Phase II Clinical Trial of Rituximab in Combination With Pegfilgrastim in Patients With Indolent B-Cell (CD-20-Positive) Lymphoma
Phase: PHASE2
Conditions: Contiguous Stage II Grade 1 Follicular Lymphoma, Contiguous Stage II Grade 2 Follicular Lymphoma, Contiguous Stage II Grade 3 Follicular Lymphoma, Contiguous Stage II Marginal Zone Lymphoma, Contiguous Stage II Small Lymphocytic Lymphoma, Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue, Nodal Marginal Zone B-cell Lymphoma, Noncontiguous Stage II Grade 1 Follicular Lymphoma, Noncontiguous Stage II Grade 2 Follicular Lymphoma, Noncontiguous Stage II Grade 3 Follicular Lymphoma, Noncontiguous Stage II Marginal Zone Lymphoma, Noncontiguous Stage II Small Lymphocytic Lymphoma, Recurrent Grade 1 Follicular Lymphoma, Recurrent Grade 2 Follicular Lymphoma, Recurrent Grade 3 Follicular Lymphoma, Recurrent Marginal Zone Lymphoma, Recurrent Small Lymphocytic Lymphoma, Splenic Marginal Zone Lymphoma, Stage I Grade 1 Follicular Lymphoma, Stage I Grade 2 Follicular Lymphoma, Stage I Grade 3 Follicular Lymphoma, Stage I Marginal Zone Lymphoma, Stage I Small Lymphocytic Lymphoma, Stage III Grade 1 Follicular Lymphoma, Stage III Grade 2 Follicular Lymphoma, Stage III Grade 3 Follicular Lymphoma, Stage III Marginal Zone Lymphoma, Stage III Small Lymphocytic Lymphoma, Stage IV Grade 1 Follicular Lymphoma, Stage IV Grade 2 Follicular Lymphoma, Stage IV Grade 3 Follicular Lymphoma, Stage IV Marginal Zone Lymphoma, Stage IV Small Lymphocytic Lymphoma
Sponsor: Roswell Park Cancer Institute

Page 1 of 2
August 23, 2017
Francisco Hernandez-Ilizaliturri, MD
Francisco.Hernandez@RoswellPark.org
Dear Dr. Francisco Hernandez-Ilizaliturri:
On 8/22/2017, the IRB reviewed the following submission:
Type of Submission:
Modification and Continuing Review
Type of Review: 
 Full Board  
 Expedited  
 Exempt  
 Non-Human Research
Title of Study:
Phase II Clinical Trial of Rituximab in Combination with Pegfilgrastim 
in Patients with Indolent B-Cell (CD-20-Positive) Lymphoma
Investigator:
Francisco Hernandez-Ilizaliturri, MD
IRB ID:
MODCR00000440 / I 83106
Funding:
Name: ROSWELL PARK CANCER INSTITUTE
Grant ID:
None
IND, IDE, or HDE:
IND #I00396, HOLDER Roswell Park Cancer Institute
Documents Reviewed:
• I 83106 PROT AMD#7 CLN 10.4.13.pdf, Category: IRB Protocol;
The IRB approved the study from 8/22/2017 to 9/6/2018 inclusive.  Before 9/6/2018 or 
within 30 days of study closure, whichever is earlier, you are to submit a continuing 
review with required explanations. You can submit a continuing review by navigating to 
the active study and clicking Create Modification / CR.  If continuing review approval is 
not granted on or before 9/6/2018, approval of this study expires after that date.
The principal investigator is responsible for ensuring that the research complies with 
all applicable regulations.  Any modifications in the research project are subject to 
approval by the Board prior to initiation by the investigator. The Board reserves the 
right to stop the research for violations of regulatory or IRB requirements.
A progress report must be submitted to the IRB at least one month prior to the 
expiration date noted above for continuing review as required by federal regulations 
and/or institutional requirements.  
Please be advised that your research study may be audited periodically by the IRB for 
compliance.
This activity has been reviewed and approved by an IRB in accordance with the 
requirements of 45 CFR 46, including its relevant Subparts.  This protocol fulfills, when 
Elm & Carlton Streets
Buffalo, New York 14263
Institutional Review Board
Approval Notice
This institution has an approved assurance of compliance on file with HHS which 
covers this activity FWA 00006731 Federal Wide Assurance identification 
number

Page 2 of 2
applicable, requirements for certifying FDA status for each investigational new drug or 
device.
The study documents have been submitted to Clinical Research Services (CRS) 
Compliance Office for processing prior to release and protocol implementation.  Please 
contact CRS Compliance for information regarding the protocol implementation release 
date. 
In conducting this protocol you are required to follow the requirements listed in the 
INVESTIGATOR MANUAL (HRP-103), including the reporting of Unanticipated Problems 
and any other Reportable New Information.
Sincerely,
Donald Handley MSc, MBA
Camille P Wicher, PhD, Esq., RN, MSN

 Protocol Date:  10/4/13 
Francisco J Hernandez-Ilizaliturri MD
                                              I 83106
Page 1 of 83
RPCI PROTOCOL NO.:      I 83106
PROTOCOL TITLE:
PHASE II CLINICAL TRIAL OF RITUXIMAB IN COMBINATION WITH PEGFILGRASTIM IN PATIENTS WITH INDOLENT 
B-CELL (CD-20-POSITIVE) LYMPHOMA.
PRESENTED TO AMGEN, INC.
ROSWELL PARK CANCER INSTITUTE
ELM AND CARLTON STREETS
BUFFALO, NY  14263
PRINCIPAL INVESTIGATOR:
FRANCISCO J. HERNANDEZ-ILIZALITURRI MD
TELEPHONE:
716 845-3560
This study is classified as a Roswell Park Cancer Institute
Investigator Initiated Study with sponsorship from 
Amgen, Inc.  group of companies
INITIAL SUBMISSION:
DATE:   JULY 11, 2006
AMENDMENT #1
DATE:  OCTOBER 27, 2006
AMENDMENT #2
DATE:  JULY 14, 2008
AMENDMENT #3
DATE:  FEBRUARY 23, 2009
AMENDMENT #4
DATE:  JANUARY 11, 2010
AMENDMENT #5
DATE:  JULY 20, 2011
AMENDMENT #6
DATE: APRIL 16, 2012
AMENDMENT #7
DATE:  OCTOBER 4, 2013
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                                              I 83106
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TABLE OF CONTENTS
1.0
INTRODUCTION
5
1.1
BACKGROUNDS AND OVERVIEW
5
1.2
RITUXIMAB BACKGROUND
6
1.2.1
Clinical Experience
7
1.2.2. Cellular mediated immunity and Rituximab anti-tumor activity.
8
1.3
NEUTROPHILS AND TUMOR IMMUNOLOGY
10
1.4
RATIONALE FOR RITUXIMAB AND PEGFILGRASTIM COMBINATION STUDY
11
1.5 
CLINICAL EXPERIENCE WITH RITUXIMAB IN COMBINATION WITH G-CSF
14
1.6          CLINICAL EXPERIENCE WITH PEGFILGRASTIM
15
2.0
OBJECTIVES
17
2.1
PRIMARY
17
2.2.
SECONDARY
17
3.0
STUDY DESIGN OVERVIEW
17
4.0
STUDY POPULATION
17
4.1
PATIENT ELIGIBILITY
18
4.1.1
INCLUSION CRITERIA
18
4.1.2
EXCLUSION CRITERIA
18
5.0          DOSE-SCHEDULE AND FORMULATION
19
6.0
COMPLIANCE
20
7.0 
PROCEDURES
20
7.1
STUDY PROCEDURES
20
7.1.1
SCREENING AND PRETREATMENT ASSESSMENTS
20
7.1.2
ASSESSMENTS DURING TREATMENT PERIOD
21
7.1.3
END OF THE STUDY ASSESMENTS 
22
7.1.4
ASSESSMENTS DURING FOLLOW-UP PERIOD
22
7.2
PATIENT DISCONTINUATION
23
7.3
STUDY DISCONTINUATION
23
7.4 
SAFETY EVALUATIONS
23
7.5 
EFFICACY EVALUATIONS
24
7.6
CORRELATIVE STUDIES
24
8.0 
ADVERSE EVENT REPORTING
25
8.1
DEFINITIONS
25
8.1.1
Adverse Event Classification Definitions
25
8.1.2.
 Attribution Definitions
27
8.2
PROCEDURES
27
8.2.1
All Adverse Events
27
8.2.2
Serious Adverse Events
28
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                                              I 83106
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8.2.3
Pregnancies
28
8.3 
REPORTING PROCEDURES FOR SERIOUS ADVERSE EVENTS
29
8.4
INTERNAL DATA SAFETY AND MONITORING
29
9.0
STATISTICAL METHODS
30
9.1
ANALYSIS OF THE CONDUCT OF THE STUDY
30
9.2
BASE-LINE DEMOGRAPHICS
30
9.3
SAFETY
30
9.4
EFFICACY 
31
9.4.1  METHODOLOGY
31
9.5
DETERMINATION OF SAMPLE SIZE
32
10.0
DRUG STUDY INFORMATION AND ACCOUNTABILITY 
32
10.1
RITUXIMAB
32
10.1.1 Formulation and Storage
32
10.1.2 Adverse reactions and Warnings
32
10.2      PEGFILGRASTIM
40
10.2.1 Package and Formulation
40
10.2.2 Labeling
40
10.2.3 Supply and Return of Drug
40
10.2.4   Drug Accountability
41
10.2.5   Storage Conditions and Stability
41
10.2.6     Preparation and Administration
42
10.2.7 Adverse Reactions
42
11.0
ETHICAL CONSIDERATIONS
44
11.1
INVESTIGATOR REQUIREMENTS
44
11.1.1 STUDY INITIATION
44
11.1.2 STUDY COMPLETION
45
11.2
INFORMED CONSENT
45
11.3 
INSTITUTIONAL REVIEW BOARD OR ETHICS COMMITTEE APPROVAL
46
12.0
DATA QUALITY ASSURANCE
46
13.0
DISCLOSURE OF DATA
46
14.0
REFERENCES
47
APPENDICES
A
PEGFILGRASTIM AND RITUXIMAB FULL PRESCRIBING INFORMATION BOOKLET
50
B
WORLD HEALTH ORGANIZATION (WHO) INDOLENT LYMPHOMA CLASSIFICATION SCHEMA  78
C
CRITERIA FOR EVALUATION OF RESPONSE
79
D
PERFORMANCE STATUS CRITERIA
82
E
STUDY FLOW CHARTS
   83
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                                              I 83106
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1. INTRODUCTION
Low grade and/or follicular non-Hodgkin's lymphoma
1.1 
Background and Overview
Non-Hodgkin's 
lymphomas 
(NHLs) 
are 
a 
heterogeneous 
group 
of 
lymphoproliferative malignancies with variable patterns of behavior and responses 
to treatment [1]. Like Hodgkin's disease, NHL usually originates in lymphoid 
tissues and can spread to other organs. However, NHL is much less predictable 
than Hodgkin's disease and has a far greater predilection to disseminate to 
extranodal sites. The prognosis depends on the histologic type, stage, and 
treatment. The working formulation divides NHL into three prognostic groups: low-
grade, intermediate-grade, and high-grade. Low-grade NHL subtypes have a 
median survival of approximately 6.2 years and although initially chemosensitive 
become increasingly more treatment-resistant as demonstrated by decreasing 
remission durations seen with subsequent therapeutic intervention.  The vast 
majority of low-grade B-cell lymphomas are felt to be incurable with standard 
chemotherapy [2].  Therefore, new agents and treatment strategies need to be 
evaluated in these patients.
State-of-the-art treatment for non-Hodgkin's lymphoma (NHL) depends on the 
histologic type and stage. Recently, improvements in disease-free survival have 
been demonstrated in clinical trials (experimental therapy) that have improved on 
the best available accepted therapy (conventional or standard therapy) by 
combining them with novel target-specific agents (e.g. monoclonal antibodies 
[mAbs], etc.)  Monoclonal antibodies (mAbs) were developed to target and kill 
tumors with less toxic effects on normal tissues.  MAbs directed against tumor-
associated antigens, offer less non-specific toxicity than most chemotherapy 
agents.  One characteristic of monoclonal antibodies, is their ability to fix human 
complement and activate complement-mediated cytotoxicity (CMC).  Another 
mechanism of anti-tumor activity by mAbs is antibody-dependent cellular 
cytotoxicity (ADCC) through the binding of the Fc portion of the monoclonal 
antibodies to Fc receptors on lymphocytes, monocytes, macrophages, 
granulocytes, and eosinophils.  Among human antibodies, IgG1 is the only class 
that binds to macrophage Fc receptors.  Clinical trials have evaluated a number of 
mAbs as potential treatments of hematological malignancies.  The results of these 
clinical trials have been highly variable [3].  Nevertheless, the results of some 
clinical trials of mAbs have shown promising activity and safety in patients with B-
cell lymphomas that were (at times) resistant or refractory to conventional 
treatments.
Rituximab is the first mAb approved by the US FDA for the treatment of cancer.  It 
is a genetically engineered chimeric (human/murine) mAb with a human IgG1 
constant region directed against the CD20 antigen found on the surface of normal 
and malignant B cells.  A Phase III pivotal study demonstrated a 48% (80/166) 
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                                              I 83106
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overall response rate in previously treated low grade and follicular B-cell 
lymphoma patients receiving out-patient rituximab at a dose of 375 mg/m2/week 
for 4 weeks [4].  The median time to progression (TTP) was 13.1 months in 
responders.  The most common side effect seen was an infusion-related symptom 
complex consisting of fever and chills/rigors which occurred in the majority of 
patients during the first antibody infusion.  Rituximab has been combined with 
standard dose CHOP chemotherapy in a separate Phase II chemoimmunotherapy 
study in low grade NHL and demonstrated a 100% response rate with minimal 
additional toxicity than that typically seen with CHOP chemotherapy alone [5].  
Furthermore, CHOP plus rituximab (CHOP-R) combination therapy has been 
evaluated in additional Phase II [6] and Phase III [7] studies.  In the Phase III study 
a statistically significant improvement in complete response (CR) rate, disease-
free survival (DFS) and overall survival (OS) was found in elderly patients with 
diffuse large B-cell lymphoma (DLBCL) treated with CHOP-R, compared to those 
treated with CHOP alone.  Due to its unique immunologic mechanism(s) of action 
and good safety profile, rituximab has been studied in combination with other 
chemotherapeutic and/or biologic agents in an attempt to improve anti-tumor 
activity while decreasing the non-specific toxicities typically associated with a 
CHOP-like regimen alone. This current proposal plans to evaluate the safety and 
efficacy of a combination of rituximab plus Pegfilgrastim.
Modulating the innate immune system is an attractive strategy to improve 
rituximab activity. It has been demonstrated by various groups of investigators not 
only that neutrophils play a significant role in rituximab activity but that priming 
neutrophils with cytokines augments rituximab anti-tumor activity in pre-clinical 
models. Clinical studies using G-CSF in combination with rituximab had shown 
improvement in complete response rates when compared to rituximab 
monotherapy 
historical 
controls. 
As 
pegfilgrastim 
possesses 
different 
pharmacokinetics and pharmacodynamics than G-CSF, the biological interaction 
with rituximab might be stronger.  
1.2
Rituximab Background
Rituximab is a chimeric monoclonal antibody, with mouse variable and human 
IgG1 constant regions that recognizes the CD20 antigen expressed on normal B 
cells and most malignant B-cell lymphomas.  This antigen, important in cell cycle 
initiation and differentiation, is expressed strongly in over 90% of B-cell 
lymphomas [8].  Rituximab demonstrates specificity for CD20 and binds with an 
apparent affinity of 5.2 x 10-9M.  In vitro mechanism of action studies have 
demonstrated that this antibody binds human complement and lyses lymphoid B 
cell lines and it has significant activity in assays for antibody dependent cellular 
cytotoxicity.  Rituximab has also been shown to have antiproliferative effects in 
titrated Thymidine incorporation assays and to directly induce apoptosis in several 
CD20-positive cell lines, while some other anti- CD20 antibodies do not [9].  High 
dose safety studies in cynomolgous monkeys have revealed no adverse clinical 
events.  There were no significant abnormalities on laboratory tests or on 
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                                              I 83106
Page 6 of 83
histopathological analysis.  As predicted, the biologic effect of rituximab is 
manifested by B-cell depletion in peripheral blood (PB), lymph nodes (LN) and 
bone marrow (BM).  Three weeks after 4 weekly doses there was a > 85% 
depletion of B cells in the lymph nodes and a > 75% decrease of B cells in the 
bone marrow.  Recovery of the B cells in the peripheral blood (to > 75% of 
baseline) usually occurred within 60 days following the last dose.
1.2.1
Clinical Experience
Initial human clinical trials were conducted primarily in patients with 
multiple relapses of low-grade non-Hodgkin's lymphomas.  A Phase I, 
single-dose, dose-escalation trial demonstrated that rituximab was well 
tolerated at doses ranging from 10 to 500 mg/m2.  The mean half-life (t1/2) 
observed for rituximab in this study was 118 hours.  CD20+ B-cells were 
rapidly depleted 24-72 hours following rituximab administration and 
remained depleted for 2-3 months [10].  A subsequent Phase I/II, multiple-
dose study demonstrated that a regimen of four weekly IV infusions of 
rituximab at doses of 125-375 mg/m2 was equally well tolerated.  A total of 
37 patients received four doses of 375 mg/m2.  The overall response rate 
in this study was 50%, with a mean time to progression of 10.2 months 
[11].  
Adverse events reported in these studies have occurred largely with the 
first infusion.  Fever, chills, headache, nausea, vomiting, rhinitis, and 
hypotension, generally of Grade 1 and 2 severities, have been reported.  
These symptoms have typically responded to an interruption of the 
antibody infusion with subsequent resumption at a slower infusion rate.  
Other 
adverse 
events 
have 
included 
transient 
neutropenia, 
thrombocytopenia, and asthenia.
A large Phase III study of four weekly infusions of rituximab at 375 mg/m2 
in patients with low-grade lymphoma has been completed.  In this open-
label, single arm, pivotal trial, 166 patients received weekly x four 
infusions of 375 mg/m2 of rituximab.  Adverse events (AE) were primarily 
related to the first infusion.  There was a marked reduction in the 
incidence of AEs in subsequent infusions.  (See Table 1 in the Rituximab 
Full Prescribing Information Booklet included in Appendix A for a list of 
possible adverse events).  None of the patients in this trial developed a 
significant human anti-chimeric antibody response (HACA) [4].
Ninety-one percent of patients (151 of 166) were evaluable for efficacy 
and an overall response rate of 48% with 6% CR and 42% PR was 
achieved.  The onset of response was documented as early as seven 
weeks and responses were seen in patients with bulky and extra nodal 
disease and in patients who had progressed following ABMT or 
anthracycline therapy.  CT scans of responders were reviewed and 
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                                              I 83106
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confirmed (blinded audit) by an independent panel of lymphoma experts 
following established response criteria.  Complete response required all 
lymph nodes to regress to < 1 x 1 cm and all signs and symptoms of 
disease to disappear.  Median time to progression for responders was 
subsequently reached at 13.1 months.
Various schedules of rituximab for initial therapy of advanced stage 
follicular lymphoma have been completed and, in general, demonstrate 
higher overall response and CR rates (range of ~70% ORR, 38 % CR) 
compared to patients receiving rituximab following prior chemotherapy.
An open-label, single-arm, Phase II study of six infusions of rituximab (375 
mg/m2) interspersed among six cycles of CHOP chemotherapy has also 
been conducted in patients with low-grade lymphoma.  The overall 
response rate in the 35 evaluable patients who completed all of the 
planned treatment was 100%, with a CR rate of 63%. Seven of 8 patients 
noted to be positive for the bcl-2 marker by polymerase chain reaction 
(PCR) converted to bcl-2 negative in bone marrow and/or blood following 
treatment suggesting the clearance of minimal residual disease in these 
patients.  
No significant additive toxicity was observed with the 
combination treatment [5].  Separate Phase II and Phase III studies of 
CHOP plus rituximab in intermediate-grade lymphoma have also 
demonstrated augmented anti-tumor activity without significant increases 
in toxicity [6, 7].  
Rituximab has been shown to be active in the treatment of CD20-positive 
indolent and aggressive lymphomas and has been noted to have a 
favorable toxicity profile both as a single agent and in combination with 
CHOP and other chemotherapy regimens.  The unique mechanism of 
action of rituximab supports its potential in augmenting anti-tumor activity 
when combined with other agents.  
1.2.2. Cellular mediated immunity and Rituximab anti-tumor activity.
Despite its evident clinical efficacy, some patients develop disease 
progression while on therapy with rituximab or relapse after initial 
response. Up to 50% of indolent NHL patients who have received prior 
chemotherapy treated with single agent rituximab fail to demonstrate an 
objective anti-tumor response (i.e. PR or CR). Several mechanisms for 
tumor resistance to monoclonal antibody therapy had been formulated. 
NHL related factors postulated are CD20-antigen density expression, 
complement inhibitory protein expression (e.g. CD55, CD54) by NHL cells 
and tumor burden. On the other hand, host-related factors such as 
pharmacokinetics and pharmacogenomics may play a significant role in 
patients that do not respond to rituximab. 
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                                              I 83106
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Several biological effects have been postulated as rituximab’s primary 
mechanism of anti-tumor activity [12-22]. Major areas of interest are the 
activation of the innate immune system and/or induction of apoptosis 
following rituximab therapy [12-21]. Recently published in vivo studies 
demonstrate that FcγR receptor expression is necessary to eradicate NHL 
in a murine animal model, suggesting that antibody-dependent cellular 
cytotoxicity (ADCC) plays a significant role in rituximab’s activity [21]. 
Furthermore, certain polymorphisms in the FcγRIIIa gene have been 
associated with variable clinical and molecular response to anti-CD20 
mAb therapy in patients with indolent NHL [22]. 
FcR receptors mediate many of the cell-dependent functions of 
antibodies, including phagocytosis of antibody-bound antigens, activation 
of mast cells, complement activation and targeting/activation of natural 
killer (NK) cells.  There are three types of Fc∂R receptors and eight 
subtypes. FcγRI or CD64 (high affinity) mediates phagocytosis by 
macrophages and neutrophils. FcγRIIb or CD32 (low affinity) that 
transduces inhibitory signals in B cells and finally FcγRIIIa (CD16), 
another low affinity receptor mediates the activation of natural killer cells 
to induce ADCC.
Based on prior studies, some investigators postulate that NK cells and 
macrophages mediate the destruction of NHL cells by rituximab; primarily 
via antibody dependent cellular cytotoxicity. The effects of neutrophils in 
tumor immunology may be largely underestimated. There is emerging 
evidence that polymorphonuclear cells (PMNs) are capable of not only 
migrating and infiltrating cancerous tissues but also in inducing anti-tumor 
activity. 
We have demonstrated that neutrophil function is necessary for the anti-
tumor activity of rituximab in a lymphoma mouse model [23].  Two sets of 
experiments were performed. Initially, NK cells were depleted in all mice 
using an anti-IL-2 receptor antibody (SCID mice lack T and B 
lymphocytes) to ensure tumor engraftment. Neutrophils were depleted in 2 
groups of mice through serial intraperitoneal injections of a rat-mAb 
against Ly-6G, a 21-25kDa GIP-anchored protein expressed specifically 
on granulocytes (myeloid differentiation Gr-1 antigen). Tumor growth was 
similar regardless of the presence or absence of circulating neutrophils in 
control mice (data not shown). Among rituximab-treated animals, anti-Gr-1 
antibody treatment eliminated the anti-tumor effect observed with 
rituximab (Figure. 1A). 
To determine the contribution of NK cells to rituximab anti-tumor activity in 
NHL-bearing SCID mice we conducted a second series of experiments. 
NK cells were not depleted. All animals were inoculated with Raji cells via 
tail vein injection and half of the SCID mice underwent neutrophil 
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                                              I 83106
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depletion as described above. Subsequently, animals were randomized to 
receive rituximab or placebo. Again, rituximab-treated animals with intact 
NK cells had better survival than untreated animals with or without NK 
cells. Moreover, SCID mice with intact neutrophil and NK function had the 
best response to treatment with rituximab (Figure. 1B).
The results from these experiments demonstrated that effector cells are 
indispensable for the biological activity of rituximab. In order to exclude 
any potential anti-tumor activity that could be contributed by rituximab-
mediated CMC and to further validate this hypothesis, we investigated 
whether rituximab could activate the murine complement system and lyse 
lymphoma cells in vitro. We conducted standard 51Cr release assays in 
the human lymphoma cell lines DHL-4 using rituximab or trastuzumab 
(isotype control) with sera isolated from human versus SCID or BALB-c 
mice as the source of complement proteins (final dilution 1:8). In the DHL-
4 cell lines therapy with anti-CD20 mAb was ineffective in inducing CMC 
in the presence of either SCID or BALBc (immunocompetent) mouse 
serum. Rituximab-induced CMC was only seen in the presence of human 
serum (60% of cell lysis).
1.3 
Neutrophils and tumor immunology:
PMNs induce tumor destruction by several mechanisms. Tumor recruited 
neutrophils produce several cytotoxic mediators such as reactive oxygen species, 
proteases, membrane-perforating agents and soluble mediators of cell killing 
(TNFα, IL-β1 and INFs). A second mechanism of neutrophil-mediated anti-tumor 
Survival in Days
120
100
80
60
40
20
0
Cumulative  Survival
1.2
1.0
.8
.6
.4
.2
0.0
-.2
Placebo/NK & Neutrophils
Placebo/NK cells
Rituximab/NK & Neutrophils
Rituximab/NK cells
P<0.0001
Survival in Days
120
100
80
60
40
20
0
Cumulative  Survival
1.2
1.0
.8
.6
.4
.2
0.0
-.2
Placebo/NK & Neutrophils
Placebo/NK cells
Rituximab/NK & Neutrophils
Rituximab/NK cells
P<0.0001
Survival in Days
120
100
80
60
40
20
0
Cumulative  Survival
1.2
1.0
.8
.6
.4
.2
0.0
-.2
Placebo (NK & Neutrophils)
Placebo (NK cells alone)
Rituximab (NK & Neutrophils)
Rituximab (NK cells alone)
P<0.0001
Survival in Days
100
80
60
40
20
0
Cumulative Survival
1.2
1.0
.8
.6
.4
.2
0.0
-.2
Rituximab 
(Neutrophils present)
Control
P<0.0001
Rituximab 
(Neutrophils depleted) 
Survival in Days
100
80
60
40
20
0
Cumulative Survival
1.2
1.0
.8
.6
.4
.2
0.0
-.2
Rituximab 
(Neutrophils present)
Control
P<0.0001
Rituximab 
(Neutrophils depleted) 
Survival in Days
120
100
80
60
40
20
0
Cumulative  Survival
1.2
1.0
.8
.6
.4
.2
0.0
-.2
Placebo/NK & Neutrophils
Placebo/NK cells
Rituximab/NK & Neutrophils
Rituximab/NK cells
P<0.0001
Survival in Days
120
100
80
60
40
20
0
Cumulative  Survival
1.2
1.0
.8
.6
.4
.2
0.0
-.2
Placebo/NK & Neutrophils
Placebo/NK cells
Rituximab/NK & Neutrophils
Rituximab/NK cells
P<0.0001
Survival in Days
120
100
80
60
40
20
0
Cumulative  Survival
1.2
1.0
.8
.6
.4
.2
0.0
-.2
Placebo/NK & Neutrophils
Placebo/NK cells
Rituximab/NK & Neutrophils
Rituximab/NK cells
P<0.0001
Survival in Days
120
100
80
60
40
20
0
Cumulative  Survival
1.2
1.0
.8
.6
.4
.2
0.0
-.2
Placebo (NK & Neutrophils)
Placebo (NK cells alone)
Rituximab (NK & Neutrophils)
Rituximab (NK cells alone)
P<0.0001
Survival in Days
120
100
80
60
40
20
0
Cumulative  Survival
1.2
1.0
.8
.6
.4
.2
0.0
-.2
Placebo/NK & Neutrophils
Placebo/NK cells
Rituximab/NK & Neutrophils
Rituximab/NK cells
P<0.0001
Survival in Days
120
100
80
60
40
20
0
Cumulative  Survival
1.2
1.0
.8
.6
.4
.2
0.0
-.2
Placebo (NK & Neutrophils)
Placebo (NK cells alone)
Rituximab (NK & Neutrophils)
Rituximab (NK cells alone)
P<0.0001
Survival in Days
100
80
60
40
20
0
Cumulative Survival
1.2
1.0
.8
.6
.4
.2
0.0
-.2
Rituximab 
(Neutrophils present)
Control
P<0.0001
Rituximab 
(Neutrophils depleted) 
Survival in Days
100
80
60
40
20
0
Cumulative Survival
1.2
1.0
.8
.6
.4
.2
0.0
-.2
Rituximab 
(Neutrophils present)
Control
P<0.0001
Rituximab 
(Neutrophils depleted) 
A. NK-cell depleted
B. Non NK-cell depleted
Figure. 1 Kaplan Meier Survival curves demonstrate that neutrophil depletion dramatically reduces the efficacy of Rituximab 
in the NK cell depleted (A) and in the non-NK cell depleted SCID mouse models (B).
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                                              I 83106
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activity is by ADCC.  PMNs express several subtypes of FcR receptors capable of 
inducing antibody-dependent cellular cytotoxicity such as FcRγIIa FcRγIIIa and 
FcRγIIIb.
Recruitment of neutrophils into the tumor bed is a process that requires a series of 
coordinated interactions between PMNs and endothelial cells. During this process, 
PMNs undergo different phenotypical changes that result in an activated effector 
cell. It is well known that the expression of P-, E- and L-selectin (CD62) and other 
adhesion molecules such as IMAC-1 (CD11b/CD18) play an important role in 
neutrophil trafficking.  The interaction between neutrophil and other immune-
effector cells activation and rituximab against B-cell malignancies and its 
relevance in the therapeutic strategies of NHL have not been extensively studied 
in the past.
1.4 
Rationale for Rituximab and Pegfilgrastim:
We recently have proved that, host immune system activation by target-specific 
molecules such as G-CSF/GM-CSF enhances the biological activity of rituximab 
and potentially other mAbs [24]. To further explore the stimulation of effector cells 
as a strategy to enhance the biological activity of rituximab, we subsequently 
investigated the effects of in vivo stimulation of innate immune cells with either 
murine G-CSF or GM-CSF on rituximab anti-tumor activity. NK cell-depleted SCID 
mice were inoculated by tail vein injection (tvi) with 1x106 Raji cells on day 0. 
Animals were divided into three groups to receive four intraperitoneal (ip) doses 
(from days +1 to +4) of placebo, 5μg/day of murine (m)-GM-CSF or 5μg/day of m-
G-CSF. Changes in CD11b/CD18 expression were performed by flow cytometric 
analysis of peripheral blood effector cells collected from each mouse. 
Subsequently, animals were subdivided to receive sequential placebo or 
rituximab (10mg/kg) on days +5, +8, +11 and + 14 via tail vein injection. A 
separate set of experiments was performed to address dose-schedule of cytokine 
administration. Lymphoma-bearing SCID mice were divided into six cohorts: 
Group A received placebo; Group B received m-G-CSF; Group C received m-GM-
CSF; Group D received rituximab, Group E received concurrently m-GCSF and 
rituximab; and Group F received concurrent m-GM-CSF and rituximab. MAb doses 
(10mg/kg) were administered via tvi on days +3, +7, +11 and +15. Murine 
cytokines were given concurrently via ip injection two consecutive days before 
each dose of rituximab. The end point of the study was overall survival. 
Treatment of lymphoma bearing SCID mice with rituximab resulted in significant 
higher anti-tumor activity and longer survival when compared with placebo 
controls. The median survival time for rituximab treated animals was 41 days 
(95%C.I. 30-52) in contrast to a median survival of 20 days (95% C.I. 20-20) for 
those animals receiving placebo (log rank test P < 0.001). No significant anti-tumor 
activity was observed in animals treated with either G-CSF or peg-GM-CSF alone, 
and the median survival was similar to control mice. The median survival for G-
CSF treated SCID mice was 20 days (95% C.I. 19-20) and 21 days (95% C.I. 20-
22) for those treated with peg-GM-CSF (P= 0.20).   
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                                              I 83106
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The administration of murine G-CSF for two consecutive days prior to mAb 
therapy enhanced the anti-tumor activity of rituximab and doubled the mean 
survival of lymphoma-bearing mice. Statistically, significant differences were 
observed between animals treated with rituximab and G-CSF + rituximab. The 
mean survival time of animals treated with G-CSF and rituximab was longer [84 
days (95% C.I. 75 to 93] than those treated with rituximab monotherapy [mean 
survival of 51 days (95%C.I. 37-64), log rank test P = 0.0036). After a median 
follow up time of three months, the median survival time for animals receiving 
rituximab in combination with G-CSF was not reached. (Figure 2A and 2B) 
The median survival for lymphoma-bearing SCID mice treated with rituximab and 
peg-GM-CSF was longer [62 days (95% C.I. 47-77)] when compared to rituximab 
treated animals [41 days (95%C.I. 30-52)]. Despite a trend towards improved 
survival, differences between rituximab-treated animals and those receiving the 
concurrent administration of rituximab in combination with peg-GM-CSF did not 
reach statistical significance (log rank P = 0.16). (Figure 3A and 3B)
After a follow up period of three months, survival rates were the highest for 
animals treated with rituximab and G-CSF (53.3%) when compared to animals 
treated with rituximab alone (13.3%) or in combination with peg-GM-CSF 
(26.67%). Pathological examination of all surviving animals at the end of the study 
failed to demonstrate any residual disease. 
days
100
80
60
40
20
0
cumulative survival
1.2
1.0
.8
.6
.4
.2
0.0
-.2
days
100
80
60
40
20
0
cumulative survival
1.2
1.0
.8
.6
.4
.2
0.0
G-CSF
Placebo
Rituximab
Rituximab + G-CSF
Rituximab
Rituximab + G-CSF
N = 30
N = 60
P < 0.001*
P = 0.0036
2A
2B
Figure 2. Kaplan Meier analysis of cumulative survival of SCID mice bearing raji lymphoma xenographs treated with 
rituximab and/or G-CSF.  Groups of 15 NK cell depleted SCID mice were inoculated with 1 x 106 raji cells via tail vein injection (iv) 
[day 0] and treated either with placebo, rituximab (10mg/kg iv on days +5, + 9, +13 and +17), G-CSF (10μg/dose on days +3, +4, 
+7, +8, +11,+12, +15 and +16), or rituximab (10mg/kg iv on days +5, + 9, +13 and +17) in combination with G-CSF(10μg/daily for 
two consecutive days before each rituximab dose) and analyzed for survival as function of time.  Significant anti-tumor activity was 
observed among animals treated with rituximab or rituximab in combination with G-CSF (3A). The administration of G-CSF for two 
consecutive days prior to each mAb dose resulted in a statistically significant enhancement in the biological activity of rituximab. The 
median survival of rituximab treated lymphoma bearing mice was only 41 days.  On the other hand, after a follow up period of 3 
months, the median survival time for animals treated with rituximab in combination with G-CSF has not been reach (log rank P = 
0.0036) (3B) 
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                                              I 83106
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The administration of m-GCSF or m-peg-GM-CSF for two consecutive days led to 
a significant increase in the number of circulating white cell blood (WBC), 
specifically granulocytes of lymphoma bearing SCID mice. Animals receiving m-
GCSF had a higher mean WBC count of 7.58 x 103/mm3 (std. +/- 3.85 x 103/mm3) 
than unstimulated SCID mice in which the mean WBC was 0.6533 x 103/mm3 (std. 
+/- 0.23 x 103/mm3]) (chi-square P < 0.001). In addition and to a lesser degree, 
animals that received peg-m-GM-CSF had a higher mean peripheral WBC count 
of 3.5 x 103/mm3 (std. 1.3 x103/mm3) (chi-square P < 0.001). 
Differences were primarily due to the number circulating granulocytes. The mean 
absolute neutrophil count (ANC) was higher among SCID mice treated with either 
m-G-CSF (4.98 +/- 2.7 x103/mm3) (chi-square P < 0.001) or m-peg-GM-CSF (1.97 
+/- 1.41 x103/mm3) than in animals were unstimulated (0.38 +/- 0.26 x103/mm3) 
(chi-square P = NS).
Flow cytometric analysis performed from whole blood collected 48 hours after the 
administration of m-GSF or peg-m-GM-CSF show phenotypic changes in the 
expression of activation markers on granulocytes. SCID mice treated with either 
cytokine (G-CSF or peg-GM-CSF) had a higher expression of CD11b/CD18 when 
compared to placebo controls. The up-regulation of CD11b/CD18 was restricted to 
Gr-1 positive cells (neutrophils). The mean percentage of circulating neutrophils 
days
100
80
60
40
20
0
cumulative survival
1.2
1.0
.8
.6
.4
.2
0.0
-.2
days
100
80
60
40
20
0
cumulative survival
1.2
1.0
.8
.6
.4
.2
0.0
Peg-GM-CSF
Placebo
Rituximab
Rituximab + peg-GM-CSF
Rituximab
Rituximab + peg-GM-CSF
N = 60
N = 30
P < 0.001*
P = 0.1663
3A
3B
Figure 3. Kaplan Meier analysis of cumulative survival of SCID mice bearing raji lymphoma xenographs treated with 
rituximab or peg-GM-CSF.  Groups of 15 NK cell depleted SCID mice were inoculated with 1 x 106 raji cells via tail vein injection 
(iv) [day 0] and treated either with placebo, rituximab (10mg/kg iv on days +5, + 9, +13 and +17), peg-GM-CSF (10μg/dose on 
days +3, +4, +7, +8, +11,+12, +15 and +16), or rituximab (10mg/kg iv on days +5, + 9, +13 and +17) in combination with peg-GM-
CSF(10μg/daily for two consecutive days before each rituximab dose) and analyzed for survival as function of time.  Treatment 
with rituximab was effective in arresting lymphoma growth and prolonging the survival of raji lymphoma xenographs when 
compared to placebo or peg-GM-CSF (4A). The addition of peg-GM-CSF to rituximab therapy resulted in longer median survival  
(62 days) when compared to rituximab single agent (median survival time of 41 days). However the difference did not reach 
statistical significance (log rank P = 0.1663) (4B)
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l
iza
l
iturr
i MD
                                              I 83106
 
