Conditions: Lymphoma, Follicular
Keywords: Refractory Safety Efficacy Rituximab refractory Oncology Ofatumumab Bendamustine Indolent B-cell Non- Hodgkin's Lymphoma Unresponsive Rituximab Rituximab-Containing Regimen
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 346
Healthy volunteers: no

Brief summary:
The purpose of this study was to evaluate the safety and efficacy of ofatumumab and bendamustine combination therapy in patients with indolent B-cell NHL that did not respond to rituximab or a rituximab-containing regimen during or within 6 months of the last rituximab treatment.

Detailed description:
Ofatumumab is an anti-CD20 monoclonal antibody shown to have monotherapy activity in patients with follicular lymphoma that has relapsed following rituximab-containing therapy. Bendamustine was approved by FDA for the treatment of in patients with indolent B-cell Non-Hodgkin's Lymphoma (NHL) that did not respond to rituximab or a rituximab-containing regimen during or within 6 months of the last rituximab treatment.

Biologics have demonstrated enhanced efficacy when added to chemotherapeutic combinations in the frontline treatment for indolent NHL. The combination of ofatumumab and bendamustine may provide additional clinical benefit and efficacy to those who no longer respond to rituximab or rituximab-containing regimens.

The objective of this study is to determine the effect of ofatumumab and bendamustine combination therapy in patients with indolent B-cell NHL that did not respond to rituximab or a rituximab-containing regimen during or within 6 months of the last rituximab treatment.

Arms:
arm 1: Up to 8 cycles of bendamustine (90 mg/m2) on Days 1,2 every 21 days with12 doses of ofatumumab (1000 mg, Day 1 q21 days when with bendamustine and q28 days when given as monotherapy) arm 2: Up to 8 cycles of bendamustine (120 mg/m2) on Days 1,2 every 21 days

Interventions: intervention 1: Ofatumumab intervention 2: Bendamustine infusion intervention 3: Ofatumumab and Bendamustine infusions (Arm A) intervention 4: Bendamustine infusion (Arm B)
Intervention descriptions: intervention 1: Ofatumumab was a liquid concentrate solution for infusion presented in glass vials containing 50 mL of solution at a concentration of 20 mg/mL to provide 1000 mg per vial. The ofatumumab infusions were prepared in 1000 mL sterile, pyrogen-free 0.9% NaCl to yield a 1 mg/mL ofatumumab concentration infusion. intervention 2: Bendamustine 100 mg/vial, injection intervention 3: Up to 8 cycles of Bendamustine (90 mg/m2 Days 1 and 2, every 21 days) given in combination with 12 doses of ofatumumab (1000 mg). Ofatumumab will be given on day 1 of each cycle of bendamustine as long as patients in Arm A receive bendamustine. Once patients in Arm A complete bendamustine therapy, the remaining doses of ofatumumab will be given monthly until all 12 doses are completed. intervention 4: Bendamustine (120 mg/m2 Days 1 and 2, every 21 days, up to 8 cycles).

Protocol document:
Prot_000.pdf: 
Clinical Development
GSK1841157
Protocol OMB110918 / NCT01077518
A Randomized, Open Label Study of Ofatumumab and 
Bendamustine Combination Therapy Compared with 
Bendamustine Monotherapy in Indolent B-cell Non-
Hodgkin’s Lymphoma Unresponsive to Rituximab or a 
Rituximab-Containing Regimen During or Within Six 
Months of Treatment
Authors
Document type
Amended Protocol Version 
EUDRACT number
2008-004177-17
Version number
11
Development phase
III
Document status
Final
Release date
13-Apr-2017
Novartis internal 
reference number
COMB157E2301
Property of Novartis
Confidential
May not be used, divulged, published, or otherwise disclosed
without the consent of Novartis


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Amendment 9 (13-Apr-2017) 
Amendment rationale 
The purpose of amendment 9 is to revise the total number of events required for the primary 
analysis of the primary end point PFS.  
The primary analysis was planned after reaching 259 PFS events as determined by an 
Independent Review Committee (IRC).  Based on the current status of the study and PFS 
event count by IRC, it is highly unlikely that the 259 PFS events will be achieved. 
The study has been ongoing since September 2010 when the first patient was enrolled and the 
study sponsorship changed in February 2016 from GSK to Novartis (Amendment 8, dated
18Mar2016). Per protocol, Interim Analysis for efficacy and futility and IDMC review 
occurred (22Feb2016) after 180 PFS events by IRC were reached (31Oct2015). IDMC 
recommended to continue the study without changes. The interim analysis of PFS was
performed by an independent Statistical Data Analysis Centre. As per IDMC charter, 
unblinded results were not communicated to the sponsor in order to maintain the integrity of 
the trial. The protocol defined full recruitment of 346 patients was achieved as of 16May2016.
As of 31Jan2017, 203 PFS events by IRC were reported with 56 events remaining to achieve 
the planned 259 events. Furthermore, there were approximately 58 patients at risk of having a 
future event at that time, so it was highly unlikely that 259 PFS events would ever be reached. 
The overall rate of discontinuation before PFS event was 21% (n=71 out of 346), due to 
reasons such as withdrawal from study, start of new anti-cancer therapy and lost to follow-up. 
This was higher than the protocol assumed discontinuation rate of 12%.
This amendment defines an updated targeted number of PFS events by IRC of approximately 
215 for the primary analysis. This number of events was selected as it is achievable in a 
timely manner (considering the current rate of PFS events), and it allows to keep an 
appropriate level of power (84%) to demonstrate the targeted treatment effect. The critical 
value for the primary analysis has been updated using the targeted number of events at the 
cut-off date, and considering the α-level spent at interim analysis, in order to achieve a 
cumulative type I error smaller than 5%.
Sixty nine percent of enrolled patients in this study have the diagnosis of follicular lymphoma 
(FL) and 31% have other histological subtypes of indolent non-Hodgkin lymphoma (iNHL).
Prior experience with the anti-CD20 monoclonal antibody obinutuzumab in the GADOLIN 
trial with very similar trial design  showed that the efficacy of this drug was demonstrated in 
the FL sub-type only (80% of the trial population), which led to the approval of obinutuzumab 
in combination with bendamustine in that particular subset of iNHL patients only. Since the 
current protocol does not include an analysis of efficacy per histological subtypes (i.e. in FL 
and non-FL patients) and based on the above considerations, secondary objectives are added 
in order to formally compare efficacy in the FL patients between treatment arms (i.e. 
“inferential secondary endpoints”). Efficacy analyses will also be performed in the non-FL 
patients to allow accurate interpretation of the results. Consequently, the hierarchical testing 
procedure is updated to include PFS, ORR and OS in the FL patients, in addition to PFS, ORR 
and OS in all patients. 


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The initial testing plan for inferential secondary endpoints (i.e. PFS according to IRC 
assessment in FL patients, overall survival and ORR in overall patients and in FL patients) has 
been updated to incorporate the additional objectives 
 
. The updated approach allows to control the type I error 
probability by using a separate alpha spending function for each inferential secondary 
endpoint, independent of the one used for the primary efficacy analysis of PFS.
A total of 173 patients were randomized to Arm B (Bendamustine monotherapy). Over time, 
there were inconsistencies in the protocol amendments regarding the need for collection of 
HACA samples for Arm B patients at Cycle 1 Day 1 (C1D1). Despite these inconsistencies, 
the general interpretation was that samples should be collected at C1D1, which resulted in 
collection of approximately 83% of Arm B (n=143 of total 173) HACA samples at that time 
point. This amendment clarifies HACA sample collection for Arm B patients stating that 
HACA samples should be collected at C1D1 for all patients in the trial.
The amendment also clarifies timing of primary and final analysis. Primary analysis will take 
place after approximately 215 PFS events by IRC are achieved and final analysis will take 
place after all patients have completed 5 year follow up or discontinued earlier.
This amendment replaces IRR (Independent Radiology Review) with IRC (Independent 
Review Committee which includes radiology and Oncology review) to correctly reflect the 
review of PFS events being done. 
Changes to the protocol
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underline for insertions.
Sponsor Information Page: Medical lead contact information changed to reflect current 
medical lead information
Protocol Summary: updated to add the Amendment 9 changes related to the revised number of 
events needed for the primary PFS analysis. Objective section modified to add new secondary 
objectives. Study end points updated to add new secondary end points. In the study design 
section, added primary analysis information.  Interim analysis section updated to clearly 
define IRC.
Independent Radiology (IRR) changed to Independent Review Committee (IRC) throughout
the document where applicable.
Summary of previous amendments was added.
Updated the list of abbreviations to add IRC.
For clarity, the term “primary analysis” is used throughout the document, to replace the 
previous term of “final analysis”, for the analysis which is planned when approximately 215 
PFS events by IRC occurs. Additionally, in Section 8.2, the definition of “final analysis” has 
been added for the analysis to be conducted at the end of study.
Section 2: Secondary objectives are added for patients with follicular lymphoma. 


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Section 3.1: Added the revised number of PFS events needed for the primary analysis.
Section 6.3.3: Updated to clarify collection of HACA samples. 
Section 8.2: Primary analysis and final analysis are clearly described.  Final was changed to 
primary wherever applicable throughout the document. Added the number of revised events 
required for primary analysis, including statistical justification.  
Sections 8.2.1, 8.3.3.1, 8.3.3.2, 8.3.5, 8.3.6.1: Added when the primary analysis will take 
place. 
Section 8.3.3.2: Hierarchical testing scheme is modified to accommodate additional secondary 
endpoints in patients with follicular lymphoma.
Section 8.3.3 and 8.3.6.1: Analyses related to patients with follicular lymphoma are added.
Section 8.3.6.3 Language regarding PRO analyses is updated
Appendix 3 is updated to reflect change of IRR to IRC
Information for IRB
A copy of this amended protocol will be sent to all applicable Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities.
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation. 
Amendment 8 (18-Mar-2016)
Amendment rationale 
Subsequent to the acquisition of GlaxoSmithKline (GSK) compound GSK1841157, the 
purpose of this protocol Amendment 8 is to:

Delete or replace references to GSK or its staff with that of Novartis and its authorized 
agents to align with the change of sponsorship;

Make administrative changes to align with Novartis processes and procedures;
As of 11-JAN-16:
336 patients have received study treatment in 16 countries; 
The changes described in this amended protocol require Institutional Review Board (IRB)/
Independent Ethics Committee (IEC) approval prior to implementation. 
A copy of this amended protocol will be sent to the IRBs/IECs and Health Authorities (HAs).
The changes herein affect the Informed Consent and all sites are required to update and 
submit for approval, a revised Informed Consent that takes into account the change of study 
sponsorship described in the protocol amendment.
Upon approval of this amendment, patients who have already been enrolled in the study will 
sign a new informed consent form indicating Novartis is the new study sponsor and continue 
the appropriate visit schedule.


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Revision Chronology
GlaxoSmithKline Document 
Number
Date
Version
UM2008/00047/00
2009-AUG-07
Original
UM2008/00047/01
2009-NOV-16
Amendment No. 1
Logo updated to describe meaning of COMPLEMENT.
Sponsor information page:  Medical Monitor contact information updated.
Addition of secondary endpoint:  Overall response rate to optional ofatumumab monotherapy in 
subjects in Arm B who progress during or following single-agent bendamustine.
Spelling correction in the Exclusion Criteria:  fludaranine replaced by fludarabine and addition of 
criteria excluding prior treatment with anti-CD20 mAb within 3 months of randomization.
Administer bendamustine therapy as monotherapy or in combination with ofatumumab for up to 8 
cycles.
There will be a total of 12 ofatumumab infusions in Arm A.  Ofatumumab will be given on day 1 of 
each cycle of bendamustine as long as subjects in Arm A receive bendamustine.  Once subjects 
in Arm A complete bendamustine therapy, the remaining doses of ofatumumab will be given 
monthly until all 12 doses are completed
UM2008/00047/02
2010-MAY-12
Amendment No. 2
Sponsor information page:  Medical Monitor phone number corrected.
Introduction includes additional rationale for infusion of 1000 mg dose upon first infusion in and 
2000 mg dose upon 2nd infusion (for those who receive ofatumumab following PD in Arm B) at 
protocol defined rate.
Inclusion criterion #1 updated:  Removed reference to bulky stage.
Clarified screening procedures.
Inclusion criterion #2 updated:  to allow CT imaging performed at least 60 days after the last dose 
of rituximab-based therapy.  Modified text for prior rituximab infusions.
Exclusion criterion #3 updated timeframe from previous autologous stem cell transplant, or 
fludarabine therapy, or radioimmunotherapy from past 12 months to last 6 months.
Exclusion criterion #5 updated timeframe for high dose steroids (7 consecutive days) and dose of 
prednisone before randomization (100 mg). 
Exclusion criterion #7 update to exclude prior use of any monoclonal antibody (other than anti-
CD20) within 3 months of randomization and anti-CD20 therapy first dose was administered 60 
days prior to randomization.
Exclusion criteria #15 updated:  specifies liver metastases related to indolent NHL.
Exclusion criterion #18 updated to include hypersensitivity to bendamustine and mannitol.
Removed exclusion criterion #20 since it duplicated criterion #7.
Subjects in Arm B who choose to receive optional ofatumumab monotherapy will receive 
ofatumumab 1000 mg for the first dose.
CT scans, lymphoma symptoms, and response assessments will be done Days 84, 168, and 252 
(±7 days).
Whole body CT scan (contrast imaging of neck when lesion is palpable, thorax, abdomen, pelvis).
Section 6.2.4.2:  removed mention of physical examination as part of CR assessment.
Updated FACT-Lym Version 4, removed FACT-G Patient Reported Outcomes (PRO) 
questionnaire.
HACA test done before first dose of ofatumumab.


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Additional PK sampling in Appendix 3 (if ofatumumab selected following PD in Arm B).
A pharmacokinetic sample (and a HAHA sample) will be collected with other withdrawal 
assessments for subjects who withdraw from treatment when receiving ofatumumab.  For 
subjects who experience progressive disease, a PK sample (and a HAHA sample) will be 
collected on one occasion after disease progression.
Investigator Brochure updated now dated 28 April 2010.
In the event the 1st infusion of bendamustine is administered on Day 2 of a cycle (in Arm A only), 
then some assessments done on Day 1 will need to be done on Day 2 and assessments done on 
Day 2 will need to be completed on Day 3.
Visit window between cycles specified:  ofatumumab and bendamustine must be given 
consecutively.  An “on within 3 days after” visit window will be allowed between cycles.
Visit window for each week of optional ofatumumab updated to ±1 day with a minimum 7 day 
interval between weekly infusions.
The time to infuse for 1000 mg and 2000 mg is the same (4.5 hours first infusion and 4.0 hours 
subsequent infusions).
Appendix 6: Update FLIP-1 and FLIPI-2 tables.
UM2008/00047/04
2012-JAN-19
Amendment 3
CT scans may be whole body or done according to local practice
No required bone marrow aspirate
Known and exploratory prognostic markers 
 objectives 
clarified.
Inclusion Criterion #1:  Type of previous biopsy changed from “lymph node” to “tissue” biopsy.
Inclusion Criterion #1 clarified.  Tumor verified to be CD20+ positive from a previous or current 
tissue biopsy.
No longer excludes fludarabine and radioimmunotherapy.
No longer excludes external beam radiation therapy to pelvis and to bony disease to the cranium, 
mediastinum, and axilla, or > 3 vertebral bodies.
Removed Exclusion criterion restricting anti-CD20 antibody within the last 60 days
Section 3.1.1.1:  Copy of documentation confirming PD (for example, an imaging report, clinical 
documentation) after subject deemed unresponsive or relapsed to rituximab-based regimen is 
required.
Follow-up visits begin 2 months after PD is confirmed by CT scan.  For all other responses, 
follow-up visits begin on Day 336 (this is 3 months after Day 252) for both arms.
Section 4.4 clarifications:  Withdrawal Criteria:  If a subject withdraws from study drug but does 
not withdraw from the study, the subject is expected to complete all scheduled visits without study 
drug.  The subject may then enter follow-up.
Section 5.1.3, Bendamustine:  Added guidance for instances when bendamustine may be given 
<8 cycles.
Section 6.2.5:  Removed requirement to exclude target and non-target lesions not previously-
irradiated.
Bendamustine dosage must be delayed in subjects with a serum creatinine > 1.5 ULN if the 
calculated creatinine clearance or creatinine clearance from a 24-hour urine collection is ≤40 
mL/min.
Section 6.4.1:  Update to liver stopping criteria.
Clarification on timing of vital signs during and after ofatumumab infusion.


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Section 6.7 updated to reflect changes in ofatumumab pharmacokinetic sample collection.  
Section 8 updated to reflect changes in data analysis.  Time and events tables updated to reflect 
changes in ofatumumab pharmacokinetic sample collection (Appendix 2, Appendix 3).
Change to frequency of HAHA sampling in Time and Events tables (Appendix 2, Appendix 3).
 
