A PHASE 3, RANDOMIZED, DOUBLE-BLIND STUDY OF PF-05280586 VERSUS RITUXIMAB FOR THE FIRST-LINE TREATMENT OF PATIENTS WITH CD20-POSITIVE, LOW TUMOR BURDEN, FOLLICULAR LYMPHOMA
Phase: PHASE3
Conditions: Follicular Lymphoma
Sponsor: Pfizer

PF-05280586
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A PHASE 3, RANDOMIZED, DOUBLE-BLIND STUDY OF 
PF-05280586 VERSUS RITUXIMAB FOR THE FIRST-LINE TREATMENT OF 
PATIENTS WITH CD20-POSITIVE, LOW TUMOR BURDEN, FOLLICULAR 
LYMPHOMA
Compound:
PF-05280586
Compound Name:
Not Applicable
US IND Number:
110,426
European Clinical Trial Database 
(EudraCT) Number:
2014-000132-41
Protocol Number:
B3281006
Phase:
3

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Document History
Document
Version Date
Summary of Changes and Rationale
Original Protocol
14 February 2014
Not Applicable
Amendment 1
08 May 2014

Added the CD-19 B-cell results from the 
Phase 1/2 PF-05280586 study to the Protocol 
Summary and Section 1.2.2.

Added text in the Protocol Summary, Section 
1.1 and Section 3 to clarify the definition of 
low tumor burden used to enroll patients in 
the study. 

Updated the Protocol Summary and Section 
4.1 to indicate that normal LDH will be 
required at Screening for inclusion.

Updated the Schedule of Assessments to 
indicate that LDH and -2 microglobulin will 
be collected throughout the study for 
increased safety monitoring.

Updated the Schedule of Assessments, 
Section 6 and Section 7 to indicate that 
Immunogenicity (ADA/Nab) samples will be 
collected at Day 15 to provide more 
information regarding the onset of any 
ADA/Nab findings.  Removed Day 
22 Immunogenicity sampling.  Made 
additional updates to clarify sample collection 
requirements for ADA/Nab, to remove 
references to cross-reactivity testing as it will 
not be conducted in this study, and to clarify
that additional follow-up will not be required 
for patients with positive ADA/Nab samples.

Updated footnotes in the Schedule of 
Assessments, Section 6 and Section 7 to 
indicate that all Physical Examinations must 
include a thorough assessment of the lymph 
nodes, liver, and spleen to ensure adequate
safety monitoring.

Updated a footnote in the Schedule of 

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Assessments, Section 6 and Section 7 to 
clarify that HIV testing is required at 
Screening unless prohibited by local 
regulations.

Updated additional footnotes in the Schedule 
of assessments to ensure that they are 
consistent with the rest of the protocol and to 
correct minor errors.

Moved the description of the results of the 
completed Phase1/2 PF-05280586 study from 
Section 1 to Section 1.2.2.

Changed the title of Section 1.2.1.1 to clarify 
that it discusses the efficacy of rituximab 
monotherapy in low tumor burden follicular 
lymphoma.

Removed the text in Section 3 that describes 
the ISRC functioning as an advisory group as 
the ISRC will meet on an ad hoc basis if 
required.

Updated Section 4.1 to indicate that both male 
and female patients of childbearing potential 
must agree to use contraception.

Updated Section 4.2 to indicate that patients 
with ≥5000/mm3 circulating lymphoma cells 
at Screening will be excluded to avoid 
patients with bone marrow involvement.

Updated Section 4.2 to indicate that patients 
with a body surface area of >3 will be 
excluded from the study.

Removed male and female condoms with 
spermicide from the list of highly effective 
methods of contraception in Section 4.4 as 
requested by regulators.

Updated Section 5.1 to refer to patients rather 
than subjects to ensure consistency with the 
rest of the protocol.

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
Clarified in Section 5.2 that Investigators 
should notify the Sponsor if the blind is 
broken for a patient, but are not required to 
contact the Sponsor prior to breaking the 
blind.

Added a restriction in Section 5.3.3 that the 
maximum dose of rituximab that can be 
administered during the study is 1125 mg.

Updated Section 5.5 to clarify that patients 
who require additional tumor targeting 
treatment for LTB-FL should be discontinued 
from the study.

Added a note to Section 6.2.1 emphasizing 
the importance of entering the correct 
FLIP2 scores into the IVRS to ensure 
appropriate stratification during 
randomization.

Updated Section 6.2.3 and Section 6.2.4 to 
clarify that a patient should receive a 
post-Screening FDG-PET or PET-CT scan
once during the study if the Investigator 
determines that the patient has experienced a 
CR. 

Updated Section 6.2.3 and Section 6.2.4 to 
clarify that a patient should receive a 
post-Screening bone marrow biopsy or 
aspiration once during the study if the 
Investigator determines that the patient has 
experienced a CR.

Updated Section 7.1 to clarify imaging 
requirements.

Updated Section 7.6 to make minor
clarifications regarding histopathological 
review of diagnostic tissue.

Updated Section 8.2 to extend the SAE 
reporting period to 28 days after the last study 
visit.

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
Additional updates to Section 8 and Section 
15 to assure consistency with the standard 
language in Pfizer’s current protocol 
template.

Renumbered references to match the order in 
which they appear in the current protocol.

Corrected typographical errors and made 
minor updates to the text for clarity 
throughout the document.
Amendment 2
05 September
2014

For Japan only:
Added an additional analysis to test whether 
the difference between the ORR of 
rituximab-Pfizer and rituximab-EU is 
between a margin of -14.9% to 14.9% 
according to a requirement from the 
regulatory authority in Japan.
Amendment 3
04 December
2014

Testing for circulating lymphoma cells at 
Screening added to the Schedule of 
Assessments and Section 6.1.

Contraception check added to Schedule of 
Assessments.

Updated information from the Ardeshna et al. 
study in the Protocol Summary and Section 
9.1 to include data reported in Lancet 
Oncology in 2014.  Previous data were from a
2010 abstract. 

Deleted ADR table in Section 1.2.1.2 for 
MabThera and instead referenced the 
MabThera SPC to avoid any inconsistencies.

Updated Section 4.1, Inclusion Criterion 1 to 
align with global requirements for age of 
consent.

Updated Section 4.1, Inclusion Criterion 
2 and Section 6.1 to require that patients 
diagnosed with fine needle aspiration 
cytology or a biopsy from non-lymphoid 
tissue will be required to have an excisional 

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or core needle tumor tissue biopsy from a 
lymph node to determine eligibility (unless 
eligibility can be confirmed by the central 
pathology reviewer prior to randomization).

Updated Section 4.1, Inclusion Criterion 6 to 
clarify the requirement for no clinically
significant serous effusions.

Updated Section 4.2, Exclusion Criterion 9 to
exclude patients with any history of allergy or 
hypersensitivity to murine, chimeric, 
humanized, or human monoclonal antibody 
treatments. 

Updated Section 4.2, Exclusion Criterion 
13 to provide clarity around exclusion of 
patients with positive tests for HBsAg, 
HBcAb, or HCVAb.

Updated Section 4.2, Exclusion Criterion 
14 to include broad antimicrobial treatment,
as opposed to antibiotics. 

Updated Section 4.2, Exclusion Criterion 
15 to clarify the exception to history of cancer 
in the last 5 years only applies to 
non-melanoma skin tumors, in situ cervical 
carcinoma, or in situ breast cancer treated 
with curative intent with no history of 
metastatic disease.

Section 4.3 updated to allow patients to be 
randomized within 5 business days of Day 
1 to accommodate IP shipment from central 
pharmacies to sites.

Sections 5.1 and 6.2.1 updated to include a 
requirement to complete an Eligibility Review 
Form and send to the Sponsor for approval 
prior to randomization.

Section 5.3.2 updated to allow IP preparation 
utilizing either the approved MabThera SPC
or the local product label for rituximab.

Section 5.3.2.1 updated to align with the 

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MabThera SPC by allowing for dilution 
concentrations of 1 mg/mL to 4 mg/mL.

Updated Section 5.3.3 to provide clarity on 
the BSA calculation requirements. 

Updated Section 5.3.3 to provide guidance on 
post-infusion observation of patients. 

Updated Section 5.5 to prohibit long term 
high dose steroid use.

Updated Section 5.5 to prohibit
administration of vaccines containing live 
viruses during the study.

Updated Schedule of Assessments and
Section 6.1 to extend the screening window to 
56 days with exception of Screening labs,
which must be performed within 28 days of 
Day 1.

Updated section 6.2.2 and 6.2.3 to clarify that 
the end of the infusion is the time when the 
entire dose of study medication has been 
administered and the 10 minute flush with 
diluent has been completed. 

Updated Sections 6.2.2, 6.2.3, 6.2.4 and the 
Schedule of Assessments to include 
assessment of follicular lymphoma signs and
symptoms, including lymphoma-related B 
symptoms, throughout the study.

Updated Schedule of Assessments and
Sections 6.2.3 and 6.2.4 to clarify that the 
follow-up PET and bone marrow biopsy 
should be performed within 4 weeks of a 
contrast-enhanced CT in which the patient 
achieves a complete remission.

Updated section 6.3 to clarify that patients 
who cannot received all four doses of study 
medication may be withdrawn from 
treatment, but may remain in the study 

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
Updated Section 7.1 and added Appendix 3 to 
provide guidance that Investigators should 
utilize the revised response criteria for 
malignant lymphoma (2007) for determining 
complete remission.

Coagulation testing at Screening and End of 
Study was removed from the Schedule of 
Assessments, Sections 6.1 and 6.2.4, and 
Section 7.2.4.

Updated Section 7.2.4 to clarify which 
laboratory tests will be performed centrally 
and which will be performed locally. 

Updated Section 7.2.4 to clarify that a single 
retest for an exclusionary laboratory value 
may be conducted during Screening.

Updated Section 7.5 to correct an error that 
indicated that WBCs must be collected to 
assess CD19 B cell counts.

Updated Section 7.6 to clarify eligibility for 
randomization based on local histopathology 
review and availability of archival tissue.

Banked biospecimen sample collection was 
removed from the Schedule of Assessments 
and Section 7.7 deleted.

Updated Section 8.7 to reference CTCAE 
V4.03 instead of listing the specific 
intensities. Additionally, NCI CTCAE 
severity grades for infusion related reactions 
were added. 

Changed “subject” to “patient” to ensure 
consistency throughout the document.

Changed “IVRS” to “IMPALA” throughout 
the document.
Corrected typographical errors

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Amendment 4
19 April 2016

Changed “central radiology review” to 
“central review” as the central assessment of 
response also involves clinical data, including 
the development of B symptoms and bone 
marrow biopsy results. Sections impacted: 
Protocol Summary, Section 2.2.1, 
Section 9.3.2.2 and Section 9.3.2.3.

Revised protocol to allow patients with LDH 
values of up to 1.5 the upper limit of normal 
to enroll in the study. Sections impacted: 
Protocol Summary, Section 1.1, Section 3, 
and Section 4.1.

Clarified that sites may perform either a 
diagnostic quality PET/CT or a separate CT 
scan at visits where imaging is required 
(Screening, Week 13, Week 26, Week 39, and 
Week 52). Also clarified that PET/CT scans 
should encompass the base of the skull to the 
proximal femurs and provided additional 
guidance on imaging requirements for 
patients who cannot receive IV contrast. 
Sections impacted: Schedule of Assessments, 
Section 6.1, Section 6.2.3, Section 6.2.4, and 
Section 7.1.

Expanded visit window from 7 days to 
14 days for Visits 7, 8, 9, and 10. Sections 
impacted: Schedule of Assessments.

Clarified the vital signs which should be 
collected every 30 minutes during IP infusion 
(heart rate, seated blood pressure, respiratory 
rate, and oral or tympanic body temperature) 
and specified that a 5 minute window is 
acceptable for the collection of vital signs 
during IP infusion. Sections impacted: 
Schedule of Assessments, Section 5.3.3 and 
Section 7.2.2.

Extended the window for patients who have 
had a previous bone marrow biopsy from 
8 weeks to 12 weeks prior to Day 1 and allow 
patients who have had a positive bone marrow 
biopsy or aspiration to enter the study without 

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requiring a repeat biopsy or aspiration to 
confirm marrow involvement. Sections 
impacted: Schedule of Assessments and 
Section 6.1.

Removed the requirement for steroid 
premedication to be administered 30 minutes 
prior to the start of IP infusion as appropriate 
timing of steroid administration will vary 
depending on the route of administration and 
premedications may be administered in 
accordance with the institution’s standard of 
care. Clarified that changes in pre-medication 
doses after the first infusion should be made 
in accordance with standard of care and local 
rituximab labeling. Sections impacted: 
Schedule of Assessments and Section 5.3.2.2.

Removed “untreated” from Inclusion 
Criterion 2 and updated Exclusion Criterion 6 
to clarify that patients who have received 
previous systemic therapy for follicular 
lymphoma (FL) are not eligible for 
participation, but patients who have received 
localized radiotherapy for FL may participate 
in the study. Sections impacted: Section 4.1 
and Section 4.2.

Clarified that either a tissue blocks or slides 
are acceptable for the retrospective central 
pathology review. Removed the requirement 
that patients diagnosed by fine needle 
aspiration or a biopsy from non-lymphoid 
tissue undergo central pathology review prior 
to be enrolled in the study. Section impacted: 
Schedule of Assessments, Section 4.1, 
Section 6.1 and Section 7.6.

Revised Inclusion Criterion 5 regarding 
measurable disease to clarify that lesions must 
be measurable via imaging and to provide 
minimum measurements for both nodal and 
extra-nodal lesions. Sections impacted: 
Section 4.1 and Section 9.2.2.

Clarified that contraception is required for 

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sexually active patients who are biologically 
capable of having children and at risk for 
pregnancy in accordance with the current 
Pfizer protocol template. Section impacted: 
Section 4.4.

Clarified that brain imaging is not required to 
rule out CNS involvement, but may be 
conducted if clinically indicated. Section 
impacted: Section 4.2.

Clarified that patients with any history of 
T-cell lymphoma are excluded from 
participation. Section impacted: Section 4.2.

Clarified that an Early Termination Visit is 
not required for patients who withdraw from 
the study at a scheduled study visit. Section 
impacted: Section 6.3.

Corrected the list of required clinical 
laboratory tests and clarified that local 
laboratory testing may be used to determine 
eligibility or monitor safety if it is not feasible 
to do so using the central laboratory. Section 
impacted: Section 7.2.4.

Clarified the Per-Protocol Population 
definition to include all randomized patients 
who receive at least one dose of treatment and 
have measurable disease at baseline 
confirmed by central review.  Section 
impacted: Section 9.2.2.

Clarified the definition of Time to Treatment 
Failure as time from date of randomization to 
discontinuation from study for any reason.  
Section impacted: Section 9.3.2.1.

Corrected “objective tumor response” to 
“overall response” in the discussion regarding 
the Duration of Response endpoint. Section 
impacted: Section 9.3.2.3.

Updated safety reporting text to be consistent 
with current Pfizer protocol template. Section 

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impacted: Section 8.

Updated text regarding communication of 
study results to be consistent with current 
Pfizer protocol template. Section impacted: 
Section 15.

Corrected minor typographical errors and 
clarified abbreviations throughout the 
document.
This amendment incorporates all revisions to date, including amendments made at the 
request of country health authorities and institutional review boards/ethics committees 
(IRBs/ECs).

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PROTOCOL SUMMARY
Background and 
Rationale:
PF-05280586 (hereafter designated rituximab-Pfizer) is being 
developed as a potential biosimilar to rituximab.  Rituximab is 
approved for two broad indications: musculoskeletal and connective 
tissue diseases and B-cell malignancies.  Rituximab is an effective 
therapy for the treatment of patients with CD-20 positive, B-cell 
malignancies.1,2 Rituxan® is the commercially available product in 
the United States and will be referred to as rituximab-US; MabThera 
is the commercially available product in the European Union and will 
be referred to as rituximab-EU.  In Japan the commercially available 
product is Rituxan®.
Rituximab is a chimeric monoclonal antibody comprised of a human 
IgG1K Fc region and a murine variable region that binds specifically 
to human CD20.  Rituximab contains 2 heavy (H) chains, each 
comprising 451 amino acids and 2 kappa light (L) chains each 
comprising of 213 amino acids, which are disulfide-bonded to form a 
4-chain molecule (H2L2).  Rituximab-Pfizer has the same primary 
amino acid sequence as the commercially available rituximab 
product.
The term “biosimilar” refers to a biologic drug that is developed to be 
highly similar to an existing licensed reference biologic.  Biosimilars 
are intended to treat the same diseases as the reference biologic using 
the same dose and treatment regimen.  Unlike generic versions of 
chemically-synthesized small molecule therapies, biosimilars are not 
structurally identical to their reference biologic.  This is due to the 
purity, characteristics, and activity of a specific biologic being 
dependent on and sensitive to changes in the process by which it was 
manufactured.  Therefore, the aim is to create a product with no 
clinically meaningful differences between the biosimilar and the
reference biologic in terms of chemistry, manufacturing, and controls 
(CMC), purity, potency, pharmacokinetics (PK), safety, 
immunogenicity, and efficacy.
The PK of rituximab-Pfizer, rituximab-EU and rituximab-US were 
compared in a Phase 1/2 study conducted in patients with rheumatoid 
arthritis (Protocol B3281001).  The results showed that the 90% 
confidence intervals (CIs) for the test-to-reference ratios of the 
maximum serum concentration (Cmax), area under the 
concentration-time curve (AUC) from time zero to the last 
quantifiable time point (AUCT), and AUC from time zero 
extrapolated to infinity (AUC0-∞) were within the pre-specified 
window of 80.00% to 125.00% for the comparisons of 
rituximab-Pfizer to rituximab-EU and rituximab-US, and for the 

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comparison of rituximab-EU to rituximab-US, demonstrating the PK 
similarity of the 3 products.  The study results also showed that the 
safety and immunogenicity profiles and CD-19 positive B-cell 
reductions were comparable across rituximab-Pfizer, rituximab-EU, 
and rituximab-US. Because of the similarity between rituximab-US 
and rituximab-EU, only rituximab-EU will be used as a comparator in 
the current study.
The demonstration of similarity in efficacy between a biosimilar and 
the innovator product is an essential component of a clinical trial 
program that collectively provides the evidence of biosimilarity. The 
current study will evaluate the efficacy, safety, PK, and 
immunogenicity of rituximab-Pfizer versus rituximab-EU in patients 
with CD20-positive, low tumor burden follicular lymphoma 
(LTB-FL) in the first-line treatment setting.  While rituximab 
monotherapy in the first line setting is not an approved indication, it 
is an acceptable treatment option in low tumor burden follicular 
lymphoma.4,5 Using rituximab monotherapy allows the assessment of 
biosimilarity without the potentially confounding factors that would 
be introduced by combining rituximab with chemotherapy in more 
advanced stage patients; this is particularly important for the 
evaluation of comparative immunogenicity. 
Throughout this clinical trial protocol, PF-05280586 is referred to as 
rituximab-Pfizer; however, biosimilarity has not yet been established 
and is not claimed. Likewise, the general term rituximab is 
sometimes used for convenience when discussing the 2 blinded study 
treatments but is not a claim of biosimilarity.  Biosimilarity will be 
supported by analytical, non-clinical, clinical PK, pharmacodynamic 
(PD), safety and efficacy studies.
Objectives and 
Endpoints:
Primary Objective

To compare the efficacy of rituximab-Pfizer to rituximab-EU 
when administered as a first-line treatment to patients with 
CD20-positive, low tumor burden follicular lymphoma 
(LTB-FL).
Secondary Objectives

To evaluate the safety of rituximab-Pfizer and rituximab-EU.

To evaluate the population pharmacokinetics of 
rituximab-Pfizer and rituximab-EU.

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
To evaluate the immunogenicity of rituximab-Pfizer and 
rituximab-EU.

To characterize CD19-positive B-cell depletion and recovery 
in patients receiving rituximab-Pfizer and rituximab-EU.
Primary Endpoint

Overall Response Rate (ORR) at Week 26 of rituximab-Pfizer 
and rituximab-EU based on central review in accordance with 
the revised response criteria for malignant lymphoma.11
Secondary Endpoints

Safety characterized by type, incidence, severity, timing, 
seriousness, and relationship to study therapy of adverse 
events and laboratory abnormalities.

Time to Treatment Failure (TTF).

Progression-Free Survival (PFS).