Page 13 of 83
express
ing CD11b/CD18 iso
lated from contro
l m
ice was lower (46.81% +/- 6.73) 
than G-CSF pr
imed (96.63% +/- 1.7) or peg-GM-CSF (88.21 +/- 5.1) [F
igure 4]. On 
the other hand, no s
ign
if
icant changes were observed in the express
ion of L-
se
lect
in (CD62)
.
 
In summary, the resu
lts of these mouse exper
iments demonstrate the prom
ise of 
st
imu
lat
ing the immune effector ce
l
ls (neutroph
i
ls) us
ing G-CSF in order to 
enhance the b
io
log
ica
l ant
i-tumor act
iv
ity of r
itux
imab. The mo
lecu
lar bas
is for the 
effects of G-CSF on the ant
i-tumor act
iv
ity of r
itux
imab is yet to be fu
l
ly def
ined. 
However, an increase in the traff
ick
ing of neutroph
i
ls into the tumor bed and 
enhancement of r
itux
imab-med
iated ADCC v
ia upregu
lat
ion of CD11b/CD18 are 
be
l
ieved to p
lay a s
ign
if
icant ro
le. Other contr
ibut
ing factors such as the product
ion 
of free oxygen rad
ica
l spec
ies, comp
lement act
ivat
ion by a
lternat
ive pathways, 
cytok
ine “storms” fo
l
low
ing cytok
ine/r
itux
imab therapy, and the upregu
lat
ion of 
CD20 ant
igen by pharmaco
log
ica
l
ly ach
ievab
le doses of G-CSF needs to a
lso be 
cons
idered. Our data support the bas
is for the deve
lopment of c
l
in
ica
l tr
ia
ls 
exp
lor
ing the comb
inat
ion of r
itux
imab 
in comb
inat
ion w
ith G-CSF/PEG-F
i
lgrast
im.
1.5  
C
l
in
ica
l Exper
ience w
ith R
itux
imab 
in Comb
inat
ion w
ith G-CSF
C
l
in
ica
l
ly, the comb
inat
ion of G-CSF w
ith r
itux
imab has been stud
ied in a recent
ly 
pub
l
ished phase I/II c
l
in
ica
l tr
ia
l. Pat
ients w
ith indo
lent and intermed
iate-grade 
NHL rece
ived G-CSF at 5g/kg/dose for three consecut
ive days start
ing 48 hours 
pr
ior to each r
itux
imab infus
ion. R
itux
imab was adm
in
istered intravenous
ly at 
Placebo 
G-CSF 
GM-CSF
0.0
25.0
50.0
75.0
100.0
Gr-1



Placebo 
G-CSF 
GM-CSF
0.0
25.0
50.0
75.0
100.0
CD11b/CD18



F
igure 4. F
low cytometr
ic ana
lys
is of per
iphera
l b
lood co
l
lected from SCID m
ice show d
ifferences in the express
ion of 
act
ivat
ion markers among neutroph
i
ls treated w
ith mur
ine cytok
ines. A s
ign
if
icant
ly h
igher number of granu
locytes (Gr-1 + 
ce
l
ls) were observed among an
ima
ls rece
iv
ing mur
ine G-CSF and to a lesser degree mur
ine peg-GM-CSF. In add
it
ion, the 
surface express
ion of the act
ivat
ion marker CD11b/CD18 was upregu
lated in lymphoma bear
ing m
ice treated w
ith cytok
ines 
when compared to contro
l an
ima
ls.
2A
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                                              I 83106
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375mg/m2 weekly for four doses. The combination of G-CSF and rituximab was 
well tolerated and while the response rate was similar to historical rituximab 
monotherapy treated controls, the duration of response was longer [25]. Similarly 
to what we observed, G-CSF therapy resulted in an incremental increase in the 
neutrophil count of patients prior to rituximab therapy [25]. Notably, in contrast with 
our animal study results, a downregulation of CD11b/CD18 expression in 
circulating neutrophils were observed at 24 hours prior to rituximab therapy. 
Differences in the expression of CD11b/CD18 observed could be the result of 
inter-species variations in the degree and speed of neutrophil responsiveness and 
migration. 
The molecular basis for the effects of G-CSF on the anti-tumor activity of rituximab 
need to be fully defined. However, an increase in the trafficking of neutrophils into 
the tumor bed and enhancement of rituximab-mediated ADCC via upregulation of 
CD11b/CD18 likely play significant roles. Recently studies conducted in 
CD11b/CD18 deficient mice demonstrated that the capacity of neutrophils to 
induce ADCC against antibody-coated melanoma cells was impaired [26].  
Another group of investigators have demonstrated changes in CD20 antigen 
expression following in vitro exposure to various cytokines [27]. In our studies we 
could not demonstrate a significant upregulation of surface CD20 following in vitro 
exposure of lymphoma cells to either G-CSF or GM-CSF. Discrepancies between 
our results and those reported by Dr. Venugopal could be related to differences in 
cytokine dose, timing, and use of cell lines versus freshly isolated patient 
specimens.  A better understanding in the physiological events that occur following 
the administration of G-CSF and rituximab will hopefully lead to an improvement in 
rituximab-associated anti-tumor activity in patients with B-cell lymphoma.
1.6
Clinical Experience with Pegfilgrastim
Neulasta® (pegfilgrastim) is a covalent conjugate of recombinant methionyl human 
G-CSF (Filgrastim) and monomethoxypolyethylene glycol. Both Filgrastim and 
pegfilgrastim are Colony Stimulating Factors that act on hematopoietic cells by 
binding to specific cell surface receptors thereby stimulating proliferation, 
differentiation, commitment, and end cell functional activation.  Studies on cellular 
proliferation, receptor binding, and neutrophil function demonstrate that Filgrastim 
and pegfilgrastim have the same mechanism of action. Pegfilgrastim has reduced 
renal clearance and prolonged persistence in vivo as compared to Filgrastim.
Neulasta® is indicated to decrease the incidence of infection, as manifested by 
febrile neutropenia, in patients with non-myeloid malignancies receiving 
myelosuppressive anti-cancer drugs associated with a clinically significant 
incidence of febrile neutropenia.
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                                              I 83106
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Clinical Experience
Pegfilgrastim was evaluated in three randomized, double-blind, controlled studies.  
Studies 1 and 2 were active-controlled studies that employed doxorubicin 60 
mg/m2 and docetaxel 75 mg/m2 administered every 21 days for up to 4 cycles for 
the treatment of metastatic breast cancer.[27,28] Study 1 investigated the utility of 
a fixed dose of pegfilgrastim. Study 2 employed a weight-adjusted dose. In the 
absence of growth factor support, similar chemotherapy regimens have been 
reported to result in a 100% incidence of severe neutropenia (absolute neutrophil 
count [ANC] < 0.5 x 109/L) with a mean duration of 5-7 days, and a 30%-40% 
incidence of febrile neutropenia. [29]
 
In study 1, 157 subjects were randomized to receive a single subcutaneous (SC) 
dose of 6 mg of pegfilgrastim on day 2 of each chemotherapy cycle or Filgrastim at 
5 mcg/kg/day SC beginning on day 2 of each cycle. In study 2, 310 subjects were 
randomized to receive a single SC injection of pegfilgrastim at 100 mcg/kg on day 
2 or Filgrastim at 5 mcg/kg/day SC beginning on day 2 of each cycle of 
chemotherapy.
Both studies met the primary objective of demonstrating that the mean days of 
severe neutropenia (ANC<0.5 x 109/L) of pegfilgrastim-treated patients did not 
exceed that of Filgrastim-treated patients by more than one day in cycle 1 of 
chemotherapy.  
The rates of febrile neutropenia were 13% and 9% for 
pegfilgrastim vs. 20% and 18% for Filgrastim in studies 1 and 2, respectively. 
[27,28] Other secondary endpoints included days of severe neutropenia in cycles 
2-4, the depth of ANC nadir in cycles 1-4, and the time to ANC recovery after 
nadir. In both studies, the results for the secondary endpoints were similar 
between the two treatment groups.
Study 3 was a randomized, double-blind, placebo-controlled study that employed 
docetaxel 100 mg/m2 administered every 21 days for up to 4 cycles for the 
treatment of metastatic or non-metastatic breast cancer. In this study, 928 patients 
were randomized to receive a single subcutaneous injection of Neulasta® 6 mg or 
placebo on day 2 of each chemotherapy cycle. Study 3 met the primary objective 
of demonstrating that the incidence of febrile neutropenia (defined as temperature 
> 38.2°C and ANC < 0.5 x109/L) was lower for Neulasta®-treated patients as 
compared to placebo-treated patients (1% versus 17%, p < 0.001). The incidence 
of hospitalizations (1% versus 14%) and IV anti-infective use (2% versus 10%) for 
the treatment of febrile neutropenia were also lower in the Neulasta®-treated 
patients compared with the placebo-treated patients. [30]
The safety and efficacy of once-per-cycle pegfilgrastim was also found to be 
comparable to daily Filgrastim in phase 2 studies in patients with non-small cell 
lung cancer being treated with carboplatin and paclitaxel and patients with non-
Hodgkin’s lymphoma (NHL) or Hodgkin’s lymphoma being treated with ESHAP 
(etoposide, methylprednisolone, high-dose cytarabine, cisplatin) or CHOP 
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                                              I 83106
Page 16 of 83
(cyclophosphamide, doxorubicin, vincristine, prednisone) chemotherapy. [31, 32, 
33] 
Refer to the Package Insert for additional information on the clinical pharmacology, 
pharmacokinetics and precautions of pegfilgrastim.
2.0  OBJECTIVES
2.1
Primary objective:
To evaluate the safety of Pegfilgrastim in combination with rituximab in patients 
with untreated or relapsed/refractory follicular, small lymphocytic lymphoma (SLL) 
or marginal zone lymphoma (MZL). 
2.2
 Secondary objectives:
To evaluate the efficacy (including overall response rate and durability of objective 
responses) of Pegfilgrastim in combination with rituximab in patients with 
untreated or relapsed/refractory follicular, small lymphocytic lymphoma (SLL) or 
marginal zone lymphoma (MZL).
To evaluate functional and phenotypic characteristics of host neutrophils 
undergoing treatment with Pegfilgrastim and rituximab
To evaluate changes in CD20 antigen expression and density of expression in 
patients receiving Pegfilgrastim and rituximab
To evaluate changes in serum levels of tumor necrosis factor (TNF), interferon 
alpha (INFα) and free radical levels in patients undergoing treatment with 
Pegfilgrastim and rituximab
3.0. STUDY DESIGN OVERVIEW 
This open-label, single-arm, single-center Phase II study will evaluate the safety, 
tolerability and efficacy of rituximab antibody in combination with Pegfilgrastim in patients 
with untreated or relapsing/refractory follicular, SLL or MZL.  We expect to enroll 40 
patients from Roswell Park Cancer Institute over thirteen years.
4.0. STUDY POPULATION
Eligible REAL disease classifications include untreated, or relapsed / refractory:
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                                              I 83106
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1.
Follicular lymphoma; grade 1, 2, 3a
2.
Small lymphocytic lymphoma.
3.
Marginal zone lymphoma.
4.1
Patient Eligibility
4.1.1
Inclusion Criteria
Patients must meet the following criteria to be eligible for study admission: 
•
Untreated or relapsed/refractory follicular, small lymphocytic 
lymphoma or marginal zone lymphoma (i.e. no limit to number of 
prior treatments as long as patients meet other study criteria)
•
ECOG performance status 0 or 1
•
Age >18 years
•
Measurable tumor size (at least one node measuring 4 cm2 in 
bidimensional measurement)
•
Expected survival of > 6 months.
•
Prior rituximab or other monoclonal immunotherapy permitted and 
eligible for rituximab monotherapy.
•
Full recovery from any significant toxicity associated with prior 
surgery, radiation therapy, chemotherapy, or immunotherapy.
•
Absolute neutrophil count > 1.0 x 109/L
•
Platelets > 50 x 109/L
•
Patients may receive erythropoietin growth factors to maintain 
adequate hemoglobin levels (> 8.0 mg/dl).
•
Creatinine <1.5 x UNL
•
Total bilirubin < 1.5 mg/dL (> 25.65 μmol/L).
•
Aspartate aminotransferase < 5 x UNL
•
Alkaline phosphatase < 5 x UNL
•
Informed consent approved in institutional IRB
•
CD20+ B-cell lymphoma
4.1.2
Exclusion Criteria
Patients will be excluded from the study based on the following criteria:
•
Prior history of HIV-positivity (Routine HIV testing is required pre-
treatment)
•
Serious non-malignant disease (e.g. active uncontrolled bacterial, 
viral, or fungal infections) or other conditions which, in the opinion 
of the principal investigator would compromise other protocol 
objectives
•
Presence of CNS lymphoma
•
Chemotherapy within 4 weeks of the first scheduled study 
treatment 
•
Another primary malignancy (other than squamous or basal cell 
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                                              I 83106
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carcinoma of the skin or in-situ carcinoma of the cervix) for which 
the patient has not been disease-free for at least five years.
•
Major surgery, other than diagnostic surgery, within four weeks.
•
Patients with NHL other than relapsed/refractory folicullar, MZL or 
SLL
•
Patients must not have a history of cardiac disease, defined as 
New York Heart Association Class II or greater or clinical 
evidence of congestive heart failure.  
•
Concurrent use of other investigational agents
•
Pregnant or breast feeding
•
Subjects of reproductive potential who are not using adequate 
contraceptive precautions, in the judgment of the investigator
•
Known hypersensitivity to any recombinant E coli-derived product, 
murine proteins, or any components of the study medications
•
Concerns for the subject’s compliance with the protocol
•
Any premalignant myeloid condition or any malignancy with 
myeloid characteristics (e.g. myelodysplastic syndromes, acute or 
chronic myelogenous leukemia)
•
Patient is currently enrolled in, or has not yet completed at least 
30 days since ending another investigational device or drug trial
5.0 DOSE-SCHEDULE AND FORMULATION:
 