.
Clarification:  Monthly ofatumumab dosing in Arm A begins 28 days after Day 1 of the previous 
cycle.
Acceptable but not encouraged for blood draw to be taken no more than 3 days ahead of the visit 
date, however, absolute neutrophil count, platelet count, peripheral blood lymphocytes, and 
hemoglobin local results must also be entered into the eCRF if it is used for a treatment decision.
Follow-up #1 schedule, in both arms, begins on Day 336 and continues every 3 months until 
Month 18 of the F/U phase.  The frequency of Follow-up #2 schedule comes after the end of 
follow-up schedule #1 and continues until Month 60.  The last required CT scan is done on month 
54.  The frequency of follow-up 2 will be every 12 months until Month 54.
Clarification:  The one month follow-up in Arm A will occur regardless of response.
Time and Events tables updated to reflect changes throughout protocol.
Screen failure rate changed from 10% to 15% and dropout rate changed from 10% to 12%; 
impacts estimated subject numbers.  Screening period is 21 days.
IDMC section updated to reflect their decision to not alter the dose of bendamustine in Arm A.
Section 6.5.7:  All SAEs and AEs will be collected from the first dose of investigational product to 
60 days after the last dose of investigational product and will be documented on the eCRF.  Only 
SAEs, regardless of causality, will be reported from 61 Days after the last dose of treatment to the 
end of the follow-up period.
UM2008/00047/05
2013-FEB-07
Amendment 4
Minor changes for spelling, grammar, consistency throughout document.
Administrative changes.
Edited text due to updates found in Investigator Brochure update.
Correction in footnotes to Time and Events Table (Appendix 1):  baseline CT scans required ≤1 
month of randomization.
Section 6.5.7:  Correct reference for Table updated.
High dose steroids ≥ 25 mg prednisolone/day (or equivalent) for 7 consecutive days are 
excluded.  Updated from excluding ≥ 100 mg prednisolone/day (or equivalent).
Section 6.5.7:  All SAEs regardless of causality will be reported from 61 days after the last dose 
of investigational product to the end of the follow-up period or until initiation of subsequent anti-
lymphoma therapy is initiated. Any SAE brought to the investigator's attention after the start of 
subsequent anti-lymphoma therapy and considered by the investigator as possibly related to 
either ofatumumab or bendamustine must be reported to GSK.
Additional biochemistry testing added to time and events table for ofatumumab monotherapy 
following progression in Arm B.
For Japan only:  additional directions for Hepatitis monitoring added to an Appendix.
Minor updates for consistency throughout protocol and in time and events tables.
Investigator Brochure reference updated.
UM2008/00047/06
2013-FEB-07
Amendment 5
 safety related information from the Study 
Procedures Manual (SPM) was added into Section 6.5.4.
UM2008/00047/07
2013-DEC-02
Amendment 6
Added additional instructions for monitoring subjects who are HBsAg negative, anti-HBc positive 


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and HBV DNA negative.  This instruction was added to the relevant Time and Events tables.
Exclusion criteria now specifies that physician experienced in care and management of subjects 
with Hepatitis B to manage/treat subjects who are anti-HBc positive must be consulted
Changes for countries currently using Amendment 4 include specific details on how to manage 
AEs and SAEs such as infusion reactions, tumor lysis syndrome, progressive multifocal 
leukoencephalopathyand hepatitis are described.
Minor clarifications throughout document
Universal Trial Number added
Administrative changes
UM2008/00047/08
2015-JUN-30
Amendment 7
Authors and Sponsor Contact Information Updated
Table of Contents updated to include Appendix 15: Protocol Changes for Amendment #7 from 
Amendment #6
Total number of events increased to 259 events
Total study duration increased to 77 months
Total accrual rate decreased to 5.1pt/month
Clarification of randomization strategy
An Interim Analysis added for efficacy when two thirds of IRR events occur.
Details of a further Independent Data Monitoring Committee (IDMC) added to review the safety, 
efficacy, and futility data and recommend whether the study should continue without any 
changes, be stopped to further enrollment, or be terminated. 
Liver stopping criteria updated to reflect stopping criteria applies to all patients on study, 
regardless of Arm assignment. 
Clarification of instructions regarding how patients move into Survival Follow-Up
Administrative changes
UM2008/00047/09
2015-JUL-07
Amendment 7
Republished due to typographical error
UM2008/00047/10
2016-MAR-18
Amendment 8
The purpose of this protocol amendment is to:

Delete or replace references to GSK or its staff with that of Novartis and its authorized agents 
to align with the change of sponsorship

Make administrative changes to align with Novartis processes and procedures
Sponsor Signatory:
Novartis Pharmaceuticals Corporation
Date
SPONSOR INFORMATION PAGE
Clinical Study Identifier:
OMB110918


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Sponsor Contact Information:
Novartis Pharmaceuticals Corporation
In some countries, the clinical trial sponsor may be the local Novartis and its authorized 
agents. Where applicable, the details of the Sponsor and contact person will be provided to the 
relevant regulatory authority as part of the clinical trial submission. Please refer to Study 
Procedures Manual for further details on contact information.
Sponsor Serious Adverse Events (SAE) Contact Information: For study conduct questions 
not related to patient safety, the first line of contact will be with the designated local country 
company contact. In the event that the designated company contact is not available please 
contact the Medical Lead.
 Contact Information:
, MD
Telephone: 
Email: 
 Contact Information:
Telephone: 
Email: 
If you have any questions regarding the protocol, please contact your local Novartis office.
Agency Identifying Numbers: IND Numbers: 11,465; EudraCT Number 2008-004177-17
Universal Trial Number (UTN): U1111-1145-5175
Investigator PROTOCOL Agreement Page
For protocol number: OMB110918 (COMPLEMENT A+B):
I confirm agreement to conduct the study in compliance with the protocol, as amended by this 
protocol amendment.
I acknowledge that I am responsible for overall study conduct. I agree to personally conduct 
or supervise the described study.
I agree to ensure that all associates, colleagues and employees assisting in the conduct of the 
study are informed about their obligations. Mechanisms are in place to ensure that site staff 
receives the appropriate information throughout the study.
Investigator Name:  _____________________________
Investigator Signature
Date


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Table of contents
Amendment 9 (13-Apr-2017)..............................................................................................2
Amendment 8 (18-Mar-2016) .............................................................................................4
Table of contents ...............................................................................................................10
LIST OF ABBREVIATIONS ...........................................................................................17
PROTOCOL SUMMARY ................................................................................................20
Objectives..........................................................................................................................20
Study Design .....................................................................................................................20
Dose Confirmation Cohort ................................................................................................22
Interim Analysis ................................................................................................................22
Study Endpoints and Assessments ....................................................................................22
Primary Endpoint: .............................................................................................................22
Secondary Endpoints.........................................................................................................22
Known and Exploratory Prognostic Markers Correlating with Response to 
ofatumumab:..........................................................................................................23
23
1
Introduction .......................................................................................................................24
1.1
Indolent Non-Hodgkin’s Lymphoma ....................................................................24
1.2
Current Treatment for Indolent Non-Hodgkin’s Lymphoma ................................24
1.2.1
Frontline Treatment...............................................................................24
1.2.2
Treatment for Relapsed and Refractory Diseases .................................25
1.3
Ofatumumab ..........................................................................................................26
1.4
Rationale................................................................................................................27
2
OBJECTIVES....................................................................................................................28
Primary objective: .............................................................................................................28
Secondary objectives:........................................................................................................28
28
3
investigational plan............................................................................................................29
3.1
Study Design..........................................................................................................29
3.1.1
Screening Phase ....................................................................................31
3.1.2
Randomization and Stratification..........................................................33
3.1.3
Dose Confirmation for Safety and Tolerability ....................................33
3.1.4
Treatment Phase....................................................................................34
3.1.5
Follow-up Phase....................................................................................35
Follow-up for Progressive Disease...........................................................................................37


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3.1.6
Ofatumumab Following Progressive Disease for Arm B .....................37
3.1.7
Study Endpoints ....................................................................................38
Primary Endpoint:.....................................................................................................................38
Secondary Endpoints ................................................................................................................38
39
3.2
Discussion of Design and Dose Rationale.............................................................39
3.2.1
Bendamustine Dosing ...........................................................................39
3.2.2
Ofatumumab dosing when administered with bendamustine ...............40
4
subject selection and withdrawal criteria ..........................................................................43
4.1
Number of Subjects ...............................................................................................43
4.2
Inclusion Criteria ...................................................................................................43
4.3
Exclusion Criteria..................................................................................................44
4.4
Withdrawal Criteria ...............................................................................................46
5
Study treatments ................................................................................................................47
5.1
Investigational Product and Reference Therapy....................................................47
5.1.1
Pre-Medication......................................................................................48
5.1.2
Ofatumumab..........................................................................................48
5.1.3
Bendamustine........................................................................................50
5.2
Treatment Assignment...........................................................................................53
5.3
Permitted Medications...........................................................................................53
5.4
Product Accountability..........................................................................................53
5.5
Prohibited Concomitant Medication or Therapies.................................................53
6
Study Assessments and Procedures...................................................................................54
6.1
Clinical Assessments .............................................................................................54
6.1.1
Demographics .......................................................................................54
6.1.2
Disease Characteristics and Medical History........................................54
6.1.3
Previous Indolent Lymphoma Therapy.................................................54
6.1.4
Follicular Lymphoma International Prognostic Index (FLIPI).............54
6.1.5
Height and Weight ................................................................................54
6.1.6
Concomitant Medication.......................................................................54
6.1.7
Physical Examination............................................................................55
6.1.8
Electrocardiogram.................................................................................55
6.1.9
Vital Signs.............................................................................................55
6.1.10
ECOG Performance Status....................................................................55
6.1.11
Constitutional Symptoms:.....................................................................56


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6.1.12
Pre-treatment Computed Tomography (CT) Scans and/or Imaging.....56
6.1.13
Pre-treatment Bone Marrow Examination ............................................56
6.2
Efficacy Assessments ............................................................................................56
6.2.1
Disease Responses ................................................................................56
6.2.2
CT Scans ...............................................................................................57
6.2.3
Bone Marrow Examination...................................................................57
6.2.4
Lymphoma Disease-Related Symptoms: ..............................................57
6.2.5
Documentation of Target and Non-target Lesions................................58
Baseline Documentation of Target and Non-target Lesions ....................................................58
6.2.6
Independent Review of Disease Response............................................62
6.3
Laboratory Assessments ........................................................................................62
6.3.1
Flow Cytometry for B Lymphocytes ....................................................62
6.3.2
Peripheral Blood Sampling for Hematology and Biochemistry ...........62
6.3.3
Prognostic Factors.................................................................................63
6.3.4
Peripheral Blood Sampling for Safety and Disease Status ...................63
6.4
Safety Assessments................................................................................................64
6.4.1
Liver Interruption/Stopping and Follow- up Criteria............................64
6.5
Adverse Events ......................................................................................................68
6.5.1
Definition of an AE...............................................................................68
6.5.2
Definition of a SAE...............................................................................69
6.5.3
Toxicity Assessment of AEs and SAEs ................................................69
6.5.4
Laboratory and Other Safety Assessment Abnormalities Reported 
as AEs and SAEs...................................................................................69
6.5.5
Disease-Related Events and/or Disease-Related Outcomes Not 
Qualifying as SAEs...............................................................................72
6.5.6
Pregnancy..............................................................................................72
6.5.7
Time Period and Frequency of Detecting AEs and SAEs.....................73
6.5.8
Prompt Reporting of Serious Adverse Events and Other Events to 
Novartis.................................................................................................74
6.5.9
Regulatory reporting requirements for SAEs........................................74
6.6
PRO Measures .......................................................................................................74
6.6.1
Functional Assessment of Cancer Therapy - Lymphoma (FACT-
Lym) Subscale.......................................................................................75
6.6.2
EuroQoL Five-Dimension (EQ-5D) .....................................................75
6.6.3
Health Change Questionnaire ...............................................................77
6.7
Ofatumumab Pharmacokinetic Sample Collection................................................77


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6.7.1
Sample Collection for Subjects in Arm A.............................................77
6.7.2
Sample Collection for Subjects in Arm B Who Receive 
Ofatumumab Monotherapy after Disease Progression .........................77
78
7
data management...............................................................................................................79
8
Data Analysis and Statistical Considerations ....................................................................79
8.1
Hypotheses.............................................................................................................79
8.2
Study Design Considerations.................................................................................79
Interim Analysis .......................................................................................................................80
Primary Analysis ......................................................................................................................80
8.2.1
Sample Size Assumptions.....................................................................81
8.2.2
Sample Size Sensitivity.........................................................................82
8.2.3
Sample Size Re-estimation ...................................................................82
8.3
Data Analysis Considerations................................................................................82
8.3.1
Analysis Populations.............................................................................82
8.3.2
Analysis Data Sets.................................................................................83
8.3.3
Treatment Comparisons ........................................................................83
8.3.4
Interim Analysis for Safety ...................................................................84
8.3.5
Interim Analysis for Efficacy and Futility ............................................84
8.3.6
Key Elements of Analysis Plan.............................................................84
9
Study CONDUCT CONSIDERATIONS..........................................................................90
9.1
Regulatory and Ethical Considerations, Including the Informed Consent 
Process ...................................................................................................................90
9.2
Quality Control (Study Monitoring)......................................................................91
9.3
Quality Assurance..................................................................................................91
9.4
Study and Site Closure...........................................................................................91
9.5
Records Retention..................................................................................................92
9.6
Provision of Study Results and Information to Investigators................................92
9.7
Independent Data Monitoring Committee (IDMC)...............................................93
9.7.1
Dose Confirmation for Safety and Tolerability ....................................93
Stage 1 Results from IDMC Data Review................................................................................94
9.7.2
Interim Analysis....................................................................................94
9.8
Publication Policy..................................................................................................94
10 References .........................................................................................................................95
11 Appendices ......................................................................................................................100
11.1
Appendix 1:  Time and Events Table for Treatment and Follow-Up..................100


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11.2
Appendix 2:  Time and Events Table for Laboratory Assessments ....................105
Appendix 2:  Time and Events Table for Laboratory Assessments (Continued)...................106
11.3
Appendix 3:  Time and Events:  Ofatumumab Following PD for 
Bendamustine Monotherapy Arm........................................................................108
Appendix 3:
Time and Events:  Ofatumumab Following PD for Bendamustine 
Monotherapy Arm (Continued).......................................................................................110
Appendix 3:
Time and Events:  Ofatumumab Following PD for Bendamustine 
Monotherapy Arm (Continued ........................................................................................111
112
112
112
112
113
114
114
115
115
115
117
117
118
11.5
Appendix 5: Patient Reported Outcome Measures..............................................120
11.5.1
Functional Assessment of Cancer Therapy - Lymphoma (FACT-
Lym, version 4) ...................................................................................120
11.5.2
EuorQoL Five-Dimension (EQ-5D) ...................................................123
11.5.3
Health Change Questionnaire .............................................................125
11.6
Appendix 6:  Follicular Lymphoma International Prognostic Index-1 (FLIPI-
1)..........................................................................................................................126
Table I:  The Five Parameters Retained for Building the FLIPI ............................................126
Table II:  Outcome and relative risk of death according to risk group as ..............................126
11.7
Appendix 7:  Follicular Lymphoma International Prognostic Index-2 (FLIPI-
2)..........................................................................................................................127
Table III:  The Five Parameters Retained for Building the FLIPI..........................................127
Table IV: Outcome and relative risk of death according to risk group as defined by the 
FLIPI-2 ............................................................................................................................127
11.8
Appendix 8:  Instructions for Japanese Hepatitis Testing ...................................128


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11.9
Appendix 9: General Protocol Changes for Amendment 1 (16-November-
2009) from Protocol (dated 7-AUG-2009)..........................................................129
Where the Amendment Applies .............................................................................................129
Summary and Rationale for Amendment Changes ................................................................129
Administrative Changes .........................................................................................................129
Number of Cycles changed from 6 to up to 8 cycles in both Arms .......................................129
Ofatumumab Dosing Frequency:  12 infusions of ofatumumab in Arm A............................129
Ofatumumab monotherapy for patients who progress in Arm B ...........................................130
Ofatumumab Dosing Frequency:  12 infusions of ofatumumab in Arm A............................131
Response Criteria....................................................................................................................131
Specific Protocol Changes for Amendment 1 (16-November-2009) from Protocol (dated 
7-AUG-2009) ..................................................................................................................131
List of Specific Changes.........................................................................................................131
Example:.................................................................................................................................131
Known and Exploratory Prognostic markers Correlating with Response..............................141
Known and Exploratory Prognostic markers Correlating with Response..............................141
Ofatumumab monotherapy for subjects who progress in Arm B...........................................145
Table 4
Bendamustine Dose Reduction Schedule ............................................................149
Table 4
Bendamustine Dose Reduction Schedule for Arm A ..........................................150
Table 5
Bendamustine Dose Reduction Schedule for Arm B ..........................................150
Table 7
Ofatumumab pharmacokinetic sample collection schedule (for subjects in the 
ofatumumab-bendamustine arm only).............................................................................154
Table 7
Ofatumumab pharmacokinetic sample collection schedule (for subjects in the 
ofatumumab-bendamustine arm only).............................................................................156
Table 10
Primary Endpoint power calculation ...................................................................159
Table 10
Primary Endpoint power calculation ...................................................................159
Stage 1: ...................................................................................................................................163
Stage 2: ...................................................................................................................................163
Stage 3: ...................................................................................................................................164
11.10 Appendix 10:  General Protocol Changes for Amendment 2 (12-May-2010) 
from Amendment 1 (dated 16-NOV-2009).........................................................165
Where the Amendment Applies .............................................................................................165
Summary and Rationale for Amendment Changes Implemented Throughout Amendment 
2 .......................................................................................................................................165
Administrative Changes .........................................................................................................165
Initial Infusion for Optional Ofatumumab..............................................................................165
Visit Windows........................................................................................................................165