Complete Remission (CR) rate at Week 26.

Duration of response.

Overall survival.

Peak and trough drug concentrations.

CD19-positive B-cell counts.

Incidence of anti-drug antibodies (ADA), including 
neutralizing antibodies (Nab), and safety associated with 
immune response.
Study Design:
This is a double-blind, randomized, Phase 3 clinical trial evaluating 
the efficacy, safety, PK and immunogenicity of rituximab-Pfizer and 
rituximab-EU in patients with CD20-positive, low tumor burden, 
follicular lymphoma in the first-line treatment setting. 
To select patients appropriate for treatment with rituximab 
monotherapy in accordance with various international treatment 
guidelines, including the National Comprehensive Cancer Network 
(NCCN) and European Society for Medical Oncology (ESMO),4,5 the 
study will enroll patients with low tumor burden follicular lymphoma 
who are asymptomatic for lymphoma specific B-symptoms.
Low tumor burden will be assessed according to the Groupe d’Etude 

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des Lymphomes Folliculaires (GELF) criteria.6  Clinically 
non-significant elevations in serum lactate dehydrogenase (LDH) or
-2 microglobulin (1.5 times upper limit of normal) at Screening
will be allowed. These patient eligibility criteria are similar to other 
recent randomized studies conducted with rituximab monotherapy in
low tumor burden follicular lymphoma.7
The hypothesis to be tested in this study is that the efficacy (ORR) of 
rituximab-Pfizer is similar to that of rituximab-EU.  Retrospective 
histological confirmation of CD20-positive FL will be obtained by a 
central pathology review. Central imaging review will be performed 
for all disease assessments up through Week 52. The primary 
endpoint is Overall Response Rate (ORR) at Week 26 in accordance 
with the revised response criteria for malignant lymphoma.11
Secondary endpoints include safety, TTF, PFS, CR, duration of 
response, OS, selected peak and trough drug concentrations, 
CD19-positive B-cell depletion, and immunogenicity.
Approximately 394 patients will be randomized in a 1:1 ratio to 
receive rituximab-Pfizer or rituximab-EU. Randomization will be 
stratified by low, medium, and high risk patients using the Follicular 
Lymphoma International Prognostic Index 2 (FLIPI2).12
Safety will be reviewed throughout the trial in a blinded manner by 
the study team and by an unblinded external Data Monitoring 
Committee (E-DMC).
Study Treatments:
During the study, patients will receive 4 weekly doses of 
rituximab-Pfizer or rituximab-EU administered via intravenous 
infusion.  The dose of rituximab-Pfizer or rituximab-EU will be 
375 mg/m2 of body surface area.
Statistical 
Methods:
The primary hypothesis to be tested in this study is that the difference 
between the ORR of rituximab-Pfizer and that of rituximab-EU is 
within a pre-specified margin of -16% to 16%.  A sample size of 
approximately 394 patients (197 per treatment arm) provides 
approximately 93% power for achieving equivalence under the 
specified margin with 2.5% type I error rate, assuming an ORR of 
77% in both treatment arms.

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SCHEDULE OF ACTIVITIES
The Schedule of Activities table provides an overview of the protocol visits and procedures.  Refer to Study Procedures and 
Assessments sections of the protocol for detailed information on each procedure and assessment required for compliance with the 
protocol.
The investigator may schedule visits (unplanned visits) in addition to those listed on the schedule of activities, in order to conduct 
evaluations or assessments required to protect the well being of the patient.
Study Period
Screening1
Treatment
Follow -Up
End of Study/
Early
Termination
Study Week
Week 1 – 4
Week 5
Weeks 13, 26, 39
Week 52
Visit Timing
Day -56 to 0
Day 1
Day 8
Day 15
Day 22
Day 29
Approximately Every Three Months
Visit Number
1
2
3
4
5
6
7, 8, 9
10
Allowable Visit Window
1 Day
1 Day
1 Day
3 Days
14 Days
Informed Consent2
X
Inclusion/Exclusion Criteria3
X
X
Histological Confirmation of 
Diagnosis4
X
Demography
X
Medical and Oncologic History
X
Lymphoma-Related Signs & 
Symptoms
X
X
X
X
X
X
X
X
FLIPI& FLIPI2
X
Prior Medications
X
Complete Physical Examination5
X
X
Targeted Physical Examination6
X
X
X
X
X
X
Vital Signs7
X
X
X
X
X
X
X
X
ECOG Performance Status 
X
X
X
X
Laboratory Testing8
Hematology
X
X
X
X
X
Chemistry
X
X
X
X
X
Urinalysis
X
X
Pregnancy Test9
X
X
X
2-microglobulin and LDH
X
X
X
X
X

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Study Period
Screening1
Treatment
Follow -Up
End of Study/
Early
Termination
Study Week
Week 1 – 4
Week 5
Weeks 13, 26, 39
Week 52
Visit Timing
Day -56 to 0
Day 1
Day 8
Day 15
Day 22
Day 29
Approximately Every Three Months
Visit Number
1
2
3
4
5
6
7, 8, 9
10
Allowable Visit Window
1 Day
1 Day
1 Day
3 Days
14 Days
Viral Disease Screen10
X
Circulating lymphoma cells
X
Electrocardiogram11
X
X
[18F]FDG-PET/CT or CT Scan12
X
X
X
[18F]FDG-PET
X
X13
Bone Marrow Biopsy or Aspiration
X
X14
Randomization
X
Serum PK Sampling15
X
X
X
X
X
X
X
CD19+ B-cell Count Sampling16
X
X
X
X
X
X
X
Immunogenicity Sampling17
X
X
X
X
X
IgG Sampling
X
X
X
X
X
X
X
IgM Sampling
X
X
X
X
X
X
X
Premedications18
X
X
X
X
Study Drug Administration
X
X
X
X
Concomitant Medications
X
X
X
X
X
X
X
Adverse Event Assessment
X
X
X
X
X
X
X
Contraception Check19
X
X
X
X
X
X
X
1.
The screening period may last up to 56 days (8 weeks).  Patients must have all screening lab tests conducted within 28 days (4 weeks) of the first dose of 
study medication (Day 1).
2.
Informed Consent must be obtained prior to the patient undergoing any study specific procedure and may occur prior to the screening period.
3.
All eligibility requirements must be met in order to randomize a patient.  Patients who do not meet all requirements at initial screening can be re-screened if 
appropriate.
4.
Patients can be entered based on a diagnosis of CD20+ follicular lymphoma confirmed at the investigational site.  Archival tissue or slides must be sent to 
the central pathology reviewer for confirmation of diagnosis.  Patients must have tissue available for the central pathology review to be enrolled.
5.
A complete physical examination is to be conducted at Screening (Visit 1) and End of Study/Early Termination (Visit 10 – Week 52).  The genitourinary 
system may be excluded unless there are signs or symptoms involving that system.  The PE must include a thorough assessment of the lymph nodes, liver
and spleen.

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6.
Complete or targeted physical examinations must be conducted at study visits other than Screening and End of Study/Early Termination.  Targeted PEs 
should be targeted to specific symptoms or complaints and be consistent with local standard of care.  All Targeted PEs must include, at a minimum, an 
assessment of the lymph nodes, liver and spleen.
7.
Vital signs include heart rate, seated blood pressure, respiratory rate, and oral or tympanic body temperature.  On treatment days, vital signs should be 
monitored at least every 30 minutes (5 minutes) during rituximab administration and more frequently as necessary.
8.
Screening laboratory tests must be conducted within 28 days of Day 1. 
9.
For female patients of childbearing potential, a serum pregnancy test will be performed during Screening and a urine pregnancy test will be performed on 
Day 1 prior to dosing. A serum pregnancy test will also be repeated at End of Study/Early Termination. Additional pregnancy tests should be performed 
whenever one menstrual cycle is missed or when potential pregnancy is otherwise suspected.  Additional pregnancy tests may also be conducted as
requested by IRB/IECs or if required by local regulations.
10. Viral disease screening for hepatitis B surface antigen (HBsAg), hepatitis B core antibody (HBcAb), and hepatitis C antibody (HCVAb). HIV testing will
be performed unless prohibited by local regulations.
11. 12-Lead electrocardiograms are required at Screening and at End of Study/Early Termination.  ECGs should be performed after the patient has rested
quietly for at least 10 minutes. 
12. Diagnostic quality [18F]FDG-PET/CT or CT scan with contrast.  Scans acquired up to 8 weeks prior to Day 1 may be used for Screening provided they are 
of adequate quality for central imaging review.  The quality of the scan must be sufficient for accurate anatomical measurement of lymphoma lesions and 
for central review. PET/CT scans should be performed from the base of the skull to the proximal femurs; CT scans should include the neck, chest, 
abdomen, and pelvis. Patients for whom IV contrast is medically contraindicated should have an MRI of the neck, abdomen and pelvis and a non-contrast 
CT of the chest.
13. If the patient has not undergone an [18F]FDG-PET/CT, an [18F]FDG-PET scan from the base of the skull to the proximal femurs must be obtained at 
Screening. PET scans acquired up to 8 weeks prior to Day 1 may be used for Screening provided they are of adequate quality for central imaging review.  
For patients with positive findings at Screening who have not undergone PET/CT scans at the follow up visits, a second PET scan should be obtained 
during Follow-Up (Weeks 13-39) or at End of Study/Early Termination (Week 52) when a patient experiences a complete remission based on the 
investigator’s review of the CT scan results.  The follow-up PET should be performed within 4 weeks of the contrast enhanced CT.
14. Bone marrow biopsy or aspiration should be completed at Screening unless the patient has had a previous bone marrow biopsy or aspiration that was 
positive for bone marrow involvement. Bone marrow biopsies or aspirations done up to 12 weeks prior to Day 1 may be used for Screening. A second 
bone marrow biopsy is required during Follow-Up (Weeks 13-39) or at End of Study/Early Termination (Week 52) for patients who had bone marrow 
involvement at Screening and experience complete remission based on the investigator’s review of the CT scan results.  The follow-up bone marrow biopsy 
or aspiration should be performed within 4 weeks of the contrast enhanced PET/CT or CT.
15. On days where study drug is administered (Days 1, 8, 15, and 22), serum samples for measurement of drug concentrations will be collected prior to dose 
administration (within 4 hours of the start of dosing). On Days 1 and 22, additional drug concentration samples will also be collected within 15 minutes 
prior to the end of infusion.  Additionally, drug concentration samples will also be collected at Weeks 5 (Day 29), 13, 26, 39 and 52.
16. Blood samples for analysis of CD19+ B-cell counts will be collected prior to dose administration on Days 1, 8, 15, and 22.  Additional samples for analysis 
of CD19+ B-cell counts will be collected at Weeks 5 (Day 29), 13, 26, 39 and 52.

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17. Serum samples for detection of anti-drug antibodies (ADA) and neutralizing antibodies (Nab) will be collected within 4 hours prior to dose administration 
on Day 1 and Day 15.  Additional samples for detection of ADA and Nab will be collected at Weeks 5 (Day 29), 13, 26, 39, and 52. 
18. Premedication with 100 mg IV methylprednisolone or its equivalent prior to the start of the study drug infusion.  In addition, an anti-pyretic and an 
antihistamine (eg, paracetamol [acetaminophen] and diphenhydramine) should be administered before study drug infusion.  Any reduction in dose of 
premedications after the first infusion should be in compliance with local labeling and regulations.
19. The investigator or a qualified-designee must confirm and document that all patients or their partners who are biologically capable of having children and 
are sexually active are using a highly effective method of contraception listed in Section 4.4 consistently and correctly.

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TABLE OF CONTENTS
LIST OF TABLES...................................................................................................................25
APPENDICES .........................................................................................................................25
1. INTRODUCTION ...............................................................................................................26
1.1. Indication.................................................................................................................26
1.2. Background and Rationale ......................................................................................27
1.2.1. Rituximab ...................................................................................................27
1.2.1.1. Efficacy of Rituximab Monotherapy in Low Tumor 
Burden Follicular Lymphoma ...........................................................29
1.2.1.2. Safety of Rituximab ..................................................................30
1.2.1.3. Immunogenicity ........................................................................34
1.2.1.4. Pharmacokinetics ......................................................................35
1.2.1.5. Pharmacodynamics....................................................................35
1.2.2. Rituximab-Pfizer (PF-05280586)...............................................................36
1.2.3. Drug Product Similarity..............................................................................36
1.2.4. Rationale.....................................................................................................36
1.3. Single Reference Safety Document.........................................................................37
2. STUDY OBJECTIVES AND ENDPOINTS.......................................................................37
2.1. Objectives................................................................................................................37
2.1.1. Primary Objective.......................................................................................37
2.1.2. Secondary Objectives .................................................................................37
2.2. Endpoints.................................................................................................................37
2.2.1. Primary Endpoint........................................................................................37
2.2.2. Secondary Endpoints ..................................................................................37
3. STUDY DESIGN.................................................................................................................38
4. PATIENT SELECTION......................................................................................................39
4.1. Inclusion Criteria.....................................................................................................39
4.2. Exclusion Criteria....................................................................................................40
4.3. Randomization Criteria ...........................................................................................42
4.4. Life Style Guidelines...............................................................................................42
4.5. Sponsor Qualified Medical Personnel.....................................................................43
5. STUDY TREATMENTS.....................................................................................................43

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5.1. Allocation to Treatment ..........................................................................................43
5.2. Breaking the Blind ..................................................................................................44
5.3. Drug Supplies..........................................................................................................44
5.3.1. Formulation and Packaging........................................................................44
5.3.2. Preparation and Dispensing........................................................................45
5.3.2.1. Rituximab Infusion Preparation ................................................45
5.3.2.2. Pre-Medication for Rituximab Infusions...................................45
5.3.3. Rituximab Administration ..........................................................................45
5.3.4. Compliance.................................................................................................47
5.4. Drug Storage and Drug Accountability...................................................................47
5.5. Concomitant and Prohibited Medication(s) ............................................................48
6. STUDY PROCEDURES .....................................................................................................48
6.1. Screening (Visit 1 - Study Days -56 to 0) ...............................................................48
6.2. Study Period ............................................................................................................50
6.2.1. Day 1 Visit (Visit 2) ...................................................................................50
6.2.2. Treatment Visits (Visits 3, 4, and 5 - Study Days 8, 15, and 22)...............51
6.2.3. Follow-up Visits (Visits 6, 7, 8, and 9 – Weeks 5, 13, 26, and 39)............51
6.2.4. End of Study/Early Termination Visit (Visit 10 - Week 52)......................52
6.3. Patient Withdrawal..................................................................................................54
7. ASSESSMENTS..................................................................................................................54
7.1. Efficacy Assessments..............................................................................................54
7.2. Safety Assessments .................................................................................................55
7.2.1. Physical Examination .................................................................................55
7.2.1.1. Complete Physical Examination ...............................................55
7.2.1.2. Targeted Physical Examination.................................................55
7.2.2. Vital Signs ..................................................................................................56
7.2.3. ECOG Performance Status .........................................................................56
7.2.4. Clinical Laboratory Tests ...........................................................................56
7.2.5. Viral Disease Screening..............................................................................57
7.2.6. Pregnancy Testing ......................................................................................57
7.2.7. Electrocardiogram.......................................................................................58
7.2.8. Adverse Events ...........................................................................................58

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7.3. Pharmacokinetic Assessments.................................................................................58
7.4. Immunogenicity Assessments.................................................................................58
7.5. Pharmacodynamic Assessments..............................................................................58
7.6. Histopathological Review of Diagnostic Tissue .....................................................59
8. ADVERSE EVENT REPORTING......................................................................................59
8.1. Adverse Events........................................................................................................59
8.2. Reporting Period .....................................................................................................59
8.3. Definition of an Adverse Event...............................................................................60
8.4. Abnormal Test Findings..........................................................................................61
8.5. Serious Adverse Events...........................................................................................61
8.5.1. Protocol-Specified Serious Adverse Events...............................................62
8.5.2. Potential Cases of Drug-Induced Liver Injury............................................62
8.6. Hospitalization ........................................................................................................63
8.7. Severity Assessment................................................................................................64
8.8. Causality Assessment..............................................................................................65
8.9. Exposure During Pregnancy....................................................................................65
8.10. Occupational Exposure .........................................................................................67
8.11. Withdrawal Due to Adverse Events (See Also the Section on Patient 
Withdrawal)...............................................................................................................67
8.12. Eliciting Adverse Event Information ....................................................................67
8.13. Reporting Requirements........................................................................................67
8.13.1. Serious Adverse Event Reporting Requirements .....................................67
8.13.2. Non-Serious Adverse Event Reporting Requirements .............................68
8.13.3. Sponsor’s Reporting Requirements to Regulatory Authorities ................68
9. DATA ANALYSIS/STATISTICAL METHODS...............................................................68
9.1. Sample Size Determination.....................................................................................68
9.2. Analysis Population.................................................................................................69
9.2.1. Intent-to-Treat Population ..........................................................................69
9.2.2. Per-Protocol Population..............................................................................69
9.2.3. Safety Population........................................................................................69
9.3. Efficacy Analysis ....................................................................................................69
9.3.1. Analysis of Primary Endpoint ....................................................................69

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9.3.2. Analysis of Other Efficacy Endpoints ........................................................70
9.3.2.1. Time to Treatment Failure.........................................................70
9.3.2.2. Progression Free Survival .........................................................70
9.3.2.3. Complete Remission at Week 26 ..............................................71
9.3.2.4. Duration of Response................................................................71
9.3.2.5. Overall Survival ........................................................................71
9.4. Safety Analysis........................................................................................................71
9.5. Pharmacokinetics, Biomarkers and Immunogenicity..............................................72
9.5.1. Pharmacokinetics Analysis.........................................................................72
9.5.2. Biomarker Analysis ....................................................................................72
9.5.3. Immunogenicity..........................................................................................72
9.6. Other Endpoints.......................................................................................................73
9.7. Interim Analysis ......................................................................................................73
9.8. External Data Monitoring Committee.....................................................................73
10. QUALITY CONTROL AND QUALITY ASSURANCE.................................................73
11. DATA HANDLING AND RECORD KEEPING .............................................................74
11.1. Case Report Forms/Electronic Data Record .........................................................74
11.2. Record Retention...................................................................................................74
12. ETHICS..............................................................................................................................75
12.1. Institutional Review Board (IRB)/Independent Ethics Committee (IEC) ............75
12.2. Ethical Conduct of the Study ................................................................................75
12.3. Patient Information and Consent...........................................................................75
12.4. Patient Recruitment...............................................................................................76
12.5. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH 
GCP ...........................................................................................................................76
13. DEFINITION OF END OF TRIAL...................................................................................76
13.1. End of Trial in a Member......................................................................................76
13.2. End of Trial in all Participating Countries ............................................................76
14. SPONSOR DISCONTINUATION CRITERIA ................................................................77
15. PUBLICATION OF STUDY RESULTS..........................................................................77
15.1. Communication of Results by Pfizer ....................................................................77
15.2. Publications by Investigators ................................................................................78

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16. REFERENCES ..................................................................................................................79
LIST OF TABLES
Table 1.
ECOG Performance Status Definitions ................................................................56
Table 2.
Required Laboratory Tests ...................................................................................57
APPENDICES
Appendix 1. Ann Arbor Staging System .................................................................................80
Appendix 2. Follicular Lymphoma International Prognostic Index (FLIPI)...........................81
Appendix 3. Revised Response Criteria for Malignant Lymphoma (2007)............................82

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1. INTRODUCTION
PF-05280586 (hereafter designated rituximab-Pfizer) is being developed as a potential 
biosimilar to rituximab. Rituximab is approved for two broad indications: musculoskeletal 
and connective tissue diseases and B-cell malignancies.  Rituximab is an effective therapy for 
the treatment of patients with CD-20 positive, B-cell malignancies.1,2 Rituxan® is the 
commercially available product in the United States and will be referred to as rituximab-US; 
MabThera® is the commercially available product in the European Union and will be referred 
to as rituximab-EU.  In Japan the commercially available product is Rituxan®.
Rituximab is a chimeric monoclonal antibody comprised of a human IgG1K Fc region and a 
murine variable region that binds specifically to human CD20.  Rituximab contains 2 heavy 
(H) chains, each comprising 451 amino acids and 2 kappa light (L) chains each comprising of 
213 amino acids, which are disulfide-bonded to form a 4-chain molecule (H2L2).  
Rituximab-Pfizer has the same primary amino acid sequence as the commercially available
rituximab product.
The term “biosimilar” refers to a biologic drug that is developed to be highly similar to an 
existing licensed reference biologic. Biosimilars are intended to treat the same diseases as 
the reference biologic using the same dose and treatment regimen. Unlike generic versions 
of chemically-synthesized small molecule therapies, biosimilars are not structurally identical 
to their reference biologic. This is due to the purity, characteristics, and activity of a specific 
biologic being dependent on, and sensitive to changes in the process by which it was 
manufactured. Therefore, the aim is to create a product with no clinically meaningful 
differences between the biosimilar and the reference biologic in terms of chemistry, 
manufacturing, and controls (CMC), purity, potency, pharmacokinetics (PK), safety, 
immunogenicity, and efficacy.
The demonstration of similarity in efficacy between a biosimilar and the innovator product is 
an essential component of a clinical trial program that collectively provides the evidence of 
biosimilarity. The current study will evaluate the efficacy, safety, PK, and immunogenicity 
of rituximab-Pfizer in patients with low tumor burden (LTB), CD20-positive, follicular 
lymphoma (FL) in the first-line treatment setting.
Throughout this clinical trial protocol, PF-05280586 is referred to as rituximab-Pfizer, 
however, biosimilarity has not yet been established and is not claimed. Likewise, the general 
term rituximab is sometimes used for convenience when discussing the 2 blinded study 
treatments but is not a claim of biosimilarity.  Biosimilarity will be supported by analytical, 
non-clinical, clinical PK, pharmacodynamic (PD), safety and efficacy studies.
1.1. Indication
CD-20 positive, B-cell non-Hodgkin’s Lymphoma (NHL) is a heterogeneous group of 
malignancies with varying clinical outcomes.3 Classification of NHL is extremely complex 
and has undergone extensive revisions to include morphological, immunophenotypical, 
genetic, and clinical characteristics. This diverse set of diseases is characterized by varied 
pathogeneses and clinical outcomes that make management of NHL clinically challenging. 