Enrolled patients will receive Pegfilgrastim 6mg subcutaneously (sq) 3 days before each dose of 
rituximab. Monoclonal antibody therapy will consist of rituximab (Rituxan®) administered 
intravenously (iv) at a dose of 375mg/m2 every other week for four doses and after 8 weeks every 2 
months for four additional doses. All patients are expected to receive a total of 8 doses of 
Pegfilgrastim and eight doses of rituximab (Rituxan®). The treatment will be administered over a 
total period of 39 weeks. 
The standard administration of rituximab single agent is 375mg/m2 weekly x 4. However various 
schedules had been studied in clinical trials. Two “extended” regimens were studied by The Minnie 
Pearl Cancer Center and by the Swiss Group for Clinical Cancer Research. The first group studied 
the administration of rituximab at the standard dose of 375mg/m2 weekly x 4 follow by maintenance 
rituximab at the same dose weekly x 4 every 6 months for 2 years. The second group compared 
the standard regimens of rituximab versus an extended 8 regimen consisting of rituximab 
administered at 375mg/m2 weekly x 4 follow by 4 additional doses of rituximab (375mg/m2) every 8 
weeks starting 12 weeks after the completion of the induction rituximab therapy. In both studies 
there was a prolongation in the time to treatment failure compared to rituximab historical controls. 
However a survival advantage was not observed. 
In our current study we are seeking to study if by enhancing the innate immune system with 
pegfilgrastim, we can modulate rituximab activity without adding significant toxicity.  Because of the 
pharmacokinetics of pegfilgrastim we decided to administer the first 4 doses of rituximab every 2 
weeks instead of the standard weekly schedule. Based on pharmacokinetic data in early rituximab 
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clinical trials, the modification in the first four doses of rituximab should not affect rituximab levels 
as the half life of this antibody is extremely long. The additional four doses are administered as 
previously done by the Swiss Group. It is important from the safety stand point to note that the 
Swiss schedule has been adopted by several Oncologist in the United States as their preferred 
schedule given the safety profile and better anti-tumor activity over the standard schedule of four 
doses of rituximab.
Table 1. Dose-schedule administration of Pegfilgrastim in combination with rituximab
Week
1
3
5
7
9
11
13
15
17
19
21
23
25
27
29
31
33
35
37
39
Rituximab
◙
◙
◙
◙
◙
◙
◙
◙
Pegfilgrastim ◙
◙
◙
◙
◙
◙
◙
◙
Pegfilgrastim will be administered sq 3 days (day 1 of each treatment week) before each dose of rituximab 
(day 4 of each treatment week)
Pegfilgrastim is supplied as a preservative-free solution containing 6 mg (0.6 mL) of Pegfilgrastim 
(10 mg/mL) in a single-dose syringe with a 27 gauge, 1/2 inch needle with an UltraSafe® Needle 
Guard. 
Rituximab (Rituxan®) is a sterile, clear, colorless, preservative free liquid concentrate for 
intravenous (IV) administration. Rituximab is supplied at a concentration of 10 mg/mL in either 100 
mg (10 mL) or 500 mg (50 mL) single use vials. The product is formulated for IV administration in 
9.0 mg/mL sodium chloride, 7.35 mg/mL sodium citrate dihydrate, 0.7 mg/mL polysorbate 80, and 
Sterile Water for Injection. The pH is adjusted to 6.5.
Premedication with acetaminophen 650 mg PO and diphenhydramine hydrochloride 25 mg IV.  
Premedication will be done before each rituximab dose.  The initial dose rate at the time of the first 
rituximab infusion will be 50 mg/hr for the first hour.  If no toxicity is seen, the dose rate will be 
escalated in 50 mg/hr increments in 30-minute intervals to maximum of 400 mg/hr.  If the first dose 
of rituximab is well tolerated, the starting flow rate for administration of subsequent doses will be 
100 mg/hr then escalated in 100 mg/hr increments at 30-minute intervals not to exceed 400 mg/hr.
6.0 COMPLIANCE
This study will be conducted in accordance with current U.S. Food and Drug Administration (FDA) 
Good Clinical Practices (GCPs), the Declaration of Helsinki, and local ethical and legal 
requirements.
7.0 PROCEDURES 
7.1
Study Procedures by Visit (For a summary of the treatment procedures and 
evaluations see Appendix section)
7.1.1
Screening and Pretreatment Assessments
All patients must have signed the Informed Consent Form prior to initiation of any study-related 
evaluations. All screening procedures must be completed within 4 weeks of study enrollment and 
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initiation of treatment with Pegfilgrastim/rituximab. The following evaluations and procedures will be 
performed during the screening period:  
•
Medical history
•
Physical exam (including lymph node, liver and spleen evaluation) and 
vital signs
•
Height and body weight (BSA calculation)
•
ECOG performance status
•
CBC with 5-part differential and platelet count.
•
Chemistry panel (electrolytes, albumin, BUN, creatinine, bilirubin, alkaline 
phosphatase, LDH, ALT, AST, calcium, phosphorous); in addition, 
peripheral blood sample will be sent for Bcl-2 detection
•
Pregnancy test (if applicable)
•
Bone marrow aspirate, biopsy and sample for markers, cytogenetic 
analysis, PCR for Ig gene rearrangement 
•
     Lymph node biopsy and sample for surface antigen markers (e.g. 
CD20, CD19, etc.); PCR for Ig gene rearrangement in FL patients; and 
Bcl-2 detection for patients with accessible and enlarged lymph node. As 
long as they do not have any medical contraindications for biopsy as 
determined 
by 
the 
treating 
physician. 
For 
patients with 
no 
accessible tumor lesions or with medical contraindications for surgical 
procedure, archived pathological material will be analyzed for confirmation 
of diagnosis, CD20 expression and in cases of FL for IgH gene 
rearrangement and Bcl-2 studies Beta 2 microglobulin (β2M)
•
Urinalysis
•
Tumor measurements (bidimensional by physical examination and/or 
radiological studies
•
Imaging studies for disease assessment (a minimum of one and a 
maximum of six sentinel lesions will be selected for determining the 
efficacy of the study treatment) within 4 weeks prior to treatment.
o
PET scan, CT scan or MRI of chest, abdomen, and pelvis (and 
when appropriate, neck).
•
Quantitative immunoglobulins (IgG, IgA, IgM)
•
Screening of patients for HBV and HCV
7.1.2.
Assessments during Treatment Period (Weeks 1,3,5,7, 11, 15, 23, 27, 31, 
39 and 43)
Patients with easily accessible lymphomatous lesions will be requested to undergo 
an excisional biopsy after completion of the first dose of Pegfilgrastim and rituximab (within 
24 hrs after completion of the antibody infusion). Clinical and laboratory evaluations will be 
performed before each rituximab treatment for weeks 1,3,5,7, 15, 23, 31 and 39. Imaging 
evaluations will be performed on week 11, before entering into the extended rituximab 
schedule, at the middle of the extended rituximab schedule (week 27) and at week 43 
following completion of therapy.
The following evaluations and procedures will be performed during the 
treatment period at each time interval as described above:
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•
Physical exam (including lymph node, liver and spleen evaluation) and 
vital signs
•
Body weight 
•
ECOG performance status
•
CBC with 5-part differential and platelet count.
•
Chemistry panel (electrolytes, albumin, BUN, creatinine, bilirubin, alkaline 
phosphatase, LDH, ALT, AST, calcium, phosphorous)
•
Imaging studies for disease assessment (week11) prior to the fifth dose of 
pegfilgrastim and rituximab, in the middle of the extended schedule (week 
27) and approximately 1 month after the last dose of study treatment 
[week 43]
o
PET scan, CT scan (or when necessary, MRI) of chest, abdomen, 
pelvis, (and neck if appropriate)
o
The sentinel lesions chosen at baseline will be assessed at the times 
indicated above.  If the patient has a response (PR or CR), the patient 
must be reassessed 1 to 4 months later to confirm the response.  
Bone marrow studies will be repeated at one month after completion 
of therapy [i.e., week 43] in all patients with lymphomatous 
involvement evaluate “complete response” status in patients achieving 
“natal” CR on exam/radiological studies
•
Record adverse events and concomitant medications (throughout the 
treatment period)
7.1.3. End of the study assessments (Week 43 studies).
The following tests and/or data collection must be performed or obtained during 
week 43 and four weeks or greater after completing all therapy. 
•
Physical exam (including lymph node, liver and spleen evaluation) and 
vital signs
•
ECOG performance status
•
CBC with 5-part differential and platelet count.
•
Chemistry panel (electrolytes, albumin, BUN, creatinine, bilirubin, alkaline 
phosphatase, LDH, ALT, AST, calcium, phosphorous)
•
Bone marrow aspirate, biopsy and sample for previously measured 
antigen markers, for Ig gene rearrangement (and Bcl-2 by PCR in FL patients 
only) 
•
Beta 2 microglobulin (β2M) (if elevated pre-therapy)
•
Tumor measurements (using same methodology utilized pre-therapy)
•
Quantitative immunoglobulins (IgG, IgA, IgM)
7.1.4
Assessments during Follow-up Period
All patients will be followed for assessment of time to progression and survival 
only, for 4 years (48 months) after the last study treatment.  
•
The following assessments and/or studies must be performed or obtained 
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every 4 months during the first year of follow-up; then 
every 6 months during the second and third years of 
follow-up;  and yearly thereafter. History and Physical 
Examination
•
ECOG performance status
•
Imaging studies for disease assessment. Response classifications 
(definitions) are fully described in Appendix.  
o
PET scan if clinically indicated, CT scan (or MRI) of chest, abdomen 
and pelvis (and when appropriate, neck). CT will be performed during 
the first two years of follow-up only.
•
Laboratory studies 
o
Hematology:  CBC with differential and platelet count.  In the event of 
Grade 3 or 4 hematologic toxicity, follow-up evaluations will be 
performed as clinically indicated until the toxicity has resolved.
o
Serum Chemistries:  creatinine, uric acid, total bilirubin, alkaline 
phosphatase, LDH, total protein, albumin, glucose, AST (SGOT), 
calcium, phosphate, sodium, potassium, and BUN.
The following studies will be performed annually during the 4 year (48 month) follow-up 
period:
•
Laboratory studies 
o
Peripheral blood (and bone marrow samples when available) for bcl-2 
testing if the baseline assessment was positive for this marker
7.2
Patient Discontinuation
Patients may choose to withdraw from the study at any time.
The Principal Investigator for the following reasons may discontinue patients from 
the study:
•
Adverse experiences
o
Patients with persistent Grade >3 non-hematologic toxicity or any 
significant adverse event that, in the opinion of the investigator, 
compromises the patient's ability to participate in the study will be 
withdrawn from the study.  
o
Patients requiring treatment interruption for more than 3 weeks 
will be removed from the study.  
•
Disease progression
o
Patients with progressive disease (as defined in Appendix C) or 
clinically significant deterioration at any time during the study will 
be withdrawn from the study.
•
Investigator judgment
o
Patients may be withdrawn from the study if, in the opinion of the 
investigator, it is not in the patient's best interest to continue, e.g., 
an adverse experience, intercurrent illness, pregnancy, lack of 
efficacy, etc.
All patients discontinuing the study will be requested to complete the Week 11 and 
43 assessments.  
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7.3
Study Discontinuation
Reasons for terminating the study may include the following:
•
The incidence or severity of adverse events in this or other studies 
indicates a potential health hazard to patients
•
Patient enrollment is unsatisfactory
•
Data recording is inaccurate or incomplete
7.4
Safety Evaluations
The primary objective of this study will be to evaluate the safety of pegfilgrastim in 
combination with rituximab in patients with relapsed / refractory follicular, small lymphocytic 
or marginal zone lymphoma.
Safety will be assessed by
•
continuous monitoring for adverse events
•
laboratory studies prior to each cycle of therapy
•
vital signs
•
physical examinations
•
restaging prior as indicated above
All adverse events will be continuously monitored until resolution.
Adverse events that may be seen in this study include:
•
Events related to the administration of rituximab, such as asthenia, infusion-related 
symptoms (e.g. fever, chills, and hypotension) most common with the first infusion, 
and rarely mild thrombocytopenia and neutropenia.
•
Events related to the administration of pegfilgrastim, such as bone pain. 
7.5
Efficacy Evaluations
As a secondary objective this study will evaluate the antitumor efficacy of rituximab in 
combination with pegfilgrastim in this patient population.  
Efficacy assessments will include
•
clinical evaluation of disease (to be performed during  week number 11,27 and 43 
•
radiologic evaluation of the extent of disease following therapy (to be performed on 
weeks 11, 27 and 43) will be used to assess response according to the standard 
World Health Organization (WHO) response criteria (Appendix).
o
PET scans, computerized tomography (CT) scans, or magnetic resonance 
imaging (MRI). CT scans will be performed during the first two years of 
follow-up only.
o
other relevant x-ray studies, will be performed 
•
periodic (during week 43 and annually thereafter for four years) assessment of bcl-
2 (chromosome 14;18 translocation) by PCR in peripheral blood (and when 
possible, in bone marrow) for those follicular lymphoma patients testing positive for 
this genetic marker pretreatment
Efficacy parameters to be evaluated include:
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•
overall response rates
•
complete response (CR) rates
•
partial response (PR) rates
•
time to progression
7.6. Correlative studies description:
In this particular study we will study the mechanisms by which pegfilgrastim may improve rituximab 
activity. In our preclinical studies using lymphoma cells lines and lymphoma xenografts, we found 
that G-CSF increases not only the number of neutrophils but also the expression of adhesion 
molecules such as CD11b that were partially responsible for the improvement in rituximab activity. 
Therefore we will conduct similar studies in enrolled patients that may validate our pre-clinical data.  
Various laboratory parameters will be analyzed for each patient enrolled in the study before 
treatment (baseline) and before each dose of rituximab. Laboratory studies will study the changes 
in neutrophils induced by Pegfilgrastim and will be correlated with clinical response and duration of 
response in each patient completing the study.
1.
Phenotype changes in neutrophils: Flow cytometry will be analyzed for changes in the 
surface expression of CD11b/CD18, CD16, CD32 and CD64.  Differences in antigen 
density will be determined by mean fluorescence units.
2.
Changes in the oxidative burst by neutrophils stimulated with Pegfilgrastim as measured 
by flow cytometry studies and measurement of free radicals in serum from patients treated 
with rituximab and Pegfilgrastim. Oxidative burst will be measured as by flow cytometry 
analysis. 
3.
Functional Assays in vitro: ADCC assays: The capacity to lyse tumor cells in the presence 
of rituximab by Peripheral Blood mononuclear cells (PBMC’s) of each patient will be 
studied by standardized 51Cr release assays.  Briefly 2 x106 lymphoma cells (Raji cells) will 
be labeled with 51Cr. Labeled cells will be then exposed to rituximab or isotype control 
(10μg/ml) and peripheral blood mononuclear cells isolated from each patient be at the 
intervals described above (Effector: Target ratio 40:1)51Cr-release was measured and the 
percentage of lysis was calculated using the following formula:
% Lysis = [CPM sample – CPM background/ CPM positive control – CPM background] * 100.
4.
Monitor serum levels of INFα and TNF in patients treated with rituximab in combination 
with Pegfilgrastim.  Cytokines levels will be measured by flow cytometry in the Roswell 
Park Cancer Institute Flow Cytometry Department. 
In addition, patients with easily accessible lymphomatous lesions will be requested to undergo an 
excisional biopsy after completion of the first dose of Pegfilgrastim and rituximab (within 24 hrs 
after completion of the antibody infusion). Tissue will be analyzed for the following:
1.
Infiltration of neutrophils into the tumor bed
2.
Changes in CD20 expression as determined by immunohistochemistry (L26 staining), flow 
cytometry, and Western blotting studies for evaluation of cell viability and evidence of 
apoptosis; comparison to pre-treatment lymphoma biopsy specimens
3.
Pathological examination
8.0
ADVERSE EVENT REPORTING
In the event of an adverse experience, the first concern will be for the safety of the patient.  Timely, 
accurate, and complete reporting and analysis of safety information from clinical trials are crucial 
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for the protection of patients, investigators, and the Sponsor, and is mandated by regulatory 
agencies worldwide. Adverse events will be classified according to the NCI Common Toxicity 
Criteria  using the Toxicity Scale version CTCAE v3.0. 
8.1. Definitions
8.1.1
Adverse Event Classification Definitions
Adverse Event:
Any untoward medical occurrence in a patient or clinical investigation patient 
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 finding), symptom, or disease 
temporally associated with the use of a medicinal (investigational) product, 
whether or not related to the medicinal (investigational) product.
This includes any occurrence that is new in onset or aggravated in severity or 
frequency from the baseline condition, abnormal results of diagnostic procedures 
including laboratory test abnormalities which are considered AEs if they:
•
result in discontinuation from the study,
•
require treatment or any other therapeutic intervention,
•
require further diagnostic evaluation (excluding a repetition of the same 
procedure to confirm the abnormality),
•
are associated with clinical signs or symptoms judged by the investigator to 
have a significant clinical impact.
Serious Adverse Event (SAE):
Any untoward medical occurrence that at any dose:
•
results in death,
•
is life-threatening (The patient was at risk of death at the time of the event. It 
does not refer to an event which hypothetically might have caused death if it 
were more severe),
•
requires inpatient hospitalization or prolongation of existing hospitalization, 
•
results in persistent or significant disability/incapacity,
or
•
in a congenital anomaly/birth defect. 
Note: Medical and scientific judgment should be exercised in deciding whether 
expedited reporting is appropriate in other situations, such as important medical 
events that may not be immediately life-threatening or result in death or 
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hospitalization but may jeopardize the patient or may require intervention to 
prevent one of the outcomes listed in the definition above.
Unlisted (Unexpected) Adverse Event:
An AE, the nature or severity of which is not consistent with the applicable product 
information (e.g. Investigator’s Brochure) for an unapproved investigational 
product or package insert/summary of product characteristics for an approved 
product.
Associated With the Use of the Drug:
An AE is considered associated with the use of the drug if the attribution is 
possible, probable or very likely.
8.1.2. Attribution Definitions
Not related
An AE which is not related to the use of the drug.
Unlikely
An AE for which an alternative explanation is more likely - e.g. concomitant 
drug(s), concomitant disease(s), and/or the relationship in time suggests that a 
causal relationship is unlikely.
Possible
An AE which might be due to the use of the drug. An alternative explanation - e.g. 
concomitant drug(s), concomitant disease(s) - is inconclusive. The relationship in 
time is reasonable; therefore the causal relationship cannot be excluded.
Probable
An AE which might be due to the use of the drug. The relationship in time is 
suggestive (e.g. confirmed by dechallenge). An alternative explanation is less 
likely - e.g. concomitant drug(s), concomitant disease(s).
Likely
An AE which is listed as a possible adverse reaction and cannot be reasonably 
explained by an alternative explanation - e.g. concomitant drug(s), concomitant 
disease(s).  The relationship in time is very suggestive (e.g. it is confirmed by 
dechallenge and rechallenge).
8.2 Procedures
8.2.1  All Adverse Events
All AEs and SAEs experienced by enrolled patients for whom study drug is 
provided must be reported according to this procedure.  All AEs will be reported 
between the first trial related procedure and the last dose of study drug. Any AE 
that is ongoing must be followed for 90 days following the last trial related 
procedure.  Those meeting the definition of SAE must be reported between the 
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first trial related procedure and 90 days after the last trial related procedure using 
the SAE Form. Patients should voluntarily report any AEs or in response to 
general, non-directed questioning (e.g., “How has your health been since the last 
visit?”). For each AE volunteered by the patient, the investigator should obtain all 
the information required to complete the AE page of the CRF, in accordance with 
the guidelines that accompany it.
All AEs, regardless of seriousness, severity, or presumed relationship to study 
therapy, must be recorded using medical terminology in the source document and 
on the CRF. Whenever possible, diagnoses should be given when signs and 
symptoms are due to a common etiology (e.g., cough, runny nose, sneezing, sore 
throat, and head congestion should be reported as “upper respiratory infection”). 
Investigators must record on the CRF their opinion concerning the relationship of 
the AE to study therapy.  All measures required for AE management must be 
recorded in the source document and reported according to Sponsor instructions.
The principal investigator assumes responsibility for appropriate reporting of AEs 
to the regulatory authorities. The Sponsor will also report to the investigator all 
serious AEs that are unlisted and associated with the use of the drug. The 
investigator must report these events to the appropriate Institutional Review Board 
(IRB) in accordance with local regulations.
8.2.2
Serious Adverse Events
All SAEs occurring during clinical trials must be reported within one working day 
(24 hours) to IRB.  This includes but is not limited to type, grade, action taken and 
relationship to the study medications.
The cause of death of a patient in a clinical trial, whether the event is expected or 
associated with the study drug, is an SAE.
The initial report of an SAE may be made by telephone or facsimile (FAX). The 
investigator must provide the minimal information: i.e. protocol number, patient’s 
initials and date of birth, patient number or medication code number, period of 
intake, nature of the adverse event and investigator’s attribution.
All oral reports of an SAE must be confirmed within three days by a written, more 
detailed report and signed by the investigator. For this purpose, the Sponsor will 
provide the investigator with the Serious Adverse Event Form.
All SAEs that have not resolved by the end of the study, or that have not resolved 
upon discontinuation of the patient’s participation in the study, must be followed 
until either:
•
the event resolves, or
•
the event stabilizes, or
•
the event returns to baseline, if a baseline value is available, or
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•
the event can be attributed to other than the study drug, or to other than study 
conduct.
8.2.3
Pregnancies
Pregnancies occurring between the first trial-related procedure and 90 days after 
the last trial-related procedure must be reported to IRB within one working day 
after the investigator or study staff has gained knowledge of them, using the 
Serious Adverse Event Form. Follow-up information regarding the outcome of the 
pregnancy and any postnatal sequelae in the infant will be requested from 
Amgen’s Drug Safety and Surveillance (DSS).
All patients who become pregnant during participation in this trial must be promptly 
withdrawn from the trial.  
Although pregnancy is not an adverse event, manufacturers should be notified of 
pregnancies occurring on study.
8.3
Reporting Procedures for Serious Adverse Events
All serious adverse events related to study drug must be reported to Amgen 
Global Safety within one working day of discovery or notification of the event.  Use 
a MedWatch form or appropriate institutional form for reporting adverse events to 
Amgen.  Initial serious adverse event information and all follow-up information 
must be recorded on a Serious Adverse Event form and faxed using the Amgen 
Serious Adverse Event Report Cover Page to:
Amgen Global Safety (Fax: 888-814-8653 / Phone: 866-264-3650)
The investigator should notify the IRB of serious adverse events occurring at the 
site, in accordance with local procedures.  All serious and medically significant 
adverse events considered related to pegfilgrastim by the investigator will be 
followed until resolved or considered stable. 
In addition, any serious adverse events related to the use of Rituximab will be also 
need to be reported to Genentech/Biogen Idec: Monic Stuart, MD, Genentech, 1 
DNA Way, South San Francisco, California 94080 (Fax 650-225-5862 / Phone: 
650-467-1256)
8.4 Internal Data Safety and Monitoring
The same monitoring process in effect for all RPCI investigator initiated studies will 
monitor this trial. All patients on study are reviewed for any toxicity or other 
untoward events during the Data Safety and Monitoring Board (DSMB). The 
primary responsibilities of the DSMB are to 1) periodically review and evaluate the 
accumulated study data for participant safety, study conduct and progress, and, 
when appropriate, efficacy, and 2) make recommendations to the IRB concerning 
the continuation, modification, or termination of the trial. 
The first review is planned to be conducted after the first six patients complete the 
proposed treatment.  Patient recruitment, accrual and retention will also be 
discussed at DSMB meetings as needed.  Toxicity is reported to the DSMB.The 
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principal investigator will continuously monitor the study and will submit safety and 
monitoring reports to the institution IRB and DSMB as required.
If any literature becomes available which suggests that conducting this trial is no 
longer ethical, the study will be terminated and the IRB will be notified of the new 
findings. The IRB will be notified of any change in the risk/benefit ratio that would 
affect whether the study should continue.  All SAEs will be reported to the IRB 
according to the established guidelines.  A cumulative summary of all AEs 
occurring on this study will also be submitted to the IRB with the annual periodic 
review.  Toxicity is reported, as required, to the FDA and study sponsors.  All study 
data reviewed and discussed during these meetings will be kept confidential.  Any 
breech in patient confidentiality will be reported to the IRB.
9.0 STATISTICAL METHODS
9.1
Analysis of the Conduct of the Study
Patient enrollment, major protocol deviations and violations, withdrawals from the 
study, and adherence to study medication will be summarized by the study center.
9.2
Baseline Demographics
The demographic and baseline data will be summarized by participating center.  
Means and standard deviations will be used for the demographic continuous variables.  
Absolute and relative frequencies will describe categorical variables.
Demographic and baseline variables are the following:
•
Sex
•
Age
•
Weight (kg)
•
Height (cm)
•
Body surface area (BSA = Square Root (weight x height)/3600) (m2)
•
Performance status
•
Histologic classification
•
Free radical species levels
•
Levels of INFα and TNF 
•
CD11b/CD18, CD62, , CD56, FcγIII and FcγII receptor polymorphism 
status of PMNs
•
% of cell lysis by ADCC pre and post pegfilgrastim and rituximab
9.3. 
Safety
The study will be conducted in two parts. Evaluation of the safety of rituximab and 
pegfilgrastim will be done after the collection of the first twenty patients (First part of the 
study). All patients who complete at least one dose of pegfilgrastim will be considered 
evaluable for safety analysis.  Patients who are not evaluable for safety will be replaced. 
The first twenty patients evaluable for safety will be used determine if the combination of 
rituximab and pegfilgrastim is tolerable.  This number of patients is sufficient to determine 
the safety of the combination.  The combination of rituximab and pegfilgrastim will be 
deemed tolerable if at least 75% of patients (15/20) tolerate the combination as measured 
by the absence of dose limiting toxicity (DLT). DLT is defined as any grade >3 
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hematological (excluding isolated lymphopenia or leukopenia) or non-hematological 
toxicity at any time during protocol therapy that is related to the study drug combination. 
Isolated lymphopenia is expected following rituximab therapy as a result of peripheral B-
cell depletion. The collection of twenty additional patients will take place only if this 
standard is met. All 40 subjects will be reviewed for safety.
Previously, other investigators had investigated the safety and efficacy of rituximab 
in combination with G-CSF in patients with relapsed/refractory NHL. In that study the 
combination of rituximab and G-CSF was well tolerated. Adverse events, which occurred in 
25/26 patients, were mainly consisted of (grade I/II) fever (29%) and allergic reactions 
(19%) [25]. In the present clinical study if during the first phase of enrollment, four (20%) 
patients experience dose-limiting toxicity (DLT) accrual of patients will stop and the 
combination of rituximab and pegfilgrastim will be determined intolerable. Safety will be 
monitored as described in section 7. 
9.4 
Efficacy
Response to treatment for all patients will be assessed at weeks 11, 27, and 43.  
Responses will be confirmed within 4 months after completion of all therapy for all patients. 
The primary efficacy endpoint for this study is the overall response rate (ORR) at weeks 
11, 27, and 43.  Secondary endpoints are the complete response (CR), partial response 
(PR) rates at weeks 11, 27, and 43, the time to disease progression, and survival.  The 
primary and secondary efficacy endpoints are largely based on radiological assessment of 
the tumor.  In addition, efficacy endpoints will be compared to historical previously 
published clinical data with rituximab given as a single agent (i.e. historical controls). 
9.4.1. Methodology
The primary patient population will be based on the intent-to-treat 
approach and will include all enrolled patients.  Patients who die as the result of 
disease progression or related complications before a tumor evaluation, or who 
take concomitant chemotherapeutic medication not specified in the protocol, or 
who withdraw from the study will be considered treatment failures.
The secondary patient population will include patients who complete the 
full treatment cycle. The full treatment cycle includes eight doses of rituximab and 
eight doses of pegfilgrastim administered over a 39 week period as described in 
table 1. 
Primary and Secondary analyses.  After the 43-week data from all 
patients enrolled have been entered into the database, an analysis of the 
response rates will be conducted.  The ORR, CR and PR rates will be estimated 
for all enrolled patients (intent-to-treat approach).  
Two-sided 95% exact 
confidence intervals around the estimates will be calculated.
The estimate and the 95% exact confidence intervals of the ORR rate and 
the CR/PR rates will also be computed for evaluable patients only.  A detailed 
response status (complete response, partial response, stable, and progressive 
disease) will be summarized overall for the intent-to-treat and the evaluable 
populations.  All responses, regardless of the duration, will be included in the 
above analyses.
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Additional secondary efficacy endpoints are time to disease progression 
and survival.  These will be analyzed after the 2- and 4-year data from all patients 
have been collected.  
Time to progression is defined as date of 
progression/death/last contact - date treatment started.  Survival is defined as date 
of death/last contact - date treatment started.  
If the specified event 
(death/progression) did not occur during the follow-up period, the above variables 
will be censored at the last contact date.
Descriptive statistics such as median, minimum, and maximum values will 
be used to summarize the time to event data.  Kaplan-Meier estimates will be used 
to present the time to progression data.  Correlation between response to 
treatment and immunological parameter gathered from the correlative studies will 
be performed by Cox regression analysis. 
A descriptive analysis of the correlative studies will be performed to define 
antibody-dependent 
cell-mediated 
cytotoxicty 
(ADCC) 
pre 
or 
post-
pegfilgrastim/rituximab and CD20 cell levels.  The study parameters will be 
summarized with simple summary statistics, including means, medians, ranges, 
and standard deviations.  All data summaries based on these correlative studies 
will be descriptive and exploratory in nature, with the goal of developing further 
questions regarding the modulation of therapy, or regarding reasons for efficacy or 
lack of efficacy. 
Supportive Efficacy.  The supportive analysis will include 2-and 4-year 
survival estimates, overall performance on study (weight loss, change in Karnofsky 
Score), and exploratory analysis of the effects of baseline characteristics on 
response rates, time to progression, and survival.
9.5 Determination of Sample Size
Twenty patients will be used for the first end point which is safety evaluation and 
the primary analysis.  The standard error of the percentage of patients who did not 
experience a DLT will be at most 11 percentage points. With a sample size of 40 evaluable 
patients, the precision of the estimate of the ORR rate, which is reflected by the width of 
the 95% confidence interval, will be at most 31 percentage points.  
10.0
STUDY DRUG INFORMATION AND ACCOUNTABILITY
10.1
Rituximab (Rituxan) – commercially available drug
10.1.1 Formulation and Storage
Provided in 100 mg (10 mL) or 500 mg (50 mL) vials at a concentration of 
10 mg/mL.
The rituximab drug product is formulated in 25 mm sodium citrate, 150 
mm sodium chloride, 0.07% polysorbate 80 and buffered to a pH of 6.5 
using either hydrochloric acid or sodium hydroxide.
Rituximab must be diluted in normal saline to achieve a final concentration 
of between 1 mg/mL and 4 mg/mL.  Care should be taken during drug 
dilution to avoid shaking, as this can lead to aggregation of precipitation of 
the antibody.  Rituximab for clinical use should be stored in a secure 
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refrigerator at 2˚C to 8˚C.  Rituximab must be stored, prepared, and 
administered according to the directions in the package insert.  
10.1.2 Adverse reactions and Warnings 
For further details on rituximab including adverse reactions and warning, 
see appendix A. 
Severe Infusion Reactions (See BOXED WARNINGS, ADVERSE 
REACTIONS and Hypersensitivity Reactions)
RITUXAN has caused severe infusion reactions. In some cases, these 
reactions were fatal. These severe reactions typically occurred during the 
first infusion with time to onset of 30 to 120 minutes. Signs and symptoms 
of severe infusion reactions may include hypotension, angioedema, 
hypoxia or bronchospasm, and may require interruption of RITUXAN 
administration. The most severe manifestations and sequelae include 
pulmonary infiltrates, acute respiratory distress syndrome, myocardial 
infarction, ventricular fibrillation, and cardiogenic shock. In the reported 
cases, the following factors were more frequently associated with fatal 
outcomes: female gender, pulmonary infiltrates, and chronic lymphocytic 
leukemia or mantle cell lymphoma. 
Management of severe infusion reactions: The RITUXAN infusion should 
be interrupted for severe reactions and supportive care measures 
instituted as medically indicated (e.g., intravenous fluids, vasopressors, 
oxygen, bronchodilators, diphenhydramine, and acetaminophen). In most 
cases, the infusion can be resumed at a 50% reduction in rate (e.g., from 
100 mg/hr to 50 mg/hr) when symptoms have completely resolved. 
Patients requiring close monitoring during first and all subsequent 
infusions include those with pre-existing cardiac and pulmonary 
conditions, those with prior clinically significant cardiopulmonary adverse 
events and those with high numbers of circulating malignant cells (> 
25,000/mm3) with or without evidence of high tumor burden.
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Tumor Lysis Syndrome [TLS] (See BOXED WARNINGS and 
ADVERSE REACTIONS) Rapid reduction in tumor volume followed by 
acute renal failure, hyperkalemia, hypocalcemia, hyperuricemia, or 
hyperphosphatasemia, have been reported within 12 to 24 hours after the 
first RITUXAN infusion. Rare instances of fatal outcome have been 
reported in the setting of TLS following treatment with RITUXAN. The risks 
of TLS appear to be greater in patients with high numbers of circulating 
malignant cells (> 25,000/mm3) or high tumor burden. Prophylaxis for TLS 
should be considered for patients at high risk. Correction of electrolyte 
abnormalities, monitoring of renal function and fluid balance, and 
administration of supportive care, including dialysis, should be initiated as 
indicated. Following complete resolution of the complications of TLS, 
RITUXAN has been tolerated when re-administered in conjunction with 
prophylactic therapy for TLS in a limited number of cases.
Hepatitis B Reactivation with Related Fulminant Hepatitis and Other 
Viral Infections Hepatitis B virus (HBV) reactivation with fulminant 
hepatitis, hepatic failure, and death has been reported in some patients 
with hematologic malignancies treated with RITUXAN. The majority of 
patients received RITUXAN in combination with chemotherapy. The 
median time to the diagnosis of hepatitis was approximately 4 months 
after the initiation of RITUXAN and approximately one month after the last 
dose.
Persons at high risk of HBV infection should be screened before initiation 
of RITUXAN. Carriers of hepatitis B should be closely monitored for 
clinical and laboratory signs of active HBV infection and for signs of 
hepatitis during and for up to several months following RITUXAN therapy. 
In patients who develop viral hepatitis, RITUXAN and any concomitant 
chemotherapy should be discontinued and appropriate treatment including 
antiviral therapy initiated. There are insufficient data regarding the safety 
of resuming RITUXAN therapy in patients who develop hepatitis 
subsequent to HBV reactivation.
The following additional serious viral infections, either new, reactivated or 
exacerbated, have been identified in clinical studies or postmarketing 
reports. The majority of patients received RITUXAN in combination with 
chemotherapy or as part of a hematopoietic stem cell transplant. These 
viral 
infections 
included 
JC 
virus 
[progressive 
multifocal 
leukoencephalopathy (PML)], cytomegalovirus, herpes simplex virus, 
parvovirus B19, varicella zoster virus, West Nile virus, and hepatitis C. In 
some cases, the viral infections occurred up to one year following 
discontinuation of RITUXAN and have resulted in death.
Hypersensitivity Reactions RITUXAN has been associated with 
hypersensitivity reactions (non-IgE-mediated reactions) which may 
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respond to adjustments in the infusion rate and in medical management. 
Hypotension, bronchospasm, and angioedema have occurred in 
association with RITUXAN infusion (see Severe Infusion Reactions). 
RITUXAN infusion should be interrupted for severe hypersensitivity 
reactions and can be resumed at a 50% reduction in rate (e.g., from 100 
mg/hr to 50 mg/hr) when symptoms have completely resolved. Treatment 
of these symptoms with diphenhydramine and acetaminophen is 
recommended; additional treatment with bronchodilators or IV saline may 
be indicated. In most cases, patients who have experienced non-life-
threatening hypersensitivity reactions have been able to complete the full 
course of therapy. (See DOSAGE and ADMINISTRATION.) Medications 
for the treatment of hypersensitivity reactions, e.g., epinephrine, 
antihistamines and corticosteroids, should be available for immediate use 
in the event of a reaction during administration.
Cardiovascular Infusions should be discontinued in the event of serious 
or life-threatening cardiac arrhythmias. Patients who develop clinically 
significant arrhythmias should undergo cardiac monitoring during and after 
subsequent infusions of RITUXAN. Patients with pre-existing cardiac 
conditions including arrhythmias and angina have had recurrences of 
these events during RITUXAN therapy and should be monitored 
throughout the infusion and immediate post-infusion period.
Renal (See BOXED WARNINGS: Tumor Lysis Syndrome [TLS] and 
ADVERSE REACTIONS) RITUXAN administration has been associated 
with severe renal toxicity including acute renal failure requiring dialysis 
and in some cases, has led to a fatal outcome. Renal toxicity has occurred 
in patients with high numbers of circulating malignant cells (>25,000/mm3) 
or high tumor burden who experience tumor lysis syndrome (see Tumor 
Lysis Syndrome) and in patients administered concomitant cisplatin 
therapy during clinical trials. The combination of cisplatin and RITUXAN is 
not an approved treatment regimen. If this combination is used in clinical 
trials extreme caution should be exercised; patients should be monitored 
closely for signs of renal failure. Discontinuation of RITUXAN should be 
considered for those with rising serum creatinine or oliguria. 
Severe Mucocutaneous Reactions (See BOXED WARNINGS) 
Mucocutaneous reactions, some with fatal outcome, have been reported 
in patients treated with RITUXAN. These reports include paraneoplastic 
pemphigus (an uncommon disorder which is a manifestation of the 
patient's underlying malignancy),18 Stevens-Johnson syndrome, lichenoid 
dermatitis, vesiculobullous dermatitis, and toxic epidermal necrolysis. The 
onset of the reaction in the reported cases has varied from 1 to 13 weeks 
following RITUXAN exposure. Patients experiencing a severe 
mucocutaneous reaction should not receive any further infusions and seek 
prompt medical evaluation. Skin biopsy may help to distinguish among 
different mucocutaneous reactions and guide subsequent treatment. The 
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safety of readministration of RITUXAN to patients with any of these 
mucocutaneous reactions has not been determined.
Bowel Obstruction and Perforation Abdominal pain, bowel obstruction 
and perforation, in some cases leading to death, were observed in 
patients receiving RITUXAN in combination with chemotherapy for 
DLBCL. In post-marketing reports, which include both patients with low-
grade or follicular NHL and DLBCL, the mean time to onset of symptoms 
was 6 days (range 1–77) in patients with documented gastro-intestinal 
perforation. Complaints of abdominal pain, especially early in the course 
of treatment, should prompt a thorough diagnostic evaluation and 
appropriate treatment.
Adverse Reactions
Because clinical trials are conducted under 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 another drug and may not 
reflect the rates observed in practice. The adverse reaction information 
from clinical trials does, however, provide a basis for identifying the 
adverse events that appear to be related to drug use and for 
approximating rates.
The overall safety database for RITUXAN is based on clinical trial data 
from 1283 patients with NHL, who received RITUXAN either as a single 
agent or in combination with chemotherapy. Additional safety information 
was obtained from post-marketing safety surveillance. The most common 
adverse reactions were infusion reactions (see INFUSION REACTIONS 
below).
The following serious adverse reactions, some with fatal outcomes, have 
been reported in patients treated with RITUXAN (see BOXED 
WARNINGS and WARNINGS): severe or fatal infusion reactions, tumor 
lysis syndrome, severe mucocutaneous reactions, hepatitis B reactivation 
with fulminant hepatitis, other viral infections, hypersensitivity reactions, 
cardiac arrhythmias, renal toxicity, bowel obstruction and perforation.
Except as noted, adverse events described below occurred in the setting 
of relapsed or refractory, low-grade or follicular, CD20-positive, B-cell, 
NHL and are based on 356 patients treated in nonrandomized, single-arm 
studies of RITUXAN administered as a single agent. Most patients 
received RITUXAN 375 mg/m2 weekly for 4 doses.
Infusion Reactions (See BOXED WARNINGS and WARNINGS)
Mild to moderate infusion reactions consisting of fever and chills/rigors 
occurred in the majority of patients during the first RITUXAN infusion. 
Other frequent infusion reaction symptoms included nausea, pruritus, 
angioedema, asthenia, hypotension, headache, bronchospasm, throat 
irritation, rhinitis, urticaria, rash, vomiting, myalgia, dizziness, and 
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hypertension. These reactions generally occurred within 30 to 120 
minutes of beginning the first infusion, and resolved with slowing or 
interruption of the RITUXAN infusion and with supportive care 
(diphenhydramine, acetaminophen, IV saline, and vasopressors). The 
incidence of infusion reactions was highest during the first infusion (77%) 
and decreased with each subsequent infusion (30% with fourth infusion 
and 14% with eighth infusion). Injection site pain was reported in less than 
5% of patients.
Infectious Events (See WARNINGS: Hepatitis B Reactivation with 
Related Fulminant Hepatitis and Other Viral Infections)
RITUXAN induced B-cell depletion in 70% to 80% of patients and was 
associated with decreased serum immunoglobulins in a minority of 
patients; the lymphopenia lasted a median of 14 days (range, 1 to 588 
days). Infectious events occurred in 31% of patients: 19% of patients had 
bacterial infections, 10% had viral infections, 1% had fungal infections, 
and 6% were unknown infections. Incidence is not additive because a 
single patient may have had more than one type of infection. Serious 
infectious events (Grade 3 or 4), including sepsis, occurred in 2% of 
patients.
Hematologic Events
Grade 3 and 4 cytopenias were reported in 48% of patients treated with 
RITUXAN; these include: lymphopenia (40%), neutropenia (6%), 
leukopenia (4%), anemia (3%), and thrombocytopenia (2%). The median 
duration of lymphopenia was 14 days (range, 1 to 588 days) and of 
neutropenia was 13 days (range, 2 to 116 days). A single occurrence of 
transient aplastic anemia (pure red cell aplasia) and two occurrences of 
hemolytic anemia following RITUXAN therapy were reported.
Pulmonary Events
135 patients (38%) experienced pulmonary events in clinical trials. The 
most common respiratory system adverse events experienced were 
increased cough, rhinitis, bronchospasm, dyspnea, and sinusitis. In both 
clinical studies and post-marketing surveillance, there have been a limited 
number of reports of bronchiolitis obliterans presenting up to 6 months 
post-RITUXAN infusion and a limited number of reports of pneumonitis 
(including interstitial pneumonitis) presenting up to 3 months post-
RITUXAN infusion, some of which resulted in fatal outcomes. The safety 
of resumption or continued administration of RITUXAN in patients with 
pneumonitis or bronchiolitis obliterans is unknown.
Immunogenicity
The observed incidence of antibody positivity in an assay is highly 
dependent on the sensitivity and specificity of the assay and may be 
influenced by several factors including sample handling, concomitant 
medications, and underlying disease. For these reasons, comparison of 
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the incidence of antibodies to RITUXAN with the incidence of antibodies to 
other products may be misleading.
In clinical studies of patients with low-grade or follicular NHL receiving 
single-agent RITUXAN, human antichimeric antibody (HACA) was 
detected in 4 of 356 (1.1%) patients and 3 had an objective clinical 
response. These data reflect the percentage of patients whose test results 
were considered positive for antibodies to RITUXAN using an enzyme-
linked immunosorbant assay (limit of detection = 7 ng/mL).
Single Agent RITUXAN for Relapsed or Refractory, Low-Grade or 
Follicular, CD20-Positive, B-Cell, NHL
Study subjects ranged from 22 to 81 years of age. Sixty percent were 
male; 93% were Caucasian, 1% were African American, 2% were 
Hispanic, 2% were Asian, and 2% were from other racial groups. Table 4 
lists the most common, as well as Grade 3 and 4, adverse events 
observed.
Table 4
Incidence of Adverse Events in > 5% of Patients
with Relapsed or Refractory, Low-Grade or Follicular
NHL, Receiving Single-agent RITUXAN (N=356)a,b
 