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CT Scans.................................................................................................................................165
Complete Remission...............................................................................................................165
PRO ........................................................................................................................................165
HACA.....................................................................................................................................166
PK...........................................................................................................................................166
166
Study schematics updated to reflect protocol updates............................................................167
References Updated................................................................................................................167
Specific Protocol Changes for Amendment 2 (12-MAY-2010) from Amendment 1 (dated 
16-NOV-2009) ................................................................................................................167
List of Specific Changes.........................................................................................................167
Example:.................................................................................................................................167
Section 3.2.2:
Ofatumumab dosing when administered with bendamustine .............170
Table 7
Criteria for determining PD for new lesions and target lesions...........................176
Table 10
Pharmacokinetic sample collection schedule for subjects that progress in Arm 
B and select ofatumumab monotherapy ..........................................................................179
11.11 Appendix 11:  Protocol Changes for Amendment 3 (19 JANUARY 2012) 
from Amendment 2 (dated 12 MAY 2010) .........................................................181
Specific Protocol Changes for Amendment 3 (19-JAN.-2012) from Amendment 2 (dated 
12-MAY-2010)................................................................................................................184
11.12 Appendix 12:  Protocol Changes for Amendment 4 (09-April-2012) from 
Amendment 3 (dated 19-Jan-2012) .....................................................................203
11.13 Appendix 13:  Protocol Changes for Amendment 5 (07-Feb.-2013) from 
Amendment 4 (dated 09-April-2012)..................................................................206
11.14 Appendix 14: Protocol Changes for Amendment 6 (02-DEC.-2013) from 
Amendment 4 (dated 09-April-2012)..................................................................207
11.15 Appendix 15:  Protocol Changes for Amendment 7 (07-JUL-2015) from
Amendment 6 (dated 02-Dec-2013)....................................................................208
Interim Analysis .....................................................................................................................209
Section 3.1.2  Randomization and Stratification ....................................................................211
Table 1
Follow-up visit schedule and CT scan requirements for Arm A and Arm B ......212
Table 1
Follow-up visit schedule and CT scan requirements for Arm A and Arm B ......213
Interim Analysis .....................................................................................................................215
8.3.5 
Interim Analysis for Efficacy and Futility...........................................................219
Stage 1 Results from IDMC Data Review..............................................................................221
Stage 1 Results from IDMC Data Review..............................................................................221


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11.16 Appendix 16:  Protocol Changes for Amendment 8 (18-MAR-2016) from 
Amendment 7 (dated 07-JUL-2015)....................................................................222
LIST OF ABBREVIATIONS
AE
Adverse Event
ALC
Absolute Lymphocyte Count
ALT
Alanine Aminotransferase
ANC
Absolute Neutrophil Count
AST
Aspartate Aminotransferase
AUC
Area under the concentration-time curve 
B
Bendamustine
BP
Blood Pressure
CBC
Complete Blood Count
CD
Cluster of differentiation
CHOP
Cyclophosphamide, doxorubicin, vincristine, prednisone
CLL
Chronic Lymphocytic Leukemia
CR
Complete Remission
eCRF
Electronic Case Report Form
CT
Computed Tomography 
D, d
Day(s)
DILI
Drug Induced Liver Injury
DLBCL
Diffuse Large B Cell Lymphoma
DNA
Deoxyribonucleic Acid
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
EMA
European Medicines Agency
EOI
End of Infusion
EORTC-QLQ-C30
European Organization for Research and Treatment of Cancer
EQ-5D
EuroQoL Five Dimension
EU
European Union
FA
Futility Analysis
FcR
Fc Gamma Receptor
FL
Follicular Lymphoma
FACT-Lym
Functional Assessment of Cancer Therapy-Lymphoma
FACT-Lym TOI
Functional Assessment of Cancer Therapy-Lymphoma- Trial 
Outcome Index
FDA
Food and Drug Administration (US)
FLIPI
Follicular Lymphoma International Prognostic Index
GCSP
Global Clinical Safety and Pharmacovigilance


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GSK
GlaxoSmithKline
HACA
Human Anti-Chimeric Antibody
HAHA
Human Anti-Human Antibody
HBcAb
Hepatitis B Core Antibody
HBsAg
Hepatitis B Surface Antigen
HCG
Human Chorionic Gonadotrophin(s)
HCQ
Health Change Questionnaire
HRQL
Health Related Quality of Life
HIV
Human Immunodeficiency Virus
h, hr
Hour(s)
IA
Interim Analysis
IB
Investigator Brochure
IDMC
Independent Data Monitoring Committee
IND
Investigational New Drug
INR
International normalized Ratio
IEC
Independent Ethics Committee
IgA, IgG, IgM
Immunoglobulin A, G, M
IRB
Internal Review Board
IRR
Independent Radiology Review
ITT
Intent to Treat
IRC
Independent Review Committee
IV/i.v.
Intravenous
LDH
Lactate Dehydrogenase
M
Month(s)
m2
Meter squared
mAb
Monoclonal Antibody
MeDRA
Medical Dictionary for Regulatoy Activities
mg
Milligram(s)
MSDS
Material Safety Data Sheet
MTD
Maximum Tolerated Dose
NCI-CTCAE
National Cancer Institute Common Terminology Criteria for Adverse 
Events
NHL
Non-Hodgkin’s Lymphoma
O
Ofatumumab
ORR
Overall Response Rate
OS
Overall Survival
PD
Progressive Disease
(m)PFS
(median) Progression-Free Survival
PI
Prescribing Information
PP
Patient Population


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PPD
Product of perpendicular diameters
po
Orally (Per Os, Latin: by mouth)
PR
Partial Remission / Response
PRO
Patient reported outcome
q
Every (quaque, Latin)
R
Rituximab
RAP
Reporting and Analysis Plan
RR
Response Rate
RRCML
Revised Response Criteria for Malignant Lymphoma
SAE
Serious Adverse Event
SD
Stable Disease
SPC
Summary of Product Characteristics
SPD
Sum of the products of the greatest diameter
SPM
Study Procedures Manual
t½
Half-life
TTP
Time to progression
tmax
Time at which maximum concentration is observed
ULN
Upper Limit Normal
US
United States
VAS
Visual Analogue Scale
Vss
Volume of distribution at steady state
yr, YR
Year(s)


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PROTOCOL SUMMARY
Rationale
Patients with indolent lymphomas have a variable course. Most present with stage III or IV 
disease and eventually require treatment.
Indolent lymphomas are sensitive to alkylating 
agents and to combinations with biologics, but subsequently follow a pattern of multiple 
relapses and progressively shorter periods of remission between relapses. Options are limited 
for those who no longer respond to rituximab-containing regimens.
Bendamustine is a synthetic nitrogen mustard compound that has been approved by Food and 
Drug Administration (FDA) for the treatment of chronic lymphocytic leukemia, and has 
activity in the treatment of indolent non-Hodgkin’s lymphoma (NHL) that has progressed 
during or within 6 months of treatment with rituximab or a rituximab–containing regimen 
[Treanda Prescribing Information , 2010; Kahl, 2010; Friedberg, 2008].  Biologics have 
demonstrated enhanced efficacy when added to chemotherapeutic combinations in the 
frontline treatment for indolent NHL. Ofatumumab is an anti-CD20 mAb shown to have 
monotherapy activity in a Phase I/II study in relapsed follicular lymphoma following 
rituximab-containing therapy.  The combination of ofatumumab and bendamustine may 
provide additional clinical benefit to those who no longer respond to rituximab or rituximab-
containing regimens.  
Objectives
The primary objective of the study is to test whether the ofatumumab and bendamustine 
combination therapy will improve disease progression-free survival (PFS) in subjects with 
indolent B-cell NHL who had stable disease to, or progressed during or within 6 months of 
the end of a rituximab or a rituximab-containing regimen.
Secondary objectives evaluate clinical benefit, changes in health-related quality of life (HRQL) 
measures, safety, tolerability, exploratory prognostic markers in subjects treated with 
ofatumumab and bendamustine, and ofatumumab pharmacokinetics in subjects receiving 
ofatumumab alone after disease progression. In addition, secondary objectives are added in 
order to formally compare efficacy in the FL patients between treatment arms (i.e. “inferential 
secondary endpoints”). 
Study Design
This randomized, open label, two-arm, Phase III study consists of two treatment groups:  
ofatumumab and bendamustine combination therapy (Arm A) or bendamustine monotherapy 
(Arm B).


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Subjects will be randomized to receive:
Arm A:  Up to 8 cycles of bendamustine (90 mg/m2 Days 1 and 2, every 21 days) given in 
combination with 12 doses of ofatumumab (1000 mg).  Ofatumumab will be given on Day 1 
of each cycle of bendamustine as long as subjects in Arm A receive bendamustine.  Once 
subjects in Arm A complete bendamustine therapy, the remaining doses of ofatumumab will 
be given monthly (q28 days) until all 12 doses are completed.
Or
Arm B:  Bendamustine (120 mg/m2 Days 1 and 2, every 21 days, up to 8 cycles). 
Subjects in Arm A and Arm B who cannot complete 8 cycles of therapy with bendamustine 
must still have all planned Day 1 assessments (Visits 1-20) done including scheduled CT 
scans and assessments that occur on Days 84, 168, and 252.
At the discretion of the investigator, ofatumumab will be offered to those with progressive 
disease (PD) in Arm B.  If these subjects select ofatumumab, therapy must begin 120 days 
following PD.  PD must be verified by CT scan.  This CT scan must be confirmed by an 
independent radiologist before ofatumumab therapy begins.  Subjects will receive 
ofatumumab (1000 mg for the first infusion on Week 1 followed by 2000 mg, one infusion 
every week for a total of 3 infusions (Weeks 2-4) followed by 2000 mg, one infusion every
month for 8 infusions, total: 12 doses).
Eligible subjects will be stratified by type of last prior rituximab therapy: rituximab plus 
chemotherapy or rituximab alone (either in maintenance or monotherapy) and by prior 
exposure to bendamustine: exposed or not exposed.
Screening assessments include physical exam, vital signs, biochemistry, and blood tests.  
Blood samples (hematology and biochemistry including human anti-human antibodies, human 
anti-chimeric antibodies), flow cytometry and immunoglobulin assessments, vital signs are 
taken throughout the treatment phase.  Follow-up assessments begin on Day 336 post 
randomization (3 months after Day 252), then according to Appendix 1 and Appendix 2 time 
and events tables.  In the event of PD, Survival Follow-Up visits begin 2 months after PD is 
confirmed by CT scan.  A bone marrow examination is required to confirm Complete 
Remission (CR) when a subject fulfills the complete response criteria, based on the Revised 
Response Criteria for Malignant Lymphoma definition of a CR if the subject had bone 
marrow involvement at baseline.  CT imaging is required for confirmation of all responses 
(CR, PR, SD, PD).  During this study, CT imaging of the neck (when lesion is palpable), 
thorax, abdomen, and pelvis will be performed at baseline, and on Days 84, 168, and 252 (+7 
days), regardless of the number of completed cycles of therapy in Arm A and Arm B.
A total of 259 events in a sample size of 304 evaluable subjects (152 subjects per arm) are 
needed for the study to have a 90% power to detect a 50% improvement in PFS (PFS) 
between study arms.  Assuming a dropout rate of 12%, the total sample size randomized for 
both arms combined will be 346 subjects, with approximate study duration of 77 months.  
Assuming a screening failure rate of 15%, the total number of subjects screened will be 
approximately 408.


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Per Amendment 9, the primary analysis will be performed after approximately 215 PFS 
events by IRC have been observed.  This targeted number of 215 PFS events by IRC for the 
primary analysis was calculated in order to achieve a cumulative power of 84% to detect a 50% 
improvement in PFS between study arms. See Section 8.2 - Primary Analysis for details.
Dose Confirmation Cohort
Subjects will be randomized (1:1) into 2 arms:  Arm A (OB) vs. Arm B (B) from the start of 
study.
The Independent Data Monitoring Committee (IDMC) reviewed safety and tolerability data 
for Arm A at specific points throughout the study.  The IDMC initially review ed the data to 
determine whether the bendamustine cycle length (q21 days) should be lengthened to 28 days 
in Arm A or if the cycle length should remain unchanged. 
The IDMC met after the first 20 subjects in Arm A received at least 3 cycles of OB.  Based on 
the review of the data available as well as the IDMC charter-defined criteria to alter the dose 
in Arm A, the IDMC recommended that the study continue without any changes to the dosage 
of Arm A [IDMC Communication, 2011]. Consequently, there will be no further IDMC 
meetings to assess dose safety and no further dose modifications other than the protocol-
directed dose reductions and delays already described.  The safety of subjects enrolled into the 
study will continue to be monitored by Novartis.
Interim Analysis
An Interim Analysis (IA) for efficacy of the primary endpoint, progression free survival, 
occured when approximately two thirds of the total Independent Review Committee (IRC,
including radiology and oncology review) initial number of events was achieved.  At the same 
time as the IA, a Futility Analysis (FA) was performed and an Independent Data Monitoring 
Committee (IDMC) reviewed the data.  Based on the IDMC review of the data available the 
IDMC recommended that the study continue without any changes.
Study Endpoints and Assessments
Primary Endpoint:

Progression-free survival, defined as the time interval between randomization and disease 
progression or death
Secondary Endpoints
Clinical

Progression-free survival in patients with follicular lymphoma

Overall response rate in all patients and patients with follicular lymphoma

Overall survival in all patients and patients with follicular lymphoma

Changes in HRQL measures in all patients and patients with follicular lymphoma


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
Time to response and duration of response in all patients and patients with follicular 
lymphoma

Time to progression and time to next therapy in all patients and patients with follicular 
lymphoma

Reduction in tumor size

Improvement in Eastern Cooperative Oncology Group (ECOG) Performance status 

Incidence and severity of adverse events (AEs), serious adverse events (SAEs), and other 
safety parameters including frequency of transfusions, development of Human Anti-
Human Antibodies (HAHA), incidence of Grade 3 and 4 infections and myelosuppression 
(anemia, neutropenia, and thrombocytopenia)

Overall response rate to ofatumumab monotherapy in subjects in Arm B who progress 
during or following single-agent bendamustine

Quantitative assessments of immunoglobulins (IgG, IgA, IgM)

Changes in clinical laboratory values

Plasma ofatumumab concentrations

B-cell monitoring (CD19+, CD20+)
Known and Exploratory Prognostic Markers Correlating with Response 
to ofatumumab:

Baseline Follicular Lymphoma International Prognostic Index  (FLIPI-1 and FLIPI-2)
scores Appendix 6 and Appendix 7

Baseline Absolute Lymphocyte Count (ALC)

Genetic variation in FcR gamma 3A

Human Anti-Chimeric Antibodies (HACA)


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1
Introduction
1.1
Indolent Non-Hodgkin’s Lymphoma
The projected worldwide incidence in 2009 for Non-Hodgkin’s Lymphoma (NHL) is 335,500 
persons (195,042 men; 140,458 women) with 193,671 deaths (111,452 men; 82,219 women) 
[IARC, 2002; Ferlay, 2004].  Follicular lymphoma (FL) accounts for 11% to 35% of all NHL 
[WHO, 2008], and is the most common lymphoma in the United States (US) and Europe. 
Between 10–15% of patients with FL are diagnosed with Stage I or II disease.  Patients with
Stage III or IV disease make up the majority and are generally not cured by conventional 
therapeutic approaches [Ardeshna, 2003; Apostolidis, 2000].  Other indolent NHL histologies
include small lymphocytic, marginal zone, and lymphoplasmacytic lymphomas.
Indolent lymphomas have a variable course. Some patients have waxing and waning disease 
for years before they become symptomatic. Other patients present with disseminated disease, 
symptoms and lymphoma progression, which require treatment.  Indolent lymphomas are 
sensitive to chemotherapy combined with biologics, but subsequently follow a pattern of 
multiple relapses and progressively shorter periods of remission between relapses. At 
presentation of disease, median survival is 9.2 years. [Johnson, 1995; Fisher, 2005; Swenson, 
2005].
1.2
Current Treatment for Indolent Non-Hodgkin’s Lymphoma
1.2.1
Frontline Treatment
Early-stage, indolent NHL is managed with primary radiation therapy.
However, patients 
with newly diagnosed, disseminated disease have multiple treatment options.
Current 
treatment strategies focus on establishing maximal disease control and prolonged survival.
Asymptomatic, non-bulky disease may be observed, but single-agent rituximab has activity in 
this population. Patients with symptomatic or bulky disease are managed with combination 
chemotherapy, which includes alkylating agents or purine analogs and rituximab. While 
indolent lymphoma is responsive to single-agent and combination chemotherapy, thirty years 
of clinical research has not produced a chemotherapy regimen that provides superior 
definitive 
progression-free 
survival 
(PFS)
or 
overall 
survival
(OS)
[Marcus, 2005; Hiddemann, 2005; Herold, 2007].
Bendamustine hydrochloride (Ribomustin) is currently approved in Germany (i.e., 60 mg/m² 
IV on days 1-5, vincristine 2 mg IV on day 1, prednisone 100 mg/m² IV on days 1-5; cycle 
repeated after 3 weeks) for the primary treatment of advanced, indolent NHL in combination 
regimens and as a single agent or combination therapy for multiple myeloma and chronic 
lymphocytic leukemia (CLL) [Ribomustin Prescribing Information, 2009; Levact SPC, 2010].  
Bendamustine is approved for indolent NHL that relapsed during or within 6 months of 
receiving a rituximab-containing regimen.  In the US, bendamustine hydrochloride (Treanda) 
as a single agent is also approved for the treatment of CLL and rituximab-refractory indolent 
NHL [Treanda Prescribing Information, 2010].