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The risk of mortality from NHL depends on whether it is indolent or aggressive; indolent 
forms of NHL, such as follicular lymphoma (FL), have significantly better prognosis than 
more aggressive forms like diffuse large B cell lymphoma (DLBCL) and mantle cell 
lymphoma (MCL). 
The current standard of care in advanced follicular lymphoma is rituximab in combination 
with chemotherapy.  The indication for this study, anatomically defined, low tumor burden, 
CD-20 positive, follicular lymphoma, is a slow growing malignancy and rituximab 
monotherapy is an acceptable treatment option according to various treatment guidelines.5,6  
The goal of treatment with rituximab monotherapy in LTB-FL is to relieve disease 
symptoms, to delay the time to more difficult to tolerate treatments such as chemotherapy, 
and to relieve the patient’s anxiety related to disease.
To select patients appropriate for treatment with rituximab monotherapy in accordance with 
various international treatment guidelines, including NCCN and ESMO,5,6 the study will 
enroll patients with low tumor burden follicular lymphoma who are asymptomatic for 
lymphoma specific B-symptoms.
Low tumor burden will be assessed according to the Groupe d’Etude des Lymphomes 
Folliculaires (GELF) criteria.6  Clinically non-significant elevations in serum LDH or
-2 microglobulin (1.5 times upper limit of normal) at Screening will be allowed.  These 
patient eligibility criteria are similar to other recent randomized studies conducted with 
rituximab monotherapy in low tumor burden follicular lymphoma.7,8
The current study will evaluate the efficacy, safety, pharmacokinetics, and immunogenicity 
of rituximab-Pfizer versus rituximab-EU in patients with CD20-positive, low tumor burden 
follicular lymphoma (LTB-FL) in the first-line treatment setting.  Using rituximab 
monotherapy allows the assessment of biosimilarity without the potentially confounding 
factors that would be introduced by combining rituximab with chemotherapy in more 
advanced stage patients; this is particularly important for the assessment of comparative 
immunogenicity.
Pfizer has conferred with regulatory agencies in the US, EU, and Japan and has determined 
that treatment of patients with LTB-FL in the first line setting is acceptable in the context of 
a comparative trial of biosimilarity.
1.2. Background and Rationale
1.2.1. Rituximab
Rituximab is a chimeric monoclonal antibody comprised of a human IgG1K Fc region and a 
murine variable region that binds specifically to human CD20. Rituximab is approved for 
the treatment of CD20-positive B-cell malignancies.  It is estimated that over 
500,000 patients with B cell lymphoma or leukemia have been treated with rituximab since 
market availability.  Further information is contained within both the Investigators’ Brochure 
(IB), and public information including the Summary of Product Characteristics for 
MabThera.

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According to the rituximab prescribing information, the mechanism of action across the 
oncology indications is believed to be that rituximab binds specifically to the antigen 
CD20 (human B-lymphocyte-restricted differentiation antigen, Bp35).  The antigen, a 
hydrophobic transmembrane protein located on pre-B and mature B lymphocytes, is 
expressed on 90% of B-cell NHL.  CD20 is not found on hematopoietic stem cells, 
pro-B-cells, normal plasma cells, or other normal tissues.  CD20 regulates an early step(s) in 
the activation process for cell cycle initiation and differentiation, and possibly functions as a 
calcium ion channel.  Free CD20 is not found in circulating blood.
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) and 
antibody-dependent cell mediated cytotoxicity (ADCC).  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.
Multiple clinical trials were conducted that allowed approval of multiple indications within 
CD20-positive B-cell malignancies for rituximab. Indications for the use of rituximab as a 
single agent in FL that appear to be uniform across multiple regions including the US, EU, 
and Japan include:

Relapsed or refractory, low-grade or follicular, CD20-positive, B-cell NHL;

Maintenance therapy in patients achieving a complete or partial response to Rituxan 
in combination with chemotherapy;

Non-progressing (including stable disease), low-grade, CD20-positive, B-cell NHL 
after first-line CVP chemotherapy.
Many patients with follicular lymphoma present with advanced, but asymptomatic disease. 
Several randomized, controlled trials have shown there is no benefit in overall survival to 
treating these subjects with chemotherapy immediately. Therefore, many of these patients 
are followed (watchful waiting) rather than treated immediately. However, these older 
studies all evaluated toxic chemotherapeutic regimens. The use of single-agent rituximab has 
the potential to serve as a useful alternative to watchful waiting by delaying the time to 
initiation of chemotherapy. A recent study evaluated the use of 4 weekly doses of 
375 mg/m2 of rituximab and demonstrated a delay in the time to next treatment.7 The 
estimated median time to initiation of new therapy for watchful waiting in this study was 
33 months, similar to a previous trial of watchful waiting.9 The time to initiation of new 
therapy was significantly longer in the rituximab monotherapy arm (p value of log-rank test 
<0.001) and the median time had not been reached at 4 years. While the use of rituximab 
monotherapy as a first-line treatment of LTB-FL is not indicated in the US or EU, it is an 
acceptable treatment option4,5 and has the potential to replace watchful waiting as the 
treatment of choice for asymptomatic, low tumor burden FL patients.

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1.2.1.1. Efficacy of Rituximab Monotherapy in Low Tumor Burden Follicular 
Lymphoma
For patients with asymptomatic, advanced stage, follicular lymphoma, immediate 
chemotherapy when compared with a watch and wait approach shows no benefit. Deferring 
chemotherapy spares the patient of the side effects of the chemotherapy. Rituximab has a 
favorable side effect profile compared to chemotherapy, so a study was conducted to 
compare a watchful waiting approach versus immediate treatment with rituximab in patients 
with low tumor burden follicular lymphoma (LTB-FL).7
Adult patients with asymptomatic Stage II, III or IV follicular lymphoma (Grades 1–2 & 3a) 
were randomly assigned in a ratio of 1:1:1 to watchful waiting (Arm A), rituximab 
375 mg/m2 weekly for 4 weeks (Arm B) or rituximab 375 mg/m2 weekly for 4 weeks 
followed by rituximab maintenance every 2 months for 2 years (from Month 3 to Month 25)
(Arm C). The primary endpoints were time to initiation of new therapy (chemotherapy or 
radiotherapy) and effect on quality of life. After an interim analysis, the rituximab without 
maintenance group (Arm B) was discontinued.  Overall response rate was assessed by 
investigators using the 1999 Response Criteria for Lymphoma10 at Month 7, 13 and 25.
There were 463 patients who were randomized (187 Arm A, 84 Arm B, and 192 Arm C) with
95% of patients having low tumor burden by GELF criteria.  The other 5% had raised LDH 
but fulfilled the remaining GELF criteria. Responses were assessed at Months 7, 13 and 25.  
At Month 7, Arm A had a spontaneous remission rate (CR)=2% and a PR=4%, (ORR=6%).  
Arm B had a CR+CRu=47% and a PR=30% (ORR=77%). Arm C had a CR+CRu=59% and 
a PR=29% (ORR=88%). The estimated median time to initiation of new therapy in Arm A 
was 33 months.
There was a significant difference observed in the time to start of new treatment, with 46% 
(95% CI 39–53) of patients in the watchful waiting group not needing treatment at 3 years 
compared with 88% (83–92) in the maintenance rituximab group (hazard ratio [HR] 0.21, 
95% CI 0.14–0.31; p<0.0001).  78% (95% CI 69–87) of patients in the rituximab induction 
group did not need treatment at 3 years, which was significantly more than in the watchful 
waiting group (HR 0.35, 95% CI 0.22–0.56; p<0.0001), but no different compared with the 
maintenance rituximab group (0.75, 0.41–1.34; p=0.33).  These data indicate that initial 
treatment with rituximab significantly delays the need for new therapy.
Another study, RESORT, looked at the role of maintenance therapy in patients with LTB-FL 
who received single agent rituximab.8 Patients received 4 doses of rituximab (375 mg/m2) 
and responders were randomized to maintenance rituximab (MR - single dose rituximab
every 3 months) or rituximab retreatment (RR - rituximab weekly x 4 at disease progression).  
Each strategy was continued until treatment failure and the primary endpoint was time to 
treatment failure (TTF).  There were 384 patients enrolled. Complete or partial response was 
achieved in 274 patients (71%), who were then randomized to MR (n=140) or RR (n=134).  
The mean number of rituximab doses/patient (including the 4 induction doses) was 
15.8 (range 5- 31) for MR and 4.5 (range 4-16) for RR. With a median follow-up of 3.8 yrs, 
TTF was 3.9 years for MR versus 3.6 years for RR (p=NS). At 12 months post 
randomization, there was no discernible difference in health related quality of life and 

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anxiety between the two arms. This study suggested that there was no advantage of 
rituximab maintenance therapy over rituximab treatment at progression after rituximab 
induction treatment in LTB-FL.
1.2.1.2. Safety of Rituximab
The safety profile of rituximab is described in the Summary of Product Characteristics (SPC) 
for MabThera (rituximab).2
Rituximab is contraindicated in patients with hypersensitivity to the active substance or to 
any of the excipients or to murine proteins.
According to the SPC the following (as abstracted) are special warnings and precautions for 
use in patients with non-Hodgkin’s lymphoma:
Infusion related adverse reactions including cytokine release syndrome accompanied by 
hypotension and bronchospasm have been observed in 10 % of patients treated with 
MabThera.  These symptoms are usually reversible with interruption of MabThera infusion 
and administration of an anti-pyretic, an antihistaminic, and, occasionally, oxygen, 
intravenous saline or bronchodilators, and glucocorticoids if required.
Anaphylactic and other hypersensitivity reactions have been reported following the 
intravenous administration of proteins to patients.  In contrast to cytokine release syndrome, 
true hypersensitivity reactions typically occur within minutes after starting infusion.  
Medicinal products for the treatment of hypersensitivity reactions, eg, epinephrine 
(adrenaline), antihistamines and glucocorticoids, should be available for immediate use in 
the event of an allergic reaction during administration of MabThera.
Clinical manifestations of anaphylaxis may appear similar to clinical manifestations of the 
cytokine release syndrome.  Reactions attributed to hypersensitivity have been reported less 
frequently than those attributed to cytokine release.
Since hypotension may occur during MabThera infusion, consideration should be given to 
withholding anti-hypertensive medicines 12 hours prior to the MabThera infusion.
Angina pectoris, or cardiac arrhythmias such as atrial flutter and fibrillation heart failure or 
myocardial infarction have occurred in patients treated with MabThera.  Therefore patients 
with a history of cardiac disease and/or cardiotoxic chemotherapy should be monitored 
closely.
Very rare cases of hepatitis B reactivation have been reported in subjects receiving
rituximab including fulminant hepatitis with fatal outcome.  The majority of these subjects 
were also exposed to cytotoxic chemotherapy.  The reports are confounded by both the 
underlying disease state and the cytotoxic chemotherapy.  Patients with a history of hepatitis 
B infection should be carefully monitored for signs of active hepatitis B infection.
Very rare cases of Progressive Multifocal Leukoencephalopathy (PML) have been reported 
during post-marketing use of MabThera in NHL.  The majority of patients had received 
rituximab in combination with chemotherapy or as part of a hematopoietic stem cell 

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transplant.  Physicians treating patients with non-Hodgkin’s lymphoma should consider 
PML in the differential diagnosis of patients reporting neurological symptoms and 
consultation with a Neurologist should be considered as clinically indicated.
The safety of immunization with any vaccine, particularly live viral vaccines, following 
MabThera therapy has not been studied.  The ability to generate a primary or anamnestic 
humoral response to any vaccine has also not been studied.
Pregnancy
IgG immunoglobulins are known to cross the placental barrier.  B cell levels in human 
neonates following maternal exposure to MabThera have not been studied in clinical trials.  
There are no adequate and well-controlled data from studies in pregnant women, however 
transient B-cell depletion and lymphocytopenia have been reported in some infants born to 
mothers exposed to rituximab during pregnancy.  For these reasons MabThera/Rituxan 
should not be administered to pregnant women unless the possible benefit outweighs the 
potential risk.
Due to the long retention time of rituximab in B cell depleted patients, women of 
childbearing potential should use effective contraceptive methods during treatment and for 
12 months following MabThera therapy.
Developmental toxicity studies performed in cynomolgus monkeys revealed no evidence of 
embryotoxicity in utero.  New born offspring of maternal animals exposed to MabThera were 
noted to have depleted B cell populations during the post natal phase.
Lactation
Whether rituximab is excreted in human milk is not known.  However, because maternal IgG 
is excreted in human milk, and rituximab was detectable in milk from lactating monkeys, 
women should not breastfeed while treated with MabThera and for 12 months following 
MabThera treatment.
Effects on ability to drive and use machines
No studies on the effects of MabThera on the ability to drive and use machines have been 
performed, although the pharmacological activity and adverse events reported to date do not 
indicate that such an effect is likely.
Overall safety profile of MabThera in non-Hodgkin’s lymphoma
The overall safety profile of MabThera in non-Hodgkin’s lymphoma is based on data from 
patients from clinical trials and from post-marketing surveillance.  These patients were 
predominantly treated either with MabThera monotherapy (as induction treatment or 
maintenance treatment following induction treatment) or in combination with chemotherapy.

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The most frequently observed adverse drug reactions (ADRs) in patients receiving MabThera 
were infusion-related reactions which occurred in the majority of patients during the first 
infusion.  The incidence of infusion-related symptoms decreases substantially with 
subsequent infusions and is less than 1% after eight doses of MabThera.
Infectious events (predominantly bacterial and viral) occurred in approximately 30-55 % of 
patients during clinical trials in patients with NHL.
The most frequent reported or observed serious adverse drug reactions were infusion-related 
reactions (including cytokine-release syndrome, tumour-lysis syndrome), infections, and 
cardiovascular events.  Other serious ADRs reported include hepatitis B reactivation and 
PML.
The frequencies of ADRs reported with MabThera alone or in combination with 
chemotherapy are summarized in the SPC. 
Infusion-related reactions
Signs and symptoms suggestive of an infusion-related reaction were reported in more than 
50% of patients in clinical trials, and were predominantly seen during the first infusion, 
usually in the first one to two hours.  These symptoms mainly comprised fever, chills and 
rigors.  Other symptoms included flushing, angioedema, bronchospasm, vomiting, nausea, 
urticaria/rash, fatigue, headache, throat irritation, rhinitis, pruritus, pain, tachycardia, 
hypertension, hypotension, dyspnoea, dyspepsia, asthenia and features of tumor lysis 
syndrome.  Severe infusion-related reactions (such as bronchospasm, hypotension) occurred 
in about 10 % of the cases.  Additional reactions reported in some cases were myocardial 
infarction, atrial fibrillation and pulmonary oedema.  Exacerbations of pre-existing cardiac 
conditions such as angina pectoris or congestive heart failure or severe cardiac events (heart 
failure, myocardial infarction, atrial fibrillation), pulmonary oedema, multi-organ failure, 
tumour lysis syndrome, cytokine release syndrome, renal failure, and respiratory failure 
were reported at lower or unknown frequencies.  The incidence of infusion-related symptoms 
decreased substantially with subsequent infusions and is <1 % of patients by the eighth cycle 
of MabThera-containing treatment.
Infections
MabThera induces B-cell depletion in about 70-80% of patients, but was associated with 
decreased serum immunoglobulins only in a minority of patients.
Localized candida infections as well as Herpes zoster was reported at a higher incidence in 
the MabThera-containing arm of randomized studies.  Severe infections were reported in 
about 4% of patients.  Higher frequencies of infections overall, including grade 3 or 
4 infections, were observed during MabThera maintenance treatment up to 2 years when 
compared to observation.  There was no cumulative toxicity in terms of infections reported 
over a 2-year treatment period.  In addition, other serious viral infections either new, 
reactivated or exacerbated, some of which were fatal, have been reported with MabThera 
treatment.  The majority of patients had received MabThera in combination with 

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chemotherapy or as part of a hematopoetic stem cell transplant.  Examples of these serious 
viral infections are infections caused by the herpes viruses (Cytomegalovirus, Varicella 
Zoster Virus and Herpes Simplex Virus), JC virus (progressive multifocal 
leukoencephalopathy (PML)) and hepatitis C virus.  Cases of hepatitis B reactivation, have 
been reported, the majority of which were in subjects receiving MabThera in combination 
with cytotoxic chemotherapy.  Progression of Kaposi’s sarcoma has been observed in 
rituximab-exposed patients with pre-existing Kaposi’s sarcoma.  These cases occurred in 
non-approved indications and the majority of patients were HIV positive.
Haematologic Adverse Reactions
In clinical trials with MabThera monotherapy given for 4 weeks, haematological 
abnormalities occurred in a minority of patients and were usually mild and reversible.  
Severe (grade 3/4) neutropenia was reported in 4.2 %, anaemia in 1.1 % and 
thrombocytopenia in 1.7 % of the patients.  During MabThera maintenance treatment for up 
to 2 years, leucopenia (5% vs 2%, grade 3/4) and neutropenia (10% vs.4%, grade 3/4) were 
reported at a higher incidence when compared to observation.  The incidence of 
thrombocytopenia was low (<1, grade 3/4%) and was not different between treatment arms.  
In studies with MabThera in combination with chemotherapy, grade 3/4 leucopenia (88% vs 
79%), neutropenia (R-CVP 24% vs CVP 14%; R-CHOP 97% vs. CHOP 88%) were reported 
higher frequencies when compared to chemotherapy alone.  However, the higher incidence 
of neutropenia in patients treated with MabThera and chemotherapy was not associated with 
a higher incidence of infections and infestations compared to patients treated with 
chemotherapy alone and the neutropenia was not prolonged in the MabThera group. There 
were no differences reported for the incidence of thrombocytopenia or anaemia.  Some cases 
of late neutropenia occurring more than four weeks after the last infusion of MabThera were 
reported.
Cardiovascular reactions
Cardiovascular reactions during clinical trials with MabThera monotherapy were reported 
in 18.8 % of patients with the most frequently reported events being hypotension and 
hypertension.  Cases of grade 3 or 4 arrhythmia (including ventricular and supraventricular 
tachycardia) and angina pectoris during infusion were reported.  During maintenance 
treatment, the incidence of grade 3/4 cardiac disorders was comparable between patients 
treated with MabThera and observation.  Cardiac events were reported as serious adverse 
events (including atrial fibrillation, myocardial infarction, left ventricular failure, 
myocardial ischemia) in 3 % of patients treated with MabThera compared to <1% on 
observation.  In studies evaluating MabThera in combination with chemotherapy, the 
incidence of grade 3 and 4 cardiac arrhythmias, predominantly supraventricular 
arrhythmias such as tachycardia and atrial flutter/fibrillation, was higher in the R-CHOP 
group (14 patients, 6.9 %) as compared to the CHOP group (3 patients, 1.5 %).  All of these 
arrhythmias either occurred in the context of a MabThera infusion or were associated with 
predisposing conditions such as fever, infection, acute myocardial infarction or pre-existing 
respiratory and cardiovascular disease.

