolyte alteration that is reversible to ≤ Grade 1 within 24 hours 
after it occurs
•
Any Grade 3 liver function test elevation that resolves to ≤ Grade 1 within 24 hours after 
it occurs
Grade 3 or higher hematologic toxicities were considered DLTs with the following 
exceptions:
•
≥ Grade 3 lymphopenia or leukopenia in the absence of neutropenia
•
≤ Grade 4 neutropenia in the absence of fever that resolves within 5 days
•
≤ Grade 4 thrombocytopenia that resolves within 5 days
•
≤ Grade 4 anemia in a subject who was transfusion dependent at study entry, or had a 
history of hemolysis
Arms B and C
The period for evaluating DLTs was from the time of first administration of MEDI-551 
through the first 28-day cycle. Grading of DLTs was according to the NCI CTCAE V4.03 
(CTCAE, 2010).
A DLT was defined as:
•
A MEDI-551 (or rituximab for Arm C) treatment-related AE of any toxicity grade that 
led to an inability to receive a full cycle of MEDI-551 (or rituximab for Arm C).
•
NOTE: During the DLT period, a delay in therapy due to a reversible non-DLT toxicity 
lasting ≤7 days total would not be considered a DLT as long as the subject received the 
full intended dose.
Nonhematologic DLTs were any Grade 3 or higher MEDI-551 (or rituximab for Arm C) 
treatment-related toxicity not attributable to another cause with the following exceptions:
•
Grade 3 fever that lasted≤ 24 hours with or without medical therapy and is not considered 
an SAE
•
Grade 3 rigors or chills lasting < 6 hours that respond to optimum medical therapy


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•
Grade 3 IRR (first occurrence and in the absence of steroid prophylaxis) that resolves 
within 6 hours with appropriate clinical management
•
Grade 3 tumor lysis syndrome that resolves to ≤ Grade 2 within 72 hours after initiation 
of treatment
•
Any Grade 3 electrolyte alteration that is reversible to ≤ Grade 1 within 72 hours after it 
occurs
•
Any Grade 3 liver function test elevation up to 8 × ULN and total bilirubin up to 
5 × ULN that resolves to ≤ Grade 1 within 72 hours after it occurs. Any liver function test 
elevation > 8 × ULN or total bilirubin elevation > 5 × ULN that is attributed to 
investigational product requires discontinuation of investigational product.
Hematologic DLTs were any Grade 3 or higher MEDI-551 (or rituximab for Arm C) 
treatment-related toxicity not attributable to another cause, with the following exceptions:
•
Grade 3 or 4 neutropenia in the absence of fever or infection that resolves to Grade 2 
within 7 days
•
Grade 3 or 4 thrombocytopenia that resolves to Grade 2 within 7 days and does not 
require a transfusion
•
Grade 3 anemia that resolves to Grade 2 within 7 days and does not require a transfusion
•
Grade 3 or 4 lymphopenia
4.6
Monitoring Subject Compliance
Investigational product is administered by study site personnel; subject compliance and 
investigational product administration will be reviewed during monitoring visits to the site 
and to the pharmacy.
4.7
Subject Status
Subject Completion
An individual subject will be considered to have completed the study if the subject was 
followed for survival until death or end of the study, regardless of the number of doses of 
investigational product that was received. Once Version 13.0 is in effect, all subjects who 
have completed treatment and the 90-Day Post Last Dose Visit for safety follow-up will be 
considered to have completed the study.
Until Version 13.0, is in effect, subjects will be considered not to have completed the study if 
one of the following conditions applies:


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•
Withdrawal of consent: If consent for follow-up is withdrawn, the subject will not receive 
any further investigational product or further study observation. Note that the subject may 
need to undergo additional tests or tapering of treatment to withdraw safely. 
•
Lost to follow-up: Subjects will be considered lost-to-follow-up only if no contact has 
been established by the time the study is completed such that there is insufficient 
information to determine the subject’s status on the last day of the study. 
Note: Subjects refusing to return to the site or to continue participation in the study should be 
documented as “withdrawal of consent” rather than “lost to follow-up.” Investigators should 
document attempts to re-establish contact with missing subjects throughout the study period. 
If contact with a missing subject is re-established, the subject should not be considered 
lost-to-follow-up and any evaluations should resume according to the protocol at the point 
that they would be if no evaluations had been skipped.
Permanent Discontinuation of Investigational Product
Subjects who do not receive all protocol-specified doses of the investigational product, 
regardless of the reason (withdrawal of consent, due to an AE, other), will be identified as 
having permanently discontinued treatment.
4.8
Study Completion
Study completion is defined as the date of the last protocol-specified visit for the last subject 
in the study. All materials or supplies provided by the sponsor will be returned to the sponsor 
or designee upon study completion, as directed by the site monitor, and/or destroyed by the 
site/IRB/IEC instructions. The investigator will notify the IRB/IEC when the study has been 
completed.
5
ASSESSMENT OF EFFICACY AND CLINICAL PHARMACOLOGY
5.1
Efficacy and Clinical Pharmacology Parameters
The efficacy of MEDI-551 will be evaluated in subjects with advanced B-cell malignancies, 
including CLL (including SLL), DLBCL, FL, MCL, and other transformed indolent 
lymphomas. The efficacy profile will be assessed using CR, duration of CR, OR, disease 
control, time to response (TTR), duration of objective response, duration of disease control, 
progression-free survival (PFS), and overall survival (OS). Clinical activity in subjects in 
Arms B, C, and D will also be assessed by the percentage of MRD-negative CRs achieved 
with single-agent MEDI-551 in Arms B and D, and with the combination of MEDI-551 and 
rituximab in Arm C.


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MEDI-551 PK will be described by area under the concentration-time curve from time 0 to 
last measurable concentration (AUCt), area under the concentration-time curve from time 
0 to infinity (AUC), clearance, steady-state volume of distribution, and terminal-phase 
half-life (t½) estimated by non-compartmental analysis. Circulating levels of blood 
mononuclear cells, including T cells, B cells, natural killer (NK) cells, and monocytes will be 
determined using standard clinically available flow cytometry. The production of human 
anti-human antibodies (HAHA) will be evaluated during treatment and in follow-up.
5.2
Schedule of Study Procedures
All subjects who are assigned an SID number and receive any investigational product will be 
followed according to the protocol regardless of the number of doses received, unless consent 
for follow-up is withdrawn. The investigator must notify the sponsor or designee of 
deviations from protocol visits or evaluations and these evaluations, if applicable, must be 
rescheduled or performed at the nearest possible time to the original schedule. Protocol 
deviations will be recorded on the source document with an explanation for the deviation. 
The investigator must comply with the applicable requirements related to the reporting of 
protocol deviations to the IRB/IEC.
Subjects/legal representatives will be instructed to call study personnel to report any 
abnormalities during the intervals between study visits and to come to the study site if 
medical evaluation is needed and the urgency of the situation permits. For emergency and 
other unscheduled visits to a medical facility other than the study site, medical records will 
be obtained by the investigator and made available to the sponsor or designee during 
monitoring visits.
The purpose of Protocol Version 13.0 is discontinue participation for all subjects who are no 
longer dosing and have completed at least the 90-day post treatment safety follow-up, while 
allowing subjects who are benefiting from MEDI-551 to continue treatment.  Subjects who 
are currently on treatment will be allowed to continue to receive MEDI-551 with a simplified 
schedule of evaluations focused on safety. The 90-Day Post Last Dose Visit for safety 
follow-up (approximately 90 days after last dose of study drug[s]) will be conducted when 
subjects come off treatment. Long-term follow-up for PFS and OS will be discontinued. 
Once Version 13.0 is in effect, all subjects who have completed treatment and safety follow-
up through at least the 90-Day Post Last Dose Visit will be considered to have completed the 
study. 
A summary of changes implemented in Version 13.0 is provided in Section 15 of the 
protocol.  Key safety assessments relevant to MEDI-551 are retained.  Table 5.2.1-1


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describes the frequency and type of procedure to be conducted for subjects who remain on 
treatment:  
5.2.1
Schedule of Study Procedures - All Subjects Approved for Version 
13.0 of the Protocol
AE = adverse event; ECG = electrocardiogram; EOS = End of Study; EOT = End of Treatment; Ig= 
immunoglobulin; SAE = serious adverse event;
a
Subjects with FL, DLBCL, MCL, and transformed indolent lymphoma: Assess by CT scan (FDG-PET or 
PET-CT if clinically indicated) and physical exam every 2 months during the first year of treatment and 
then every 6 months. Additional scans may be performed if clinically indicated.  Subjects with CLL
“(including SLL)” will perform chest, abdomen, pelvis, and neck (if applicable). CT scans are only 
required after the first year of treatment if clinically indicated (eg previous indication to treat was based on 
predominantly nodal disease) or if indicated based on hematology findings.
b
Disease assessment not required if performed within 8 weeks prior to the EOT visit.
Table 5.2.1-1
Schedule of Evaluations
Evaluations
Day 1, All Cycles 
Once Version 13.0 
Is In Effect 
(± 7 Days)
EOT Visit
(± 7 Days)
EOS or 
90-Day Post Last 
Dose Visit
(± 7 Days)
Verify eligibility criteria
X
Medical history
X
Concomitant medications
X
X
X
Pregnancy test (females of childbearing 
potential)
X
Karnofsky performance status
X
X
X
Physical examination (focused)
X
X
X
AE/SAE assessment
X
X
X
Weight
X
X
Vital signs
Pre and post dose
X
X
ECG (single)
X
X
Serum chemistry
X
X
X
Hematology 
X
X
X
Coagulation tests
X
X
Urinalysis
X
X
Quantitative IgM, IgG, IgA
X
X
Flow cytometry of whole blood for T/B cell 
and effector cell subsets
X
X
MEDI-551 serum concentrations
X
X
Anti-MEDI-551 antibodies
X
X
Disease assessment a
Every 2-6 months
Xb
MEDI-551 administration
X


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5.3
Description of Study Procedures
Simplified study procedures implemented in Version 13.0 are described in this section.  
A Laboratory Manual will be provided to the sites that specifies the procedures for 
collection, processing, storage, and shipment of samples, as well as laboratory contact 
information.
5.3.1
Medical History and Physical Examination, ECG, Weight, and Vital 
Signs
In Arms A, B, C, and D, medical history, physical examinations, ECG, weight, and vital 
signs will be evaluated according to the schedule in Section 5.2. Physical examination should 
be focused (symptom-directed).
Findings from medical history and physical exam shall be given a baseline grade according 
to the procedure for AEs. Increases in severity of pre-existing conditions during the study 
will be considered AEs, with resolution occurring when the grade returns to at or below the 
pre-study baseline.
As of Version 13.0, single ECGs will be obtained at the specified time points in the Schedule 
of Study Procedures in Section 5.2.1 . Vital signs include temperature, blood pressure, pulse 
rate, respiratory rate, and pulse oximetry.
Body weight will be recorded at Screening, and on Day 1 of each treatment cycle, and at 
EOT Visit.
5.3.2
Clinical Laboratory Tests
In Arms A, B, C, and D, clinical laboratory safety tests will be performed in a licensed
clinical laboratory following the schedule shown in Section 5.2.1. Urine pregnancy tests
(women of childbearing potential only) on Day 1 of each cycle prior to dosing will be 
performed in the clinic using a licensed test (dipstick). New abnormal laboratory results that 
are clinically significant should be repeated as soon as possible (preferably within 24 to 48 
hours). Tests for AST, ALT, alkaline phosphatase, and total bilirubin must be conducted 
concurrently and assessed concurrently.  The following clinical laboratory tests will be 
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Serum Chemistry
•
Bicarbonate
•
Lactate dehydrogenase 
•
Calcium
•
Blood urea nitrogen 
•
Chloride
•
Uric acid
•
Magnesium
•
Creatinine
•
Potassium
•
Total bilirubin
•
Sodium
•
Glucose
•
Aspartate aminotransferase
•
Albumin
•
Alanine aminotransferase 
•
Total protein
•
Alkaline phosphatase 
•
Triglycerides
•
Gamma glutamyl transferase 
•
Cholesterol
Hematology
•
WBC count with differential
•
Platelet count
•
Red blood cell count
•
Mean corpuscular volume 
•
Hematocrit
•
Mean corpuscular hemoglobin concentration 
•
Hemoglobin
Urinalysis
•
Glucose
•
Ketones
•
Blood
•
Bilirubin
•
Protein
Pregnancy Test (females of childbearing potential only)
•
Urine human chorionic gonadotropin 
Other Safety Tests
•
Coagulation tests: prothrombin time, partial thromboplastin time, fibrinogen


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5.3.3
T/B-cell and Immunoglobulin Levels
For Arms A, B, C, and D, flow cytometry performed at a central laboratory will be used to 
determine circulating T/B-cell levels and effector cell subsets. Samples for quantitative IgM, 
IgG, and IgA levels will be collected and local clinical laboratories will determine Ig levels.
5.3.4
Pharmacokinetic Evaluation and Methods
For Arms A, B, C, and D, blood samples for MEDI-551 PK evaluation will be collected 
according to the schedule shown in Section 5.2.1.  MEDI-551 concentrations in serum
samples will be measured using a validated immunoassay.
5.3.5
Immunogenicity Evaluation and Methods
For Arms A, B, C, and D, anti-MEDI-551 antibodies will be assessed according to the 
schedule shown in Section 5.2.1. Samples will be assessed for the presence of 
anti-MEDI-551 antibodies using a validated drug-tolerant solution -phase bridging assay. 
Tiered analysis will be performed to include screening, confirmatory and titer assay 
components, and positive-negative cutpoints, which were statistically determined from drug-
naïve validation samples, will be employed.
5.3.6
Disease Evaluation and Methods
Subjects with FL, DLBCL, MCL, or transformed indolent lymphoma will be assessed by CT 
scan and physical examination according to the schedule shown in Section 5.2.  
Fluorodeoxyglucose-positron emission tomography (FDG-PET) or positron emission 
tomography (PET-CT) are not required unless clinically indicated. Criteria for CR and PR 
will be according to the International Working Group criteria (Cheson et al, 2007). Complete 
response unconfirmed will not be used to assess response.
Subjects with CLL (including SLL) will be assessed by hematology and disease assessment
according to the schedule shown in Section 5.2.1. CT scans are only required after the first 
year of treatment if clinically indicated (eg previous indication to treat was based on 
predominantly nodal disease) or if indicated based on hematology findings. Assessment of 
disease response for CLL (including SLL), will be determined according to the National 
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5.3.7
Estimate of Blood Volume Collection
Beginning with Version 13.0, subjects will have approximately 15 mL of blood drawn on any 
single visit during the treatment period.  The estimated volume of blood to be collected 
during the EOT Visit or the 90-Day Post Last Dose Visit will be no more than 20 mL each 
visit.  The total volume of blood to be collected for a subject will depend on the number of 
cycles completed.  
6
ASSESSMENT OF SAFETY
6.1
Safety Parameters
6.1.1
Adverse Events
The International Council for Harmonisation (ICH) Guideline for Good Clinical Practice 
(GCP) E6 (R1) defines an AE as:
Any untoward medical occurrence in a patient or clinical investigation subject 
administered a pharmaceutical product and which does not necessarily have a causal 
relationship with this treatment. An AE can therefore be any unfavorable and unintended 
sign (including an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of a medicinal product, whether or not considered related to the 
medicinal product.
An AE includes but is not limited to any clinically significant worsening of a subject’s 
pre-existing condition.
Adverse events may be treatment emergent (ie, occurring after initial receipt of 
investigational product) or nontreatment emergent. A nontreatment-emergent AE is any new 
sign or symptom, disease, or other untoward medical event that begins after the subject/legal 
representative signs the informed consent form but before the subject has received 
investigational product.
Elective treatment or surgery (that was scheduled prior to the subject being enrolled into the 
study) for a documented pre-existing condition that did not worsen from baseline is not 
considered an AE.
6.1.2
Serious Adverse Events
An SAE is any AE that:
•
Results in death


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•
Is immediately life-threatening
This term refers to an event in which the subject was at risk of death at the time of the 
event; it does not refer to an event that may have led to death.
•
Requires inpatient hospitalization or prolongation of existing hospitalization 
In general, hospitalization signifies that the subject has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for 
observation and/or treatment that would not have been appropriate in an outpatient 
setting. 
•
Results in persistent or significant disability/incapacity 
The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions. 
•
Is a congenital anomaly/birth defect in offspring of the subject
•
Is an important medical event that may jeopardize the subject or may require medical 
intervention to prevent one of the outcomes listed above.
Medical or scientific judgment should be exercised in deciding whether expedited 
reporting is appropriate in this situation. Examples of medically important events are 
intensive treatment in an emergency room or at home for allergic bronchospasm, 
blood dyscrasias, or convulsions that do not result in hospitalizations; or development 
of drug dependency or drug abuse.
6.1.3
Other Events of Special Interest
6.1.3.1
Hepatic Function Abnormality
A ‘hepatic function abnormality’ of special interest to the sponsor is defined as any increase 
in ALT or AST to greater than 3 × ULN and concurrent increase in bilirubin to greater than 
2 × ULN. Concurrent findings are those that derive from a single blood draw or from 
separate blood draws taken within 8 days of each other. In the event of hepatic function 
abnormality, where the etiology is unknown, follow-up investigations and inquiries should be 
initiated promptly by the investigational site based on medical judgment to make an informed 
decision regarding the etiology of the event.
6.1.3.2
Infusion Reactions
Any IRR resulting in permanent discontinuation of investigational product must be reported 
within 24 hours of knowledge of the event to MedImmune Patient Safety or designee using 
the Fax Notification Form. See Section 6.2.5 and Section 6.3.5.5 for instructions.


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6.2
Assessment and Recording of Safety Parameters
6.2.1
Assessment of Severity
Assessment of severity is one of the responsibilities of the investigator in the evaluation of 
AEs and SAEs. The determination of severity should be made by the investigator based upon 
medical judgment and the severity categories of Grade 1 to 5 as generally defined below.
Grade 1
An event that is usually transient and may require only minimal 
treatment or therapeutic intervention. The event does not generally 
interfere with usual activities of daily living.
Grade 2
An event that is usually alleviated with additional specific therapeutic 
intervention. The event interferes with usual activities of daily living, 
causing discomfort but poses no significant or permanent risk of harm 
to the subject.
Grade 3
An event that requires intensive therapeutic intervention. The event 
interrupts usual activities of daily living, or significantly affects the 
clinical status of the subject. The event poses a significant risk of harm 
to the subject, and hospitalization may be required.
Grade 4
An event, and/or its immediate sequelae, that is associated with an 
imminent risk of death or is with physical or mental disabilities that 
affect or limit the ability of the subject to perform activities of daily 
living (eating, ambulation, toileting, etc).
Grade 5
The termination of life as a result of an event.
Severity will be graded according to the NCI CTCAE V4.03 (CTCAE, 2010). 
It is important to distinguish between serious criteria and severity of an AE. Severity is a 
measure of intensity whereas seriousness is defined by the criteria in Section 6.1.2. A 
Grade 3 need not necessarily be considered an SAE. For example, a Grade 3 headache that 
persists for several hours may not meet the seriousness criteria and would be considered an 
AE, whereas a Grade 2 myocarditis requiring hospitalization for pain management would be 
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6.2.2
Assessment of Relationship
An event is considered “product-related” for the purposes of regulatory reporting if the 
investigator, the MedImmune medical monitor, or the MedImmune Patient Safety Physician 
assesses the event as possibly, probably, or definitely related to the investigational product. 
This is not a conclusive determination of causal association between the product and the 
event.
Whenever the investigator’s assessment is unknown or unclear, the event is treated as 
product-related for the purposes of reporting to regulatory authorities.
An event may be deemed to be not related to the product for purposes of regulatory reporting 
only if the investigator, MedImmune medical monitor, and MedImmune Patient Safety 
physician, if applicable, agree that the event is not product-related.
The investigator is required to provide an assessment of relationship of AEs and SAEs to the 
investigational product. A number of factors should be considered in making this assessment 
including: 1) the temporal relationship of the event to the administration of investigational 
product; 2) whether an alternative etiology has been identified; and 3) biological plausibility. 
The following guidelines should be used by investigators to assess the relationship of an 
event to investigational product administration.
Relationship assessments that indicate an “Unlikely Relationship” to investigational 
product: 
None:
The event is related to an etiology other than the investigational product (the 
alternative etiology must be documented in the study subject’s medical 
record).
Remote:
The event is unlikely to be related to the investigational product and likely to 
be related to factors other than investigational product.
Relationship assessments that indicate a “Likely Relationship” to investigational product:
Possible:
There is an association between the event and the administration of the 
investigational product, and there is a plausible mechanism for the event to be 
related to investigational product; but there may also be alternative etiology, 
such as characteristics of the subject’s clinical status or underlying disease.
Probable:
There is an association between the event and the administration of 
investigational product, a plausible mechanism for the event to be related to 


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the investigational product, and the event could not be reasonably explained 
by known characteristics of the subject’s clinical status or an alternative 
etiology is not apparent.
Definite:
There is an association between the event and the administration of 
investigational product, a plausible mechanism for the event to be related to 
the investigational product, and causes other than the investigational product 
have been ruled out and/or the event re-appeared on re-exposure to the 
investigational product.
6.2.3
Recording of Adverse Events
Adverse events will be recorded on the case report form (CRF) using a recognized medical 
term or diagnosis that accurately reflects the event. Adverse events will be assessed by the 
investigator for severity, relationship to the investigational product, possible etiologies, and 
whether the event meets criteria of an SAE and therefore requires immediate notification of 
the sponsor. See Section 6.1.2 for the definition of SAEs, and Section 6.2.1 and Section 6.2.2
for guidelines for assessment of severity and relationship, respectively. If an AE evolves into 
a condition that meets the regulatory definition of “serious,” it will be reported on the SAE 
Report Form (Section 6.2.4).
6.2.4
Recording of Serious Adverse Events
Serious adverse events will be recorded on the SAE Report Form using a recognized medical 
term or diagnosis that accurately reflects the event. Serious adverse events will be assessed 
by the investigator for severity, relationship to the investigational product, and possible 
etiologies. See Section 6.1.2 for the definition of SAEs, and Section 6.2.1 and Section 6.2.2
regarding guidelines for assessment of severity and relationship, respectively.
For all SAEs that occur prior to the administration of investigational product, an assessment 
of protocol relatedness must be made by the investigator. A protocol-related SAE may occur 
as a result of a procedure or intervention required during the study (eg, blood collection, 
washout of an existing medication). The following guidelines should be used by investigators 
to assess the relationship of SAEs:


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Protocol related:
The event occurred due to a procedure/intervention that was described 
in the protocol for which there is no alternative etiology present in the 
subject’s medical record.
Not protocol related: The event is related to an etiology other than the procedure/ 
intervention that was described in the protocol (the alternative etiology 
must be documented in the study subject’s medical record).
6.2.5
Recording of Other Events of Special Interest
Hepatic Function Abnormality
Events of hepatic function abnormality (as defined in Section 6.1.3.1) should be recorded 
according to the definitions of AE and SAE (Section 6.1.1 and Section 6.1.2, respectively):
If an event of hepatic function abnormality is a pre-existing condition, the event does not 
meet the definition of an AE and does not need to be recorded as such.
If the etiology of the hepatic function abnormality is known (including progression of 
primary or metastatic malignancy) and/or not a pre-existing condition, the diagnosis should 
be recorded as an AE/SAE per Section 6.2.3 and Section 6.2.4.
If the hepatic function abnormality remains unexpected, the term “hepatic function 
abnormal” should be used to report the AE/SAE per Section 6.2.3 and Section 6.2.4.
Infusion-related Reactions
Infusion reactions meeting the criteria noted in Section 6.1.3.2 should be recorded using 
recognized medical terms or diagnosis that accurately reflects the event in the same manner 
all AEs and SAEs (Section 6.1.1 and Section 6.1.2, respectively). See Section 6.3.5.5 for 
additional reporting requirements. Infusion reactions and related signs and symptoms should 
only be recorded on the infusion reaction eCRF.
6.3
Reporting Requirements for Safety Parameters
6.3.1
Study Reporting Period for Adverse Events
All AEs that occur after a subject has signed the written informed consent form through the 
90-Day Post Last Dose Visit must be reported by the investigator.


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Any new sign or symptom, disease, or other untoward medical event that occurs after the 
subject/legal representative signs the informed consent form must be reported by the 
investigator as an AE in the same way as AEs that occur after the subject receives 
investigational product.
6.3.2
Study Reporting Period for Serious Adverse Events
The reporting period for SAEs is the period immediately following the time that written 
informed consent is obtained through the 90-Day Post Last Dose Visit. After the initial SAE 
report the investigator is required to follow each subject proactively and provide further 
information on the subject’s condition to MedImmune Patient Safety.
All SAEs should be followed up to resolution by the investigator, even if this extends beyond 
the study reporting period. Resolution of an SAE is defined as the return to baseline status or 
stabilization of the condition with the expectation that it will remain chronic.
At any time after completion of the study, if an investigator or qualified designee becomes 
aware of an SAE that is suspected by the investigator or qualified designee to be related to 
investigational product, the event should be reported to MedImmune Patient Safety.
6.3.3
Notification of Sponsor of Serious Adverse Events
Within 24 hours of identifying an SAE, regardless of the presumed relationship to the 
investigational product, the investigator or qualified designee must complete the SAE 
Report Form and fax to MedImmune Patient Safety or designee (ie, contract research 
organization).
MedImmune contact information:
Patient Safety 
MedImmune
One MedImmune Way
Gaithersburg, MD 20878
Fax: 1 301 398 4205
MedImmune will provide international fax numbers to the sites in countries outside of the 
US.
MedImmune, as sponsor of the study is responsible for reporting certain SAEs as expedited 
safety reports to applicable regulatory authorities, ethics committees, and participating 
investigators, in accordance with ICH Guidelines and/or local regulatory requirements. 
MedImmune may be required to report certain SAEs to regulatory authorities within 


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7 calendar days of being notified about the event; therefore, it is important that investigators 
submit additional information requested by MedImmune as soon as it becomes available.
Investigators should provide all available information at the time of SAE Report Form 
completion. Investigators should not wait to collect additional information to fully document 
the event before notifying MedImmune Patient Safety of an SAE. When additional 
information becomes available, submit a follow-up SAE Report Form (separate from the 
initial report form) with the new information. Any follow-up information to an SAE also 
needs to be provided to MedImmune Patient Safety within 24 hours of learning of the new 
information.
6.3.4
Notification of Institutional Review Board or Independent Ethics 
Committee of Serious Adverse Events
The investigator must comply with the applicable regulatory requirements related to the 
reporting of SAEs to the IRB/IEC. The IRB/IEC must be informed in a timely manner by the 
investigator of SAEs occurring at their site during the study. The sponsor will submit 
information on serious unexpected and related events to any EU IECs. Investigators must also 
submit safety information provided by MedImmune to the IRB/IEC as detailed in 
Section 10.1 and Section 10.2.
6.3.5
Other Events Requiring Immediate Reporting
6.3.5.1
Pregnancy and Overdose
The following events are not necessarily considered to be AEs but are considered 
immediately reportable events and are required to be reported in real time (i.e., within 24 
hours of learning about the event) to MedImmune Patient Safety using the Fax Notification 
Form:
1. Pregnancy
2. Investigational product overdose (whether or not the overdose is associated with an AE 
or SAE)
Subjects who become pregnant during the study period must not receive additional doses of 
investigational product. If the subject requests to know which treatment she received, this 
information will be provided to her. After obtaining the subject’s consent, the subject will be 
followed for the duration of the pregnancy. A pregnancy should be followed for outcome and 
any premature terminations reported. In addition, the health status of the mother and child, 
including date of delivery, and the child’s gender and weight should be reported to 
MedImmune Patient Safety after delivery.


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6.3.5.2
Other Protocol-specific Events 
The following events are also considered IREs and must be reported within 24 hours to 
MedImmune Patient Safety using the Fax Notification Form:
1. Any withdrawal of consent during the study
2. Any event resulting in discontinuation of investigational product
6.3.5.3
Hepatic Function Abnormality
Hepatic function abnormality (as defined in Section 6.1.3.1) in a study subject, with or 
without associated clinical manifestations, where the etiology is unknown, is required to be 
reported as “hepatic function abnormal” within 24 hours of knowledge of the event to 
MedImmune Patient Safety using the Safety Fax Notification Form (see Section 6.3.3 for 
contact information). The investigator shall review the data with the medical monitor. The 
investigator should use clinical judgment to establish the cause based on local standard of 
care and follow the subject by conducting testing as clinically indicated. If, after appropriate 
workup, in the opinion of the investigator, the underlying diagnosis for the abnormality 
remains unexplained, discontinuation of dosing for this subject should be considered.
Each reported event of hepatic function abnormality will be followed by the investigator and 
evaluated by the sponsor. If the etiology of the event remains unconfirmed and/or is 
considered related to investigational product (see Section 6.2.2), a prompt cumulative review 
of safety data and the circumstances of the event in question will be conducted and assessed 
by the MedImmune safety review committee (see Section 6.4) to determine whether 
continued dosing of current study subjects and/or study entry should be interrupted, whether 
the protocol will be modified, or whether the study will be discontinued permanently. 
Review and approval by the MedImmune safety review committee is required for resumption 
of subject dosing or study entry in the event that the study is interrupted. Where applicable, 
regulatory authorities and IRBs/IECs will be notified of any actions taken with the study.
6.3.5.4
Hepatitis Reactivation
Any event of hepatitis reactivation must be reported immediately (i.e., within 24 hours of 
learning about the event), regardless of the amount of time that has passed since the subject’s 
last MEDI-551 dose.
6.3.5.5
Infusion-related Reactions
Any infusion-related reaction of a study subject with the investigational product causing 
permanent discontinuation of dosing with investigational product, with or without associated 


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AEs/SAEs, is required to be reported within 24 hours of knowledge of the event to 
MedImmune Patient Safety or designee using the Fax Notification Form (see Section 6.3.3
for contact information). An infusion reaction does not automatically make an AE serious, 
but if the consequences of the reaction are serious, for example death or hospitalization, the 
event is serious and must be reported as an SAE (see Section 6.2.4 and Section 6.3).
6.3.5.6
Progressive Multifocal Leukoencephalopathy
Any suspected case of PML should be immediately reported (i.e., within 24 hours of learning 
about the event) to MedImmune and discussed with the medical monitor.
6.4
Safety Management During the Study
The MedImmune medical monitor has primary responsibility for the ongoing medical review 
of safety data throughout the study. This includes review of SAEs and timely review of AEs 
and “other events” reported during the study. MedImmune Patient Safety is responsible for 
the receipt, immediate review, investigation, and follow-up of SAEs reported from the 
clinical study sites.
A study-specific Dose-Escalation Committee will provide ongoing safety surveillance of the 
study, with regularly scheduled reviews of safety and other relevant data. This committee 
will be responsible for dose-escalation decisions and making recommendations regarding 
further conduct of the study. The Dose-Escalation Committee includes the MedImmune 
medical monitor for the study, the MedImmune Patient Safety physician for the study, and 
the principal investigator from each actively enrolling study site. This committee will review 
data, including all AEs, laboratory parameters, PK, and pharmacodynamic data, following 
the full enrollment of any dose-escalation cohort and completion of the DLT evaluation 
period. This committee will also review data at other time points in response to AEs assessed 
as medically relevant by the medical monitor. Dose-escalation decisions and outcomes of 
reviews of safety and other relevant data will be communicated to the MedImmune safety 
review committee. The sponsor will notify sites when enrollment into each dose cohort has 
been completed and when enrollment into the next dose cohort is permitted.
A MedImmune safety review committee provides safety surveillance, guidance, and 
oversight for all clinical development studies in which MedImmune has sponsor 
accountabilities. Committee members include, but are not limited to, appropriate 
representatives from Patient Safety, Clinical Development, and Regulatory Affairs. The 
committee reviews protocol-specific safety data and assesses changes to the benefit/risk 
profile of the molecule during early phases of development. Based on review of safety data, 


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the committee may suspend enrollment or subject dosing in clinical studies, request 
modification of study documents, or take other actions as deemed necessary.
6.4.1
Interruption or Permanent Discontinuation of Study Dosing in 
Individual Subjects
Dosing of MEDI-551 may be interrupted for up to 4 hours in subjects experiencing Grade 2 
or 3 infusion reactions as described in Section 4.5.2.
An individual subject will not receive any further investigational product (i.e., permanent 
discontinuation) if any of the following occur in the subject in question:
1. Withdrawal of consent;
2. Allergic reactions ≥ Grade 2 or any allergic reaction that necessitates the use of systemic 
pressors. 
◦
Grade 3 infusion reactions that do not respond to medical therapy (including 
interruption of infusion for ≤ 4 hours) or that occur despite steroid prophylaxis. Any 
Grade 4 infusion reaction or any infusion reaction that necessitates the use of 
systemic pressors.
3. Grade 3 infusion reactions that respond to medical therapy or slowing the infusion rate 
and that are of limited duration will not necessitate dose interruption or discontinuation. 
4. Pregnancy;
5. DLT (see Section 4.5.6 for definition of DLTs). The Medical Monitor may decide that 
certain events meeting the criteria for DLT are controllable and that retreatment is 
considered safe. 
a.
Subjects whose DLT resolves to ≤ Grade 1 or baseline within 7 days can be retreated 
during the DLT period at one dose level below the subject’s prior dose for all arms of 
the study except the first dose-escalation cohort of Arms B and C.
b. Subjects with toxicities considered DLTs that persist beyond 7 days will not be 
retreated for Arm A only.
c.
Recurrence of the DLT following retreatment will necessitate permanent 
discontinuation of treatment with MEDI-551 for Arm A only.
6. Delay in administration of MEDI-551 for more than 21 days for reason of toxicity within 
any 3 consecutive cycles for Arm A or delay in cycles as dictated in Section 6.4.1 for 
Arms B, C, and D;
7. Recurrence of any ≥ Grade 3 toxicity not attributable to other causes unless otherwise 
specified in Section 6.4.1;
8. Documentation of disease progression; 
9. Any event which, in the opinion of the investigator, contraindicates further dosing such 
as intercurrent illnesses, significant drug toxicities or complications if judged by the 
investigator to be in the best interest of the subject;
10. Subject non-compliance;


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11. Treatment with another investigational agent;
12. Initiation of alternative anticancer therapy;
13. Achievement of a CR and a maximum of 2 additional cycles after CR. For the purposes 
of discontinuation of drug, CR shall be defined as the time of hematological and 
radiological CR without necessity of BM confirmation.
Subjects who are permanently discontinued from investigational product will be followed for 
safety for approximately 90 days post last dose. In addition, until Version 13.0, subjects were 
to be followed for disease evaluation every 3 months after the 90-Day Post Last Dose Visit
until disease progression, death, initiation of alternative therapy, withdrawal of consent, or 
end of study. Upon disease progression, subjects were to be followed only for survival every 
3 months until death, withdrawal of consent, or end of study.
6.4.2
Study Stopping Criteria
If any of the following occur, no further administration of investigational product will take 
place and no further subjects will be entered into the study:
1.
The incidence or severity of adverse events in this or other studies indicates a 
potential health hazard to subjects in the current study, determined after review of 
relevant information through internal MedImmune safety data review procedures.
2.
Subject enrollment is unsatisfactory.
3.
Non-compliance that might significantly jeopardize the validity or integrity of the 
study.
4.
Sponsor decision to terminate development.
In case a safety event requiring enrollment suspension occurs, a prompt cumulative review of 
safety data and the circumstances of the event in question will be conducted by the medical 
monitor and the MedImmune safety review committee to determine whether dosing and 
study entry/randomization should be resumed, whether the protocol will be modified, or 
whether the study will be discontinued permanently. The relevant competent health 
authorities in participating countries and IRB/IEC will be notified of any event that triggers 
suspension of enrollment in this study.  If the study is suspended for safety reasons and it is 
deemed appropriate by the sponsor to resume the study, approval from the relevant regulatory 
authorities (and IRBs/IECs when applicable) will be obtained prior to resuming the study.
Decisions regarding ongoing treatment for any subjects who have already received 
investigational product and are currently in the study at the time study-stopping criteria are 
met will be made on a case-by-case basis after discussion with the subject, principal 
investigator, and the sponsor. In the case that a safety event requiring enrollment suspension 


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occurs, all subjects on treatment will be re-consented. Regardless of whether dosing is 
continued or not, all subjects who were on treatment at the time study-stopping criteria were 
met will continue to be followed by the principal investigator for safety until the end of the 
study.
Withdrawal criteria for individual subjects are provided in Section 6.4.1.
6.4.3
Monitoring of Dose Administration
Arm A
Vital signs will be evaluated prior to infusion and at the end of infusion only; additional 
monitoring may be performed if clinically indicated.  Vital signs include temperature, blood 
pressure, pulse rate, respiratory rate, and pulse oximetry.
As with any antibody, allergic reactions to dose administration are possible. Therefore,
appropriate drugs and medical equipment to treat acute anaphylactic reactions must be 
immediately available, and study personnel must be trained to recognize and treat 
anaphylaxis.
In the event of an IRR, the infusion of MEDI-551 may be decreased by 50% or interrupted 
until resolution of the event (up to 4 hours) and re-initiated at 50% of the initial rate until 
completion of the infusion. Acetaminophen and/or an antihistamine (eg, diphenhydramine), 
or institutional equivalents, may be administered at the discretion of the investigator. If the 
infusion reaction is severe or prolonged, methylprednisolone 100 mg (or the equivalent) 
should be administered as well. For subsequent infusions in subjects who experience an IRR
and do not require discontinuation of MEDI-551 (see Section 6.4.1), acetaminophen and an 
antihistamine may be administered prior to initiation of the MEDI-551 infusion. If a subject 
experiences a Grade 3 IRR, all subsequent administration of MEDI-551 must be preceded by 
IV methylprednisolone 100 mg (or the equivalent) 30 minutes prior to initiation of MEDI-
551 infusion.
Arms B, C, and D
Vital signs are evaluated prior to infusion and at the end of infusion as well as at the EOT 
and 90-Day Post Last Dose visits; additional monitoring may be performed if clinically 
indicated.
As described in Section 6.4.1, all subjects receiving MEDI-551 in Arms B, C, and D must 
receive mandatory premedication consisting of a minimum dose of 60 mg IV 


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methylprednisolone (or its equivalent), 500 to 650 mg oral acetaminophen (or paracetamol 
equivalent), and 50 mg IV diphenhydramine (or its equivalent) before the initial MEDI-551 
infusion on Day 1 of Cycle 1 in Arms B and D, and on Day 2 of Cycle 1 in Arm C. 
In the event of an IRR, the infusion of MEDI-551 may be interrupted until resolution of the 
event (up to 4 hours) and re-initiated at the 1 mL/minute rate. The rate may be slowly 
increased by 50% every 15 minutes until completion of the infusion. If the infusion reaction 
is severe or prolonged, methylprednisolone 100 mg (or the equivalent) may be 
administered in addition to acetaminophen (or institutional equivalent) and/or an 
antihistamine at the discretion of the investigator for management of the IRR (Simons, 2010; 
Sampson et al, 2006). In the event of a Grade 4 IRR, the subject should have MEDI-551 
permanently discontinued (see Sections 4.5.2.1 and 4.5.6).
If a subject experiences a Grade 3 IRR and does not require permanent discontinuation of 
MEDI-551 (see Sections 4.5.2.1 and 4.5.6), all subsequent administration of MEDI-551 must 
be preceded by IV methylprednisolone 100 mg (or the equivalent), oral acetaminophen 500 
to 650 mg (or equivalent dose of paracetamol), and IV diphenhydramine 50 mg 30 to 60 
minutes prior to initiation of MEDI-551 infusion. Subjects who only experience a Grade 1 or 
2 IRR and do not require permanent discontinuation of MEDI-551 (see Section 4.5.2.1) may 
receive methylprednisolone (or the equivalent), acetaminophen (or paracetamol equivalent), 
and diphenhydramine 30 to 60 minutes prior to initiation of the MEDI-551 infusion at the 
investigator’s discretion.
Monitoring of the administration of rituximab in Arm C will be performed according to 
institutional protocols.
As with any antibody, allergic reactions to dose administration are possible. Therefore, 
appropriate drugs and medical equipment to treat acute anaphylactic reactions must be 
immediately available, and study personnel must be trained to recognize and treat 
anaphylaxis.
7
STATISTICAL CONSIDERATIONS
7.1
General Considerations
Data will be provided in data listings sorted by treatment group and subject number. Tabular 
summaries will be presented by treatment group. Categorical data will be summarized by the 
number and percentage of subjects in each category. Continuous variables will be 
summarized by descriptive statistics, including mean, standard deviation, median, minimum, 
and maximum. Details of endpoint analyses will be described in the statistical analysis plan.