All Grades (%) Grade 3 and 4 (%)
Any Adverse Events
99
57
Body as a Whole
86
10
  Fever
53
1
  Chills
33
3
  Infection
31
4
  Asthenia
26
1
  Headache
19
1
  Abdominal Pain
14
1
  Pain
12
1
  Back Pain
10
1
  Throat Irritation
9
0
  Flushing
5
0
Cardiovascular System
25
3
  Hypotension
10
1
  Hypertension
6
1
Digestive System
37
2
  Nausea
23
1
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  Diarrhea
10
1
  Vomiting
10
1
Hemic and Lymphatic System
67
48
  Lymphopenia
48
40
  Leukopenia
14
4
  Neutropenia
14
6
  Thrombocytopenia
12
2
  Anemia
8
3
Metabolic and Nutritional Disorders 38
3
  Angioedema
11
1
  Hyperglycemia
9
1
  Peripheral Edema
8
0
  LDH Increase
7
0
Musculoskeletal System
26
3
  Myalgia
10
1
  Arthralgia
10
1
Nervous System
32
1
  Dizziness
10
1
  Anxiety
5
1
Respiratory System
38
4
  Increased Cough
13
1
  Rhinitis
12
1
  Bronchospasm
8
1
  Dyspnea
7
1
  Sinusitis
6
0
Skin and Appendages
44
2
  Night Sweats
15
1
  Rash
15
1
  Pruritus
14
1
  Urticaria
8
1
a Adverse Events observed up to 12 months following RITUXAN.
b Adverse Events graded for severity by NCI-CTC criteria.19
Risk Factors Associated with Increased Rates of Adverse Events
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Administration of RITUXAN weekly for 8 doses resulted in higher rates of 
Grade 3 and 4 adverse events14 overall (70%) compared with 
administration weekly for 4 doses (57%). The incidence of Grade 3 or 4 
adverse events was similar in patients retreated with RITUXAN compared 
with initial treatment (58% and 57%, respectively). The incidence of the 
following clinically significant adverse events was higher in patients with 
bulky disease (lesions > 10 cm) (N = 39) versus patients with lesions < 10 
cm (N = 195): abdominal pain, anemia, dyspnea, hypotension, and 
neutropenia.
10.2  Pegfilgrastim Drug Information – investigational drug provided 
10.2.1 Packaging and Formulation
Pegfilgrastim will be manufactured and packaged by Amgen Inc. and 
distributed using Amgen clinical trial drug distribution procedures.
Pegfilgrastim  is supplied as a preservative-free solution containing 6 mg 
(0.6 mL) of pegfilgrastim (10 mg/mL) in a single-dose syringe with a 27 
gauge, 1/2 inch needle with an UltraSafe® Needle Guard. 
Neulasta® is supplied in 0.6 mL prefilled syringes for subcutaneous 
injection. Each syringe contains 6 mg pegfilgrastim (based on protein 
weight), in a sterile, clear, colorless, preservative-free solution (pH 4.0) 
containing acetate (0.35 mg), sorbitol (30.0 mg), polysorbate 20 (0.02 
mg), and sodium (0.02 mg) in water for injection, USP.
10.2.2 Labeling
Drug labeling will comply with the requirements of the U.S. FDA.
EACH PREFILLED SYRINGE OF PEGFILGRASTIM WILL BE LABELED WITH THE 
FOLLOWING:
pegfilgrastim 10 mg/mL
0.6 mL s.c.
CAUTION: New drug – Limited
by Federal Law to
Investigational Use
Amgen Inc. 2°C - 8°C
10.2.3. Supply and Return of Drug
At study initiation and as needed thereafter, pegfilgrastim will be shipped 
to the Pharmacist at the investigator’s institution, who will check the 
amount and condition of the drug and enter these data into the Proof of 
Receipt form and Investigational Product Accountability Record. The Proof 
of Receipt form should then be faxed to Amgen and the original retained 
at the center. At the end of the study, or as directed, all pegfilgrastim 
unused prefilled syringes will be destroyed per the site’s standard 
operating procedures.
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10.2.4. Drug Accountability
An Accountability Record for the clinical trial product, pegfilgrastim, must 
be kept current, and should contain:
•
the dates and quantities of drug received from Amgen, Inc
•
subject’s identification (subject number and initials and lot 
number)
•
date and quantity of drug dispensed (and remaining)
•
the initials of the dispenser, and
•
date and quantity of drug returned to the investigator/pharmacy, if 
appropriate
Pegfilgrastim prefilled syringes that have been used will be discarded per 
institution policy. At the end of the study, the Final Product Reconciliation 
Statement must be completed and provided to Amgen. These inventories 
must be made available for inspection by an authorized Amgen 
representative or designee and regulatory agency inspectors. The 
investigator is responsible for the accountability of all used and unused 
trial supplies.
10.2.5. Storage Conditions and Stability
Pegfilgrastim should be stored refrigerated at 2° to 8°C (36° to 46°F); 
syringes should be kept in their carton to protect from light until time of 
use. Shaking should be avoided. Before injection, pegfilgrastim may be 
allowed to reach room temperature for a maximum of 48 hours but should 
be protected from light. Pegfilgrastim left at room temperature for more 
than 48 hours should be discarded. Freezing should be avoided; however, 
if accidentally frozen, pegfilgrastim should be allowed to thaw in the 
refrigerator before administration. If frozen a second time, pegfilgrastim 
should be discarded.  Pegfilgrastim should be visually inspected for 
discoloration and particulate matter before administration.  Pegfilgrastim 
should not be administered if discoloration or particulates are observed.  
Since pegfilgrastim provided for clinical trials contains no preservatives, 
prefilled syringes are designed for single use only. Contact your Amgen 
representative, or their designee, if storage conditions fall out of the 
specified range. Before investigational product that has been exposed to 
storage conditions out of the specified range can be used, Amgen’s 
Stability Department must issue a memo. This memo must be sent to and 
maintained at the site.
Records of the actual storage conditions during the period of the study 
must be maintained (eg, records of the date and time and initials of person 
checking, and the daily temperatures of the refrigerator used for storage of 
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investigational product, continuous temperature recordings, or regularly 
maintained temperature alarm systems).
10.2.6. Preparation and Administration
No preparation is required for administration of pegfilgrastim. Each subject 
will receive afixed dose of 6 mg of pegfilgrastim. The entire contents of the 
0.6 mL prefilled syringe should be administered irrespective of the 
subject’s actual weight.
For method of administration please see patient package insert.
10.2.7. Adverse Reactions
In a placebo-controlled trial, bone pain occurred at a higher incidence in 
pegfilgrastim-treated patients as compared to placebo-treated patients 
(Pegfilgrastim, n = 467; Placebo, n = 461). The incidence of other 
commonly reported adverse events were similar in the pegfilgrastim- and 
placebo-treated patients, and were consistent with the underlying cancer 
diagnosis and its treatment with chemotherapy. Those adverse events 
occurred at rates between 48% and 10% in the pegfilgrastim treated 
patients and included: alopecia, bone pain, diarrhea, pyrexia (not 
including febrile neutropenia), myalgia, headache, arthralgia, vomiting, 
asthenia, edema peripheral, and constipation.
In the active controlled studies, common adverse events occurred at 
similar rates and severities in both treatment arms (Pegfilgrastim, n = 
465; Filgrastim, n = 331). These adverse experiences occurred at rates 
between 72% and 15% and included: nausea, fatigue, alopecia, diarrhea, 
vomiting, constipation, fever, anorexia, skeletal pain, headache, taste 
perversion, dyspepsia, myalgia, insomnia, abdominal pain, arthralgia, 
generalized weakness, peripheral edema, dizziness, granulocytopenia, 
stomatitis, mucositis, and neutropenic fever. 
Bone Pain
In the placebo-controlled study, the incidence of bone pain was 57% in 
Neulasta®-treated patients compared to 50% in placebo-treated patients. 
Bone pain was generally reported to be of mild-to-moderate severity. 
Among patients experiencing bone pain, approximately 37% of 
Neulasta®- and 31% of placebo-treated patients utilized non-narcotic 
analgesics and 10% of Neulasta®- and 9% of placebo-treated patients 
utilized narcotic analgesics. 
In the active-controlled studies, the use of non-narcotic and narcotic 
analgesics in association with bone pain was similar between Neulasta®- 
and Filgrastim-treated patients. No patient withdrew from study due to 
bone pain. 
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Laboratory Abnormalities
In clinical studies, leukocytosis (WBC counts > 100 x 109/L) was 
observed in less than 1% of 932 patients with non-myeloid malignancies 
receiving Neulasta®.  Leukocytosis was not associated with any adverse 
effects.  
In the placebo-controlled study, reversible elevations in LDH, alkaline 
phosphatase, and uric acid that did not require treatment occurred at 
similar rates in Neulasta®- and placebo-treated patients.
Overdosage
The maximum amount of Neulasta® that can be safely administered in 
single or multiple doses has not been determined. Single doses of 300 
mcg/kg have been administered SC to 8 normal volunteers and 3 
patients with non-small cell lung cancer without serious adverse effects. 
These subjects experienced a mean maximum ANC of 55 x 109/L, with 
a corresponding mean maximum WBC of 67 x 109/L. The absolute 
maximum ANC observed was 96 x 109/L with a corresponding absolute 
maximum WBC observed of 120 x 109/L. The duration of leukocytosis 
ranged from 6 to 13 days. Leukapheresis should be considered in the 
management of symptomatic individuals.
Toxicity/Warnings
Pegfilgrastim is contraindicated inpatients with known hypersensitivity to E 
coli-derived proteins, pegfilgrastim, Filgrastim, or any other component of 
the product.
Rare cases of splenic rupture have been reported following the 
administration of Neulasta®. Splenic rupture, in some cases resulting in 
death, has also been associated with filgrastim, the parent compound of 
pegfilgrastim.  Patients receiving pegfilgrastim who report left upper 
abdominal and/or shoulder tip pain should be evaluated for an enlarged 
spleen or splenic rupture.
Adult respiratory distress syndrome (ARDS) has been reported in 
neutropenic patients with sepsis receiving Filgrastim, the parent 
compound of pegfilgrastim, and is postulated to be secondary to an influx 
of neutrophils to sites of inflammation in the lungs. Neutropenic patients 
receiving pegfilgrastim who develop fever, lung infiltrates, or respiratory 
distress should be evaluated for the possibility of ARDS. In the event that 
ARDS occurs, pegfilgrastim should be discontinued and/or withheld until 
resolution of ARDS and patients should receive appropriate medical 
management for this condition. Moreover It is unknown if the risk of acute 
respiratory distress syndrome with Rituximab will be higher with the use of 
pegfilgrastim.  
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Allergic reactions to pegfilgrastim, including anaphylaxis, skin rash, and 
urticaria, have been reported in post marketing experience. The majority 
of reported events occurred upon initial exposure. In some cases, 
symptoms recurred with rechallenge, suggesting a causal relationship. In 
rare cases, allergic reactions including anaphylaxis, recurred within days 
after initial anti-allergic treatment was discontinued. If a serious allergic 
reaction occurs, appropriate therapy should be administered, with close 
patient follow-up over several days. Pegfilgrastim should be permanently 
discontinued in patients with serious allergic reactions.
Severe sickle cell crises have been associated with the use of Neulasta® 
in patients with sickle cell disease. Severe sickle cell crises, in some 
cases resulting in death, have also been associated with Filgrastim, the 
parent compound of pegfilgrastim. Only physicians qualified by 
specialized training or experience in the treatment of patients with sickle 
cell disease should prescribe Neulasta® for such patients, and only after 
careful consideration of the potential risks and benefits.  
Pregnancy and Lactation
There are no adequate and well-controlled studies in pregnant women. 
The risks of the study drug to an unborn or newborn child are not known. 
In addition, it is not known whether pegfilgrastim is secreted in human 
milk. Therefore, pregnant or nursing mothers may not take part in this 
study.
Drug Interactions
No formal drug interaction studies between Neulasta® and other drugs 
have been performed. Drugs such as lithium may potentiate the release of 
neutrophils; patients receiving lithium and Neulasta® should have more 
frequent monitoring of neutrophil counts.
11.0
ETHICAL CONSIDERATIONS
11.1
Investigator Requirements
11.1.1 Study Initiation
Before the start of this study, the following documents must be on file with Amgen or an Amgen 
representative:
•
Original U.S. FDA Form 1572 (for all studies conducted under U.S. 
Investigational New Drug [IND] regulations), signed by all Principal 
Investigators.
o
The names of any sub investigators must appear on this form.  
Investigators must also complete all regulatory documentation as required 
by local and national regulations.
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•
Current curricula vitae of the Principal Investigator and all sub investigators.
•
Institutional Review Board/Ethical Committee (IRB/EC) membership list and/or 
Department of Health and Human Services number.
•
written documentation of IRB/EC approval of protocol (identified by Amgen 
protocol number or title and date of approval) and informed consent document 
(identified by Amgen protocol number or title and date of approval).
•
a copy of the IRB/EC approved informed consent document.
•
written documentation of IRB/EC review and approval of any advertising 
materials to be used for study recruitment, if applicable.
•
Current laboratory certification of the laboratory performing the analysis (if 
other than a Genentech approved central laboratory), as well as current 
normal laboratory ranges for all laboratory tests.
•
A signed Clinical Research Agreement.
•
Certified translations of IRB/EC approval letters, pertinent correspondence, 
and approved informed consent document (when applicable).
•
A signed and dated protocol signature page.
11.1.2 Study Completion
The following data and materials are required before a study can be considered 
complete or terminated:
•
Laboratory findings, clinical data, and all special test result from screening 
through the end of the study follow-up period.
•
All Electronic Data Capture Reports properly maintained by study personnel 
and the investigator.
•
Completed Drug Accountability Records (Investigational New Drug Retrieval 
Record [INDRR-1], Drug Inventory Log, and Inventory of Returned Clinical 
Material forms).
•
Copies of protocol amendments and IRB/EC approval/notification, if 
appropriate.
•
A summary of the study prepared by the Principal Investigator (will accept IRB 
summary close letter).
11.2
Informed Consent
An informed consent document for this proposed study has been written .
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The patient or the patient’s legal guardian before his or her participation in the 
study must sign the informed consent document.  A copy of the informed consent 
document must be provided to the patient or the patient's legal guardian.  If 
applicable, it will be translated to the language understood by the patient.
Signed consent forms must remain in each patient's study file and must be 
available for verification by study monitors at any time. 
11.3
Institutional Review Board or Ethics Committee Approval
This protocol, the informed consent document, and relevant supporting information 
must be submitted to the IRB/EC for review and must be approved before the 
study is initiated.
The Principal Investigator is responsible for keeping the IRB/EC appraised of the 
progress of the study and of any changes made to the protocol as deemed 
appropriate, but in any case at least once a year.  The Principal Investigator must 
also keep the IRB/EC informed of any significant adverse events. 
12.0
DATA QUALITY ASSURANCE
Accurate, consistent, and reliable data will be ensured though the use of standard 
practices and procedures.
13.0
DISCLOSURE OF DATA
Patient medical information obtained by this study is confidential, and disclosure to third 
parties other than those noted below is prohibited.
Upon the patient's permission, medical information may be given to his or her personal 
physician or other appropriate medical personnel responsible for his or her welfare.
Data generated by this study must be available for inspection upon request by 
representatives of the U.S. FDA, national and local health authorities, and the IRB/EC for 
each study site, if appropriate.
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14.0        REFERENCES:
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Grossbard ML, Press OW, Appelbaum FR, et al.  Monoclonal antibody-based therapies 
of leukemia and lymphoma.  Blood 80:863-878, 1992.
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McLaughlin P, Grillo-Lopez AJ, Link BK, et al.  Chimeric Anti-CD20 monoclonal antibody 
therapy for relapsed indolent lymphoma:  Half of patients respond to a 4-dose, 22 day 
treatment program.  J Clin Oncol 16:2825-2833, 1998.
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Czuczman MS, Grillo-Lopez AJ, White CA, et al.  Treatment of Patients with Low-Grade 
B-cell Lymphoma with the Combination of Chimeric Anti-CD20 Monoclonal Antibody and 
CHOP Chemotherapy.  J Clin Oncol 17:268-276, 1999.
6.
Vose JM, Link BK, Grossbard ML, et al.  Phase II study of rituximab in combination with 
CHOP chemotherapy in patients with previously untreated aggressive non-Hodgkin’s 
lymphoma.  J Clin Oncol.  19(2):389-397, 2001.
7.
Coiffier B, Ferme C, Hermine O, et al.  Rituximab plus CHOP (R-CHOP) in the treatment 
of elderly patients with diffuse large B-cell lymphoma.  An update of the GELA study.  
Blood 98(11):725a, 2001.
8.
Anderson KC, Bates MP, Slaughenhoupt BL, et al.  Expression of human B cell-
associated antigens on leukemias and lymphomas:  a model of human B cell 
differentiation.  Blood 63:1424-1433, 1984.
9.
Maloney D, Smith B, Appelbaum F.  The anti-tumor effect of monoclonal anti-CD20 
antibody (MAB) therapy includes direct anti-proliferative activity and induction of 
apoptosis in CD20 positive non-Hodgkin's lymphoma (NHL) cell lines.  Blood 88 
(10):637a, 1996.
10. Maloney DG, Liles TM, Czerwinski DK, et al.  Phase I clinical trial using escalating 
single-dose infusion of chimeric anti-CD20 monoclonal antibody (IDEC-C2B8) in patients 
with recurrent B-cell lymphoma.  Blood 84:2457-2466, 1994.
11. Maloney D, Bodkin D, Grillo-Lopez A, et al.  IDEC-C2B8: final report of a Phase II trial in 
relapsed non-Hodgkin's lymphoma.  Blood 169a, 1994.
12. Deans JP, Schieven GL, Shu GL, Valentine MA, Gilliand LA, Aruffo A, Clark EA and 
Ledbetter JA. Association of Tyrosine and Serine Kinases with B cell surface antigen 
CD20. Journal of Immunology 1993; 151:4494-4504.
13. Shan D, Ledbetter JA and Press OW. Apoptosis of Malignant human B cell by ligation of 
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CD20 with monoclonal antibodies. Blood 1998; 91:1644-1652.
14. Shan D, Ledbetter JA and Press OW. Signaling events involved in anti-CD20 –induced 
apoptosis of malignant human B-cells. Cancer Immunology Immunotherapeutics 2000; 
48:673-683.
15. Popoff IJ, Savage JA, Blake J, Johnson P and Deans JP. The association between 
CD20 and Src-family tyrosine kinases requires an additional factor. Molecular 
Immunology 1998; 35:207-214.
16. Taji H, Kagami Y, Okada Y, Andou M, Nishi Y, Saito H, Seto M and Morishima Y. 1998. 
Growth inhibition of CD20-positive B lymphoma cell lines by IDEC-C2B8 anti-CD20 
monoclonal antibody. Jpn. Journal Cancer Research 1998; 89:748-756.
17. Holder M, Grafton G, MacDonald I, Finney M and Gordon J. Engagement of CD20 
suppress apoptosis in germinal center B cells. Eur. J. Immunology. 25:3160-3164.
18. Mathas S, Rickers A, Bommert  K, Dorken B and Mapara MY. Anti-CD20 and B-cell 
receptor-mediated apoptosis: evidence for shared intracellular signaling pathways. 
Cancer Research 2000; 60:7170-7176.
19. Hofmeister JK, Cooney D and Coggeshall KM. Clustered CD20 induced apoptosis: Src-
family kinase, the proximal regulator of tyrosine phosphorylation, calcium influx, and 
caspase 3-dependent apoptosis. Blood Cells, Molecules and Diseases 2000; 26:133-
143.
20. Harjunpaa A, Junnikkala S and Meri S.  Rituximab (Anti-CD20) therapy of B-cell 
lymphomas: Direct Complement Killing is superior to cellular effector mechanisms. Scan 
J. Immunol 2000; 51: 634-641.
21. Clynes RA, Towers TL, Presta LG and Ravetch JV. Inhibitory Fc receptors modulate in 
vivo cytotoxicity against tumor targets. Nature Medicine 2000; 4:443-446.
22. Cartron G, Dacheux L, Salles G, Solal-Celligny P, Bardoantis P, Colombat P and Watier 
H. Therapeutic activity of humanized anti-CD20 monoclonal antibodies and 
polymorphism in IgG Fc receptor FcγRIIIa gene. Blood 2002; 99:754-758.
23. Hernandez-Ilizaliturri F.J., Jupudy V, Oflazoglu E., Huberman A, Ostberg J, Repasky E.A 
and Czuczman M.S. Neutrophil Function is Necessary for the in vivo Anti-tumor activity 
of rituximab in a Severe Combined Immunodeficiency (SCID) Mouse Model. Clinical 
Cancer Research 2003: 9; 5866-5873.
24. Czuczman M.S., Jupudy V., Reising S., Repasky E.A., and Hernandez-Ilizaliturri F.J. 
Sequential administration of Granulocyte colony-stimulating factor (G-CSF) enhances 
rituximab’s biological activity and up-regulation of CD11b in a severe combined 
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immunodeficiency (SCID) mouse lymphoma model. Leukemia and Lymphoma 2005 (In 
press).
25. van der Kolk LE, Grillo-Lopez AJ, Baars JW, van Oers MH. Treatment of relapsed B-cell 
non-Hodgkin's lymphoma with a combination of chimeric anti-CD20 monoclonal 
antibodies (rituximab) and G-CSF: final report on safety and efficacy. Leukemia 
2003;17:1658-64.
26. van Spriel AB, van Ojik HH, Bakker A, Jansen MJ, van de Winkel JG. Mac-1 
(CD11b/CD18) is crucial for effective Fc receptor-mediated immunity to melanoma. 
Blood 2003;101:253-8.
27. Venugopal P, Sivaraman S, Huang XK, Nayini J, Gregory SA, and Preisler HD. Effects 
of cytokines on CD20 antigen expression on tumor cells from patients with chronic 
lymphocytic leukemia. Leuk Res. 2000;24:411-5.
28. Green M, Koelbl H, Baselga J, et al. A Randomized Double-Blind, Phase 3 Study 
Evaluating Fixed-dose, Once-per-cycle pegylated filgrastim (SD/01) vs Daily Filgrastim to 
Support Chemotherapy for Breast Cancer. Proc ASCO 2001;a90.
29. Holmes FA, O’Shaughnessy JA, Vulkelja S, et al. Blinded, Randomized, Multicenter Study 
to Evaluate Single Administration Pegfilgrastim Once per Cycle Versus Daily Filgrastim as 
an Adjunct to Chemotherapy in Patients With High-Risk Stage II or Stage III/IV Breast 
Cancer. J Clin Onc 2002 20: 727-731.
30. Misset JL, Dieras V, Gruia G, et al. Dose-finding Study of Docetaxel and Doxorubicin in 
First-line Treatment of Patients with Metastatic Breast Cancer. Ann Oncol 1999;10(5):553-
60.
31. Vogel CL, Wojtukiewicz MZ, Carroll RR, et al. First and Subsequent Cycle Use of 
Pegfilgrastim Prevents Febrile Neutropenia in Patients With Breast Cancer: A Multicenter, 
Double-Blind, Placebo-Controlled Phase III Study. J Clin Onc 2005, 23(6): 1178-1184.
32. Johnston E, Crawford J, Blackwell S, et al. Randomized, Dose-Escalation Study of SD/01 
Compared with Daily Filgrastim in Patients Receiving Chemotherapy. J Clin Onc 
2000;18(13):2522-2528.
33. Vose JM, Crump M, Lazarus H, et al. Single Dose Pegfilgrastim (SD/01) is as Effective as 
Daily Filgrastim Following ESHAP Chemotherapy for Subjects with Non-Hodgkin’s 
Lymphoma or Hodgkin’s Disease: Results of a Randomized, Open-label Study. Blood 
2001;98(11) Suppl.:799a.
34. Hiddemann W, Grigg A, Solal-Celigny P et al. An Open-label Randomised, Parallel, Dose-
ranging Study of Single Administration SD/01 vs Daily Filgrastim as an Adjunct to 
Chemotherapy in Elderly Patients with Non-Hodgkin’s. Hematol J 2001;1 Suppl. 1:184.
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Appendix A: 
[Neulasta
®] (pegfilgrastim) Prescribing Information
DESCRIPTION 
Neulasta
® (pegfilgrastim) is a covalent conjugate of recombinant methionyl human G-CSF 
(Filgrastim) and monomethoxypolyethylene glycol. Filgrastim is a water-soluble 175 amino acid 
protein with a molecular weight of approximately 19 kilodaltons (kD). Filgrastim is obtained from the 
bacterial fermentation of a strain of Escherichia coli transformed with a genetically engineered 
plasmid containing the human G-CSF gene. To produce pegfilgrastim, a 20 kD 
monomethoxypolyethylene glycol molecule is covalently bound to the N-terminal methionyl residue 
of Filgrastim. The average molecular weight of pegfilgrastim is approximately 39 kD. 
Neulasta
® is supplied in 0.6 mL prefilled syringes for subcutaneous injection. Each syringe contains 
6 mg pegfilgrastim (based on protein weight), in a sterile, clear, colorless, preservative-free solution 
(pH 4.0) containing acetate (0.35 mg), sorbitol (30.0 mg), polysorbate 20 (0.02 mg), and sodium 
(0.02 mg) in water for injection, USP. 
CLINICAL PHARMACOLOGY 
Both Filgrastim and pegfilgrastim are Colony Stimulating Factors that act on hematopoietic cells by 
binding to specific cell surface receptors thereby stimulating proliferation, differentiation, 
commitment, and end cell functional activation.
1,2 Studies on cellular proliferation, receptor binding, 
and neutrophil function demonstrate that Filgrastim and pegfilgrastim have the same mechanism of 
action. Pegfilgrastim has reduced renal clearance and prolonged persistence in vivo as compared 
to Filgrastim. 
Pharmacokinetics 
The pharmacokinetics and pharmacodynamics of Neulasta
® were studied in 379 patients with 
cancer. The pharmacokinetics of Neulasta
® were nonlinear in cancer patients and clearance 
decreased with increases in dose. Neutrophil receptor binding is an important component of the 
clearance of Neulasta
®, and serum clearance is directly related to the number of neutrophils. For 
example, the concentration of Neulasta
® declined rapidly at the onset of neutrophil recovery that 
followed myelosuppressive chemotherapy. In addition to numbers of neutrophils, body weight 
appeared to be a factor. Patients with higher body weights experienced higher systemic exposure 
to Neulasta
® after receiving a dose normalized for body weight. A large variability in the 
pharmacokinetics of Neulasta
® was observed in cancer patients. The half-life of Neulasta
® ranged 
from 15 to 80 hours after subcutaneous injection. 
Special Populations 
No gender-related differences were observed in the pharmacokinetics of Neulasta
®, and no 
differences were observed in the pharmacokinetics of geriatric patients (≥ 65 years of age) 
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compared to younger patients (< 65 years of age) (see PRECAUTIONS, Geriatric Use). In a study 
of 30 patients with varying degrees of renal dysfunction including end-stage renal disease, renal 
dysfunction had no effect on the pharmacokinetics of pegfilgrastim; thus, dose adjustment in 
patients with renal dysfunction is not necessary. The pharmacokinetic profile in pediatric 
populations or in patients with hepatic insufficiency has not been assessed. 
CLINICAL STUDIES 
Neulasta
® was evaluated in three randomized, double-blind, controlled studies. Studies 1 and 2 
were active-controlled studies that employed doxorubicin 60 mg/m
2 and docetaxel 75 mg/m
2 
administered every 21 days for up to 4 cycles for the treatment of metastatic breast cancer. Study 
1 investigated the utility of a fixed dose of Neulasta
®. Study 2 employed a weight-adjusted dose. In 
the absence of growth factor support, similar chemotherapy regimens have been reported to result 
in a 100% incidence of severe neutropenia (absolute neutrophil count [ANC] < 0.5 x 10
9/L) with a 
mean duration of 5-7 days, and a 30%-40% incidence of febrile neutropenia. Based on the 
correlation between the duration of severe neutropenia and the incidence of febrile neutropenia 
found in studies with Filgrastim, duration of severe neutropenia was chosen as the primary 
endpoint in both studies, and the efficacy of Neulasta
® was demonstrated by establishing 
comparability to Filgrastim-treated patients in the mean days of severe neutropenia. 
In Study 1, 157 patients were randomized to receive a single subcutaneous injection of Neulasta
® 6 
mg on day 2 of each chemotherapy cycle or daily subcutaneous Filgrastim 5 mcg/kg/day beginning 
on day 2 of each chemotherapy cycle. In Study 2, 310 patients were randomized to receive a 
single subcutaneous injection of Neulasta
® 100 mcg/kg on day 2 or daily subcutaneous Filgrastim 5 
mcg/kg/day beginning on day 2 of each chemotherapy cycle. 
Both studies met the primary objective of demonstrating that the mean days of severe neutropenia 
of Neulasta
®-treated patients did not exceed that of Filgrastim-treated patients by more than one 
day in cycle 1 of chemotherapy (see Table 1). The rates of febrile neutropenia in the two studies 
were comparable for Neulasta
® and Filgrastim (in the range of 10% to 20%). Other secondary 
endpoints included days of severe neutropenia in cycles 2-4, the depth of ANC nadir in cycles 1-4, 
and the time to ANC recovery after nadir. In both studies, the results for the secondary endpoints 
were similar between the two treatment groups. 
Table 1. Mean Days of Severe Neutropenia (in Cycle 1) 
Mean days of severe neutropenia
Study
Neulasta®
Filgrastim (5 mcg/kg/day)
Difference in means (95% CI)
Study 1 n = 157 
1.8 
1.6 
0.2  (-0.2, 0.6) 
Study 2 n = 310 
1.7 
1.6 
0.1 (-0.2, 0.4) 
 