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Neurologic events
During the treatment period, four patients (2 %) treated with R-CHOP, all with 
cardiovascular risk factors, experienced thromboembolic cerebrovascular accidents during 
the first treatment cycle.  There was no difference between the treatment groups in the 
incidence of other thromboembolic events.  In contrast, three patients (1.5 %) had 
cerebrovascular events in the CHOP group, all of which occurred during the follow-up 
period.
Gastrointestinal Disorders
Gastrointestinal perforation in some cases leading to death has been observed in patients 
receiving MabThera for treatment of non Hodgkin’s lymphoma.  In the majority of these 
cases, MabThera was administered with chemotherapy.
IgG levels
In the clinical trial evaluating MabThera maintenance treatment, median IgG levels were 
below the lower limit of normal (LLN) (<7 g/L) after induction treatment in both the 
observation and the MabThera groups.  In the observation group, the median IgG level 
subsequently increased to above the LLN, but remained constant in the MabThera group.  
The proportion of patients with IgG levels below the LLN was about 60% in the MabThera 
group throughout the 2 year treatment period, while it decreased in the observation group 
(36 % after 2 years).
Elderly patients (≥65 years):
The incidence of ADRs of all grades and grade 3 /4 ADR was similar in elderly patients 
compared to younger patients (<65 years).
1.2.1.3. Immunogenicity
Immunogenicity of rituximab is discussed in the US Prescribing information for Rituxan®
(rituximab).
As with all therapeutic proteins, there is a potential for immunogenicity.  The observed 
incidence of antibody (including neutralizing antibody) positivity in an assay is highly 
dependent on several factors including assay sensitivity and specificity, assay methodology, 
sample handling, timing of sample collection, 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. 
Using an ELISA assay, anti-human anti-chimeric antibody (HACA) was detected in 4 of 
356 (1.1%) patients with low-grade or follicular NHL receiving single-agent Rituxan.  Three 
of the four patients had an objective clinical response. 

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1.2.1.4. Pharmacokinetics
The pharmacokinetics of rituximab are described in the MabThera SPC.
Based on a population pharmacokinetic analysis in 298 NHL patients who received single or 
multiple infusions of rituximab as a single agent or in combination with CHOP therapy 
(applied rituximab doses ranged from 100 to 500 mg/m2), the typical population estimates of 
nonspecific clearance (CL1), specific clearance (CL2) likely contributed by B cells or tumor 
burden, and central compartment volume of distribution (V1) were 0.14 L/day, 0.59 L/day, 
and 2.7 L, respectively.  The estimated median terminal elimination half-life of rituximab was 
22 days (range, 6.1 to 52 days).  Baseline CD19-positive cell counts and size of measurable 
tumor lesions contributed to some of the variability in CL2 of rituximab in data from 
161 patients given 375 mg/m2 as an intravenous infusion for 4 weekly doses.  Patients with 
higher CD19-positive cell counts or tumor lesions had a higher CL2.  However, a large 
component of inter-individual variability remained for CL2 after correction for 
CD19-positive cell counts and tumor lesion size.  V1 varied by body surface area (BSA) and 
CHOP therapy.  This variability in V1 (27.1% and 19.0%) contributed by the range in BSA 
(1.53 to 2.32 m2) and concurrent CHOP therapy, respectively, were relatively small.  Age, 
gender and WHO performance status had no effect on the pharmacokinetics of rituximab.  
This analysis suggests that dose adjustment of rituximab with any of the tested covariates is 
not expected to result in a meaningful reduction in its pharmacokinetic variability.
Rituximab, administered as an intravenous infusion at a dose of 375 mg/m2 at weekly 
intervals for 4 doses to 203 patients with NHL naive to rituximab, yielded a mean Cmax 
following the fourth infusion of 486 μg/mL (range, 77.5 to 996.6 μg/mL).  Rituximab was 
detectable in the serum of patients 3 – 6 months after completion of last treatment.  Upon 
administration of rituximab at a dose of 375 mg/m2 as an intravenous infusion at weekly 
intervals for 8 doses to 37 patients with NHL, the mean Cmax increased with each successive 
infusion, spanning from a mean of 243 μg/mL (range, 16 – 582 μg/mL) after the first infusion 
to 550 μg/mL (range, 171 – 1177 μg/mL) after the eighth infusion.
1.2.1.5. Pharmacodynamics
The following is a reprint of the information pertaining to rituximab-EU pharmacodynamics 
in patients with NHL in the MabThera SPC:
Rituximab binds specifically to the transmembrane antigen, CD20, a non-glycosylated 
phosphoprotein, located on pre-B and mature B lymphocytes.  The antigen is expressed on 
>95% of all B cell non-Hodgkin’s lymphomas.
CD20 is found on both normal and malignant B cells, but not on haematopoietic stem cells, 
pro-B cells, normal plasma cells or other normal tissue.  This antigen does not internalise 
upon antibody binding and is not shed from the cell surface.  CD20 does not circulate in the 
plasma as a free antigen and, thus, does not compete for antibody binding.
The Fab domain of rituximab binds to the CD20 antigen on B lymphocytes and the Fc 
domain can recruit immune effector functions to mediate B cell lysis.  Possible mechanisms 
of effector-mediated cell lysis include complement-dependent cytotoxicity (CDC) resulting 

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from C1q binding, and antibody-dependent cellular cytotoxicity (ADCC) mediated by one or 
more of the Fcγ receptors on the surface of granulocytes, macrophages and NK cells.  
Rituximab binding to CD 20 antigen on B lymphocytes has also been demonstrated to induce 
cell death via apoptosis.
Peripheral B cell counts declined below normal following completion of the first dose of 
MabThera.  In patients treated for hematological malignancies, B cell recovery began within 
6 months of treatment and generally returned to normal levels within 12 months after 
completion of therapy, although in some patients this may take longer (up to a median 
recovery time of 23 months post-induction therapy).
1.2.2. Rituximab-Pfizer (PF-05280586)
Rituximab-Pfizer (PF-05280586) is an investigational, genetically engineered chimeric
mouse/human IgG1 monoclonal antibody (mAb) directed against the CD20 antigen.  
Rituximab-Pfizer contains 2 heavy (H) chains, each comprising 451 amino acids and 2 kappa
light (L) chains each comprising of 213 amino acids, which are disulfide-bonded to form a
4-chain molecule (H2L2). Rituximab-Pfizer has the same primary amino acid sequence as
rituximab-EU (MabThera) and rituximab-US (Rituxan) and is being developed to be similar
to the licensed products. Reference the PF-05280586 Investigator’s Brochure (IB) for further 
details.
 
1.2.3. Drug Product Similarity
The development of rituximab-Pfizer has focused on molecular and functional similarity to
rituximab-EU.  The physicochemical and functional characterization has demonstrated a high 
degree of similarity between these products as described in the Investigator’s Brochure.  
Reference the IB for further definition of parameters and most recent information on product 
characterization.
1.2.4. Rationale
The evaluation of efficacy and safety (including immunogenicity assessment) between a 
biosimilar and the innovator product is an essential component of an efficient clinical trial 
program collectively providing the evidence of biosimilarity.  The current study will compare 
CCI

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the efficacy, safety, pharmacokinetics, and immunogenicity of rituximab-Pfizer in patients 
with low tumor burden (LTB), CD20-positive, follicular lymphoma (FL) in the first-line 
treatment setting.  While the use of rituximab monotherapy as first-line treatment of LTB-FL 
is not indicated in the US or EU, it is a standard of care (SOC)4,5 and has the potential to 
replace watchful waiting as the treatment of choice for asymptomatic, low tumor burden FL 
patients.
1.3. Single Reference Safety Document
Complete information for this compound may be found in the Single Reference Safety 
Document (SRSD), which for this study is the Investigator’s Brochure. The Single 
Reference Safety Document for the comparator agent is the Summary of Product
Characteristics (SPC) for MabThera.2
2. STUDY OBJECTIVES AND ENDPOINTS
2.1. Objectives
2.1.1. Primary Objective

To compare the efficacy of rituximab-Pfizer to rituximab-EU when administered as a 
first-line treatment to patients with CD20-positive, low tumor burden follicular 
lymphoma (LTB-FL). 
2.1.2. Secondary Objectives

To evaluate the safety of rituximab-Pfizer and rituximab-EU.

To evaluate the population pharmacokinetics of rituximab-Pfizer and rituximab-EU.

To evaluate the immunogenicity of rituximab-Pfizer and rituximab-EU.

To characterize CD19-positive B-cell depletion and recovery in patients receiving 
rituximab-Pfizer and rituximab-EU.
2.2. Endpoints
2.2.1. Primary Endpoint

Overall Response Rate (ORR) at Week 26 of rituximab-Pfizer and rituximab-EU 
based on central review in accordance with the revised response criteria for malignant 
lymphoma.11
2.2.2. Secondary Endpoints

Safety characterized by type, incidence, severity, timing, seriousness, and relationship 
to study therapy of adverse events and laboratory abnormalities.

Time to Treatment Failure (TTF).

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
Progression-Free Survival (PFS).

Complete Remission (CR) rate at Week 26.

Duration of response.

Overall survival.

Peak and trough drug concentrations.

CD19-positive B-cell counts.

Incidence of anti-drug antibodies (ADA), including neutralizing antibodies (NAb), 
and safety associated with immune response.
3. STUDY DESIGN
This is a double-blind, randomized, Phase 3 clinical trial evaluating the efficacy, safety, PK 
and immunogenicity of rituximab-Pfizer versus rituximab-EU in patients with 
CD20-positive, low tumor burden, follicular lymphoma in the first-line treatment setting.
The study will enroll patients with low tumor burden follicular lymphoma who are 
asymptomatic for lymphoma specific B-symptoms.  Low tumor burden will be assessed 
according to the Groupe d’Etude des Lymphomes Folliculaires (GELF) criteria.6 Clinically 
non-significant elevations in serum LDH or -2 microglobulin (1.5 times upper limit of 
normal) at Screening will be allowed.  These patient eligibility criteria are similar to other 
recent randomized studies conducted with rituximab monotherapy in low tumor burden 
follicular lymphoma.7,8
Retrospective histological confirmation of CD20-positive FL will be obtained by a central 
pathology review.  Central imaging review will be performed for all disease assessments up 
through Week 52.  The primary endpoint is Overall Response Rate (ORR) at Week 26 in 
accordance with the revised response criteria for malignant lymphoma.11 Secondary 
endpoints include safety, TTF, PFS, CR, duration of response, OS, selected peak and trough 
drug concentrations, CD19-positive B-cell depletion, and immunogenicity.
Approximately 394 Patients will be randomized in a 1:1 ratio to receive rituximab-Pfizer or 
rituximab-EU.  Randomization will be stratified by low, medium, and high risk patients using 
the Follicular Lymphoma International Prognostic Index 2 (FLIPI2).12 During the study, 
patients will receive 4 weekly doses of rituximab-Pfizer or rituximab-EU administered via 
intravenous infusion.  The dose of rituximab-Pfizer or rituximab-EU will be 375 mg/m2 of 
body surface area.  The maximum dose that can be administered is 1125 mg. 
Safety will be reviewed throughout the trial in a blinded manner by the study team and in an 
unblinded manner by an external Data Monitoring Committee (E-DMC).  Population PK 
assessment for rituximab-Pfizer and rituximab-EU will be conducted in this study.  Serum 
samples for determination of drug concentrations will be collected at specified time points.

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The primary hypothesis to be tested in this study is that the efficacy of rituximab-Pfizer as 
measured by the ORR is similar to rituximab-EU.  Using ORR as determined by the one 
randomized trial of watchful waiting versus rituximab administered as a first-line treatment 
to patients with low tumor burden CD20+ FL7 a trial of at least 394 patients will be required 
to demonstrate similarity.
4. PATIENT SELECTION
This study can fulfill its objectives only if appropriate patients are enrolled.  The following 
eligibility criteria are designed to select patients for whom protocol treatment is considered 
appropriate.  All relevant medical and non-medical conditions should be taken into 
consideration when deciding whether this protocol is suitable for a particular patient.
4.1. Inclusion Criteria
Patient eligibility should be reviewed and documented by an appropriately qualified member 
of the investigator’s study team before patients are included in the study.
Patients must meet all of the following inclusion criteria to be eligible for enrollment into the 
study:
1. Male or female patients aged 18 years (or local age of maturity for providing 
informed consent if greater than 18 years) or older.
2. Histologically confirmed, Grade 1-3a, CD20-positive follicular lymphoma 
(containing no elements of diffuse large B-cell lymphoma).
NOTE: Patients can be entered based on a diagnosis of CD20+ follicular lymphoma 
confirmed at the investigational site.  Archival tissue or slides must be sent to the 
central pathology reviewer for confirmation of diagnosis.  Patients must have tissue 
specimens available for the central pathology review to be enrolled.  
3. Ann Arbor Stage II, III, or IV (Appendix 1).
4. Eastern Cooperative Oncology Group (ECOG) status of 0 to 1.
5. At least 1 measureable disease lesion identifiable by imaging:

A nodal lesion must be at least 11 mm x 11 mm OR 16 mm in the greatest 
transverse diameter [regardless of short axis measurement].

An extranodal lesion must be at least 10 mm x 10 mm.
6. Patient has low tumor burden FL, defined as:
a.
Serum LDH 1.5 upper limit of normal.
b. 2-microglobulin 1.5 upper limit of normal.

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c.
Largest nodal or extra-nodal mass <7 cm in diameter.
d. No more than 3 nodal sites with a diameter >3 cm.
e.
No clinically significant serous effusions detectible on chest radiography.
f.
Spleen enlargement 16 cm by CT (computed tomography) scan.
g. No complications such as organ compression or impairment.
h. No B symptoms:

fever >38C for 3 consecutive days;

recurrent, drenching night sweats;

unintentional weight loss exceeding 10% body weight in 6 months.
NOTE: Patients with mild FL symptoms may be enrolled in the study as long as 
they do not meet the criteria for B symptoms.
7. Men and women of childbearing potential must agree to use a highly effective 
method of contraception throughout the study and for 12 months after the last dose 
of assigned treatment.  A man or woman is of childbearing potential if, in the 
opinion of the investigator, he or she is biologically capable of having children and 
is sexually active.
8. Evidence of a personally signed and dated informed consent document indicating 
that the patient has been informed of all pertinent aspects of the study.
9. Patients who are willing and able to comply with scheduled visits, treatment plan, 
laboratory tests, and other study procedures.
4.2. Exclusion Criteria
Patients presenting with any of the following will not be included in the study:
1. Patients who are not candidates for rituximab monotherapy in the opinion of the 
investigator.
2. Evidence of histologic transformation to high-grade or diffuse large B-cell 
lymphoma.
3. Central nervous system or meningeal involvement or cord compression by the 
lymphoma (Brain imaging is not required, but may be conducted if clinically 
indicated).
4. Any previous history of T-cell lymphoma.

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5. Patients with 5000/mm3 circulating lymphoma cells.
6. Any prior systemic therapy for B-cell NHL, including chemotherapy, 
immunotherapy, or steroids.  Patients may have received prior localized 
radiotherapy for FL (Low dose [10 mg oral prednisone or equivalent] or inhaled 
steroids for other conditions are acceptable).
7. Any prior treatment with rituximab.
8. Hypersensitivity to the active substances or to any of the excipients in 
rituximab-Pfizer or rituximab-EU. 
9. History of allergy or prior hypersensitivity to murine, chimeric, humanized, or 
human monoclonal antibody treatments.
10. Impaired bone marrow function as evidenced by hemoglobin <9.0 g/dL, absolute 
neutrophil count (ANC) <1.5 x 109 cells/L (1500/mm3) or a platelet count 
<75 x 109cells/L (75,000/mm3).
11. Symptomatic ischemic heart disease or NYHA Class II, III, or IV congestive heart 
failure.
12. Active infection with tuberculosis (TB). Patients with evidence of latent TB or a 
history of TB must have completed treatment or have initiated treatment for at 
least 1 month before the first dose of study treatment (Day 1).  TB testing is 
required only if it is required by local regulations or practice.
13. Positive test for hepatitis B surface antigen (HBsAg), hepatitis B core antibody 
(HBcAb), or anti-hepatitis C antibody (HCVAb), or seropositivity for human 
immunodeficiency virus (HIV). 
14. Any other active uncontrolled infection.  Patients with an infection must have 
initiated a course of treatment with an effective antimicrobial a minimum of 7 days 
before the first dose of study treatment (Day 1) and be free of symptoms from the 
infection.
15. Any history of another cancer during the last 5 years with the exception of 
non-melanoma skin tumors, in situ cervical carcinoma, or in situ breast cancer
treated with curative intent with no history of metastatic disease.
16. Administration of a live vaccine 6 weeks before first dose of study treatment
(Day 1).
17. Major surgery 28 days before first dose of study treatment.

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18. Anticipated need for concomitant administration of any other experimental drug,
or a concomitant chemotherapy, anticancer hormonal therapy, radiotherapy, or 
immunotherapy during study participation.
19. Participation in other studies involving investigational drug(s) (Phases 1-4) within 
4 weeks or 5 half-lives, whichever is longer, before the current study begins and/or 
during study participation.
20. Any other severe acute or chronic medical or psychiatric condition or laboratory 
abnormality that may increase the risk associated with study participation or 
investigational product administration or may interfere with the interpretation of 
study results and, in the judgment of the investigator, would make the patient
inappropriate for entry into this study.
21. Patients who are investigational site staff members directly involved in the conduct 
of the trial and their family members, site staff members otherwise supervised by 
the investigator, or patients who are Pfizer employees directly involved in the 
conduct of the trial.
22. Pregnant females; breastfeeding females; males and females of childbearing 
potential who are unwilling or unable to use a highly effective method of 
contraception as outlined in this protocol for the duration of the study and for 
12 months after last dose of investigational product.
23. Patients with a body surface area >3.0 m2.
4.3. Randomization Criteria 
Patients who have signed informed consent to participate in the study, have undergone all 
screening procedures, and meet all inclusion and exclusion criteria for participation in the 
trial, may be randomized into this study. Randomization will be conducted using a 
web-based automated response system (IMPALA). Patients should be randomized on Day 1
if at all possible; however, patients may be randomized up to 5 business days in advance of
Day 1 if required in order to allow time to dispense the study drug and ensure receipt at the 
site.  Sponsor confirmation of eligibility must be obtained prior to randomization of patients.
4.4. Life Style Guidelines
All male patients who are able to father children and female patients who are of childbearing 
potential, and are sexually active and at risk for pregnancy must agree to use a highly 
effective method of contraception consistently and correctly for the duration of the active 
treatment period and for 12 months after the last dose of investigational product.  The 
investigator, in consultation with the patient, will select the most appropriate method of 
contraception for the individual patient from the permitted list of contraception methods, and 
instruct the patient in its consistent and correct use.  The investigator, at each study visit, will 
confirm and document consistent and correct use.  In addition, the investigator will instruct 
the patient to call immediately if the selected birth control method is discontinued or if 
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Highly effective methods of contraception are those that, alone or in combination, result in a 
failure rate of less than 1% per year when used consistently and correctly (ie, perfect use) and 
include:
1. Established use of oral, inserted, injected or implanted hormonal methods of 
contraception are allowed provided the patient remains on the same treatment 
throughout the entire study and has been using that hormonal contraceptive for an 
adequate period of time to ensure effectiveness.
2. Correctly placed copper containing intrauterine device (IUD).
3. Male sterilization with appropriately confirmed absence of sperm in the 
post-vasectomy ejaculate.
4. Bilateral tubal ligation or bilateral salpingectomy.
4.5. Sponsor Qualified Medical Personnel
The contact information for the sponsor's appropriately qualified medical personnel for the 
trial is documented in the study contact list. To facilitate access to appropriately qualified 
medical personnel on study related medical questions or problems, patients are provided with 
a contact card. The contact card contains, at a minimum, protocol and investigational 
compound identifiers, patient study number, contact information for the investigational site 
and contact details for a help desk in the event that the investigational site staff cannot be 
reached to provide advice on a medical question or problem originating from another 
healthcare professional not involved in the patients participation in the study. The help desk 
number can also be used by investigational staff if they are seeking advice on medical 
questions or problems, however it should only be used in the event that the established 
communication pathways between the investigational site and the study team are not 
available. It is therefore intended to augment, but not replace the established communication 
pathways between the investigational site and study team for advice on medical questions or 
problems that may arise during the study. The help desk number is not intended for use by 
the patient directly and if a patient calls that number they will be directed back to the 
investigational site.
5. STUDY TREATMENTS
5.1. Allocation to Treatment
This study is a double-blind, randomized clinical trial.
After a patient has provided written informed consent and completed the necessary Screening
assessments, the clinical site must complete an Eligibility Review Form and send to the 
sponsor for approval of randomization. Upon receipt of the sponsor’s approval, the site may 
randomize the patient in IMPALA. 
A computer-generated randomization schedule will be used to assign patients to the treatment 
groups.  Patients will be assigned a patient number in the order of their acceptance into the 
study.  This identifying number will be retained throughout the study.