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Rituximab (R), a chimeric, anti-CD20+ monoclonal antibody (mAb), as a single agent or in 
combination with chemotherapy, is part of standard, primary treatment for newly-diagnosed, 
CD20 positive, indolent NHL.  Prolonged treatment with rituximab enhances response rates 
and PFS [Hoechster, 2009; Collins-Burow, 2007; Wenger, 2008].  Studies of R-CHOP 
(rituximab added to cyclophosphamide, doxorubicin, vincristine, prednisone) have 
demonstrated 96% overall response rate (ORR), with 20% complete remission (CR); while 
patients treated with R-CVP (rituximab added to cyclophosphamide, vincristine, prednisone)  
have shown 81% ORR, with 41% CR [Marcus, 2005; Ghielmini, 2004; Hainsworth, 2005; 
Hiddemann, 2005; Van Oers, 2006].
1.2.2
Treatment for Relapsed and Refractory Diseases
Despite complete remission with biologic therapy in combination with chemotherapy, most 
patients 
develop 
progressive 
disease 
(PD)
and 
require 
salvage 
therapy.  
Radioimmunoconjugates directed against CD20-expressing B cells have high response rates 
in patients that require salvage treatment for relapsed or refractory indolent NHL. Yttrium-90 
ibritumomab tiuxetan (Zevalin) received Food and Drug Administration (FDA) approval in 
2002 for the treatment of relapsed, refractory, or transformed indolent NHL. Compared to the 
56% ORR achieved with rituximab in this population, yttrium-90 ibritumomab tiuxetan 
achieved an 80% ORR (30%CR, 50% partial response [PR]), and 11 months PFS [Witzig, 
2002a; Witzig, 2002b].  I-131-tositumomab (BEXXAR™; 33% CR, 35% PR, >11 month PFS) 
achieved similar results. Nevertheless, these modalities remain underutilized in the clinical 
setting [Vose, 2004; Witzig, 2003].
Autologous and allogeneic hematopoietic stem cell transplants are also performed for patients 
with relapsed FL [Apostolidis, 2000; Van Besien, 1998].  An International Bone Marrow 
Transplantation Registry study evaluated 904 patients undergoing transplantation for FL. In 
multivariate analyses, allotransplantation had higher transplant-related mortality and lower 
disease recurrence [Van Besien, 2003]. Purged autotransplantation had a 26% lower 
recurrence risk than unpurged autotransplantation. Five-year survivals were 51%, 62% and 55% 
after allogeneic, purged and unpurged autotransplantation, respectively. More research is 
needed; however, there is a subset of recurrent autologous transplant patients who could 
benefit from salvage therapy.
1.2.2.1
Bendamustine in the Relapsed and Refractory Settings
Bendamustine (Treanda, Ribomustin, Levact, bendamustine hydrochloride) is a cytostatic 
drug which structurally combines a purine-like benzamidazol nucleus and a bifunctional 
alkylating nitrogen mustard group.  It has shown monotherapy activity in the treatment of 
rituximab-relapsed and refractory-indolent NHL [Treanda Prescribing Information ,2010; 
Kahl, 2010; Friedberg, 2008; Rummel, 2005; Weide, 2007] and is indicated in the for the 
treatment of indolent NHL that has progressed during or within 6 months of treatment with 
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Bendamustine has a unique mechanism of action that is not yet fully understood [Leoni, 2003].  
Several studies show that it has a substantial effect against lymphomas resistant to alkylators 
or purine analogues [Schöffski, 2000; Heider, 2001; Friedberg, 2008].
Bendamustine approval for the treatment of indolent B-cell NHL was based on its high ORR 
in a single arm, Phase II study (4% ORR, 25% CR, 49% PR) and its prolonged PFS in a single 
arm, pivotal study (84% ORR, 29% CR, 53% PR, 9.3 m median PFS (mPFS) [Kahl, 2010; 
Friedberg, 2008].  The primary grade 3, 4 toxicities were hematologic (leukopenia 60%, 
neutropenia 60%, thrombocytopenia 24%, lymphocytopenia 95%, and anemia 5%).
Two single-arm studies of bendamustine and rituximab were done for the treatment of 
relapsed mantle cell and relapsed low grade indolent B-cell NHL [Rummel, 2005; 
Robinson, 2008].  In both studies, bendamustine was dosed at 90 mg/m 2 on Days 1, 2 of each 
cycle, every 28 days. Activity increased when bendamustine was combined with rituximab. 
Median PFS reached approximately 24 months with less toxicity than with bendamustine 120 
mg/m2 monotherapy dose on Days 1, 2, every 21 days [Rummel, 2005; Robinson, 2008].  
Patients with FL (96% ORR; 1% CR; 25% PR) experienced higher response rates than mantle 
cell lymphoma (5% ORR; 50% CR; 25% PR) [Rummel, 2005].
1.3
Ofatumumab
Ofatumumab is an immunoglobulin G1(IgG1) human monoclonal antibody that 
specifically recognizes a distinct epitope encompassing both large and small extracellular 
loops on the human CD20 molecule expressed on B cells [Teeling, 2006] and binds to this site 
with high affinity with a dissociation half-life of 3 hours [Teeling, 2004].  Ofatumumab 
induces more efficient complement-dependent cytotoxicity (CDC) mediated cell lysis in-vitro, 
compared to rituximab, especially in low CD20 density cells [Teeling, 2004].  The FDA 
recently approved ofatumumab (ARZERRA™) for chronic lymphocytic leukemia (CLL) 
refractory to fludarabine and alemtuzumab.
In a Phase I dose-ranging trial of ofatumumab for the treatment of relapsed or refractory CLL 
[Study Hx-CD20-402], subjects were given ofatumumab weekly for 4 weeks [100 mg + 3 x 
500 mg (n=3), 300 mg + 3 x 1000 mg (n=3), and 500 mg + 3 x 2000 mg (n=27)]. Among 
relapsed CLL subjects, a 48% partial remission was observed in the highest dose group 
[Coiffier, 2008].  The MTD (maximum tolerated dose) was not reached.
The pivotal trial Study OMB111773 (Hx-CD20-406) in subjects with fludarabine-refractory 
CLL [refractory to both fludarabine and alemtuzumab (DR, n=95) or refractory to fludarabine 
and with bulky lymphadenopathy for whom alemtuzumab is not suitable (BFR, n=112)] 
evaluated 300 mg + 7 x 2000 mg for eight weekly doses, followed by four monthly 2000 mg 
doses.  The investigator-determined overall objective response rate of patient refractory to 
fludarabine and alemtuzumab was 49% with a median duration of response of 5.5 months. 
The best response was CR in two subjects in the BFR group.  In this study, ofatumumab was 
generally well tolerated.  Specifically, in the DR group, the most frequently reported adverse 
events (AEs) (>15% frequency) were pyrexia, diarrhea, dyspnea, cough, neutropenia, anemia 
and pneumonia. There were no unexpected safety findings [OFATUMUMAB, 2012].  The
interim results of this pivotal study served as the basis for the grant of accelerated approval by 


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the FDA for ofatumumab (ARZERRA) for the treatment of patients with CLL refractory to 
fludarabine and alemtuzumab (DR population) in October 2009.
A Phase I/II dose escalation study of ofatumumab in subjects with relapsed or refractory FL
tested four weekly doses of ofatumumab at 300, 500, 700, or 1000 mg [Study Hx -CD20-001; 
Hagenbeek, 2008]. Results demonstrated clinical activity with reversible Grade 3, 4 AEs
occurring on the day of initial infusion. Those AEs included chills, rash, fatigue, pruritus, 
pyrexia, and uricaria. The ORR in 37 evaluable subjects was 41%.  Median duration of 
response was 29.9 months.  Response did not correlate with ofatumumab dose.
A Phase II study in patients with previously untreated FL (Study Hx -CD20-409, Study 
OMB111775) compared ofatumumab at two dose levels in combination with CHOP
(cyclophosphamide, doxorubicin, vincristine, prednisone) [OFATUMUMAB, 2012].  Patients 
were randomized into two dose groups (N= 29 per group):  300 mg of ofatumumab at the first 
infusion, followed by 5 infusions of either 500 or 1000 mg of ofatumumab every 3 weeks in 
combination with 6 cycles of CHOP.  Results demonstrated an ORR of 90% and CR of 21%
for the 500 mg group, N=29.  In patients treated with 1000 mg of ofatumumab (n=29), the 
ORR was 100% including 31% CR.  There were no unexpected safety findings reported 
during treatment and within 30 days after last infusion.  The most common AEs of grade 3 or 
4 (>10%) were leukopenia and neutropenia.
In a single-arm, double-blind study of single-agent ofatumumab (Study Hx-CD20-405, Study 
OMB111772), a total of 116 rituximab-refractory FL patientsubjects were treated with two 
dose levels of ofatumumab [OFATUMUMAB, 2012].  This group of patients was highly 
refractory with 65% refractory to their last chemotherapy.  Patients in the study had 
previously received a median of 4 prior treatment regimens.  The 1000 mg dose group (N=86) 
demonstrated an ORR of 10% (included 1 CR, 8 PR).  In addition, 50% (43) of patients in the 
1000 mg treatment arm had stable disease (SD).  The ORR among patients who were 
refractory to prior rituximab monotherapy (N=27) was 22%.  For patients considered 
refractory to rituximab in combination with chemotherapy the RR was 7% and among patients 
considered refractory to rituximab maintenance the RR was 9%. The PFS was 6 months.  
There were no unexpected safety findings reported during treatment and within 30 days after 
last infusion. The most common AEs (>10%) were rash, urticaria, pruritus, fatigue, nausea, 
pyrexia, asthenia, peripheral edema, and cough.
1.4
Rationale
Treatment options are limited for patients who become refractory to rituximab or rituximab-
containing therapy. Testing new treatments for this population may advance clinical care for 
this population.
Ofatumumab is an anti-CD20 mAb shown to have monotherapy activity in a Phase I/II study 
in patients with FL that has relapsed following rituximab-containing therapy.  Bendamustine 
is a synthetic nitrogen mustard compound that has shown activity in the treatment of indolent 
NHL that has progressed during or within 6 months of treatment with rituximab or a 
rituximab–containing regimen [Treanda
Prescribing
Information, 2010; Ribomustin
Prescribing Information, 2009; Levact SPC, 2010].  Bendamustine has been shown to have 
activity in lymphoma that is refractory to other alkylators.  Furthermore, biologics have 


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enhanced the efficacy of primary chemotherapy for indolent NHL and may also enhance the 
efficacy of an active agent in the refractory settings. The addition of ofatumumab to 
bendamustine may provide additional clinical benefit for subjects who no longer respond to 
rituximab or rituximab-containing regimens.
2
OBJECTIVES
Primary objective:

To establish effectiveness of ofatumumab in combination with bendamustine in subjects
with indolent B-cell NHL disease refractory to rituximab-containing therapy
Secondary objectives:

To establish effectiveness of ofatumumab in combination with bendamustine in subjects 
with follicular lymphoma refractory to rituximab-containing therapy

To evaluate and compare ORR, OS, time toand duration of response, and time to 
progression (TTP) in subjects treated with ofatumumab and bendamustine combination 
therapy to those treated with bendamustine alone

To evaluate and compare ORR, OS, time to and duration of response, and time to 
progression (TTP) in subjects with follicular lymphoma treated with ofatumumab and 
bendamustine combination therapy to those treated with bendamustine alone

To evaluate and compare the safety and tolerability in subjects treated with ofatumumab 
and bendamustine combination therapy to those treated with bendamustine alone

To evaluate and compare the two treatment arms with respect to changes in subjects’ 
health-related quality of life 

To evaluate and compare the two treatment arms with respect to changes in subjects’ 
health-related quality of life in patients with follicular lymphoma

To evaluate and compare known and exploratory prognostic markers and their correlation 
with clinical responses in subjects treated with ofatumumab and bendamustine compared 
to those treated with bendamustine monotherapy (i.e. absolute lymphocyte count (ALC),
FcR gamma 3A genetic variants, human anti-chimeric antibody [HACA])

To evaluate the ORR to ofatumumab monotherapy in subjects who progress during or 
following single-agent bendamustine

To evaluate ofatumumab pharmacokinetics (PK) when given as monotherapy to subjects 
who progress during or following single-agent bendamustine


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3
investigational plan
3.1
Study Design
This randomized, open label, two-arm Phase III study consists of two treatment groups:  Arm 
A which is ofatumumab and bendamustine (OB), or Arm B, which is bendamustine 
monotherapy (B).  Subjects will be stratified by type of last prior rituximab: R -chemotherapy 
or rituximab alone, and by prior exposure to bendamustine: exposed or not exposed.
An independent data monitoring committee (IDMC) reviewed safety and tolerability data for 
Arm A at a specific time point in the study, as specified in the IDMC charter and summarized 
in Section 9.7.  Briefly, the IDMC initially reviewed data from the first 20 subjects to
complete 3 cycles (or complete bendamustine therapy with fewer than 3 cycles) in Arm A to 
determine whether the bendamustine cycle length should be lengthened to q28 days or if the 
cycle length should remain unchanged.  If cycle length of bendamustine was lengthened in 
Arm A, the IDMC would review the data to determine whether the dose of bendamustine in 
Arm A should be reduced to 70 mg/m2 or if it is appropriate for the dose to remain as it is.  If 
the dose of bendamustine in Arm A was reduced, the IDMC will once more review the data to 
determine if it is appropriate for the study to continue.  For each decision the IDMC would 
follow a decision rule that will be defined in the IDMC charter.  Arm B data will be made 
available to the IDMC each time they assess Arm A.
Update:  Decision from IDMC Meeting (Stage 1):
The IDMC met after the first 20 subjects in Arm A received at least 3 cycles of OB.  Based on 
the review of the data available as well as the IDMC charter-defined criteria to alter the dose 
in Arm A, the IDMC recommended that the study continue without any changes to the dosage 
of Arm A in the study [IDMC communication, 2011]. Consequently, there will be no further 
IDMC meetings to assess dose safety and no further dose modifications other than the 
protocol-directed dose reductions and delays already described.  The safety of subjects 
enrolled into the study will continue to be monitored by Novartis.
Primary Analysis
The primary analysis of PFS was planned to use 90% power to detect a 50% treatment effect; 
a 13.5 vs. 9 month improvement in Arm A (ofatumumab and bendamustine combination 
therapy) vs. Arm B (bendamustine monotherapy).  This trial is an event-driven study design 
with an event-driven sample size. The final primary analysis was planned to take place at the 
time of occurrence of the 259th event. The guideline for the study reaching 259 total events 
with respect to previously stated assumptions was planned to require the screening of 408 
subjects to ensure 346 subjects are randomized and to have a study duration of approximately
77 months from the first day of first subject until the time of the 259th event.
Per Amendment 9, the primary analysis will be performed after approximately 215 PFS 
events by IRC have been observed.  This targeted number of 215 PFS events by IRC for the 
primary analysis was calculated in order to achieve a cumulative power of 84% to detect a 50% 
improvement in PFS between study arms. See Section 8.2 - Primary Analysis for details.