a Study 1 dose = 6 mg x 1; study 2 dose = 100 mcg/kg x 1 
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Study 3 was a randomized, double-blind, placebo-controlled study that employed docetaxel 100 
mg/m
2 administered every 21 days for up to 4 cycles for the treatment of metastatic or non-
metastatic breast cancer. In this study, 928 patients were randomized to receive a single 
subcutaneous injection of Neulasta
® 6 mg or placebo on day 2 of each chemotherapy cycle. Study 
3 met the primary objective of demonstrating that the incidence of febrile neutropenia (defined as 
temperature ≥ 38.2°C and ANC ≤ 0.5 x10
9/L) was lower for Neulasta
®-treated patients as 
compared to placebo-treated patients (1% versus 17%, p < 0.001). The incidence of 
hospitalizations (1% versus 14%) and IV anti-infective use (2% versus 10%) for the treatment of 
febrile neutropenia were also lower in the Neulasta
®-treated patients compared with the placebo-
treated patients. 
INDICATIONS AND USAGE 
Neulasta
® is indicated to decrease the incidence of infection, as manifested by febrile neutropenia, 
in patients with non-myeloid malignancies receiving myelosuppressive anti-cancer drugs 
associated with a clinically significant incidence of febrile neutropenia (See CLINICAL STUDIES). 
CONTRAINDICATIONS 
Neulasta
® is contraindicated in patients with known hypersensitivity to E coli-derived proteins‚ 
pegfilgrastim‚ Filgrastim, or any other component of the product. 
WARNINGS 
General 
The safety and efficacy of Neulasta
® for peripheral blood progenitor cell (PBPC) mobilization has 
not been evaluated in adequate and well-controlled studies. Neulasta
® should not be used for 
PBPC mobilization. 
Splenic Rupture 
Rare cases of splenic rupture have been reported following the administration of neulasta
®. Splenic 
rupture, in some cases resulting in death, has also been associated with filgrastim, the parent 
compound of neulasta
®.  Patients receiving neulasta
® who report left upper abdominal and/or 
shoulder tip pain should be evaluated for an enlarged spleen or splenic rupture. 
Adult Respiratory Distress Syndrome (ARDS) 
Adult respiratory distress syndrome (ARDS) has been reported in neutropenic patients with sepsis 
receiving Filgrastim, the parent compound of Neulasta
®, and is postulated to be secondary to an 
influx of neutrophils to sites of inflammation in the lungs. Neutropenic patients receiving Neulasta
® 
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who develop fever, lung infiltrates, or respiratory distress should be evaluated for the possibility of 
ARDS. In the event that ARDS occurs, Neulasta
® should be discontinued and/or withheld until 
resolution of ARDS and patients should receive appropriate medical management for this 
condition. 
Allergic Reactions 
Allergic reactions to Neulasta
®, including anaphylaxis, skin rash, and urticaria, have been reported 
in post marketing experience. The majority of reported events occurred upon initial exposure. In 
some cases, symptoms recurred with rechallenge, suggesting a causal relationship. In rare cases, 
allergic reactions including anaphylaxis, recurred within days after initial anti-allergic treatment was 
discontinued. If a serious allergic reaction occurs, appropriate therapy should be administered, with 
close patient follow-up over several days. Neulasta
® should be permanently discontinued in 
patients with serious allergic reactions. 
Sickle Cell Disease 
Severe sickle cell crises have been associated with the use of Neulasta
® in patients with sickle cell 
disease. Severe sickle cell crises, in some cases resulting in death, have also been associated 
with Filgrastim, the parent compound of pegfilgrastim. Only physicians qualified by specialized 
training or experience in the treatment of patients with sickle cell disease should prescribe 
Neulasta
® for such patients, and only after careful consideration of the potential risks and benefits. 
PRECAUTIONS 
General 
Use With Chemotherapy and/or Radiation Therapy 
Neulasta
® should not be administered in the period between 14 days before and 24 hours after 
administration of cytotoxic chemotherapy (see DOSAGE AND ADMINISTRATION) because of the 
potential for an increase in sensitivity of rapidly dividing myeloid cells to cytotoxic chemotherapy. 
The use of Neulasta
® has not been studied in patients receiving chemotherapy associated with 
delayed myelosuppression (eg, nitrosoureas, mitomycin C).
The administration of Neulasta
® concomitantly with 5-fluorouracil or other antimetabolites has not 
been evaluated in patients. Administration of pegfilgrastim at 0, 1, and 3 days before 5-fluorouracil 
resulted in increased mortality in mice; administration of pegfilgrastim 24 hours after 5-fluorouracil 
did not adversely affect survival. 
The use of Neulasta
® has not been studied in patients receiving radiation therapy. 
Potential Effect on Malignant Cells 
Pegfilgrastim is a growth factor that primarily stimulates neutrophils and neutrophil precursors; 
however, the G-CSF receptor through which pegfilgrastim and Filgrastim act has been found on 
tumor cell lines, including some myeloid, T-lymphoid, lung, head and neck, and bladder tumor cell 
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lines. The possibility that pegfilgrastim can act as a growth factor for any tumor type cannot be 
excluded. Use of Neulasta
® in myeloid malignancies and myelodysplasia (MDS) has not been 
studied. In a randomized study comparing the effects of the parent compound of Neulasta
®, 
Filgrastim, to placebo in patients undergoing remission induction and consolidation chemotherapy 
for acute myeloid leukemia, important differences in remission rate between the two arms were 
excluded. Disease-free survival and overall survival were comparable; however, the study was not 
designed to detect important differences in these endpoints.
3 
Information for Patients 
Patients should be informed of the possible side effects of Neulasta
®, and be instructed to report 
them to the prescribing physician. Patients should be informed of the signs and symptoms of 
allergic drug reactions and be advised of appropriate actions. Patients should be counseled on the 
importance of compliance with their Neulasta
® treatment, including regular monitoring of blood 
counts. 
If it is determined that a patient or caregiver can safely and effectively administer Neulasta
® 
(pegfilgrastim) at home, appropriate instruction on the proper use of Neulasta
® (pegfilgrastim) 
should be provided for patients and their caregivers, including careful review of the “Information for 
Patients and Caregivers” insert. Patients and caregivers should be cautioned against the reuse of 
needles, syringes, or drug product, and be thoroughly instructed in their proper disposal. A 
puncture-resistant container for the disposal of used syringes and needles should be available. 
Laboratory Monitoring 
To assess a patient’s hematologic status and ability to tolerate myelosuppressive chemotherapy, a 
complete blood count and platelet count should be obtained before chemotherapy is administered. 
Regular 
monitoring 
of 
hematocrit 
value 
and 
platelet 
count 
is 
recommended.
Drug Interaction 
No formal drug interaction studies between Neulasta
® and other drugs have been performed. 
Drugs such as lithium may potentiate the release of neutrophils; patients receiving lithium and 
Neulasta
® should have more frequent monitoring of neutrophil counts. 
Carcinogenesis, Mutagenesis, Impairment of Fertility 
No mutagenesis studies were conducted with pegfilgrastim. The carcinogenic potential of 
pegfilgrastim has not been evaluated in long-term animal studies. In a toxicity study of 6 months 
duration in rats given once weekly subcutaneous injections of up to 1000 mcg/kg of pegfilgrastim 
(approximately 23-fold higher than the recommended human dose), no precancerous or cancerous 
lesions were noted. 
When administered once weekly via subcutaneous injections to male and female rats at doses up 
to 1000 mcg/kg prior to, and during mating, reproductive performance, fertility, and sperm 
assessment parameters were not affected. 
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Pregnancy Category C 
Pegfilgrastim has been shown to have adverse effects in pregnant rabbits when administered 
subcutaneously every other day during gestation at doses as low as 50 mcg/kg/dose 
(approximately 4-fold higher than the recommended human dose). Decreased maternal food 
consumption, accompanied by a decreased maternal body weight gain and decreased fetal body 
weights were observed at 50 to 1000 mcg/kg/dose. Pegfilgrastim doses of 200 and 250 
mcg/kg/dose resulted in an increased incidence of abortions. Increased post-implantation loss due 
to early resorptions was observed at doses of 200 to 1000 mcg/kg/dose, and decreased numbers 
of live rabbit fetuses were observed at pegfilgrastim doses of 200 to 1000 mcg/kg/dose, given 
every other day. 
Subcutaneous injections of pegfilgrastim of up to 1000 mcg/kg/dose every other day during the 
period of organogenesis in rats were not associated with an embryotoxic or fetotoxic outcome. 
However, an increased incidence (compared to historical controls) of wavy ribs was observed in rat 
fetuses at 1000 mcg/kg/dose every other day. Very low levels (< 0.5%) of pegfilgrastim crossed the 
placenta when administered subcutaneously to pregnant rats every other day during gestation. 
Once weekly subcutaneous injections of pegfilgrastim to female rats from day 6 of gestation 
through day 18 of lactation at doses up to 1000 mcg/kg/dose did not result in any adverse maternal 
effects. There were no deleterious effects on the growth and development of the offspring and no 
adverse effects were found upon assessment of fertility indices. There are no adequate and well-
controlled studies in pregnant women. Neulasta
® should be used during pregnancy only if the 
potential benefit to the mother justifies the potential risk to the fetus. 
Nursing Mothers 
It is not known whether pegfilgrastim is excreted in human milk. Because many drugs are excreted 
in human milk‚ caution should be exercised when Neulasta
® is administered to a nursing woman. 
Pediatric Use 
The safety and effectiveness of Neulasta
® in pediatric patients have not been established. The 6 
mg fixed dose single-use syringe formulation should not be used in infants, children, and smaller 
adolescents weighing less than 45 kg. 
Geriatric Use 
Of the 932 patients with cancer who received Neulasta
® in clinical studies, 139 (15%) were age 65 
and over, and 18 (2%) were age 75 and over. No overall differences in safety or effectiveness were 
observed between patients age 65 and older and younger patients. 
ADVERSE REACTIONS 
See WARNINGS sections regarding Splenic Rupture, ARDS, Allergic Reactions, and Sickle Cell 
Disease. Because clinical trials are conducted under widely varying conditions, adverse reaction 
rates observed in the clinical trials of Neulasta
® cannot be directly compared to rates in the clinical 
trials of other drugs and may not reflect the rates observed in practice. The adverse reaction 
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information from clinical trials does, however, provide a basis for identifying the adverse events that 
appear to be related to Neulasta
® use and for approximating rates. 
The data described below reflect exposure to Neulasta
® in 932 patients. Neulasta
® was studied in 
placebo- and active-controlled trials (n = 467, and n = 465, respectively). The population 
encompassed an age range of 21 to 88 years. Ninety-two percent of patients were female. The 
ethnicity of the patients was as follows: 75% Caucasian, 18% Hispanic, 5% Black, and 1% Asian. 
Patients with solid tumors (breast [n = 823], lung and thoracic tumors [n = 53]) or lymphoma (n = 
56) received Neulasta
® after nonmyeloablative cytotoxic chemotherapy. Most patients received a 
single 100 mcg/kg (n = 259) or a single 6 mg (n = 546) dose per chemotherapy cycle over 4 cycles. 
In the placebo-controlled trial, bone pain occurred at a higher incidence in Neulasta
®-treated 
patients as compared to placebo-treated patients. The incidence of other commonly reported 
adverse events were similar in the Neulasta
®- and placebo-treated patients, and were consistent 
with the underlying cancer diagnosis and its treatment with chemotherapy. The data in Table 2 
reflect those adverse events occurring in at least 10% of patients treated with Neulasta
® in the 
placebo-controlled study. 
TABLE 2. Adverse Events Occurring in ≥ 10%
a of Patients in The Placebo-Controlled Study. 
Event 
Neulasta
® (n = 467) 
Placebo (n = 461) 
Alopecia 
48% 
47% 
Bone Pain
b
31% 
26% 
Diarrhea 
29% 
28% 
Pyrexia (not including febrile neutropenia) 
23% 
22% 
Myalgia 
21% 
18% 
Headache 
16% 
14% 
Arthralgia 
16% 
13% 
Vomiting 
13% 
11% 
Asthenia 
13% 
11% 
Edema peripheral 
12% 
10% 
Constipation 
10% 
6% 
a Events occurring in ≥ 10% of Neulasta®-treated patients and at a higher incidence as compared to placebo-treated 
patients. 
b Bone pain is limited to the specified adverse event term “bone pain.” 
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In the active controlled studies, common adverse events occurred at similar rates and severities in 
both treatment arms (Neulasta
®, n = 465; Filgrastim, n = 331). These adverse experiences 
occurred at rates between 72% and 15% and included: nausea, fatigue, alopecia, diarrhea, 
vomiting, constipation, fever, anorexia, skeletal pain, headache, taste perversion, dyspepsia, 
myalgia, insomnia, abdominal pain, arthralgia, generalized weakness, peripheral edema, dizziness, 
granulocytopenia, stomatitis, mucositis, and neutropenic fever. 
Bone Pain 
The analysis of bone pain described below is based on a composite analysis using multiple, 
related, adverse event terms. 
In the placebo-controlled study, the incidence of bone pain was 57% in Neulasta
®-treated patients 
compared to 50% in placebo-treated patients. Bone pain was generally reported to be of mild-to-
moderate severity. 
Among patients experiencing bone pain, approximately 37% of Neulasta
®- and 31% of placebo-
treated patients utilized non-narcotic analgesics and 10% of Neulasta
®- and 9% of placebo-treated 
patients utilized narcotic analgesics.
In the active-controlled studies, the use of non-narcotic and narcotic analgesics in association with 
bone pain was similar between Neulasta
®- and Filgrastim-treated patients. No patient withdrew 
from study due to bone pain. 
Laboratory Abnormalities 
In clinical studies, leukocytosis (WBC counts > 100 x 10
9/L) was observed in less than 1% of 932 
patients with non-myeloid malignancies receiving Neulasta
®. Leukocytosis was not associated with 
any adverse effects. 
In the placebo-controlled study, reversible elevations in LDH, alkaline phosphatase, and uric acid 
that did not require treatment occurred at similar rates in Neulasta
®- and placebo-treated patients. 
Immunogenicity 
As with all therapeutic proteins, there is a potential for immunogenicity. The incidence of antibody 
development in patients receiving Neulasta
® has not been adequately determined. While available 
data suggest that a small proportion of patients developed binding antibodies to Filgrastim or 
pegfilgrastim, the nature and specificity of these antibodies has not been adequately studied. No 
neutralizing antibodies have been detected using a cell-based bioassay in 46 patients who 
apparently developed binding antibodies. The detection of antibody formation is highly dependent 
on the sensitivity and specificity of the assay, and the observed incidence of antibody positivity in 
an assay may be influenced by several factors including sample handling, concomitant 
medications, and underlying disease. Therefore, comparison of the incidence of antibodies to 
Neulasta
® with the incidence of antibodies to other products may be misleading. 
Cytopenias resulting from an antibody response to exogenous growth factors have been reported 
on rare occasions in patients treated with other recombinant growth factors. There is a theoretical 
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possibility that an antibody directed against pegfilgrastim may cross-react with endogenous G-
CSF, resulting in immune-mediated neutropenia, but this has not been observed in clinical studies. 
OVERDOSAGE 
The maximum amount of Neulasta
® that can be safely administered in single or multiple doses has 
not been determined. Single subcutaneous doses of 300 mcg/kg have been administered to 8 
healthy volunteers and 3 patients with non-small cell lung cancer without serious adverse effects. 
These patients experienced a mean maximum ANC of 55 x 10
9/L, with a corresponding mean 
maximum WBC of 67 x 10
9/L. The absolute maximum ANC observed was 96 x 10
9/L with a 
corresponding absolute maximum WBC observed of 120 x 10
9/L. The duration of leukocytosis 
ranged from 6 to 13 days. Leukapheresis should be considered in the management of symptomatic 
individuals. 
DOSAGE AND ADMINISTRATION 
The recommended dosage of Neulasta
® is a single subcutaneous injection of 6 mg administered 
once per chemotherapy cycle. Neulasta
® should not be administered in the period between 14 days 
before and 24 hours after administration of cytotoxic chemotherapy (see PRECAUTIONS). 
The 6 mg fixed-dose formulation should not be used in infants, children, and smaller adolescents 
weighing less than 45 kg. 
No dosing adjustment is necessary for renal dysfunction (see CLINICAL PHARMACOLOGY, 
Special Populations). 
Neulasta
® should be visually inspected for discoloration and particulate matter before 
administration. Neulasta
® should not be administered if discoloration or particulates are observed. 
For method of administration please see patient package insert. 
Storage 
Neulasta
® should be stored refrigerated at 2° to 8°C (36° to 46°F); syringes should be kept in their 
carton to protect from light until time of use. Shaking should be avoided. Before injection‚ Neulasta
® 
may be allowed to reach room temperature for a maximum of 48 hours but should be protected 
from light. Neulasta
® left at room temperature for more than 48 hours should be discarded. 
Freezing should be avoided; however, if accidentally frozen, Neulasta
® should be allowed to thaw 
in the refrigerator before administration. If frozen a second time, Neulasta
® should be discarded. 
HOW SUPPLIED 
Neulasta
® is supplied as a preservative-free solution containing 6 mg (0.6 mL) of pegfilgrastim (10 
mg/mL) in a single-dose syringe with a 27 gauge, 1/2 inch needle with an UltraSafe
® Needle 
Guard. 
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Neulasta
® is provided in a dispensing pack containing one syringe (NDC 55513-190-01). 
Rx Only 
This product, its production, and/or its use may be covered by one or more US Patents, including 
US Patent Nos. 5,824,784; 4,810,643; 4,999,291; 5,582,823; 5,580,755 as well as other patents or 
patents pending.
REFERENCES 
1. Morstyn G, Dexter T, Foote M. Filgrastim (r-metHuG-CSF) in clinical practice. 2nd Edition. 
1998;3:51-71. 
2. Valerius T, Elsasser D, Repp R, et al. HLA Class-II antibodies recruit G-CSF activated 
neutrophils for treatment of B-cell malignancies. Leukemia and Lymphoma. 1997;26, 261-269. 
3. Heil G, Hoelzer D, Sanz MA, et al. A randomized, double-blind, placebo-controlled, phase III 
study of Filgrastim in remission induction and consolidation therapy for adults with de novo 
Acute Myeloid Leukemia. Blood. 1997;90:4710-4718. 
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[RITUXAN
®] (RITUXIMAB) Prescribing Information
Boxed warnings
DESCRIPTION
The RITUXAN® (Rituximab) antibody is a genetically engineered chimeric murine/human 
monoclonal antibody directed against the CD20 antigen found on the surface of normal and 
malignant B lymphocytes. The antibody is an IgG1 kappa immunoglobulin containing murine light- 
and heavy-chain variable region sequences and human constant region sequences. Rituximab is 
composed of two heavy chains of 451 amino acids and two light chains of 213 amino acids (based 
on cDNA analysis) and has an approximate molecular weight of 145 kD. Rituximab has a binding 
affinity for the CD20 antigen of approximately 8.0 nM.
The chimeric anti-CD20 antibody is produced by mammalian cell (Chinese Hamster Ovary) 
suspension culture in a nutrient medium containing the antibiotic gentamicin. Gentamicin is not 
detectable in the final product. The anti-CD20 antibody is purified by affinity and ion exchange 
chromatography. The purification process includes specific viral inactivation and removal 
procedures. Rituximab drug product is manufactured from bulk drug substance manufactured by 
Genentech, Inc. (US License No. 1048).
RITUXAN is a sterile, clear, colorless, preservative-free liquid concentrate for intravenous (IV) 
administration. RITUXAN is supplied at a concentration of 10 mg/mL in either 100 mg (10 mL) or 
500 mg (50 mL) single-use vials. The product is formulated for IV administration in 9 mg/mL 
sodium chloride, 7.35 mg/mL sodium citrate dihydrate, 0.7 mg/mL polysorbate 80, and Water for 
Injection. The pH is adjusted to 6.5.
CLINICAL PHARMACOLOGY
General
Rituximab binds specifically to the antigen CD20 (human B-lymphocyte-restricted differentiation 
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antigen, Bp35), a hydrophobic transmembrane protein with a molecular weight of approximately 35 
kD located on pre-B and mature B lymphocytes.1,2 The antigen is also expressed on > 90% of B-
cell non-Hodgkin's lymphomas (NHL),3 but is not found on hematopoietic stem cells, pro-B cells, 
normal plasma cells or other normal tissues.4 CD20 regulates an early step(s) in the activation 
process for cell cycle initiation and differentiation,4 and possibly functions as a calcium ion 
channel.5 CD20 is not shed from the cell surface and does not internalize upon antibody binding.6 
Free CD20 antigen is not found in the circulation.2
Preclinical Pharmacology and Toxicology
Mechanism of Action: The Fab domain of Rituximab binds to the CD20 antigen on B lymphocytes, 
and the Fc domain recruits immune effector functions to mediate B-cell lysis in vitro. Possible 
mechanisms of cell lysis include complement-dependent cytotoxicity (CDC)7 and antibody-
dependent cell mediated cytotoxicity (ADCC). The antibody has been shown to induce apoptosis in 
the DHL-4 human B-cell lymphoma line.8
Normal Tissue Cross reactivity: Rituximab binding was observed on lymphoid cells in the thymus, 
the white pulp of the spleen, and a majority of B lymphocytes in peripheral blood and lymph nodes. 
Little or no binding was observed in the non-lymphoid tissues examined.
Human Pharmacokinetics/Pharmacodynamics
In patients given single doses at 10, 50, 100, 250 or 500 mg/m2 as an IV infusion, serum levels and 
the half-life of Rituximab were proportional to dose.9 In 14 patients given 375 mg/m2 as an IV 
infusion for 4 weekly doses, the mean serum half-life was 76.3 hours (range, 31.5 to 152.6 hours) 
after the first infusion and 205.8 hours (range, 83.9 to 407.0 hours); after the fourth infusion.10,11,12 
The wide range of half-lives may reflect the variable tumor burden among patients and the changes 
in CD20-positive (normal and malignant) B-cell populations upon repeated administrations.
RITUXAN at a dose of 375 mg/m2 was administered as an IV infusion at weekly intervals for 4 
doses to 203 patients naive to RITUXAN.12,13 The mean Cmax following the fourth infusion was 486 
μg/mL (range, 77.5 to 996.6 μg/mL). The peak and trough serum levels of Rituximab were 
inversely correlated with baseline values for the number of circulating CD20-positive B cells and 
measures of disease burden. Median steady-state serum levels were higher for responders 
compared with nonresponders; however, no difference was found in the rate of elimination as 
measured by serum half-life. Serum levels were higher in patients with International Working 
Formulation (IWF) subtypes B, C, and D as compared with those with subtype A.10,13 Rituximab 
was detectable in the serum of patients 3 to 6 months after completion of treatment.
RITUXAN at a dose of 375 mg/m2 was administered as an IV infusion at weekly intervals for 8 
doses to 37 patients.14 The mean Cmax after 8 infusions was 550 μg/mL (range, 171 to 1177 
μg/mL). The mean Cmax increased with each successive infusion through the eighth infusion (Table 
1).
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Table 1. Rituximab Cmax Values
Infusion Number Mean 
Cmax
μg/mL
Range
μg/mL
1
242.6
16.1-581.9
2
357.5
106.8-948.6
3
381.3
110.5-731.2
4
460.0
138.0-835.8
5
475.3
156.0-929.1
6
515.4
152.7-865.2
7
544.6
187.0-936.8
8
550.0
170.6-1177.0
The pharmacokinetic profile of RITUXAN when administered as 6 infusions of 375 mg/m2 in 
combination with 6 cycles of CHOP chemotherapy was similar to that seen with RITUXAN alone.15
Administration of RITUXAN resulted in a rapid and sustained depletion of circulating and tissue-
based B cells. Lymph node biopsies performed 14 days after therapy showed a decrease in the 
percentage of B cells in seven of eight patients who had received single doses of Rituximab >100 
mg/m2. 9 Among the 166 patients in the pivotal study, circulating B cells (measured as CD19-
positive cells) were depleted within the first three doses with sustained depletion for up to 6 to 9 
months post-treatment in 83% of patients.13 Of the responding patients assessed (n = 80), 1% 
failed to show significant depletion of CD19-positive cells after the third infusion of Rituximab as 
compared to 19% of the nonresponding patients. B-cell recovery began at approximately 6 months 
following completion of treatment. Median B-cell levels returned to normal by 12 months following 
completion of treatment.13
There were sustained and statistically significant reductions in both IgM and IgG serum levels 
observed from 5 through 11 months following Rituximab administration. However, only 14% of 
patients had reductions in IgM and/or IgG serum levels, resulting in values below the normal 
range.13
CLINICAL STUDIES
Relapsed or Refractory, Low-Grade or Follicular, CD20-Positive, B-Cell, NHL. 
RITUXAN regimens tested include treatment weekly for 4 doses and treatment weekly for 8 doses. 
Results for studies with a collective enrollment of 296 patients are summarized below (Table 2): 
Table 2. Summary of RITUXAN Efficacy Data by Schedule and Clinical Setting
(See ADVERSE REACTIONS for Risk Factors Associated
with Increased Rates of Adverse Events.)
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Weekly 
x 
4
N = 166
Weekly 
x 
8
N = 37
Bulky 
disease,
Weekly 
x 
4
N = 39a
Retreatment, 
Weekly 
x 
4
N = 60
Overall Response 
Rate
48%
57%
36%
38%
Complete 
Response Rate
6%
14%
3%
10%
Median 
Duration 
Of Responseb, c, d
(Months)[Range]
11.2
[1.9 to 42.1+]
13.4
[2.5 to 36.5+]
6.9
[2.8 to 25.0+]
15.0
[3.0 to 25.1+]
a Six of these patients are included in the first column. Thus, data from 296 intent to treat patients are provided in this 
table.
b Kaplan-Meier projected with observed range.
c "+" indicates an ongoing response.
d Duration of response: interval from the onset of response to disease progression.
Weekly for 4 doses
A multicenter, open-label, single-arm study was conducted in 166 patients with relapsed or 
refractory low-grade or follicular B-cell NHL who received 375 mg/m2 of RITUXAN given as an IV 
infusion weekly for 4 doses.13 Patients with tumor masses >10 cm or with >5,000 lymphocytes/μL 
in the peripheral blood were excluded from the study. Results are summarized in Table 2. The 
median time to onset of response was 50 days and the median duration of response was 11.2 
months (range, 1.9 to 42.1+). Disease-related signs and symptoms (including B-symptoms) were 
present in 23% (39/166) of patients at study entry and resolved in 64% (25/39) of those patients.
In a multivariate analysis, the ORR was higher in patients with IWF B, C, and D histologic subtypes 
as compared to IWF subtype A (58% vs. 12%), higher in patients whose largest lesion was <5 cm 
vs. >7 cm (maximum, 21 cm) in greatest diameter (53% vs. 38%), and higher in patients with 
chemosensitive relapse as compared with chemoresistant (defined as duration of response <3 
months) relapse (53% vs. 36%). ORR in patients previously treated with autologous bone marrow 
transplant was 78% (18/23). The following adverse prognostic factors were not associated with a 
lower response rate: age >60 years, extranodal disease, prior anthracycline therapy, and bone 
marrow involvement.
Weekly for 8 Doses In a multicenter, single-arm study, 37 patients with relapsed or refractory, low-
grade NHL received 375 mg/m2 of RITUXAN weekly for 8 doses. Results are summarized in Table 
2. (see ADVERSE REACTIONS, Risk Factors Associated with Increased Rates of Adverse 
Events.)
Bulky Disease, Weekly for 4 Doses In pooled data from multiple studies of RITUXAN, 39 patients 
with relapsed or refractory, bulky disease (single lesion >10 cm in diameter), low-grade NHL 
received 375 mg/m2 of RITUXAN weekly for 4 doses. Results are summarized in Table 2.15,16 (For 
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information on the higher incidence of Grade 3 and 4 adverse events, see ADVERSE 
REACTIONS, Risk Factors Associated with Increased Rates of Adverse Events.)
Retreatment Weekly for 4 Doses In a multi-center, single-arm study, 60 patients received 375 
mg/m2 of RITUXAN weekly for 4 doses.17 All patients had relapsed or refractory, low-grade or 
follicular B-cell NHL and had achieved an objective clinical response to RITUXAN administered 
3.8-35.6 months (median 14.5 months) prior to retreatment with RITUXAN. Of these 60 patients, 
55 received their second course of RITUXAN, 3 patients received their third course and 2 patients 
received their second and third courses of RITUXAN in this study. Results are summarized in 
Table 2.
Diffuse, Large B-Cell, NHL
The safety and effectiveness of RITUXAN were evaluated in three, randomized, active-controlled, 
open-label, multicenter studies with a collective enrollment of 1854 patients. Patients with 
previously untreated diffuse, large B-cell, NHL received RITUXAN in combination with 
cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) or other anthracycline-based 
chemotherapy regimens.
Study 1. A total of 632 patients aged >60 years with either B-cell NHL Grade F, G, or H by the 
International Working Formulation classification or DLBCL (including primary mediastinal B-cell 
lymphoma) in the REAL classification were randomized in a 1:1 ratio to treatment with CHOP or R-
CHOP. Patients were given 6 or 8, 21 day cycles of CHOP. Patients in the R-CHOP arm also 
received 4 or 5 doses of RITUXAN 375 mg/m2 on Days -7 and -3 (prior to Cycle 1), and 48 to 72 
hours pre-Cycle 3, pre-Cycle 5, and pre-Cycle 7 for patients receiving 8 cycles of CHOP induction. 
The main outcome measure of the study was progression-free survival (PFS), defined as the time 
from randomization to the first of progression, relapse or death. Responding patients underwent a 
second randomization to receive RITUXAN or no further therapy.
Among all enrolled patients, 62% had centrally confirmed DLBCL histology, 73% had Stage III-IV 
disease, 56% had IPI scores >2, 86% had ECOG performance status of <2, 57% had elevated 
LDH levels, and 30% had two or more extranodal disease sites involved. Efficacy results are 
presented in Table 3. These results reflect a statistical approach which allows for an evaluation of 
RITUXAN administered in the induction setting that excludes any potential impact of RITUXAN 
given after the second randomization.
Analysis of results after the second randomization in Study 1 demonstrates that for patients 
randomized to R-CHOP, additional RITUXAN exposure beyond induction was not associated with 
further improvements in progression free survival or overall survival.
Study 2. A total of 399 patients with DLBCL, aged >60 years, were randomized in a 1:1 ratio to 
receive CHOP or R-CHOP induction. All patients received up to 8, 3-week cycles of CHOP 
induction; patients in the R-CHOP arm received RITUXAN 375 mg/m2 on Day 1 of each cycle. The 
main outcome measure of the study was event free survival (EFS), defined as the time from 
randomization to relapse, progression, change in therapy or death from any cause. Among all 
enrolled patients, 80% had stage III or IV disease, 60% of patients had an age-adjusted IPI >2, 
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80% had ECOG performance status scores <2, 66% had elevated LDH levels, and 52% had 
extranodal involvement in at least two sites. Efficacy results are presented in Table 3.
Study 3. A total of 823 patients with DLBCL, aged 18-60 years, were randomized in a 1:1 ratio to 
receive an anthracycline-containing chemotherapy alone or in combination with RITUXAN. The 
main outcome measure of the study was time to treatment failure (TTF), 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% had Stage III-IV disease, 100% had IPI scores 
of <1, 99% had ECOG performance status of <2, 29% had elevated LDH levels, 49% had bulky 
disease and 34% had extranodal involvement. Efficacy results are presented in Table 3.
Table 3
Efficacy Results in Studies 1, 2, and 3
Study 
1
(n=632)
Study 
2 
(n=399)
Study 
3 
(n=823)
CHOP
R-CHOP
CHOP
R-CHOP
Chemo
R-Chemo
Main outcome
Progression-free survival
(years)
Event-free 
survival
(years) 
Time to treatment failure
(years)
Median 
of 
main 
outcome measure 
1.6
3.1
1.1
2.9
NEb
NEb
Hazard ratiodd
0.69a
0.60a
0.45a
Overall survival at 2 
yearsc
63%
74%
58%
69%
86%
95%
Hazard ratiodd
0.72a
0.68a
0.40a
a Significant at p<0.05, 2-sided.
b NE=Not reliably estimable.
c Kaplan-Meier estimates.
d R-CHOP vs. CHOP.
In Study 2, overall survival estimates at 5 years were 58% vs. 46% for R-CHOP and CHOP, 
respectively.
INDICATIONS AND USAGE
RITUXAN® (Rituximab) is indicated for the treatment of patients with relapsed or refractory, low-
grade or follicular, CD20-positive, B-cell non-Hodgkin's lymphoma. 
RITUXAN®(Rituximab) is indicated for the first-line treatment of diffuse large B-cell, CD20-positive, 
non-Hodgkin's lymphoma in combination with CHOP or other anthracycline-based chemotherapy 
regimens.
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CONTRAINDICATIONS
RITUXAN is contraindicated in patients with known anaphylaxis or IgE-mediated hypersensitivity to 
murine proteins or to any component of this product. (See WARNINGS.)
WARNINGS (See BOXED WARNINGS.) 
Severe Infusion Reactions (See BOXED WARNINGS, ADVERSE REACTIONS and 
Hypersensitivity Reactions)
RITUXAN has caused severe infusion reactions. In some cases, these reactions were fatal. These 
severe reactions typically occurred during the first infusion with time to onset of 30 to 120 minutes. 
Signs and symptoms of severe infusion reactions may include hypotension, angioedema, hypoxia 
or bronchospasm, and may require interruption of RITUXAN administration. The most severe 
manifestations and sequelae include pulmonary infiltrates, acute respiratory distress syndrome, 
myocardial infarction, ventricular fibrillation, and cardiogenic shock. In the reported cases, the 
following factors were more frequently associated with fatal outcomes: female gender, pulmonary 
infiltrates, and chronic lymphocytic leukemia or mantle cell lymphoma. 
Management of severe infusion reactions: The RITUXAN infusion should be interrupted for severe 
reactions and supportive care measures instituted as medically indicated (e.g., intravenous fluids, 
vasopressors, oxygen, bronchodilators, diphenhydramine, and acetaminophen). In most cases, the 
infusion can be resumed at a 50% reduction in rate (e.g., from 100 mg/hr to 50 mg/hr) when 
symptoms have completely resolved. Patients requiring close monitoring during first and all 
subsequent infusions include those with pre-existing cardiac and pulmonary conditions, those with 
prior clinically significant cardiopulmonary adverse events and those with high numbers of 
circulating malignant cells (> 25,000/mm3) with or without evidence of high tumor burden.
Tumor Lysis Syndrome [TLS] (See BOXED WARNINGS and ADVERSE REACTIONS) Rapid 
reduction in tumor volume followed by acute renal failure, hyperkalemia, hypocalcemia, 
hyperuricemia, or hyperphosphatasemia, have been reported within 12 to 24 hours after the first 
RITUXAN infusion. Rare instances of fatal outcome have been reported in the setting of TLS 
following treatment with RITUXAN. The risks of TLS appear to be greater in patients with high 
numbers of circulating malignant cells (> 25,000/mm3) or high tumor burden. Prophylaxis for TLS 
should be considered for patients at high risk. Correction of electrolyte abnormalities, monitoring of 
renal function and fluid balance, and administration of supportive care, including dialysis, should be 
initiated as indicated. Following complete resolution of the complications of TLS, RITUXAN has 
been tolerated when re-administered in conjunction with prophylactic therapy for TLS in a limited 
number of cases.
Hepatitis B Reactivation with Related Fulminant Hepatitis and Other Viral Infections Hepatitis 
B virus (HBV) reactivation with fulminant hepatitis, hepatic failure, and death has been reported in 
some patients with hematologic malignancies treated with RITUXAN. The majority of patients 
received RITUXAN in combination with chemotherapy. The median time to the diagnosis of 
hepatitis was approximately 4 months after the initiation of RITUXAN and approximately one month 
after the last dose.
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Persons at high risk of HBV infection should be screened before initiation of RITUXAN. Carriers of 
hepatitis B should be closely monitored for clinical and laboratory signs of active HBV infection and 
for signs of hepatitis during and for up to several months following RITUXAN therapy. In patients 
who develop viral hepatitis, RITUXAN and any concomitant chemotherapy should be discontinued 
and appropriate treatment including antiviral therapy initiated. There are insufficient data regarding 
the safety of resuming RITUXAN therapy in patients who develop hepatitis subsequent to HBV 
reactivation.
The following additional serious viral infections, either new, reactivated or exacerbated, have been 
identified in clinical studies or postmarketing reports. The majority of patients received RITUXAN in 
combination with chemotherapy or as part of a hematopoietic stem cell transplant. These viral 
infections included JC virus [progressive multifocal leukoencephalopathy (PML)], cytomegalovirus, 
herpes simplex virus, parvovirus B19, varicella zoster virus,West Nile virus, and hepatitis C. In 
some cases, the viral infections occurred up to one year following discontinuation of RITUXAN and 
have resulted in death.
Hypersensitivity Reactions RITUXAN has been associated with hypersensitivity reactions (non-
IgE-mediated reactions) which may respond to adjustments in the infusion rate and in medical 
management. Hypotension, bronchospasm, and angioedema have occurred in association with 
RITUXAN infusion (see Severe Infusion Reactions). RITUXAN infusion should be interrupted for 
severe hypersensitivity reactions and can be resumed at a 50% reduction in rate (e.g., from 100 
mg/hr to 50 mg/hr) when symptoms have completely resolved. Treatment of these symptoms with 
diphenhydramine and acetaminophen is recommended; additional treatment with bronchodilators 
or IV saline may be indicated. In most cases, patients who have experienced non-life-threatening 
hypersensitivity reactions have been able to complete the full course of therapy. (See DOSAGE 
and ADMINISTRATION.) Medications for the treatment of hypersensitivity reactions, e.g., 
epinephrine, antihistamines and corticosteroids, should be available for immediate use in the event 
of a reaction during administration.
Cardiovascular Infusions should be discontinued in the event of serious or life-threatening cardiac 
arrhythmias. Patients who develop clinically significant arrhythmias should undergo cardiac 
monitoring during and after subsequent infusions of RITUXAN. Patients with pre-existing cardiac 
conditions including arrhythmias and angina have had recurrences of these events during 
RITUXAN therapy and should be monitored throughout the infusion and immediate post-infusion 
period.
Renal (See BOXED WARNINGS: Tumor Lysis Syndrome [TLS] and ADVERSE REACTIONS) 
RITUXAN administration has been associated with severe renal toxicity including acute renal 
failure requiring dialysis and in some cases, has led to a fatal outcome. Renal toxicity has occurred 
in patients with high numbers of circulating malignant cells (>25,000/mm3) or high tumor burden 
who experience tumor lysis syndrome (see Tumor Lysis Syndrome) and in patients administered 
concomitant cisplatin therapy during clinical trials. The combination of cisplatin and RITUXAN is not 
an approved treatment regimen. If this combination is used in clinical trials extreme caution should 
be exercised; patients should be monitored closely for signs of renal failure. Discontinuation of 
RITUXAN should be considered for those with rising serum creatinine or oliguria. 
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Severe Mucocutaneous Reactions (See BOXED WARNINGS) Mucocutaneous reactions, some 
with fatal outcome, have been reported in patients treated with RITUXAN. These reports include 
paraneoplastic pemphigus (an uncommon disorder which is a manifestation of the patient's 
underlying malignancy),18 Stevens-Johnson syndrome, lichenoid dermatitis, vesiculobullous 
dermatitis, and toxic epidermal necrolysis. The onset of the reaction in the reported cases has 
varied from 1 to 13 weeks following RITUXAN exposure. Patients experiencing a severe 
mucocutaneous reaction should not receive any further infusions and seek prompt medical 
evaluation. Skin biopsy may help to distinguish among different mucocutaneous reactions and 
guide subsequent treatment. The safety of readministration of RITUXAN to patients with any of 
these mucocutaneous reactions has not been determined.
Bowel Obstruction and Perforation Abdominal pain, bowel obstruction and perforation, in some 
cases leading to death, were observed in patients receiving RITUXAN in combination with 
chemotherapy for DLBCL. In post-marketing reports, which include both patients with low-grade or 
follicular NHL and DLBCL, the mean time to onset of symptoms was 6 days (range 1–77) in 
patients with documented gastro-intestinal perforation. Complaints of abdominal pain, especially 
early in the course of treatment, should prompt a thorough diagnostic evaluation and appropriate 
treatment.
PRECAUTIONS
Laboratory Monitoring
Because RITUXAN targets all CD20-positive B lymphocytes, malignant and nonmalignant, 
complete blood counts (CBC) and platelet counts should be obtained at regular intervals during 
RITUXAN therapy and more frequently in patients who develop cytopenias (see ADVERSE 
REACTIONS). The duration of cytopenias caused by RITUXAN can extend well beyond the 
treatment period. 
Drug/Laboratory Interactions
There have been no formal drug interaction studies performed with RITUXAN. However, renal 
toxicity was seen with this drug in combination with cisplatin in clinical trials. (See WARNINGS, 
Renal.)
Immunization
The safety of immunization with live viral vaccines following RITUXAN therapy has not been 
studied. The ability to generate a primary or anamnestic humoral response to vaccination is 
currently being studied. 
Carcinogenesis, Mutagenesis, Impairment of Fertility
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No long-term animal studies have been performed to establish the carcinogenic or mutagenic 
potential of RITUXAN, or to determine its effects on fertility in males or females. Individuals of 
childbearing potential should use effective contraceptive methods during treatment and for up to 12 
months following RITUXAN therapy.
Pregnancy Category C
Animal reproduction studies have not been conducted with RITUXAN. It is not known whether 
RITUXAN can cause fetal harm when administered to a pregnant woman or whether it can affect 
reproductive capacity. Human IgG is known to pass the placental barrier, and thus may potentially 
cause fetal B-cell depletion; therefore, RITUXAN should be given to a pregnant woman only if 
clearly needed.
Nursing Mothers
It is not known whether RITUXAN is excreted in human milk. Because human IgG is excreted in 
human milk and the potential for absorption and immunosuppression in the infant is unknown, 
women should be advised to discontinue nursing until circulating drug levels are no longer 
detectable. (See CLINICAL PHARMACOLOGY.)
Pediatric Use
The safety and effectiveness of RITUXAN in pediatric patients have not been established.
Geriatric Use
Among patients with DLBCL in three randomized, active-controlled trials, 927 patients received 
RITUXAN in combination with chemotherapy. Of these, 396 (43%) were age 65 or greater and 123 
(13%) were age 75 or greater. No overall differences in effectiveness were observed between 
these subjects and younger subjects. However, elderly patients were more likely to experience 
cardiac adverse events, mostly supraventricular arrhythmias. Serious pulmonary adverse events 
were also more common among the elderly, including pneumonia and pneumonitis.
Among the 331 patients with low-grade or follicular lymphoma enrolled in clinical studies of single 
agent RITUXAN, 24% were 65 to 75 years old and 5% were 75 years old and older. No overall 
differences in safety or effectiveness were observed between these subjects and younger subjects.
ADVERSE REACTIONS
Because clinical trials are conducted under 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 
another drug and may not reflect the rates observed in practice. The adverse reaction information 
from clinical trials does, however, provide a basis for identifying the adverse events that appear to 
be related to drug use and for approximating rates.
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The overall safety database for RITUXAN is based on clinical trial data from 1283 patients with 
NHL, who received RITUXAN either as a single agent or in combination with chemotherapy. 
Additional safety information was obtained from post-marketing safety surveillance. The most 
common adverse reactions were infusion reactions (see INFUSION REACTIONS below).
The following serious adverse reactions, some with fatal outcomes, have been reported in patients 
treated with RITUXAN (see BOXED WARNINGS and WARNINGS): severe or fatal infusion 
reactions, tumor lysis syndrome, severe mucocutaneous reactions, hepatitis B reactivation with 
fulminant hepatitis, other viral infections, hypersensitivity reactions, cardiac arrhythmias, renal 
toxicity, bowel obstruction and perforation.
Except as noted, adverse events described below occurred in the setting of relapsed or refractory, 
low-grade or follicular, CD20-positive, B-cell, NHL and are based on 356 patients treated in 
nonrandomized, single-arm studies of RITUXAN administered as a single agent. Most patients 
received RITUXAN 375 mg/m2 weekly for 4 doses.
Infusion Reactions (See BOXED WARNINGS and WARNINGS)
Mild to moderate infusion reactions consisting of fever and chills/rigors occurred in the majority of 
patients during the first RITUXAN infusion. Other frequent infusion reaction symptoms included 
nausea, pruritus, angioedema, asthenia, hypotension, headache, bronchospasm, throat irritation, 
rhinitis, urticaria, rash, vomiting, myalgia, dizziness, and hypertension. These reactions generally 
occurred within 30 to 120 minutes of beginning the first infusion, and resolved with slowing or 
interruption of the RITUXAN infusion and with supportive care (diphenhydramine, acetaminophen, 
IV saline, and vasopressors). The incidence of infusion reactions was highest during the first 
infusion (77%) and decreased with each subsequent infusion (30% with fourth infusion and 14% 
with eighth infusion). Injection site pain was reported in less than 5% of patients.
Infectious Events (See WARNINGS: Hepatitis B Reactivation with Related Fulminant 
Hepatitis and Other Viral Infections)
RITUXAN induced B-cell depletion in 70% to 80% of patients and was associated with decreased 
serum immunoglobulins in a minority of patients; the lymphopenia lasted a median of 14 days 
(range, 1 to 588 days). Infectious events occurred in 31% of patients: 19% of patients had bacterial 
infections, 10% had viral infections, 1% had fungal infections, and 6% were unknown infections. 
Incidence is not additive because a single patient may have had more than one type of infection. 
Serious infectious events (Grade 3 or 4), including sepsis, occurred in 2% of patients.
Hematologic Events
Grade 3 and 4 cytopenias were reported in 48% of patients treated with RITUXAN; these include: 
lymphopenia (40%), neutropenia (6%), leukopenia (4%), anemia (3%), and thrombocytopenia 
(2%). The median duration of lymphopenia was 14 days (range, 1 to 588 days) and of neutropenia 
was 13 days (range, 2 to 116 days). A single occurrence of transient aplastic anemia (pure red cell 
aplasia) and two occurrences of hemolytic anemia following RITUXAN therapy were reported.
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Pulmonary Events
135 patients (38%) experienced pulmonary events in clinical trials. The most common respiratory 
system adverse events experienced were increased cough, rhinitis, bronchospasm, dyspnea, and 
sinusitis. In both clinical studies and post-marketing surveillance, there have been a limited number 
of reports of bronchiolitis obliterans presenting up to 6 months post-RITUXAN infusion and a 
limited number of reports of pneumonitis (including interstitial pneumonitis) presenting up to 3 
months post-RITUXAN infusion, some of which resulted in fatal outcomes. The safety of 
resumption or continued administration of RITUXAN in patients with pneumonitis or bronchiolitis 
obliterans is unknown.
Immunogenicity
The observed incidence of antibody positivity in an assay is highly dependent on the sensitivity and 
specificity of the assay and may be influenced by several factors including sample handling, 
concomitant medications, and underlying disease. For these reasons, comparison of the incidence 
of antibodies to RITUXAN with the incidence of antibodies to other products may be misleading.
In clinical studies of patients with low-grade or follicular NHL receiving single-agent RITUXAN, 
human antichimeric antibody (HACA) was detected in 4 of 356 (1.1%) patients and 3 had an 
objective clinical response. These data reflect the percentage of patients whose test results were 
considered positive for antibodies to RITUXAN using an enzyme-linked immunosorbant assay (limit 
of detection = 7 ng/mL).
Single Agent RITUXAN for Relapsed or Refractory, Low-Grade or Follicular, CD20-Positive, 
B-Cell, NHL
Study subjects ranged from 22 to 81 years of age. Sixty percent were male; 93% were Caucasian, 
1% were African American, 2% were Hispanic, 2% were Asian, and 2% were from other racial 
groups. Table 4 lists the most common, as well as Grade 3 and 4, adverse events observed.
Table 4
Incidence of Adverse Events in > 5% of Patients
with Relapsed or Refractory, Low-Grade or Follicular
NHL, Receiving Single-agent RITUXAN (N=356)a,b
 