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Following signing of informed consent, patients will be registered into the study using an 
automated web-based randomization system (IMPALA) provided by the sponsor to receive a 
unique patient identification number.  Randomization will be performed using IMPALA.
Patients will be randomized in a 1:1 ratio to one of the 2 study treatment arms:  

Arm A:
Rituximab-Pfizer

Arm B:
Rituximab-EU (MabThera)
Randomization will be stratified by low, medium, and high risk patients using the Follicular 
Lymphoma International Prognostic Index 2 (FLIPI2).
5.2. Breaking the Blind 
This double-blind study will be blinded to the patients and investigator/site staff, with the 
exception of the pharmacy staff preparing study treatment infusions.  The study will be 
conducted in a double blinded fashion through Week 26 when the primary endpoint will be 
evaluated. Prior to Week 26, the patients, investigators and sponsor will be blinded to 
randomized study treatments. After Week 26, some members of the study team will be 
unblinded so that a study report for the corresponding data collected through Week 26 can be 
generated.  The patients and investigators will continue to be blinded to individual study 
treatments until the end of the study.
At the initiation of the study, the study site will be instructed on using IMPALA for breaking 
the blind.  Blinding should only be broken in emergency situations for reasons of individual 
patient safety when knowledge of the investigational product (IP) assignment is required for 
medical management.  At all other times, treatment and randomization information will be 
kept confidential and will not be released to the investigator/study staff until the conclusion 
of the study.
If the blind for a patient has been broken, the Sponsor must be notified and the reason must 
be fully documented in source documents and entered on the electronic Case Report Form 
(eCRF).  Any adverse event (AE) or serious adverse event (SAE) associated with breaking 
the blind must be recorded and reported as specified in this protocol.
5.3. Drug Supplies
5.3.1. Formulation and Packaging
Rituximab-Pfizer and rituximab-EU will be supplied as sterile, preservative-free, 
non-pyrogenic, single use vials.  Rituximab concentrate for solution for infusion will be 
supplied packaged as blinded supplies in which the external packaging (carton) for both
products will appear identical and identified with a unique container number.  Each blinded 
carton will contain 1 vial of study medication.  Each carton will be packaged with a 
tamper-resistant seal.  The Sponsor must be notified of any study medication in which the 
tamper- resistant seal has been broken and this medication should not be used.  Further 
details will be detailed in the Investigational Product Manual. 

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Each vial of rituximab-Pfizer will contain 500 mg of PF-05280586 in 50 mL clear glass vials.  
Each vial of rituximab-EU (MabThera) will contain 500 mg of rituximab in 50 mL clear 
glass vials. 
5.3.2. Preparation and Dispensing
Rituximab-Pfizer will be prepared and dispensed in accordance with the European Medicines 
Authority (EMA) approved labeling for MabThera (rituximab-EU) or the local product label 
for rituximab.
Only qualified personnel who are familiar with procedures that minimize undue exposure to 
them and to the environment should undertake the preparation, handling, and safe disposal of 
chemotherapeutic agents.
5.3.2.1. Rituximab Infusion Preparation
Rituximab (rituximab-Pfizer or rituximab-EU) solutions for infusion will be prepared by a 
pharmacist designated as participating in this study as an unblinded pharmacist.  Unblinded 
pharmacists will receive study specific training on the obligations of the role and will sign an 
agreement that will be maintained in the Site Master File.  No information concerning patient
treatment assignments will be communicated from the unblinded pharmacist to investigators, 
site study staff, sponsor study staff, or study patients.  Rituximab will be administered by 
intravenous (IV) infusion.  Pharmacists should use aseptic technique appropriate to parenteral 
administration projects.  Rituximab vials and prepared solutions should be inspected visually 
for particulate matter and discoloration prior to administration.  Do not use vials if 
particulates or discoloration are present. Following the Dosage and Administration 
Instructions, withdraw the necessary amount of rituximab (rituximab-Pfizer or rituximab-EU) 
and dilute to a final concentration of 1 mg/mL to 4 mg/mL in an infusion bag containing 
either 0.9% Sodium Chloride, USP, or 5% Dextrose in Water, USP. Gently invert the bag to 
mix the solution. Do not mix or dilute the study drug product with other drugs. Reference 
the Dosage and Administration Instructions for further details.
5.3.2.2. Pre-Medication for Rituximab Infusions
All patients should receive premedication with 100 mg IV methylprednisolone or its 
equivalent prior to rituximab infusion to decrease the incidence rate and severity of acute 
infusion related reactions.  Premedication consisting of an anti-pyretic and an antihistamine
(eg, paracetamol [acetaminophen] and diphenhydramine) should be administered before 
infusion of rituximab.  Acute infusion reactions are most often observed during the first 
infusion of rituximab.  Any reduction in dose of premedications during subsequent infusions 
should be in compliance with local labeling and regulation.
5.3.3. Rituximab Administration 
Blinded rituximab (rituximab-Pfizer or rituximab-EU) will be administered by IV infusion 
using the escalating infusion rate described in the Health Authority approved product label.  
The rituximab infusion rate must be well controlled to reduce the incidence of serious 
infusion reactions. 

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Only qualified personnel who are familiar with procedures that minimize undue exposure to 
them and to the environment should undertake the preparation, handling, and safe disposal of 
chemotherapeutic agents.
Rituximab infusions should be administered under close medical supervision and in an 
environment where full resuscitation facilities are immediately available. Vital signs,
including heart rate, seated blood pressure, respiratory rate and oral or tympanic body 
temperature should be monitored every 30 minutes (5 minutes) during the course of the 
treatment administration or more frequently as necessary.
Rituximab will be administered at a dose of 375 mg/m2 at Visits 2, 3, 4, and 5 (Days 1, 8, 15, 
and 22).  The body surface area (BSA) for the patient should be calculated using a standard 
formula and the patient’s weight and height.  The weight and height at Screening may be 
used to calculate the BSA for all doses unless the patient has had a clinically significant 
change in weight.  If a patient appears to have a significant change in weight from Screening 
at a dosing visit, please check his or her weight prior to administering study medication and 
adjust the dose if there has been a change of more than 10%.  The maximum dose of 
rituximab that can be administered is 1125 mg.
The instructions below provide a summary of guidance provided in the MabThera product 
labeling, which should also be followed for rituximab-Pfizer; rituximab should be 
administered according to the local product labeling if it differs from these instructions.

Day 1 Infusion:  Initiate infusion at a rate of 50 mg/hr.  After 30 minutes and in the 
absence of infusion toxicity, increase infusion rate by 50 mg/hr increments every 
30 minutes, to a maximum of 400 mg/hr. 

Day 8, 15, and 22 Infusions:  Initiate infusion at a rate of 100 mg/hr.  After 
30 minutes and in the absence of infusion toxicity, increase rate by 100 mg/hr 
increments at 30-minute intervals, to a maximum of 400 mg/hr.

Patients should be closely monitored for the onset of cytokine release syndrome.  
Patients who develop evidence of severe reactions, especially severe dyspnea, 
bronchospasm or hypoxia should have the infusion interrupted immediately.  In all 
patients, the infusion should not be restarted until complete resolution of all 
symptoms, and normalization of laboratory values.  At this time, the infusion can be 
initially resumed at not more than one-half the previous rate.  If the same severe 
adverse reactions occur for a second time, the decision to stop the treatment should be 
seriously considered on a case by case basis. 

Mild to moderate infusion-related reactions usually respond to a reduction in the rate 
of infusion.  The infusion rate may be increased upon improvement of symptoms.

The patient should be observed post-infusion if necessary based on the investigator’s 
medical judgment.

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Medication errors may result, in this study, from the administration or consumption of the 
wrong product, by the wrong patient, at the wrong time, or at the wrong dosage strength.
Such medication errors occurring to a study participant are to be captured on the medication 
error case report form (CRF) which is a specific version of the adverse event (AE) page and 
on the SAE form when appropriate.  In the event of medication dosing error, the sponsor 
should be notified immediately.
Medication errors are reportable irrespective of the presence of an associated AE/SAE, 
including:

Medication errors involving patient exposure to the investigational product;

Potential medication errors or uses outside of what is foreseen in the protocol that do 
or do not involve the participating patient.
Whether or not the medication error is accompanied by an AE, as determined by the 
investigator, the medication error is captured on the medication error version of the AE page 
and, if applicable, any associated adverse event(s) is captured on an adverse event (AE) CRF 
page.
5.3.4. Compliance
Study treatment will be administered under the supervision of the investigator and site 
personnel.  Compliance will be monitored by study personnel at the site by using the source 
documents and the eCRFs.  The unblinded site study pharmacist is responsible for drug 
preparation, the maintenance of accurate and complete dispensing and accountability forms 
showing the receipt and dispensation of rituximab.  The unblinded pharmacist will also be 
responsible for performing accountability and reconciliation of the investigational products.
5.4. Drug Storage and Drug Accountability
All drug supplies for this study must be stored according to labeled storage conditions.  The 
investigator, or an approved representative (eg, pharmacist), will ensure that all study drug is 
stored in a secured (locked) area with restricted access, and in accordance with applicable 
regulatory requirements.
Drug should be stored in accordance with the drug label. Storage conditions stated in the 
Single Reference Safety Document (SRSD) (ie, Investigator Brochure (IB)) will be 
superseded by the label storage.
Investigators and site staff are reminded to check temperatures daily (manually or by using 
alarm systems to alert of any excursions) and ensure that thermometers are working correctly 
as required for proper storage of investigational products.  These include thermometers for 
refrigerator storage.  Any temperature excursions should be reported to the sponsor.
The investigational product(s) must be stored as indicated. Deviations from the storage 
requirements, including any actions taken, must be documented and reported to the sponsor. 
Once a deviation is identified, the investigational product must be quarantined and not used 
until the sponsor provides documentation of permission to use the investigational product.

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5.5. Concomitant and Prohibited Medication(s)
The use of concomitant therapy, including prescription and nonprescription drugs, non-drug 
therapy, and dietary supplements and herbal preparations, is permitted as appropriate to treat 
adverse events or co-morbid conditions.  Patients should not receive long term, high dose 
steroid treatment during the study.  Patients should not receive a live virus vaccine during the 
study as rituximab treatment will reduce the B lymphocyte count and B lymphocyte recovery 
may take up to 1 year post-treatment.  Patients may be vaccinated with non-live vaccines, 
although the response rate for these vaccines may be reduced.  Patients who receive 
prohibited steroid medication or a live vaccine do not have to be withdrawn from the study. 
Concomitant administration of any other experimental drug or a concomitant chemotherapy, 
anticancer hormonal therapy, radiotherapy, or immunotherapy is prohibited during study 
participation. This includes additional doses of rituximab after the initial 4-weekly doses.  If 
a patient requires tumor targeting treatment for FL other than the protocol-defined treatment 
with rituximab monotherapy, he or she will be considered a treatment failure and should be 
withdrawn from the study.
6. STUDY PROCEDURES
6.1. Screening (Visit 1 - Study Days -56 to 0)
The following screening procedures will be performed within 56 days prior to the first day of 
blinded study drug administration (Day 1) unless otherwise stated. 

Informed consent (must be obtained prior to the patient undergoing any study specific 
procedures and may occur prior to the 56-day screening period as permitted by local 
regulations or IRB/EC guidelines).

Confirm diagnosis of Grade 1 – 3a, CD20+ FL and ensure tissue or slides are 
available for the central pathology reviewer.  

Evaluate lymphoma-related signs and symptoms and ensure the patient is not 
experiencing B symptoms (fever >38C for 3 consecutive days, recurrent, drenching 
night sweats, and unintentional weight loss exceeding 10% body weight in 6 months).

Ensure the patient is Ann Arbor Stage II, III, or IV (Appendix 1).

Collect information for FLIPI and FLIPI2 (Appendix 2).

Collection of demographic information.

Medical history, including prior and current treatments for FL and other medical 
conditions, history of other significant medical conditions (active or resolved), and 
concomitant illnesses.

Prior and current medications.

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
Complete physical examination (PE), including examination of major body systems, 
body weight, and height.  The PE must include a thorough assessment of the lymph 
nodes, spleen, and liver.

Vital signs, including heart rate, seated blood pressure, respiratory and oral or 
tympanic body temperature.

ECOG performance status assessment.

Laboratory testing, including hematology, blood chemistry, urinalysis, serum 
2-microglobulin, lactate dehydrogenase (LDH), viral disease screening (hepatitis B 
surface antigen, hepatitis B core antibody, hepatitis C antibody, and HIV), and testing 
for circulating lymphoma cells. HIV testing should be conducted unless prohibited 
by local regulations.  Screening laboratory tests must be conducted within 28 days of 
the first dose of study medication (Day 1).  Screening lab tests may be repeated one 
time to re-evaluate potentially exclusionary values.

Serum pregnancy test (human chorionic gonadotrophin - hCG) for women of 
childbearing potential.  Female patients with documented history of hysterectomy, 
bilateral oophorectomy, medically confirmed ovarian failure, or follicle-stimulating 
hormone (FSH) test demonstrating post-menopausal status are exempted from 
pregnancy testing.

12-lead electrocardiogram (ECG).

Diagnostic quality [18F]FDG-PET/CT or a CT scan with contrast and a separate 
[18F]FDG-PET scan.  Scans acquired up to 8 weeks prior to Day 1 may be used for 
Screening provided they are of adequate quality for central imaging review.  The 
quality of all CT scans must be sufficient for accurate anatomical measurement of 
lymphoma lesions and for central review. PET/CT scans should be performed from 
the base of the skull to the proximal femurs; CT scans should include the neck, chest, 
abdomen, and pelvis. Patients for whom IV contrast is medically contraindicated 
should have an MRI of the neck, abdomen and pelvis and a non-contrast CT of the 
chest.

Bone marrow biopsy or aspiration, unless the patient has had a previous bone marrow 
biopsy or aspiration that was positive for bone marrow involvement (biopsies or 
aspirations performed up to 12 weeks prior to Day 1 may be used for Screening).  
Bone marrow aspiration and/or biopsy should be confirmed as adequate for 
evaluation and interpretation by the Investigator or medically qualified designee.

Review inclusion/exclusion criteria.

Record screening visit in IMPALA.

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6.2. Study Period
6.2.1. Day 1 Visit (Visit 2)

Review inclusion/exclusion criteria to ensure patient eligibility.

Randomization via IMPALA (may be conducted up to 5 business days prior to 
Day 1).  Sponsor confirmation of eligibility must be received prior to randomization.
NOTE: Randomization will be stratified based on low, medium and high risk patients 
using the Follicular Lymphoma International Prognostic Index 2 (FLIPI2).  It is 
critical that the FLIPI2 is scored correctly and that this information is entered into 
IMPALA accurately.

IMPALA study drug assignment (performed by the unblinded pharmacist - may be 
conducted up to 5 business days prior to Day 1).

Targeted PE, including body weight.  The Targeted PE must include a thorough 
assessment of the lymph nodes, spleen, and liver.

Vital signs, including heart rate, seated blood pressure, respiratory rate and oral or 
tympanic body temperature.

Laboratory testing, including chemistry, hematology, serum β2-microglobulin and 
lactate dehydrogenase (LDH).

Urine pregnancy test for female patients of childbearing potential.

Serum PK sampling.  One PK sample will be collected within 4 hours prior to the 
start of the study medication infusion and another sample will be collected within 
15 minutes prior to end of study medication infusion.  The end of the infusion is the 
time when the entire dose of study medication has been administered and the 
10 minute flush with diluent has been completed. 

CD19+ B-cell count sampling.  The CD19+ B-cell sample will be collected within 
4 hours prior to the start of the study medication infusion.

Immunogenicity (ADA/Nab) sampling.  The ADA/Nab sample will be collected 
within 4 hours prior to the start of the study medication infusion.

IgG and IgM sampling.  The IgG and IgM sample will be collected within 4 hours 
prior to the start of the study medication infusion.

Evaluate lymphoma-related signs and symptoms, including B symptoms (fever >38◦C 
for 3 consecutive days, recurrent, drenching night sweats, and unintentional weight 
loss exceeding 10% body weight in 6 months).

Contraception check.

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
Administration of premedications.

Study drug administration.

Concomitant medications.

Adverse events.
6.2.2. Treatment Visits (Visits 3, 4, and 5 - Study Days 8, 15, and 22)

Targeted PE, including body weight.  The Targeted PE must include a thorough 
assessment of the lymph nodes, liver and spleen.

Vital signs, including heart rate, seated blood pressure, respiratory rate and oral or 
tympanic body temperature.

Serum PK sampling.  One PK sample will be collected within 4 hours prior to each 
infusion.  On Day 22 only, an additional PK sample will be collected within 
15 minutes prior to end of infusion.  The end of the infusion is the time when the 
entire dose of study medication has been administered and the 10 minute flush with 
diluent has been completed. 

CD19+ B-cell count sampling.

Immunogenicity (ADA/Nab) sampling (Visit 4, Day 15 only).

IgG and IgM sampling.

Administration of premedications.

Study drug administration.

Concomitant medications.

Contraception check.

Adverse events.
6.2.3. Follow-up Visits (Visits 6, 7, 8, and 9 – Weeks 5, 13, 26, and 39)

Evaluate lymphoma-related signs and symptoms, including B symptoms (fever 
>38C for 3 consecutive days, recurrent, drenching night sweats, and unintentional 
weight loss exceeding 10% body weight in 6 months).

Targeted PE, including body weight.  The Targeted PE must include a thorough 
assessment of the lymph nodes, liver and spleen.

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
Vital signs, including heart rate, seated blood pressure, respiratory rate and oral or 
tympanic body temperature.

ECOG performance status assessment.

Laboratory testing, including chemistry, hematology, serum β2-microglobulin and 
lactate dehydrogenase (LDH).

Diagnostic quality [18F]FDG-PET/CT or CT scan with contrast.  PET/CT scans 
should be performed from the base of the skull to the proximal femurs; CT scans 
should include the neck, chest, abdomen, and pelvis. Patients for whom IV contrast is 
medically contraindicated should have an MRI of the neck, abdomen and pelvis and a 
non-contrast CT of the chest.

For patients with positive PET findings at Screening who have not undergone 
PET/CT scans at the follow up visits, a second PET scan should be obtained during 
Follow-Up (Weeks 13-39) or at End of Study/Early Termination (Week 52) when the
patient experiences a complete remission based on the investigator’s review of the CT 
scan results.  The follow-up PET should be performed within 4 weeks of the contrast 
enhanced CT.

Bone marrow biopsy or aspiration for patients with positive findings at Screening 
who have experienced a complete response based on the Investigator’s review of the 
CT or PET/CT scan.  A follow-up bone marrow biopsy or aspiration should be
performed once between Week 13 and Week 52 for patients who have bone marrow 
involvement at Screening at the time when the Investigator determines that the patient 
has achieved a Complete Remission – the bone marrow biopsy or aspiration should
be performed within 4 weeks of the contrast enhanced PET/CT or CT.

Serum PK sampling.

CD19+ B-cell count sampling.

Immunogenicity (ADA/Nab) sampling.

IgG and IgM sampling.

Concomitant medications.

Contraception check.

Adverse events.
6.2.4. End of Study/Early Termination Visit (Visit 10 - Week 52)

Evaluate lymphoma-related signs and symptoms, including B symptoms (fever 
>38C for 3 consecutive days, recurrent, drenching night sweats, and unintentional 
weight loss exceeding 10% body weight in 6 months).