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7.2
Analysis Populations
The Evaluable population for DLT will include all subjects in the dose-escalation phase 
who receive at least 1 full cycle of MEDI-551 and complete safety follow-up through the 
DLT evaluation period (defined in Section 4.5.6) or experience any DLT during the DLT 
evaluation period. The Evaluable population for DLT will be used for the MTD analysis.
The Safety population will include all subjects who receive any treatment of MEDI-551. 
The Safety population will be used to evaluate baseline characteristics as well as all 
endpoints for safety.
The Evaluable population for efficacy will include all subjects who receive any treatment 
of MEDI-551 and complete at least one post-baseline disease assessment. The Evaluable 
population for efficacy will be used to evaluate the efficacy endpoints.
7.3
Endpoints
The primary, secondary, and exploratory endpoints are listed in this section, and assessment 
of the endpoints is described in Section 7.4.
7.3.1
Primary Endpoints
Arm A
1. MTD or OBD: DLTs
2. Safety: AEs, SAEs, laboratory evaluations, vital signs, physical examinations, and ECGs
Arms B and C
1. MTD is defined as the highest dose where ≤ 1 out of 6 subjects experience a DLT during 
the DLT evaluation period or the highest protocol-specified dose not exceeding MTD: 
DLTs
2. Safety: AEs, SAEs, laboratory evaluations, vital signs, physical examinations, and ECGs
3. Clinical activity/efficacy: CR, duration of CR, PR, objective response, disease control, 
TTR, duration of objective response, duration of disease control, PFS, and OS
Arm D
1. Clinical activity/efficacy: CR, duration of CR, PR, objective response, disease control, 
TTR, duration of objective response, duration of disease control, PFS, and OS


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7.3.2
Secondary Endpoints
Arm A
1. Clinical activity/efficacy: CR, duration of CR, PR, objective response, disease control, 
TTR, duration of objective response, duration of disease control, PFS, and OS
1. Effect of MEDI-551 on circulating lymphocyte populations: circulating levels of blood 
mononuclear cells, including T-cells, B-cells, NK cells and monocytes 
2. Pharmacokinetics: PK profiles and parameters, including maximum observed 
concentration (Cmax), AUC, clearance (CL), and t½, of MEDI-551 
3. Incidence of anti-MEDI-551 antibodies based on samples obtained from each subject at 
multiple timepoints before and after dosing 
Arms B and C
1. Pharmacokinetics: PK profiles and parameters, including Cmax, AUC, CL, and t½, of 
MEDI-551
1. Incidence of anti-MEDI-551 antibodies based on samples obtained from each subject at 
multiple timepoints before and after dosing
2. Effect of MEDI-551 on B-lymphocyte levels in peripheral blood, including time to 
recovery of B-lymphocyte level
Arm D
1. Safety: AEs, SAEs, laboratory evaluations, vital signs, physical examinations, and ECGs
2. Pharmacokinetics: PK profiles and parameters, including Cmax, AUC, CL, and t½, of 
MEDI-551
3. Incidence of anti-MEDI-551 antibodies based on samples obtained from each subject at 
multiple timepoints before and after dosing
4. Effect of MEDI-551 on B-lymphocyte levels in peripheral blood, including time to 
recovery of B-lymphocyte level
7.3.3
Exploratory Endpoints
Descriptive statistics will be used to describe the exploratory analyses when possible. 
Depending on the nature of the data, geometric mean and other appropriate statistical 
summaries might be used as well. The variables likely to be included in the exploratory 
analyses are described below.
Arm B
1.


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7.4
Assessments
7.4.1
MTD or OBD/Highest Protocol-defined Dose
The MTD was based on the evaluable population for DLT and was defined as the highest 
dose at which ≤ 1 out of 6 subjects experience a DLT during the DLT evaluation period. The 
number and percentage of subjects with a DLT will be presented by dose level and overall. 
Since the MTD was not reached, the OBD (Arm A) or highest protocol-defined dose (Arms 
B and C) was determined based upon analysis of all available data, including safety, PK, 
pharmacodynamic, and response.
7.4.2
Safety Assessments
Safety endpoints will be summarized descriptively. The occurrence of AEs, abnormal 
laboratory values, and SAEs reported from the time that written informed consent is obtained 
through approximately 90 days post last dose will be summarized for all subjects who 
received any MEDI-551. Adverse events and SAEs will be graded according to the NCI 
CTCAE V4.03 and described by system organ class and by Medical Dictionary for 
Regulatory Activities (MedDRA) preferred term, severity, and relationship to MEDI-551. 
Frequency rates will be calculated for each system organ class and MedDRA preferred term.
7.4.3
Efficacy Assessments
The efficacy will be assessed based on CR, duration of CR, objective response, disease 
control, TTR, duration of objective response, duration of disease control, PFS, and OS.
•
Complete response: The definition of CR varies by disease type (see Section 5.3.6). 
•
MRD-negative CR: Subjects with CR and negative MRD defined as the proportion of 
subjects with a best response of CR and without MRD.
•
Duration of complete response: Duration of CR will be measured from the first 
documentation of a CR to the time of PD/relapse. Duration of CR will be censored on the 
date of last disease assessment for subjects who have no documented relapse prior to data 
cutoff, dropout, or the initiation of alternative anticancer therapy. Duration of CR will 
only be calculated for the subgroup of subjects with CR using the Kaplan-Meier method.
•
Objective response: Objective response includes CR and PR. 
•
Disease control: Disease control includes CR, PR, or SD for at least 8 weeks.
•
Time to response: Time to response will be measured from the start of MEDI-551 
administration to the first documentation of response (CR or PR) and will only be 
assessed in subjects who have achieved objective response.


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•
Duration of objective response: Duration of objective response will be measured from 
the first documentation of objective response to the event of PD/relapse. Duration of 
objective response will be censored on the date of last disease assessment for subjects 
who have no documented relapse prior to data cutoff, dropout, or the initiation of 
alternative anticancer therapy. Duration of objective response will only be calculated for 
the subgroup of subjects with an objective response.
•
Duration of disease control: Duration of disease control will be defined as the time 
period from start of MEDI-551 administration to the event of PD/relapse. Duration of 
disease control will be censored on the date of last disease assessment for subjects who 
have no documented PD/relapse prior to data cutoff, dropout, or the initiation of 
alternative anticancer therapy. Duration of disease control will only be calculated for the 
subgroup of subjects with best response of CR, PR, or SD.
•
Progression-free survival: Progression-free survival will be measured from start of 
MEDI-551 administration until the first documentation of PD/relapse or death, whichever 
occurs first. Progression-free survival will be censored on the date of last disease 
assessment for subjects who have no documented PD/relapse or death prior to data cutoff, 
dropout, or the initiation of alternative anticancer therapy. 
•
Overall survival: Overall survival will be determined as the time from the start of 
MEDI-551 administration until death. For subjects who are alive at the end of study or 
lost to follow-up, OS will be censored on the last date when subjects are known to be 
alive. 
The analysis methods will differ by the types of endpoints. For categorical endpoints, 
proportions will be summarized, 80% and 95% confidence intervals will be calculated using 
the Clopper-Pearson exact method. For time-to-event endpoints, Kaplan-Meier method will 
be used to describe the endpoints graphically and to estimate the median or the event rates at 
time of interest.
7.4.4
Pharmacokinetic Assessment
The PK of MEDI-551 will be estimated by non-compartmental analysis. A population PK 
analysis may also be performed to obtain additional PK parameters. Those PK parameters 
will be summarized by descriptive statistics including N, mean, standard deviation, 
coefficient of variation, median, minimum, maximum, and geometric mean.
7.4.5
Assessment of Effect on Circulating Lymphocyte Populations
Circulating levels of blood mononuclear cells, including T-cells, B-cells, NK cells and 
monocytes will be determined using standard clinically available flow cytometry. B-cell 
levels will be monitored from start of treatment until recovery or study discontinuation due to 
initiation of alternative anticancer therapy or subject withdrawal. Recovery will be defined as 
a B-cell count of ≥200 cells/μL in subjects with baseline B-cells of ≥ 200 cells/μL or two 


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consecutive B-cell counts within ± 20% of baseline in subjects with baseline B-cell counts of 
< 200 cells/μL. Time to B-cell recovery will be analyzed. The correlation between Ig levels 
and B cell counts during treatment and recovery will also be evaluated.
7.4.6
Immunogenicity Assessment
Immunogenicity of MEDI-551 will be assessed and summarized descriptively by dose 
cohort.
7.5
Sample Size and Power Calculations
Arm A
For the dose-escalation phase, a minimum of 18 evaluable subjects (3 subjects each in Dose 
Cohort 1 through 6) or up to approximately 36 evaluable subjects (3+3 subjects per dose 
cohort) were required to determine the MTD; 26 were enrolled. A subject was considered 
evaluable for assessment of DLT if the subject received at least one full cycle (4 doses for 
Cohorts 1 and 2; 2 doses for Cohorts 3 to 6) of MEDI-551 and completed the safety follow-
up through the DLT evaluation period (as defined in Section 4.5.6), or the subject 
experienced a DLT. Any nonevaluable subject would be replaced in the same dose cohort. 
Table 7.5-1 provides the probability of dose escalation to the next higher lever for each 
underlying true DLT rate. For example, for a common toxicity that occurs in 10% of 
subjects, there is a greater than 90% probability of escalating to the next higher dose level. 
Conversely, for a toxicity that occurs with a rate of 60%, the probability of escalating to the 
next higher dose level is less than 10%.
Table 7.5-1
True Underlying DLT Rate at a Given Dose Level
True Underlying DLT Rate
10%
20%
30%
40%
50%
60%
70%
80%
90%
Probability of Escalating Dose
0.91
0.71
0.49
0.31
0.17
0.08
0.03
0.009
0.001
DLT = dose-limiting toxicity.
For the dose-expansion phase, approximately 20 subjects were to be entered into each of 
3 arms to determine the preliminary efficacy profile of MEDI-551 in the treatment of 
advanced CLL (including SLL), DLBCL, and FL. A total of 69 subjects (24 CLL, 21
DLBCL, 23 FL, and 1 MM) were enrolled. The primary objective of the dose-expansion 
phase was to determine the preliminary efficacy profile of MEDI-551 in these subjects. The 
sample size estimation was based on the CR rate and the exact binomial test. A total of 
20 subjects per arm would be required to have approximately 80% power for testing the 
following hypotheses at 1-sided significance level of 0.1.


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
Null hypothesis: undesirable CR rate = 5%

Alternative hypothesis: desirable CR rate = 20% 
Arms B and C
Dose Escalation
There were 4 planned dose levels (6, 12, 24, and 48 mg/kg) for MEDI-551 in the Arm B 
dose- escalation phase and 2 planned dose levels (8 and 12 mg/kg) for Arm C dose 
escalation. Using a standard 3+3 design, approximately 24 to 36 subjects were to be enrolled 
during the dose-escalation phase in Arms B and C depending on the observed safety profile 
and total number of dose levels evaluated.
A total of 7 subjects were enrolled in Arm B; all were in dose escalation (n = 3 each for 6 and 
12 mg/kg, n = 1 for 24 mg/kg). Based on emerging PK and pharmacodynamic data, a dose of 
12 mg/kg, administered weekly during Cycle 1 and then monthly in subsequent cycles, was 
determined to be sufficient to saturate the B-cell sink and achieve full exposure.  At the 
sponsor’s discretion and not due to any safety issues, no further dose-escalation was 
conducted.  The MTD was not reached.
Arm C dose escalation was completed as planned, with 3 subjects each in the 8 and 12 mg/kg 
cohorts.
Dose Expansion
A sample size of 26 subjects was planned for each dose-expansion cohort in Arms B and C. 
Given an expected response rate of 50% for both cohorts, this would provide 80% power at a 
significance level of 0.20 (2-sided) to exclude the historical response rate of 30%, and 
associated 80% confidence intervals for the response rate would have a precision of ± 13%. 
The 30% historical response rate was selected for both Arms B and C expansion cohorts 
based on the following reported data:
•
In relapsed CLL patients, OR rates between 15% and 30% were reported for rituximab 
monotherapy (O’Brien et al, 2001; Mavromatis and Cheson, 2003).
•
In DLBCL patients with 2 prior lines of therapy, response rates were only about 30% 
with single-agent rituximab (Coiffier et al, 1998; Wang et al, 2013; Churpek et al, 2013).
Enrollment in Arm B was discontinued prior to dose expansion at the sponsor’s discretion 
and not due to any safety issues..


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Further enrollment in Arm C was halted at the sponsor’s discretion (and not due to any safety 
issues) after enrollment of 19 subjects (3 in the 8 mg/kg MEDI-551 cohort and 16 who 
received 12 mg/kg MEDI-551).  Of the 19 subjects there were only 7 responders, and there 
was about a 13% probability of meeting the protocol-specified target response rate of 50%.  
Arm D
A sample size of approximately 26 subjects was planned for Arm D. Given an expected 
response rate of 50% for this cohort, this would provide 80% power at a significance 
level of 0.20 (2-sided) to exclude the historical response rate of 30% (Zinzani et al, 2013; 
Witzig et al, 2011), and associated 80% confidence intervals for the response rate would have 
a precision of ± 13%.
Further enrollment was halted at the sponsor’s discretion (and not due to any safety issues) 
after enrollment of 16 subjects.  Of the 16 subjects there were only 3 responders, and there 
was about a 1% probability of meeting the protocol-specified target response rate of 50%.  
8
DIRECT ACCESS TO SOURCE DATA AND DOCUMENTS
The study will be monitored by MedImmune or its designee on a regular basis throughout the 
study period. During monitoring visits, the investigator will provide direct access to all 
source documentation relevant to the subject’s participation in the study. Source 
documentation includes, but is not limited to, the subject’s clinic and/or office chart, hospital 
chart, informed consent forms, treatment notes, laboratory reports, pharmacy records, 
radiographs, and any other records maintained to conduct and evaluate the clinical study. 
The investigator must also ensure that direct access to study documents be made available for 
study-related audits, IRB/IEC review, or regulatory inspection.
9
QUALITY CONTROL AND QUALITY ASSURANCE
9.1
Data Collection
As part of the responsibilities assumed by participating in the study, the investigator agrees to 
maintain adequate and accurate case histories for the subjects treated under this protocol. 
Case histories include CRFs and supporting data including, but not limited to, signed and 
dated informed consent forms, progress notes, hospital charts, nurse’s notes, diary cards, 
laboratory reports, ECG strips, etc.


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9.2
Study Monitoring
The primary source document for this study will be the subject’s medical record. If separate 
research records are maintained by the investigator(s), both the medical record and the 
research records will be monitored/audited for the purposes of the study.
The investigator and institutions involved in the study will permit study-related monitoring 
and provide direct access to all study records and facilities. Adequate time and space for 
monitoring visits should be made by the investigator or other investigator site staff.
The monitor will visit study facilities at periodic intervals, in addition to maintaining 
necessary contact through telephone, e-mail, and letter. The monitor will assess subject 
enrollment and informed consent procedures; investigational product storage, dispensing, 
administration and accountability; compliance with protocol procedures; completeness and 
accuracy of data entered onto validated data collection instruments (paper CRF or electronic 
data screen) against original source documents; and the occurrence of AEs/SAEs. All aspects 
of the study will be carefully monitored for compliance with the protocol, applicable 
government regulations, GCP, and the site’s standard operating procedures.
The monitor will discuss the conduct and progress of the study with the investigator and 
other site staff. The investigator must cooperate with the monitor to ensure that any problems 
noted in the course of the monitoring are resolved.
9.3
Audit and Inspection of the Study
During the conduct of the study, the sponsor or its representative may conduct audits of any 
data and facility participating in the study. The investigator and institutions involved in the 
study will permit such study-related audits and provide direct access to all study records and 
facilities. The investigator must maintain a comprehensive and centralized filing system of 
all study-related documentation that is suitable for inspection by the sponsor or its designated 
monitors, Quality Assurance monitors, or regulatory agency representatives. The investigator 
agrees to participate in audits conducted at a convenient time in a reasonable manner.
Government regulatory authorities may also perform inspections either during or after the 
study. In the event of an inspection by any regulatory authority, the investigator should 
promptly notify the sponsor. The investigator agrees to cooperate fully with inspections 
conducted by regulatory authorities and to allow representatives of the regulatory authority 
access to all study records. The investigator will forward to the sponsor a copy of any 
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10 ETHICS
10.1
Regulatory Considerations
The study will be conducted in accordance with the ICH guidelines on GCP, the GCPs 
applicable to any region where the study is conducted, and the ethical principles set forth in 
the Declaration of Helsinki. Good Clinical Practice is defined as a standard for the design, 
conduct, performance, monitoring, auditing, recording, analysis, and reporting of clinical 
studies in a way that provides assurance that the data and reported results are credible and 
accurate, and that the rights, safety, and well-being of study subjects are protected.
Per GCP, the protocol will be reviewed and approved by the IRB or IEC of each participating 
center prior to study initiation. Serious adverse events regardless of causality will be reported 
to the sponsor and to the IRB/IEC, and the investigator will keep the IRB/IEC informed as to 
the progress of the study.
The investigator will explain the nature of the study and will inform the subject/legal 
representative that participation is voluntary and that the subject can withdraw or be 
withdrawn from the study at any time. Written informed consent will be obtained from each 
subject/legal representative prior to the screening procedures to determine if study eligibility 
criteria are met. A copy of the signed consent form will be given to every subject/legal 
representative, and the original will be maintained with the subject’s records.
10.2
Institutional Review Board or Independent Ethics Committee
A list of IRB/IEC members or a Statement of GCP Compliance should be obtained by the 
investigator and provided to the sponsor.
Any documents that the IRB/IEC may need to fulfill its responsibilities, such as protocol 
amendments, and information concerning subject recruitment, payment, or compensation 
procedures, or information from the sponsor will be submitted to the IRB/IEC. The 
IRB/IEC’s written unconditional approval of the study protocol, the informed consent 
form(s), and any other written materials to be provided to subjects will be in the possession 
of the investigator and the sponsor before the study is initiated. The IRB/IEC’s unconditional 
approval statement will be transmitted by the investigator to the sponsor prior to shipment of 
investigational product supplies to the site. This approval must refer to the study by exact 
protocol title and number, and should identify the documents reviewed and the date of 
review.
Protocol modifications or changes may not be initiated without prior written IRB/IEC 
approval except when necessary to eliminate immediate hazards to the subjects or when the 


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change(s) involves only logistical or administrative aspects of the study. Such modifications 
will be submitted to the IRB/IEC and written verification that the modification was submitted 
should be obtained.
The IRB/IEC must be informed by the investigator of informed consent form changes or 
revisions of other documents originally submitted for review; serious and/or unexpected 
adverse experiences occurring during the study; new information that may affect adversely 
the safety of the subjects or the conduct of the study; an annual update and/or request for 
re-approval; and when the study has been completed.
10.3
Informed Consent
Freely given informed consent will be obtained and documented for all subjects under this 
protocol (or a subject’s legally authorized representative, if the subject is unable to provide 
informed consent) in accordance with the ICH guidelines on GCP, the GCPs applicable to 
any region where the study is conducted, and the ethical principles set forth in the 
Declaration of Helsinki.
Information should be given in both oral and written form, and subjects or their legal 
representatives must be given ample opportunity to inquire about details of the study. 
Subjects or their legal representatives must be informed of the following:
•
The study involves research.
•
The aims, expected benefits, possible risks (including a statement that the particular 
treatment or procedure may involve risks to the subject or the fetus of the subject, if the 
subject should become pregnant) that are currently unforeseeable.
•
The study procedures to be followed and alternative treatment available to them. Subjects 
or their legal representatives must receive an explanation as to whether any compensation 
and any medical treatments are available if injury occurs and, if so, what they consist of, 
or where further information may be obtained.
•
Who to contact for answers to any questions relating to the research project.
•
Participation is voluntary and that they are free to withdraw or withdraw their child from 
the study for any reason at any time, without penalty or loss of benefits to which they are 
otherwise entitled.
•
The extent of the confidentiality of subject records must be defined, and subjects or their 
legal representatives must be informed that applicable data protection legislation will be 
complied with. 
•
The monitor(s), auditor(s), IRB/IEC members, and the regulatory authorities will be 
granted direct access to the subject’s original medical records for verification of clinical 
study procedures and/or data, without violating the confidentiality of the subject, to the 


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extent permitted by the applicable laws and regulations and that, by signing a written 
informed consent form, the subject or the subject’s legally acceptable representative is 
authorizing such access.
The consent form generated by the investigator must be approved by the IRB/IEC and be 
acceptable to MedImmune. Consent forms must be written so as to be understood by the 
prospective subject/legal representative. Informed consent will be documented by the use of 
a written consent form approved by the IRB/IEC and signed and dated by the subject or the 
subject’s legally authorized representative, and by the person who conducted the informed 
consent discussion. The signature confirms the consent is based on information that has been 
understood. Each subject’s signed informed consent form must be kept on file by the 
investigator for possible inspection by regulatory authorities and/or MedImmune professional 
and regulatory compliance persons. The subject or the subject’s legally acceptable 
representative should receive a copy of the signed and dated written informed consent form 
and any other written information provided to the subject, and should receive copies of any 
signed and dated consent form updates and any amendments to the written information 
provided to subjects.


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11 DATA HANDLING AND RECORD KEEPING
To maintain confidentiality, all laboratory specimens, evaluation forms, reports, and other 
records transmitted outside the clinical site will be identified by an SID number or coded 
number and date of birth. All study records, source medical records, and code sheets or logs 
linking a subject’s name to an SID number will be kept in a secure location. Study records 
such as CRFs may be maintained electronically and require the same security and 
confidentiality as paper. Clinical information will not be released without written permission 
of the subject/legal representative, except as specified in the informed consent form 
(eg, necessary for monitoring by regulatory authorities or the sponsor of the clinical study). 
The investigator must also comply with all applicable privacy regulations (eg, HIPAA 1996, 
EU Data Protection Directive 95/46/EC).
Study documents (including subject records, copies of data submitted to the sponsor, study 
notebook, and pharmacy records) must be kept secured in accordance with MedImmune 
policies and applicable regulatory requirements for a period of 2 years following the last 
regulatory authority approval of a marketing application of MEDI-551 and until there are no 
pending or contemplated marketing applications, or for 2 years after centers have been 
notified that clinical development of MEDI-551 has been discontinued, or as otherwise 
required by local requirements, whichever is longer. There may be other circumstances for 
which MedImmune is required to maintain study records and, therefore, MedImmune should 
be contacted prior to removing study records for any reason.
12 FINANCING AND INSURANCE
Financing and insurance are addressed in the individual site contracts.
13 PUBLICATION POLICY
Publication by the site of any data from this study must be carried out in accordance with the 
clinical study agreement.


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14 REFERENCES
Anderson KC, Bates MP, Slaughenhoupt BL, Pinkus GS, Schlossman SF, Nadler LM. 
Expression of human B cell-associated antigens on leukemias and lymphomas: a model of 
human B cell differentiation. Blood. 1984;(63):1424-33.
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15 SUMMARY OF PROTOCOL AMENDMENTS AND 
ADMINISTRATIVE CHANGES TO THE PROTOCOL
Protocol Version 2.0, 28 May 2009
Version 1.0 of protocol MI-CP204, dated 01Apr2009, has been amended to create 
Version 2.0, dated 28 May 2009. This protocol was amended in response to requests from the 
FDA following review of CP204 after submission of the IND on 29 April 2009. The 
language in the requested changes was agreed to by the FDA following submission of 
proposed changes on 26 May 2009.
All text revisions resulting from this amendment are incorporated in the body of protocol 
Version 2.0. Major changes to the protocol are described below. Added text is shown bolded 
and underlined (eg, text) and deleted text is shown with strikethrough (eg, text).

Section 4.2.1 (Inclusion Criteria) and Study Abstract:
2)
Bilirubin ≤ 1.5 × ULN except in the case of subjects with documented Gilbert’s 
disease, ≤ 2.5 × ULN;

Section 4.2.2 (Exclusion Criteria) and Study Abstract:
2. Any available standard line of therapy known to be life-prolonging or life-saving;

Section 4.5.2 (Treatment Regimens)
Dose Modification for Toxicity Management
In rare circumstances and under the authority of the Medical Monitor, subjects may be 
retreated following a DLT as described in Section 6.4.1.
The following AEs are exceptions to the dose modification and stopping rules described 
below in Table 4.5.2.1-1 and require NO modification of MEDI-551 dosing: lymphopenia 
(any grade) and ≤Grade 3 baseline hematologic toxicity abnormalities.


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Dose modification for Grade 4 hematologic toxicity (other than lymphopenia) will occur as 
described in Table 4.5.2.1-1 with the exception that resolution only to ≤Grade 2 or subject’s 
baseline, and not to Grade 1, will be required to re-initiate treatment.

Table 4.5.2-1 (MEDI-551 Dose Modification Table) – Footnotes 
a Except Grade ≤3 < 2 or subject’s baseline hematologic toxicity, which requires no dose modification, or 
lymphopenia (any grade). Lymphopenia (any grade) also will not require modification of treatment.
b Except Grade 3 or 4 toxicities noted as exceptions to the DLT criteria. Lymphopenia (any grade) will not 
require modification of treatment.
c For Grade 4 hematologic toxicities other than lymphopenia, resolution only to ≤ Grade 2 or subject’s 
baseline, and not to Grade 1, will be required to re-initiate treatment. 

Section 4.5.3 (Investigational Product Preparation and Administration) 
In the event of an infusion-related reaction, the infusion of MEDI-551 may be interrupted 
until resolution of the event, and the infusion re-initiated at 50% of the initial rate until 
completion of the infusion. Acetaminophen (750-1000 mg) and/or an antihistamine (eg, 
diphenydramine 25-50 mg) may be administered. If the infusion reaction is severe or 
prolonged, methylprednisolone 100 mg (or the equivalent) should be administered as 
well. For subsequent infusions in subjects who experience an infusion reaction and do not 
require discontinuation of MEDI-551 (see Section 6.4.1), acetaminophen and an 
antihistamine may be administered prior to initiation of the MEDI-551 infusion. If a subject 
experiences a Grade 3 infusion reaction, all subsequent administration of MEDI-551 
must be preceded by IV methylprednisolone 100 mg (or the equivalent) 30 minutes 
prior to initiation of MEDI-551 infusion.

Section 5.3.9 (Disease Evaluation and Methods) 
CLL
Subjects will be assessed by hematology and physical exam every cycle. For subjects who 
achieve hematological CR and had evidence of nodal disease by CT scan at screening, a 
repeat CT scan will be performed. Bone marrow biopsy will be performed 3 months 
following CR to confirm CR. A repeat BM biopsy will be performed 4 weeks later in 
subjects where the initial BM biopsy is considered hypocellular. Subjects who do not 
achieve CR need not have a follow-up BM biopsy. 

Section 6.4.1 (Interruption or Permanent Discontinuation of Study Dosing in Individual 
Subjects)
An individual subject will not receive any further investigational product if any of the 
following occur in the subject in question:


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1. Withdrawal of consent;
2. Allergic reactions ≥ Grade 2. Infusion reactions ≤ Grade 3 that respond to medical 
therapy or slowing the infusion rate and that are of limited duration will not necessitate 
dose interruption or discontinuation. Infusion reactions ≥Grade 3 that do not respond 
to medical therapy or that occur despite steroid prophylaxis will require permanent 
discontinuation of MEDI-551 in that subject. Any Grade 4 infusion or allergic 
reaction or one that necessitates the use of systemic pressor agents will cause permanent
dose discontinuation of MEDI-551 in that subject;
3. Pregnancy or intent to become pregnant;
4. DLT (see Section 4.5.6 for definition of DLTs). The Medical Monitor may decide that 
certain events meeting the criteria for DLT are controllable and that retreatment is 
considered safe. 
5. If such subjects are retreated during the DLT period, they will be treated at one dose level 
below the subject’s prior dose provided that the DLT resolves to ≤Grade 1 or baseline 
within 7 days. 
6. Subjects with toxicities considered DLTs that persist beyond 7 days will not be retreated.
7. Recurrence of the DLT following retreatment will necessitate permanent discontinuation 
of treatment with MEDI-551.

Section 6.4.3 (Monitoring of Dose Administration)
If a subject experiences an infusion reaction during administration of MEDI-551, 
diphenhydramine (Benadryl®) 50 mg and acetaminophen (Tylenol®) 650 mg, or the 
institutional equivalents, may be administered. If the infusion reaction is severe or 
prolonged, methylprednisolone 100 mg (or the equivalent) should be administered as 
well. Alternatively, or in addition, the rate of the MEDI-551 infusion may be diminished. 
Any such activities must be recorded appropriately. For patients who experience an infusion 
reaction, prophylactic administration of acetaminophen and/or diphenhydramine or the 
equivalents may be considered prior to subsequent administrations of MEDI-551. If a 
subject experiences a Grade 3 infusion reaction, all subsequent administration of 
MEDI-551 must be preceded by IV methylprednisolone 100 mg (or the equivalent) 
30 minutes prior to initiation of MEDI-551 infusion.


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Protocol Version 3.0, 06Nov2009
Version 2.0 of protocol MI-CP204, dated 28 May 2009, has been amended to create 
Version 3.0, dated 06Nov2009. The protocol was amended to add clarification to certain 
sections, perform minor copyedits, and to add specific language for non-US studies. 
All text revisions resulting from this amendment are incorporated in the body of protocol 
Version 3.0. Major changes to the protocol are described below.
Title Page:
•
The EudraCT Number was added for EU compliance.
•
A new Medical Monitor was assigned to this study. Therefore, the name, title, and 
contact information for the Medical Monitor was updated (also in the Sponsor Agreement 
section on Page 2).
•
The protocol title was changed to more accurately reflect the study design (ie, added 
“open-label and Phase 1/2” and deleted “dose-escalation.”
Section 1.0:
A risk-benefit summary was added per EU regulatory guidance.
Section 3.1 and the Study Abstract:
•
Text was added to clarify that FL/MM and CLL/DLBCL are grouped separately based 
upon differences in tumor burden and aggressiveness.
•
Text was added to indicate that an interim safety analysis will be conducted when the 
MTD or OBD has been established. This analysis is being done to examine treatment 
effects on key safety endpoints. This information was also added to a new Interim 
Analysis section (Section 7.6).
•
For clarity, text was added to specify that FDA will be consulted concerning the 
possibility of additional treatment with MEDI-551 for subjects within the United States 
who achieve CR and subsequently relapse.
Section 3.2 and Study Abstract
For clarity, text was revised to state that subjects may continue to receive MEDI-551 until 
CR, disease progression, toxicity, or another reason to discontinue therapy intervenes.