All Grades (%) Grade 3 and 4 (%)
Any Adverse Events
99
57
Body as a Whole
86
10
  Fever
53
1
  Chills
33
3
  Infection
31
4
  Asthenia
26
1
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  Headache
19
1
  Abdominal Pain
14
1
  Pain
12
1
  Back Pain
10
1
  Throat Irritation
9
0
  Flushing
5
0
Cardiovascular System
25
3
  Hypotension
10
1
  Hypertension
6
1
Digestive System
37
2
  Nausea
23
1
  Diarrhea
10
1
  Vomiting
10
1
Hemic and Lymphatic System
67
48
  Lymphopenia
48
40
  Leukopenia
14
4
  Neutropenia
14
6
  Thrombocytopenia
12
2
  Anemia
8
3
Metabolic and Nutritional Disorders 38
3
  Angioedema
11
1
  Hyperglycemia
9
1
  Peripheral Edema
8
0
  LDH Increase
7
0
Musculoskeletal System
26
3
  Myalgia
10
1
  Arthralgia
10
1
Nervous System
32
1
  Dizziness
10
1
  Anxiety
5
1
Respiratory System
38
4
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  Increased Cough
13
1
  Rhinitis
12
1
  Bronchospasm
8
1
  Dyspnea
7
1
  Sinusitis
6
0
Skin and Appendages
44
2
  Night Sweats
15
1
  Rash
15
1
  Pruritus
14
1
  Urticaria
8
1
a Adverse Events observed up to 12 months following RITUXAN.
b Adverse Events graded for severity by NCI-CTC criteria.19
Risk Factors Associated with Increased Rates of Adverse Events
Administration of RITUXAN weekly for 8 doses resulted in higher rates of Grade 3 and 4 adverse 
events14 overall (70%) compared with administration weekly for 4 doses (57%). The incidence of 
Grade 3 or 4 adverse events was similar in patients retreated with RITUXAN compared with initial 
treatment (58% and 57%, respectively). The incidence of the following clinically significant adverse 
events was higher in patients with bulky disease (lesions > 10 cm) (N = 39) versus patients with 
lesions < 10 cm (N = 195): abdominal pain, anemia, dyspnea, hypotension, and neutropenia.
RITUXAN in Combination with Chemotherapy for DLBCL
Except as noted, adverse events described in the setting of DLBCL are based on three 
randomized, active-controlled clinical trials in which 927 patients received RITUXAN in combination 
with chemotherapy and 802 received chemotherapy alone. Detailed safety data collection was 
primarily limited to Grade 3 and 4 adverse events and serious adverse events.
The population varied from 18 to 92 years of age and 55% were male; racial distribution was 
collected only for Study 1 (see CLINICAL STUDIES section) where 90% of patients were 
Caucasian, 5% were African American, 3% were Hispanic and 2% were from other racial groups. 
Patients received 4–8 doses of RITUXAN at 375 mg/m2.
The following adverse events, regardless of severity, were reported more frequently (>5%) in 
patients age >60 years receiving R-CHOP as compared to CHOP alone: cardiac disorder (29% vs. 
21%), pyrexia (56% vs. 46%), chills (13% vs. 4%) and lung disorder (31% vs. 24%). In one of these 
studies (Study 2), more detailed assessment of cardiac toxicity revealed that supraventricular 
arrhythmias or tachycardia accounted for most of the difference in cardiac disorders, with 4.5% vs. 
1.0% incidences for R-CHOP and CHOP, respectively.
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The following Grade 3 or 4 adverse events were reported more frequently among patients in the R-
CHOP arm compared with those in the CHOP arm: thrombocytopenia (9% vs. 7%) and lung 
disorder (6% vs. 3%). Other severe adverse events reported more commonly among patients 
receiving R-CHOP in one or more studies were viral infection, neutropenia and anemia.
Post-Marketing Reports
The following adverse reactions have been identified during post-approval use of RITUXAN. 
Because these reactions are reported voluntarily from a population of uncertain size, it is not 
always possible to reliably estimate their frequency or establish a causal relationship to drug 
exposure. Decisions to include these reactions in labeling are typically based on one or more of the 
following factors: (1) seriousness of the reaction, (2) frequency of reporting, or (3) strength of 
causal connection to RITUXAN.
Hematologic: prolonged pancytopenia, marrow hypoplasia, and late onset neutropenia, 
hyperviscosity syndrome in Waldenstrom's macroglobulinemia.
Cardiac: fatal cardiac failure.
Immune/Autoimmune Events: uveitis, optic neuritis, systemic vasculitis, pleuritis, lupus-like 
syndrome, serum sickness, polyarticular arthritis and vasculitis with rash.
Infection: increased in fatal infections in HIV-associated lymphoma.
Skin: severe mucocutaneous reactions.
Gastrointestinal: bowel obstruction and perforation.
OVERDOSAGE
There has been no experience with overdosage in human clinical trials. Single doses of up to 500 
mg/m2 have been given in dose-escalating clinical trials.9
DOSAGE AND ADMINISTRATION
Relapsed or Refractory, Low-Grade or Follicular, CD20-Positive, B-Cell, Non-Hodgkin's 
Lymphoma The recommended dose of RITUXAN is 375 mg/m2 IV infusion once weekly for 4 or 8 
doses.
Retreatment Therapy. The recommended dose of RITUXAN is 375 mg/m2 IV infusion once 
weekly for 4 doses in responding patients who develop progressive disease after previous 
RITUXAN therapy. Currently there are limited data concerning more than 2 courses.
Diffuse Large B-Cell NHL
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The recommended dose of RITUXAN is 375 mg/m2 IV per infusion given on Day 1 of each cycle of 
chemotherapy for up to 8 infusions.
RITUXAN as a Component of Zevalin™ (Ibritumomab Tiuxetan) Therapeutic Regimen
As a required component of the Zevalin therapeutic regimen, RITUXAN 250 mg/m2 should be 
infused within 4 hours prior to the administration of Indium-111- (In-111-) Zevalin and within 4 
hours prior to the administration of Yttrium90- (Y-90-) Zevalin. Administration of RITUXAN and In-
111-Zevalin should precede RITUXAN and Y-90-Zevalin by 7–9 days. Refer to the Zevalin 
package insert for full prescribing information regarding the Zevalin therapeutic regimen. RITUXAN 
may be administered in an outpatient setting. DO NOT ADMINISTER AS AN INTRAVENOUS 
PUSH OR BOLUS. (See Administration.)
Instructions for Administration
Preparation for Administration. Use appropriate aseptic technique. Withdraw the necessary 
amount of RITUXAN and dilute to a final concentration of 1 to 4 mg/mL into an infusion bag 
containing either 0.9% Sodium Chloride, USP, or 5% Dextrose in Water, USP. Gently invert the 
bag to mix the solution. Discard any unused portion left in the vial. Parenteral drug products should 
be inspected visually for particulate matter and discoloration prior to administration.
RITUXAN solutions for infusion may be stored at 2-8°C (36-46°F) for 24 hours. RITUXAN solutions 
for infusion have been shown to be stable for an additional 24 hours at room temperature. 
However, since RITUXAN solutions do not contain a preservative, diluted solutions should be 
stored refrigerated (2-8°C). No incompatibilities between RITUXAN and polyvinylchloride or 
polyethylene bags have been observed. 
Administration: DO NOT ADMINISTER AS AN INTRAVENOUS PUSH OR BOLUS
Infusion and hypersensitivity reactions may occur (see BOXED WARNINGS, WARNINGS, and 
ADVERSE REACTIONS). Premedication consisting of acetaminophen and diphenhydramine 
should be considered before each infusion of RITUXAN. Premedication may attenuate infusion 
reactions. Since transient hypotension may occur during RITUXAN infusion, consideration should 
be given to withholding antihypertensive medications 12 hours prior to RITUXAN infusion.
First Infusion. The RITUXAN solution for infusion should be administered intravenously at an initial 
rate of 50 mg/hr. RITUXAN should not be mixed or diluted with other drugs. If hypersensitivity or 
infusion reactions do not occur, escalate the infusion rate in 50 mg/hr increments every 30 minutes, 
to a maximum of 400 mg/hr. If a hypersensitivity (non-IgE-mediated) or an infusion reaction 
develops, the infusion should be temporarily slowed or interrupted (see BOXED WARNINGS and 
WARNINGS). The infusion can continue at one-half the previous rate upon improvement of patient 
symptoms.
Subsequent Infusions. If the patient tolerated the first infusion well, subsequent RITUXAN infusions 
can be administered at an initial rate of 100 mg/hr, and increased by 100 mg/hr increments at 30-
minute intervals, to a maximum of 400 mg/hr as tolerated. If the patient did not tolerate the first 
infusion well, follow the guidelines under First Infusion.
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Stability and Storage
RITUXAN vials are stable at 2-8°C (36-46°F). Do not use beyond expiration date stamped on 
carton. RITUXAN vials should be protected from direct sunlight. Do not freeze or shake. Refer to 
the "Preparation for Administration" section for information on the stability and storage of solutions 
of RITUXAN diluted for infusion.
HOW SUPPLIED 
RITUXAN® (Rituximab) is supplied as 100 mg and 500 mg of sterile, preservative-free, single-use 
vials.
Single unit 100 mg carton: Contains one 10 mL vial of RITUXAN (10 mg/mL). NDC 50242-051-21
Single unit 500 mg carton: Contains one 50 mL vial of RITUXAN (10 mg/mL).
NDC 50242-053-06
REFERENCES FOR RITUXIMAB PRESCRIBING INFORMATION. 
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Valentine MA, Meier KE, Rossie S, et al. Phosphorylation of the CD20 phosphoprotein in 
resting B lymphocytes. J Biol Chem 1989 264(19): 11282—11287.
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Einfeld DA, Brown JP, Valentine MA, et al. Molecular cloning of the human B cell CD20 
receptor predicts a hydrophobic protein with multiple transmembrane domains. EMBO J 
1988 7(3):711-717.
3.
Anderson KC, Bates MP, Slaughenhoupt BL, et al. Expression of human B cell-associated 
antigens on leukemias and lymphomas: A model of human B cell differentiation. Blood 
1984 63(6):1424-1433.
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Tedder TF, Boyd AW, Freedman AS, et al. The B cell surface molecule B1 is functionally 
linked with B cell activation and differentiation. J Immunol 1985 135(2):973-979.
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Tedder TF, Zhou LJ, Bell PD, et al. The CD20 surface molecule of B lymphocytes 
functions as a calcium channel. J Cell Biochem 1990 14D:195.
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Press OW, Applebaum F, Ledbetter JA, Martin PJ, Zarling J, Kidd P, et al. Monoclonal 
antibody 1F5 (anti-CD20) serotherapy of human B-cell lymphomas. Blood 1987 69(2):584-
591.
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Reff ME, Carner C, Chambers KS, Chinn PC, Leonard JE, Raab R, et al. Depletion of B 
cells in vivo by a chimeric mouse human monoclonal antibody to CD20. Blood 1994 
83(2):435-445.
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Demidem A, Lam T, Alas S, Hariharan K, Hanna N, and Bonavida B. Chimeric anti-CD20 
(IDEC-C2B8) monoclonal antibody sensitizes a B cell lymphoma cell line to cell killing by 
cytotoxic drugs. Cancer Biotherapy & Radiopharmaceuticals 1997 12(3):177-186.
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9.
Maloney DG, Liles TM, Czerwinski C, Waldichuk J, Rosenberg J, Grillo-López A, et al. 
Phase I clinical trial using escalating single dose infusion of chimeric anti-CD20 
monoclonal antibody (IDEC-C2B8) in patients with recurrent B-cell lymphoma. Blood 1994 
84(8):2457-2466.
10. Berinstein NL, Grillo-López AJ, White CA, Bence-Bruckler I, Maloney D, Czuczman M, et 
al. Association of serum Rituximab (IDEC-C2B8) concentration and anti-tumor response in 
the treatment of recurrent low-grade or follicular non-Hodgkin's lymphoma. Annals of 
Oncology 1998, 9:995-1001.
11. Maloney DG, Grillo-López AJ, Bodkin D, White CA, Liles T-M, Royston I, et al. IDEC-
C2B8: Results of a phase I multiple-dose trial in patients with relapsed non-Hodgkin's 
lymphoma. J Clin Oncol 1997 15(10):3266-3274.
12. Maloney DG, Grillo-López AJ, White CA, Bodkin D, Schilder RJ, Neidhart JA, et al. IDEC-
C2B8 (Rituximab) anti-CD20 monoclonal antibody therapy in patients with relapsed low-
grade non-Hodgkin's lymphoma. Blood 1997 90(6):2188-2195.
13. McLaughlin P, Grillo-López AJ, Link BK, Levy R, Czuczman MS, Williams ME, et al. 
Rituximab chimeric anti-CD20 monoclonal antibody therapy for relapsed indolent 
lymphoma: half of patients respond to a four dose treatment program. J Clin Oncol 1998 
16(8):2825-2833.
14. Piro LD, White CA, Grillo-López AJ, Janakiraman N, Saven A, Beck TM, et al. Extended 
Rituximab (anti-CD20 monoclonal antibody) therapy for relapsed or refractory low-grade or 
follicular non-Hodgkin's lymphoma. Annals of Oncology 1999 10:655-661.
15. Data on file.
16. Davis TA, White CA, Grillo-López AJ, et al. Single-agent monoclonal antibody efficacy in 
bulky non-Hodgkin's lymphoma: results of a phase II trial of rituximab. J Clin Oncol. 
1999;17:1851-1857.
17. Davis TA, Grillo-López AJ, White CA, McLaughlin P, Czuczman MS, Link BK, Maloney 
DG, Weaver RL, Rosenberg J, Levy R. Rituximab anti-CD20 monoclonal antibody therapy 
in non-hodgkin's lymphoma: safety and efficacy of re-treatment. J Clin Oncol 2000 18(17): 
3135-3143.
18. Anhalt GJ, Kim SC, Stanley JR, Korman NJ, Jabs DA, Kory M, Izumi H, Ratrie H, Mutasim 
D, Ariss-Abdo L, Labib RS. Paraneoplastic Pemphigus, an autoimmune mucocutaneous 
disease associated with neoplasia. NEJM 1990 323(25): 1729-1735.
19. National Cancer Institute. Common Toxicity Criteria. Bethesda, MD: National Institutes of 
Health; 1998:73.
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APPENDIX B