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
Complete PE, including body weight.  The PE must include a thorough assessment of 
the lymph nodes, liver and spleen.

Vital signs, including heart rate, seated blood pressure, respiratory and oral or 
tympanic body temperature.

ECOG performance status assessment.

Laboratory testing, including chemistry, hematology, urinalysis, serum 
2-microglobulin, and lactate dehydrogenase (LDH).

Serum pregnancy test (HCG) for women of childbearing potential. 

12-lead ECG.

Diagnostic quality [18F]FDG-PET/CT or CT scan with contrast.  PET/CT scans 
should be performed from the base of the skull to the proximal femurs; CT scans 
should include the neck, chest, abdomen, and pelvis. Patients for whom IV contrast is 
medically contraindicated should have an MRI of the neck, abdomen and pelvis and a 
non-contrast CT of the chest.

For patients with positive PET findings at Screening who have not undergone 
PET/CT scans at the follow up visits, a second PET scan should be obtained during 
Follow-Up (Weeks 13-39) or at End of Study/Early Termination (Week 52) when the
patient experiences a complete remission based on the investigator’s review of the CT 
scan results.  The follow-up PET should be performed within 4 weeks of the contrast 
enhanced CT.

Bone marrow biopsy or aspirate for patients with positive findings at Screening who 
have experienced a complete response based on the Investigator’s review of the CT or 
PET/CT scan. A follow-up bone marrow biopsy or aspiration should be performed 
once between Week 13 and Week 52 for patients who have bone marrow 
involvement at Screening at the time when the Investigator determines that the patient 
has achieved a Complete Remission – the bone marrow biopsy or aspiration should 
be performed within 4 weeks of the contrast enhanced PET/CT or CT.

Serum PK sampling.

CD19+ B-cell count sampling.

Immunogenicity (ADA/Nab) sampling.

IgG and IgM sampling.

Concomitant medications.

Contraception check.

Adverse events.

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6.3. Patient Withdrawal
Patients may withdraw from the study at any time at their own request, or they may be 
withdrawn at any time at the discretion of the investigator or sponsor for safety or behavioral 
reasons, or the inability of the patient to comply with the protocol required schedule of study 
visits or procedures at a given study site.
Patients who cannot receive all four doses of study medication may be withdrawn from 
treatment, but may remain in the study.
If a patient does not return for a scheduled visit, every effort should be made to contact the 
patient.  All attempts to contact the patient and information received during contact attempts
must be documented in the patient’s medical record.  In any circumstance, every effort 
should be made to document patient outcome, if possible.  The investigator should inquire 
about the reason for withdrawal, request the patient to return for a final visit, if applicable, 
and follow up with the patient regarding any unresolved AEs.
Patients who withdraw from the study should have an End of Study (Visit 10 – Week 52) 
/Early Termination Visit completed if they are not discontinued at a scheduled study visit.  If 
the patient withdraws from the study, and also withdraws consent for disclosure of future 
information, no further evaluations should be performed, and no additional data should be 
collected.  The sponsor may retain and continue to use any data collected before such 
withdrawal of consent.
7. ASSESSMENTS
Every effort should be made to ensure that the protocol required tests and procedures are 
completed as described.  However it is anticipated that from time to time there may be 
circumstances, outside of the control of the investigator, that may make it unfeasible to 
perform the test.  In these cases the investigator will take all steps necessary to ensure the 
safety and well being of the patient.  When a protocol required test cannot be performed the 
investigator will document the reason for this and any corrective and preventive actions 
which he/she has taken to ensure that normal processes are adhered to as soon as possible.  
The study team will be informed of these incidents in a timely fashion.
7.1. Efficacy Assessments
Disease assessments are to be performed as scheduled according to calendar days, regardless 
of treatment delays resulting from toxicity. Care must be taken in scheduling disease 
assessments to prevent the introduction of bias based on treatment delays. 
Failure to perform any of the required disease assessments will result in the inability to 
determine disease status for the impacted time point. A series of incomplete disease 
assessments will result in inability to determine disease response status. Frequently 
off-schedule or incomplete disease assessments have the potential to weaken the conclusion 
of this clinical trial.

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Assessments are NOT to be scheduled based on the previous imaging timepoint, but rather 
Day 1 should be used as the baseline when calculating when the on-study tumor assessments 
are to be performed. Diagnostic quality PET/CT or CT scans should be performed with 
contrast agents, unless contraindicated for medical reasons. Patients for whom IV contrast is 
medically contraindicated should have an MRI of the neck, abdomen and pelvis and a 
non-contrast CT of the chest.
All imaging performed for the study will be forwarded to the central imaging vendor for 
review and assessment of response for the primary and secondary efficacy assessments.  
Details of the response assessment procedures are provided in the imaging charter.
Investigators will review the Screening PET/CT or CT scans to determine patient eligibility 
for the study.  Investigators will review the post-treatment PET/CT or CT scans to determine 
if a Complete Remission (CR) has occurred and to provide appropriate medical care to 
patients.  The Investigator should make the determination of whether a patient has 
experienced a CR using the revised response criteria for malignant lymphoma (2007)11 – see 
Appendix 3.  If a patient who had PET-avid disease at Screening has experienced a CR based 
on the Investigator’s review of the CT scan and has not undergone a PET/CT scan, a 
follow-up PET should be scheduled as soon as feasible.  Patients with bone marrow 
involvement at Screening should have a follow up bone marrow biopsy or aspiration 
conducted as soon as feasible once the Investigator determines they have experienced a CR. 
The PET and bone marrow biopsy should be conducted within 4 weeks of the PET/CT or 
CT.  All scans are to be acquired in accordance with the specifications provided in the 
imaging manuals.
7.2. Safety Assessments
7.2.1. Physical Examination
7.2.1.1. Complete Physical Examination
A standard physical examination will be performed at Screening and End of Study (Week 52) 
as indicated in the Schedule of Activities.  The following parameters and body systems will 
be examined and any abnormalities described: weight, height (at Screening), general 
appearance, skin (eg, presence of rash), head, eyes, ears, nose, and throat (HEENT), lungs 
(auscultation), heart (auscultation for presence of murmurs, gallops, rubs), extremity exam 
for the presence of peripheral edema, abdominal (palpation and auscultation), and neurologic 
(mental status and motor and sensory function).  The PE must include a thorough assessment
of the lymph nodes, liver and spleen.  The genitourinary system may be excluded unless 
there are signs or symptoms involving that system.  Any clinically significant changes from 
the screening visit after initial dosing with study drug should be recorded as adverse events 
(AEs).
7.2.1.2. Targeted Physical Examination
Targeted physical examinations will be performed as indicated in the Schedule of Activities.  
Targeted examinations will be guided by signs and symptoms, will include weight and will 
be consistent with local standard of care.  The Targeted PE must include, at a minimum, a 

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thorough assessment of the lymph nodes, liver and spleen.  Any clinically significant changes 
from the screening visit after initial dosing must be documented and should be recorded as 
adverse events (AEs).
7.2.2. Vital Signs
Vital signs, including heart rate, blood pressure, respiratory rate and oral or tympanic body 
temperature, will be measured as detailed in the Schedule of Activities and in the event of an 
infusion reaction.
Blood pressure will be measured in the patient’s arm and recorded to the nearest mmHg after 
the patient has been seated quietly for at least 2 minutes.  The same arm and position should 
be used throughout the study, using an appropriate cuff size.  When the timing of these 
measurements coincides with blood collection, the blood pressure and heart rate should be 
obtained first.
Vital signs are to be obtained prior to each study treatment infusion, every 30 minutes 
(5 minutes) during infusion, at the end of infusion and as clinically indicated.  Vital signs 
should be collected every 30 minutes even if an infusion is interrupted. In the event of 
hypersensitivity reaction vital signs should be obtained at additional time points until 
recovery per Investigator judgment. 
7.2.3. ECOG Performance Status
ECOG performance status will be graded according to the following definitions in Table 1.
Table 1.
ECOG Performance Status Definitions
Grade
ECOG Definition
0
Fully active, able to carry on all pre-disease performance without restriction
1
Restricted in physically strenuous activity but ambulatory and able to carry 
out work of a light or sedentary nature, eg, light house work, office work
2
Ambulatory and capable of all selfcare but unable to carry out any work 
activities.  Up and about more than 50% of waking hours
3
Capable of only limited selfcare, confined to bed or chair more than 50% of 
waking hours
4
Completely disabled.  Cannot carry on any selfcare.  Totally confined to bed 
or chair
5
Dead
7.2.4. Clinical Laboratory Tests
Blood and urine samples will be collected at the time points identified in the Schedule of 
Activities.  Hematology and blood chemistry tests will include the parameters presented in
Table 2.  Unscheduled clinical labs may be obtained at any time during the study to assess 
any perceived safety concerns.  All laboratory testing except for urine pregnancy tests will be 
performed by the central laboratory whenever possible; urine pregnancy tests will be 
provided by the central lab, but testing will be conducted at the site for female patients of 

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childbearing potential. Local laboratory testing may be conducted to verify patient eligibility 
or monitor patient safety if central laboratory results cannot be obtained in a timely fashion. 
Local laboratory values used to verify eligibility should be entered into the eCRF. 
Screening lab tests may be repeated one time to re-evaluate potentially exclusionary values.
Table 2.
Required Laboratory Tests
Laboratory Test
Panel
Parameters Included
Hematology
Hemoglobin, white blood cell (WBC), count, platelet count, and neutrophils (ANC)
Chemistry
ALT (SGPT), AST (SGOT), alkaline phosphatase, serum sodium, sodium potassium, 
total calcium (EDTA), total bilirubin, urea nitrogen, creatinine, serum uric acid, and 
albumin-QT.  If drug-induced liver disease is suspected (potential Hy’s law cases), in 
addition to repeating AST and ALT, laboratory tests should include albumin, creatine 
kinase, total bilirubin, direct and indirect bilirubin, gamma-glutamyl transferase, 
prothrombin time (PT)/INR, and alkaline phosphatase.
Urinalysis
If abnormal, a microscopic examination of spun sediment will be performed.  
Pregnancy Tests
Serum pregnancy test at Screening and End of Study/Early Termination and urine 
pregnancy test (performed by site personnel) at Day 1 for female patients of childbearing 
potential
Other Tests
Circulating lymphoma cells and viral disease screen (at Screening), -2 microglobulin, 
LDH
Details about the required laboratory testing and sample processing are provided in the 
Covance Lab Manual.
7.2.5. Viral Disease Screening  
Patients will be tested for Human Immunodeficiency Virus (HIV), hepatitis B surface antigen 
(HBsAg), hepatitis B core antibody (HBcAb), and hepatitis C antibody (HCVAb) to 
determine eligibility.  Screening for HIV infection should be performed unless prohibited by 
local regulations. 
7.2.6. Pregnancy Testing
For female patients of childbearing potential, a serum pregnancy test, with sensitivity of at 
least 25 mIU/mL, will be performed at Screening.  A urine pregnancy test will be performed 
on Day 1 prior to dosing.  A negative pregnancy result is required before the patient may 
receive the investigational product.  Serum pregnancy tests will also be done whenever one 
menstrual cycle is missed during the active treatment period (or when potential pregnancy is 
otherwise suspected) and at the end of the study to confirm the patient has not become 
pregnant during the study.  Patients should not be treated with study medication if pregnancy 
is suspected.  In the case of a confirmed positive hCG test, the patient will be withdrawn 
from treatment, but may remain in the study.  Additional pregnancy tests may also be 
conducted as requested by IRB/IECs or if required by local regulations. 

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7.2.7. Electrocardiogram
Twelve-lead ECGs should be performed after the patient has rested quietly for at least 
10 minutes.  End of Treatment ECGs will be compared to Screening ECGs and any clinically 
significant changes will be recorded as adverse events and evaluated further, as clinically 
warranted.
7.2.8. Adverse Events
Assessment of adverse events will include type, incidence, severity (graded by the National
Cancer Institute [NCI] Common Terminology Criteria for Adverse Events [CTCAE], 
Version 4.03), timing, seriousness, and relatedness.
Baseline tumor-related signs and symptoms will be recorded as adverse events during the 
trial if they worsen in severity or increase in frequency.
7.3. Pharmacokinetic Assessments
Samples for the determination of serum concentrations of rituximab-Pfizer and rituximab-EU 
will be collected at the time points specified in the Schedule of Activities.  The actual time of 
each sample collection will be recorded on the source document and CRF.  Samples collected 
within the allowable visit window specified in the Schedule of Activities are acceptable.
Details on sample collection, processing, and shipment will be provided in the central 
laboratory manual.  All samples will be analyzed by the designated analytical laboratory 
using a validated analytical method in compliance with Pfizer standard operating procedures.
7.4. Immunogenicity Assessments
Blood samples for assessment of ADA and Nab will be collected at time points specified on 
the Schedule of Activities.  Details on sample collection, processing, and shipment are 
provided in the central laboratory manual.  All samples will be analyzed by designated 
analytical laboratory using a validated analytical method in compliance with Pfizer standard 
operating procedures.
Analysis of ADA samples will follow a tiered approach of screening, confirmation, and titer 
determination. Samples that are confirmed positive for ADA will be further tested for 
neutralizing antibodies using validated neutralizing antibody assays. 
7.5. Pharmacodynamic Assessments
The PD of rituximab-Pfizer and rituximab-EU will be evaluated using circulating 
CD19 positive B-cell counts (surrogate marker for CD20+ B-cells).
Blood samples for circulating CD19+ B-cell counts will be collected according to the 
Schedule of Activities.
Because rituximab depletes B-cells, circulating levels of IgM and IgG may decrease.  Blood 
samples for IgG and IgM will be collected according to the Schedule of Activities.

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For details on obtaining, processing and shipping samples, see the Laboratory Manual.  The 
shipment address and assay lab contact information will be provided to the investigator site 
prior to initiation of the trial.  All samples will be analyzed by a central laboratory using a 
validated analytical method in compliance with Pfizer standard operating procedures. 
7.6. Histopathological Review of Diagnostic Tissue
To be eligible for this trial, patients must have tumor tissue or slides available for a central 
pathology review.  The patient may be enrolled in the study and randomized based on a
diagnosis of Grade 1-3a, CD20-positive follicular lymphoma with no elements of high grade 
or diffuse large B-cell lymphoma documented in a histopathological report that has been 
reviewed by the Investigator.  Tumor tissue blocks or slides will be collected and sent to the 
central laboratory for standardized evaluation of the diagnosis.  The tissue blocks will be 
returned to the site upon request.  The primary analysis for study outcome will be based on 
diagnosis confirmed by the Investigator.  Supportive analyses may consider diagnosis 
documented during the retrospective evaluation.
8. ADVERSE EVENT REPORTING
8.1. Adverse Events
All observed or volunteered AEs regardless of treatment group or suspected causal 
relationship to the investigational product(s) will be reported as described in the following 
sections. 
For all AEs, the investigator must pursue and obtain information adequate both to determine 
the outcome of the AE and to assess whether it meets the criteria for classification as an SAE
requiring immediate notification to Pfizer or its designated representative.  For all AEs, 
sufficient information should be obtained by the investigator to determine the causality of the 
AE.  The investigator is required to assess causality.  Follow-up by the investigator may be 
required until the event or its sequelae resolve or stabilize at a level acceptable to the 
investigator, and Pfizer concurs with that assessment.
As part of ongoing safety reviews conducted by the Sponsor, any non-serious adverse event 
that is determined by the Sponsor to be serious will be reported by the Sponsor as an SAE.  
To assist in the determination of case seriousness further information may be requested from 
the investigator to provide clarity and understanding of the event in the context of the clinical 
study. 
8.2. Reporting Period
For SAEs, the active reporting period to Pfizer or its designated representative begins from 
the time that the patient provides informed consent, which is obtained prior to the patient’s 
participation in the study, ie, prior to undergoing any study-related procedure and/or 
receiving investigational product, through and including 28 calendar days after the last study 
visit.  Serious adverse events occurring to a patient after the active reporting period has ended 
should be reported to the Sponsor if the investigator becomes aware of them; at a minimum, 
all serious adverse events that the investigator believes have at least a reasonable possibility 
of being related to investigational product are to be reported to the Sponsor.

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AEs (serious and non-serious) should be recorded on the CRF from the time the patient has 
taken at least one dose of investigational product through patient’s last visit.  If a patient 
begins a new anticancer therapy, the AE reporting period for non-serious AEs ends at the 
time the new treatment is started.  Death must be reported if it occurs during the SAE
reporting period after the last dose of investigational product, irrespective of any intervening 
treatment.
8.3. Definition of an Adverse Event
An AE is any untoward medical occurrence in a clinical investigation patient administered a 
product or medical device; the event need not necessarily have a causal relationship with the 
treatment or usage.  Examples of AEs include but are not limited to: 

Abnormal test findings;

Clinically significant symptoms and signs;

Changes in physical examination findings;

Hypersensitivity;

Drug abuse;

Drug dependency.
Additionally, they may include the signs or symptoms resulting from:

Drug overdose;

Drug withdrawal;

Drug misuse; 

Drug interactions;

Extravasation;

Exposure during pregnancy (EDP);

Exposure via breastfeeding;

Medication error;

Occupational exposure;

Worsening of signs and symptoms of the malignancy under study should be reported 
as AEs in the appropriate section of the CRF.  Disease progression assessed by 

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measurement of malignant lesions on radiographs or other methods should not be 
reported as AEs.
8.4. Abnormal Test Findings
The criteria for determining whether an abnormal objective test finding should be reported as 
an AE are as follows: 

Test result is associated with accompanying symptoms; and/or

Test result requires additional diagnostic testing or medical/surgical intervention;
and/or

Test result leads to a change in study dosing or discontinuation from the study, 
significant additional concomitant drug treatment, or other therapy; and/or

Test result is considered to be an AE by the investigator or sponsor.
Merely repeating an abnormal test, in the absence of any of the above conditions, does not 
constitute an AE.  Any abnormal test result that is determined to be an error does not require 
reporting as an AE.
8.5. Serious Adverse Events
An SAE is any untoward medical occurrence at any dose that:

Results in death;

Is life-threatening (immediate risk of death);

Requires inpatient hospitalization or prolongation of existing hospitalization;

Results in persistent or significant disability/incapacity (substantial disruption of the 
ability to conduct normal life functions);

Results in congenital anomaly/birth defect.
Progression of the malignancy under study (including signs and symptoms of progression) 
should not be reported as an SAE unless the outcome is fatal within the safety reporting 
period. Hospitalization due to signs and symptoms of disease progression should not be 
reported as an SAE. If the malignancy has a fatal outcome during the study or within the 
safety reporting period, then the event leading to death must be recorded as an AE and as an
SAE with CTCAE Grade 5 (see Section on Severity Assessment).
Medical and scientific judgment is exercised in determining whether an event is an important 
medical event.  An important medical event may not be immediately life-threatening and/or 
result in death or hospitalization.  However, if it is determined that the event may jeopardize 

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the patient or may require intervention to prevent one of the other AE outcomes, the 
important medical event should be reported as serious.
Examples of such events are intensive treatment in an emergency room or at home for 
allergic bronchospasm; blood dyscrasias or convulsions that do not result in hospitalization; 
or development of drug dependency or drug abuse.
8.5.1. Protocol-Specified Serious Adverse Events 
There are no protocol-specified SAEs in this study. All SAEs will be reported by the 
investigator as described in previous sections and will be handled as SAEs in the safety 
database (see Section on SAE Reporting Requirements).
8.5.2. Potential Cases of Drug-Induced Liver Injury 
Liver function tests (LFTs) are not required as a routine safety monitoring procedure in this 
study.  However, should an investigator deem it necessary to run LFTs because of a clinical 
sign/symptom presentation in a patient, such LFT results should be handled and followed up 
as described below. 
Abnormal values in aspartate aminotransferase (AST) and/or alanine aminotransferase(ALT) 
levels concurrent with abnormal elevations in total bilirubin level that meet the criteria 
outlined below in the absence of other causes of liver injury are considered potential cases of 
drug-induced liver injury (potential Hy’s Law cases) and should always be considered 
important medical events. 
The threshold of laboratory abnormalities for a potential case of drug-induced liver injury 
depends on the patient’s individual baseline values and underlying conditions. Patients who 
present with the following laboratory abnormalities should be evaluated further to 
definitively determine the etiology of the abnormal laboratory values:

Patients with AST or ALT and total bilirubin baseline values within the normal range 
who subsequently present with AST or ALT values 3 times the upper limit of 
normal (X ULN) concurrent with a total bilirubin value 2 X ULN with no evidence 
of hemolysis and an alkaline phosphatase value 2 X ULN or not available;

For patients with preexisting ALT OR AST OR total bilirubin values above the 
upper limit of normal, the following threshold values should be used in the 
definition mentioned above:

For patients with pre-existing AST or ALT baseline values above the normal 
range: AST or ALT values 2 times the baseline values and 3 X ULN, or 
8 X ULN (whichever is smaller).