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Interim Analysis 
An Interim Analysis (IA) for efficacy of the primary endpoint, progression free survival, was 
planned when approximately two thirds (or approximately 172) of the total 259 PFS events by 
IRC is achieved.  The IA was planned to be conducted at a significance level of 0.012.
At the time of amendment 9, the IA occurred when 180 PFS events by IRC were recorded. At 
the same time as the IA, a Futility analysis (FA) occured.  The IDMC reviewed the efficacy 
and futility data at this timepoint.  
Figure 1
Study Schema
Figure 1 abbreviations:  CT= computed tomography; F/U= Follow-Up; IDMC=independent data monitoring committee;
IRC= independent review committee; M= month; N= number of subjects; PD= progressive disease; PFS= progression-
free survival; q= every.
1.
A total of 12 ofatumumab infusions will be administered in Arm A regardless of the number of completed 
ofatumumab + bendamustine cycles (q 21 days).  Once subjects in Arm A complete bendamustine therapy, the 
remaining doses of ofatumumab will be given monthly (q28 days) until 12 doses are completed.
2.
Refer to Section 5.1.3.1 for any changes in bendamustine dose.  
3.
Subjects who cannot complete 8 cycles of therapy with bendamustine in Arm A and Arm B must come to the clinic 
for all planned Day 1 assessments (Visits 1-20) and all planned CT scans.
4.
The IDMC met and confirmed the safety and tolerability of the Arm A combination therapy.  A further IDMC 
meeting will review the IA and FA data.
5.
PD must be confirmed by an IRC prior to receiving ofatumumab monotherapy.  See Figure 2.
6.
The last required CT scan will be done on Month 54 of the F/U phase. Following Month 54, there will be a Month 
60 F/U visit without a required CT scan.   In addition to the required CT scans within the F/U period, unscheduled 
CT scans will be done to confirm clinical signs or suspicion of progression.
IDMC evaluated IA 
Efficacy and Futility
4


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Figure 2
Study Schema for those who progress on Arm B
Figure 2 abbreviations:  F/U= Follow-Up; IRC = Independent Review Committee;; M= month; PD= progressive disease, 
q= every; RR= response rate.
1.
The last required CT scan will be done on Month 54 as part of the F/U phase (Table 1).  Following Month 54, there 
will be a Month 60 F/U visit without a required CT scan.  Outside the F/U schedule, unscheduled CT scans will be 
done to confirm clinical signs or suspicion of progression.
3.1.1
Screening Phase
Please refer to Appendix 1 and Appendix 2 for a complete list of screening timing and 
procedures.
Subjects will provide informed consent before protocol-specific screening assessments.
Baseline Bone Marrow Sample:
Two types of bone marrow samples will be accepted:
1.
An historical bone marrow biopsy sample (obtained at any time prior to study entry) 
may be used to fulfill the study’s needs if:

The bone marrow biopsy showed involvement by lymphoma and

The subject has received no lymphoma therapy in the intervening time period.
2.
A study specific (screening) sample will be required if any of the following points 
are met: 

The subject has no previous bone marrow biopsy, or

The bone marrow biopsy was taken >1 month prior to randomization and showed 
no involvement by lymphoma, or 

The subject has received lymphoma therapy in the intervening time period since 
the prior bone marrow biopsy. 
Biopsy if Transformation to Diffuse Large B-cell Lymphom is Suspected:
If the investigator has clinical suspicion that the protocol candidate has transformed to Diffuse 
Large B-cell Lymphoma (DLBCL), the investigator must not consider that subject for the trial 
unless a biopsy or fine needle aspiration is performed prior to enrolment.  To confirm that 
disease has not transformed to a DLBCL, an incisional or excisional lymph node biopsy of 
accessible adenopathy is highly recommended.  In less accessible lymph nodes, 4 to 8 core 
biopsies are recommended, but not required.
Primary endpoint= RR
Follow-Up q3 M until 
Month 18 of F/.U; then 
q12 M  until Month 541, 
then Month 60
Ofatumumab (1000 mg 1st infusion, 
then 2000 mg once a week x3 
followed by 2000 mg q1M, x8)
If subjects in Arm B
(bendamustine 
monotherapy) 
progress, they will be 
offered ofatumumab
within 120 days
following confirmation 
of PD by  IRC 


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Review of Materials:
Bone marrow biopsy slides will be sent for central review. It is recommended that both the
core and aspirate be sent for review, but a core alone or aspirate alone may be sent if an 
adequate aspirate or core sample is not available. If bone marrow biopsy slides are not 
available, a tissue pathology report including details confirming CD20+ tumor status will be 
sent for central review.  Please see SPM for more details.  Blood samples, physical 
examination, and computed tomography (CT) imaging (with contrast imaging of the neck
when lesion is palpable, thorax, abdomen, and pelvis; may be whole body CT scan or 
according to standard of care) will be provided to determine baseline disease and study 
eligibility (See Imaging Acquisition Guidelines).  All examinations must be performed ≤21
days prior to randomization with the exception of the CT imaging and bone marrow biopsy 
and aspirate as mentioned above.  CT imaging done 1 month (+7 days) prior to 
randomization may be used as the baseline CT scan.  If the investigator wants to use a CT 
scan done >1 month (+7 days) prior to randomization, the Medical Lead must be contacted to 
determine if CT scan can be accepted.
3.1.1.1
Documentation of indolent B-cell NHL that is stable or has progressed 
during or within six months of the end of treatment with rituximab or 
a rituximab–containing regimen
A documentation worksheet verifying the investigator’s diagnosis of SD following, or 
progression during or within 6 months of treatment with rituximab or a rituximab-containing 
regimen will be required at screening.  This documentation worksheet must be sent to 
Novartis prior to randomization and will ask for:
Information about last qualifying rituximab therapy:

Dates before and dates after last qualifying rituximab-containing regimen

Type of rituximab therapy and regimen (examples: weekly, monthly):

Rituximab (includes monotherapy and maintenance), or

Rituximab added to chemotherapy

Date and type of response associated with last qualifying rituximab-containing regimen
Information regarding imaging:

Copy of documentation (for example, an imaging report, clinical documentation) prior to 
last qualifying rituximab-containing regimen is required (if available)

Copy of documentation confirming PD (for example, an imaging report, clinical 
documentation) after subject deemed unresponsive or relapsed to rituximab-based 
regimen is required


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
Assurance of an ability to submit, for each subject 

imaging or other documentation showing disease status before the start of the last 
qualifying rituximab-containing regimen is requested

imaging or other documentation confirming unresponsive or relapse following the 
last qualifying rituximab regimen is required

CT imaging is performed at screening
Subjects will not be enrolled in the study unless the investigator or designate verifies SD
following, or progression during or within six months of treatment with rituximab or a 
rituximab–containing regimen.  Submission of the subject’s imaging is expected be sent to 
Novartis within one month following randomization.  
Further details will be provided in the SPM.
3.1.2
Randomization and Stratification
Subjects will be randomized 1:1 to Arm A (OB combination therapy) or to Arm B (B
monotherapy) for the duration of the treatment period.
Subjects will be stratified according to the type of last prior rituximab therapy: rituximab-
chemotherapy or rituximab alone (administered as monotherapy or maintenance therapy) and 
by prior exposure to bendamustine: exposed or not exposed.
Centralized randomization numbers within each stratum will be created for treatment 
assignment to ensure balance, with respect to the number of subjects assigned to each 
treatment group within each stratum, using a randomization system (with randomly permuted 
blocks within strata).  The investigator will access the Interactive Voice Response System by 
telephone to receive the subject's randomization number and initial study medication 
container number.
3.1.3
Dose Confirmation for Safety and Tolerability
The first 20 subjects who entered and completed 3 cycles (or upon complete bendamustine 
therapy if less than 3 cycles) in Arm A of this study were part of a dose confirmation cohort 
for evaluation of safety and tolerability of ofatumumab and bendamustine combination 
therapy.  Data from Arm B were made available during each of the IDMC reviews.
The IDMC involved in this study followed a decision rule, described in the IDMC charter and 
summarized in Section 9.7, to decide whether the cycle length of OB in Arm A should be 
changed to q28 days for improved safety and tolerability.  The IDMC decision rule accounted 
for dose delays, the nature and severity of serious adverse events, and dose-limiting toxicities 
in Arm A.  If the cycle length was changed, the IDMC would compare the nature and severity 
of serious adverse events and dose-limiting toxicities of another 10 subjects who would enroll 
in Arm A.  Data from Arm B was to be made available at this time.  The IDMC would have 
had the option to make a second treatment regimen change and reduce the bendamustine dose 
from 90 mg/m2, Days 1, 2; every 28 days to 70 mg/m2, Days 1, 2; every 28 days.
If the IDMC decided to change the cycle length or reduce the dose of bendamustine if the 
nature and severity of serious adverse events or dose-limiting toxicities in Arm A are 


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considered excessive even though they do not exceed the toxicities observed in Arm B, then 
the dose and dose reduction schedule found in the IDMC charter will be followed for the 
remainder of the study.  Also see Section 9.7 for further details.
Update:  Decision from IDMC Meeting (Stage 1):
The IDMC met after the first 20 subjects in Arm A received at least 3 cycles of OB.  Based on 
the review of the data available as well as the IDMC charter-defined criteria to alter the dose 
in Arm A, the IDMC recommended that the study can continue without any changes to the 
dosage of Arm A in the study [IDMC communication, 2011]. Consequently, there will be no 
further IDMC meetings to assess dose safety and no further dose modifications other than the 
protocol-directed dose reductions and delays already described.  The safety of subjects 
enrolled into the study will continue to be monitored by Novartis.
3.1.4
Treatment Phase
Subjects will be followed as described in Appendix 1 and Appendix 2 with specified visit 
windows.  Subjects will be randomized 1:1 to receive either:

Arm A: Up to 8 cycles of bendamustine (90 mg/m2, Days 1, 2; q21 days) in combination 
with 12 doses of ofatumumab (1000 mg).  Beginning in Cycle 2, ofatumumab may be 
given on Day 1 (or within 3 days after Day 1) of each cycle of bendamustine as long as 
subjects in Arm A receive bendamustine.  Once subjects in Arm A complete 
bendamustine therapy, the remaining doses of ofatumumab will be given monthly, q28 
days (on or within 3 days after Day 1 of each month) until all 12 doses are completed.  
Administer the first dose of ofatumumab monotherapy 28 days after Day 1 of the last 
cycle where combination (ofatumumab+bendamustine) was scheduled to be given.

Arm B:  Up to 8 cycles of bendamustine (120 mg/m2, on or within 3 days after Days 1, 2; 
q21 days.).
Subjects who cannot complete the planned therapy with bendamustine (in Arm A and Arm B) 
must still come in for all planned Day 1 visits and assessments (Visits 1-20) according to the 
schedule presented in Appendix 1 and Appendix 2.  Also see SPM for more details.  Subjects 
in Arm A and Arm B are required to come for all planned CT scans with corresponding 
assessments for these days (Days 84, 168, 252; +7 days).
Subjects with PD in Arm B may receive ofatumumab after PD is confirmed by an IRC (See 
Section 3.1.6).
Blood samples are required at the start of each cycle and throughout the treatment phase.


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Assessments to determine subject response or progression will be performed for both arms 
including:

Peripheral blood sample evaluation for complete blood count (CBC) and differential 
with both percent and absolute number of lymphocytes

CT scans, assessment of lymphoma disease symptoms, and response assessments
will be done on Days 84, 168, and 252 (+7 days) to assess clinical response based on 
the Revised Response Criteria for Malignant Lymphoma (RRCML; Section 6.2).  
Subjects who are unable to complete 8 cycles of therapy with bendamustine must 
still have CT scans, assessment of lymphoma disease symptoms, and response 
assessments done on Days 84, 168, and 252 (+7 days).

In subjects whose bone marrow biopsy was positive at the start of the study, a 
confirmatory bone marrow examination is required 8 weeks after a subject fulfils
requirements based on the RRCML for CR (Section 6.2.5.2).

In addition, subjects will be monitored for safety and efficacy (Appendix 1 and 
Appendix 2 for a complete list of treatment phase procedures.
Patient reported outcome (PRO) questionnaires (FACT-Lym and EQ-5D) are described in
Appendix 1.  The Health Change Questionnaire (HCQ) questionnaire is not administered at 
the baseline (screening visit), but administered on all other visits, as per Section 6.6 and
Appendix 1.
3.1.5
Follow-up Phase
Following study treatment, subjects who have CR, PR or SD will receive regular follow-up 
for 5 years in Arm A.  The last required CT scan will be done on Month 54 (Table 1).  
Unscheduled CT scans will be required in addition to the scheduled CT scans if there are 
clinical signs or suspicion of progression throughout the study. Arm B will also follow this 
schedule if Arm B subjects do not select ofatumumab monotherapy.


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Table 1
Follow-up visit schedule and CT scan requirements for Arm A and Arm B
F/U phase
CT scan
3 M F/U 1
Required
6 M F/U 1
Required
9 M F/U 1
Required
12 M F/U 1
Required
15 M F/U 1
Required
18 M F/U 1
Required
30 M F/U 2
Required
42 M F/U 2
Required
54 M F/U 2
Required
60 M F/U 2
Not required1
Abbreviations:  Follow-Up 1= F/U 1; Follow-Up 2= F/U 2; Month= M
1.
CT scans are required during scheduled F/U 1 and F/U 2 visits in Arm A and Arm B (Appendix 1) with the last required 
CT scan on Month 54.  CT scans for ofatumumab monotherapy following PD in Arm B will be done according to the 
schedule presented in Appendix 1.  CT scans will be required to confirm clinical signs or suspicion of progression if 
observed outside all scheduled F/U 1 and F/U 2 visits.  CT scans are not required for Survival F/U.  
For patients with SD, PR, or CR, follow-up assessments begin on Day 336 (3 months after 
Day 252), then continue according to Appendix 1, Appendix 2 and Table 1 (also see SPM).  
For patients with PD during the treatment period, Survival Follow-Up visits begin 2 months 
after PD is confirmed by CT scan and will follow the time intervals described in Appendix 1, 
Appendix 2 and Table 1, beginning with the 3M F/U visit one month after the 2 M F/U visit.  .
For patients with PD during the follow up period, Survival Follow-Up visits begin 2 months 
after PD is confirmed by CT scan.  After the 2M F/U visit they will continue on their current 
follow up schedule according to Appendix 1, Appendix 2 and Table 1.
Each follow-up visit and assessment will have a time window of ±7 days for Follow-Up Visit 
#1 and a time window of ±14 days for Follow-Up Visit #2.  Follow-up visits will include 
collection of survival status, concomitant medications, and response assessments, based on 
RRCML. Survival follow-up visits may be phone calls instead of physician office visits.  In 
addition, subjects will be monitored for safety and efficacy as described.  See Appendix 1 and 
Appendix 2 for a complete list of follow-up procedures.
Subjects without PD who stop protocol treatment and begin non-protocol treatment must enter
Survival Follow-Up.
Bone marrow biopsy results will confirm complete remission and is required ≤ 8 weeks after 
the subject achieves CR (as decided by investigator) if positive for lymphoma at baseline.  CT 
imaging is required for confirmation of response.
PRO measures (FACT-Lym, EQ-5D, HCQ) will be administered for completion by the 
subjects at all follow-up visits as per Section 6.6 and Appendix 1.
Subjects who withdraw from treatment will follow the withdrawal schedule in Section 4.4.
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If a subject in Arm B decides to receive ofatumumab monotherapy following PD, they will 
not follow the schedule described in Section 3.1.5, Appendix 1 and Appendix 2, but will be 
monitored according to the follow-up schedule described in Section 3.1.6, Appendix 3, and 
Table 1 (where 3 month F/U begins 3 months after last dose of ofatumumab).
FOLLOW-UP FOR PROGRESSIVE DISEASE
Subjects receiving ofatumumab and bendamustine combination therapy (Arm A) or 
bendamustine monotherapy (Arm B) who experience disease progression, as defined in 
Section 6.2.5.5, will be assessed for safety and followed as described in Appendix 1 and 
Appendix 2 (Survival/PD).  Progressive disease must be confirmed by a CT scan.  A PD 
Worksheet will be completed following the CT scan.  Instructions for this worksheet are 
found in the SPM.  
Survival Follow-up visits will begin 2 months after PD is confirmed by CT scan as described 
in Appendix 1 and Appendix 2 and Table 1.  Each follow-up visit will have a time window of 
±7 days for Follow-Up Visit #1 and a time window of ±14 days for Follow-Up Visit #2.
Survival follow-up visits may be a phone call instead of physician office visit.  
If an Arm B subject selects ofatumumab monotherapy following PD, the subject will not 
follow the schedule described in Section 3.1.5, Appendix 1 and Appendix 2, but follow the 
treatment and follow-up schedules described in Section 3.1.6 and Appendix 3.
Subjects who withdraw from treatment will follow the withdrawal schedule in Section 4.4.
Supplementary study conduct information is provided in the accompanying Study Procedures 
Manual (SPM).  The SPM will provide the site personnel with additional administrative and 
detailed technical information.
3.1.6
Ofatumumab Following Progressive Disease for Arm B
At the discretion of the physician in consultation with the study subject, ofatumumab may be 
administered to subjects within 120 days who develop PD during or following treatment with 
bendamustine monotherapy in Arm B, as defined in Section 6.2.5.5 (See Appendix 3 for 
follow-up procedures).  Subjects with PD in Arm B must have a CT scan done with IRC
confirmation of PD.  This CT scan (or a CT scan done after IRC confirmation) will determine 
baseline measurements of pre-ofatumumab disease before exercising the option to receive 
ofatumumab.  A PD Worksheet must be completed upon diagnosis of PD (See SPM for 
details).
Subjects who receive ofatumumab following diagnosis of PD must fulfill the inclusion criteria 
found in Section 4.2 and the exclusion criteria found in Section 4.3 (except for exclusion 
criteria #4).  Subjects in Arm B who choose to receive optional ofatumumab monotherapy 
will receive ofatumumab, 1000 mg for the first infusion (Week 1) followed by 2000 mg 
weekly (+1 day) for 3 doses (Weeks 2-4), followed by 2000 mg every month (±3 days; q28 
days) for 8 additional doses (total: 12 doses).
The first follow-up visit will occur one month following the last infusion of ofatumumab 
monotherapy and continue as described in Appendix 3 and Table 1.