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APPENDIX C
Criteria for Evaluation of Response
1. Response Classifications
After study entry, disease activity evaluations will be made and recorded by using the following criteria and designated codes:
A.     Complete Response (CR): During observation no disease is apparent, including measurable and non-measurable disease, and no 
evidence of disease is observed for at least 28 days, as confirmed by a second assessment following the original observation of no disease.  
All nodes visualized on imaging studies or palpable on exams must have regressed to normal size (≤1.5 cm in their greatest transverse 
diameter for nodes > 1.5 cm before therapy).  Previously involved nodes that were 1.1 to 1.5 cm in their greatest transverse diameter before 
treatment must have decreased to ≤ 1 cm in their greatest transverse diameter after treatment, or by more than 75% in the sum of the 
products of the greatest diameters (SPD). (A1)  = The patient must also be free from symptoms related to lymphoma, if present before 
therapy with no worsening in performance status from baseline. (A2) = Bone marrow, if initially positive at baseline, must be histologically 
negative for lymphoma and the liver and spleen, if enlarged due to lymphoma at baseline, should be normalized.  
In addition, gallium-avid-disease or PET-positive at baseline that converts to negative will be accepted as confirmation of response, 
regardless of nodal size.
B.
Partial Response (PR): A 50% or greater decrease from baseline in the sum of the products of the longest perpendicular diameters 
of all the measured lesions is noted for at least 28 days as confirmed by a second assessment following the observation of the > or = to 50% 
decrease.  Additionally, no appearance of new lesions is noted.
C.
CR/Unconfirmed (CRu): Includes those patients who fulfill criteria (A1) and (A2) see above, but with one or more of the following 
features:
1.
A residual lymph node mass greater than 1.5 cm in greatest transverse diameter then that has regressed by more than 75% in the SPD. 
Individual nodes that were previously confluent must have regressed by more than 75% in their SPD compared with the size of the 
original mass.
2.
Indeterminate bone marrow (increased number or size of aggregates without cytologic or architectural atypia).
D.
Stable Disease (SD): Patients have stable disease if they neither exhibit at least a 50% decrease in the sum of the products of the 
longest perpendicular diameters of all the measured lesions, nor exhibit at least a 50% increase in the sum of the products of the longest 
perpendicular diameters of all the measured lesions.  In addition no new lesions may have appeared.