Concurrent with

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
For patients with pre-existing values of total bilirubin above the normal range: 
Total bilirubin increased from baseline by an amount of at least one time the 
upper limit of normal or if the value reaches ≥3 times the upper limit of normal 
(whichever is smaller).
The patient should return to the investigational site and be evaluated as soon as possible, 
preferably within 48 hours from awareness of the abnormal results.  This evaluation should 
include laboratory tests, detailed history and physical assessment.  In addition to repeating 
measurements of AST and ALT, laboratory tests should include albumin, creatine kinase, 
total bilirubin, direct and indirect bilirubin, gamma-glutamyl transferase, prothrombin time
(PT)/ international normalized ratio (INR), and alkaline phosphatase.  A detailed history, 
including relevant information, such as review of ethanol, acetaminophen, recreational drug 
and supplement consumption, family history, occupational exposure, sexual history, travel 
history, history of contact with a jaundiced person, surgery, blood transfusion, history of liver 
or allergic disease, and work exposure, should be collected.  Further testing for acute 
hepatitis A, B, or C infection and liver imaging (eg, biliary tract) may be warranted.  All 
cases confirmed on repeat testing as meeting the laboratory criteria defined above, with no 
other cause for LFT abnormalities identified at the time should be considered potential Hy’s 
Law cases irrespective of availability of all the results of the investigations performed to 
determine etiology of the abnormal LFTs.  Such potential Hy’s Law cases should be reported 
as SAEs.
8.6. Hospitalization
Hospitalization is defined as any initial admission (even less than 24 hours) in a hospital or 
equivalent healthcare facility or any prolongation of an existing admission.  Admission also 
includes transfer within the hospital to an acute/intensive care unit (eg, from the psychiatric 
wing to a medical floor, medical floor to a coronary care unit, or neurological floor to a 
tuberculosis unit).  An emergency room visit does not necessarily constitute a hospitalization; 
however, the event leading to the emergency room visit should be assessed for medical 
importance.
Hospitalization does not include the following:

Rehabilitation facilities;

Hospice facilities;

Respite care (eg, caregiver relief);

Skilled nursing facilities;

Nursing homes;

Same day surgeries (as outpatient/same day/ambulatory procedures).
Hospitalization or prolongation of hospitalization in the absence of a precipitating, clinical 
AE is not in itself an SAE.  Examples include: 

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
Admission for treatment of a preexisting condition not associated with the 
development of a new AE or with a worsening of the preexisting condition (eg, for 
work-up of persistent pre-treatment lab abnormality);

Social admission (eg, patient has no place to sleep);

Administrative admission (eg, for yearly physical exam);

Protocol-specified admission during a study (eg, for a procedure required by the study 
protocol);

Optional admission not associated with a precipitating clinical AE (eg, for elective 
cosmetic surgery);

Hospitalization for observation without a medical AE;

Pre-planned treatments or surgical procedures.  These should be noted in the baseline 
documentation for the entire protocol and/or for the individual patient;

Admission exclusively for the administration of blood products.
Diagnostic and therapeutic non-invasive and invasive procedures, such as surgery, should not 
be reported as AEs.  However, the medical condition for which the procedure was performed 
should be reported if it meets the definition of an AE.  For example, an acute appendicitis 
that begins during the AE reporting period should be reported as the AE, and the resulting 
appendectomy should be recorded as treatment of the AE.
8.7. Severity Assessment
The investigator will describe the maximum intensity of the AE.  The US National Cancer 
Institute (NCI) Common Terminology Criteria for Adverse Events, Version 
4.03 (CTCAEv4.03) will be used to grade severity.  A printable version of these criteria can 
be found at 
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf.
GRADE
CLINICAL DESCRIPTION OF SEVERITY
0
No Change from Normal or Reference Range (This grade is not included in 
the Version 4.03 CTCAE document but may be used in certain 
circumstances.)
1
MILD Adverse Event
2
MODERATE Adverse Event
3
SEVERE Adverse Event
4
LIFE-THREATENING consequences; urgent intervention indicated
5
DEATH RELATED TO Adverse Event
The NCI CTCAE severity grades for an infusion related reaction should be used to grade the 
severity of adverse events that the investigator deems infusion-related reaction (allergic or 
hypersensitivity reactions):

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GRADE
CLINICAL DESCRIPTION OF SEVERITY FOR IRRs
1
Mild transient reaction; infusion interruption not indicated; intervention not 
indicated
2
Therapy or infusion interruption indicated but responds promptly to 
symptomatic treatment (eg,
antihistamines, NSAIDS, narcotics, IV fluids); prophylactic medications 
indicated for <=24 hours
3
Prolonged (eg, not rapidly responsive to symptomatic medication and/or brief 
interruption of infusion); recurrence of symptoms following initial 
improvement; hospitalization indicated for clinical sequelae
4
Life-threatening consequences; urgent intervention indicated
5
Death
Note the distinction between the severity and the seriousness of an AE.  A severe event is not 
necessarily an SAE.  For example, a headache may be severe (interferes significantly with 
patient's usual function) but would not be classified as serious unless it met one of the criteria 
for SAEs, listed above.
8.8. Causality Assessment
The investigator’s assessment of causality must be provided for all AEs (serious and 
non-serious); the investigator must record the causal relationship in the CRF, as appropriate, 
and report such an assessment in accordance with the serious adverse reporting requirements 
if applicable.  An investigator’s causality assessment is the determination of whether there 
exists a reasonable possibility that the investigational product caused or contributed to an 
AE; generally the facts (evidence) or arguments to suggest a causal relationship should be 
provided.  If the investigator does not know whether or not the investigational product caused 
the event, then the event will be handled as “related to investigational product” for reporting 
purposes, as defined by the Sponsor (see Section on Reporting Requirements).  If the 
investigator's causality assessment is “unknown but not related to investigational product”, 
this should be clearly documented on study records. 
In addition, if the investigator determines an SAE is associated with study procedures, the 
investigator must record this causal relationship in the source documents and CRF, as 
appropriate, and report such an assessment in accordance with the SAE reporting 
requirements, if applicable.
8.9. Exposure During Pregnancy
For both unapproved/unlicensed products and for marketed products, an exposure during 
pregnancy occurs if:
1. A female becomes, or is found to be, pregnant either while receiving or having 
been exposed (eg, because of treatment or environmental exposure) to the 
investigational product; or the female becomes, or is found to be pregnant after 
discontinuing and/or being exposed to the investigational product; 

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An example of environmental exposure would be a case involving direct contact with 
a Pfizer product in a pregnant woman (eg, a nurse reports that she is pregnant and has 
been exposed to chemotherapeutic products).
2. A male has been exposed (eg, because of treatment or environmental exposure) to 
the investigational product prior to or around the time of conception and/or is 
exposed during his partner’s pregnancy.
If a study patient or study patient’s partner becomes or is found to be pregnant during the 
study patient’s treatment with the investigational product, the investigator must submit this 
information to the Pfizer Drug Safety Unit on a Serious Adverse Event (SAE) Report Form 
and Exposure During Pregnancy supplemental form, regardless of whether an SAE has 
occurred.  In addition, the investigator must submit information regarding environmental 
exposure to a Pfizer product in a pregnant woman (eg, a patient reports that she is pregnant 
and has been exposed to a cytotoxic product by inhalation or spillage) using the EDP 
supplemental form.  This must be done irrespective of whether an AE has occurred and 
within 24 hours of awareness of the exposure. The information submitted should include the 
anticipated date of delivery (see below for information related to termination of pregnancy).
Follow-up is conducted to obtain general information about the pregnancy and its outcome 
for all EDP reports with an unknown outcome.  The investigator will follow the pregnancy 
until completion (or until pregnancy termination) and notify Pfizer of the outcome as a 
follow up to the initial EDP supplemental form.  In the case of a live birth, the structural 
integrity of the neonate can be assessed at the time of birth.  In the event of a termination, the 
reason(s) for termination should be specified and, if clinically possible, the structural 
integrity of the terminated fetus should be assessed by gross visual inspection (unless 
pre-procedure test findings are conclusive for a congenital anomaly and the findings are 
reported).
If the outcome of the pregnancy meets the criteria for an SAE (ie, ectopic pregnancy, 
spontaneous abortion, intrauterine fetal demise, neonatal death, or congenital anomaly [in a 
live born baby, a terminated fetus, an intrauterine fetal demise, or a neonatal death]), the 
investigator should follow the procedures for reporting SAEs.
Additional information about pregnancy outcomes that are reported as SAEs follows: 

Spontaneous abortion includes miscarriage and missed abortion;

Neonatal deaths that occur within 1 month of birth should be reported, without regard 
to causality, as SAEs.  In addition, infant deaths after 1 month should be reported as 
serious adverse events when the investigator assesses the infant death as related or 
possibly related to exposure to the investigational product.
Additional information regarding the exposure during pregnancy may be requested by the 
investigator.  Further follow-up of birth outcomes will be handled on a case-by-case basis 
(eg, follow-up on preterm infants to identify developmental delays). In the case of paternal 
exposure, the investigator will provide the study patient with the Pregnant Partner Release of 
Information Form to deliver to his partner. The Investigator must document in the source 

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documents that the patient was given the Pregnant Partner Release of Information Form to 
provide to his partner.
8.10. Occupational Exposure
An occupational exposure occurs when during the performance of job duties, a person 
(whether a healthcare professional or otherwise) gets in unplanned direct contact with the 
product, which may or may not lead to the occurrence of an adverse event.
An occupational exposure is reported to the drug safety unit within 24 hours of the
Investigator’s awareness, using the SAE Report form, regardless of whether there is an 
associated AE/SAE.  Since the information does not pertain to a patient enrolled in the study, 
the information is not reported on a Case Report Form (CRF), however a copy of the 
completed SAE Report form is maintained in the investigator site file.
8.11. Withdrawal Due to Adverse Events (See Also the Section on Patient Withdrawal)
Withdrawal due to AEs should be distinguished from withdrawal due to other causes, 
according to the definition of AE noted earlier, and recorded on the appropriate AE CRF 
page. 
When a patient withdraws because of an SAE, the SAE must be reported in accordance with 
the reporting requirements defined below.
8.12. Eliciting Adverse Event Information
The investigator is to report all directly observed AEs and all AEs spontaneously reported by 
the study patient. In addition, each study patient will be questioned about AEs.
8.13. Reporting Requirements
Each AE is to be assessed to determine if it meets the criteria for SAEs.  If an SAE
occurs, expedited reporting will follow local and international regulations, as appropriate.
8.13.1. Serious Adverse Event Reporting Requirements
If an SAE occurs, Pfizer is to be notified within 24 hours of investigator awareness of the 
event.  In particular, if the SAE is fatal or life-threatening, notification to Pfizer must be 
made immediately, irrespective of the extent of available AE information.  This timeframe 
also applies to additional new information (follow-up) on previously forwarded SAE reports 
as well as to the initial and follow-up reporting of exposure during pregnancy, exposure via 
breastfeeding and occupational exposure cases.
In the rare event that the investigator does not become aware of the occurrence of an SAE
immediately (eg, if an outpatient study patient initially seeks treatment elsewhere), the 
investigator is to report the event within 24 hours after learning of it and document the time 
of his/her first awareness of the AE.

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For all SAEs, the investigator is obligated to pursue and provide information to Pfizer in 
accordance with the timeframes for reporting specified above.  In addition, an investigator 
may be requested by Pfizer to obtain specific additional follow-up information in an
expedited fashion.  This information collected for SAEs is more detailed than that captured 
on the AE CRF.  In general, this will include a description of the AE in sufficient detail to 
allow for a complete medical assessment of the case and independent determination of 
possible causality.  Information on other possible causes of the event, such as concomitant 
medications, vaccines and/or illnesses must be provided.  In the case of a patient death, a 
summary of available autopsy findings must be submitted as soon as possible to Pfizer or its 
designated representative. 
8.13.2. Non-Serious Adverse Event Reporting Requirements
All AEs will be reported on the AE page(s) of the CRF.  It should be noted that the form for 
collection of SAE information is not the same as the AE CRF.  Where the same data are 
collected, the forms must be completed in a consistent manner.  For example, the same AE
term should be used on both forms.  AEs should be reported using concise medical 
terminology on the CRFs as well as on the form for collection of SAE information.
8.13.3. Sponsor’s Reporting Requirements to Regulatory Authorities
Adverse event reporting, including suspected unexpected serious adverse reactions, will be 
carried out in accordance with applicable local regulations.
9. DATA ANALYSIS/STATISTICAL METHODS
Detailed methodology for summary and statistical analyses of the data collected in this study 
will be documented in a Statistical Analysis Plan (SAP), which will be maintained by the 
Sponsor. The SAP may modify the plans outlined in the protocol; however, any major 
modifications of the primary endpoint definition and/or its analysis will also be reflected in a 
protocol amendment.
9.1. Sample Size Determination
The primary hypothesis to be tested in this study is that the difference between the ORR of 
rituximab-Pfizer versus that of rituximab-EU is within a pre-specified margin of -16% to 
16% (the margin derivation is described below).  A sample size of approximately 
394 patients (~197 per treatment arm) provides approximately 93% power for achieving 
equivalence under the specified margin with 2.5% type I error rate assuming an ORR of 77% 
in both treatment arms.
Pfizer conducted an extensive, systematic literature search for rituximab and FL.  The 
Ardeshna7 study was the only randomized trial which compared the treatment of rituximab 
alone with the treatment of “watchful waiting” (WW).  In this study, at Month 7 the response 
rate to rituximab therapy (weekly for 4 weeks) was estimated to be 77% and the response rate 
in the WW arm was estimated to be 6%.  The difference (rituximab - WW) was estimated to 
be 71% with the 95% confidence interval of (60%, 79%).  Based on these results, the 
proposed margin of (-16%, 16%) will preserve at least 73% efficacy based on the lower 
bound of 95% CI in the ORR difference (rituximab-WW) as seen in the Ardeshna study.7

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9.2. Analysis Population
9.2.1. Intent-to-Treat Population
The Intent-to-Treat (ITT) Population is defined as all patients who are randomized to study 
treatment.  The ITT population will be used as the primary efficacy analysis population.
9.2.2. Per-Protocol Population
The Per-Protocol (PP) Population is defined as all randomized patients who receive at least 
one dose of study treatment, have measurable disease at baseline as confirmed by central 
review, and have no important protocol deviations that would impact the study outcome 
significantly, as determined by blinded medical review.  The PP population will be used for 
sensitivity analyses of the efficacy and biomarker analyses.  All decisions to exclude patients 
from the PP population will be made prior to database release.
9.2.3. Safety Population
The safety population is defined as all patients who received at least one dose of study 
treatment.  The safety population will be used for the safety analyses including AE, 
concomitant medication, laboratory tests, vital signs, ADA and neutralizing antibody 
analyses, etc.
9.3. Efficacy Analysis
9.3.1. Analysis of Primary Endpoint
The primary efficacy endpoint of the study is ORR defined as the percent of patients within 
each treatment group that achieved Complete Remission (CR) or Partial Remission (PR) at 
the end of Week 26. 
The following primary hypothesis will be tested for ORR in order to show that 
rituximab-Pfizer is equivalent to rituximab-EU:
TEST 1: H0c: θ1 - θ2 ≥Dub vs. H1c: θ1 - θ2 < Dub
TEST 2: H0d: θ1 - θ2 ≤ Dlb vs. H1d: θ1 - θ2 > Dlb
Where θ1 is the ORR at Week 26 for patients randomized to rituximab-Pfizer, θ2 is the ORR 
at Week 26 for patients randomized to rituximab-EU, Dub is the largest acceptable risk 
difference for equivalence, and Dlb is the smallest acceptable risk difference for equivalence.  
In this study, Dub=16% and Dlb=-16%. 
According to a requirement from the regulatory authority in Japan, an additional analysis will 
be conducted to test equivalence using Dub = 14.9% and Dlb = -14.9% if equivalence is 
established with the margins of Dub=16% and Dlb=-16%. 
The stratified Miettinen and Nurminen method13 will be used to obtain the estimated 
difference (rituximab-Pfizer minus rituximab-EU) and its 95% confidence interval. 

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The study will meet the primary objective if the 95% confidence interval for the ORR 
difference (rituximab-Pfizer minus rituximab-EU) is within the pre-specified margin of 
(-16%, 16%).  For the regulatory authority in Japan, equivalence will be demonstrated if the 
95% confidence interval for the ORR difference (rituximab-Pfizer minus rituximab-EU) is 
within the margin of (-14.9%, 14.9%).
Descriptive statistics (frequency and percentage) for CR, PR, and ORR will be presented by 
treatment group.  The 95% confidence intervals of these response rates will be constructed.  
Other details will be described in the Statistical Analysis Plan (SAP).
9.3.2. Analysis of Other Efficacy Endpoints
Other efficacy endpoints include:

Time to Treatment Failure (TTF).

Progression-Free Survival (PFS).

Complete Remission (CR) rate at Week 26.

Duration of response.

Overall survival.
The analyses for these endpoints are briefly described below. Details of planned analyses for 
these efficacy endpoints will be described in the SAP.
9.3.2.1. Time to Treatment Failure
Time to Treatment Failure is defined as the time from date of randomization to 
discontinuation from study for any reason, including disease progression, treatment toxicity,
patient preference, or death. A stratified log-rank test will be used to compare the TTF
curves between the two treatment groups.  TTF will also be summarized using Kaplan-Meier 
survival curves.  The Kaplan-Meier survival estimates, together with the number of patients, 
percentage of patients to experience the event, and the number and percentage of patients 
censored will be summarized in a table by treatment group.
9.3.2.2. Progression Free Survival
Progression-Free Survival (PFS) is defined as the time from date of randomization to first 
progression of disease (PD) or death due to any cause in the absence of documented PD.  
Censoring for the PFS endpoint will be assigned on the date of the last tumor assessment if 
no assessment of tumor progression is identified and the patient does not die while on study.  
Progression will be based on central review.  Patients lacking of an evaluation of disease 
after randomization will have their PFS time censored on the date of randomization with 
duration of 1 day.  

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A stratified log-rank test will be used to compare PFS curves between the two treatment 
groups.  PFS will also be summarized using the Kaplan-Meier method.  The Kaplan-Meier 
estimates for the 1-y PFS rates and the 2-sided 95% confidence interval of the rates using the 
Greenwood’s formula will be reported.
9.3.2.3. Complete Remission at Week 26
Complete Remission (CR) is defined as per the revised response criteria for malignant 
lymphoma.6 CR rate will be summarized by treatment group and visit. CR will be assessed 
by central review based on scans done at Week 26. CR will be analyzed in a similar fashion 
as for ORR. 
9.3.2.4. Duration of Response
Duration of Response (DOR) is defined as the time from date of the first documentation of 
overall response (CR or PR) to the first documentation of progressive disease (PD) or to 
death due to any cause in the absence of documented PD.  Censoring for the DOR endpoint 
will be assigned on the date of the last tumor assessment if no assessment of tumor 
progression is identified and the patient does not die while on study.  DOR will only be 
calculated for the subgroup of patients who have a response and who have measurable 
disease at baseline and at least 1 post baseline response assessment.  A stratified log-rank test 
will be used to compare the treatment groups with respect to DOR at a 2-sided alpha level of 
0.05.  DOR will also be summarized using Kaplan-Meier survival curves.  The Kaplan-Meier 
survival estimates, together with the number of patients, percentage of patients to experience 
the event, and the number and percentage of patients censored will be summarized in a table 
by treatment group.
9.3.2.5. Overall Survival 
Time to death is defined as the time from date of randomization to death due to any cause. 
Patients will be censored for this endpoint on the date of the last tumor assessment if they do 
not die at that time. A stratified log-rank test will be used to compare the overall survival
(OS) curves between the two treatment groups. Overall survival will also be summarized 
using the Kaplan-Meier method.  The Kaplan-Meier estimates for the 1-y OS rates and the 
2-sided 95% confidence interval of the rates using the Greenwood’s formula will be reported.
9.4. Safety Analysis
All patients treated with at least one dose of study treatment will be included in the safety 
analyses. Adverse events will be classified using the medical dictionary for regulatory 
activities (MedDRA) classification system. The severity of adverse events will be graded 
according to the NCI CTCAE version 4.03 whenever possible. 
Safety data will be evaluated by the incidence of AEs, severity and type of AEs, and by 
changes from baseline in the patient’s vital signs, weight, and clinical laboratory results using 
the safety population. Exposure to the study drug regimen and reasons for discontinuation 
will be tabulated.  Collected prior and concomitant medications will also be listed and 
summarized. 