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3.1.7
Study Endpoints
PRIMARY ENDPOINT:

Progression-free survival (PFS), defined as the time interval between randomization 
until disease progression or death
SECONDARY ENDPOINTS
Clinical

Overall response rate (ORR) in all patients and patients with follicular lymphoma

Overall survival (OS) in all patients and patients with follicular lymphoma

Time to response and duration of response in all patients and patients with follicular 
lymphoma

Time to progression and time to next therapy in all patients and patients with follicular 
lymphoma

Changes in health-related quality of life (HRQL) measures in all patients and patients 
with follicular lymphoma

Reduction in tumor size

Improvement in Eastern Cooperative Oncology Group (ECOG) Performance status 

Incidence and severity of AEs, serious adverse events (SAEs) and other safety 
parameters including frequency of transfusions, development of Human Anti-Human 
Antibodies (HAHA), incidence of 3 and 4 infections, and myelosuppression (anemia, 
neutropenia, and thrombocytopenia)

Overall response rate (ORR) to ofatumumab monotherapy in subjects in Arm B who 
progress during or following single-agent bendamustine

Changes in clinical laboratory values

Quantitative assessments of immunoglobulins G, A and M (IgG, IgA, IgM)

Plasma ofatumumab concentrations

B-cell monitoring (CD19+, CD20+)


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Known and Exploratory Prognostic Markers Correlating with Response to ofatumumab:

Baseline Follicular Lymphoma International Prognostic Index (FLIPI) (FLIPI-1 and 
FLIPI-2) ( and )

Baseline Absolute Lymphocyte Count (ALC)

Genetic variation in FcR gamma 3A

Human Anti-Chimeric Antibodies (HACA)
The Study Procedures Manual (SPM) provides supplementary study conduct information. The 
SPM will provide the site personnel with administrative and detailed technical information 
that does not impact subject safety.
3.2
Discussion of Design and Dose Rationale
3.2.1
Bendamustine Dosing
We acknowledge the existence of different bendamustine regimens based on clinical practice 
and prescribing information.  Bendamustine is approved in Germany for the primary 
treatment of advanced indolent NHL in a combination regimen (i.e., 60 mg/m² IV on days 1-5, 
vincristine 2 mg IV on day 1, prednisone 100 mg/m² I.V. on days 1-5; cycle repeated after 3 
weeks) Ribomustin Prescribing Information, 2009].  Bendamustine, as monotherapy, was 
approved by the FDA and European Medicines Agency (EMA) for the treatment of indolent 
NHL that has progressed during or within 6 months of treatment with rituximab or a 
rituximab-containing regimen (120 mg/m2 Days 1, 2 q21 days, up to 8 cycles) 
[Treanda Prescribing Information, 2010; Levact SPC, 2010].
In a multi-center, single-arm, Phase II study, bendamustine monotherapy (120 mg/m2, Days 1,
2 q21 days) resulted in a median 9.3 month duration of response and mPFS of 9.3 months 
[Treanda Prescribing Information, 2010].  These results corroborate data from a multi-center, 
Phase II study using bendamustine monotherapy (120 mg/m2 Days 1, 2 q21days, up to 8 
cycles)  in rituximab-refractory FL subjects (for FL:  3% CR/CRu; 44% PR; 9 months 
duration of response) [Friedberg, 2008; Treanda Prescribing Information, 2010].
In subjects who relapsed after prior therapy, the combination of rituximab with bendamustine 
(90 mg/m2 Days 1, 2 q28 days) produced a high objective response rate.  The subject 
population included subjects with indolent B-cell NHL who may have been refractory to prior 
chemotherapy but who had never received rituximab.  Data from these trials suggest that the 
bendamustine at a 90 mg/m2 dose could provide clinical benefit when added to an anti-CD20 
mAb (1% CR; 25% PR; 24 months mPFS) [Rummel, 2005; Ribomustin, 2009; Kahl, 2010; 
Friedberg, 2008].
In a Phase II study by the German Low Grade Lymphoma Study Group, the combination of a 
CD20 mAb with bendamustine and mitoxantrone allowed for a lower bendamustine dose, 90 
mg/m2 Days 1, 2, q28D in a relapsed and refractory FL subject population who had received 


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between 1-2 prior regimens without compromising overall responses (55% CR; 41% PR; 19m 
mPFS) [Weide, 2007].  The ability to lower the bendamustine dose in combination with an 
anti CD20 mAb and mitoxantrone allowed AEs to be less frequent than at the higher, 
monotherapy dose.
The FDA has approved a bendamustine monotherapy regimen [Treanda Prescribing 
Information, 2010].  As such, the FDA-approved bendamustine monotherapy regimen (120 
mg/m2 Days 1, 2; q21 day) will serve as the control for this study, OMB110918.  Although 
the FDA has not defined a bendamustine regimen to be used in combination therapy, the 
precedence of different dosing regimens for bendamustine in combination with rituximab
justifies the evaluation of the 90 mg/m2 q21 day regimen of bendamustine in Arm A of this 
trial and the use of a dose confirmation cohort of 20 subjects in Arm A.  
3.2.2
Ofatumumab dosing when administered with bendamustine
The ofatumumab dose in this study, 1000 mg, was selected based on several considerations:  
preclinical data with ofatumumab and clinical population PK modeling and simulation; prior 
clinical experience with ofatumumab (Study Hx-CD20-001, [Hagenbeek, 2008]); ongoing 
clinical experience with ofatumumab (Studies Hx-CD20-405 and Hx-CD20-409); and prior 
clinical experience with rituximab.
A total of 12 doses of ofatumumab will be given in Arm A.  Ofatumumab will be given on 
Day 1 of each cycle of bendamustine as long as subjects in Arm A receive bendamustine (up 
to 8 cycles).  Once subjects in Arm A complete bendamustine therapy, additional doses of 
ofatumumab will be given monthly (q28 days) for a total of 12 ofatumumab doses.
Preclinical data suggest that ofatumumab plasma concentrations >10 g/mL are sufficient to 
suppress peripheral B-cell recovery in cynomolgus monkeys as well as to suppress tumor cell 
growth in Daudi tumor-bearing SCID mice [Bleeker, 2008].  Severe combined 
immunodeficiency (SCID) mice previously inoculated with Daudi B-cells received 
ofatumumab at 0.5 and 50 mg/kg and were observed for tumor growth.  Tumor growth was 
delayed 3-4 weeks after ofatumumab administration, with a greater duration of tumor growth 
inhibition at the higher dose level.  Acceleration of tumor growth was observed at the time 
point at which ofatumumab concentrations had dropped below 0.4 g/mL.
In the Bleeker study, cynomolgus monkeys received ofatumumab at three dose levels:  1.25, 
6.25, or 12.5 mg daily for four consecutive days (cumulative doses 5, 25, or 50 mg/kg).  A 
profound B-cell depletion was induced both peripherally and in the lymph nodes, with a 
longer time to recovery at higher dose levels.  Ofatumumab concentrations above 50 g/mL 
were sufficient for complete B-cell depletion.  Recovery of CD20+ cells in peripheral blood 
and lymph nodes was detected when plasma ofatumumab concentrations had dropped below 
5-10 g/mL.  Thus, a potential target in developing ofatumumab dosing regimens is 
prolonged maintenance of plasma concentrations >10 g/mL.
Pharmacokinetic data from the Phase I study in subjects with relapsed or refractory FL (Study 
Hx-CD20-001) were analyzed using a two-compartment model with a decrease in clearance 
after the first dose and assuming a stepped-rate infusion using a nonlinear mixed-effects 
modeling approach (NONMEM).  The resulting model was used to simulate concentration-
time data for 500 subjects receiving ofatumumab infusions at 1000 mg on the first day of each 


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21-day or 28-day cycle for a total of six cycles.  Based on the simulations, the probability of 
maintaining plasma ofatumumab concentrations >10 µg/mL was high with both dosing 
schedules.  With a 21-day cycle length, the probability of maintaining Cp >10 g/mL was >90% 
after the first cycle and >95% throughout the remainder of the six-cycle dosing period and for 
four weeks after the last dose; the probability of Cp >10 µg/mL was approximately 89% at 
eight weeks after the last dose.  With a 28-day cycle length, the probability of maintaining 
Cp >10 g/mL was 84% after the first cycle and >95% throughout the remainder of the six-
cycle dosing period and for four weeks after the last dose; the probability of Cp >10 g/mL 
was approximately 85% at eight weeks after the last dose.  Thus, a dosing schedule of 1000 
mg infusions on Day 1 of each 21-day or 28-day cycle for 12 doses is expected to achieve 
prolonged maintenance of plasma concentrations >10 μg/mL in a high proportion of subjects 
with FL.
Prior clinical experience in a Phase I/II trial of ofatumumab in subjects with relapsed or 
refractory FL suggests that four weekly infusions of 300 mg to 1000 mg are effective [Study 
Hx-CD20-001; Hagenbeek, 2008].  Responses were observed in all four dose groups [300 mg: 
5 of 8 subjects (63%); 500 mg: 3 of 9 subjects (33%); 700 mg: 2 of 10 subjects (20%); and 
1000 mg: 5 of 10 subjects (50%)].  Thus, a regimen using twelve 1000 mg doses of 
ofatumumab at 21-day or 28-day intervals is expected to be effective.
In ongoing studies in subjects with FL, repeated doses of 500 mg or 1000 mg of ofatumumab 
have been administered.  In Study Hx-CD20-405, ofatumumab was administered at 500 mg or 
1000 mg weekly for seven weeks after an initial infusion of 300 mg in subjects with FL 
refractory to rituximab in combination with chemotherapy; in Study Hx-CD20-409, 
ofatumumab doses of 500 mg or 1000 mg were administered every three weeks after an initial 
infusion of 300 mg in combination with CHOP for a total of six cycles in subjects with 
previously untreated FL.  In these two studies, there were no unexpected safety findings 
reported during treatment and within 30 days of last infusion.  The results from these studies 
suggest that administration of 1000 mg at 21- or 28-day intervals is expected to be well 
tolerated.
An important safety factor of any antibody therapy concerns infusion reaction, particularly 
following the first intravenous administration.  Both the proportion of patients experiencing 
infusion reactions to rituximab and the severity of the reactions are higher for the first 
infusion than for subsequent infusions [Chung, 2007]. Early experience with ofatumumab 
showed a similar pattern of infusion reactions [Coiffier, 2008; Hagenbeek, 2008], and a first 
infusion dose of 300 mg was therefore adopted in all studies in the ofatumumab development 
program to minimize first dose infusion reaction.  However, upon further review of the data 
collected in the phase I/II study of ofatumumab in subjects with relapsed or refractory FL
grade I-II (Study Hx-CD20-001), no clinically significant differences in the severity or 
frequency of AEs were observed with increasing dose.  As a result, the median duration of the 
first infusion and the number of infusion reactions between subjects with FL receiving 
ofatumumab at doses of 300 mg, 500 mg, 700 mg, or 1000 mg did not differ significantly
[OFATUMUMAB, 2012; Hagenbeek, 2008]. Thus, the use of 1000 mg at first infusion is 
proposed in study OMB110918.
Prior clinical experience with rituximab suggests that prolonged administration schedules 
enhance response duration in subjects with NHL [reviewed in Collins-Burow, 2007; 


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Ghielmini, 2004; Cersosimo, 2003].  Prior clinical experience with ofatumumab demonstrated 
longer median duration of response with the addition of four infusions at four-week intervals 
after the end of weekly ofatumumab treatment in subjects with fludarabine-refractory CLL 
(Study Hx-CD20-406).  The proposed regimen is twelve infusions of ofatumumab to be 
administered with up to 8 cycles of bendamustine.  The proposed ofatumumab regimen of 12 
doses increases the duration of ofatumumab exposure, which should maintain chemo-
sensitization of FL to concomitant chemotherapy while enhancing response duration.
3.2.2.1
Ofatumumab monotherapy for subjects who progress in Arm B
Subjects who progress during or after therapy in Arm B (bendamustine alone) will be offered 
ofatumumab monotherapy.  Data regarding ofatumumab monotherapy in this population were 
obtained in Study Hx-CD20-405, in which subjects with rituximab-refractory FL were 
randomized to single agent ofatumumab at 500 mg or 1000 mg weekly for 7 doses after a 300 
mg initial dose (total of 8 doses).  The response rate was 11%, and mPFS was 6 months, with 
no difference between the dose groups.  Experience in CLL indicates that increasing the dose 
intensity of rituximab was able to improve the ORR significantly from 10-15% to 45% [Byrd, 
2001].  In addition, ofatumumab at a dose of 2000 mg showed significant clinical activity 
with an acceptable safety profile in subjects with fludarabine-refractory CLL in Study Hx-
CD20-406.  Therefore, it is reasonable to examine the 2000 mg dose in patients with 
refractory indolent NHL.
The optimal duration of therapy in this setting is unclear.  Study Hx-CD20-406 administered 
eight weekly doses of ofatumumab 2000 mg (first dose 300 mg) followed by four monthly 
doses of 2000 mg; however, the standard length of weekly rituximab therapy in FL is four 
weeks, and there are no convincing data that increasing the number of weekly rituximab 
infusions from 4 to 8 is of benefit.
The rituximab-refractory FL population in this study may have more disease (and thus, faster 
clearance) and shorter PFS following four weeks of ofatumumab monotherapy than subjects 
with rituximab-sensitive FL.  Thus, more frequent administration may be necessary for 
extended dosing in this refractory population, similar to the subjects with fludarabine-
refractory CLL in Study Hx-CD20-406, who received monthly extended doses.
Infusion reactions occur more frequently at the initial infusion. Patients with indolent NHL 
are less likely to have severe infusion toxicity than CLL patients because they do not have 
circulating peripheral blood tumor cells which react with antibody.
To date, no subjects have received 2000 mg as the initial dose, while subjects with FL
received an initial infusion of 1000 mg in Study Hx-CD20-001.  Thus, a first dose of 1000 mg 
will be used in Arm A (Appendix 1 , Section 3.1.4) and for subjects that progress on Arm B 
and select optional ofatumumab (Appendix 3, Section 3.1.6).  Study Hx-CD20-001 infused a 
2 mg/mL concentration of ofatumumab at an initial rate of 25 mL/hr.  Due to the observed 
tolerability associated with this concentration and rate, Study OMB110918 will infuse 
ofatumumab (2 mg/mL) at a starting rate of 25 mL/hr for infusions that follow the initial 
infusion for subjects that select ofatumumab following PD in Arm B (Appendix 3, Section 
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Thus, a regimen of 1000 mg at the first week, followed by 2000 mg ofatumumab for three 
doses at weekly intervals, then 2000 mg ofatumumab every month for eight additional doses 
(for a total of 12 doses) will be offered to the subjects in Arm B who have PD during or after 
bendamustine monotherapy.
4
subject selection and withdrawal criteria
4.1
Number of Subjects
Subjects who meet all the following inclusion and exclusion criteria will be eligible for 
enrollment into the study.  Approximately 408 subjects will be screened to randomize 346 
subjects. See Section 8.2 for further details on assumptions for subject numbers.
4.2
Inclusion Criteria
The current investigator brochure provides specific information regarding warnings, 
precautions, contraindications, AEs and other pertinent information about ofatumumab that 
may affect subject eligibility.
Subjects eligible for enrollment in the study must meet all of the following criteria:
1.
Small lymphocytic lymphoma (SLL), lymphoplasmacytic lymphoma, marginal zone 
lymphoma, and follicular lymphoma; grades 1, 2 and 3A, defined according to 
World Health Organization guidelines.  Subjects with a diagnosis of SLL who have a 
peripheral blood monoclonal B lymphocyte count of ≥5,000/L are considered to 
have CLL and are not eligible for this study.

Tumor verified to be CD20+ positive from a previous or current tissue biopsy.

CT imaging in screening phase (based on local evaluation) showing 2 or more 
clearly demarcated lesions/nodes with a long axis >1.5 cm and short axis 1.0 cm 
or 1 clearly demarcated lesion/node with a long axis >2.0 cm and short axis ≥1.0 
cm (Section 6.2.5). CT imaging performed at screening as baseline image.
2.
Indolent B-cell NHL with failure to achieve at least a partial response lasting 6 
months beyond the end of treatment with rituximab or a rituximab-containing 
regimen (See Section 6.2.5.4– Section 6.2.5.5 for details on response criteria), i.e.:

Stable disease (SD) after rituximab or a rituximab-containing regimen 
(imaging will support this finding. NOTE: in cases of SD after rituximab 
monotherapy as induction treatment, the minimum time to confirm SD by 
imaging is 60 days from start of first rituximab infusion)
or,

Disease progression during or within 6 months of treatment with rituximab or 
a rituximab-containing regimen. Imaging must support this finding and will 
be done ≤ 6 months after the last infusion of rituximab. 