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Section 4.2.1 and the Study Abstract:
•
Inclusion Criterion 3 was edited to specify that the CLL population is to include subjects 
with SLL.
•
The units for anemia were corrected to g/dL.
•
Inclusion Criterion 10 was edited to specify platelet count ≥ 75,000/mm3 (except for CLL 
subjects with evidence of bone marrow disease, who must have a platelet count 
≥50,000/mm3).
•
Inclusion Criterion 12 was edited to clarify the recommended methods of contraception 
and to state that subjects must use adequate contraception methods through 90 days after 
the last dose of MEDI-551.
•
Inclusion Criterion 13 was edited to specify that for subjects with DLBCL or FL only, 
disease is to be evaluable by the International Working Group criteria (formerly RECIST 
criteria; references to RECIST criteria were thus removed from the List of Abbreviations 
and from Appendix 1. 
Section 4.3:
Paragraph 1 was edited to clarify that a subject is considered entered into the study when the 
investigator notifies the IVRS that the subject meets eligibility criteria and the IVRS provides 
the assignment of a dose cohort or treatment arm to the subject. The text formerly specified 
study entry upon subject receipt of a kit number; however, the IVRS assigns a dose cohort or 
treatment arm and not a kit number. 
Section 4.5.2
Table 4.5.2-1 was revised to make it consistent with Section 6.4.1. Text was added to the 
table to state that (1) for Grade 2 infusion reaction, infusion rate may be decreased by 50% or 
interrupted for up to 4 hours and symptomatic care instituted as clinically indicated; (2) 
following interruption, infusion should be resumed at 50% of original rate for remainder of 
infusion. 
Sections 4.5.3 and 6.4.3:
The text was edited to clarify that in the event of an infusion reaction, diphenhydramine 
and/or acetaminophen administration would be at the investigator’s discretion. Further, 
references to specific doses of both drugs were removed. The text was changed because the 
investigator will determine the circumstances under which these drugs would be used, and at 
what dose. Added a clarification to the text to state that in the event of an infusion-related 


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reaction, the infusion of MEDI-551 may be decreased by 50% or interrupted until resolution 
of the event (up to 4 hours).
Section 4.5.5:
•
Rule 1 was modified to add a definition of subjects evaluable for DLT assessment.
•
Rule 3 was modified to provide the rationale behind using a staggered enrollment.
•
Rule 7 was modified to specify that if a lower dose than the MTD is used for dose 
expansion, that dose is the OBD.
•
Text was added to clarify the role and composition of the Dose Escalation Committee and 
to add a reference to the SMC (also in Section 6.4).
Sections 5.2, 5.2.1, 5.2.2, and 5.2.3:
Lymph node palpation was removed from the Schedule of Assessments because subjects 
already undergo CT scans which are considered more accurate for assessing lymph node size 
and disease progression.
Section 5.2.4:
Added visit window of ± 48 hours for the 30-day post-therapy visit and ± 1 week for the 
every 3 months post-therapy follow-up visit.
Section 5.3.6:
The text was edited to clarify that the additional sampling to be performed in the first 
10 subjects in the expansion cohorts is planned in order to obtain additional PK data.
Section 6.2.1 and the Study Abstract:
The text was edited to specify that AE severity will be graded according to the NCI CTCAE 
V4.0 (formerly V3.0), since the CTCAE version was updated subsequent to the finalization 
of Version 2.0 of this protocol. The CTCAE version number was also updated in the List of 
Abbreviations.
Section 6.4.1 and 6.4.3
Language concerning interruption or discontinuation of treatment due to infusion reactions 
was clarified and updated:


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•
Added text to state that dosing of MEDI-551 may be interrupted for up to 4 hours in 
subjects experiencing Grade 2 or 3 infusion reactions. 
•
List item #3 was revised to state that discontinuation of treatment would result from 
Grade 3 infusion reactions that do not respond to medical therapy (including interruption 
of infusion for ≤ 4 hours) or that occur despite steroid prophylaxis, or from any Grade 4 
infusion reaction or any infusion reaction that necessitates the use of systemic pressors.
Section 6.4.3
Added text to clarify that in the event of an infusion-related reaction, the infusion of 
MEDI-551 may be decreased by 50% or interrupted until resolution of the event (up to 
4 hours) and re-initiated at 50% of the initial rate until completion of the infusion.
Section 7.2
An additional analysis population, the Per-Protocol population (defined as all subjects who 
complete 2 cycles of treatment or who discontinue treatment for toxicity due to MEDI-551, 
disease progression, or death due to disease) was added for evaluation of efficacy endpoints.
Section 7.4.1:
References to confirmatory or confirmed CR and confirmed PR were removed. The text was 
modified to include the 80% CI in estimations of CR rate.
Section 7.4.3
Added language to clarify recovery of B-cell counts.
Appendices:
Appendix 1 was changed to provide a link to the International Working Group criteria. 
Appendix 5 (formerly the link to the International Working Group criteria) was removed.
Other Text Edits:
Throughout the document, MedImmune Product Safety was changed to MedImmune Patient 
Safety.
Protocol Version 4.0, 27Jan2010
Version 3.0 of protocol MI-CP204, dated 06Nov2009, has been amended to create 
Version 4.0, dated 27Jan2010. The protocol was amended to add FDA requested DLT 


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language, add clarification to certain sections, update the Medical Monitor, and make minor 
copy edits.
All text revisions resulting from this amendment are incorporated in the body of protocol 
Version 4.0. Major changes to the protocol are described below.
Title Page:
A new Medical Monitor was assigned to this study. Therefore, the name, title, and contact 
information for the Medical Monitor was updated (also in the Sponsor Agreement section on 
Page 2)
Study Abstract and Section 4.2.2:
Exclusion criterion 13 was edited to clarify that subjects with active hepatitis B or C 
infection as defined by seropositivity for hepatitis B (HBsAg) or hepatitis C antibody, and 
elevated liver transaminases are not eligible to participate in the study.
Sections 4.5.2
Added text to clarify that dose modification is not permitted during the DLT period; 
however, a delay in therapy due to a reversible non-DLT toxicity is permitted as long as the 
total delay within the cycle is ≤ 5 days total. Any toxicity leading to a delay > 5 days in 
duration during the DLT period will be considered a DLT.
Section 4.5.5 and 4.5.6:
The text was edited to specify that during the DLT period, any MEDI-551 treatment-related 
toxicity (regardless of grade) leading to an inability to receive a full cycle of MEDI-551 
would be considered a DLT. Further, the text was edited to clarify that during the DLT 
period, a delay in therapy due to a reversible non-DLT toxicity lasting ≤ 5 days total would 
not be considered a DLT as long as the subject was able to receive the full intended dose of 
MEDI-551. Added clarification that delays of up to 5 days total within a cycle due to 
reversible non-DLT toxicities are allowed during the DLT period; in that case, the DLT 
period will be no greater than 33 days.
Study Abstract, Sections 2.3, and 7.5
Revised one of the exploratory objectives to state that the effect of 
 


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Protocol Version 5.0, 23Sep2010
Version 4.0 of protocol MI-CP204, dated 27Jan2010, has been amended to create 
Version 5.0, dated 23Sep2010. The protocol was amended to make the study population for 
dose-escalation inclusive of subjects with FL, MM, CLL, and DLBCL and to add FDA 
requests for monitoring of post-treatment hepatitis reactivation. In addition, clarification was 
added to certain sections, and minor copyedits were performed.
All text revisions resulting from this amendment are incorporated in the body of protocol 
Version 4.0. Major changes to the protocol are described below.
Title Page:
The name, title, and contact information for the Medical Monitor was updated (also in the 
Sponsor Agreement section on Page 2).
Study Abstract and Sections 3.1 and 4.5.2 
Study Design and Treatment Sections
•
The Study Design and treatment sections were updated to specify that dose escalation 
began in subjects with FL or MM per protocol Version 4.0 (27Jan2010) through Cohort 
2, and that Cohorts 3 to 6 will enroll subjects with FL, MM, CLL or DLBCL with a 
modified dosing schedule. Specifically, subjects in Cohorts 1 and 2 will continue to 
follow the protocol Version 4.0 dose schedule of 0.5 mg/kg (Cohort 1) or 1 mg/kg 
(Cohort 2) MEDI-551 IV infusion once every week in 4-week cycles. Subjects enrolled 
in Cohorts 3 and higher will receive 2, 4, 8, or 12 mg/kg MEDI-551 (Cohorts 3 to 6, 
respectively) IV once per week on Days 1 and 8 in the 1st cycle (loading doses) and then 
once every 28 days at the start of each subsequent cycle.
•
The number of evaluable subjects required for dose-escalation was changed to 18 to 36.
•
The treatment schedule for the expansion phase was modified to specify that subjects will 
be treated on Days 1 and 8 in the 1st cycle (loading doses) and then once every 28 days at 
the start of each subsequent cycle at the MTD or OBD as determined in the 
dose-escalation phase.
•
Text regarding the possibility of different MTDs/OBDs in different tumor types was 
deleted.
Section 4.5.3
The following text was added: “MEDI-551 must be administered within 8 hours after 
preparation. If the dose is not administered within 8 hours, a new dose must be prepared 
using a new vial, as the MEDI-551 product contains no bacteriostatic agents.”


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Section 4.5.5
The rules for dose escalation were modified to reflect the change in study design as discussed 
above.
Section 4.5.6
The text was updated to specify that subjects who do not receive at least one full cycle 
(4 doses for Cohorts 1 and 2; 2 doses for Cohorts 3 to 6) of MEDI-551 during the first 
treatment cycle for reasons other than toxicity will be replaced with another subject at the 
same dose level.
Section 5.2
The study schedule for Cohorts 1 and 2 and a new schedule of assessments for Cohorts 3 to 6 
were added. Text regarding monitoring post treatment hepatitis reactivation was added as per 
FDA request.
Section 6.3.5 (Other Events Requiring Immediate Reporting)
A subsection for hepatitis reactivation was added to this section as per FDA request. 
Section 6.4.1
Rule #6 was modified to specify that delay in administration of MEDI-551 for more than 
21 days for reason of toxicity within any 3 consecutive cycles would lead to dose interruption 
or discontinuation.
Section 7.3.1
Text regarding the conduct of additional studies to determine MTD in different disease 
indication was removed from this section.
Appendix 2
The link to the National Cancer Institute CTCAE Version 4.0 was updated.
Protocol Version 6.0, 18Jul2011
Version 5.0 of protocol MI-CP204, dated 23Sep2010, has been amended to create 
Version 6.0, dated 18Jul2011. The protocol was amended to allow for subjects who achieve a 
CR to be dosed with 2 additional cycles of MEDI-551 per FDA request. In addition, 
clarification was added to certain sections, and minor copyedits were performed.


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All text revisions resulting from this amendment are incorporated in the body of protocol 
Version 5.0. Major changes to the protocol are described below.
Title Page
A new Medical Monitor was assigned to this study. Therefore, the name, title, and contact 
information for the Medical Monitor was updated (also in the Sponsor Agreement section on 
Page 2).
Study Abstract and Sections 3.0, 4.5.2, 6.4.1
Study Design and Treatment Sections
•
The text was updated to specify that all subjects (US and non-US) who achieve a CR may 
receive an additional 2 cycles of MEDI-551 at the same dose level per the FDA. The 
FDA will be consulted concerning the possibility of additional treatment with MEDI-551 
for subjects within the US who achieve a CR and subsequently relapse; however, non-US 
subjects will not be re-treated on subsequent relapse. 
Section 1.4
The clinical experience with MEDI-551 was updated to include results from the MI-CP204 
study as of 09 May 2011 and to provide information on any toxicities observed through 
Cohort 4 (4 mg/kg).
Section 4.5.4
The text was edited to specify that routine use of pre-medications prior to administration of 
MEDI-551 in the absence of documented prior reaction to MEDI-551 infusion is allowed 
when it is clinically indicated or in accordance with institutional guidelines for administration 
of a MAb.
Section 5.2
The study schedule for Cohorts 3 to 6 were updated to add the collection of exploratory post 
end of infusion biomarkers and updated the PK samples collected for the cohort expansion. 
The visit window for the Every 3 months post-therapy visits was modified from 7 to 14 days 
to allow for potential scheduling issues. 


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Sections 5.3.2 and 6.0
Text for hepatic function abnormality was added to these section as per revised MedImmune 
protocol template Version 14.1 and oncology-specific modifications.
Section 7.4.1
The objective response rate was revised from 12 weeks to 8 weeks in order to align with the 
disease assessment schedule.
Protocol Version 7.0, 04Oct2011 
Version 6.0 of protocol MI-CP204, dated 18Jul2011, has been amended to create 
Version 7.0, dated 04Oct2011. The protocol was amended to state that the maximum dose-
escalation phase dose of 12 mg/kg was selected for the expansion phase of the study. An 
additional safety follow-up visit at 60 days after the last dose was also added. In addition, 
information about the selection of the maximum dose of 12 mg/kg and an updated clinical 
experience section were added to the introduction. Infusion reactions were added as an event 
of special interest. The date of the Version 5.0 protocol in this section was corrected to 
23Sep2010. 
Section 1.3
Information supporting the selection of 12 mg/kg as the maximum dose to be tested was 
provided.
Section 1.4
The completion of Cohort 6 and the number of subjects enrolled was noted. Safety 
information was updated.
Section 3.1
The completion of Cohort 6, selection of the dose for the expansion phase and the completion 
of the interim safety analysis were documented. 
Section 5.2
The 60-day post-therapy visit was added. The procedures for Cohorts 3 to 6 were edited to 
show that they also apply to the expansion cohort.


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Sections 5.3, 6.3, and 7.3
The addition of the 60-day post-therapy safety visit, and the extended safety monitoring 
period were noted. The estimate of blood volume collection in Section 5.3.11 was updated.
Sections 6.1.3.2, 6.2.5 and 6.3.5.5 
Infusion reactions were added as an event of special interest.
The study abstract was updated as needed to reflect the changes in the protocol.
Protocol Version 8.0, 02May2012
Version 7.0 of protocol MI-CP204, dated 24Oct2011, has been amended to create 
Version 8.0, dated 02May2012.
All changes to the protocol were also made, if applicable, in the abstract
Sections 1.5, 3.1, 4.2, 4.5.2, 5.2.2, 5.3 
Sections were modified to note discontinuation of enrollment of MM subjects based on data 
from this study and recent nonclinical studies, which suggest lack of activity in the 
advanced/refractory MM setting. The expansion phase will enroll approximately 60 subjects: 
20 subjects each with FL, CLL (including SLL), or DLBCL.
Sections 3.1, 4.2, 5.1, 5.3.4, 5.3.9, 7.4 and 7.9
References to CLL in these sections were modified to say CLL (including SLL).
Section 4.2
All eligibility criteria pertaining to subjects with MM have been removed. The subjects 
enrolled in this study as of Protocol Version 8.0 will be adults with relapsed or refractory 
B-cell malignancies: CLL (including SLL), DLBCL, and FL.
Section 4.2.1
Inclusion criterion #3 was modified to state that subjects with a diagnosis of CLL (including 
SLL), DLBCL, or FL are included and that SLL, DLBCL, and FL must be histologically 
confirmed.
Inclusion criterion #6 for subjects with MM was removed; subsequent criteria were 
renumbered. 


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Inclusion criterion #8 was revised to specify that permitted prior radiation therapy must have 
occurred at least 6 weeks before the first dose of MEDI-551.
Inclusion criterion #9 was changed to provide different hematological criteria for CLL 
subjects with bone marrow involvement. 
Inclusion criterion #10 was changed to modify the definition of adequate organ function.
Section 4.2.2
Exclusion criterion #4 was modified to note that radiation therapy is not permitted within 
6 weeks prior to the first dose of MEDI-551.
Section 4.5.2
The size and composition of the expansion phase were updated to reflect approximately 
60 subjects and removal of the MM group.
Section 4.5.3
Preparation information for MEDI-551 is provided. In addition, directions state that infusion 
will be done using a 0.2 micron filter.
Section 4.5.4
Both red cell and platelet transfusions are acceptable in subjects who are transfusion-
dependent.
Section 5.2.2
Evaluations related to subjects with MM have been removed. 
IgE testing has been removed
References to HIV-1 and HIV-2 are revised to read HIV, as it is not necessary for 
investigators to evaluate for HIV-2.
Section 5.2.1 refers only to subjects in Cohorts 1 and 2. All subjects in those cohorts have 
completed the study; therefore Section 5.2.1 has not been altered.


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Section 5.3
Descriptions of procedures related to subjects with MM have been removed. Details of 
response criteria for subjects with MM have been removed.
Appendices
Appendix 1 includes the signatures of sponsor representatives to document approval of the 
protocol, according to the revised Clinical Study Protocol Standard Operating Procedure. 
Other appendices have been renumbered. 
Protocol Version 9.0, 15Jul2013
Version 8.0 of protocol MI-CP204, dated 02May2012, has been amended to create 
Version 9.0, dated 15Jul2013. The purpose of the amendment is to redefine the end of study. 
All text revisions resulting from this amendment are incorporated in the body of protocol 
Version 9.0. Major changes to the protocol are described below.
Abstract and Sections 3.2, 4.7, 5.2.1.4, 5.2.2.4, 6.4.1, and 7.4.1 
The definition of end of study, “defined as 1 year after the last subject begins treatment” was 
removed from these sections. The revised definition was added to the abstract and to 
Sections 1 and 4.8.
Abstract
The following sentence was added to the end of the study design section of the abstract: “The 
end of the study will occur after the deaths of 50% of all planned subjects or the date the 
sponsor stops the study.”
Section 3.2 Estimated Study Duration
An estimated study duration of 8 to 10years, based on the revised end of study, was provided.
Section 4.8 Study Completion
The second, bolded sentence was added to this section: “Study completion is defined as the 
date of the last protocol-specified visit or assessment (including telephone contact) for the 
last subject in the study. This date will be after the deaths of 50% of all planned subjects 
or the date the sponsor stops the study.”


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Section 4.2.1 Inclusion Criterion # 4
The term SLL was removed from the expression beginning, “Subjects with histologically-
confirmed B-cell NHL ...” as it was incorrect. The same correction was made in the abstract.
Protocol Version 10.0, 07Oct2013
Version 9.0 of protocol MI-CP204, dated 15Jul2013, has been amended to create 
Version 10.0, dated 07Oct2013. The purpose of the amendment is to add 2 arms to 
Study MI-CP204: dose escalation and expansion in subjects with CLL receiving MEDI-551 
monotherapy (Arm B); and dose escalation and expansion in subjects with aggressive 
lymphoma receiving MEDI-551 in combination with rituximab (Arm C). Note that dose 
escalation and expansion in advanced B-cell malignancies from the original protocol are 
referred to as Arm A. All text revisions resulting from this amendment are incorporated in 
the body of protocol Version 10.0. Major changes to the protocol are described below.
Abstract
The abstract was revised to reflect the changes made to the body of the protocol. 
Section 1.1 (Disease Background)
Under the subsection, “Treatment of B-cell Malignancies,” a paragraph was added to provide 
background on the rituximab-refractory population.
Section 1.3 (Nonclinical Experience with MEDI-551)
A paragraph describing the findings from the nonclinical SC dosing and embryofetal 
development studies were added to this section.
Section 1.4 (Clinical Experience with MEDI-551)
This section was modified to reflect the updated data from Arm A of Study MI-CP204 and 
the other 3 ongoing MEDI-551 studies in advanced B-cell malignancies.
Section 1.5 (Rationale for Study)
This section was revised to include justification for the new study arms (Arms B and C).


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Section 1.6 (Risk-benefit Summary)
The risk-benefit summary was revised to reflect the preliminary data from Study MI-CP204 
and the potential for additive toxicities with the combination of MEDI-551 and rituximab.
Section 2 (Study Objectives)
The exploratory objectives (on biomarkers) of Arm A were simplified into a single objective, 
with the detail provided in Section 7.3 (Endpoints). In addition, primary, secondary, and 
exploratory objectives were added for Arms B and C. 
Section 3 (Study Design)
The description of Arm A was revised to indicate that enrollment in the dose-escalation and 
expansion phases of this arm is complete. In addition, descriptions and flow diagrams of dose 
escalation and expansion in Arms B and C were added to the study design section. 
Section 4.2.1 (Inclusion Criteria)
Inclusion criteria #3 through #13 were revised to reflect the subjects to be included in 
Arms B and C. 
Section 4.2.2 (Exclusion Criteria)
Exclusion criterion #11 was modified to indicate that it applies only to Arm A.
Sections 4.5.1.1 (Investigational Product Inspection) and 4.5.1.2 (Reporting Product 
Complaints)
Two subsections were added under Section 4.5.1 (Investigational Product) to describe 
investigational product inspection and the reporting procedure for product complaints.
Sections 4.5.2 (Treatment Regimens) 
The text for Arm A was edited to reduce repetition of study design information (presented in 
Section 3), focusing only on the treatment regimen. In addition, the treatment regimens for 
Arms B and C were added to this section.
Sections 4.5.2.1 (Dose Modification for Toxicity Management) 
Dose modification criteria for Arms B and C were added to this section. In addition, the text 
for Arm A was edited to specify that AE severity will be graded according to the NCI 


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CTCAE V4.03 (formerly V4.0). The CTCAE version number was also updated in the List of 
Abbreviations.
Section 4.5.3 (Investigational Product Preparation and Administration)
The following equation for weight-based dose calculation was added:
Drug Volume (mL) = Dose (mg/kg) × Patient Weight (kg) ÷ Product Concentration (mg/mL)
In addition, descriptions for investigational production preparation and administration were 
added for Arms B and C. 
Section 4.5.4 (Concomitant Medications)
The following text was added to the concomitant medications section: “Prophylactic 
intravenous Ig to prevent infections.”
Section 4.5.5 (Dose Escalation)
Dose-escalation criteria for Arms B and C were added. Additionally, in the last paragraph of 
this section, the first sentence was revised to indicate that the Dose Escalation Committee 
consists of all study investigators and the sponsor’s medical monitor. Reference to the 
MedImmune Safety Monitoring Committee was removed.
Section 4.5.6 (Dose-limiting Toxicities)
Dose-limiting toxicity criteria for Arms B and C were added to this section. In addition, the 
text for Arm A was edited to specify that AE severity will be graded according to the NCI 
CTCAE V4.03 (formerly V4.0).
Section 5.2 (Schedule of Study Procedures)
A sentence was added to indicate that the schedule of study procedures for Arms A, B, and C 
are presented in separate subsections. The schedule of study procedures and by-visit 
descriptions of procedures were added in Section 5.2.2 for Arm B and in Section 5.2.3 for 
Arm C.


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Sections 5.3.1 (Medical History and Physical Examination, ECG, Weight, and Vital 
Signs), 5.3.2 (Clinical Laboratory Tests), 5.3.4 (Bone Marrow Biopsy), 5.3.6 
(Pharmacokinetic Evaluation and Methods), 5.3.7 (Immunogenicity Evaluation and 
Methods), 5.3.8 (Biomarker Evaluation and Methods), and 5.3.11 (Estimate of Blood 
Volume Collection)
In each of these sections, descriptions of study procedures were added for Arms B and C.
Sections 6.2.1 (Assessment of Severity)
The text was edited to specify that AE severity will be graded according to the NCI CTCAE 
V4.03 (formerly V4.0).
Sections 6.3.5.3 (Hepatic Function Abnormality), 6.4 (Safety Management During the 
Study), and 6.4.2 (Study Stopping Criteria)
The “MedImmune Safety Monitoring Committee (SMC)” was replaced with the
“MedImmune safety review committee.” In Section 6.4, the last paragraph describing the 
MedImmune SMC was replaced with a description of the MedImmune safety review 
committee.
Section 7.2 (Analysis Populations)
The Per-Protocol Population was removed.
Section 7.3 (Endpoints)
This section was revised to align endpoints with the study objectives. 
Section 7.4 (Assessments)
Assessment of the endpoints were removed from Section 7.3 and described in this section.
Sections 7.4.1 (MTD or OBD/Highest Protocol-defined Dose) 
Assessments for Arms A, B, and C were specified. 
Sections 7.4.2 (Safety Assessments)
Assessments for Arms A, B, and C were specified. In addition, the text was edited to specify 
that AE severity will be graded according to the NCI CTCAE V4.03 (formerly V4.0).
Section 7.5 (Sample Size and Power Calculations)
Sample size and power calculations were added for Arms B and C.


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Section 14 (References)
New references cited in the protocol were added to the reference list.
Appendices 2 (International Working Group Criteria for Malignant Lymphoma), 
3 (National Cancer Institute’s Common Terminology Criteria for Adverse Events 
Version 4.0), 4 (International Uniform Response Criteria for Multiple Myeloma), and 5 
(National Cancer Institute - Working Group Guidelines)
Appendices 2 through 5 were deleted. These appendices only included a URL to guideline 
documents. These URLs were included in the reference list. 
Appendix 2 (Rituximab Prescribing Information)
Given that Arm C will evaluate MEDI-551 in combination with rituximab, the prescribing 
information for rituximab was included in Appendix 2.
Protocol Version 11.0, 21Mar2014
Version 10.0 of protocol MI-CP204, dated 07Oct2013, has been amended to create 
Version 11.0, dated 21Mar2014. The purpose of the amendment is to add a fourth arm 
(Arm D) to Study MI-CP204: subjects with anti-CD20-refractory aggressive lymphomas 
receiving MEDI-551 monotherapy. All text revisions resulting from this amendment are 
incorporated in the body of protocol Version 11.0. Major changes to the protocol are 
described below.
Abstract
The abstract was revised to reflect the changes made to the body of the protocol. 
Section 1.5 (Rationale for Study)
This section was revised to include justification for Arm D.
Section 1.6 (Risk-benefit Summary)
The risk-benefit summary was revised to reflect the addition of Arm D.
Section 2 (Study Objectives)
Primary, secondary, and exploratory objectives were added for Arm D. 


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Section 3 (Study Design)
A description and flow diagram of Arm D were added to the study design section. 
Section 4.2.1 (Inclusion Criteria)
The following changes were made to the inclusion criteria:
•
Inclusion criterion #3 (diagnosis) was revised to reflect the subjects to be included in 
Arm D. 
•
Inclusion criterion #4 was revised to indicate that the fresh tumor biopsy is optional
•
Inclusion criterion #5 (evaluable/measurable disease) was revised to reflect the subjects 
to be included in Arm D. 
•
Inclusion criterion #6 (prior therapy) was revised to reflect the subjects to be included in 
Arm D. 
•
Inclusion criterion #10 (adequate hematologic function) was revised to reflect the 
subjects to be included in Arm D. 
•
Inclusion criterion #12 (contraception) was revised to further define “postmenopausal.”
Section 4.2.2 (Exclusion Criteria)
The following changes were made to the exclusion criteria:
•
Exclusion criteria #4 and #5 were revised to reflect a washout period of 28 days or 5 half-
lives instead of 6 weeks.
•
Exclusion criterion #7 was revised to indicate “live or attenuated” vaccines.
•
Exclusion criterion #9 (history of other invasive malignancies) was removed.
•
Exclusion criteria #18 (ECG abnormality) and #20 (concurrent enrollment in another 
study) were revised to provide additional clarification.
•
Exclusion criterion #21 was modified to indicate that subjects related to employees of a 
clinical study site directly involved with the conduct of the study may be treated at 
another participating site.
Section 4.5.1 (Investigational Product [MEDI-551])
This section was updated to reflect the 2 manufacturing processes and the dosage strengths 
(
 and 
mg/mL).


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Section 4.5.2 (Treatment Regimens) 
The treatment regimen for Arm D was added to this section.
Section 4.5.2.1 (Dose Modification for Toxicity Management) 
This section was revised to include Arm D, which will follow the same dose modification 
criteria as Arms B and C. 
Section 4.5.3 (Investigational Product Preparation and Administration)
This section was revised to include Arm D, which will follow the same investigational 
product preparation and administration procedures as Arm B. 
Section 4.5.4 (Concomitant Medications)
The following text was added to the concomitant medications section: “intrathecal 
prophylaxis with either methotrexate or cytarabine, if clinically indicated, and prophylactic 
antibiotics.”
Section 5.1 (Efficacy and Clinical Pharmacology Parameters) 
This section was revised to reflect Arms B, C, and D. 
Section 5.2 (Schedule of Study Procedures)
The schedule of study procedures and by-visit descriptions of procedures for Arm D were 
added in Section 5.2.4. In addition, the schedule of study procedures and by-visit descriptions 
of procedures for Arms B and C were updated to include Karnofsky performance status 
assessment and BM biopsy with MRD analysis.
Sections 5.3.1 (Medical History and Physical Examination, ECG, Weight, and Vital 
Signs), 5.3.2 (Clinical Laboratory Tests), 5.3.3 (B-cell and Immunoglobulin Levels), 
5.3.4 (Bone Marrow Biopsy), 5.3.5 (Cytogenetic Analysis), 5.3.6 (Minimal Residual 
Disease Analysis), 5.3.7 (Pharmacokinetic Evaluation and Methods), 
5.3.8 (Immunogenicity Evaluation and Methods), 5.3.9 (Biomarker Evaluation and 
Methods), 5.3.10 (Disease Evaluation Methods), and 5.3.12 (Estimate of Blood Volume 
Collection)
In each of these sections, descriptions of study procedures were added for Arm D. In 
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Sections 5.3.6 (Minimal Residual Disease Analysis)
This section was added to describe MRD analysis for Arms B, C, and D.
Sections 6.4.1 (Interruption of Permanent Discontinuation of Study Dosing in 
Individual Subjects)
This section was revised to reflect Arms A, B, C, and D.
Section 6.4.2 (Study Stopping Criteria)
This section was revised to be consistent with the new protocol template (v16.2).
Sections 6.4.3 (Monitoring of Dose Administration)
This section was revised to reflect Arm D, which will follow the same monitoring procedures 
as Arms B and C.
Section 7.3 (Endpoints)
The primary, secondary, and exploratory endpoints of Arm D were added.
Section 7.4.3 (Efficacy Assessments)
The definition of MRD-negative CR was added to efficacy assessments.
Section 7.5 (Sample Size and Power Calculations)
Sample size and power calculations were added for Arm D.
Section 14 (References)
New references cited in the protocol were added to the reference list.
Protocol Version 12.0, 27Jan2015
Version 11.0 of protocol MI-CP204, dated 21Mar2014, has been amended to create 
Version 12.0, dated 12Jan2015. The purpose of the amendment is to add information 
regarding the 
 dosage strength and to remove references to the 
 
dosage strength of MEDI-551. Modifications to CT/PET scan frequency were made to 
minimize radiation exposure. In Arm B, subjects receiving doses ≥ 24 mg/kg will receive the 
initial weekly doses in Cycle 1 over Days 1-2 as mitigation for infusion-related reactions. 


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This is being implemented in addition to existing safeguards of prophylactic medications 
(including antihistamines and corticosteroids) and the option to decrease infusion rate 
because 2 out of 3 subjects at the 6 mg/kg dose level experienced Grade 3 infusion-related 
reactions during the first infusion.
An allowance for prophylaxis against tumor lysis syndrome in subjects with large tumor 
burden was added. Appendix 2, Rituximab Prescribing Information, was updated. Other 
changes were made for clarity and consistency. In addition, changes from Administrative 
Change 1, dated 30Jun2014, were incorporated. All text revisions resulting from this 
amendment are incorporated in the body of protocol Version 12.0. Major changes to the 
protocol are described below.
1. Cover page – Change in medical monitor.
2. Study Abstract – The abstract was modified to mirror the changes made to the protocol 
body.
3. Section 3.1 (Overview of Study Design) – Language was added to describe the dosing 
schedule for subjects in Arm B receiving 24 or 48 mg/kg dose levels of MEDI-551. The 
initial doses will be administered over 2 days on Day 1 and Day 2 in Cycle 1. The flow 
diagram for Arm B was updated to be consistent with this change.
4. Section 4.2.2 (Exclusion Criteria) – Exclusion criterion 12 was modified to align with 
allowances for hepatitis B in other MEDI-551 studies. Exclusion criterion 22, history of 
other invasive malignancy within 5 years except for localized/in situ carcinomas, was 
added to align with other MEDI-551 studies.
5. Section 4.5.1 (Investigational Product [MEDI-551]) – References to the 
 dose 
were removed and the 
 dose was added.
6. Section 4.5.1.1 (Investigational Product Inspection) – References to the 
 dose 
were removed and the 
 dose was added.
7. Section 4.5.2 (Treatment Regimens) – Text was added to Arm B to specify that for 
MEDI-551 doses ≥24 mg/kg, the initial weekly doses will be administered over 2 days 
on Day 1 and Day 2 in Cycle 1. This change was made to minimize infusion-related 
reactions at higher dose levels. Subsequent doses at the 24 and 48 mg/kg dose levels will 
be administered weekly on Days 8, 15, and 22 in Cycle 1 and then on Day 1 of each 
28-day cycle in Cycle 2 and beyond.
8. Section 4.5.3 (Investigational Product Preparation and Administration) –
◦
Arms B, C, and D – Reference to the 
 dosage strength was removed. 
Added text to specify that subjects in cohorts of Arms B, C and D receiving 
MEDI-551 at dose levels of 12 mg/kg or less will receive the 10 mg/mL dosage form. 
Added text to specify that subjects receiving doses ≥ 24 mg/kg in Arm B will receive 
the initial infusion over 2 days on Day 1 and Day 2 of Cycle 1 and that the Day 1 
infusion will be administered over a minimum of 81 minutes, and the Day 2 infusion 
will be administered over a minimum of 60 minutes (+ 15 minutes at the 
investigator’s discretion). Added text to state that MEDI-551 infusion must be 
completed within 4 hours after the initial start of the infusion and that a new IP 


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solution is required to be prepared if MEDI-551 infusion is not able to be completed 
within 4 hours after the initial start of the infusion.
◦
For Arm C only: Added text to clarify the timing of MEDI-551 dosing and state that 
on Day 8 of Cycle 1 and Day 1 of Cycle 2, MEDI-551 should be administered first 
with rituximab administration a minimum of 30 minutes after completion of the 
MEDI-551 infusion.
9. Section 4.5.2.1 (Dose Modification for Toxicity Management) – The duration of infusion 
interruption was changed from 6 hours to 4 hours in Table 4.5.2.1-2 for Grade 3 infusion 
reactions that do not respond to medical therapy as follows: For Grade 3 infusion reaction 
that does not respond to medical therapy (including interruption of infusion for ≤ 6 4
hours) or that occurs despite steroid prophylaxis, discontinue MEDI-551.
10. Section 4.5.3 (Investigational Product Preparation and Administration) – Text was 
modified in the section for Arms B, C, and D to indicate that 
 dosage 
strengths will be used as specified by the sponsor. Text was added to describe that 
subjects receiving doses ≥ 24 mg/kg in Arm B will receive the initial infusion over 2 days 
on Day 1 and Day 2 of Cycle 1. Text was added to indicate that the MEDI-551 infusion 
must be completed within 4 hours after the initial start of the infusion. Text was added for 
Arm C to reiterate that MEDI-551 will be administered over a minimum of 81 minutes 
after mandatory premedications, and that on Day 8 of Cycle 1 and Day 1 of Cycle 2, 
MEDI-551 should be administered first with rituximab administration a minimum of 30 
minutes after completion of the MEDI-551 infusion.
11. (Section 4.5.4 (Concomitant Medications) – Text was added to recommend 
premedication with acetaminophen, diphenhydramine, and corticosteroids before the first 
infusion. A statement was added to allow for prophylaxis against tumor lysis syndrome 
according to institutional guidelines in subjects with large tumor burden.
12. Section 5.2.2 (Study Procedures for Arm B) and Table 5.2.2-1 (Schedule of Study 
Procedures for Dose Escalation and Expansion in Arm B) – A column was added for 
Cycle 1 Day 2 to accommodate the 2-day dosing for doses ≥ 24 mg/kg. Aspirate was 
added to BM biopsy. In Cycle 2+, CT scan and disease response was changed to Q3M. 
Footnote b was modified to indicate that only subjects who had a positive BM biopsy at 
baseline and achieve CR will be required to undergo repeat BM biopsy for confirmation 
of CR. Footnote c was modified to require CT scans every 3 months during treatment for 
the first 1 year to decrease radiation exposure while still allowing sufficient monitoring of 
disease response. Cycle 1, Day 2 and the associated assessments were added to the visit-
by-visit lists of procedures. Windows around timing for completion of ECGs were added 
and standardized for clarity. Follow-up visits every 3 months after Day 60 post-EOT visit 
were changed to every 3 months post-EOT visit to align with the schedule for follow-up 
scans.
13. Section 5.2.3 (Study Procedures for Arm C) and Table 5.2.3-1 (Schedule of Study 
Procedures for Dose Escalation and Expansion in Arm C) - Aspirate was added to BM 
biopsy. Cycle 3+, Day 22 was added to allow for completion of CT/PET scans prior to 
Day 1 of every other cycle. Footnote b was modified to indicate that only subjects who 
had a positive BM biopsy at baseline and achieve CR will be required to undergo repeat 
BM biopsy for confirmation of CR. Footnote c was modified to require CT scans every 
2 months during treatment for the first 1 year and every 3 months during the first year of 
follow-up to decrease radiation exposure while still allowing sufficient monitoring of 


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disease response. Text was modified to clarify that CTs are required, while FDG-PET 
scans are optional. Windows around timing for completion of ECGs were added and 
standardized for clarity. Follow-up visits every 3 months after Day 60 post-EOT visit 
were changed to every 3 months post-EOT visit to align with the schedule for follow-up 
scans.
14. Section 5.2.4 (Study Procedures for Arm D) and Table 5.2.4-1 (Schedule of Study 
Procedures for Arm D) - Aspirate was added to BM biopsy. Cycle 3+, Day 22 was added 
to allow for completion of CT/PET scans prior to Day 1 of every other cycle. Footnote b 
was modified to indicate that only subjects who had a positive BM biopsy at baseline and 
achieve CR will be required to undergo repeat BM biopsy for confirmation of CR. 
Footnote c was modified to require CT scans every 2 months during treatment for the 
first 1 year, then every 6 months and at EOT, and during follow-up every 3 months for 
the first 1 year to decrease radiation exposure while still allowing sufficient monitoring of 
disease response. Text was modified to clarify that CTs are required, while FDG-PET 
scans are optional. Windows around timing for completion of ECGs were added and 
standardized for clarity. Follow-up visits every 3 months after Day 60 post-EOT visit 
were changed to every 3 months post-EOT visit to align with the schedule for follow-up 
scans.
15. Section 5.3.1 (Medical History and Physical Examination, ECG, Weight, and Vital Signs) 
– Windows for completion of ECGs were added for each arm. 
16. Section 5.3.7 (Pharmacokinetic Evaluation and Methods) – Blood samples for MEDI-551 
serum concentrations were added at for Arm B at Cycle 1, Day 2 (newly added samples); 
and for Arm C at Cycle 1, Days 15 and 22 (to align with samples required in Table 5.2.3-1).
17. Section 5.3.10 (Disease Evaluation and Methods) – The section for FL, DLBCL, MCL, 
and Transformed Indolent Lymphoma was modified to require scans every 2 cycles 
beginning with Cycle 3 for a period of 1 year, then every 3 cycles during follow-up for a 
year.
18. Section 5.3.12 (Estimate of Blood Volume Collection) – The blood volume for Arm B 
was increased to 105 mL (7.1 tablespoons) for the 6 and 12 mg/kg cohorts and to less 
than 116 mL (7.8 tablespoons) for the 24 and 48 mg/kg cohorts.
19. Appendix 2, Rituximab Prescribing Information, was updated with the most recent 
version, dated 8/2014.
Protocol Version 13.0, 01Jun2017
Version 12.0 of protocol MI-CP204, dated 27Jan2015, has been amended to create 
Version 13.0, dated 01Jun2017. The purpose of Version 13.0 is to discontinue participation 
for all subjects who are no longer dosing and have completed at least the 90-Day Post Last 
Dose Visit, while allowing subjects who are benefiting from MEDI-551 to continue 
treatment. 
Enrollment in the study was closed as of 30Sep2015. Arm A was completed as planned, with 
a total of 95 subjects enrolled (26 in dose-escalation and 69 in expansion). A total of 
7 subjects were enrolled in Arm B dose-escalation, including one at a dose of 24 mg/kg.