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Details of the safety analyses will be described in the Statistical Analysis Plan (SAP).
9.5. Pharmacokinetics, Biomarkers and Immunogenicity
9.5.1. Pharmacokinetics Analysis
The drug concentration-time data will be summarized by descriptive statistics (mean, 
standard deviation, median, minimum, and maximum) according to treatment.
Population PK assessment will be conducted with the drug concentration-time data using the
nonlinear mixed effect modeling approach in accordance with regulatory guidances.  All 
patients from the PP population who are treated with rituximab-Pfizer or rituximab-EU and 
provide at least one post-dose drug concentration measurement will be included in the 
population PK analysis. The population PK analysis will estimate typical value and 
variability for parameters including half-life (t1/2), clearance (CL) and volume of distribution 
(Vd).  Also, the influence of selected potential covariates on the PK parameters will be 
explored; the potential covariates to be explored will include drug product, selected 
demographics (eg, body weight, sex, age), and ADA status.
The detailed procedures for the population PK analysis, including the model implementation
and evaluation, will be described prospectively in the Population Modeling Analysis Plan 
(PMAP). The results of the analysis will be summarized in a Population Modeling and 
Analysis Report (PMAR), separate from the clinical study report of this study.
9.5.2. Biomarker Analysis
Summary statistics by treatment and visit will be provided for biomarkers, including 
CD19-positive B-cell counts, IgM and IgG, etc.  Mean change (or percent change) from 
baseline will be also summarized by treatment and visit and presented in tabular form and/or 
graphically. 
9.5.3. Immunogenicity
For the immunogenicity data, the percentage of patients with positive ADA and neutralizing 
antibodies will be summarized for each treatment. For patients with positive ADA, the 
magnitude (titer), time of onset, and duration of ADA response will also be described, if data 
permit. In addition, efforts will be made, as appropriate, to examine possible correlations of 
the ADA response with clinical data on the PK, safety and/or efficacy of each product. 
Because the observed incidence of ADA is highly dependent on multiple factors including 
the assays used for ADA detection, timing of sample collection and immune status of the 
patients, the incidence of ADA observed in the planned study may differ from the incidence 
reported in historical clinical trials.
CCI

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9.6. Other Endpoints
Demographic and baseline characteristics such as patient age, sex, height, weight, ethnicity, 
prior therapy, medical history, ECOG performance status and FLIPI and FLIPI2 risk 
classification will be tabulated and summarized using descriptive statistics. Relationships
between baseline patient characteristics and study outcome variables will be explored with 
appropriate techniques.
Study drug administration will be described in terms of the total number of cycles 
administered, the median (range) of cycles administered, dose intensity, and reasons for the 
deviations from planned therapy.
9.7. Interim Analysis
There will be no interim analysis in this study.
9.8. External Data Monitoring Committee 
Safety monitoring will be conducted throughout the study by the Pfizer study team. In 
addition, this study will use an External Data Monitoring Committee (E-DMC). 
The E-DMC will be a 3-member panel of external experts that will meet at approximate 
3-month intervals throughout the course of the study unless safety concerns requiring their 
attention arise earlier.  An E-DMC liaison will be appointed; this is an individual who 
represents Pfizer to coordinate communications and facilitates access to Pfizer’s resources, 
but is not involved in the study design, study management, site management, data accrual, or 
study analysis.  The SAP will outline plans for data review.  An E-DMC charter will outline 
the operating procedures of the committee, including a specific description of the scope of 
their responsibilities, and a communication plan.  Records of E-DMC meetings, interactions 
with Pfizer contacts, assessments and recommendations and materials reviewed will be 
maintained and kept proprietary and confidential by the E-DMC. 
The E-DMC will be responsible for ongoing monitoring of the safety of patients in the study 
according to the Charter.  The recommendations made by the E-DMC to alter the conduct of 
the study will be forwarded to Pfizer for final decision.  Pfizer will forward such decisions, 
which may include summaries of aggregate analyses of endpoint events and of safety data 
which are not endpoints, to regulatory authorities, as appropriate.  In this instance, such 
disease-related efficacy endpoints are not reported individually as SAEs.
The E-DMC will be responsible for the periodic review of accumulating safety data.  The 
E-DMC will advise the Sponsor regarding the safety of patients enrolled in the study.
Additionally, significant findings observed by Study Team will be communicated to the 
E-DMC for further review and advice. 
10. QUALITY CONTROL AND QUALITY ASSURANCE
During study conduct, Pfizer or its agent will conduct periodic monitoring visits to ensure 
that the protocol and Good Clinical Practices (GCPs) are being followed.  The monitors may 
review source documents to confirm that the data recorded on CRFs is accurate.  The 

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investigator and institution will allow Pfizer monitors/auditors or its agents and appropriate 
regulatory authorities direct access to source documents to perform this verification.
The study site may be patient to review by the Institutional Review Board (IRB)/Independent 
Ethics Committee (IEC), and/or to quality assurance audits performed by Pfizer, or 
companies working with or on behalf of Pfizer, and/or to inspection by appropriate 
regulatory authorities.
It is important that the investigator(s) and their relevant personnel are available during the 
monitoring visits and possible audits or inspections and that sufficient time is devoted to the 
process.
11. DATA HANDLING AND RECORD KEEPING
11.1. Case Report Forms/Electronic Data Record
As used in this protocol, the term CRF should be understood to refer to either a paper form or 
an electronic data record or both, depending on the data collection method used in this study.
A CRF is required and should be completed for each included patient.  The completed 
original CRFs are the sole property of Pfizer and should not be made available in any form to 
third parties, except for authorized representatives of Pfizer or appropriate regulatory 
authorities, without written permission from Pfizer.
The investigator has ultimate responsibility for the collection and reporting of all clinical, 
safety and laboratory data entered on the CRFs and any other data collection forms (source 
documents) and ensuring that they are accurate, authentic / original, attributable, complete, 
consistent, legible, timely (contemporaneous), enduring and available when required.  The 
CRFs must be signed by the investigator or by an authorized staff member to attest that the 
data contained on the CRFs is true. Any corrections to entries made in the CRFs, source 
documents must be dated, initialed and explained (if necessary) and should not obscure the 
original entry. 
In most cases, the source documents are the hospital's or the physician's patient chart.  In 
these cases data collected on the CRFs must match the data in those charts. 
In some cases, the CRF, or part of the CRF, may also serve as source documents.  In these 
cases, a document should be available at the investigator’s site as well as at Pfizer and clearly 
identify those data that will be recorded in the CRF, and for which the CRF will stand as the 
source document.
11.2. Record Retention
To enable evaluations and/or audits from regulatory authorities or Pfizer, the investigator 
agrees to keep records, including the identity of all participating patients (sufficient 
information to link records, eg, CRFs and hospital records), all original signed informed 
consent documents, copies of all CRFs, safety reporting forms, source documents, and 
detailed records of treatment disposition, and adequate documentation of relevant 
correspondence (eg, letters, meeting minutes, telephone calls reports).  The records should be 

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retained by the investigator according to International Conference on Harmonisation (ICH), 
local regulations, or as specified in the Clinical Study Agreement (CSA), whichever is 
longer.
If the investigator becomes unable for any reason to continue to retain study records for the 
required period (eg, retirement, relocation), Pfizer should be prospectively notified.  The 
study records must be transferred to a designee acceptable to Pfizer, such as another 
investigator, another institution, or to an independent third party arranged by Pfizer. 
Investigator records must be kept for a minimum of 15 years after completion or 
discontinuation of the study or for longer if required by applicable local regulations.
The investigator must obtain Pfizer's written permission before disposing of any records, 
even if retention requirements have been met.
12. ETHICS
12.1. Institutional Review Board (IRB)/Independent Ethics Committee (IEC)
It is the responsibility of the investigator to have prospective approval of the study protocol, 
protocol amendments, informed consent documents, and other relevant documents, eg,
recruitment advertisements, if applicable, from the IRB/IEC.  All correspondence with the 
IRB/IEC should be retained in the Investigator File.  Copies of IRB/IEC approvals should be 
forwarded to Pfizer.
The only circumstance in which an amendment may be initiated prior to IRB/IEC approval is 
where the change is necessary to eliminate apparent immediate hazards to the patients.  In 
that event, the investigator must notify the IRB/IEC and Pfizer in writing immediately after 
the implementation.
12.2. Ethical Conduct of the Study
The study will be conducted in accordance with legal and regulatory requirements, as well as 
the general principles set forth in the International Ethical Guidelines for Biomedical 
Research Involving Human Subjects (Council for International Organizations of Medical 
Sciences 2002), Guidelines for GCP (ICH 1996), and the Declaration of Helsinki (World 
Medical Association 1996 & 2008). 
In addition, the study will be conducted in accordance with the protocol, the ICH guideline 
on GCP, and applicable local regulatory requirements and laws.
12.3. Patient Information and Consent
All parties will ensure protection of patient personal data and will not include patient names 
on any sponsor forms, reports, publications, or in any other disclosures, except where
required by laws.
Patient names, initials, address, birth date and other identifiable data will be replaced by a 
numerical code consisting of a numbering system provided by Pfizer in order to de-identify 
the trial patient. In case of data transfer, Pfizer will maintain high standards of 
confidentiality and protection of patient personal data.

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The informed consent document must be in compliance with ICH GCP, local regulatory 
requirements, and legal requirements.
The informed consent document(s) used during the informed consent process must be 
reviewed by the sponsor, approved by the IRB/IEC before use, and available for inspection.
The investigator must ensure that each study patient, or his/her legal representative, is fully 
informed about the nature and objectives of the study and possible risks associated with 
participation.  The investigator, or a person designated by the investigator, will obtain written 
informed consent from each patient or the patient's legal representative before any 
study-specific activity is performed. The investigator will retain the original of each patient's 
signed consent document.
12.4. Patient Recruitment
Patient recruitment efforts are not required for this study because the indication is follicular 
lymphoma and patients with follicular lymphoma are usually invited by their healthcare 
professional to participate.  However, for those sites that think advertisements are useful, 
advertisements approved by ethics committees and investigator databases may be used as 
recruitment procedures.
12.5. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH GCP
In the event of any prohibition or restriction imposed (ie, clinical hold) by an applicable 
Competent Authority in any area of the World, or if the investigator is aware of any new 
information which might influence the evaluation of the benefits and risks of the 
investigational product, Pfizer should be informed immediately. 
In addition, the investigator will inform Pfizer immediately of any urgent safety measures 
taken by the investigator to protect the study subjects against any immediate hazard, and of 
any serious breaches of this protocol or of ICH GCP that the investigator becomes aware of.
13. DEFINITION OF END OF TRIAL
13.1. End of Trial in a Member
End of Trial in a Member State of the European Union is defined as the time at which it is 
deemed that sufficient patients have been recruited and completed the study as stated in the 
regulatory application (ie, Clinical Trial Application (CTA)) and ethics application in the 
Member State.  Poor recruitment (recruiting less than the anticipated number in the CTA) by 
a Member State is not a reason for premature termination but is considered a normal 
conclusion to the study in that Member State.
13.2. End of Trial in all Participating Countries
End of Trial in all participating countries is defined as all patients have been followed for 
12 months unless lost to follow-up or the patient has died.  This is the Last Patient Last Visit
plus the time it takes for the Investigator to review all results from that visit.  For the 
purposes of analysis, the study will be unblinded to the Sponsor (but not Investigators or 

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patients) once all patients have reached the primary endpoint and the database is locked 
through the end of Week 26.
14. SPONSOR DISCONTINUATION CRITERIA
Premature termination of this study may occur because of a regulatory authority decision, 
change in opinion of the IRB/IEC, drug safety problems, or at the discretion of Pfizer.  In 
addition, Pfizer retains the right to discontinue development of PF-05280586 at any time.
If a study is prematurely terminated or discontinued, Pfizer will promptly notify the 
investigator.  After notification, the investigator must contact all participating patients and 
the hospital pharmacy (if applicable) within 14 calendar days.  As directed by Pfizer, all 
study materials must be collected and all CRFs completed to the greatest extent possible.
15. PUBLICATION OF STUDY RESULTS
15.1. Communication of Results by Pfizer
Pfizer fulfills its commitment to publicly disclose clinical trial results through posting the 
results of studies on www.clinicaltrials.gov (ClinicalTrials.gov), the European Clinical Trials 
Database (EudraCT), and/or www.pfizer.com, and other public registries in accordance with 
applicable local laws/regulations.
In all cases, study results are reported by Pfizer in an objective, accurate, balanced, and 
complete manner and are reported regardless of the outcome of the study or the country in 
which the study was conducted.
www.clinicaltrials.gov
Pfizer posts clinical trial US Basic Results on www.clinicaltrials.gov for Pfizer-sponsored 
interventional studies conducted in patients that evaluate the safety and/or efficacy of a Pfizer 
product, regardless of the geographical location in which the study is conducted.  US Basic 
Results are submitted for posting within 1 year of the primary completion date for studies in 
adult populations or within 6 months of the primary completion date for studies in pediatric 
populations.
Primary Completion Date is defined as the date that the final patient was examined or 
received an intervention for the purposes of final collection of data for the primary outcome, 
whether the clinical trial concluded according to the pre-specified protocol or was 
terminated.  
EudraCT
Pfizer posts EU Basic Results on EudraCT for all Pfizer-sponsored interventional studies that 
are in scope of EU requirements.  EU Basic Results are submitted for posting within 1 year 
of the primary completion date for studies in adult populations or within 6 months of the 
primary completion date for studies in pediatric populations.

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www.pfizer.com
Pfizer posts Public Disclosure Synopses (clinical study report synopses in which any data 
that could be used to identify individual patients has been removed) on www.pfizer.com for 
Pfizer-sponsored interventional studies at the same time the US Basic Results document is 
posted to www.clinicaltrials.gov.
15.2. Publications by Investigators
Pfizer has no objection to publication by Investigator of any information collected or 
generated by Investigator, whether or not the results are favorable to the Investigational 
Drug. However, to ensure against inadvertent disclosure of Confidential Information or 
unprotected Inventions, Investigator will provide Pfizer an opportunity to review any 
proposed publication or other type of disclosure before it is submitted or otherwise disclosed.
Investigator will provide manuscripts, abstracts, or the full text of any other intended 
disclosure (poster presentation, invited speaker or guest lecturer presentation, etc.) to Pfizer 
at least 30 days before they are submitted for publication or otherwise disclosed. If any 
patent action is required to protect intellectual property rights, Investigator agrees to delay 
the disclosure for a period not to exceed an additional 60 days.
Investigator will, on request, remove any previously undisclosed Confidential Information 
(other than the Study results themselves) before disclosure.
If the Study is part of a multi-centre study, Investigator agrees that the first publication is to 
be a joint publication covering all centers. However, if a joint manuscript has not been 
submitted for publication within 12 months of completion or termination of the Study at all 
participating sites, Investigator is free to publish separately, patient to the other requirements 
of this Section.
For all publications relating to the Study, Institution will comply with recognized ethical 
standards concerning publications and authorship, including Section II - “Ethical 
Considerations in the Conduct and Reporting of Research” of the Uniform Requirements for 
Manuscripts Submitted to Biomedical Journals, http://www.icmje.org/index.html#authorship, 
established by the International Committee of Medical Journal Editors.
Publication of study results is also provided for in the Clinical Study Agreement between 
Pfizer and the institution.  In this section entitled Publications by Investigators, the defined 
terms shall have the meanings given to them in the Clinical Study Agreement.

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16. REFERENCES
1.
Rituxan® (rituximab) Prescribing Information. 
http://www.gene.com/download/pdf/rituxan_prescribing.pdf
2.
MabThera® (rituximab): Summary of Product Characteristics (SPC). January 3, 2014.
http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-
_Product_Information/human/000165/WC500025821.pdf
3.
Ujjani C and Cheson BD (2013) The optimal management of follicular lymphoma: an 
evolving field.  Drugs 73:1395-1403.
4.
NCCN Clinical Practice Guidelines in Oncology: Non-Hodgkin's Lymphomas. Version 
3, 2011.(http://www.nccn.org/professionals/physician_gls/pdf/nhl.pdf).
5.
ESMO Guidelines (http://www.esmo.org/Guidelines-Practice/Clinical-Practice-
Guidelines/Haematologic-Malignancies/Newly-Diagnosed-and-Relapsed-Follicular-
Lymphoma).
6.
Brice P et al. (1997) Comparison in Low-Tumor-Burden Follicular Lymphomas 
Between an Initial No-Treatment Policy, Prednimustine, or Interferon Alfa: A 
Randomized Study From the Groupe D'Etude des Lymphomes Folliculaires.  J Clin 
Oncol;15:1110- 1117.
7.
Ardeshna KM, Qian W, Smith P, et al. Rituximab versus a watch-and-wait approach in 
patients with advanced-stage, asymptomatic, non-bulky follicular lymphoma: an 
open-label randomized phase 3 trial. Lancet Oncology 2014; 15: 424-35.
8.
Kahl B et al. (2011) Results of Eastern Cooperative Oncology Group Protocol E4402 
(RESORT): A randomized phase III study comparing two different rituximab dosing 
strategies for low tumor burden follicular lymphoma. 53rd American Society of 
Hematology Annual Meeting. Abstract LBA-6.
9.
Ardeshna KM et al. (2003) Long-term effect of a watch and wait policy versus 
immediate systemic treatment for asymptomatic advanced-stage non-Hodgkin 
lymphoma: a randomised controlled trial.  Lancet; 362: 516–22.
10.
Cheson BD et al: (1999) Report of an International Workshop to Standardize Response 
Criteria for Non-Hodgkin’s Lymphomas J Clin Oncol 17:1244-1253.
11.
Cheson BD et al: (2007) Revised response criteria for malignant lymphoma. J Clin 
Oncol 25:579-86.
12.
Federico et al. (2009) Follicular lymphoma international prognostic index 2: a new 
prognostic index for follicular lymphoma developed by the International Lymphoma 
Prognostic Factor Project. J Clin Oncol; 27:4555-4562.
13.
Miettinen O and Nurminen M.  (1985) Comparative analysis of two rates Stat 
Med.;Apr-Jun;4(2):213-26.

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Appendix 1. Ann Arbor Staging System
ANN ARBOR STAGING SYSTEM
Stage
Area of involvement
I
Single lymph node group
II
Multiple lymph node groups on same side of diaphragm
III
Multiple lymph node groups on both sides of diaphragm
IV
Multiple extranodal sites or lymph nodes and extranodal disease

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Appendix 2. Follicular Lymphoma International Prognostic Index (FLIPI)
FOLLICULAR LYMPHOMA INTERNATIONAL PROGNOSTIC INDEX (FLIPI)
Parameter
Adverse factors
Age
>60 years
Ann Arbor stage
III–IV
Hemoglobin level
<120 g/L
Serum lactate dehydrogenase (LDH) level
Above upper limit of normal
Number of nodal areas involved
>4
Risk group
Number of adverse factors
Low risk
0–1
Intermediate risk
2
High risk
≥3
FOLLICULAR LYMPHOMA INTERNATIONAL PROGNOSTIC INDEX 2 (FLIPI2)
Parameter
Adverse factors
Age
>60 years
Hemoglobin level
<120 g/L
β2-microglobulin level
Above upper limit of normal
Longest diameter of largest involved node >6 cm
Bone marrow involvement
Present
Risk group
  
Number of adverse factors
Low risk 
0
Intermediate risk
1–2
High risk
3–5

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Appendix 3. Revised Response Criteria for Malignant Lymphoma (2007)
Complete Remission

Complete disappearance of all detectable evidence of disease

All nodal index lesions must have regressed to normal size

All splenic and hepatic nodules and other extranodal sites of disease resolved

No new sites of disease should be observed