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Note: Subjects must have received a minimum of 4 rituximab infusions as monotherapy 
or 3 infusions as part of rituximab-containing combination regimens
3.
ECOG Performance Status of 0, 1, or 2
4.
Age ≥ 18 years
5.
Life expectancy of at least 6 months
6.
Signed written informed consent prior to performing any study-specific procedures
French subjects:  In France, a subject will be eligible for inclusion in this study only if either 
affiliated to or a beneficiary of a social security category.
4.3
Exclusion Criteria
Subjects meeting any of the following criteria will not be enrolled in the study:
1.
Grade 3b FL or evidence that the indolent lymphoma has transformed to aggressive 
lymphoma as verified by biopsy confirmation [e.g., constitutional symptoms, poor 
performance status, fast growing tumor or increasing lactate dehydrogenase (LDH) 
level]
2.
Previous autologous stem cell transplant in the last 6 months or previous allogeneic 
stem cell transplant at any time.
3.
High dose steroids ≥ 25 mg prednisolone/day (or equivalent) for 7 consecutive days, 
given as concomitant medication, within 3 months prior to randomization. No more 
than 10 mg prednisone daily at the time of randomization
4.
Prior bendamustine treatment within 1 year of randomization not resulting in a CR or 
PR for at least 6 months
5.
Prior use of any monoclonal antibody (other than anti-CD20) within 3 months prior 
to randomization
6.
Known central nervous system (CNS) involvement by indolent lymphoma
7.
Other past or current malignancy. Subjects who have been free of malignancy for at 
least 5 years, or have a history of definitively treated non-melanoma skin cancer, or 
successfully treated in situ carcinoma, are eligible*
8.
Chronic or current active infectious disease requiring systemic antibiotics, antifungal, 
or antiviral treatment such as, but not limited to, chronic renal infection, chronic 
chest infection with bronchiectasis, tuberculosis, and active Hepatitis C
9.
Clinically significant cardiac disease as judged by the investigator including unstable 
angina, acute myocardial infarction within 6 months of randomization, congestive 
heart failure, and arrhythmia requiring therapy
10. History of significant cerebrovascular disease or event with significant symptoms or 
sequelae
11. Significant concurrent, uncontrolled medical condition that in the opinion of the 
investigator or Novartis Medical Lead contraindicates participation this study


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12. Positive serology for Hepatitis B (HB) defined as a positive test for Hepatitis B 
surface antigen (HbsAg). In addition, if negative for HBsAg but Hepatits B core 
antibody (HBcAb) positive (regardless of HBsAb status), a HBV DNA test will be 
performed and if positive the subject will be excluded

Consult with a physician experienced in care and management of subjects with 
Hepatitis B to manage/treat subjects who are anti-HBc positive

If HBV DNA is negative, subject may be included but must undergo HBV DNA 
monitoring (see Section 6.5.7.1). Prophylactic antiviral therapy may be initiated 
at the discretion of the investigator
13. Current active liver or biliary disease (subjects with Gilbert’s syndrome or 
asymptomatic gallstones, liver metastases related to indolent NHL or otherwise 
stable chronic liver disease per investigator assessment, are eligible)
14. Known human immunodeficiency virus (HIV) positive
15. Screening laboratory values:

platelets < 100 x 109/L (unless due to indolent lymphoma involvement of the 
bone marrow)

neutrophils < 1.5 x 109/L (unless due to indolent lymphoma involvement of the 
bone marrow)

Serum creatinine > 1.5 times the institution’s upper limit of normal (ULN); 
subjects with a serum creatinine > 1.5 ULN will be eligible if the calculated 
creatinine clearance [Cockcroft, 1976] or creatinine clearance from a 24-hour 
urine collection is 40 mL/min

Total bilirubin > 1.5 times ULN (unless due to liver involvement by FL or 
Gilbert’s disease) 

Transaminases > 3 times ULN
16. Known or suspected hypersensitivity to ofatumumab, bendamustine, or mannitol
17. Treatment with any known non-marketed drug substance or experimental therapy 
within 5 terminal half-lives or 4 weeks prior to Visit 1, whichever is longer or 
currently participating in any other interventional clinical study
18. Known or suspected inability to comply with study protocol
19. Lactating women, women with a positive pregnancy test at Visit 1 or women (of 
childbearing potential) as well as men with partners of childbearing potential, who 
are not willing to use adequate contraception from study start through one year 
following last treatment dose. Adequate contraception is defined as abstinence, oral 
hormonal birth control, hormonal birth control injections, implants of levonorgestrel, 
estrogenic vaginal ring, percutaneous contraceptive patches, intrauterine device, and 
male partner sterilization if male partner is sole partner for that subject. The double 
barrier method can be used in regions where considered acceptable and adequate 


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(condom and/or occlusive cap plus spermicidal agent, as per local acceptable 
standards)
*Subjects can participate in the study if in the opinion of the investigator and Medical Lead it 
is thought not to affect the subject’s safety, the conduct of the study or the interpretation of the 
data
4.4
Withdrawal Criteria
Two types of withdrawal exist in this study:
1.
Withdrawal from investigational product:
Subjects may withdraw early from investigational product for any reason at any time if it 
is their wish, or if the investigator judges it necessary for medical reasons.  Following 
withdrawal, the subject will be asked to complete all regularly scheduled visit 
assessments (per time and events tables in Appendix 1 and Appendix 2 or Appendix 3). 
2.
Withdrawal from study:
Subjects may withdraw from study participation (i.e. withdraw consent) at any time for 
any reason, or if the investigator judges it necessary for medical reasons. The reason for 
withdrawal from study participation must be documented in the electronic Case Report 
Form (eCRF). The investigator must make every effort to perform and document the 
following assessments in the eCRF as per the WD visit in the Time and Events tables in 
Appendix 1 and Appendix 2 or Appendix 3, when applicable:

Disease assessment

Response Assessment

Survival Assessment

ECOG

CT scans

Constitutional symptoms

Subject completion of PRO measures (FACT-Lym, EQ-5D, HCQ) (Appendix 1).  
PRO not required for subjects in Arm B who receive optional ofatumumab following 
PD (Appendix 3)

Concomitant medication assessment

Physical examination, vital signs and body weight assessment

Hematology and Chemistry

AE/SAE Assessment

HAHA and ofatumumab PK concentration (as indicated in Appendix 2 and 
Appendix 3)


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For data collection purposes, subjects are considered to have completed the study if they 
completed all scheduled visits, died during the treatment or follow-up phases, are lost to 
follow-up, or withdraw consent. 
5
Study treatments
5.1
Investigational Product and Reference Therapy
The contents of the label will be in accordance with all applicable regulatory requirements.
Under normal conditions of handling and administration, the investigational product is not 
expected to pose significant safety risks to site staff.  Take adequate precautions to avoid 
direct eye or skin contact and the generation of aerosols or mists.  Notify the monitor of any 
unintentional occupational exposure.  A Material Safety Data Sheet (MSDS) describing the 
occupational hazards and recommended handling precautions will be provided to site staff if 
required by local laws or will otherwise be available from Novartis upon request.
Adequate precautions must be taken to avoid direct contact with the investigational product.  
The occupational hazards and recommended handling procedures are provided in the MSDS.
Investigational product must be stored in a secure area under the appropriate physical 
conditions for the product.  Access to and administration of the investigational product will be 
limited to the investigator and authorized site staff.  Investigational product must be dispensed 
or administered only to subjects enrolled in the study and in accordance with the protocol.
The investigational medical product, ofatumumab, is a liquid concentrate for solution for 
infusion.
Please refer to the SPM for instructions related to:

infusion preparation

pre-medication

dosing schedule 

active comparator dose reduction/modifications 

handling of infusion reactions

observations required during infusions


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5.1.1
Pre-Medication
Pre-medication before each infusion is given within 30 minutes to 2 hours prior to the 
treatment.  Pre-medication will be required for the first infusion of ofatumumab.  If there 
are no severe infusion reactions, investigators will be allowed to choose whether pre-
medication is required for further infusions (See Table 2).  Pre-medication for ofatumumab 
infusion is as follows:

Acetaminophen (PO) approximately 1000 mg or equivalent

Antihistamine (IV or PO) equivalent to approximately 50 mg diphenhydramine

Glucocorticoid (IV) equivalent to approximately 50 mg prednisolone
Please refer to the SPM for glucocorticoid equivalent doses and further details.
Table 2
Pre-Medication Schedule
Infusion Number
30 minutes to 2 hours prior to treatment
Acetaminophen (PO) 
~1000 mg or equivalent
Antihistamine (IV or 
PO) equivalent to ~50 
mg diphenhydramine
Glucocorticoid (IV) 
equivalent to ~50 mg 
prednisolone
1st
X
X
X
>11
X1
X1
X1
1.
Administration of premedication in Arm A (and in Arm B, as applicable) will be at investigator discretion if severe infusion 
reactions did not occur during first infusion.
5.1.2
Ofatumumab
The contents of the ofatumumab label will be in accordance with all applicable regulatory 
requirements. See Section 5.1 for more details on the MSDS.  Ofatumumab must be stored in 
a secure area under the appropriate physical conditions for the product. Access to and 
administration of ofatumumab will be limited to the investigator and authorized site staff. 
Ofatumumab must be dispensed or administered only to subjects enrolled in the study and in 
accordance with the protocol.
Refer to the SPM for details on the ofatumumab supply, preparation of infusions, observations 
required during infusions and management of supplies.
In Arm A, ofatumumab 1000 mg will be given on Day 1 of each cycle of bendamustine as 
long as subjects in Arm A receive bendamustine.  Once subjects in Arm A complete 
bendamustine therapy, the remaining doses of ofatumumab will be given monthly until all 12 
doses have been administered. A total of 12 ofatumumab infusions will be administered in 
Arm A regardless of the number of bendamustine cycles completed.
Subjects developing PD in the bendamustine monotherapy arm (Arm B) will have the option 
to receive ofatumumab.  Subjects who select this option will receive ofatumumab, 1000 mg 
for the first infusion (Week 1) followed by 2000 mg once a week for 3 infusions (Weeks 2-4) 
followed by additional ofatumumab (2000 mg) infusions, once every month for 8 doses (total: 


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12 doses).  Subjects in Arm B who select this option must begin ofatumumab therapy within 
120 days following diagnosis of PD, which can occur at any time during treatment or follow-
up.  Progressive disease must be confirmed by an IRC.
When ofatumumab and bendamustine are given on the same day, ofatumumab will be 
administered first.  Response assessments will be done according to the schedule presented in 
Appendix 1 and Appendix 2.  If a subject from Arm A (OB) develops PD, treatment with both 
bendamustine and ofatumumab will be terminated. The subject will remain in the study for 
follow-up. 
5.1.2.1
Ofatumumab Treatment Schedule
Infusion rate escalation schedules in this section are recommendations. The investigator may 
use clinical judgment to optimize subject safety by escalating the infusion more slowly.
Please refer to the SPM for the preparation of the ofatumumab infusion.
Initial Infusion of ofatumumab
The starting rate of the initial infusion of 1000 mg (Section 3.1.4, Appendix 1, Section 3.1.6
and Appendix 3) ofatumumab (1.0 mg/mL) will be 12 mL/hour (hr). If no infusion reactions 
occur, we recommend that the infusion rate be increased every 30 minutes, to a maximum of 
400 mL/hr, according to Table 3. If this schedule is followed, the 1000 mg infusion duration 
will be approximately 4.5 hours. 
Table 3
Infusion rate at Initial ofatumumab infusion
Time
mL/hour
0 – 30 minutes
12
31 – 60 minutes
25
61 – 90 minutes
50
91 – 120 minutes
100
121 - 150 minutes
200
151 - 180 minutes
300
181+ minutes
400
If an infusion reaction develops, the infusion must be temporarily slowed or interrupted, as 
described in the SPM. We recommend that the infusion rate restart at half the infusion rate at 
the time the infusion was interrupted. If, however, the infusion rate was 12 mL/hr before the 
pause, the recommendation is for the infusion to be restarted at 12 mL/hr. Thereafter, the 
infusion rate may be increased according to the judgment of the investigator, in the manner 
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Subsequent infusions of ofatumumab
If the previous infusion has been completed without grade ≥ 3 infusion-associated AEs, we 
recommend that the subsequent infusion of 1000 mg (Section 3.1.4, Appendix 1) or 2000 mg 
(Section 3.1.6 and Appendix 3) ofatumumab (1.0 mg/mL or 2.0 mg/mL) start at a rate of 25 
mL/hr.  We recommend that the rate be doubled every 30 minutes up to a maximum of 400 
mL/hr, according to Table 4. Duration of the infusion will be approximately 4 hours if this 
schedule is followed. If the previous infusion has been completed with grade ≥ 3 infusion 
associated AEs, we recommend that the subsequent infusion start at a rate of 12 mL/hr 
according to Table 3.
Table 4
Infusion rate at subsequent ofatumumab infusion
Time
mL/hour 
0 – 30 minutes
25
31 – 60 minutes
50
61 – 90 minutes
100
91 – 120 minutes
200
121+ minutes
400
During infusion, the subject must be monitored closely and appropriate measurements must 
be performed whenever judged necessary. For details, please refer to the study procedures 
manual. 
5.1.3
Bendamustine
Bendamustine (IV) is available as a single-use vial of bendamustine HCl as lyophilized 
powder.  In the combination arm (Arm A), the bendamustine dose is 90 mg/m2, given on days 
1 and 2, every 21 days for up to 8 cycles.  In the monotherapy arm (Arm B), the bendamustine 
dose is 120 mg/m2, given on Days 1 and 2, every 21 days for up to 8 cycles.  Investigators 
will follow the label dose reduction schedule if subjects require lower doses as they advance 
through treatment. 
Bendamustine will be given for up to 8 cycles in both Arm A and Arm B.  However, in the 
following instances, bendamustine may be given for fewer than 8 cycles:
1.
If a subject cannot tolerate bendamustine and is unable to receive further treatment with 
bendamustine, the subject may stop bendamustine treatment.  

If this occurs in Arm A:  the subject will continue to receive all 12 doses of 
ofatumumab and continue to attend all scheduled visits on Day 1. Day 2 visits are 
not required unless the investigator requires additional tests.

If this occurs in Arm B:  the subject will continue to attend all scheduled visits.  
Note:  Subjects will only be required to attend the equivalent of the Day 1 visit.  The 
Day 2 visit is not required unless assessed as necessary by the investigator.


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2.
The number of cycles will be contingent upon the response to the first 4 cycles.  Subjects 
achieving CR after 4 cycles in either Arm will be treated with a total of 6 cycles only, 
whereas all other subjects will  receive 8 courses of bendamustine as monotherapy (Arm 
B) or in combination with ofatumumab (Arm A).  