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Based on emerging PK and pharmacodynamic data, a dose of 12 mg/kg, administered weekly 
during Cycle 1 and then monthly in subsequent cycles, was determined to be sufficient to 
saturate the B-cell sink and achieve full exposure; at the sponsor’s discretion and not due to 
any safety issues, no further Arm B dose-escalation was conducted and Arm B dose-
expansion was not initiated. A total of 19 subjects were enrolled in Arm C. Of these 19 
subjects there were only 7 responders, and there was about a 13% probability of meeting the 
protocol-specified target response rate of 50%. Further enrollment in Arm C was therefore 
halted at the sponsor’s discretion and not due to any safety issues. A total of 16 subjects were 
enrolled in Arm D. Of these 16 subjects there were only 3 responders, and there was about a 
1% probability of meeting the protocol-specified target response rate of 50%. Further 
enrollment in Arm D was therefore halted at the sponsor’s discretion and not due to any 
safety issues.
As of 19Jan2017, 9 subjects remain on treatment; all have completed at least 1 year of 
treatment.
Subjects who are currently on treatment will be allowed to continue to receive MEDI-551 
with a simplified schedule of evaluations focused on safety. The 90-Day Post Last Dose Visit
(60 days post-EOT Visit) will be conducted when subjects come off treatment.  Long-term 
follow-up for progression-free survival and overall survival will be discontinued. As of 
Version 13.0, all subjects who have completed treatment and safety follow-up will be 
considered to have completed the study.
•
On treatment days, the schedule of evaluations is simplified.
◦
Key safety assessments relevant to MEDI-551 are retained. Vital signs will be
evaluated pre-dose and at end of infusion only.
◦
Additional safety assessments that have not been informative during later cycles of 
MEDI-551 will not be required at each cycle (note these evaluations are retained at 
EOT). This includes (when applicable) ECG, coagulation, urinalysis; liver function 
will continue to be evaluated at each cycle), PK, ADA, and B-cell monitoring (B-cell 
levels in non-CLL subjects were generally very low at baseline, likely due to prior 
anti-cancer treatments.  B-cell levels in CLL subjects were often elevated at baseline; 
however, this is likely reflects malignant rather than normal B cells. Across 
populations, B cells were nearly or fully depleted following > 6 cycles).
◦
Exploratory evaluations are removed.
◦
Disease evaluations will be performed at regular intervals to determine whether 
MEDI-551 is continuing to provide clinical benefit.  
▪
Subjects with DLBCL, FL, MCL, or transformed indolent lymphoma who have 
completed > 1 year of treatment: disease evaluation is required once every 6 
months.


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▪
Subjects with CLL who have completed > 1 year of treatment: after which CT 
scans for disease evaluation are only required once every 6 months if clinically 
indicated (eg previous indication to treat was based on predominantly nodal 
disease) or if indicated based on hematology findings.
•
At the EOT Visit, all safety assessments will be performed, but exploratory evaluations 
are removed. Evaluations used to confirm CR are removed (where applicable).
•
Safety follow-up will be conducted at the 90-Day Post Last Dose Visit (also known as 
End of Study). All safety assessments will be performed; exploratory evaluations are 
removed. The 30 Days post-EOT visit is removed.  
•
Long-term follow-up for progression-free survival and overall survival will be 
discontinued once Version 13.0 is in effect.  All subjects who have completed treatment 
and safety follow-up through at least the 90-Day Post Last Dose Visit (ie approximately 
90 days post last dose), withdrawn consent, or been lost to follow-up will be considered 
to have completed the study.  
Major changes to the protocol are described below.
1. Title Page: The Medical Monitor was changed from Dr. Boyd Mudenda to Dr. Nai Shun 
Yao as the primary medical monitor. Dr. Yao’s title and contact information were
updated. 
2. Dr. Mohammed Dar was added as the secondary medical monitor. 
3. Study Abstract:
a.
The abstract was modified to mirror the changes made to the protocol body.
b. Subject numbers were updated to reflect actual enrollment
c.
Rationale for discontinuing enrollment in Arms B, C, and D added
d. Exploratory Objectives amended
4. Section 1.4 (Clinical Experience with MEDI-551): Updated to be consistent with the 
current MEDI-551 Oncology Investigators Brochure. 
5. Section 3.1 (Overview of Study Design):
a.
Number of subjects treated was updated as well as 90 Day Post Last Dose Visit 
added and defined.
b. To make the protocol more consistent, subjects in all arms who achieve a CR may 
receive an additional 2 cycles of MEDI-551 at the same dose prior to EOT.  
Previously this applied to Arm A only.  Subjects in Arm A who reached CR and 
then came off treatment had durable responses of > 1 year in all cases.
c.
Retreatment will not be provided for subjects who come off treatment in CR and 
later progress.  Prior to implementation of Version 13.0, the option of retreatment
would be considered for subjects in the US only.  
6. Section 3.2 (Estimated Study Duration): Clarified to state that safety follow-up 
assessments will be conducted through approximately 90 days after the last dose of 
investigational product, which is equivalent to approximately 60 days post-EOT Visit, 
and revised to state that study completion is defined as the date of the last protocol-
specified visit for the last subject in the study.
7. Section 4.5.2 (Treatment Regimens): Updated to reflect changes described above.
8. Section 4.5.5 (Dose Escalation): Updated to reflect actual enrollment.


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9. Section 4.7 (Subject Status): The following statement was added: Once Version 13.0 is in 
effect, all subjects who have completed treatment and safety follow-up, withdrawn 
consent, or been lost to follow-up will be considered to have completed the study.
10. Section 4.8 (Study Completion): The following statement was updated. Study completion 
is defined as the date of the last protocol-specified visit for the last subject in the study.
All materials or supplies provided by the sponsor will be returned to the sponsor or 
designee upon study completion, as directed by the site monitor, and/or destroyed by the 
site/IRB/IEC instructions.
11. Section 5.2 (Schedule of Study Procedures): Added rationale and summary of changes in 
study procedures.
Section 5.2.1 (Schedule of Study Procedures – All Subjects Approved for Version 13.0 of 
the Protocol): This section title changed from Study Procedures for Arm A
12. 5.2.1 Title was Study Procedures for Arm A. 
a.
The following tables and instructions were removed and all subjects are to follow 
newly entered Table 5.2.1-1: 
i.
Table 5.2.1.1-1 (Schedule of Study Procedures for Dose-escalation 
Cohorts 1 and 2 [Screening and Cycles 1 - 3 and All Subsequent Odd 
Cycles] of Arm A) and Table 5.2.1.1-2 (Schedule of Study Procedures for 
Dose-escalation Cohorts 1 and 2 [Cycle 4, All Even Cycles, End of 
Treatment, and Post-therapy] of Arm A)
ii. Tables 5.2.1.2-1 and 5.2.1.2-2 (Dose-Escalation Cohorts 3-6 and 
Expansion (Screening and Cycles 1-3) Arm A and (Cycle 4 and Follow 
up) Arm A 
iii. Table 5.2.2-1 Dose-Escalation and Expansion Arm B
iv. Table 5.2.3-1 Dose-Escalation and Expansion Arm C
v. Table 5.2.4-1 Procedures for Arm D
The following procedures were completely removed and are no longer collected:
a.
Day 30 and Day 60 post dose visits were removed as well as all long term follow 
up visits, which were replaced with a single 90-Day Post Last Dose Visit (also 
defined as End of Study visit).  
b. Hepatitis B, C; HIV-1 and HIV-2
c.
Serum βhCG and Urine βhCG have been changed to “Pregnancy Test (females of 
childbearing potential)”
d. Triplicate ECGs were changed to single ECGs and are no longer collected during 
dosing visits.  Single ECGs will be collected at the EOT visit and the 90-Day Post 
Last Dose Visit.
e.
Physical examination is now only focused (symptom-directed)
f.
Height
g. Cytogenetic analysis is no longer required
h. Liver and spleen palpation
i.
Collection of bone marrow biopsy and aspirates as well as tumor tissue
j.
Collection of exploratory post-infusion biomarkers
k. Collection of circulating biomarkers
l.
Collection of RNA samples for analysis
m. Collection of DNA samples for analysis
n. Subsequent anticancer therapy 


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01Jun2017 Version 13.0, Final
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o. Collection of blood tumor biomarkers
p. Flow Cytometry for MRD
q. Peripheral blood for MRD
r.
Molecular analysis of whole blood DNA
13. Section 5.3 Description of Study Procedures: This section was modified to mirror the 
changes described above in Section 5.2:
a.
5.3.1 (Medical History and Physical Exam, ECG, Weight, and Vital Signs):
i. Physical Examinations updated from “post-screening exams may be 
primarily focused on disease findings” to “Physical examination should be 
focused (symptom-directed)”.
ii. ECGs are no longer required on all dosing days (Day 1 of each treatment 
cycle) and are to be done as single ECGs, not triplicate.
iii. On dosing days, vital signs will be monitored prior to MEDI-551 infusion 
and at End Of Infusion only.
b. 5.3.2 (Clinical Laboratory Tests):
i. The hyperlink was added for reference to Section 5.2 laboratory 
assessments schedule
ii. Women of childbearing potential only added to clarify Day 1 urine 
pregnancy tests.
c.
5.3.3 (B-cell and Immunoglobulin Levels):
i. Separate paragraphs were consolidated into 1 paragraph for Arms A, B, C, 
and D.
d. Sections 5.3.4 Bone Marrow Biopsy, 5.3.5 Cytogenetic Analysis, and 5.3.6 
Minimal Residual Disease Analysis were all removed due to removal of all 
relevant samples and testing.  
e.
5.3.4 (Pharmacokinetic Evaluation and Methods):
i. Most of this section was removed and a reference to Section 5.2 was 
added as well a statement that MEDI-551 concentrations in serum samples 
will be measured using a validated immunoassay.
f.
5.3.5 (Immunogenicity Evaluation and Methods:
i. The visits for assessing antibodies in Section 5.3.8 was simplified to refer 
to Section 5.2 and will only be collected at EOT and 90-Day Post Last 
Dose Visits.
g.
5.3.9 Biomarker Evaluation and Methods was removed.
h.
5.3.6 (Disease Evaluation and Methods) section was modified to a different 
frequency: 
i. FL, DLBCL, MCL, and transformed indolent lymphoma: Subjects will be 
assessed by CT scan (FDG-PET or PET-CT if clinically indicated) and 
physical .  CLL (and SLL) : Subjects will be assessed by chest, abdomen, 
pelvis, and neck (if applicable) CT scan and disease response assessment 
(physical exam) if clinically indicated (eg previous indication to treat was 
based on predominantly nodal disease) or when indicated based on 
hematology findings.  
i.
Section 5.3.11 Experimental Sample Collection was removed entirely.


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01Jun2017 Version 13.0, Final
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j.
5.3.7 (Estimate of Blood Volume Collection) was renumbered and all Arms were 
condensed to one section.  
14. Section 6.3.2 (Study Reporting Period for Serious Adverse Events): Updated language to 
reflect that reporting period for SAEs is the period immediately following the time that 
written informed consent is obtained through the 90-Day Post Last Dose.
15. Section 6.4.1 (Interruption or Permanent Discontinuation of Study Dosing in Individual 
Subjects): Modified language to state that until Version 13.0 is implemented, the protocol 
required long-term follow-up of subjects who are permanently discontinued from 
investigational product.
16. Section 6.4.3 (Monitoring of Dose Administration): This section was modified to mirror 
the changes described above in Sections 5.2.1 - 5.2.4 and Section 5.3.1.
17. Section 7 (Statistical Considerations):
a.
Updated to include the actual numbers of subjects enrolled in each Arm.
b. Added rationale for discontinuing enrollment in Arms B, C, and D.
c.
Updated the number of exploratory endpoints 


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Appendix 1
Signatures
Sponsor Signature 
An Open-label, Phase 1/2 Study of MEDI-551, a Humanized Monoclonal Antibody Directed 
Against CD19, in Adult Subjects With Relapsed or Refractory Advanced B-cell 
Malignancies 
I agree to the terms of this protocol and all amendments/administrative changes.
Signature and date: An electronic signature is appended
One MedImmune Way, Gaithersburg MD, 20878, USA
Telephone number: 


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01Jun2017 Version 13.0, Final
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Signature of Principal Investigator
An Open-label, Phase 1/2 Study of MEDI-551, a Humanized Monoclonal Antibody Directed 
Against CD19, in Adult Subjects With Relapsed or Refractory Advanced B-cell 
Malignancies I agree to the terms of this protocol and all amendments/administrative 
changes.
I, the undersigned, have reviewed this protocol and all amendments, and I agree to conduct 
this protocol in accordance with ethical principles that have their origin in the Declaration of 
Helsinki and are consistent with the International Council for Harmonisation (ICH) 
guidelines on Good Clinical Practice (GCP), any applicable laws and requirements, and any 
conditions required by a regulatory authority and/or Institutional Review Board/Independent 
Ethics Committee (IRB/IEC). 
I understand that the protocol may not be modified without written approval of the sponsor. 
All changes to the protocol must be submitted to the applicable regulatory authority and 
IRB/IEC, and must be approved by the IRB/IEC prior to implementation except when 
necessary to eliminate immediate hazards to the subjects or when the change(s), as deemed 
by the sponsor, involves only logistical or administrative changes. Documentation of 
IRB/IEC approval must be sent to the sponsor immediately upon receipt.
Signature and date: 
Name and title: 
Address including postal code: 
Telephone number: 
Site/Center Number (if available)
This document contains confidential information, which should not be copied, referred to, released, or published 
without written approval from MedImmune or AstraZeneca. Investigators are cautioned that the information in 
this protocol may be subject to change and revision.


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Appendix 2
Rituximab Prescribing Information
lnGIILIGHIS OF PRESCRIBL'IiG NORUU!Oli 
n.e.. ~h 
do oot iododt all tbt iofollltllioo ....Std to"'' 
RIIUX.\.~ sa!tly aod tffectivtly. Sttloll prucri\iac iolormatioo 
ror RITliXA .. N'. 
RIIUX.\.'1' (ritlllimab) injtctioo, for iDrramoiiS"" 
loitW US. Appronl: 1997 
WARJ>"IKG: FATAL INFUSION R!.4CTIONS, SEVER! 
~WCOCL'TANtOUS REACTIONS, IlEPA TinS B VIRUS 
RE.~CTIVATION >od PROCRESS!IE :I!Ul:TIFOC.U 
L£tlKOrNC!PH.UOP!TIIY 
Steflt/l pmcribi•t ill/.,moti•• for ""IJ!Itte bo.wdt1YJ17tiJiz. 
Fat>! iDflosioo rnrtions witmo U hom of Rillii,. iDID.Iioo; 
•pprol:im>ttly 81m or !a tal rtl<tioD.I ocnnrtd with lirst iDfnlioa. 
~ionifor p:ttifoats :llld cfuc.oatinut Rihll:o illfusion for ~\'trf 
reactio11> (S.l~ 
Suere mococol>otm rtactiOtiS, .. mtwitl lata! oottotll<> (5.2). 
Htp:ttifU 8 \iraS {HBV) rtxtiYttiGD, in SOIDt CA\tS rtstltiD: in 
filliDiuDI btpatifu, btpotic failure, ond dtalh (5.3). 
Progres>ivt mulliforalleal:otoctpbalopallay ~n.) rtsaltinc iD dtotb 
<•··~ 
-----RICE.'ITALUORCII.\.~GES>------
a .. e<tw• 
W:1lllin~s ami PrecaU!lOD.I 
9/lOll 
9/lOll 
-----l'liDICATIONSA.'ID 05.\C.'t.----
Rirux:m' (nnronub) is • CD20-dinct!d C)10l)'li< antibody itll!ic!r!d for lhe 
treatmem of pAden~ wllb: 
Noo·!lodgiiD'• Lyllll>l¥>ma (NHI.) (1.1) 
C,brollic Lymp""'ytic Ltukeml!l (Cll) (1.2) 
Rbewrurotd Anhrim (RAJ i!l rombi0.1tian wtth mtthorre.ure m ildult 
patimn v.itb modent;ely·<o smiely·acth·e RA wbo b.m Ul3deql1Xe 
l!lpOilSt to ••• "'"""' Th'F -~anilt th!<'¢t> (LJ) 
Grmu!Dillll'.OsU uilb Polympiril (G!>A) (W!l""''' GratrulO!IIll'.osU) ami 
~liaoscopit Pol)'llllgijlii (MPA) iD adult paliwn iD CQIIlbio.ttioo with 
~oromroidl (1.4) 
Limlt!tioo• ow .. : Rirwcaa Is .. , reco"""'DII;d for use iD patien~ •irh 
"'""' >Clit~ ill!ec1ians (1.5). 
----DOSAGE AND.WliOOSIRATIOli---
Admminer only .u 2Illlillll\ 'tDtm fnflnian. 
Do not adlmnloo a> an iD.Jnn.oous pus:b ot OOha 
Rinwo ;.hould only be admiolslatd by a bealtbc,. prolt;;ianal v.itb 
~te 
ll!fdi<al wppon to IIWI.'I~_e ~\'eft infusion rNCticm th:lt Wl 
be ti1.1nl if they occur. 
Tbe dose fxlr NIII. is 375 ~m' (2.2). 
Tbe dose rx. CLL i; 315 ~m' In me lint cy:le ami 500 ~m' In 
cyd" 2-6, iD cl1f0bilutioo •irh FC, i!dminismtd "'t!J' 28 daY' (2.J~ 
TbedOS<! a; orompolltlll ofZ"1lliD• (lbrirumamab tiuxe<JID) Tbenptutk 
~ illl0 mg/m'(2.4J. 
• Tbe dost rx. RAiD corubiutio>llirh metboom:e Is 11\ ... Iooo ~ 
illl!at'!llOIIS iofuoons ;ep!llited by 2 weel<s (one c0111") ""'Y ~4 weel:; 
or ba;ed oo clillicalevalll>'ioa. blllll<IC 10011e: tll."' t\'tl)' 16 weel:1. 
~feiliylJ:-'ftdniwloll! 100 m: imr.!\uous or eqtli\·alem :Iucoconicoid ii 
rtrornmended 30 minu~e; prior to e>ch inMioo (2.5). 
Tbe dose fxlr GPA aodMPA iD ccmbinlri<lo wuh glucoromr«ds is 
375 ~lm'onre \\'!eltly for 4 ••el" (2.6). 
----DOSAGE FOR.\15 .\.>iD STRI!\GTHS; ___ _ 
lojection: 100mdl0 mL t!ld ;oo onwso mL .olutioo iD. sill~ tilll 
(l) 
-----CONTRAOOJ!CATIOJ\:'5-----
Nott. 
-----'WAR.'WCS AND PRICAUTIONS'------
1\uoor lysi; ;)lld.'Olllf'. AGomiste: aggre;sitt izllm'ellOUI hydntioa 
tmti~h)'Perm:icfmic a:Ml!S1 omitor reonl fiution (5.5). 
lllfernoos: \Vidtbold RiliiXlllaod imn1w.e appropna<e llllli·ioferm·e 
tbernpy (5.6). 
Ca."diac mb)~ 
and ~.UU: Discomim.lt infutio!U iD case of sl!riott\: 
or life·tbreattni!lf mms (i.l). 
Bou·el ~1111<0011 and ptrlorarioo: COI!IlOO and i'o'llll:ltt f« abdowi!lal 
p:Wl, I'ODritil!;, 01' reJ•ttd l)1!liXOOIS (5,9). 
l.h·e\inls \'3CcinK: Do DOt a.dministerli\'t\irus ncc:in6 pnorto 0!' 
durillg Rit.t<Jill (S.IO). 
C}'!Opellio;. ~lanitof b!oocic= ar ,.~ mteMI! (5.11, 6.1) 
·---AD~RE.ACTION~---
l>.·f~Ml common advene ma:hus ill clinical aials: ~"@l'e: 
NIII. (• 25~1). m!u;iol rea:rloos, fmt, ljmpbopeni.t, cbilli, iofertiool!ld 
:udlellia (6.1). 
Cll (•2511): inMioo Ie>cti01l6 !Dd oeu<ropellia (6.1). 
RA (> 10!1): upper rel]limiOI)' In\(( lllfer1ioo, !1l!O]>lw}"!in~ 11.'1!W)' 
net ulfer1io11, !Dd btoorhili; (otb!f import:mi adrene rucnoD< !lldudt 
inM1011 reacri<lo~ 1erious iof>ctians, !Dd c.rd!o\-.scu!M e~·en~) (6.2). 
GPA Qnd MPA (:: 15 %): llfeclions, !l3U!e~ di..Wiel, be:lClac.be, lllllide 
''"""'· ontlllia, periphernl ed""' (Dliw impomui advme reer1ioo; 
illcJude iDfilliOD Ie!Ctiooi)(6J). 
To rtparl SUSPECTED .W\'ERSERE.-\CTIONS, conta<l Ct•enttcb at 
I.stJS.335-l505 or FDA at 1-!00·FDA·IOU or 11111\'.fda.zov/m!dwatch. 
------DRVC ~11J\ACTION5----­
Reml roxidry 1\ilto w:ed ill c<mbinltioo 11irh ruplatio (5.8). 
----USE !NSFEC1FICPOPUUTIONS----
~ 
LiDtired bma.1n data;B~elllympbO<)'opema ocomd ill 
lllf:m:s "'JXl'ed m 
utero (S I). 
Gfli.'iric U;e: II> Cll !>'tiW> older t1w1 70 ytm or ago. explo~Utol)' 
wl)'SeiSUGest no beuefi! \\lth the Jddttioo ofRinruo to FC (8.5). 
S..l11or PA TIE~'T COlJ)ISIL!NG l!iFOR.\L-\TION •ad Mtdicatioa 
Guidt. 
R!l'istd: 0&'2014 


MedImmune
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Flll.l PRESCRIBISC L\TOIUIATIOS: COllii:NTS' 
WAR.'I'ISC: FATAL L\Jt'SIOX RL\CI10l\S, SE\"DU: 
lWCOCUTA.\'EOt'S RIACI10l\S, HEPATITIS 8 \'IRUS 
RUC'm'ATIOX••PROCRLSSIHlllllmOCAL 
I.It'KOEXCUHALOPAlliY(I'lQ.) 
I L\'DICA TIOl\S A.'iD l>..I.Ct 
II ~'•Lyq>bom(XIll.) 
12 0... L)lll[llloc)1lc l.M..,..(CU) 
lJ R.lltummd A111rlm(RA) 
14 
~10!11111l11Poi)'Upllii (GPA)(Wt,•toors 
Gruu!ocwow) adMICIOKcpic Pol)u:i-'lil (MPA) 
1..1 
U..:ts!!Omotliw 
DOSACt A.'iD ADllL\lSTRA110S 
ll Admm:JnDOD 
ll 
Rlclllllmtlldld 0... fer N..,.l!od&im' s L yq>ilam 
(Nl!l.) 
l.l 
Roc~O... fer C1IIOnic Lyu:;:il«juc 
IAuktmiJ (Cll) 
2.4 
Roc~O...ouC'~to!Zflm•far 
lltOIDIIDI ofl\'lll 
2.5 
Roc~ 
0... fer Rbtum:uoid Anllrilll (RA) 
2.6 
Roc~ 
0... fer Gnnulo1D3101il ~ilb 
Pol~m (GPA) (Wtttner'• OronulooJ:i:oli•) lllld 
MiciOICopic PolyiiJIIliti• CIIPA) 
2.7 
RlcCIIIUDlllded Co:.:o .. lllllt M!dicodom 
2.8 
Prtparatioo fcr Admiltiltrllion 
J DOSAGE FOIUIS Ml> S'IRDiCTHS 
4 COXl'IL\ISDICATIOSS 
S WARNINC$ AND PRECAUTIONS 
5.1 
ltiClnJOD IWctlooli 
5.2 
Sfl'flt Mll<OCUIIDIOUI Ruc1iool 
5.3 
illplnlll 8 V'INI (I!B\1) R.tactil·lllOD 
5.4 
Ptopt~111dlltltifoal I..Moactpbalopa:lly (PM!.) 
5..1 
1\lmor!.ysH~)'·t-(IU) 
s 6 
l'lttctl .... 
5.1 
Criol'll<llllr 
5.a Rail 
5.9 8on1 ~~~~~~ Prinlloo 
S.IO ~ 
5.11 
Ubonloly~~ 
5.12 CCIICGIIIIIII liw 1l'l1l BioJop: Apots IIIII 
DMARDS oct. tmaM•dromu:t mRA. GPA ad 
~A 
5.13 Uw mRA p,,.,. \\'!lo 1!1\<t Nclllbd Pn« 
~ 
Rllpacw 10 1\lmor Ntmm Ft<10r 
(00).~ 
S.l4 :RmmommPI!itoam~111111 
Pci)~(GPA)(Wo;ar't~)ud 
}licJo.ccpic Pclyl:lplm ()IPA) 
' ADVERSE REACTIOSS 
6.1 
O:cia!Tn.lls~tmL)~~IIh;:laaH 
61 
C1::11ita1 Tmls UporitDCt t1 Rlloa!!wald Mlrul1 
63 
ct:ciaJ Tti>h Upolim:t m Gnraloawo\u •1111 
PciJ'11l:J!tS (GP.~ (We:-'• Gncla!ocuiOni) ud 
~OO..Ccpic ~!!!! ()IPA) 
6.4 
lll:t!tltooti!IICit)' 
6..1 
l'olmwt~ Expeneoct 
7 DRUG INTERACTIONS 
I USE IN SPECIFIC POPULATIONS 
8.1 
:Pre~ 
8J 
N~nm; ~Wdlm 
8. 4 Pediatric Uu 
8.S 
(;eriatric Use 
10 OVERDOSAGE 
11 DESCRIPTION 
12 CLIN:ICAL PHAR~IACOLOGY 
12.1 l1ecmi!Jllo!Acrlo• 
12.2 Pbannxod)u.lmio 
12.3 Pbannxokinotics 
1J NONCL!NICAL TOXICOLOGY 
. 
13.1 C II!Cinoten!ili, ~!uu,.,..;,, lmplumout ofF 11111ity 
14 CLINICAL STUDIES 
14.1 ~or 
Rmc!OIJ', Low·Gndur Follicullt, 
cmo-P.,.ith'f, B.C.II Nlll. 
14.2 PmiDitlly Utltm.ltd, Low-Gndt or Follicttlar, 
CD2()..P"'iln'f, B.Ctll Nlll. 
14.3 D1W!t Lr,t B.ctliNIII. (DLBCL) 
14.4 l\lllety·Mioulf Inm!iaH ill Prtnomly lit~:rt~r.d 
FollicW Nlll. mel DL.Ba. 
14.5 <b:tl:lic Lym;itoiC)'tiC l..t!ll:l!lllll (Cll) 
14.6 :Rlmm:Dld Al1hrilis (RA) 
14.7 Ga:mloa:llom 111111 ~~~~ 
(GPA) (\\'tpoor't 
<ln:mlcm:.1lom) DI~OO..C.pc Polycplns()IPA) 
I' BOW SUPPLIED/STOIUCE A.'ID HA.'IDLING 
17 PATIENT COUNSELING INFOUIATJON 
'Seaioosar~CIItttedblllllf filii~ tllfcrmaDat1 .. 
"'"!imd. 


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FULL PRESCRIBING I!';TOIULUI0:-1 
WARL'I'ING: F.-\ TAL ll'<TUSION RHCTIO:-!S, SE' UU: MUCOCUHNEOUS 
RHCTIO:-!S. HEPATITIS B HRUS REACffi'A liON and PROGRESSIYE 
. MliLillOCALLHIKOENCEPHALOPATHY 
Infusion Rtactions 
Rihtun administration cnn l'tsult in stlious, including fatal infusioo ructions. Deaths 
n1thin 2~ bonr.s ofRituxan infmion ban occmnd. Appro:tim.1ttly 80% of £1tnl infmion 
l'tactiom o<eWTtd in association nitb tht fi1~t infusion. Moniio1· patitntl closely. Disconrinut 
Rinuan inlU'iion for snere nacdoll'i and pro\ ide medical treahnent for Grade 3 or ~ infusion 
l'tacriolt< (see Wnmi11gs n11d Precn111iollt (5.1), Adn•ne Rencfiom (6.1)]. 
Serere Mucocutant"Ous Rtactions 
Senn·, indudin; f.1ta~ mucocutanf'Ous reactions c-an oc·cur in patients nc.ehing Rituun 
(see Wnmi11gs n11d Precn11tiorlt (5.1), Ado·trli Renctiorlt (6)]. 
Hepatitis B Yi1111 <HB') RuctiYntioo 
HBY l'tncti,·ation cnn oocw· in paritnts irtaitd nitb Rinnan, in .1om• cMts mulring in 
fuhninant htpadti1, btpatic failnrt, and dtath. Scrttn nil patitntl fo1· HBY inftction htfort 
h't"ahntnt initiation, and monitor patitnt~; dutin; and afte-r h't"ahntnt nith RitUian. 
Di;courinu• Rinuao and concomitaot mtdicatious in tbt twni of HBY l'tactintion (see 
Wami11gs n11d Precn11tioru (S.J), .~d ... erse Rencrioru (6)]. 
Pro:r•ssiw Mulrlfocal Ltukotuctpbalopatby (PAIL), iodudio: fatal P~IL, cao occur in 
paritntl rtcthiof Rituxan (see fl'nmill.ft n11d Precn111iollt (5.4), Ad•·"" Renctio111 (6)]. 
l 
INDICATIONS .-\1\'D US.-\GE 
l.l 
Non-Hodgkin's L)1nphoma ~lU.) 
RihL'<311< (ritmcimab) is indicated for the treatment of patients "ith: 
Rtlapsed or refractocy, low-grndt or follicular, CD20-positive, B-001 NHL as a single a gmt 
Pre\iously untreated folliet~ar, CD20-positive, B-cell NHL in cOlllbination nith lint line 
chemotherapy and, in patieJlls ac.bieving a complete or panial response to Ritman in 
combination \\ith chemotherapy, as sin$le-agent maintenance thernpy. 
Non-progressing (including stable disease), low-grndt, CD20-positi\>e, B«D NHL as a single 
agent after firnt-line CVP cbtmothtrnpy 
Pre\iously llDlreattd diffuse large B-ceU, CD20-positive NHL in combination with CHOP or 
other antluacydine-based chemotherapy regimens 
1.2 
Chronic L~mphocyric Ltukemia (CLL) 
Ritu'UUI' (rinc-omab) is indicated, in combination with fludmbint and cyclophosphamide (FC), 
for the treatment of patients with prtviously lmtre.ated and pre,iously treated CD20.positive CLL. 
lJ 
RheUIIloioid Arthritis (RA) 
Ritm<ror (ritll'<imab) in combination \\i!h methotrexate is indicated for the. treatment ofodult 
patients \\i!h moderately. to severtJy. active rheumatoid artluitis who have had an inadequate 
response to one or more ThT antagonist tberapits. 
U 
G•·anulomnto.~is \\itb Pol~·angiitis (GPA) (\Vegene1·'.1 Gronulomaiosil) nnd Micro.~eopic 
Polyongiiris (MPA) 
Ritm<ror (rillt'<imab), in combination \\i!h glucocorticoids, is indicated for the treatment of adult 
patients \\i!h Granulomatosis "' !h Polyangiitis (GPA) (Wegener's Granulomatosis) and Microscopic 
Polyangiitis (MP A). 
1.5 
Umiiarions ofU.~e 
Rilllxall is not reeollllll<Ddtd for use in patients with sev•re, active. infections. 


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2 
DOSAGE AND ADAUNISTRUION 
2.1 
Administration 
Administer only as an Intr.l\'enous Infusion [see Dosage and Adminislraff<»l (2.7)]. 
Do not administer as an in1Iavenons push or bolus. 
Premtdicate before each infusioo [see Dosaf.e ru1d Admillislraffon (2. 7)]. 
Rituxllll. should only be administered by a healtbcare prof~siooal with apprOI)riate medical 
support to mana~e severe infusioo reactions that can be fatal if they occur [see Wami11gs m1d 
Precmtffons (5.1)]. 
Fh~t Iulmion: Initiate infusion at a rate of 50 mglbr. In the absence of infusion toxicity, 
increase infusion rate by 50 mgllu: increweuts "''ery 3() minute$, to a maxinnun of 400 mgllu:. 
Subsoqutni Infusions: 
Sta11dard lnfiai<»•: Initiate infusiooat a rate of 100 OJ&'hr. In the absence of infusion toxicity, 
increase rate by 100 mglbr increments at 30-mhmte intervals, to a ma:<innun of 400 "'&'l>r. 
For previously un/Tealed follicular NHL ru1d DI.BCL paffentr: 
If patients did not e'-perienoe a Grade 3 or 4 infusion related adverse event during Cycle 1, a 
90-mintrte infusi011 can be administered in Cycle 2 wiih a glucocorticoid-containing 
c.hemotherapy re~t 
hlitiate at a rate of20% of dte total dose given in the first 30 minutes aud the remaiuiug 80'!. 
of the total dose given over the next 60 mhmtes. If the 90-minllle infusion is tolerated in 
Cycle 2, the same rate can be used when administering the remainder of the treatment 
regimen (thr011gh Cycle 6 or 8). 
Patients who have clinically si!"ificant cardiovasctdar disease or who have a circnlating 
lympbocyte count :;:5000/mm' before Cycle 2 should not be administered the 90-milmte 
infhsion [see Clinical Studies (14.4)). 
Intemlpt the infusion or slow the infusion rate for infusion reactions [see Boxed Waming, 
Warnings ru1d Prccaudons (5.1)). Continue the inftJSion at one-half the pre•ious rate upon 
inlprovement of symptolllS. 
2.2 
Recomm•nd•d Dost for Non-Hod:kin's LJmphomo (NHL) 
The recommended dose is 3751llfim1 as an intravenous infusion according to the following 
schedules: 
RtL1p.s«l or Rtft·actot~·, l olV-Gudt or Folli<ular, •C:D~O-Po1irin, B-C:t ll NHl 
Administer once weekly for 4 or 8 doses. 
Rtn·.anntni for Rtbps«l or Rtft'llctoo~·, Low-Gradt or F olticu1ar, C:O:O-Positin, 
B-C•Il NHl 
Administer once weekly for4 doses. 
Pmiously Untr•ated, FollimL•r, CD20-Posith·•, B-Ctll NHl 
Administer on Day 1 of each qde of d ttmotherapy, for tlp to 8 doses. In patieuts "'th 
COillplete or portia! response, initiate Rittc.ru> maintenllll.Ce eight weeks following completion 
ofRittL-.an in combination \\1th chemotherapy. Administer RillL'<llll as a single-agent every 8 
weeks for 12 doses. 
Non-p1·ogre.'ising, Low-Grade, CD·lO-Positin•, B-ce11 NID..-, after fi1-st-line C\ "P 
cbtonotbtrap~· 
Follo\\iug oorupletion of 6-8 C}des ofCVP chemothtrapy, administer OllC< weekly for 
4 doses at 6-month intervals to a ma'<imtnn of 16 dos~. 
Diffnse l ar;e B-C•Il NHl 
Administer on Day 1 of each qde of chemotherapy fur up to 8 inftJSion<. 
2.3 
Recommtnded Dost for Chronic L~1nphocytic Lt·uktoni.1 (Cll) 
The rteollllllt.llded dose is: 
375 OJ&'m2 the day prior to the initiation ofFC cllelllOtherapy, then 500 OJ&'m2 on Day 1 of 
cycles 2-6 (eveoy 28 days). 


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U 
Rtcomrntndtd !)()se •s • Cornpontnt of :zt,·olio• for n·eonntnt of N'HL 
Infuse rituximab 250 tntJrn' \\1thin 4 boon prior to lhe odministtation of 
lndiwn-111-(ln-111-) Zevalin and "' thin 4 boon prior to the administration of 
Yttritun-90- {Y-90-) Zevalin. 
Administer Riruxan and In-111-Zevalin 7-9 days prior to RittL-.an and Y-90- Ze\'lllin. 
Refer to the Zevalin padage insert for full prescribing infonnation regarding the Zevalin 
thernpeutic regimeJt 
2.5 
Rtcormntodtd !)()se for Rht mn..roid At·thritil (RA) 
Administer Riruxan as twa-I 000 tug inttavenous infusions separnted by 2 weeb. 
Glucocorticoids administered as methylprednisolone 100 tug intravenous or its equivalent 
30 mimrtes prior to each infusion are recotlllllfluled to reduce the incidence and severity of 
infusion reactions. 
Subsequent courses should be administered e\'tty 24 weeks or based on clinical evaluation, 
but not sooner lhan every 16 weeks. 
Riruxan is given in combination 1\ilh rnethotre.••te . 
2.6 
Rttornmended !)()se for Granulom31osis \\ith Pol~·au,<>iltil (GP.\) (Wegener's 
Gt'ant~otn.1tt"is) and Micr·oscopic Polyangiiris (MPA) 
• 
Administer Riruxan as a 375 tntJm' inttavenous infusion once weekly for 4 weeks. 
Glucocorticoids admini:;tered as methylprednisolone I 000 rug inttavenoosly per day for I to 3 
days followed by ornl prednisone l mglkg day (not to exceed 80 mgday and t•pered per 
clinical need) are recollllnellded to treat severe vasculitis symptoms. This regimen sboold 
begin 1\ithin 14 days prior to or 1\ith lhe initiation ofRittL-.au and may continue during and 
after lhe 4 week course of RiMcimab treatment 
Safety and efficacy of treatment \\ilh subsequent co=es ofRittt'<llll have not been established 
[seell'amings and Precautio11s (5.14)), 
2. 7 
R«ommtndtd Conromirant Aledicarions 
Premedicate before each infusion \\ith acetaminophen and an antihistamine. For patients 
administered Rittt"Wl according to the 90-minute infusion rote, the glucocorticoid component of 
their chemolherapy regimen shot~d be administered prior to infusion [su Cli11iral Slttdics (14.4)), 
For RA patients, methylprednisolone 100 mg inttavenously or its equivalent is recollllnellded 30 
minutes prior to each infusion. 
For GPA and MP A patients, gluc.oc.orticoids are given in combination with RittL-.au [see Dosage 
and Admillistralion (2.6)]. 
PneunlOC}~tis jiroveci pneumonia (PCP) and anti-ha]l"tic viral prophylaxis is recoUlllleJuled for 
patieuts \\1lb CU during treatment and for up to 12 montbs follml1ng treatment as appropriate. 
PCP prophyla.xis is also recommended for patieuts \\1th GPA and MPA dluiug treatment and for 
at least 6 months following lhe last Ritu.-.au infusion. 
2.8 
Pr·tparation for A<iminisn·atioo 
Use appropriate aseptic. teclmique. Parenteral dnrg products shot~d be inspected •isually for 
particulate matler and discoloration prior to administtatioJt Do not use \W if particulates or 
discoloration is preseut. Withdraw the necessary amount of Ritttxan and dilute to a final 
concenttation of I mglmL to 4 nWmi. in an infusion bag containing either 0_9'/. Soditun Chloride, 
USP, or 5% Dextrose in Water, IJSP. Gently in,·ert the bag to mix tbe solution. !)() not mi' or 
dilute l>ith otber drugs. Discard any unused portion left in tbe vial. 
Rintxan solutious for infusion may be stored at r c-s·c (36•f -46•F) for24 hm~n. Rinwn 
solutions for infusion have been shown to be st:tble for an additioual24 hours at room tempernture. 
However, since Riruxan solmions do not contain a preservative, diluted solutious shot~d be stored 
refrigerated (2'C-8' C). No incompatibilities between RittL-.an and polyvinylchloride or 
polyethylene bags have been observed. 