 Protocol Date:  10/4/13 
Francisco J Hernandez-Ilizaliturri MD
                                              I 83106
Page 79 of 83
E.
Progressive Disease (PD): Progressive disease will be assessed with reference to baseline values for measurable lesions unless a 
decrease in size has been observed, in which case progression will be measured from the nadir of the sum of the products of the longest 
perpendicular diameters of all measured lesions.
Any single observation of a >25% increase in the sum of the sizes of all sentinel lesions, a 50% or greater increase in the size of any 
single lesion or the appearance of a new lesion constitutes progressive disease.  A statement by the investigator indicating that clinical 
progressive disease has occurred may be used to signify progressive disease, as well as any death for which disease has occurred must 
include the date of disease progression and confirmatory documentation, i.e. of non-sentinel lesions or non-measurable disease, etc.
RESPONSE CRITERIA FOR NON-HODGKIN’S LYMPHOMA
Response Category
Physical Examination
Lymph Nodes
Lymph Node Masses
Bone Marrow
CR
Normal
Normal
Normal
Normal
CRu
Normal
Normal
Normal
Indeterminate
CRu
Normal
Normal
> 75% decrease
Normal
PR
Normal
Normal
Normal
Positive
PR
Normal
≥ 50% decrease 
≥ 50% decrease
Irrelevant
PR
Decrease in liver/spleen
≥ 50% decrease
≥ 50% decrease
Irrelevant
Relapsed/
Progression
Enlarging 
liver/spleen; 
new sites
New or increased
New or increased
Reappearance
2.
Measures of Duration
A.
Response Interval: measured from the date when the response is first noted until the last date at which the measurements satisfy 
the requirements for a partial or complete response.  An ongoing response is defined as a responder for whom no end of response 
can be determined.  In this case, the duration of response is considered as the last date when there is evidence of a continuing 
response.
B.
Progressive Disease (PD)-Free Interval: measured from the date when a CR or PR is first noted to the first date at which 
progressive disease is observed.  An ongoing PD-Free Interval occurs when there is a responder for whom progressive disease has 
not yet been noted.
C.
Time to Progression: measured from the date of first study treatment to the first date when progressive disease is documented.
D.
Survival:  duration of survival will be dated from the first day of treatment.
3.
Sentinel Lesions

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Francisco J Hernandez-Ilizaliturri MD
                                              I 83106
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A minimum of one and maximum of six sentinel lesions will be selected for determining the efficacy of study treatment.  All sentinel lesions 
must be measured at baseline by the method, which will be used, for routine tumor measurements during the study.  Sentinel lesions are 
defined as those lesions existing at baseline that most clearly represent the state of disease in the clinical judgment of the investigator, and 
need to be measurable bi dimensionally.  Sentinel lesions need to be at least 1.0 cm x 1.0 cm in size selected before treatment begins, and 
should not be in previously irradiated fields (unless progression has occurred). The liver (span) itself cannot be used as a sentinel lesion, 
although lesions within the liver are acceptable.  The minimum acceptable size of the sentinel lesions will depend on the number and 
dimension as outlined in the following table:
Number of Lesions
Dimensions
Minimum Size
≥1
Bi-dimensional
1.0 x 1.0 cm
4.
Definition of Measurable Disease
The extent of disease is measurable if the patient has one or more lesions that are clearly demarcated and may be represented with clearly 
defined margins as measured in centimeters.  These measurements will be bi-dimensional (two perpendicular measures per lesion).  Skin 
lesions must be documented by medical photography.  
5.
Measurement of Sentinel Lesions:
All sentinel lesions must be measured at baseline by the method that will be used for routine tumor measurements during the study.  Each 
sentinel lesion will be consistently measured bi-dimensionally for the duration of the study.  In addition, the routine method of measurement 
for any sentinel lesions, e.g., X-ray, PET scan, CT scan, etc., should remain the same for each evaluation throughout the study.  All 
measurements should be recorded in metric units, using a ruler or calipers.
A.
Bi-dimensional Disease: measured by two perpendicular measurements of the lesion.  The first measurement is the longest span of 
the lesion, and the other measurement is the longest measurement perpendicular to the first measurement.  The size of the lesion is 
the product of these two measurements.
B.
Overall Size of Sentinel Lesions: the sum of the products of the two dimensions of each bi dimensional lesion(s).
C.
Uni dimensional sites of disease may be used only in addition to bi dimensionally measured disease >1.0 x 1.0 cm.  Record the 
single dimension as measured by ruler or caliper.

 Protocol Date:  10/4/13 
Francisco J Hernandez-Ilizaliturri MD
                                              I 83106
Page 81 of 83
APPENDIX D
Performance Status Scale
Statusa,b
(Karnofsky)
Scale
"WHO" Statusc,d
(Zubrod-ECOG)
Normal, no complaints
100
0
Normal activity
Able to carry on normal activity; minor signs or symptoms of disease
90
1
Symptoms, but ambulatory
Normal activities for effort
80
Cares for self, unable to carry on normal activity or to do active work
70
2
Some bed time, but in bed <50% of 
normal daytime
Requires occasional assistance, but able to care for most of own needs
60
Requires considerable assistance and frequent medical care
50
3
Needs to be in bed .50% of normal 
daytime
Disabled, requires special care and assistance
40
Severely disabled, hospitalization indicated though death not imminent
30
4
Unable to get out of bed
Very sick, hospitalization necessary, active supportive treatment 
necessary
20
Moribund
10
Dead
0
a
Karnofsky DA, Abelmann WH, Craver LF, Burchenal JH.  The use of the nitrogen mustards in the palliative treatment of carcinoma.  Cancer 
1948;1:634.
b
Schag CC, Heinrich RL, Ganz PA.  Karnofsky performance status revisited:  reliability, validity, and guidelines.  Clin Oncol 1984;2:187-93.
c
Zubrod CG, et al.  Appraisal of methods for the study of chemotherapy of cancer in man.  J Chron Dis 1960;11:7-33.
d
WHO handbook for reporting results of cancer treatment.  WHO Offset Publication No. 48.  World Health Organization, Geneva, 1979.

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Francisco J Hernandez-Ilizaliturri MD
                                              I 83106
 
Page 82 of 83
APPENDIX E
Study Flow Chart
Table 2. Calendar of procedures before and during Pegfilgrastim in combination with rituximab
Week
-4 to 0
1
3
5
7
9
11
13
15
17
19
21
23
25
27
29
31
33
35
37
39
43
Medical history
◙
◙
◙
◙
◙
 
 
 
◙
 
 
 
◙
 
 
◙
 
 
 
◙
◙
Physical exam
◙
◙
◙
◙
◙
◙
  
 
 
◙
 
 
◙
 
 
 
◙
◙
Height and body weight (BSA 
calculation) at screening only; 
thereafter body weight only
◙
◙
◙
◙
◙
◙
◙
◙
◙
◙
ECOG performance status
◙
◙
◙
◙
◙
 
 
 
◙
 
 
 
◙
 
 
◙
 
 
 
◙
◙
CBC.
◙
◙
◙
◙
◙
 
 
 
◙
 
 
 
◙
 
 
◙
 
 
 
◙
◙
Chemistry panel 
◙
◙
◙
◙
◙
 
 
 
◙
 
 
 
◙
 
 
◙
 
 
 
◙
◙
Pregnancy test (if applicable)
◙
Bone marrow and peripheral 
blood studies a
◙
◙
Lymph node biopsy  b
◙
Beta 2 microglobulin (β2M)
◙
◙
◙
◙
Urinalysis
◙
Tumor measurements c
◙
◙
◙
◙
Imaging studies c, d (PET 
scan, CT scang or MRI)
◙
◙
Quantitative immunoglobulins 
(IgG, IgA, IgM)
◙
◙
◙
◙
Screening of patients for HIV, 
HBV and HCV
◙
Correlative studies e
◙
◙
◙
◙
◙
◙
◙
◙
◙
Pegfilgrastim f 
◙
◙
◙
◙
◙
◙
◙
◙
Rituximab
◙
◙
◙
◙
◙
◙
◙
◙
a Repeat bone marrow biopsy at the end of therapy only if was involved with lymphoma during the staging work up or clinically indicated by treating physician.
b   Lymph node biopsy and sample for surface antigen markers (e.g. CD20, CD19, etc.); PCR for Ig gene rearrangement in FL patients; and Bcl-2 detection for patients with accessible 
and enlarged lymph node. As long as they do not have any medical contraindications for biopsy as determined by the treating physician. For patients with no accessible tumor lesions or 
with medical contraindications for surgical procedure, archived pathological material will be analyzed for confirmation of diagnosis, CD20 expression and in cases of FL for IgH gene 
rearrangement and Bcl-2 studies
c Tumor measurements and Imaging studies – If patient has a response (PR or CR), the sentinel lesions chosen at baseline will be reassessed 1 to 4 months later to confirm the 
response.       d   Imaging studies will be done on weeks 11, 27 and 43.           e  Various laboratory parameters will be analyzed for each patient enrolled in the study before treatment 
(baseline) and before each dose of rituximab        f Pegfilgrastim will be administered sq 3 days (day 1 of each treatment week) before each dose of rituximab (day 4 of each treatment 
week) g CT scans will be performed during the first two years of follow-up only.

 Protocol Date:  10/4/13 
Francisco J Hernandez-Ilizaliturri MD
                                              I 83106
 
Page 83 of 83
APPENDIX E (contd.)
Study Flow Chart
Table 3.  Calendar of Procedures During 4-year (48 month) Follow-Up –
 For Assessment of Time to Progression and Survival Only, for 4 years (48 months) after the last study treatment
Year 1 of 
Follow-Up
Year 2 of 
Follow-Up
Year 3 of
 Follow-Up
Year 4 of
Follow-Up
Medical history
Every 4 months
Every 6 months
Every 6 months
Physical exam
Every 4 months
Every 6 months
Every 6 months
ECOG performance status
Every 4 months
Every 6 months
Every 6 months
Imaging studies 
(PET scan if clinically indicated, CT scan or MRI)
Every 4 months
Every 6 months
Every 6 months
No CT scans in 
year 3
Hematology: 
CBC with differential and platelet count.
Every 4 months
Every 6 months
Every 6 months
Serum Chemistries:  creatinine, uric acid, total bilirubin, 
alkaline phosphatase, LDH, total protein, albumin, 
glucose, AST (SGOTY), calcium, phosphate, sodium, 
potassium, and BUN
Every 4 months
Every 6 months
Every 6 months
Laboratory studies:
Peripheral blood (and bone marrow samples when 
available) for bcl-2 testing if the baseline assessment 
was positive for this marker.
Once a year
Once a year
Once a year
Once a year