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3 
DOSAGE FORI\ 1) Ai'I'D SlR.ENGTHS 
Injection: 
100 mgiO mL in a single-use vial 
• 500 mg50 mL in a single-use 11al 
4 
CO=-<IRAINDICATIONS 
None. 
5 
WAR.~GS AND PRI:CAUTIO:"'S 
5.1 
Infusion Rucriolls 
Rillc'Wl can caust severt, including fatal, infusion reactious. Severe rtactions !)pic ally occwred 
during lhe fust infusion \\1th lime to onset of 30-120 minutes. RillL'Wl-induced infusion reaetious 
and sequelae include •ltticma, hypotension, angioedema, b)')lOxia, bronchOSJl"Sm, pulmonaJ)• 
infiltrates, acute respiratory distr.ss S)'lldrome, myocardial infarction, ventria~ar fibrillation, 
cardiogenic shock, anaph)iactoid events, or death. 
fumedicate patients \\1th an antihistamine and acetaminophen prior to dosing. For RA patients, 
methylprednisolone I 00 mg intravenously or its equivalent is recommended 30 minutes prior to each 
infitsion Institute medical management (eg. glucocorticoids, epinephrine, bronchodilators, or 
oxygen) for infusion reactions as needed Depending on lhe. severity of the infusion ~taction and the. 
required interventions, temporarily or pennanendy discontinue Rittt-.an. Resume. infusion at a 
mininmrn 50% reduction in rate after symptoms have resolved. Closely monitor the. foU01viug 
patients: those "ith pre-existing cardiac or pt~ruuy co9ditions, those who e:<perieuced prior 
cardiopl~nroy adverse reactions, and those with higb muubers of ciradatiug malignant cells 
(>25,000/nuu1). [See Boxed Waming, n1m11ings m1d l'J·ec4uliotl!i (5.7), Advme ReactiOIJS (6.1)). 
5.2 
Senrt !\lucocutantom Reactions 
Mucocutaneous reactions, some \\~th fatal outcome, c.a:n oca.u in patients treated \\ith Rituxan. 
These reactions include paraneoplastic pemphi$(JS, Stevens-Jolmson S)'Udrome, lichenoid dermatitis, 
vesia dolmllous demJatitis, and toxic epidemJa! necrol}~is. The onset of these reactions bas been 
variable and includes repotts "ith onset on the first day ofRi!LL'au exposure. Discoutiime Rittc'au 
in patients who experience a severe DlllCOeulaneous reactimt The safety of readotiuistration of 
Rituxau to patients "ith severe mucocutaneous reactimtS has not been determined [S<e Boxed 
Waming; Adverse &actions (6,1). 
5.3 
Hepatitis B \'iru.• Reacti, .. rion 
Hepatitis B vinJS (HBV) reactivation, in some cases restdtiug in fulminant hepatitis, hepatic 
failure and death, can oectu in patients treated with dmgs classified as CD20-directed cytolytic 
antibodies, including RillL'Wl. Cases ha1>e been reponed in patients who are hepatitis B surface 
antigen. (HBsAg) positive and also in patients who are HBsAg negative but are hepatitis B core 
antibody (anti-HBc) positive, Reactivation abo has occlUTed in patients who appear to have 
resolved hepatitis B infection (i.e,, HBsAg negative, anti-HBc positive and hepatitis B surface 
antibody [anti-HBs) positive). 
HBV reactivation is defmed as an abmpt increase in HBV replication manifesting as a rapid 
incrM~ in serum HBV DNA level or detection ofHBsAg in a person who was previously HBsAg 
negative and anti-HBc positive. Rtaetivation ofHBV replication is often followed by hepatitis, i.e., 
incrM~ in transaminase ltl'eh. In severe cases increase iln bilimbin levels, liver failure, and death 
can oocur. 
Screen all patients for HBV infection by meaSluing HBsAg and auti-HBc before initiating 
treatruent with RillL'Wl. For patients who show evidence of prior hepatitis B infec.tion (HBsAg 
positive [rtgardless of antibody status I or HBsAg Utgative but auti-HBc positive), coDSl~t \\1th 
physicians with expertise in managing hepatitis B rtgarding monitoring and cousidention for HBV 
auti11fal therapy before and/or dtuing Rilltxan treatruent. 


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Motritor patients "ith evidence of cturent or prior HBV infection for clitrical and laboratory sigus 
of hepatitis or HBV reacth'tltion during and for severn! months following Ritu.'Ulll therapy. HBV 
reactivation has been reported up to 24 months following completion of Riht'<lllt therapy. 
In patients who devdop reactivation of HBV while on RitlllWl, inunediatdy discontinue Rituxan 
and any concomitant chernotherapy, and institltte appropriate trealment. Insufficient data exist 
regarding the safety of resuming Rittt-.an in patients who develop HBV reactivation. ReSUllljltion of 
Rituxan in patient' whose HBV reactivation resolves should be discussed with physicians with 
e'-pertise in mana~ 
hepatitis B. [See Bomlll'amhtg, Advem Reacliom (6)] 
5.~ 
Pt·ogrmin Multifocal Ltukotncephalopathy (PAIL) 
JC >irus infection resulting in PML and death can oectrr in Ritu.'<ll!l-treated patients with 
hematologic malignancies on1ith autoimmune diseases. The majority of patients ~>ith hematologic 
mlilignlmcies diagnosed \\ith PML received Ritu.xan in combinsti011 with chemotherapy or as part of 
a hematopoietic stem cell transplant. The patients with autoinmnu.e diseases had prior or cooourent 
immunosuppressive therapy. Most cases ofPML \\ere diagnosed \\ithin 12 months of their last 
infusion of Ritu.-.an 
Con1ider the diagnosis ofPML in any patient presenting 1vith new-ono;et neurologic 
manifestations. Evalu.,tion of PML indndes, but is not limited to, cotlSl~tation 11ith a ne11tologis~ 
brain MRI, and lumbar po.mctlu:e. Discontinue Rituxan and con~ider discontim~ation or reduction of 
any concomitant chemotherapy or immunosuppressive therapy in patients who develop PML [See 
Boxed Jl'm11it1g, .4dverse Reactions (6)]. 
5.5 
Tmnor Ll'sil S\'Julrome (lLS) 
Acute renal faiiure,liyped<alenria, h)]X>Calcemia, hypenuicenria, or hyperphosphatenria from 
hu:nOr lysis, some falliL can occur 11ithin 12-24 homs after the first infusi011 of Rituxan in patients 
with NHL A high number of cir~ating maliguatu cells (• 25,0001~ or high hllllOr btrrde1~ 
confers a greater lis!: of TLS. 
Administer aggressive intravenous hydration and anri-hyperuricenric therapy in patients at high 
risk for TLS. Correct electrol)1e ab110rmalitie>, monitor renal t\mction and fhtid balance, and 
administer supportive care, including dialysis as indicated. [See Wm?Jings aJJd Pl'Ccaurioii.S (5.8), 
Adn•·se Rcaclio11s (6)]. 
5.6 
Inftctions 
Serious, includirtg fatal, bacterial, t\utgal, and new or reactivated 1iral infections can occm during 
and foll01ving the completion ofRitu.xan-bao'.ed therapy. Infections have been reported in some 
patielrts \\lth prolooged h}pogammaglo~inenria (defmed as hypogannnaglo~inemia :>II months 
after ritllXimab e•posure). New or reactivated viral infections included c)1omegaloviru>, herpes 
simplex 1irus, pan'OI<irus Bl9, varicella zoster 1irus, West Nile virus, and hepatitis Band C. 
Discontinue Rituxan for serious infection~ and irutiMe appropriate anti-infective tl1erapy. [See 
Advem Reaclio11s (6, 6.1)]. 
5. 7 
CardiovaS>Cular 
Discontinue infusions for serious or life-threatening cardiac arrhythmias. Perform cardiac 
monitoring during and after all infusions of Riht-.an for patients who de~•elop clitricaUy si~6cant 
arrhythmias, or who hal'e a history of anhythmia or angina. [See Adl•et!e Reactions (6)]. 
5.8 
Rtnal 
Severe, including fatal, renal toxicity can occur after Ritu.'Ulll administration in patients 1\ith NHL. 
Renal toxicity has occurred in patients who experience h1rllor lysis syndrome and in patients with 
NHL administered concomitant cisplatin therapy during clitrical trials. The combination of cisplatin 
and Ritttxan is not an appro led treatment regimen. Monitor doo;ely for sigus of renal f.'lilure and 
discotrtinue Ritu.xan in patietrts \\ltlta rising serurn creatinine or oliguria. [See JJ'm?JiJJgs mill 
Pl~cautioJJs (5.5)]. 
5.9 
Bowel Obst111crion and Perforation 
Abdominal pa~ bowel obstruction and perforation, in some cases leading to death, can occm in 
patierus recei1ing Rituxan in combinati011 with chemotherapy. In postrn.vketing reports, the mean 


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time to documented gastrourtestinal perforation was 6 (Illl~e. l-77} days in patients w1th NHI.. 
Evaluate if symptolllS of obstmction suc.h as abdominal pam or repeated vomiting occtn. 
[S.. Mn.-se Rcactio11s (6)]. 
5.10 
Immunization 
The safety of immunization with live wal vaccines following Ritu.'<llll therapy has not been 
sn«lied and vaccination with live wm vaccines is not recollllllf2lded. 
For RA patients, ph)~icians shm~d follow ctllfenl immtmiza~on guideliMs and administer 
non-live \'llccines at least 4 weeks prior to a crurse ofRitu.<an. 
The effect ofRint<an on inmnme responses was assessed in • randomized, controlled study in 
patients w1th R..J\ treated w1th Ritu.<an and medtotre<ate (MD..') compared to patients treated with 
MTXaloue. 
A respo~ 
to pneumococcal \'3ctination (aT -cell independent antigen) as measured by an 
increase in antibody titer.; to at least 6 of 12 serotypes was lower in patients treated with Rituxan 
plus MIX as compared to patients treated with MIX alone (19'!. '~- 61 %). A lower proportion of 
patients in the Ritwtan plus MIX grm1p developed detectable levels of anti-keyhole limpet 
hemocyanin antibodies (a no1•el protein antigeu) after \'tlccination compared to patieuts on MIX 
alone (47% vs. 93%). 
A positive response to tetanllS toxoid vaccine (a T <ell deper.dent antigen with existing innnuuity) 
was similar in patients treated with RinOOUI plus MIX compare.-! to patients on MIX alone (39% vs. 
42%). The proportion of patients mainlaining a positi1·e Candida sl:in test (to evaluate delayed type 
hypmensitivity) was also similar (77% of patients on Ritmc:m plus MIX vs. 70'/o of patients on 
MTXalone). 
Most patients in the Rit\llCllll-treated ~up had B<ell counts below the lower limit of nonnal at 
the time of immtmization. The clinical unplications of these findings are not kno"u. 
5.11 
L1boratory Monitotino 
In patients with i}llljlhoid malignancies, during treatment w1th Ritwtan monotherapy, obtain 
complete blood counts (CBC) and platelet cmmts prior to each Ritwtan COilJse. During treatment 
with Rillt<an and chemotherapy, obtain CBC and platelet cotum at weekly to monthly intervals and 
more frequendy in patients who dtvelop C)1openias [S..Advcr~e Rcaciiom (6.1)]. In patients \\1th 
RA, GPA or MPA, obtllin CBC and plattltt cmmts at two to four month intm'llls dllJing Ritu.'C.'ID 
therapy. The dllJation of C)1openias caused by Rint<an can extend montru beyond the treatment 
period. 
5.12 
Concomitant Us• "i th Biologic Ag•nts and DU'\RDS other th.1n M•thotr•x•t• in R..'\, 
GP.-1. and MPA 
Umited datll are m lilable on the safety of the me ofbiologic agents or D~s 
other than 
methotre.<ate in RA patients exhibiting peripheral B-<:ell depletion following treatment \\1th 
ritu.'Cim.1b. Obstn-e patients closely for signs of infection ifbiO:ogic agents and/or DMARDs are 
used concomitruilly. Us. of concomitant inmnmosuppressants other than corticosteroids has not 
been studied in GPA or MPA patients exhibiting peripheral B-c.U depletion following treatment 
with Ritttxan. 
5.13 
Ust in R..'\ Pati•nts Who Han Not Had Prior Inad•quat• R•sponst to Tumor N•rrosis 
Factor (INF) Antagonists 
While the efficacy ofRitlt<an was st~pported in four controlled nials in patients \\1th RA with 
prior inadequate responses to llOU-biologic DMARDs, and in a controlled nial in MIX-naive 
patients, a favorable risl:-beuefit relationship has oot been established in thest popt~ations . The use 
ofRittL<an in patients with RA who have not had prior inadeqt11.te resporne to one or more TNF 
antagonists is oot recommended [S.. Clinical Studi•s (14.6)]. 


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S.U 
R<ll'eatmeot in Patients 11itb Granulomatosis 11itb Polyaogiitis (GPA) (Wegener's 
GI'Ootdomatosis) and Micr·oscopk Polyangiitis (MPA) 
Limited data are available on the safe.ty and efficacy of subsequent courses of Rituxan in patients 
with GPA and MPA. The safety aud efficacy ofretreatment ~>ith Ritu.WJ have not been established 
[Sell Dosage and AdmiJtish't!lion (1.6), Adl•ct!e Reactions (6.3), and Clinical Shunas (14.7)]. 
6 
AD\LRSE REACTIONS 
The follo~>iug serious adver.:e reactions art. discussed in greater detail in other sections of tile 
labeling; 
Inf\uion reactions [see Wm11ittgs mill Pt-e(autious (5.1)] 
Mucocutaneous reactions [see Wamiugs and Pt"ecauriou.s (5.2)] 
Hepatitis B reactivation \\1th fulminant bepatitis [see Warnings and Prccauiions (5.3)] 
Progressive nndtifocal leukoencephalopathy [see Wmnings and PIY!CI111rions (5.4)] 
Tumor lysis S)'tldrome [see Wamings mill Precautions (5.5)] 
Infectious [see Wm11ings mill Pt"eCmliiOIJS (5.6)] 
Cardiac arrhytltmias [see Wamiugs mill Pt·ecm11i011S (5. 7)] 
Renal toxicity [see Wm11h1gs mill Ptwm1ii01u (.5.8)] 
Bowel obstruction and perforation [ree Wm11i11gs mill Pt"eCmlliOIIS (5.9)] 
The most conunon ad1oerse re.actions of Rituxan (incidence k25%) observed in clinical trials of 
patients \\1tb NHL were infusion reactions, fever, lymphopenia, chills, infection, and asthenia. 
The most conunon ad1oerse reactions ofRituxan (incidence >25%) observed in clinical trials of 
patients \\1th CU. were: infusion reoctions and neutropenia. 
6.1 
Cliniral Ttials Eiptt·ience in L~1nphoid M:illgtLtncies 
Beca11.1e clinical trials are condiJCted 1utder widely varying conditions, adverse reaction rates 
observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of 
anotber drug and may not reflect the rates obsm•ed in clinical practice. 
The data described below reflect e.\')lOS\Jre to Ritu.WJ in 2783 patients, \\1th exposures ran@ng 
from a single infmion up to 2 years. RituWJ was studied in both single-arm and controlled trillls 
(11=356 and »=2427). The population included 1180 patients witil low grade or folli<War lymphoma, 
927 patients with DLBCL, and 676 patients \\ith CU. Most NHL patients received Rituxan as an 
infmion of375 nt(}m' per infusion, given as a single agent weekly for up to 8 doses, in combination 
witil cht1110tberapy for up to 8 doses, or foll01'iug cilemotherapy for up to 16 doses. CU. patients 
received Ritu.WJ 375 Wflrri as an initial infu;ion foll01ved by 500 mdm' for up to 5 doses, in 
combination \\1th ftudarabine and cyclophosphamide. Seventy-one percent of ClL patients received 
6 cycles and 90'!. received at least 3 cycles ofRituxan-based therapy. 
lltfUJion &IKiions 
In t1te majority of patie-Jlts \\~th ~ 
infttsion reactions consisting of fever, chills/rigors, nausea, 
pnuitus, angioedema, hypotension, headache, bronchospasm, 1u1icruia, rash, vomiting, mylllgia, 
dizzints~. or hypertension occurred during the fii'St Rincun infusion. Infusion reaction~ typically 
oocuned \\llhin 30 to 120 minutes of beginning the first infusion and resolved \\lth slo\\iug or 
intemtption of the Rituxan infiuion and ~>ith supportive care (diphenhydramine, acetaminophen, and 
intravenous saline). The incidence of infusion reactions was highest during the fust infi.sion (77%) 
and decreased with eat.b subsequent infusio1t [Sell Boxed 1'11m1lillg, Wm'llings and 
Pt-ecauffotu (5.1)]. In patients with pre11ously untreated follietdar NHL or previ011.1ly IDltreated 
DLBCL, wbo did not e.\'perience a Grade 3 or 4 infusion-related reaction in Cyde I and received a 
90-minute infusion ofRiiiL'lan at Cycle 2, rlte incidence of Grade 3-4 in1i1Sio11-related reactions on 
the day of, or day after tile infusion wa> 1.1% (95% CI [0.3%, 2.8%]). For Cycles 2-8, the incidence 
of Grade 3-4 in1i1~ion reactions on the day of or day after the 90-minute infusion, was 2.8% (95% Cl 
[J.W~ 5.0%]). [See JJ'amings and Precaurions (5.1), ClitJical Sh1dies (14.4)]. 


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Infections 
Serious infections (NCI CTCAE Grade 3 or 4), including sepsis, occurred in less than 5% of 
patients with NHL in lhe sing!Ml'lll studies. The overall incideuct of infections was 31% (bacterial 
19"/o, viru 10%, unkno1w 6%, and fungal 1 %). [See Wami11~ ol!Jd Pl·ecaurimu (5.4), (5.5), (5.6)). 
In randawized, controlled studies where Ritlruul was administered following chemotherapy for 
the trealnlfnt of folliCidar or low-grade NHL, d1e rate of infection wa; higher among patiem; who 
recei1oed Ritu.'Wl. In diffuse large B«lll)'llphoma patienls, viral infections occurred more 
frequently in those who ~ved Rincwt 
Cytopenia: and h)pogammaglobulinemia 
In patients with NHL receiving ritu.'timab monotherapy, NCI-CTC Grade 3 and 4 cytopenias were 
reported in 48% of patients. These included lymphopenia (40%), neutropenia (6%), leukopenia 
( 4%), anemi' (3%), and thromboc.j1openia (:!"!.). The median duration of lymphopenia was 14 days 
(range, 1- 588 da}~) and of neutropenia wa; 13 day• (range, 2- 116 day>). A single OCC\UTellCe of 
transient aplastic anemia (pure red cell aplasia) and two occurra~ees ofhemol}1ic anemia following 
Rituxau therapy occurred during the ;ingle-arru studie;. 
In ;tudies ofmouothernpy, Rincun-induced B-cell depletion occurred in 70% to 80% of patients 
withNHL. O.Crtased IgM andlgG serum levels OCCII!I'ed in 14%ofthese patiems. 
In Cll. :rials, the frequency of prolonged neutropenia and !ale-onset neutropenia was higher in 
patients treated "ith R-FC collljlared to patients treated "ith FC. Prolonged neutropenia is defined 
as Grade 3-4 neutropenia that has not resolved between 24 and t2 days after the last dose of study 
treatment. late-onset neutropenia is defined a; Grade 3-4 neutropenia starting at least 42 da)~ after 
the last treatment dose. 
In patients ,.;lh pre1oausly \llltreated Cll, the frequency of prolonged neutropenia was 8.5% for 
patiems who received R-FC 0>=402) and 5.8% for patients who received FC (n=398). In patients 
who did not have prolonged neutropenia, tl.e frequency oflate-onset neutropenia was 14.8% of209 
patients w~o received R-FC and 43% of230 patients who recei1oed FC. 
For patitnts \\ith prMously treated CU., the freq1lfllcy of prolonged neutropenia was 24.8% for 
patients w~o received R-FC {n=274) and 19.1% for patients who rteelved FC {n=274). In patiems 
who did not have .l"olonged neutropenia, the frequency of late-onset neutropenia was 38.7% in 160 
patients \\olio receiVed R-FC and 13.6% of 147 patients who received FC. 
Relapsed a· Rsjinc/01)\ LollcGinde NHL 
Adverse reactions in Table I OCCIUTed in 356 patients with relapsed or refractory, low-grade or 
follicular, CD20-positive, B<ell NHL treated in single-arm studies of RittL'Oill administered as a 
;ingle agent [SeB Clhlical SiudiGS (14.1)). Most patients received Ritu.'Wl 375 mg/m2 weel:ly for 
4 doses. 


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Tablt 1 
Incidence of Advw..e Reactions in ~5% of 
Patients with Relapsed or Refractory, Low-Grade or FoUi<1dar 
NHL. R!ceiving Single~gent RittLwt (N.356)""' 
Body as a \\+bole 
!6 
10 
Fe\-er 
53 
1 
Chilh 
)) 
J 
ln!e<nou 
31 
4 
AldlaWI 
26 
I 
Headacbf 
19 
I 
Abdomiml Pam 
14 
1 
P:lil1 
ll 
I 
Back P:lil1 
10 
I 
Th.TOO.t lnitatio3 
9 
0 
Flusbing 
; 
0 
67 
4S 
48 
40 
14 
4 
NIIUIJqltllia 
14 
6 
Th:cmbocytopt:liJ 
12 
1 
_...,.,.. 
8 
J 
44 
1 
15 
lUll> 
IS 
Pnuitus 
14 
Urticaria 
8 
38 
4 
ll 
I 
Rbinilis 
12 
1 
!llOD<hospMID 
8 
I 
~ 
7 
1 
Sim.&itu 
6 
0 
~1embohc m:l. lfu::ttitio~ 
Disorders 
J8 
J 
All;ioe<lema 
11 
I 
HYP<!Pl<emia 
9 
1 
Peripb..-.1 Edtnu 
8 
0 
LDHIDml<>e 
7 
0 
l7 
2 
23 
Dimbea 
10 
Vomitio; 
10 
l2 
10 
All.'!iely 
s 
26 
J 
10 
1 
10 
I 


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Tobit z• 
Incidence of All Ad\'el'se Reactions'' Occturing in k2"1. 
and at Least 1% Greater than Placebo Among Rheumatoid 
Arthritis Patitnts in Clinical Studits Up to Wtek 24 (Pooltd) 
Phctbo+).£I'X 
Ritmw~ + ~rrx 
N=J98 
)'(: 540 
Preferred Term 
• (l't) 
o('i) 
Hypeneosi<>D 
21 (l) 
43 (8) 
NllU)tJ 
19(5) 
41 (8) 
Upper Reopiratory Tract hlfectio!l 
23 (6) 
37(7) 
Ar1llralp. 
14 (4) 
31 (6) 
I>)TM 
8 (2) 
27 (l) 
Pnuil\U 
l (I) 
26 (l) 
('billi 
9(2) 
16 (J) 
Dy\ptp\i> 
l (<I) 
16 (l) 
RbiDitis 
6(2) 
14 (l) 
Pareldl~i.a 
l (<I) 
12 (2) 
UrticW 
l (d ) 
12 (2) 
Abdo..m.J P3ln Upper 
4 (I) 
11 (2) 
Th.'f'(l:tt ltrit3tiou 
0(0) 
11 (2) 
All!dtry 
l (I) 
9(2) 
~Ugnilli 
2 (<I) 
9(2) 
Aslbeui> 
1 (<I) 
9(2) 
•'Ibfst dlt1 m twed OD. 93 8 patitmS U'Uttd ill Plwt 211!1d 3 w diti of 
Rilllla!ll (2x 1000 ml) orpbctbo :dui!listored:i!lc-ill:!tioo widl 
metbotte.'i.'l~e. 
• •ceded tWu~ ~ledDRA. 
llifilsion &ocrions 
In the Ril\llUlll RA pooltd placebo-controlled studies, 32% of Rinc= -lreated patients experienced 
an adverse reaction during or witltin 24 hours following tlteir first infusio1~ compared to 23% of 
placebo-treattd patients receiving their first infusion. The in<:ldence of ad\>erse reactions during the 
24-bour period following ihe second in.fus io1~ Rituxan or placebo, decreased to II% and 13%, 
reo:pectively. Arute infusion rtactions (mnnifeo:ttd by fever, drills, rigors, pnuitus, urticaria!rnsh, 
angioedema, sneering, throat initatiou, cough, ruldlor bronchosp~ \\1th or \\1tl10ut associated 
hypotension or hypertension) were experienced by 27% ofRint'Ulll-treattd patients following their 
first infusion, compared to 19% of placebo-treated patients recei\1ng their first placebo infusio1t 
The incidence ofthtse actJte infusion re<~ttions following the second infusion of Rituxan or placebo 
decreased to 9% and II%, respectively. Serious arute infusion reactions were experienced by <I% 
of patients in either treabntnt group. Acute infusion reactioru required dose modification (stopping, 
slo\Ving, or interruption of the infusion) in I 0% and 2% of patients receiving rin.OOrnab or placebo, 
rtspecti\'ely, after the first coorse. The proportion ofpatitnts experiencing actJte infusion re<~ttions 
decreased "ith subs~quent courses of Rittc"lllll. The administtation of intravenous glucocorticoids 
prior to Rimxan infusions reductd the incidtnce and severity of such reoctions, however, there was 
no dem-benefit from the administration of oral gh~eocorticoids for the pre\<ention of act1te infusion 


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reactions. Patients in clinical studies also received antihistamin. .. and acetaminophen prior to 
Rituxan infusions. 
fll[ectiOIIS 
In the pooled, placebo-controUed studies, 39'!. of patients in lhe Rituxan group experienced an 
infection of any type compared to 34% of patients in O>e placebo group. The lll0$t common 
infectioru were nasopharyngitis, upper respimtory tract infectioas, urinary tract infections, 
bronchitis, and sUrusitis. 
The inddence of serions infectioru was 2% in the Rituxan-trtated patients and I% in the placebo 
group. 
In the experience with Rituxan in 25 78 RA patients, the rate of serious infectioru was 4.31 per 
I 00 patient years. TI1e lll0$t common serious infectious ( ~ 0.5'h) were pneumouia or lower 
respimtorytract infec.tions, ceUulilis and urinruy tract infections. Fatal serious infections included 
pne1uoorua, sepsis and colitis. Rates of serious infection remaii.ed stable in patieuts receiving 
subsequent coUBes. In 185 Rii\L'(JIJ]-treated RA patients 11ith active disease, subsequenl lreabnent 
with a biologic DMARD, the majority of which were TNF antagonists, did not appear to increase the 
rate of serious infection. Thirteeu serious infections were obs.,ved in 186.1 patierrt years (6.99 per 
100 patient years) prior to exposure and 10 were obsen•ed in 182.3 patient years (5.49 per 
I 00 patient years) after exposure. 
Cardiac Adl•e11e Reactfoii.S 
In the pooled, placebo-controUed studies, the proportion of ]»tients \\1th serious cll!'diovaso.~ar 
reactioru was I. 7% aud 1.3% in the RillL'an and placebo treatment groups, respectively. Three 
cll!'diovaso.W deaths occurred during the double-blind period of the RA s111dies includiug aU 
rillL'<imab tegimeru (3n 69.0.4%) as compll!'ed to none in the placebo treatment group (01389). 
In the experience 11ith Rituxan in 25 78 RA patients, the rate of serious cardiac ~ac tions was 
1.93 per 1(0 patient years. Tile rate of myocardial infarction (MI) was 0.56 per 100 patieut years 
(28 e~-.nts in 26 patients), which is consistent 11ith MI rates in the general RA popt~ation. These. 
rates did not increase over three COI.lneS ofRitt00111. 
Since patients 11ith RA are at increased risk for cardiovascular events compared \\1th ~te general 
popt~ation patieuts with RA should be JIIOnitored throughout tl:e infusion and RituxlUl should be 
discotrtinued in the event of a serious or life-lhreatening cardiac event. 
H>Popltospltalemia and lt)pet'llricemia 
In the pooled, placebo-controUed studies, ne~vly-occwrin2 h)pophosphatemia ( <2.0 lllfldl) was 
observed in 12% (67/540) of patients 011 Rin"an versus 10'7. (39/398) of patients 011 placebo. 
Hypophosph.,temia was mo~ COllllllOn in patients who recei1-.d corticosteroids. Newly.occ>IIring 
h}]Jelllricewia (>I 0 lllfldl) was obsen•ed m 1.5% (S/540) of patients on RillL'Wl versus 0.3% 
(11398) of patients on placebo. 
In the experience 11ith Rittcsan in RA patients, newly-oco.IIring hypophosphatemia was obsen•ed 
in 21% (528125 70) of patients and newly.occ>trring b)-peruricentia was obseiVed in 2% (56125 70) of 
patients. The majority of the obsen•ed hypophosphatemia OCCI4Ted at the time of the infusions and 
was tranc;ient. 
Retrealt!tetJI in Patfmt!J witlt RA 
In the experience 11ith Rituxan in RA patients, 2578 patieuts ha1-e been exposed to Rittc'Wl and 
have receil'ed up to 10 cotuses of Rituxan in RA clinical trials, 'Aith 1890, 1043, and 425 patie1rts 
having received at least two, Onee, lUld four courses, ~lively. Most of the patients who ~eived 
additional courses did so 24weeks or more after tbe pre11ous course a11d no11e were retreated sooner 
th.'ID 16 weel:s. The rates and !)opes of am-erne reactions reported for subseqt>ent cot!l'seS of Rittc'(aD 
were similar to rates and l)pes seen for a single coo.use ofRillL"ll 


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In RA Study 2, where all patient• initially received Ritt"an, the safety profile of patients who 
were retreated \\1th Rituxan was similar to those who tvtre retreated \\1th placebo [See Clinical 
Shttli•s (14.6}, mtd Dosage and ddminisb·ation (2.5)). 
6.3 
Clinical T1ials E'l"Iienre in Granulomatosis nith Po~·angiiti• (GPA) (Wegener's 
Grant~omMo•is) and Microsropk Polyangiiris (MPA) 
Became clinical trials are conch1cted twder widely Vlll)>ing conditions, adverse reaction mtes 
obsm-.d in clinical trials of a dn1g cannot be directly compared to rates in the clinical trials of 
another drug and may not reflect the mtes obse~wd in practice. 
Tite data presented below reflect the e.xpe!ience in 197 patients with GPA and MPA treated \\1tlt 
Ri~au or cyclophosphamide in a single controlled study, which wa; conducted in two phases: a 
6 month randomiztd, double-blind, double-dummy, acti\"t-<:ontrolled remission inch•ctiou pba.e and 
an additiooal l2 month remission mlUIIle!lllliCe pha.e. In UJe 6-mouth remission induction phase, 
197 patients with GPA and )>..IPA were randomized to eitlter Ri!ttxan 375 mg m2 once weekly for 
4 week; plus glucocorticoids, or oral cyclophosphamide 2 mglkg daily (adjusted for renal fimctioo, 
white blood cell cOtm~ and other factors) plus glucocorticoids to induce remission. Once remission 
was achiet'ed or at the end of lhe· 6 mouth remission induction period, the cydophosphamide group 
received azatlliopru~e to maintain remission. Tile Rilltxan group did not receive additional therapy 
to maintain remission. The primary aoaly;is was at lhe end of the 6 mouth remission induction 
period and the ;afety rerults for this period are described below. 
Adver' ... reactions presented below in Table 3 were advme et'e!lts which occuned at a mte of 
greater lhan or equal to I 0'!. in the Rilll'<lln gr"''P· TIUs table reflects experience in 99 GPA and 
MPA patients treated tvith RituxruJ, tvith a total of 47.6 patient-yem of obsen'l!tion and 98 GPA and 
MPA patients treated \\1th C)dopbosplwuide., \\1th a total of 47.0 patient-years of observation. 
Infection was the lll0$t common category of adver'.,. events reported ( 47 .62%) and is discussed 
below. 


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l11[usion &(J(tions 
Tabid 
Incidence of All Advesse Reaetion1 
OccUlTing in ~ 10% ofRillL'<lln-treated GPAand MPA 
Patients in tht Clinical Study Up to Month 6* 
Plt!mtd Ttnn 
Ri1lllWI 
C)tlopbospbamidf 
N:99 
N: 98 
u(ll) 
• (I\) 
Nausu 
18 (IS%) 
20 (2011) 
llUnbo 
17 (17!1) 
12(1211) 
Rt*bt 
17 (17!1) 
IP (1911) 
Mu;cJe spasms 
17(17%) 
IS (15!1) 
An!!llia 
16 (16%) 
20 (2011) 
Ptripbmltdtma 
16 (t6%) 
6 (6!1) 
lnsOIIIIIill 
14(14%) 
12(12'1) 
Arlhralpa 
U (U%) 
9 (911) 
Coogb 
H (H%) 
II (1111) 
Fatirue 
H (IJ%) 
21 (2tll) 
IDmastdALT 
U (ll%) 
15(1;!1) 
H}-perteasion 
12(12%) 
5 (.Ill) 
Episam 
II (II%) 
6 (6!1) 
Dr•JlOf> 
10 ( t~l) 
II (Jill) 
LlllkoptQiA 
10(10%) 
26 (2711) 
Ra;h 
10 (10%) 
17 (1711) 
•Tbe srudy desip:a allowed fer crosscnw or tteamuent by best medical 
judpnem, aud U pnieoti iD eacb aeaunent :roup receh'id a secood 
1llmpy ciiiJiD& lilt 61DCCllb •rudy period. 
Infu1iou-related reacrion1 in the active«>ntrolled, double-blind sn1dy were defined as any adverse 
evenl oocuning within 24 hours of an infusion and consid&ed to be infusion-related by 
investigators. Among the 99 patieuts treated with Rituxan, 12% e.'Jlerieuced at least one infusion 
related reaction, compared with II% of the 98 patienls in the cyclophosphamide group. 
Infusion-related reactions included C)10kint releast S)'l!drome, flushing, throat irritation, and tremor. 
In the RittL'an group, the proportion of patients experiencing an infusion related reaction was 12%, 
SY., 4%, and I% following the first, seeond, third, and fmuth infusions, rtspecti~ly. Patients were 
pre-medicated with antihistamine and acetaminophen before each Rituxan infusion and were on 
backgrmmd oral corticosteroids which may bave mitigated or masked an infusion reaction; howev&, 
these is insufficieJ~ " ' deuce to determine whether premedication diminishes the. frequency or 
Se\'erity of infusion reactions. 
Infections 
In the active.controlled, double-blind study, 62% (61/99) of patients in the RillL'Ulll group 
e><perienced an infection of any type compared to 47'/. (46198) patienls in the C)'clopbosphamide 
group by Month 6. The lllOst common infec.tioru in the RillL'Ulll group wese upper ttspiratory tract 
infections, uru•-uy tract infections, and hel)le; zoster. 


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The incidence of serious infectioll$ was 11% in the RitlllWl·lreated patient$ and 1 0'!. in the 
cydophospbrunide treated patients, with rates of approxim.,tely 25 and 28 per 100 patient-yem, 
respectiveLY. The JllOst colliJllon serious infection was pnetunonia. 
H}pogmJmJaglobulincnJia 
Hypogru:nmaglobulinemia (lgA, IgG or IgM below the lower limit of normal) has been observed in 
patients with GPA and MPA treated 11-ifl1 Rituxan. At 6 monll>S, in the Ritlt'Wl group, 
27%, 58% and 51% of patients with nollUll) inumlllOglobulin levels at baseline, had low IgA, IgG 
and lg.\1levels, respectively compared to 25%, 50% and 46% in tile cyclophosphamide group. 
Rctreatmenl ill PatieJJts ><ith GPA a11d MPA 
In the active-eontrolled, double-blind sntdy, subsequent courses of Rim= were allowed for 
patients elqltriencing a relapse of disease. The limited data preclude any conclusions regarding the 
safety of Sllbsequeut cOOJses ofRitlt.'Wl 1\ith GPA and MPA [See Dosage a11d AdmiJJistmlioJJ (2.6), 
and Wamings aJJd PrecaurioJJS (5.14)]. 
6A 
!Jrrmuuogeuidty 
As "ith all rl>erap.eutic proteins, there is a potential for imnnmogenicity. The observed incidence 
of antibody (mcluding neulralizing annoody) positivity in an assay is highly dependent on set>eral 
factors including assay sensiti>ity ruld specificity, assay metltodology, sample handling, timing of 
sampl• collection, concomitant medications, and tmdtrt)ing disoast.. For thest r.asons, comparison 
of the incidenco of antibodies to Ritux.an ~>ith the incidtnce of annoodies to other products may be 
misleading. 
Using an ELISA assay, anti-human anti-chimeric antibody (HACA) was dttected in 4 of 
356 (1.1%) patients witlt low-grade or follicular NHL recoivi:ng single-agent Rin" an. Three oftl1e 
fOOJ patients had an objectiv• cliuicalr.sponst. 
A total of273/2578 (11 %) patient$ 1vith RA tested positive for HACA at any time after receiving 
Ritux.an. HACA positi,ity was not associated with incrtased infusion reactions or oO>er adverse 
reactions. Upon ftnther treatment, the proportions of patients with inftJSion reactiollS were similar 
between HACA positive and negative patients, and most reactioll$were mild to moderate. Four 
HACA positivt. patients h.'d strious inftlSiau reactions, and the temporal relationship benvetn 
HACA positil1ty and infmion reaction was variable. 
A total of23199 (23%) Ril\Lxan-treated patients with GPA :and MPA tested positive for HACA by 
18 lllOnths. The clinical relevance of HACA formation in Rituxan-treated patients is tmclear. 
6.5 
Postmarkering Eiperience 
Becaus.-thest reactions are reported voltmtarily from a popt~ation of uncertlin size., it is not 
always possible to reliably estimate their frequency or establish a Cat1Sal relationship to drug 
"')lOSUle. Decisions to include these reactions in labeling are typically based on one or more of rl>e 
follm'ing factor.~ : (1) seriousness of the reaction, (2) frequenc.y of reporting. or (3) strength of causal 
cOUllection to Rin"an. 
Hell:llltologic: prolonged panc)1openia, marrow b~poplasia, Gradt 3-4 prolonged or late-<>usel 
neutropenia, hypervi>eosity syndrome in Waldtnsnom's macroglobulinemia, prolonged 
h}]lOgammaglobulll~emia [See IT'm11il1gs mJd !'1-ecau/ioJJs (5.6)]. 
Cardiac: fatal cardiac failure. 
Innmm~Autoinuuuue Events: uveitis, optic neuritis, systemic vasculitis, pletuitis, lupt1S-like 
syndrome, senun sickness, polyarticular arthritis, and '""culitis with rash. 
Infe.ctiau: viral infectioJ>S, including progressive mt~tifocalleukoenctphalopathy (PML), 
increase in fatal infections in HIV-associated lymphoma, and a reported increased incidence 
of Grade 3 and 4 infectioll$ (See Wm'lliJJgs and !'1-ecau.tfons (5.6)]. 
Ntoplasia: distase progression of Kaposi's sarcoma. 
Skin: severe rrntcocutaueons reactions. 
Gastrointestinal: bowel obstrttctian a~Jd perforation. 
Pulmonary: fatal bronchiolitis obliterans and fatal interstitialltmg disoast. 


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NeiVotiS system: Posterior Reversible Encephalopathy Syndrome (PRES) I Reversible 
Posterior Leukoenceph:•lopathy Syndrome (RPLS). 
7 
DRUG INTERJ\C.TIONS 
Fonnal drug interaction studies have not been perfonned with Ri!tL-wt In patients ~>ith Cll, 
Rinrun did not alter sy~temic elCJ!OOure to flud.mbint or cyclophosphamide. In dinicru trials of 
pati.,rts \\1th RJ\, concomitant administration of methotrexate or cyclophosphamide did not alter the 
phannacol:inetics of rittt'timab. 
8 
USE IN SPECIFIC POPULUIONS 
8.1 
P1•egnancy 
Pregnancy Category C 
Risk S11mmmy 
Titere are no adequate and well-controlled studies of rittL'timab in preguant women. Womelt of 
childbearing potential should use efl'ective contraception while recei~ing RillL't.'ID and for 12 UJOnths 
following treatment. RihL'<lln sltould be tiSed during pregnancy ouly if the potential benefit justifies 
the potential risk to the fents. 
H•m~nndata 
Postrnarketing data indicate that B-celllympl10C)1openia generally lasting less than si.' lllOnths 
can occur in infants •~'JlOSed to rinmmab in-utero. Ritu.'timab was detected poslllatally in the serum 
of infants e.'')lOSed in-utero. 
A.nimal Daia 
An embryo-fetal de\•eloplllelrtal toxicity stttdy was performed on pregnant cynomolgus monkeys. 
Pregnant animals received rit\OOmab via the intravenous rm1te dtuing early gestation (organogenesis 
period; post..:ointm days 20 throu!!h 50). Rinc'timab was administered as loading doses on 
postcoinun(PC) Day~ 20,21 and 22, at 15,37.5 or 75 mgkglday, and dten weekly on PC Days 29, 
36, 43 and 50, at20, 50 or 100mglkglweek. The 100 mglkg/week dose resulted in 80'/o of the 
e.')lOSllle (based on AUC) ofOIOSe achieved follO\\ing a dose of2 gr= inlnnnans. Rinmmab 
crosses the lllOnkey placenta. E"]Xlsed offSpring did not exhibit any teratogenic effects but did have 
decreased l)'lllphoid tissue B cells. 
A subsequeltt pre-and poslllatal reproductive toxicity study in cynomolgus monkeys was 
completed to asr.ess developmental effects including the recovery ofB cells and inmnme function in 
infants exposed to rittL'timab in utero. Anim..ts were treated with a loading dose ofO, 15, or 75 
mglkg e\'ery day for 3 days, followed by weekly dosing \\1th 0, 20, or 100 mglkg dose. Sub6ets of 
pregnant females wtre treated from PC Day 20 through poslp<lrtlon Day 78, PC Day 76 throum PC 
Day 134, and from PC Day 132 through delivery and poslp<lrtlun Day 28. Regardless of the tkuog 
of treatroen~ decreased B cells and inunuoomppression wtre noted in the offspring of ritu.'timab-
treated pregnant anim...Js. The B-cell COIUtts rentrued to no!lllalle\•els, and inmuutologi< function 
was restored within 6 lllODtru poslp<lrtlun. 
8.3 
Nur.1ing Mo rhe~> 
It is not kuown whether Rill"an is secreted into human milk However, Rituxan is secreted in the 
mill: of lactating C)'llOillOigtiS lllOnkeys, and IgG is excreted in htunan mill:. Publilhed data suggest 
that antibodies in breast milk do not enter the neonatal artd infant cirCldations in substantial arommts. 
The twknown risks to the infunt from oral ingestion ofRituxan shoold be weighed against the kno~>u 
benefits ofbreastfeeding. 
SA 
Pedi.1tric Use 
FDA has not required pediatric. studies in polyarticular juvenile idiopathic arthritis (PJIA) patients 
ages 0 to 16 due to concern.• regarding the pot.,ttial for prolonged inuntulOStippressiou as a restdt of 
B-001 depletion in the developing juvenile inunune system. Hypoganunaglobulinemia has been 
observed in pediatric patients treated with Rituxan. 
The safety and effectiveness of RillL= in pediatric patients have not been established. 


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8.5 
Gtriallic Ust 
DiffUse Lnrge B-Cell NHL 
Among patients with DLBCL evaluated in thr~ randomized active-controlled nials, 927 patients 
received Ritu.xan in combination with cbemothernpy. Ofthtse, 396 (43%) wm age 65 or greater 
and 123 (13%) were. age 75 or greater. No overall differeoces in effec.tiveness were obsen•ed 
betw= tl:.ese patients and younger patients. Cardiac adverse reactions, mostly supraventricular 
arrhytbmiw, occurred more frequently among elderly patients. Serious po.lbnon:uy adverse reactions 
were also more COilllllOD among the elderly, including pnelllllO!lia and pnelllllOnitis. 
LOII' Gmdg o•· Fo/liet1lm· Non-Hodgkin's Lymphoma 
Patients "itb pre>iously tmtreated follicular NHL evaluated in Stttdy 5 were randomized to 
Rituxan as single-agent maintenance therapy {1!;505) or obsen•tion (~5 13) after achieving a 
respon1e to Ritu.xan in combination \\1tb chemotherapy. Of these, 123 (24%) patients in the Ritu.x.'ID 
ann were age 65 or older. No overall differences in safety or effectiveness were obsen•ed between 
these patients and ymmgerpatients. Other clinical stttdies ofR:tuxan in low-grade or follicular, 
CD20i>o~tive, B«ll NHL did not include sufficient munbers of patients aged 65 and over to 
determint whether they respond differently from yotmger subjects. 
Chnmic Lymphocytic Llmkemia 
Among patients t>ith Cli evaluated in two randomized active-controlled trials, 243 of 
676 Ritu.xan-treated patients (36%) were 65 years of age or oldtr; of these, 100 RittLxait-lreated 
patients (15%) were 70 years of age or older. 
In eocpkrntory analy~s defined by age, there was no obsen•ed benefit from the addition of 
Rituxan to fludarabine. and cyclophosphamide among patients ';o years of age or older in Study 11 or 
in Study 12; there was aho no observed benefit from the addition ofRihLxan to fludarabiue aud 
cyclophosphamide among patients 65 years of age or older in Sludy 12 [Se.l Clinical SfudiflS (14.5)). 
Patients 70 years or older received lower dose intensity of flu&rnbine and cydophosphamide 
compared to younger patients, regardless oftlte addition ofRiltLxarc In Stttdy II, tl1e dose inten•ity 
ofRittLxan was similar in older and younger patients, however in Study 12 older patients recehoed a 
lower dose intensity ofRittLxan. 
The incideoce. of Grade 3 and 4 adverse. reactions was highet among patients receivin~ R-FC who 
were 70 years or older compared to younger patients for neulr"?fflia [44% v~. 31% (Stud)' II); 56% 
vs. 39'!. (Stttdy 12)), febrile neutropenia [16% vs. 6% {Stttdy 10)), anemia [5% vs. 2% (Stttdy II); 
21% v1. 10'!. {Stttdy 12)), lhrornboc)1openia [19'!. vs 8% (Study 12)), panc)1openia [7% vs. 2% 
(Study 1 1~ 7% v~ . 2% (Stttdy 12)) and infections [30'!. vs. 14% (Study 12)). 
Rhewuatolli AJ·t}u'iris 
Amongtl1e 2578 patients in global RA sttldies completed to date, 12% were 65-75 years old a1td 
2% were 75 years old and older. The incidences of advme rea:tions were similar betw~n older and 
younger ptrients. The rates of serious adverse reactions, including serious infections, malignancies, 
and cardiO<'llScular events were higller in older patients. 
Gnmulom.lfosis "'ith PoiymPgiilis (GPA,J (Wegeuel''s Gl·mllllOPMatosis) aud Microscopic PolymPgiilis 
Of the 99 RittLxan-treated GPA rutd MPA patients, 36 (36%)were 65 years old and over, while 
S (8%) were 75 years and O\'tr. No overall differences in eilia.cy were observed betw= patients 
that \\/ere 65 years old and over and younger patients. The ovetall incidence and rate of all serious 
adverse e\OJUS was higl~er in patients 65 years old and over. The clinical study did not include 
sufficient lllllllbers of patients aged 65 and over to determine \Vlether they respond differently from 
yotmger subjects. 
10 
0\'ERDOS.\ GE 
There has been no e.'q>flience of overdosage with RituxarL 


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11 
DESCRIPTION 
Ri!tt'<llll' (ri!tt'timab) i~ a genetically engineered clUmeric murine/human monoclonal IgG1 kappa 
antibody directed against the CD20 antigen. Rit\OOmab has an appromte molecullll weight of 
145 kD. Riltl<imab ha. a binding affinity for the CD20 antigen of appromtely 8.0 nM. 
Rittt<imab is produced by mannuali.1l! cell (Chinese H:uuster Ov:uy) suspension cldnrre in a 
nutrient medium containing the antibiotic gentamicin Gentamicin is not detectable in the 6.nal 
product. Rilll'<llll is a sterile, clw, colorless, prest!!Vative,free liquid concentrate for intrnvenous 
administration. RillL'<llll is supplied at a concentrntion of I 0 mglmL in either I 00 mgll 0 mL or 
500 mgl50 mL ~ingle -me vial~. ll1e product is formulated in polysoroate 80 (0. 7 mglml.), ~um 
chloride (9 mglml.), ~um citrate dihydrate (7.35 mglml.), and Water for Injection. Tile pHi~ 6.5. 
12 
C'LThl CALPHARMACOLOGY 
12.1 
Mechanism of Acrion 
Rittlltimab is a monoclonal antibody lh.,t targets the CD20 antigen elcpres~ on the surface of 
pre-Band mature B-lymphncytes. Upon binding to CD20, rituximab mediates B-celllj~is . Possible 
mech.misms of <'<!ll lysi~ include complement dependent C)10toxicity (CDC) and antibody dependent 
cell mediated cytoto:ticity (ADCC). The anuOody induced apoptosis in the DHL 4 htWWl B cell 
l~mphnma cell lil1e. 
B cells are beliel'ed to play a role in the pathogenesis of rhetunatoid artluitis (RA) and associated 
chronic sytto1otis. In dtis settlltg, B cell~ may be acting at multiple ~ites in the 
autoimnnme/'mfl=tol)' process, including through production of rhetunatoid factor (RF) and 
other autoantibodies, antigen presentation, T-cell activation, and/or proinflammatol)' cytoku1e 
production. 
12.1 
Phannacodynamics 
No11-Hodgkin 's Lymphoma (NHL) 
In NHL patients, administration ofRituxan resulted in depletion of cilculating and tisme-ba~ 
B cells. Among 166 patients nt Study I, circulating CDI9-positive B cells were depleted \\Otltin the 
firnt three weeks tvith sustained depletion for up to 6 to 9 months post treatment in 83% of patients. 
B-cell recovery began at appromtely 6 months and median B-ceU levels returned to normal by 
12 months followin$ completion of treatment. 
There were snstamed and statistically si¢ficant reductions in both lgM and lgG serum levels 
obser:ed from 5 through II months follmving riltl<imab admiltistratio1~ 14% of patients had 1~\1 
and/or lgG senun levels below the normal !llllge. 
Rheumatoid ..V1hritis 
In RA patients, treanueut 1\'lth Rilll'Wl induced depletion of peripheral B lymphocy1es, 1\ith the 
majority of patients demonstrating nw complete depletion (CDI9 counts below the low~ limit of 
quantification, 20 cells/!<1) 1\0dtin 2 weeks after receiving the firnt do~ ofRituxan. Tile majority of 
patients showed peripheral B-eell depletion for at least 6 months. A small proportion of patients 
(--4%) had prolonged peripheral B-cell depletion lasting more than 3 years after a single cow.e of 
treatment. 
Total serum innmmoglobtdin levels, lgM, lgG, and lgA were reduced at 6 months with the 
greatest change observed u1lgM. At Week 24 of the fust cotll'Se of RittL'OIIl treatment, small 
proportions of patients experienced dec.rea1es in lgM (10%), lgG (2.8"!.), and IgA (0.8%) levels 
belmv the lotver limit of normal (UN). In d1e experience 1vith RittL'<llll in RA patients during 
repeated Rilll'Wl treabnent, 23.3%, 5.5%, and 0.5% of patients experienced decreases in IgM, lgG, 
and lgA concentrations below W at any time after recei>ing Rituxan, Te>"Pectively. Tile dutical 
consequences of decreoses in ilumllllOglobulin lel'els in RA patients treated \\ith Rilllxan are 
twclear. 
Treabnent 1vith ri~t<imab in patients 1\'ith RA was associated 1\'ith reduction of certain biologic 
markers of inflanunation such as interleukin-6 (IL-6), C-reactive protein (CRP), senun am)ioid 


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protein (SAA), S100 A81S100 A9 het.,.odimtr comple~ (S100 A819), anti-eitrullinated ptptide 
(auti-CCP), and RF. 
Gmtmlomatosis >11th Polym1giitis (GP4) (Wegene1·'s O.·mmlon:atosis) and Microscopic Polym1giitis 
In GPA and MPA patients, peripbernl blood CD19 B-cells depleted to less than 10 cells!!~ 
following the first two infusions ofRillwln, and remained at !hAt level in most (84%) patients 
tluoo.1gh M~nth 6. By Month 12, the majority of patients (81 %) showed signs of B-cell renun \\1th 
cmmts > lQ cellsi)IL. By Month 18, most patients (87%) b.,d counts > 10 cellslfll-. 
12.3 
Phannocokinetks 
Non-Hodr)in 's Lpnphoma (NHIJ 
Phnnnatokinetics were cb.mcterized in 203 NHL patients r~i11Dg 375 mtfm' Ritwlan weeldy 
by in1ravenous infusion for 4 doses. RillOOmab was detectable in the serum of patients 3 to 
6 months after completion of treatment. 
The phrum.,cokinetie profile of rituxim.,b when administered as 6 infusions of375 mtfm1 in 
combiuation \\1th 6 cycles of CHOP chemotherapy was similas to dtat seen \\ith rituximab alone. 
Based ou a population pbanuacokinetic analysis of data from 298 NHL patients wbo received 
rituximab OI\Ce weekly or once every three weeks, the estimated median terminal elimination 
half-life 1vas 22 days (range, 6.1 to 52 days). Patients ~>ith higl:.er CD19-positive cell counts or 
lasger measurable llllllOr lesions at pretreatment had a higher cleMance. However, dose adjustment 
for pretrea<meut CD19 count or size of tumor lesion is not nece>sasy. Age and gender had no effect 
on the pb.'lllmcokinetic.s of rillOOmab. 
Pharmacokinetics were characterized in 21 patients with Cll recei'ing rinL'cimab according to the 
recommenied dose and sched1~e. The estimated median terminal half-life of rillOOmab \vas 32 da)~ 
(range, 14 to 62 days). 
Rheumatoid AJ·tlu'itis 
Following administration of2 doses ofRiiiWill in patients w:th RA, the mean ( : SD.; % Cl/) 
conc.!n1rations after the first infusion (Cma."< firsO and second infusion (Cmax second) w.,.e 
157 (: 46; 29%) and 183 (: 55; 30'/o)mcdmJ., aud 318 ( : 8e; 27%) and 381 (: 98; 26%) 
mc!ifmL for the 2 x 500 IIlli and 2 x 1000 mg doses, respectively. 
Based ru a population pllarmacoku.1etic anal)~is of data from 2005 RA patients who received 
Ritwlan, tl:.e estimated cleaillllCe of rillOOmab \vas 0.335 Uday; vohune of distn'bution was 3 .I L and 
mean terminal elimination half-life was 18.0 da)~ (range, 5.17 to 77.5 days). Age, weight and 
gender had no effect on the pharmacokinetics of rill~~b in RA patients. 
Gmnulomatosis >11th Polymlgiiffs (GP.-l) (Wegener's O.·mmlon:atosis) and Microscopic Polymlgiiffs 
Based ttl the pOQtllation phannacokinetic an.,})~is of data in 97 GPA and MP A patients who 
received 31511J(/m2 rituximab once weekly by intravenoos infusion for four weeks, the estimated 
median terminal elimination half-tife was 23 days (range, 9 to 49 da)~). RiiiL'<imab mean clearnllte 
aini vol= of distribution were 0. 312 Uday (range, 0.115 to 0.728 Uday) and 4.50 L (rnnge, 2.21 
to 7.52 L) :espectively. Male patients and patients \\1th higher BSA or positive HACA levels ha\·e 
higher deuance. Howev.,., further dose adjmtrnent based on ~der or HACA status is not 
necessary. 
The phannac(lkinetics ofritu'Cimab have not been studied in children and adolescents. No fonnal 
slltdies were conducted to ewnine. the. effects of either renal or hepatic impairment on the 
phannacokinetics ofrinL'<imab. 
13 
NONCUNICAL TOXICOLOGY 
13.1 
Cn!·cinogtntsil, Muragene.1is, Impainntnt of Ftrtili~· 
No long·term animal studies have been performed to establish the cascinogenic or mntageuic 
potential of Ritwlan or to detennine potential effects on fertility in males or fem.,}es. 


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H 
C.'Ul'<lCAL STiiDIES 
lH Rebpsed or Reft· oc!ot~', Low-Grode or Follicular, C:DlO-Po.1itin, B-Cell l\cliL 
The safely and effectiveness of Rii\L'Wl in relnpsed, refractory CD:!Ot NHL were demonstrated in 
3 single-ann sl\ulies enrolling 296 patients. 
Snidy 1 
A lllldticeuter, opeu-labe~ single-ann sl\1dy was conducted in 166 patients with relapsed or 
refractory, low-{!111de or follicular, B-<eU NHL who received 375 DJt!m' ofRincwt given a; an 
intravenous infusion weekly for 4 doles. Patients with tumor mMses > 10 em or with 
> 5000 lympbocy:esl~ 
in the peripheral blood were excluded from the sn1dy. 
ReSidts are SUllllllllrized in Table 4. Tite median time to onset ofre~ponse was 50 da)~. 
Disease-related signs and symptoms (mcluding B-symptolllS) resolved in 64% (25139) of those 
patients with such S)mptoml at study entry. 
Study 2 
In a nrulticeoter, single-ann study, 37 patients with relapsed or remctory, low-gmde NHL 
recei1..d 375 DJt!m' of Rii\L'Wl weekly for 8 doses. Restdts are summarized in Table 4. 
Sh1dy 3 
In o nrulticeoter, single-ann study, 60 patients rec~ved 375 DJt!m' ofRii\L'Wl weekly for 4 doses. 
All patients bad relnpsed or refractory, low-grade or follic.tdar, B-cell '<HL and bad ac.hieved an 
objecti1<e clinical re~ 
to RinL'Illll administered 3.8-35.6 months (median 14.5 months) prior to 
retreo1nlent with PJI\L'tllJI. Of these 60 patients, 5 received more than one additional course of 
Rit~run. Restdts !ll'estlllllltal'iztd in Table 4. 
Bulky Disros~ 
In pooled data from sl\1dies I and 3, 39 patients 11ith bull:y {single lesion> 10 em in di:uneter) and 
relapsed or refractory,low-gmde NHL received Rii\Lxan 375 DJt!m2 weekly for 4 doses. ReS!dts are 
sllllllll3rized in Table 4. 
Tobit~ 
Swmnary of Rii\IXllll Efficacy Dato by Schedule and Clinical Sttting 
!rudy l aJJd 
Srudyl 
Srudy 3 
Srudy l 
Srudyl 
Bt:lky disease, 
Re~~ 
Weeklyx4 
WeeklyxS 
Weeklyx4 
Weeklyx4 
N=l66 
Joi: l7 
N=39" 
Joi: 60 
0\'mll Rt\polllt bit 
4$% 
sni 
3Mi 
38% 
Compl@te Responst Rate 
6% 
14% 
l% 
100/o 
~ft<ti!ID 0\:u'lltioo oi Rtipa~Ut" c. 
11.1 
U.4 
6.9 
u.o 
• 
[l.P 1042.1+] 
[2.5 10 J6j + I 
[2 8 10 15.0.] 
[l.01olS.l+] 
(Moolbo) [Rmp] 
• Six of these patimts ue iDcluded iD tbe fiN colwnn. Thus, data from 296 iDteur-to-O"e!t paWs ue prodded iD 
this table. 
b Kapl."'lll-~ieierpwjecttd\\itb ~'ed 
ran~ . 
c '"+" iDdiutts nn ODtOiD& mpoust. 
• Duratico of mpoost: inttn·al from tbt onstt of rtipOil\t «o di!.tase pro:msico. 
U.l Pmiouslr Unmated, Low-Grade or F oUicular, C.'D20-Po~tiw, B-CeU NHL 
The safely and effectiveness of Rintxan in previously Wltreated, low-grade or foUie~dar, CD20+ 
NHL were demonstrated in 3 randomized, controlled trials enrolling 1,662 patients. 


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Study4 
A total of322 patients with previously tmlreated follicular N1lL were randomized (I: I) to receh<e 
up to •ight 3-tv..k cycles of CVP cJJ.mothmpy alont (CVP) or in combin.,tion ~>ith Ritlruul 
375 mg/m2 on Day I of each cycle {R-CVP) in an open-label, Ulldticenter study. The main outcome 
measure of the study wu progrwion-free survival (PFS) defined M the time from randomization to 
the first of progressio1~ relapse, or death 
Twenty-si~ percent of the study population was >60 years of age, 99'/o had Stage ill or IV disease, 
and 50% had an International Prognostic Index (IPI) score >2. The restdts for PFS as deterwilled by 
a blinded, independent assessment of progression are presented in Table 5. The point estimates may 
be infllleuced by a,. presence of informative. censoring. The PFS restdts based on investigator 
assessment of progression were similar to those obtained by the independent review assessment 
Study 5 
T•ble 5 
Efficacy R.estdts in Sn1dy 4 
1~ 
PI'S ()""')' 
ll.u31d I\Oio (!)S% Cl)' 
' p& OOOI, "'""ided!O'llliliod lo,-!W <MI. 
b E~te'i of Cox rt;rt')~OD 'iaalified by cen:e-:r. 
R-CVP 
N: IIS'l 
Srudy Ann 
CVP 
N: l60 
2.4 
1.4 
0.44 (0.29, 0.6S) 
Au open-labeL mlllticenter, randomized (1:1) study was conducted in 1,018p•tients 1vith 
previously tmlreated follicular NHL who achieved a resporue (CR or PRJ to Ritlruul in combination 
with chemotherapy. Patients were randomized to Ritu.= as single-agent m.1intenance therapy, 
375 mglm2 every S weeks for up to 12 doses or to observation. Ritu.'<lln was initiated at S weeks 
following completion of c.hemotherapy. The main outcome measure of the study was 
progression-free SlliVival (PFS), defined as a,. time from randomization in the 
maintenance/observation phase to progression, relapse, or death, as deteunined by independent 
revtew. 
Of the randomized patients, 40'!. were •60 years of age, 10'!. had Stage IV disease, 96% had 
ECOG performance slants (PS) 0-1, and 42%h.'d FLIP! scores of3-5. Prior to randomization to 
maintenance therapy, patients had received R-CHOP (75%), R-CVP (22%), or R-FCM (3%); 71% 
had a complete or unconfirmed complete rtsporue and 28% h.'d a parti'l response. 
PFS was longer in patients randomized to RittL'<llll as single age1rt maintenance therapy (HR: 0.54, 
95% CI: 0.42, 0.70). The PFS rest~ls based on ~stigator assessment of progression were similar 
to those obtailled by the independent re•iew assessment. 


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Figurt 1 
Kaplan-Meier Plot of me Assessed PFS 
" ~~~----~-----------------------------------, 
f. :: 
, .. 
l" 
!!' •• 
1 
~ 
-g •• 
~ "' 
.. •• 
'< •• 
~~-.. ---
"' ... 
~" ... .,. 
Shtdy6 
-............ 
~1>-~ 
• • " ,, ,, 
"' 
on '" .,. ... 
"' ... ... "" ... 
..... ..... '· .. 
• •• • 
• 
• 
0 
• 
,, .. " 
MontM 
"' ,,. .. 
'" "' '" 
"' 
.. .. 
. .... •, 
.. 
" " 
.. 
' ' ' ' ' 
tro~1 mont 
-
OBSEAVAllOI'I 
• • RITUXAN 
" .. 
0 
0 
A total of 322 patients wid1 pre\1ously lllllreated low-grade, B-eell J:llllL who did 110t progres• 
after 6 or 8 cycles of CVP c.hemotherapy were enrolled in an opeu-labe~ orulticeuter, randomized 
trial Patients were randomized (1:1) to receive RitlL'Gill, 375 mg!m' intraveuous infusion, once 
weekly for 4 doses every 6 months for up to 16 doses or no further therapeutic. inten•euti011 The 
main outcome measure of the stttdy was progression-free sun-ivai defined as the. rime from 
randomization to progression, relapse, or death. Thirty-seven percent of the study pop~dation was 
>60 years of age, 99% bad Stage ID or N disease, and 63% had an !PI score •2. 
There was a reduction in lhe ri$1: of progression, relapse, or dealh (hazard ratio estimate in the 
ran~ of0J6 to 0.49) for patients randomized to RittL'Wl as comp:!!ed to those who ,..cei\•ed no 
additional treatment 
U . .l 
Diffuse Large B-CeU NHL (DLBC.'L) 
The safety and effectiveness of Rittnan were evaluated in three randomized, active-controlled, 
open-!abe~ nndticenler studies wilh a collective enrollment of 1854 patients. Patients with 
previously 1mtreated diffuse l:!!ge B-<:ell NHL recei\>ed RitlL'tllll in combination wilh 
C}dophospltamide, doxontbicin, \>incristine, and prednisone (CHOP) or other anthracydine.based 
cheJDOthe!llpy regimens. 
Shtdy 7 
A total of 632 patients age • 60 years with DLBCL (including primary mediastinal B-tell 
lylllj)homa) were randomized in a 1:1 ratio to treatment with CHOP orR-CHOP. Patients received 
6 or 8 ()<des of CHOP, each cycle lasting 21 da}~ - All patients in the R-CHOP arm received 4 doses 
ofRitlL'Wl 375 mg!m' on Days -7 and -3 (priortoCyde 1) and48- 72 hOt.u. prior to C}des 3 and 
5. Patients who receh>ed 8 cycles of CHOP also received RittWlll prior to Cycle 7. The main 
outcome meaS\ut of the study was progression-free swvival, defined as lhe time from randomization 
to the fiBt of progression, relapse., or deadL Rtsponding patients lllldenvenla second randomization 
to receive Ritttxan or no further therapy. 
Among all enrolled patients, 62% had centrally confirmed DLBCL histology, 73% had 
Stage ID-N disease, 56% bad !PI scores ~ 2, 86% bad ECOO performance status of < 2, 57% bad 


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elevated IDH le\'els, and 30'/o had two or more extranodal disease sit.s involved Efficacy restdts 
are presented in Table 6. These results reflect a statistical approach which allows for an evaluation 
ofRilltxan administered in the induction setting that excludes any potential impact of RillL'Wl given 
after the second nndomizatioJt 
Anal~~is of results after the second randomization in Study 7 demollltrates that for patients 
randomized toR-CHOP, additional Riltl'Ulll expos11re beyond induction was not associated with 
further improvements in progrossion.free sun>ival or overall sun>ival. 
Study8 
A total of399 patientnvithDLBCL, age~ 60 years, wererandomi!.edin a 1:1 ratio to receive 
CHOP or R-CHOP. All patients received up to eight 3-week cycles <i CHOP induction; patients in 
the R.CHOP ann received Rilltx.m 375 JJJ.?Jm' on Day I of each cycle. The main outcome measure 
of the study was event-free sun>ival, defined as the time from randomization to relapse, progross io1~ 
change in therapy, or death from any cause. Among aU enrolled patients, 80'!. had Stage ill or IV 
disease., 60% of patients had an age-adjusted !PI ~ 2, SO'!. had ECOO perfollllance. status scores 
< 2, 66% had elevated IDH levels, and 52% had extranodal involvement in at least two sites. 
Efficacy restdts are presented in Table 6. 
Shtdy9 
A total of 823 patientnvith DLBCL, aged 18-60 years, wert randomized in a I: I ratio to reeeive 
an anthracydine-containiug chemotherapy regimen alone or in combi:Jation with Rilll'Wl. The main 
outcome measurt of the study was time to treatmtnt failure, defined as time from randomization to 
the earliest of progressive disease, failure to achieve a complete response, relapse, or death. Among 
all enrolled patients, 28%h.,d Stageill-IV disease, IOO%hadiPisccmof <I, 99%hadECOG 
perfollllance statts of < 2, 29% had elevated IDH le\'tls, 49% had boll')' dhease, and 34% had 
e'1ranodal invoh'!mellt. Efficacy results are presented in Table 6. 
Table 6 
Efficacy ReSidts in Studies 7, 8, and 9 
}I.Uin outcome 
}.~o!main~ome 
mm;we 
H..'llmi m1ilf 
Srudy 7 
(• =632) 
R-GHOP 
CHOP 
Progessioo-free sun.ival 
(yean) 
3.1 
1.6 
0.69' 
O.wall suni\rnl at 1 )'t3ff 
74'• 
63~0 
Hawd~t~io" 
' S1~1 
tt pcO.OS, 2-1ldtd. 
' NE=Notroli>bly-blt. 
• K:tplrut.).ftltr tS'Iim3tts. 
' R-CHOP " ·CHOP. 
0.72' 
~rudy8 
<• =399) 
R-CHOP 
CHOP 
E\'tllt·lret suniul 
(yean) 
2.9 
1.1 
0.60' 
69% 
S~i 
0.68' 
Srudy 9 
(• =823) 
Time to tm.tmt!lt f:illurt 
()~"') 
t-<"F' 
NF' 
0.40" 
In Study 8, ovmill s1uvival estimates at 5 years were 58% •~ . 46%for R-CHOP and CHOP, 
respectively. 


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UA Ninety-Minute Infu1ions in Pt·e•iously Untreated Follicular NHL and DLBCL 
In Study 10, a total of363 patients 111th previausly \Dltreated follicular NHL (11"113) or DLBCL 
(u=250) were evaluatfd in a prospective, open-label, umlti-ceuter, single-arm trial for the safety of 
90-minute ritiL'Cimab infusions. Patients "1tb follicular NHL recei1>ed ritll'Cimab 375 lll!fm' phts 
CVP chemotherapy. Patients "ith DLBCL receivfd ritll'Cimab 375 lll!fm2 plus CHOP 
chemothernpy. Patients 111th clinically si~ficl\Jll cardiovMcular disease were e.'OCludfd from the 
stltdy. Patients were elil9ble for a 90-minute infusion at Cycle 2 if dtey did not e.'l"'rieuce a Grade 
34 infusion-relatfd adverse event 111th C}de l lUld bad a cirouating lymphoc)1e count~ 5000hmn3 
before Cycle 2. All patients were pre-medicatfd with acetaminophen aud an antihistamine and 
recei1>ed the glucocorticoid componeut of their chemotherapy prior to Ritwtau infusion. The main 
outcome measure was dte development of Grade 34 infu1ion-relatfd reactions on the day of, or day 
after, the 90-minute infusion at Cycle 2 [See Adver.se Reactions (6.1)]. 
Elii9ble patients receivfd their C}-de 2 ritllximab infusion over 90 miimtes as follows: 20% of the 
tom] dose given in the first 30 minutes lUld the remaining 80% of the total dose given over the next 
60 miitutes [S... Dosage and Adminishntion (2. !)]. Patients who toleratfd the 90-miinrte ritllximab 
infu1ioo at Cycle 2 contimted to receive subsequent ritll'Cimab infu1ions at the 90-minute infusion 
rate for Ute remainder of the treatment regimen (tltrough Cycle 6 or CycleS). 
The incidence of Grade 34 infusioo-relatfd reactions at Cycle 2 was 1.1 '!. (95'1. CI [0.3%, 2.S%D 
among all patients, 3.5% (95% CI (1.0%, S.S'!.D for dtose patients treat.<~ with R-CVP, and 0.0% 
(95% CI [0.0%, 1.5%D for those patients treated 1vitb R-CHOP. For Cycles 2-8, the incidence of 
Grade 3-4 inlltsion-relatfd reactions was 2.8'!. (95% Cl [1.3%, 5.0%]). No acute futal infusion 
related reactions 1vere observed. 
U.S 
Chronic Lymphocytic Leukemia (CLL) 
The safety and effectiveness of RitiL'Wl 1vere evaluated in two randorui.zed (I: I) omlticenter 
ope.n-label studies comparing FC alone or in combination 111th Ritlt<an for up to 6 cycles in patients 
with previously untreated CLL [Study II (n=817)) or previously treated CLL !Study 12 (n=552)) 
Patients receivfd Oudarabine 25 lll!fm2/day aud cyclophosphamide 250 lll!fm/day on days I, 2 aud 
3 of each C)'tle, 1vith or \\1thout Ritwtan. In both studies, seventy-one percent of CLL patients 
receivfd 6 cycles aud 90'!. receivfd at least 3 cycles ofRitll'UUI-basfd thernpy. 
In Study II, 30% of patients were 65 years or older, 31% were Binet stage C, 45% bad 
B symptoms, more thau 99% had ECOG performance status (PS) 0-1, 74% \vere male, aud 100'!. 
were White. In Study 12, 44% of patients were 65 years or older, 28'!. bad B symptoms, 8:r!. 
received a prior alkylating dntg, IS% received prior fl11d.mbine, 100'/o bad ECOO PS 0-1, 67% 
were male and 98% were White. 
The main outcome meas1tre in both studies was progression-free SUI\ival (PFS), definfd as dle 
time from raudomization to progression, relapse, or death, as detennined by investigators (Study II) 
or an independent review committee (Stltdy 12). The investigator assessed results in Study 12 were 
supportive of those obtl\ined by the indepe.ndeut moew committee. Efficacy results are preseuted in 
Table 7, 


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Tablt 7 
Efficacy Rts1dts in Studies II and 12 
11e<tirul PFS (lllO!llhs) 
Haw4 rnUo (9510 CI) 
p \'llut (l.o'·Rrull< "'0 
ltspcmtn!t 
(9mC1) 
~rudy 11' 
(Prt\iouily uwru:td) 
R-FC 
FC 
N=408 
N=409 
39.8 
31.S 
0.56 (o.4l, 0.71) 
<O.GI 
86% 
1l14 
(12, 89) 
(61, 77) 
Srudy 12• 
(Prt\ic.uly uurtd) 
R-FC 
FC 
N=!76 
N=!76 
26.7 
21.7 
0.76 (0.6, 0.96) 
om 
54~' 
45% 
(48, 60) 
(37, 51) 
Across both studies, 243 of676 Ritll'<:m-lrealed patients (36'1.) were 65 years of age or older and 
I 00 Rituxan-lreated patients (15'1.) were 70 years of age or older. The results of e"!'loralory subset 
analyses in elderly patients are presented in Table 8. 
Table 8 
Efficacy Restdts in Studies I I and 12 in SubgrotlpS Defined by Age• 
Srudy 11 
Srudy 12 
Nwllbtr of 
!l.ullld RAtio for 
Numbtr of H.wrd RAtio for PFS 
Ap ...... oup 
Patiii.UI 
PFS(9mCI) 
Plltitua 
(95!1CI) 
A&• <65Y" 
572 
0.52 (OJ9, 0.70) 
lll 
0.61 (0.45, 0.34) 
Age ?:-65)n 
245 
0.62 (OJ9, 0.99) 
233 
0.99 (0.70, 1.40) 
A(e <70y5 
736 
0.51 (039, 0.67) 
438 
0.67 (O.SI, O.B7) 
Ap ~?O}t' 
81 
l.l7(0j l, 2.66) 
lOS 
1.22 (0.73, 2.04) 
• From txplon.toty aD3J)'WS. 
H.6 Rhtwnotoi<l Arduitis (RA) 
Redud ng lite Sig11s mJd S)7!ptoms: Initial a11d Re-Treamrenl Coru·ses 
The efficacy and safety ofRillL'<lllt were evaluated in two randomized, double-blind, 
placebo<onlrolled si!IC!ies of adult patients t>ith moderately to severely active RA who had a prior 
madequate respon<e to at least one 1NF inlubitor. Patients were 18 years of a~e or older, diagnosed 
with active. RA according to American College of Rheumatology (ACR) critena, and had at least 
8 swollen and 8 tender joints. 
In RA Sntdy I, patientS\vere randomized to receive either Ritm<an 2 x 1000 mg+MIX or 
placebo+MIX for 24 weeks. flniller Cotll'SeS of RihL'wt 2x 1000 mg+lviTX were administered itt 
an open label e>.i eusion slltdy at a frequency detenuined by clinical evaluation, but no sooner than 
16 weeks after tile preceding course of Ritm<an In addition to tile ittlravetlOus premedication, 
glucocorticoids were administered orally on a tapering sclledLde from baseline througll Day 14. The 
proportion< of patients ac.hieving ACR 20, 50, and 70 responses at Week 24 of the 
placebo<onlrolled period are sl10t>11 itt Table 9. 
In RA Sntdy 2, all patiettts received the tiM cmll'Se of Rincxan 2 x I 000 mg + MIX. Patiettts wl10 
experienced ongoing disease ac.th.ity were randomized to receive a second course of either Rituxan 
2 x 1000 mg + !viTXor placebo +MIX, the majority between Weeks 24-28. The proportions of 


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patients achie'>ing ACR 20, 50, and 70 respon.sts at Week 24, btfore the re.treatiOOlt cow..t, and at 
Wed< 48, after r.treatmtnt, art shO\w in Table 9. 
R.tsponst 
ACR20 
Wotll l 4 
ACR50 
Week24 
ACR70 
Wotll l 4 
Table 9 
ACR Responses in Study I and Snldy 2 (Percent of Patients) 
(Modified Intent-to-Treat Population) 
lmdequa:e Respcms.e to nJF Alua;oui>n 
Srudy l 
Study l 
24\Veek Pbc.OO·OxuroUtd 
Pbctbo·Controlltd Racre:nmtDI 
(Wtok l 4) 
(Wtok l 4lllld \VIti< 48) 
Treo.'"""' 
Tteo.lllltlll 
Dlll'>r••:t 
Pllctbo+ 
Riti.DWI + 
Dl«muce 
Pbcello + 
Rlnrom+ 
(Riru.'WI-
Ml"J( 
MTX 
(Rinrom -
Ml"J( 
MTX 
PL1ctboY 
Rttt-
Rtlru"""" 
Plactbo)"" 
•= lCI 
• =298 
(9~! C!) 
Rtsponst 
•= IS7 
• = 318 
(9S% C!) 
ACR20 
18" 
5m 
HI! 
Wotll l4 
:~g,i 
45,, 
NA 
(26%,41%) 
Wotll 48 
:mi 
.)40# ,, 
lll! 
rnuom 
ACRSO 
5,. 
27,. 
21% 
\VHk 24 
mo 
21% 
NA 
(15%, 2.,., 
IVHI< 48 
26% 
29% 
4,. 
(-4%, lll>l 
ACR70 
m 
tm 
11'4 
\VItlll4 
11'4 
m 
NA 
(11~ 151!) 
IVHI<48 
ll" 
14% 
m 
(·511, 81!) 
' In Srtll!y 2, aD ~riems rtcen"ed a tint cotm.e o!Rirtroo 2 x 1000 mg. Patients wbo t.~enced oo:oin: ch;.ease 
acthity wm f'!Uldomiztd to recei\'t a !M-ood cOUl"St of tither Rit\L'Wl2 x 1000 m:, +~fiX or pbcebo + MTX at or 
afttt Wtek 24. 
11 SiDce all pa1imts receh'Eda fiN comse of Rltu."Ull,. oo co!llp3li;oll bem"teD Placebo + M'TX :met Ritll.'::m +MIX{; 
mdeat Week 24. 
c For Srudy 1, v.-ei:;ll:ed differexe 5tr3tifie<l by repon (US, rt'>t of me world) m1 Rhe\lm.'ltoid Factor(RF) \t3ru:. 
(posirh:e ,. 20 IVfml., ne~rh:e < 20 n.JfruL) at ba:>eliDe; For Study 2, wei:lred differe-:nce \tratified by RF \tlnts at 
OOseline 3lld :: 20..• in:q>ro\--emel1 from ba:>elme in boili SJC ruld TJC a1 Week 24 (Yes.1No). 
Improvement was also noted for all components of ACR response following treatment with 
Ritwlllll, as shO\w in Table 10. 


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ToblelO 
Components of ACR Response at Week 24 in Study 1 
(Modified lntent.to-Treat Populotion) 
hladequa~e Re;pom.e to TNF Antl.:o~sts 
Pl>cobo+ ~rrx 
RiNWl+~fiX 
"""""''" 
(n: 201) 
(n=298) 
(~ 
B>ltlille 
Wl<24 -· 
Wl< 24 
Tender Joim Coum 
31.0 
2?.0 
33.0 
13.0 
S\lo"'lltn Joim Cou:::u 
20.0 
19.0 
21.0 
9.S 
P!i)•sirun G!.cbal As.wssmeut" 
11.0 
69.0 
11.0 
36.0 
Pltit:11 Global Asltmueat 
13.0 
68.0 
11.0 
41.0 
~· 
68.0 
68.0 
61.0 
3S.S 
Dil4bility Ioclex (IIAQ)' 
2.0 
1.9 
1.9 
l.S 
CRP(m;ldL) 
2.4 
2.5 
2.6 
0.9 
• Visu31AtWoguoSalo: O=be<t, 100=wcnt 
• Disability ID!Iiex of the He3ltb Asws-we-:m Questiollll3ire: O=be~ 3 =u.-om. 
The time course of ACR 20 response for Stltdy I is sbo"u in Figure 2. Although both treatment 
groups rteeived a brief course of intnll'enous ond oral glucocorticoids, resulting in similar benefits at 
Week 4, higher ACR 20 responses were observed for tiie Ritlruul group by Week 8. A similar 
proportion of patients achieved these responses through Week 24 after a single course of treatment 
(2 infttsions) "'th Ritlvtan. Similar patterns were dtlllOnstrated for ACR 50 ond 70 responses. 


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100 
90 
"' 
w 
.. 
Q) , 
c 
70 
0 
Q. 
"' 
6() 
Q) 
0:: 
~ 
5() 
0:: 
40 
() 
c( 
30 
~ 
~ .. 
20 
Q) 
0.. 
10 
0 
Figurt 2 
Ptrtmt of Patimts Aehitving ACR 20 Responst by Visit• 
Study I (Inadequate Respon<e to TNF Antagonists) 
0 
Weeks 
.... Placebo (n=201) ·•·Rituxan 2x1000mg (n=298) 
Radiographic Rssponse 
In RA Study I, stmeturnl joint damagt was asStSStd radiogrnphieally and t"PftSStd as changes in 
Genant-modified Total Sha!]> Score (TSS) and its components, the erosion score (ES) and the joint 
space ruurowi.ug (JSN) score. Ritu.xan +MIX slowed the progression of stmcnU'al damage 
compartd to placebo +MIX after I year as shown in Table II. 


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Tab1t ll 
Mean Radiographic Change From Ba;eline to 1()4 Weeks 
ID3doq\l>tt ~ 
,. n<F Awngoolm 
Ri= 
Treatmt:u DifftitDct 
Par!Ullittr 
2K I 000 011 + MIX' 
Plactbo+ MD( 
(Piac lbo - Riru:om) 
~'Y!:s 2-..1s: f~"ll :r 'lr 
TSS 
0.66 
t.n 
1.11 
ES 
0.44 
1.19 
0.15 
JSN!.<ort 
0.22 
o.ss 
0.36 
Cbn~t dluin; S«olld Yt3.1'" 
TSS 
0.48 
1.04 
-
ES 
0.28 
0.62 
-
JSN!.<ort 
0.20 
Ml 
-
' S.sed OD J>diop11pbic SCorilll folmii>J I04 WoW o{ Obi.!YDDOO. 
11 P:uiws rteth.'td \q) «o 2 yem of trtaunmt "itb Riftl.UD+ MTX. 
Pm CI 
(0.47, 1.75) 
(0.>2, 1.19) 
(0.10, 0.62) 
-
-
-
c ~tie-:1ts recehin; Placebo+ ~1TX. Patients rec:eMllg Placebo+M!X could l:m:e received rett&trul!lll: with 
RituwH).fTX from Week 1603\\'a!d. 
In RA Study 1lllld its open-label extension, 70% of patients initially mndomized to Ritlc'ClUl 
+ MTX and 72% of patients initially mndomized to placebo + MrX were evaluated 
radiographically at Year 2. As shown in Table 11, progression of structurnl damage in Rillcxan 
+ MTX patients was further reduced in the second year of treatment. 
Following 2 years of treatment with RiiiLxan +MIX, 57% of patients bad no progrt$sion of 
struct\ual damage. During the first yeM, 60% ofRiiiLxan + MTX treated patients had no 
progression, defined as a change in TSS of zero or less compared to baseline, compared to 46% of 
placebo + MTX treated patients. In their second )'ta! of treatment "'lh RiiiL•an + MIX, lllOre 
patients had no progression ihan in the first year (68% vs. 60'!.), and 87% of the Rilltxan + MTX 
treated patients who had 110 progression in the first year also had no progression in the second year. 
Lesser Efficacy of500 Vs. 1000 mg Tr·eatmem Courses for· Rndiog>nplric Outcomes 
RA Study 3 is a mndomized, double-blind, pla<ebo-controlled study which evaluated ihe effect of 
placebo + MTX compared to Ritw<an 2 x 500 mg + MTX liJld Rit\Lxan 2 • 1000 mg + MTX 
treatment cOtllStS in MTX-naive RA patients with modemtely to severely octive disease. Patients 
recei\oed a first course of two infusiOllS of rii\OOmab or placebo on Da~1 l and 15. MTX was 
initiated at 7.5 m@week liJld escalated up to 20 m@week by Week 8 in aU dtree treatment arms. 
After a minimum of24 weeks, patients with ongoing disease activity were eligible to receive 
re-treatrntnt wiih additioo.'\1 coun;es of their assigned treatment. After one year of treatment, the 
proportion of patients achieving ACR 20150nO responses were similar in boih Ritwtan dose groups 
liJld were higher than in dte placebo group. However, with respect to radiographic scores, only the 
Ritwtan I 000 mg treatment gr<>tlp demonstrated a statimcally sipillicallt reduction in TSS: a change 
of0.36 twits compared to 1.08 twits for the plocebo group, a 67% reduction. 
Plrysical Frmction Response 
RA St\tdy 4 is a mndomized, double-blind, pla<ebo-controlled study in adult RA patients wiih 
moderately to severely active disease \rith inadequate respon1e to !viTX. Patients were randomized 
to recehoe. an initial course. of RihL""' 500 mg, Rit\Lxan 1000 mg, or placebo in addition to 
bockgrotmd MTX. 


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Physical ftu>ction was assessed at Weeks 24 and 48ming the Health A=weul Questiormaire 
Disability Index (HAQ-DI). From baseline to Week 24, a gl"ater proportion ofRitu.xan-treated 
patients had an improvement in HAQ-DI of at least 0.22 (a minimal clinically important difference) 
and a gr.ater mtan HAQ-DI imprO\'twent cowpmd to placebo, as shO\m in Table 12. HAQ-DI 
results for the Rill""'' 500 wg treatment group were similar to tl>e Ritu.•an I 000 mg lreatwenl 
group; however radiographic respons.s were not ass.ssed (see Dosing Precaution in the 
Radlographic. Responses section abo\•e). These improvements were. maintained at 48 weel<s. 
Tobit ll 
Iwprovernent from Baselil>e ill Health Assessment 
Questiom>aire Disability Index (HAQ-Dl) at Week 24 ill Study 4 
Me,. ln>prol:emtlll flom S.U.U.. 
Ptrcflll o(patlmts wilh ''lmpm'td" Kort 
(Ch."'lt flnm B•"line • MCID)' 
Placebo +).fiX 
•=In 
0.19 
RinL'Wl 
'l•lOOO 
~+MIX 
O: t70 
0.42 
5!% 
' Millilwll Clilli<lllly lmponn:n DilferOlce: MCID for I!AQ= 0.22. 
Trt:aantm Ditrtl'tlKt 
(Ri=- Placebo}' 
(95%CI) 
0.23 (0.11, OJ4) 
11%(0%, 21%) 
• Adjusted differeJxe sa:uified b)• regioo (US, r~t of the world) :md rbetou:l:oid fuaor(RF) sum; 
(po$iti\ 't :.: 20 ruhul., lltg;lti\ 't < 20 nJ/ml ) at bastlwt. 
U.7 
Granulomatosis uiih Polyangiiris (GPA) (Wegener's Granulomatosis) ancl Microscopic 
Polyangiiris (MPA) 
A total of 197 patients wilh acti\-e, &e\..re GPA and MP A (two forms of ANCA Associated 
Vasculidities) wm lreated in a mnclowized, double-blind, active-conlrolled multicenter, 
non-inferiority snldy, conducted in two phases-a 6 mouth rewissiouulduction phase and a 
12 wand! remission maintenance phase. Patients were 15 years of age or older, diagnosed with GPA 
(75% of patients) or MPA (24% of patients) according to the Chapel Hill Consensus conference 
criteria (I% of the patients had unl:no1w vaSClilitis type). AU patients had acti,,e disease, \\id! a 
Binningham Vasauitis Activity Score for Gramuomatosis with Polyangiitis (BVAS/GPA) ::: 3, and 
their disease was severe, \\ith at least one major item on theBVAS/GPA. Ninety-six (49'/o) of 
patients had new disease and 101 (51%) of patients had relapsing disease. 
Patients in both arms received 1000 wg of pulse inlravenous mtd!ylprednisolone per day for I to 
3 days \\ithin 14 days prior to initial infn1ion. Patients were randomized ill a I: I ratio to receive 
either ~an 3751Df!m2 ouee weekly for 4 weeks or oral cyclophospb.-unide. 2 ~g 
daily for 3 to 
6 mouths in the remission induction phase. Patients were pre-medicated "ith antihistrunine and 
acetruninophtn prior to RitltXM inftiSion. FoiiO\ving inlnwenous corticosteroid administration, all 
patients received oral prednisor\e (I tngik~day, not meedil~g so wuday) tvith pre-specified 
tapering. Once remission was achieved or at the end of the 6 month remission induction period, the 
cyclophosphamide group received azathioprine. to maintain remission. The. Ritu.xan group did not 
receive additional thera.py to mairllain renlission. The nuin outcon>e measure for both GPA and 
MP A patients was achievement of complete remission at 6 monthl defined as a BVASIGPA ofO, 
and oil' glucocorticoid therapy. The pre-specified non-inferiority mar~ was a treannent difference 
of20%. As sho\m in Table 13, the. stlldy demonstrated non-inferiority ofRitu.xan to 
C}dophosph.-unide for complete renlission at 6 wouths. 


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Tabltl.l 
Peitenmge of Patients Who Achitved 
Complete Remission at 6 Months (Intent-to-Treat Population) 
R.ttt 
Sls.uo" cr 
RilWWl 
<•=99) 
64% 
(S4'~ 73%) 
C)<lopbO!plwnklt 
<•=98) 
53% 
(43,~ 63%) 
TrUUlltDt DiffHtoct 
(RilWWl -
C)·clopbo.pbawjde) 
11% 
(- 3!-"'o, 24%). 
• nm-in!'erlo!ity was demoustr.!.ted became the lower bowd lWS higber th:m the pmped1led 
noo-in!erlorlty ll!rulin (- 3%:. - 21Mt). 
11 Tht Sl).l't <OD.fidfllc.tlt\'tl rtOtcts Ill additiODll 0.001 alpb.1 ~0 ICCOUilt far Ill i:D:trim tfficacy 
onalj"lis. 
Complete Remission (C/l) at 12 mid 18 mcntlls 
In the RiiiL'<llll group, 44% of patients achieved CR at 6 and 12 months, and 38% of patients 
achie\•ed CR at 6, 12, and 18 months. In patients treated "'ith cyclophosphamide (followed by 
azathioprine for maintenance of CRJ, 38% of patients achieved CR at 6 and 12 months, and 31% of 
patients achieved CR at 6, 12, and 18 months. 
Rctreatma1t -..ith Rinam1 
Based upon ioveo:tigator judgmm~ 15 patients rec~ved a second course ofRiiiL'Cllll therapy for 
treatment of relapse of disease activity whic.h OOCtured between 8 and 17 lllOnths after the first 
course of Rill"an. The limited data preclude any conclusions regarding the efficacy of subsequent 
courses ofRiiiL'Ulll in patients \\1th GPA and MPA [see Wamfngs and Precautfo11s (5.14)]. 
16 
HOW SliPPUED/STOR'\GE .~'0 ll~'DLING 
RiiiL'<llll vials [100 mg/10 mL single-use '1als (NDC 50242-051-21) and 500 mg/50 mL single-me 
~ials (NDC 50242-053-06)] are stable at 2•C-8•C (36"F-46•F). Ritu.'<llll vials shotdd be protected 
from direct sunlight. Do not freeze or shal:e. 
17 
PA TIL'IT COUNSELING INFORU-\TION 
Patients should be provided the Rituxan Medication Gttide and pro\1ded an opporllntity to read 
prior to each treatment session. It is important that the patient's overall bealth be asses1ed at each 
~isit and the risks of Rituxan therapy and any questions restdting from the patient's reading of the 
Medication Guide be discussed See IDA approved patient labeling (Medication Guide). 
RiiiL'GUl is detectable in sennn for up to si.~ mouths foll01,1Dg completion of therapy. Individuals 
of childbearing potential sh01dd use effective contraception during treatment and for 12 months after 
Rituxau tl>erapy. 
RI11JXAN [rituxhnob) 
Manufactured by: 
Genentecb, Inc. 
A Member of the Rodlt Group 
I DNA Way 
South San Francisco, CA 94080-4990 
US Licen1e N10uber I 048 
Rin"all" is a registered trademark of Biogen Idee, h1c. 
e2014 Biogeo Idee, Inc. and Geneotech, Inc. 


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ME DI CATION GUI DE 
Rituxan• ( .. i-tuk-san) 
( rituximab) 
injection 
Read this Medic.ation Guidt before you st• •t Rituxan •nd befort u ch Ritux1n infusion. 
The•·e may be new in fo•·mation. This Medication Guide does not take the place of 
ta lking to your doctor a bout your med ical condition or your t reatment. 
What is the most important infor~na t ion 1 should know about Rituxan? 
Rituxan can uus.e se•ious side effects that can lu d to death, including: 
Infus ion reactions. Infusion react ions a re the most common side effect of Rituxa n 
treitment. Se•ious infusion reactions can hi ppen during your infusion or within 24 
hours aft:e•· your infusion of Rituxan. You•· doctor should give you medicines before 
you•· infusion of Rituxan to decreas e you•· chance of having a severe infusion 
reaction. 
Tell your dodo•· or get medical help l'ight awa y if you get any of these symptoms 
duling or after an infusion of Ritux.an: 
hives (red itchy wtlts) or r~sh 
itching 
swelling of your lips, tongue, thro~ t or f~ct 
sudden cough 
shortness of breath, difficulty breathing, or wheezing 
weakness 
dizziness or feel faint 
palpitations (feel like your h•ea•'t is racing Ol' Rutte•·ing) 
chest pain 
Severe skin a nd mouth react ions. Tell you•· doctor o•· get medical help right 
away if you get any of these symptoms at anytime duling your treatment with 
Rituxan: 
painful so•·es Ol' ulcers on yo Ul' skin, lips o•· in you•· mouth 
blisters 
peeling skin 
rash 
pustults 
He patitis 8 virus {HBV) re activation. Before Rituxan tJ·eatment, your doctor will 
do blood tests to check for HBV infection. If you have had hepatitis 8 or art a 
car•·ier of hepatitis 8 virus, •·eceiving Rituxan could cause the virus to become an 
active infection again. Hepatitis 8 reactivation may cause serious live.· p1·oblems 
including liver failure, and death. You should not receive Rituxan if you have active 
hepatitis B liver disease. Your doctor will monitor you for hepatitis B infection 
du•ing 1nd fo•· uv•r1l months aft• r you stop r•ctiving Rituxan. 
Progressive Mult ifoca l Leukoencephalopathy {PML). PML is a rare, serious 
brain inftction uustd by il virus. !People with weakened immune systems un get 
PML You•· chance of getting PML m ay be highe•· if you are t.·eated with Rituxan 
alone or with other medicines that weaken your immune system. PML can result in 


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death or seve re disability. There is no known treatment, preve ntion, or cure for 
PML. 
Tell your doctor 1i ght a wa y if you have any of the following symptoms or if a nyone 
close to you notices t hese symptoms: 
confusion or problems th inking 
lou of bal1nct 
change in the way you walk or talk 
dec•·eased st•·ength or \veakness on one side of yoUI' body 
blurred vision or loss of vision 
See • wha t are the poss ible side effects of Rituxan?" for more information about 
side effects. 
What is Rituxan? 
Rituxa n is a prescription medicine used to treat: 
Non-Hodgkin's Lymphoma ( NHL): 1lone or wit h other chemotherapy medicines. 
Chronic Lymphocytic Leukem ia (CLL): \vith the chemotherapy medicine s 
fludarabine and cyclophosphamide. 
Rheumatoid Art h ritis ( RA ): wit h another presc•i ption medicine called 
met hotrexate, to reduce the signs and sym ptoms of moderate to severe active RA 
in adults, after treat me nt wit h at least one othe r medicine called a Tumor Necrosis 
Factor (TNF) antagonist has been used a nd did not work well e nough. 
Granulomatosis w ith Polyangiitis (GPA) (Wegen e r's Granulomatosis) and 
Microscop ic Polyangiit is ( MPA) : with glucocorticoids, to b·eat GPA and MPA. 
People with sedous infections should not receive Rituxan. 
It is not known if Rit uxan is safe or effective in ch ildren. 
What s hould I te ll my doctor before receiving Rltuxan ? 
Before receiving Rituxan, tell your doctor if you: 
have hid a severe infusion re action to Ritux1n in the put 
have a histo1y of hea1t problems, iiTegula r hea1t beat or che st pain 
have lung or kidney problem s 
have a n infection or weake ned immune system. 
have or have had a ny severe infections including: 
Hep1titis 8 virus (H BV) 
Hopatltls C vi•us (HCV) 
Cytomegalovh·us (CMV) 
He rpes simplex virus (HSV) 
Pa rvovirus 819 
Va1icella zoster virus (chickenpox or shingles) 
West Nile Virus 
have had a •·ecent vaccination o•· are scheduled to receive vaccinations. You 
should not •·eceive certa in vaccines befo•·e o•· afte•· you receive Rituxan. Tell your 
docto•· If anyone In you•· house hold Is sche duled to rece ive a vaccination. Some 


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types of vaccines can spread to people with a weakened immune system, and 
uuse se1ious problems. 
have taken Rituxan for GPA or MPA in the past. 
have any other medical conditions 
are pregnant or planning to become pregnant. Rituxan may affect the white blood 
cell counts of your unborn baby. It is not known if Rituxan may ha1m your unborn 
baby in otht:l' ways. 
Women who are able to become pre9nant should use effective birth control 
(contractption) whilt using Rituxan and for 12 months afttr you finish trntmtnt. 
Talk to your docto1· about effective bh'th control. 
are b•·ust·feedlng o•· plan to b•·ust·feed. It Is not known If Rituxan passes Into 
your breast milk. You and your doctor should decide the best 'vtay to feed your 
baby if you receive Rituxan. 
Tell your doctor about all the medicines you take, including presct·iption and over-the· 
counter medicines, vitamins, and herbal supplements. Especially tell your doctor if you 
t1kt or have tilktn: 
a Tumor Necrosis Factor (TNF) inhibitor medicine 
a Disuse Modifying Anti· Rheumatic Drug (DMARD) 
If you are not sure if )'Our medicine is one listed above, ask you r doctor or pharmacist. 
Know the medicines pu take. Keep a list of them to show to your doctor and 
pharmacist when you get a new medicine. Do not take any new medicine without 
talking with your docto•·· 
How w ill I r·ece ive Rituxan? 
Rituxan is given b•t infusion through a needle placed in a vein (intravenous 
infusion), in your ann. Talk to you•· doctor about how you will receive Rituxan. 
Your doctor may ~rescribt medicines before each infusion of Ritux1n to reduc.t side 
effects of infusions such as feve•· and chills. 
Your doctor should do •·egular blood tests to check for side effed:s to Rituxan. 
Before each Rituxan treatment. your doctor or nurse will ask you questions about your 
gene•·al health. Tell your dodo•· or nu1-se about any new symptoms. 
What a re. the possible sid e effects of Rituxa n? 
Rituxan can cause senous and life· threatening side effects, including: 
See " What is t he most important infor mation I should k now ~ bout Rituxan?" 
Tumor Lys is Syndrome (TLS ). TLS is caused by the fast breakdown of cancer 
cells. TLS can cause you to have: 
kidney failu•-e and the need fo•· dialysis tl·eatment 
abnormal heart rhythm 
Your doctor may do blood tests to check you for TLS. Your doctor may give you 
medicine to help prevent TLS. 
Serious infections. Serious infections can happen during and after b·eatment with 
Rituxan, and can lead to death. Rituxan can lower the ability of your immune 
systtm to fight inftctions. Typu of se•ious infections that un happen with Rituxan 
include bactel'ial, fungal, and vh·al lnfections. Afte•· receiving Ri t~xan, some patients 


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have d eve loped lo\v levels of ce•t a in a ntibodies in their blood for a long period of 
time (Ionge•· than 11 months). Some of these patie nts \vith low a ntibody le ve ls 
developed infections. Ca II you•· docto r •·ight a wa y if you have any symptoms of 
infection : 
feve•· 
cold s ymptoms, s uch as runny nose or sore th•·oa t that do not go a\vay 
Au s ymptoms, s uch as cough, ti•·edness, a nd body aches 
ea•·a che or headadhe 
pain dudng urination 
whit e patches in th e mouth o•· th•·oa t 
cuts, sc•·apes or inc isions t hat are •·ed, wa •m, s wollen or pa inful 
Heart problems. Rituxa n may ca use chest pain a nd in·egula r heart beats \vhich 
may need treatm ent, or you•· doctor may decide to stop you•· treatment wit h 
Rituxan. 
Kid ney problems1 espec ia lly if you a re receiving Rituxa n for NHL. You•· docto.r 
s hould do blood tests to check how well your kidneys a re working . 
S tomach a nd Serious bowe l problems t hat can sometim es lead to death . 
Bowel problems, includin.g blockage or tears in the bowel can happe n if you •·ecoeive 
Rituxan with che mothe ra py m edicines to t •·eat non-Hodgkin's lymphoma . Te ll your 
doctor 1i ght a way if you ha ve a ny stomach a rea pa in during t.·eatm ent \vith Rituxa n. 
low blood cell cou nts. Your docto•· ma y do blood tests during t.·eatm ent w ith 
Rituxan to check you•· blo od ce ll counts. 
White b lood cells. White blood cells fight against bacterial infections. l o\v 
whit e blood ce lls ca n ca use :fO U to get infections, which may be se1i ous . See 
"Inc.-eased risk of infections above fo•· a list of s ymptoms of infection. 
Red blood cells . Red blood cells car•y oxygen to your body t issues a nd 
organs. 
Platelets. Plat elet s a •·e blood cells that he lp your blood to clot. 
Common s ide effects d u ri'ng Rituxan treatme nt include: 
infus ion reactions (see " What is the m ost important information I shou ld 
know a bout Rit uxan? "') 
chills 
infections 
body a ches 
ti•·edness 
low white blood cells 
Othe r side effects with Ritux an include : 
a ching joints during or w it hin hours of •·eceiving a n infus ion 
more frequent upper res pirato•y tract infection 
Tell you•· docto r about any side effect t hat bothers you or that does not go away. 
These a re not a ll of the possible side effect s wit h Rituxan. f o•· mo•·e information, ask 
your docto•· or pha rma cist. 


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Call your doctor for medical advice about side effects. You may report side effects to 
FDA at 1-800-FDA-1088. 
General information about Rituxan 
Medicines are sometimes prescribed for purposes other than those listed in a 
Medication Guide. This Medication Guide provides a summary of the most important 
information about Rituxan. If you would like more information, talk with your doctor. 
You can ask your doctor for information about Rituxan that is written for healthcare 
professionals. 
For more information, go to www.Rituxan.com or call 1-877-474-8892. 
What are the ingredients in Rit uxan? 
Active ingredient: rituximab 
Inactive ingredients: polysorbate 80, sodium chloride, sodium citrate dihydrate, and 
water for injection. 
This Medication Guide has been approved by the U.S. Food and Drug Administration. 
Manufactured by: 
Genent ech, Inc. 
A Member of the Roche Group 
1 DNA Way 
South San Francisco, CA 94080 4990 
US License Number 1048 
Jointly Marketed by: Biogen Inc. and Genentech USA, Inc. 
Revised: April 2016 
Rituxan® is a registered trademark of Biogen Inc. 
© 2016 Biogen I nc. and Genentech, Inc. 


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Notes: (1) Document details as stored in ANGEL, an AstraZeneca document management system.  
study-protocol-mi-cp204-v13
An Open-label, Phase 1/2 Study of MEDI-551, a Humanized Monoclonal
Antibody Directed Against CD19, in Adult Subjects With Relapsed or Refractory
Advanced B-cell Malignancies
Doc ID-001136813
22.0
Approved
CURRENT
LATEST
10-Jul-2017 20:05 GMT+0100
Medical Monitor
Approval
11-Jul-2017 16:16 GMT+0100
Clinical Operations
Approval
11-Jul-2017 20:32 GMT+0100
Research Approval
12-Jul-2017 23:01 GMT+0100
Biostatistics Approval
13-Jul-2017 18:30 GMT+0100
Clinical Development
Approval

SAP_000.pdf: 
MedImmune 
 
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CONFIDENTIAL AND PROPRIETARY 
1 of 25 
 
STATISTICAL ANALYSIS PLAN  
 
Protocol Number: MI-CP204 
 
An Open-label, Phase 1/2 Study of MEDI-551, a Humanized 
Monoclonal Antibody Directed Against CD19, in Adult Subjects 
With Relapsed or Refractory Advanced B-Cell Malignancies 
 
 
 
 


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TABLE OF CONTENTS 
1 
INTRODUCTION ...................................................................................................... 3 
2 
BACKGROUND ........................................................................................................ 3 
2.1 
Study Overview ................................................................................................ 4 
2.2 
Randomization and Blinding ............................................................................. 9 
2.3 
Schedule of Study Procedures ......................................................................... 10 
2.4 
Sample Size Considerations ............................................................................ 10 
3 
STATISTICAL METHODS ...................................................................................... 11 
3.1 
General Considerations ................................................................................... 11 
3.2 
Subject Populations ......................................................................................... 12 
3.3 
Subject Disposition ......................................................................................... 12 
3.4 
Baseline Characteristics .................................................................................. 13 
3.5 
Study Drug Exposure ...................................................................................... 14 
3.6 
MTD or OBD/Highest Protocol-Defined Dose ................................................ 16 
3.7 
Safety Assessments ......................................................................................... 16 
3.8 
Efficacy Assessments ...................................................................................... 18 
3.9 
Pharmacokinetic Assessments ......................................................................... 22 
3.10 Assessment of Effect on Circulating Lymphocyte Populations ........................ 22 
3.11 Immunogenecity Assessments ......................................................................... 23 
3.12 Exploratory Summaries ................................................................................... 23 
4 
INTERIM SAFETY ANALYSES ............................................................................. 24 
5 
REFERENCES ......................................................................................................... 24 
 
LIST OF IN-TEXT TABLES 
Table 2.4-1 
True Underlying DLT Rate at a Given Dose Level............................ 10 
Table 3.8-1 
Definition and censoring information for DOR ................................. 20 
Table 3.8-2 
Definition and censoring information for TTP .................................. 21 
Table 3.8-3 
Definition and censoring information for PFS ................................... 22 
 
 
 
 
 
 


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1 
INTRODUCTION 
This document describes the statistical methodology and summaries for Study MI-CP204, an 
investigation of MEDI-551 in adult subjects with relapsed or refractory advanced B-cell 
malignancies.  As background information, an overview of the study design is provided.  The 
main portion of this document details the statistical summaries relating to each study 
objective and describes the general conventions and definitions that will be used.   
In addition, a set of table templates and specifications will be provided in a statistical 
programming plan to complement this document.   
2 
BACKGROUND 
Cluster of Differentiation (CD) antigen 19 (CD19) is a B-cell-restricted transmembrane 
protein member of the immunoglobulin (Ig) superfamily encoded by the CD19 gene (Cooper 
et al, 2004). CD19 expression in B-cell leukemias and lymphomas is widespread. CD19 is 
expressed in chronic lymphocytic leukemia (CLL), acute lymphocytic leukemia (ALL), and 
B-cell non-Hodgkin’s lymphoma (NHL) (Uckun et al, 1988; D’Arena et al, 2000; Ginaldi et 
al, 1998; Anderson et al, 1984).  
Treatment of B-cell CLL and NHL, the largest groups of hematologic malignancies, relies 
primarily on a combination of chemotherapy and biotherapy based on the monoclonal 
antibody rituximab, directed against CD20 (Robak, 2007). While many patients achieve 
long-lasting remissions with this combination in both CLL and NHL, patients whose disease 
progresses after treatment with rituximab and/or commonly used chemotherapies have few 
effective options (Robak, 2007; Coiffier, September 2005; Coiffier, March 2005). With each 
subsequent treatment, the duration of remission usually becomes shorter and, eventually, 
most CLL and NHL patients die from their disease (Hennessy et al, 2004). Therefore patients 
who have relapsed or refractory NHL or CLL that is no longer responsive to rituximab or 
chemotherapy have an unmet medical need. The broad expression profile of CD19 on B-cell 
malignancies, including ALL, CLL, and NHL, makes this an attractive target both for 
patients in whom therapy with rituximab has failed and as a potential first-line treatment 
(Uckun et al, 1988). In multiple myeloma (MM), patients who are not candidates for a stem 
cell transplant (SCT) can achieve durable remissions with first-line chemotherapeutic 
regimens (San Miguel et al, 2008), but nearly all patients will eventually experience relapse 
and require subsequent therapy (Richardson et al, 2003). As with other B-cell malignancies, 
in MM, therapy with subsequent lines has a lower effectiveness and shorter duration 
(Richardson et al, 2003). MM patients who have received multiple lines of therapy likely 
have higher percentages of CD19-expressing cells (Matsui et al, 2008) and, because this may 


MedImmune 
 
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CONFIDENTIAL AND PROPRIETARY 
4 of 25 
represent a stem cell population that is resistant to available chemotherapies, these patients 
have an unmet medical need. 
MEDI-551 is a humanized Immunoglobulin G (IgG)1 kappa monoclonal antibody (MAb) 
directed against human CD19. MEDI-551 efficiently depletes blood and tissue B cells in 
human CD19 transgenic (huCD19 Tg) mice and has antitumor activity in severe combined 
immunodeficiency (SCID) mouse models of human B cell leukemia, lymphoma and MM. 
MEDI-551 does not bind CD20, and thus activity of MEDI-551 should be independent of 
activity of rituximab or other CD20-targeted therapies. MEDI-551 is expected to selectively 
target B cells, with antitumor activity in a variety of B-cell-derived malignancies. More 
details on the clinical experience with MEDI-551 can be found in the Section 1.4 of the 
protocol. 
2.1 
Study Overview 
This is a Phase 1/2, multicenter, international, open-label, dose-escalation and expanded 
cohort study to evaluate the safety, tolerability, and potential antitumor activity of MEDI-551 
as single agent or in combination with rituximab in adult subjects with advanced B cell 
malignancies. The study design of Arm A comprises a dose-escalation phase followed by a 
dose-expansion phase in subjects with advanced B-cell malignancies receiving single-agent 
MEDI-551. This study arm included participants from 5 to 30 investigational sites in the 
United States (US), Canada, and European Union (EU). As of Version 10.0 of the protocol, 
the study design also includes dose escalation and expansion in subjects with CLL receiving 
single-agent MEDI-551 (Arm B), and dose escalation and expansion in subjects with 
aggressive lymphoma receiving MEDI-551 combined with rituximab (Arm C). As of Version 
11.0 of the protocol, the study design also includes subjects with any anti-CD20-refractory 
aggressive lymphoma receiving single-agent MEDI-551 (Arm D). Arms B, C, and D will 
include participants from 20 investigational sites in the US and 10 to 15 sites in the EU. 
Arm A 
Enrollment in the dose-escalation and expansion phases of Arm A is complete. Protocol 
Version 4.0 was amended to make the study population for dose-escalation inclusive of 
subjects with FL, multiple myeloma (MM), CLL, or DLBCL. Dose escalation in Arm A 
began in subjects with FL or MM per protocol Versions 1.0 through 4.0. Subjects were 
enrolled into the first 2 cohorts under these versions of the protocol. Starting with Version 
5.0 of the protocol, enrollment in dose-escalation Cohorts 3 and higher was open to subjects 
with the following advanced B-cell malignancies: FL, MM, CLL, or DLBCL. Subjects in 
Cohorts 1 and 2 were to continue to follow the protocol Version 4.0 dose schedule of 0.5 


MedImmune 
 
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CONFIDENTIAL AND PROPRIETARY 
5 of 25 
mg/kg (Cohort 1) or 1 mg/kg (Cohort 2) MEDI-551 administered intravenously (IV) once 
every week in 4-week cycles. Subjects enrolled in Cohorts 3 and higher received 2, 4, 8, or 
12 mg/kg MEDI-551 (Cohorts 3 to 6, respectively) IV once per week on Days 1 and 8 of 
Cycle 1 (loading doses) and then once every 28 days at the start of each subsequent cycle. As 
per Cohorts 1 and 2, dosing in Cohorts 3 and higher followed a standard 3+3 dose-escalation 
scheme. Subjects in Arm A were not to receive a MEDI-551 dose greater than 12 mg/kg. No 
intra-subject dose escalation was allowed. 
Arm B 
Based on evaluation of the PK data in CLL subjects (n = 26) from Arm A, there appeared to 
be lack of full exposure and numerically lower response rate compared to non-CLL subjects 
using the current monthly dosing regimen at the highest dose evaluated (ie, 12 mg/kg). This 
arm of the study will evaluate further dose escalation in CLL subjects utilizing a new 
schema, designed to saturate the potential B-cell sink, achieve full exposure, and maximize 
clinical activity, by employing weekly dosing of MEDI-551 for 4 weeks during Cycle 1 and 
then monthly dosing on Day 1 of each subsequent 28-day cycle to determine the MTD or the 
highest protocol-defined dose in the absence of exceeding the MTD, which will be evaluated 
subsequently in a doseexpansion phase. To further minimize infusion related reactions at 
higher dose levels, for the 24 and 48 mg/kg dose levels of MEDI-551, the initial weekly dose 
will be administered over 2 days on Day 1 and Day 2 in Cycle 1. Subsequent doses at the 24 
and 48 mg/kg dose levels will be administered in an identical fashion to lower dose levels (ie, 
weekly on Days 8, 15, and 22 in Cycle 1 and then on Day 1 of each 28-day cycle in Cycle 2 
and beyond). 
Arm C 
Given the high unmet medical need in patients with multiply relapsed aggressive lymphoma, 
the synergistic activity observed in preclinical studies with MEDI-551 and rituximab, as well 
as the promising clinical activity seen with other dual monoclonal antibody (MAb) 
combinations in patients with B-cell malignancies, this arm of the study will evaluate the 
safety and efficacy of MEDI-551 in combination with rituximab in subjects with aggressive 
lymphoma (relapsed or refractory DLBCL, Grade 3b FL, FL transforming to DLBCL and 
mantle cell lymphoma [MCL]). Using a standard 3+3 design, 3 to 6 subjects with aggressive 
non-Hodgkin lymphoma (NHL) will be enrolled per cohort in the dose-escalation portion of 
this arm, starting at a MEDI-551 dose of 8 mg/kg and escalating to 12 mg/kg. This 
population will receive 8 mg/kg of MEDI-551 on Days 2 and 8 of Cycle 1 and Day 1 of 
Cycle 2, and beyond in 28-day cycles along with weekly rituximab for 8 weeks beginning on 


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Day 1 of Cycle 1. Dose escalation will continue to 12 mg/kg if 0 of 3 or ≤ 1 of 6 subjects 
treated at the lower dose experience a DLT. The MTD will be defined as the dose at which 
no more than 1 of 6 subjects experiences a DLT. No intrasubject dose escalation will be 
allowed. Subjects will be considered evaluable for a DLT if they complete the first cycle of 
therapy or discontinue therapy during Cycle 1 due to a DLT. Nonevaluable subjects will be 
replaced in the same dose cohort. A total of up to 12 subjects will be enrolled in the dose-
escalation portion of this arm of the study. Dose escalation may be halted at the sponsor’s 
discretion. Dose escalation will be permitted after all investigators review the available data 
and unanimously agree to proceed with enrollment into the next cohort. The outcome from 
this meeting will be documented in writing and shared with all participating sites. Once an 
MTD is identified or the maximum planned dose not exceeding the MTD is reached, 
additional subjects will be enrolled and treated at the selected dose of MEDI-551 in 
combination with rituximab in the dose-expansion portion of this arm to ensure a total 
sample size of 26 efficacy evaluable subjects are available for analysis after completing one 
post-treatment disease evaluation. The 26 subjects will include subjects treated at the selected 
dose during the dose-escalation portion of this arm. Treatment may continue until the subject 
experiences unacceptable toxicity, disease progression, or withdraws consent. Subjects in 
Arm C will be stratified by their responsiveness to any prior anti-CD20-based therapy with 
the option of ensuring a minimum number of 7 subjects who are refractory to any anti-CD20-
based therapies are enrolled if clinical data from Arm D or emerging preclinical data suggest 
that the combination of anti-CD20 and anti-CD19 therapies improve response in this 
subpopulation. 
Arm D 
Given the high unmet medical need in patients with refractory aggressive lymphoma and in 
light of preservation of CD19 expression on the surface of these malignant cells, MEDI-551 
may represent a salvage therapy option for anti-CD20-refractory patients. With evidence of 
clinical activity and safety of MEDI-551 established in an unselected relapsed refractory 
lymphoma population (Arm A), it is now appropriate to investigate MEDI-551 in the anti-
CD20-refractory population. Arm D will evaluate the efficacy of MEDI-551 in subjects with 
any anti-CD20-refractory aggressive lymphomas (refractory DLBCL, Grade 3b FL, FL 
transforming to DLBCL, and MCL). Since the safety and tolerability of the 12-mg/kg dose of 
MEDI-551 has been verified in Arm A, approximately 26 subjects with any anti-CD20-
refractory disease will be enrolled and treated with single-agent MEDI-551 at the dose and 
schedule used in the expansion cohort of Arm A (ie, 12 mg/kg of MEDI-551 on Days 1 and 8 
of Cycle 1, and on Day 1 of Cycle 2 and beyond in 28-day cycles). Treatment may continue 


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until the subject experiences unacceptable toxicity, disease progression, or withdraws 
consent. 
Primary Objectives: 
Arm A (MEDI-551 monotherapy in advanced B-cell malignancies) 
• To determine the maximum tolerated dose (MTD) or optimal biologic dose (OBD) of 
MEDI-551 in subjects with relapsed or refractory advanced B-cell malignancies (chronic 
lymphocytic leukemia [CLL], including small lymphocytic lymphoma [SLL], diffuse 
large B-cell lymphoma [DLBCL], and follicular lymphoma [FL]) 
• To determine the preliminary safety profile of MEDI-551 
 
Arm B (MEDI-551 monotherapy in CLL) 
Dose Escalation 
• To determine the MTD or highest protocol-defined dose of MEDI-551 in the absence of 
exceeding the MTD in subjects with relapsed or rituximab-refractory CLL (defined as 
those with less than a partial response [PR] or progression within 6 months after 
completing therapy with rituximab) 
 
Dose Expansion 
• To evaluate further the safety and tolerability of MEDI-551 at the dose selected in the 
dose-escalation phase in subjects with relapsed or rituximab-refractory CLL 
• To evaluate the clinical activity of MEDI-551 at the dose selected in the dose-escalation 
phase in subjects with relapsed or rituximab-refractory CLL 
 
Arm C (MEDI-551 combined with rituximab in aggressive lymphoma) 
Dose Escalation 
• To determine the safety and tolerability of MEDI-551 in combination with rituximab at 
the MTD or the highest protocol-defined dose in the absence of exceeding the MTD in 
subjects with aggressive lymphomas 
 
Dose Expansion 
• To evaluate further the safety and tolerability of MEDI-551 at the dose selected in the 
dose-escalation phase in subjects with aggressive lymphomas 


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• To evaluate the clinical activity of MEDI-551 at the dose selected in the dose-escalation 
phase in combination with rituximab in relapsed and rituximab-refractory population 
(defined as those with less than a PR or progression within 6 months after completing 
therapy with rituximab) 
 
Arm D (MEDI-551 monotherapy in any anti-CD20-refractory aggressive lymphoma) 
• To evaluate the clinical activity of MEDI-551 in subjects with any anti-CD20-refractory 
aggressive lymphomas (defined as any subject with less than a PR to any prior anti-
CD20-based therapy or progression within 6 months after completing therapy with any 
anti-CD20-based regimen, including maintenance rituximab) 
 
Secondary Objectives: 
Arm A 
• To determine the preliminary efficacy profile of MEDI-551 in subjects with advanced B-
cell malignancies (CLL [including SLL], DLBCL, and FL) 
• To determine the pharmacokinetics (PK) of MEDI-551 in subjects with advanced B-cell 
malignancies  
• To determine the effect of treatment with MEDI-551 on circulating lymphocyte 
populations and immunoglobulin (Ig) levels, including time to recovery after treatment 
• To determine the immunogenicity (IM) of MEDI-551 in subjects with advanced B-cell 
malignancies 
 
Arm B 
• To evaluate the PK and IM of MEDI-551 at doses studied in subjects with relapsed or 
rituximabrefractory CLL 
• To evaluate the effect of therapy on the B-lymphocyte level in peripheral blood, 
including time to recovery of B-lymphocyte level 
 
Arm C 
• To evaluate the PK and IM of MEDI-551 when administered in combination with 
rituximab in subjects with aggressive lymphomas 
• To evaluate the effect of therapy on the B-lymphocyte level in peripheral blood, 
including time to recovery of B-lymphocyte level 
 


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Arm D
•
To determine the safety and tolerability of MEDI-551 in subjects with any anti-CD20-
refractory aggressive lymphomas
•
To evaluate the PK and IM of MEDI-551
•
To evaluate the effect of therapy on the B-lymphocyte level in peripheral blood, 
including time to recovery of B-lymphocyte level
Exploratory Objectives:
Arm A
•
Arm B
•
Arm C
•
•
Arm D
•
•
2.2
Randomization and Blinding
This is an open-label study.  Randomization and blinding are not applicable to this study.


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2.3 
Schedule of Study Procedures 
The schedule of Study Procedures is outlined in the study protocol.   
2.4 
Sample Size Considerations 
Arm A 
For the dose-escalation phase, a minimum of 18 evaluable subjects (3 subjects each in Dose 
Cohort 1 through 6) or up to approximately 36 evaluable subjects (3+3 subjects per dose 
cohort) will be required to determine the MTD. A subject will be considered evaluable for 
assessment of DLT if the subject receives at least one full cycle (4 doses for Cohorts 1 and 2; 
2 doses for Cohorts 3 to 6) of MEDI-551 and completes the safety follow-up through the 
DLT evaluation period (as defined in Section 4.5.6), or the subject experiences a DLT. Any 
nonevaluable subject will be replaced in the same dose cohort. Table 2.4-1 provides the 
probability of dose escalation to the next higher lever for each underlying true DLT rate. For 
example, for a common toxicity that occurs in 10% of subjects, there is a greater than 90% 
probability of escalating to the next higher dose level. Conversely, for a toxicity that occurs 
with a rate of 60%, the probability of escalating to the next higher dose level is less than 
10%. 
Table 2.4-1 
True Underlying DLT Rate at a Given Dose Level 
True Underlying DLT Rate 
10% 
20% 
30% 
40% 
50% 
60% 
70% 
80% 
90% 
Probability of Escalating Dose 
0.91 
0.71 
0.49 
0.31 
0.17 
0.08 
0.03 
0.009 
0.001 
 
For the dose expansion phase, approximately 20 subjects will be entered into each of 4 arms 
to determine the preliminary efficacy profile of MEDI-551 in the treatment of advanced 
CLL, DLBCL, FL, and MM. The primary objective of the dose expansion phase is to 
determine the preliminary efficacy profile of MEDI-551 in subjects with the advanced B-cell 
malignancies, including CLL, DLBCL, FL, and MM. The sample size estimation is based on 
the exact binomial test.  A total of 20 subjects will be required to have approximately 80% 
power for testing the following hypotheses at 1-sided significance level of 0.1. 
• Null hypothesis: undesirable CR rate = 5% 
• Alternative hypothesis: desirable CR rate = 20%  
 


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Arms B and C 
Dose Escalation 
There are 4 planned dose levels (6, 12, 24, and 48 mg/kg) for MEDI-551 in the Arm B dose 
escalation phase and 2 planned dose levels (8 and 12 mg/kg) for Arm C dose escalation. 
Using a standard 3+3 design, approximately 24 to 36 subjects may be enrolled during the 
dose-escalation phase in Arms B and C depending on the observed safety profile and total 
number of dose levels evaluated. 
Dose Expansion 
A sample size of 26 subjects is planned for each dose-expansion cohort in Arms B and C. 
Given an expected response rate of 50% for both cohorts, this will provide 80% power at a 
significance level of 0.20 (2-sided) to exclude the historical response rate of 30%, and 
associated 80% confidence intervals for the response rate will have a precision of ± 13%. The 
30% historical response rate was selected for both Arms B and C expansion cohorts based on 
the following reported data: 
In relapsed CLL patients, OR rates between 15% and 30% were reported for rituximab 
monotherapy (O’Brien et al, 2001; Mavromatis and Cheson, 2003). 
In DLBCL patients with 2 prior lines of therapy, response rates were only about 30% with 
single-agent rituximab (Coiffier et al, 1998; Wang et al, 2013; Churpek et al, 2013). 
Arm D 
A sample size of approximately 26 subjects is planned for Arm D. Given an 
expected response rate of 50% for this cohort, this will provide 80% power at 
a significance level of 0.20 (2-sided) to exclude the historical response rate of 30% 
(Zinzani et al, 2013; Witzig et al, 2011), and associated 80% confidence intervals for the 
response rate will have a precision of ± 13%. 
3 
STATISTICAL METHODS 
3.1 
General Considerations 
All data will be provided in data listings sorted by dose level and subject number.  All 
summary tables will be provided by dose level. The summary tables for baseline disease 
characteristics, study drug exposure, MTD evaluation and efficacy will be provided by dose 
level and disease type (CLL, DLBCL, FL, MM, MCL). Categorical data will be summarized 


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by frequency distribution (number and percentage of subjects falling within each category).  
In general, continuous variables will be summarized by descriptive statistics including N, 
mean, standard error or deviation, median, minimum, and maximum. All data collected, 
including unscheduled visits, will be presented in data listings. Summary tables will be 
limited to planned visits. 
Subjects with missing data for a parameter will be excluded from the summary of this 
parameter.  
The data analyses will be conducted using the SAS£ System (SAS Institute Inc., Cary, NC) 
Version 9.3 or above in Unix (Sun OS) environment. 
3.2 
Subject Populations 
The following subject populations will be used when summarizing the data: 
• Evaluable population for DLT: includes all subjects in the dose -escalation phase who 
receive at least 1 full cycle of MEDI-551 and complete safety follow-up through the DLT 
evaluation period (defined in Section 4.5.6 of the protocol) or experience any DLT. The 
evaluable population for DLT will be used for the MTD analysis. 
• Safety population: includes all subjects who receive any treatment of MEDI-551. It will 
be used to evaluate baseline characteristics as well as all endpoints for the safety.  
• Evaluable population for efficacy: includes all subjects who receive any treatment of 
MEDI-551 and complete at least one post-baseline disease assessment. It will be used to 
evaluate the efficacy endpoints.  
 
The number and percent of subjects in each subject population for evaluation will be 
summarized by dose level and overall (all subjects combined). The number of screen failures 
will be also summarized.  
3.3 
Subject Disposition 
The following summaries will be prepared for subject disposition by dose level and overall. 
Summary 
Population 
Number of Subjects Enrolled by Site 
All subjects enrolled 
Subject Status at the End of Study Therapy 
Safety 
Subject Status at the End of Study and Mortality Summary 
Safety  
 


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The number and percentage of subjects enrolled and the study duration will be summarized 
by site number, the primary investigator’s name, and location. The total number of subjects 
enrolled will be used as the denominator. 
The summary of subject status at the end of study therapy will include the number and 
percentage of subjects who discontinued treatment due to completion of protocol-defined end 
of treatment (up to 2 more cycles of MEDI-551 after complete response), adverse event, 
death, lost to follow-up, withdrawal of consent, physician decision, non-compliance with 
investigational product, pregnancy, progressive disease, protocol violation, technical 
problems, other. The denominator for these summaries will include all subjects in the safety 
population. 
Subject status at the end of study and mortality summary includes the number and percentage 
of subjects who ended the study due to completion of protocol-defined end of study, lost to 
follow-up, withdrawal of consent, death, or other.  For the subjects who withdrew from the 
study, the reason for withdrawal (adverse event [AE] or other) will be summarized. For the 
subjects who are dead at the end of the study, the cause of death (due to disease, not due to 
disease) and the relationship of death to investigational product (none, remote, possible, 
probable, definite) will be summarized.  For those subjects who died, the cause of death (due 
to disease, not due to disease) and the relationship of death to investigational product (none, 
remote, possible, probable, definite) will also be summarized. The denominator for these 
summaries will include all subjects in the safety population.  
3.4 
Baseline Characteristics 
Summaries on demographics, disease history, prior cancer treatment, baseline disease status, 
baseline bone marrow and aspirate assessment, Karnofsky performance status and other 
baseline disease characteristics will be provided by dose level and overall to describe the 
subject population in this study.  They will aid in interpretation of the assessment of the 
primary and secondary objectives and provide an overview of study conduct.  The following 
parameters will be summarized for the safety population:  
Summary 
Population 
Demographics 
Safety 
Disease History 
Safety 
Prior Cancer Treatment 
Safety 
Baseline Disease Status Assessment 
Safety 
Baseline Bone Marrow Biopsy and Aspirate Assessment 
Safety 
Baseline SPEP and UPEP Assessment 
Safety 
Baseline Spleen and Liver Assessment 
Safety 
Baseline Karnofsky Performance Status 
Safety 


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Demographics will be summarized for the continuous variables: age (years), height (cm) and 
weight (kg) using descriptive statistics. Frequency distributions will be provided for the 
categorical variables: gender, race and ethnicity.  
Disease history summary will include descriptive statistics for time from the initial diagnosis 
to study entry and frequency distributions for the stage of initial diagnosis (I, II, III, IV), 
constitutional symptoms at diagnosis (absent, present) and type of transplant (hematopoietic 
stem cell, bone marrow, none) for all subjects as well as by disease type (CLL, DLBCL, FL, 
MM, MCL).  
Baseline disease status assessment summary will include frequency distributions for the 
current stage (I, II, III, IV), constitutional symptoms (absent, present), any spleen 
involvement, any liver involvement and other organ involvement for all subjects as well as 
by disease type (CLL, DLBCL, FL, MM, MCL). 
The summary of prior cancer treatment will include the number and percent of subjects who 
had received prior therapies in the following categories: biologic, chemotherapy, radiation, 
surgery, hormonal and other for all subjects and by disease type. The best response to the last 
cancer treatment will be also summarized by disease type.  
Baseline bone marrow biopsy and aspirate assessment will include frequency distributions of 
subjects who have received bone marrow biopsy and aspirate, presence of malignant cells for 
DLBCL, MCL and FL subjects, presence of lymphocytes and nodules for CLL subjects, and 
presence of plasma cells for MM subjects.  
For the baseline SPEP and UPEP assessment the results of these two tests will be presented 
in a listing. 
The baseline spleen and liver assessment summary will include the number and percent of 
subjects with liver enlarged (by palpation) and spleen enlarged (by palpation) presented for 
all subjects as well as by disease type. 
Karnofsky performance status will be summarized using frequency distribution for the 
categories: <70, 70, 80, 90, and 100 for all subjects.  
3.5 
Study Drug Exposure 
The following summary of study drug exposure will be provided for the safety population by 
dose level and overall as well as by disease type (CLL, DLBCL, FL, MM, MCL). In 


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addition, summaries for study treatment change and subsequent alternative cancer treatment 
will be provided for the safety population by dose level and overall.  
Summary 
Population 
Study Treatment Exposure 
Safety 
Summary of Study Treatment Change 
Safety 
Summary of Subsequent Alternative Cancer Treatment 
Safety 
 
Summary of study treatment exposure includes descriptive statistics for the number of doses 
received during the study, total dose received, and total number of treatment cycles, defined 
as the number of cycles during which subject received at least one dose of MEDI-551. The 
total number of treatment cycles of MEDI-551 will also be summarized using frequency 
distribution for categories to be defined in the Statistical Programming Plan (SPP). The dose 
intensity of the study treatment is a percent of total actual dose that a subject received during 
the study treatment period versus total intended dose for the same study treatment period 
according to the study protocol. It will be summarized using descriptive statistics as part of 
study treatment exposure summary. The formula provided below gives calculation details for 
the dose intensity:  
 
period
treatment 
)
/
( 
dose
 
intended
)
/
( 
received
 
dose
100
(%)
Intensity 
Dose
u
u
 
¦
kg
mg
kg
mg
 
where 
mL
mL
kg
mg
kg
mg
250
 )
( 
 volume
Actual
)
/
(
level
dose
)
/
(
received
 
Dose
u
 
 
 
The summary of study treatment change will present the total number of subjects with dose 
delay, the reasons for dose delay (adverse events, scheduling conflict, other), the total 
number of subjects for whom the entire dose was not administered as scheduled, the reasons 
entire dose was not administered as scheduled (adverse events, other) and the reason subject 
did not receive investigational product (adverse events, other) will be summarized using 
frequency distribution. 
The use of subsequent alternative cancer treatment after the discontinuation of study drug 
will be summarized by type of treatment using frequency distribution. 


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3.6 
MTD or OBD/Highest Protocol-Defined Dose 
The MTD will be based on the evaluable population for DLT and will be defined as the 
highest dose at which ≤ 1 out of 6 subjects experience a DLT during the DLT evaluation 
period. The number and percentage of subjects with a DLT will be presented by dose level 
and overall. If the MTD is not reached, the OBD (Arm A) or highest protocol-defined dose 
(Arms B and C) will be determined based upon analysis of all available data, including 
safety, PK, pharmacodynamics, and response. 
3.7 
Safety Assessments 
Safety endpoints will be summarized descriptively. The occurrence of AEs, abnormal 
laboratory values, and SAEs reported will be summarized for all subjects who received any 
MEDI-551. Adverse events and SAEs will be graded according to the National Cancer 
Institute Common Terminology Criteria for Adverse Events (NCI CTCAE V4.03) and 
described by system organ class and by Medical Dictionary for Regulatory Activities 
(MedDRA) preferred term, severity, and relationship to MEDI-551. Frequency rates will be 
calculated for each system organ class and MedDRA preferred term. All summaries will be 
done by dose level and overall and will be based on the safety population. 
The toxicity profile will be assessed primarily by summarizing adverse events, serious 
adverse events, significant or important clinical findings in electrocardiogram (ECG) results, 
Karnofsky performance status (summarized by worst performance status during the study) 
and laboratory assessments during the study. All summaries for toxicity profile evaluation 
will be done by dose level and overall, and will be based on the safety population.  
Adverse Events and Serious Adverse Events 
Treatment-emergent adverse events (TEAEs), defined as events present at baseline that 
worsen in intensity after administration of study drug, or events absent at baseline that 
emerge after administration of study drug,  will be summarized by system organ class and 
preferred term using the Medical Dictionary for Regulatory Activities (MedDRA) 
dictionary, severity graded according to NCI CTCAE V4.03 (grade 1, grade 2, grade 3, grade 
4, grade 5), and relationship to study drug. 
Subjects will be counted only once for each preferred term, once for each system organ class, 
and by the highest event severity, regardless of how many events the subject experienced.  
The following treatment emergent adverse event summaries will be provided: 


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Summary 
Population 
Rate Summary of All Treatment Emergent Adverse Events 
Safety 
Number of Subjects with Treatment Emergent Adverse Events 
Safety 
Number of Subjects with Treatment Emergent Adverse Events by Highest Severity 
Safety 
Number of Subjects with Treatment Emergent Adverse Events Sorted by Frequency 
Safety 
Number of Subjects with Related Treatment Emergent Adverse Events 
Safety 
Number of Subjects with Related Treatment Emergent Adverse Events by Highest Severity 
Safety 
Number of Subjects with Treatment Emergent Serious Adverse Events 
Safety 
Number of Subjects with Treatment Emergent Serious Adverse Events by Serious Adverse Event 
Criteria 
Safety 
Number of Subjects with Related Treatment Emergent Serious Adverse Events 
Safety 
Number of Subjects with Treatment Emergent Adverse Events Resulting in Permanent 
Discontinuation of Study Drug 
Safety 
 
The AEs/SAEs occurring from the signing of the informed consent and prior to the initiation 
of study treatment will be listed. The AEs/SAEs that begin 30 days after last dose will not be 
summarized or listed. 
Laboratory Parameters 
The change in each laboratory parameter from baseline to the “worst-case” (nadir and/or 
zenith) and to the last assessment for hematology/coagulation and blood chemistry will be 
summarized by descriptive statistics (N, mean, standard deviation, median, minimum, 
maximum).  Baseline values will be defined as the last valid assessment prior to the first dose 
of MEDI-551.   
Laboratory abnormalities with toxicity grades according to the NCI CTCAE V4.03 will be 
derived according to laboratory values. Laboratory abnormalities will be presented.  Shift 
tables from baseline to the maximum severity grade and to the last assessment will be 
generated for each of laboratory parameter.  
The following summaries for lab parameters will be prepared. 
Summary 
Population 
Change from Baseline in Hematology/Coagulation Parameters 
Safety 
Change from Baseline in Chemistry Parameters 
Safety 
Toxicity Grades for Hematology/Coagulation Parameters 
Safety 
Toxicity Grades for Chemistry Parameters 
Safety 
 
Results of urine protein electrophoresis, serum protein electrophoresis, urinalysis, 
cytogenetic analysis, and flow cytometry will be listed by subject and visit.   


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ECG Parameters and Karnofsky Performance Status 
The following summaries will be provided for ECG parameters and Karnofsky performance 
status: 
Summary 
Population 
Change from Baseline in ECG parameters 
Safety 
Summary of ECG clinical findings 
Safety 
Summary of Karnofsky performance status 
Safety 
 
Descriptive statistics for ECG parameters (heart rate, PR interval, QRS duration, QT interval, 
QTcB [Bazett], QTcF [Fridericia]), including change from baseline, will be provided for 
each scheduled time point. ECG clinical findings will be summarized at each time point in 
terms of overall ECG interpretation (within normal limits, abnormal insignificant, abnormal 
significant, un-interpretable and incomplete analysis) as well as comparison with baseline 
interpretation (improved, worsened, unchanged, not compared).   
Karnofsky performance status will be summarized using a shift table from baseline to the 
worst performance status and to the last assessment. 
Vital Signs 
Descriptive statistics of value and change from baseline value for heart rate, blood pressure, 
temperature, weight and respiratory rate will be provided for each scheduled time point. The 
following summary will be prepared for vital sign parameters based on the safety population. 
Summary 
Population 
Change from Baseline in Vital Sign Parameters 
Safety 
 
3.8 
Efficacy Assessments 
The efficacy will be assessed based on CR, duration of CR, objective response, disease 
control, TTR, duration of objective response, duration of disease control, PFS, and OS. 
Anti-tumor Activity of Medi-551  
To evaluate the anti-tumor activity of MEDI-551, summaries for CR rate, duration of CR, 
best disease response, objective response rate, disease benefit rate, time to response, duration 
of objective response, time to progression, progression free survival and overall survival will 
be performed by dose level and overall (all doses combined) based on the evaluable 


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population for efficacy for each of the advanced B-cell malignancies CLL, DLBCL, FL and 
MM. These summaries will be repeated using the per-protocol population.   
Complete Response Rate  
The CR rate is defined as the proportion of subjects that have achieved CR in the safety 
population. The 95% and 80% confidence interval (CI) of the CR rate will be estimated 
based on the exact probability method (Clopper-Pearson exact interval). As a supportive 
analysis, the CR rate and its 95% and 80% CI will be estimated based on the evaluable 
population for efficacy.  
Duration of Complete Response  
Duration of CR will be measured from the first documentation of a CR to the time of 
progressive disease/relapse. Duration of CR will be censored on the date of last disease 
assessment for subjects who have no documented relapse prior to data cutoff, dropout, or the 
initiation of alternative anticancer therapy. Duration of CR will be calculated using the 
Kaplan-Meier method for the subgroup of subjects with CR. Also, as a supportive analysis, 
the duration of CR will be evaluated based on the evaluable population for efficacy.  
MRD-negative CR 
Subjects with CR and negative MRD defined as the proportion of subjects with a best 
response of CR and without MRD. The MRD rate is defined as the proportion of subjects 
that have achieved CR in the safety population. The 95% and 80% confidence interval (CI) 
of the CR rate will be estimated based on the exact probability method (Clopper-Pearson 
exact interval). 
Best Disease Response 
The best overall response during the study will be calculated and summarized with number 
and percentage of subjects for the following categories: complete response (CR), partial 
response (PR), stable disease (SD), and progressive disease (PD).  
Objective Response Rate  
Objective response rate is defined as the proportion of subjects with CR or PR. The 
denominator of ORR in the summary for the safety population will be equal to the number of 
subjects in this population. Subjects that have missing overall response assessments will be 
considered non-responders, so they will be counted in the denominator, but not in the 


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numerator of ORR. The 95% CIs of ORR will be estimated using the exact probability 
method (Clopper-Pearson exact interval).  
Disease Control 
Disease control includes CR, PR, or SD for at least 8 weeks.  
Time to Response 
Time to response (TTR) is measured from the start of MEDI-551 treatment to the first 
documentation of disease response (CR or PR) and will be evaluated only in subjects who 
receive any treatment of MEDI-551 and have achieved objective response (CR or PR). TTR 
is calculated in months as follows: 
TTR (months) = (Date of first disease response – Date of MEDI-551 start + 1) / (365.25/12) 
TTR will be summarized using Kaplan-Meier estimates (median time, 95% CI for median 
time). 
Duration of Objective Response 
Duration of objective response (DOR) is measured from the first documentation of objective 
response to the first documented progressive disease (PD) or relapse. DOR is calculated in 
months as follows:  
DOR (months) = (Date of PD/relapse or censoring – Date of first response + 1) / (365.25/12), 
where date of PD/relapse or censoring is given in Table 3.8-1. DOR will be summarized 
using Kaplan-Meier estimates (median time, 95% CI for median time). 
Table 3.8-1 
Definition and censoring information for DOR 
Situation 
Date of PD/relapse or Censoring 
Outcome 
PD or relapse  
Date of earliest sign of PD or relapse 
Progressed 
No PD or relapse 
Date of last disease assessment 
Censored 
PD or relapse after ≥ 2 missed consecutive 
disease assessments  
Date of last disease assessment 
Censored 
 


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Duration of Disease Control 
Duration of disease control will be defined as the time period from start of MEDI-551 
administration to the event of PD/relapse. Duration of disease control will be censored on the 
date of last disease assessment for subjects who have no documented PD/relapse prior to data 
cutoff, dropout, or the initiation of alternative anticancer therapy. Duration of disease control 
will only be calculated for the subgroup of subjects with best response of CR, PR, or SD, and 
will be evaluated using the Kaplan-Meier method. 
Time to disease progression/relapse 
Time to disease progression/relapse (TTP) is measured from the start of MEDI-551 treatment 
until the first documentation of disease progression or relapse. TTP is calculated in months as 
follows:  
TTP (months) = (Date of PD/relapse or censoring – Date of MEDI-551 start + 1) / 
(365.25/12), 
where date of PD/relapse or censoring is given in Table 3.8-2. TTP will be summarized using 
Kaplan-Meier estimates (median time, 95% CI for median time). 
Table 3.8-2 
Definition and censoring information for TTP 
Situation 
Date of PD or Censoring 
Outcome 
PD or relapse 
Date of earliest sign of PD or relapse 
Progressed 
No PD or relapse 
Date of last disease assessment 
Censored 
PD or relapse after ≥ 2 missed consecutive 
disease assessments  
Date of last disease assessment 
Censored 
No disease assessment at baseline or post-
baseline visits  
Date of first MEDI-551 
Censored 
 
Progression-free survival 
Progression-free survival (PFS) is measured from the start of MEDI-551 treatment until the 
first documentation of disease progression, relapse or death, whichever occurs first. PFS is 
calculated in months as follows:  
PFS (months) = (Date of PD/relapse/death or censoring – Date of MEDI-551 start + 1) /    
                           (365.25/12), 
where date of PD/relapse/death or censoring is given in Table 3.8-3. PFS will be summarized 
using Kaplan-Meier estimates (median time, 95% CI for median time). 


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Table 3.8-3 
Definition and censoring information for PFS 
Situation 
Date of PD/relapse/death or Censoring 
Outcome 
PD or relapse 
Date of earliest sign of PD or relapse 
Progressed 
Death before the first post-baseline disease 
assessment or after disease assessments 
documenting no PD 
Date of death 
Death 
No PD, death or relapse 
Date of last disease assessment 
Censored 
PD/relapse/death after ≥ 2 missed 
consecutive disease assessments  
Date of last disease assessment 
Censored 
No disease assessment at baseline or post-
baseline visits  
Date of first MEDI-551 
Censored 
 
Overall survival 
Overall survival (OS) is measured from the start of MEDI-551 treatment until death. For 
subjects who are alive at the end of study or lost to follow-up, OS will be censored on the last 
date when subjects were known to be alive. OS is calculated in months as follows:  
OS (months) = (Date of death or censoring – Date of MEDI-551 start + 1) / (365.25/12). 
OS will be summarized using Kaplan-Meier estimates (median time, 95% CI for median 
time). 
3.9 
Pharmacokinetic Assessments 
To support the pharmacokinetic assessments of MEDI-551, analysis of pharmacokinetic 
parameters of MEDI-551 will be performed and reported by the MedImmune Global PK-PD 
& Bioanalysis group. The PK of MEDI-551 will be estimated by non-compartmental 
analysis. A population PK analysis may also be performed to obtain additional PK 
parameters. Those PK parameters will be summarized by descriptive statistics including N, 
mean, standard deviation, coefficient of variation, median, minimum, maximum, and 
geometric mean. 
3.10 Assessment of Effect on Circulating Lymphocyte Populations 
Circulating levels of blood mononuclear cells, including T-cells, B-cells, NK cells and 
monocytes will be determined using standard clinically available flow cytometry. B-cell 
levels will be monitored from start of treatment until recovery.  
Recovery will be defined as a B-cell count of ≥ 200 cells/mm3 in subjects with baseline B-
cells of ≥ 200 cells/ mm3 or two consecutive B-cell counts within ± 20% of baseline or above 
in subjects with baseline B-cell counts of < 200 cells/ mm3. It will be defined only for the 


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subjects with a nadir level of < 200 cells/mm3 and baseline B-cell level greater than the nadir 
level. It will be summarized by presenting the number and percentage of subjects with B-cell 
recovery by dose level and overall. 
Time to B-cell recovery will be defined for the subjects with B-cell recovery as 
•
the time from nadir to first B-cell level ≥200 cells/mm3 for the subjects with baseline B-
cell levels ≥200 cells/mm3 or
•
the time from nadir to the first of the 2 consecutive values within ± 20% of baseline or 
above, if such 2 consecutive values are observed, for the subjects with baseline B-cell <
200 cells/mm3.
Time to recovery will be summarized in subjects with recovery using descriptive statistics.
Quantitative immunoglobulin (IgM, IgG, IgA, IgE) levels will be summarized using 
descriptive statistics for each scheduled time-point during treatment and at the time of B-cell 
recovery, if sufficient immunoglobulin level data are collected at this time. A plot of the 
immunoglobulin levels and B-cell actual values or descriptive statistics, if sufficient data is 
available, across time will be done considering all the time point at which both 
immunoglobulin and B-cell levels are collected. All summaries will be done for the safety 
population.
3.11
Immunogenecity Assessments
The immunogenic potential of MEDI-551 will be assessed by summarizing the presence of 
anti-MEDI-551 antibodies with number and percentage of subjects in each category: present, 
absent for each scheduled time point. In addition, the number of treatment cycles prior to 
developing anti-MEDI-551 antibodies will be summarized using descriptive statistics. All 
summaries will be done for the safety population.
3.12
Exploratory Summaries
  
    


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4 
INTERIM SAFETY ANALYSES 
An interim safety analysis will be undertaken when the MTD or OBD has been established, 
and prior to enrollment in the expansion phase. Treatment emergent AEs, SAEs, laboratory 
assessments and concomitant medications at subject level will be provided to evaluate the 
safety of MEDI-551. 
5 
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