If this occurs in Arm A:  the subject will continue to receive all 12 doses of 
ofatumumab and continue to attend all scheduled visits

If this occurs in Arm B:  the subject will continue to attend all scheduled visits on 
Day 1 of each cycle
3.
Subjects with PD at any time during bendamustine monotherapy (Arm B) or OB 
combination therapy (Arm A) will be taken off treatment and will continue with survival 
follow-up (Section 3.1.6 describes subjects with PD in Arm B that continue on to 
ofatumumab monotherapy).
For subjects randomized to Arm A, bendamustine may be initiated within 1 day of scheduled 
start for logistical reasons (example:  first cycle dose of bendamustine can be administered on 
Day 1 or Day 2 of the cycle).  Once the first infusion occurs, the second infusion must occur 
the following day.  The start of Cycles 2-8 may be delayed due to toxicity by up to 2 weeks 
for medical reasons at the investigator’s discretion. 
If the subject is medically unable to receive a subsequent cycle of treatment after 2 weeks’ 
delay, a decision will be made about whether the subject will withdraw from treatment. Please 
see Section 5.1.3.1.
Please refer to the SPM for bendamustine preparation instructions and infusion times [as 
described in Treanda Prescribing Information, 2010].
5.1.3.1
Bendamustine Dose Reduction
The dose of bendamustine will be reduced if, with any cycle, a subject develops grade 4 
hematologic or grade 3/4 non-hematologic toxicities, according to the National Cancer 
Institute Common Toxicity Criteria for Adverse Events (NCI-CTCAE) version 4.0 
[NCI-CTCAE, 2009].  Arm B will follow the bendamustine dose reduction specified by the 
FDA label, Table 6 [Treanda Prescribing Information, 2010].  Arm A will follow the 
bendamustine dose reduction described in Table 5.
Non-hematological toxicities must be resolved to grade 1 or baseline before beginning the 
next cycle.  Absolute neutrophil count (ANC) must have recovered to at least 1,000 cells/mm3
(1.0 x 109 cells/L) and platelets to at least 75,000 cells/mm3 (75 x 109 cells/L) by the start of 
the next cycle.  Subjects who fail to meet these requirements will have therapy held until 
counts recover to these levels, and the bendamustine dose must be delayed or modified as 
specified in Table 5 (Arm A) or Table 6 (Arm B).  Once a subject has undergone dose 
modification, subsequent cycles will give the modified dose of bendamustine.
If continued bendamustine-related toxicities occur beyond reasonable delay for recovery in 
either arm, study treatment will be discontinued (See Table 5 and Table 6).  In this event, 
subjects in Arm B will continue to come to the clinic for scheduled visits and CT scans (to 
complete all scheduled visits including CT scan, assessment for lymphoma symptoms, and 
response assessments on Days 84, 168, 252 [+7 days]) and subjects in Arm A will stop 


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bendamustine and will continue to complete 12 doses of ofatumumab or enter follow-up if the 
12 doses of ofatumumab are completed, as described in Appendix 1 and Appendix 2.
Table 5
Bendamustine Dose Reduction Schedule for Arm A
Bendamustine Dose and 
Schedule 
If Grade 4 Hematologic Toxicity
If Grades 3,4 Non-hematologic 
Toxicity
Dose
Schedule
Dose
Schedule
90 mg/m2, days 1,2 every 21 
days
90 mg/m2
Days 1,2 every 28 
days
90 mg/m2
Days 1,2 every 
28 days
90 mg/m2, days 1,2 every 28 
days
70 mg/m2
Days 1,2 every 28 
days
70 mg/m2
Days 1,2 every 
28 days
70 mg/m2, days 1,2 every 28 
days
Discontinue 
treatment
Discontinue 
treatment
Discontinue 
treatment
Discontinue 
treatment
Table 6
Bendamustine Dose Reduction Schedule for Arm B
Bendamustine Dose and 
Schedule 
If Grade 4 Hematologic Toxicity
If Grades 3,4 Non-hematologic 
Toxicity
Dose
Schedule
Dose
Schedule
120 mg/m2, days 1,2 every 
21 days
90 mg/m2
Days 1,2 every 21 
days
90 mg/m2
Days 1,2 every 
21 days
90 mg/m2, days 1,2 every 21 
days
60 mg/m2
Days 1,2 every 21 
days
60 mg/m2
Days 1,2 every 
21 days
60 mg/m2, days 1,2 every 21 
days
Discontinue 
treatment
Discontinue 
treatment
Discontinue 
treatment
Discontinue 
treatment
General Dosing Considerations for Arm A and Arm B:

Delay treatment for Grade 4 hematologic toxicity or clinically significant ≥Grade 3 
non-hematologic toxicity.

Toxicities must recover to Grade 1 or baseline before the next administration of 
treatment. If recovery is not met within 2 weeks after the prescribed start of the 
treatment cycle (i.e., after a 2 week delay), a decision will be made about continuation 
in the study following consultation with Medical Lead.

Bendamustine dosage will be delayed in subjects with a serum creatinine > 1.5 ULN if 
the calculated creatinine clearance [Cockcroft, 1976] or creatinine clearance from a 
24-hour urine collection is ≤40 mL/min.

Subjects will be monitored for safety as per local practice.


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
The protocol must be followed as closely as possible, but if as per local practice, a 
blood draw for hematology analysis prior to the visit date is required, it would be 
acceptable for hematology analysis, but the blood draw can be taken no more than 3 
days ahead of the visit date.  Blood draws performed by local laboratories (e.g. for 
quicker pre-dose response assessment or assessment of toxicity) of protocol-required 
lab assessments are acceptable; however, it is important that the sample for the central 
laboratory analysis is taken at the same time.  The local laboratory results of ANC, 
platelet count, peripheral blood lymphocytes, and hemoglobin must also be entered 
into the eCRF if it is used to manage a dose delay or reduction.  Central Laboratory 
information will also be entered into the eCRF.
5.2
Treatment Assignment
Subjects will be assigned to study treatment in accordance with the randomization schedule 
(See Section 3.1.2).  Please refer to the SPM for detailed instruction.
5.3
Permitted Medications
Subjects will receive supportive care during the study, including growth factors (e.g. G-CSF), 
transfusion of blood and blood products, and treatment with antibiotics, antiemetics, 
antidiarrheals, and analgesics, as appropriate.  Please refer to the SPM for details.
5.4
Product Accountability
In accordance with local regulatory requirements, the investigator, designated site staff,
or head of the medical institution (where applicable) must document the amount of 
bendamustine and Novartis investigational product administered to study subjects and the 
amount received from and returned to Novartis, when applicable. Product accountability 
records must be maintained throughout the course of the study.
5.5
Prohibited Concomitant Medication or Therapies
The following medications are prohibited during this study:

Anti-cancer medication not part of the protocol treatment (e.g., alkylating agents, anti-
metabolites, purine analogues, monoclonal antibodies, radioimmunotherapy, and others)

Glucocorticoids greater than 10 mg prednisone daily or equivalent, unless given to treat 
allergy or asthma exacerbations or unless given as pre-medication for or during 
ofatumumab infusions

Any non-marketed drug substance or experimental therapy
Therapeutic alternatives to cytochrome P450 1A2 (CYP1A2) inhibitors or inducers must be 
considered with bendamustine.  Please refer to the SPM for a list of CYP1A2 inhibitors and 
inducers.


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6
Study Assessments and Procedures
6.1
Clinical Assessments
6.1.1
Demographics
At screening, date of birth, sex, and race/ethnicity is collected.
6.1.2
Disease Characteristics and Medical History
At screening, relevant medical history is collected including:

Date of initial indolent lymphoma diagnosis 

Ann Arbor staging at diagnosis and screening

ECOG Performance Status 

Listing of relevant past and current diseases

Follicular Lymphoma Prognostic Index Score at screening (FLIPI-1, FLIPI-2)

Dates and results of bone marrow biopsy and/or aspirate at or prior to screening (if 
appropriate, prior bone marrow sample provided per guidance in Section 3.1.1)
6.1.3
Previous Indolent Lymphoma Therapy
Prior treatment of indolent lymphoma will be recorded including name of therapy or regimen, 
start and end date, dosing information, response and duration of response.
6.1.4
Follicular Lymphoma International Prognostic Index (FLIPI)
The Follicular Lymphoma International Prognostic Index (FLIPI) will be assessed at 
screening.  The FLIPI is a prognostic tool that may be used to evaluate and select treatments 
based on differences in survival between risk groups (low, medium, high).  This index 
includes parameters related to subject characteristics; such as, age, tumor burden (Ann Arbor 
stage, number of nodal sites), tumor aggressiveness (serum LDH level), and consequences of 
the lymphoma on the host (hemoglobin level).
FLIPI-2 incorporates beta-2-microglobulin in the prognostic score.  Both FLIPI-1 and FLIPI-2 
at time of study entry will be calculated for subjects in this study. 
See Appendix 6 and [Solal-Celigny, 2004].
6.1.5
Height and Weight
Height (without shoes) will be measured at screening and recorded in the eCRF.  Body weight 
(without shoes) will be measured at each visit and recorded on the eCRF.
6.1.6
Concomitant Medication
Any medication other than the trial drug is considered concomitant medication apart from 
protocol defined pre-medication given prior to the infusions of ofatumumab combination 
therapy will be documented, including the following information:


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
Indication

Dose information

Start date 

Stop date of administration or ongoing at study termination 
6.1.7
Physical Examination
A general physical examination is required at the screening visit and as shown in Appendix 1
and Appendix 3. This physical examination will include general appearance including 
examination of the following: skin, extremities, abdomen, respiratory, cardiovascular, 
musculoskeletal, and neurological systems.
6.1.8
Electrocardiogram
A standard pre-treatment 12-lead electrocardiogram (ECG) is required at screening.  The 
investigator will perform an overall interpretation of the ECG or may delegate this task to a 
cardiologist, if applicable.  This screening ECG will be retained as part of the subject’s source 
documentation.
6.1.9
Vital Signs
Vital signs including temperature, blood pressure (BP), and pulse are documented per
Appendix 1 and Appendix 3, at screening and for the remainder of the study in both treatment 
arms. Temperatures for individual subjects must be measured using the same method at all 
visits.
All subjects must be monitored as per standard of care for changes in BP, heart rate, and 
temperature and for Adverse Events. All recorded values must be documented in the 
subject’s source documentation. 
If the subject suffers an AE (Grade ≥1) during the infusion (including asymptomatic fever, 
hypotension or tachycardia), which is determined by the investigator to be related to either the 
study procedures or study treatment, vital sign measurements (BP, heart rate and temperature) 
must be recorded in appropriate source documentation AND the BP and heart rate recorded in 
the eCRF , for the following time-points:

At the time of event onset.

Then every 30 minutes, or more frequently if clinically indicated if in the investigator’s
opinion the vital sign results at the time of event onset are clinically significant. The 
subject’s vital sign measurements must continue to be recorded until they have returned 
to normal or pre-infusion levels.
6.1.10
ECOG Performance Status
An Eastern Cooperative Oncology Group (ECOG) Performance Status value [Oken, 1982] is 
required at screening, and throughout treatment and follow-up phases, to evaluate daily living 
abilities.
0 = Fully active, able to carry on all pre-disease performance without restriction 


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1 = Restricted in physically strenuous activity but ambulatory and able to carry out work of a 
light or sedentary nature, e.g., light house work, office work 
2 = Ambulatory and capable of all self-care but unable to carry out any work activities. Up 
and about more than 50% of waking hours 
3 = Capable of only limited self-care, confined to bed or chair more than 50% of waking 
hours 
4 = Completely disabled; cannot carry on any self care. Totally confined to bed or chair 
5 = Dead
6.1.11
Constitutional Symptoms:
Assessment for the presence of the following symptoms (done as per Appendix 1 and 
Appendix 3):

night sweats without signs of infection

unintentional weight loss 10% within the previous 6 months

recurrent, unexplained fever of greater than 100.5F (38C) for 2 weeks without signs of 
infection

extreme fatigue
6.1.12
Pre-treatment Computed Tomography (CT) Scans and/or Imaging
All subjects must have CT scan (with contrast of the neck when lesions are palpable, thorax, 
abdomen, and pelvis).  CT scan may be whole body or per local practice during screening if a 
CT scan was not done within 1 month (+ 7 days) prior to randomization.  If a CT scan was 
done within 1 month prior to randomization, a copy of the image along with an image report
(if available) must be provided prior to randomization.  The copy of the CT scan must be 
adequate to allow comparison to subsequent CT scans for response assessment.  This will be 
considered the baseline CT scan.
In addition to the CT scan required at screening, rituximab-refractory indolent lymphoma 
must be confirmed as described in Section 3.1.1.1.
6.1.13
Pre-treatment Bone Marrow Examination
See Section 3.1.1 for details on the timing and types of acceptable bone marrow examinations.  
Further details regarding collection of bone marrow samples are provided in SPM.  A 
pathologist at a central laboratory will evaluate the biopsy.
6.2
Efficacy Assessments
6.2.1
Disease Responses
Complete remission (CR), partial remission (PR), stable disease (SD) or progressive disease 
(PD) will be based upon the criteria defined in the RRCML guidelines [Cheson, 2007].  
Responses will be documented at visits as outlined in Appendix 1 and Appendix 3.


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The same physician will evaluate the subject’s response and corresponding assessments that 
are part of the response, wherever possible.  Response imaging will be subject to a 
retrospective blinded independent review by an IRC and the final determination of 
progression will be based on the evaluations from the independent review and will be used for 
the study’s efficacy analysis and submission to regulatory agencies.
Please refer to SPM for details of submission of imaging for review.
6.2.2
CT Scans
CT scans (with contrast of the neck when lesion is palpable, thorax, abdomen, and pelvis; may 
be whole body CT scan or according to standard of care) will be done as part of the efficacy 
evaluation and after treatment has been completed.  The scans must be implemented
according to a CT scan manual to be provided to Novartis (Imaging Acquisition Guidelines) 
as mentioned in the SPM.
In situations where PD is apparent through physical examination (such as massive 
lymphadenopathy), only the body area where PD is apparent must be scanned to confirm PD.
All subjects (Arm A and Arm B) must have a CT scan done on Days 84, 168, and 252 (+7 
days).  In the event subjects in Arm A or Arm B cannot complete 8 cycles of therapy with 
bendamustine, then subjects must come to the clinic for all scheduled Day 1 assessments.  
Subjects will have CT scans at each follow-up visit as described in Table 1, Appendix 1, and 
Appendix 3.  Survival Follow-up visits will begin 2 months after PD is confirmed by CT scan.  
CT scans will be done to confirm any clinical signs or suspicion of PD.  CT scans which are 
unscheduled and are performed to confirm PD in event of clinical signs or suspicion of 
progression may be done only of the suspected body area with progression.  In the event that 
an unscheduled CT scan does NOT show PD, the subject will resume the planned CT scan 
schedule (i.e. the next CT scan will be done based on the date of the last scheduled CT scan 
and not the day of the unscheduled CT scan).  For all other responses, follow-up visits will 
begin on Day 336 (this is 3 months after Day 252) for both arms and continue until initiation 
of alternative indolent lymphoma treatment, PD, or withdrawal (WD), See Appendix 1 and 
Appendix 2 and Appendix 3 for details.
CT scans will be assessed according to an independent review.  The independent review will 
be described in an independent review charter.  See Section 6.2.6 for a description of this 
independent review.
6.2.3
Bone Marrow Examination
Bone marrow examination (both aspirate smear and core, if possible) to confirm CR, as 
determined by the clinical and laboratory results listed in Section 6.2.5.2 is required no later 
than 8 weeks following onset of CR if there was disease involvement in the bone marrow at 
baseline.  Samples are to be reviewed in conjunction with the prior pathology. 
6.2.4
Lymphoma Disease-Related Symptoms:
Assessment for the presence of the following symptoms (done as per Appendix 1 and 
Appendix 3):

Night sweats due to lymphoma (not due to infection or treatment)


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
Fever due to lymphoma (not due to infection or treatment)

Loss of appetite due to lymphoma (not due to treatment)

Clinically significant weight loss, since the previous disease assessment, which is due to 
lymphoma (not due to treatment)

Fatigue due to lymphoma (not due to treatment)

Other symptoms due to lymphoma (not due to treatment)
6.2.5
Documentation of Target and Non-target Lesions
Eligibility Criterion
CT scan showing at least:

2 or more clearly demarcated lesions/nodes with a long axis >1.5 cm and short axis 1.0
cm
OR

1 clearly demarcated lesion/node with a long axis >2.0 cm and short axis 1.0cm
BASELINE DOCUMENTATION OF TARGET AND NON-TARGET LESIONS
Target lesions will be identified from each of the following categories at baseline and 
followed throughout the study:
1.
lymph nodes/masses (maximum 6)
2.
hepatic & splenic nodules (maximum 6)
3.
Other extranodal lesions (excludes hepatic & splenic nodules) (maximum 6)


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The target lesions will be selected according to the following criteria:

Clearly measurable in two perpendicular dimensions by CT scan with a long axis >1.5 cm 
and short axis 1.0 cm

The largest lesion from different regions of the body

Lesions in mediastinal and retroperitoneal areas will be included if these sites have 
measurable lesions
The longest and perpendicular short diameter (cm) of each lesion will be measured and the 
product of the perpendicular diameters (PPD) calculated. The sum of the products of the 
diameters (SPD) will be calculated for each category of target lesions when there are multiple 
target lesions present in the category. For guidance on calculation of the SPD refer to SPM
and Table 7.
During follow-up, with the exception of lesions that regress to >0 cm x >0 cm and 0.5 cm x 
0.5 cm the best estimate of the lesion dimensions must be reported even if necrosis, fibrosis 
or cavitation are present. If a lesion is present but has regressed to between >0 cm x >0 cm 
and 0.5cm x 0.5cm, ‘too small to measure’ will be assigned and a default size of 0.5 cm x 
0.5 cm will be used for calculation purposes.  A lesion that is absent would be recorded as >0 
cm x >0 cm.
All other lesions (measurable or non-measurable) will be identified as non-target lesions and 
recorded at baseline. Measurements of non-target lesions are not required, but the 
presence/absence or unequivocal progression of each will be noted throughout follow-up.
Liver and spleen size will be reported as normal, enlarged not due to lymphoma, enlarged due 
to lymphoma (nodules must be present for this to be reported), or unequivocal progression 
(nodules must be present for this to be reported).
The definition of unequivocal progression of non-target disease is based on the definition 
applied in RECIST 1.1 [Eisenhauer, 2009] as an overall level of substantial worsening in non-
target disease such that, even in the presence of SD or PR in target disease, the overall tumor 
burden has increased significantly to merit discontinuation of therapy, or if therapy has 
already been completed, commencement of anti-cancer therapy.  A modest ‘increase’ in the 
size of one or more non-target lesions is usually not sufficient to qualify for unequivocal 
progression status.  The designation of progression solely on the basis of change in non-target 
disease in the face of SD or PR of target disease will therefore be extremely rare.
6.2.5.1
Calculation of SPD
Increase or decrease of SPD of target lesions will be calculated based on the formula as seen 
in Table 7.
Table 7
Sum of Products Greatest Diameter Measurements (SPD)


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Decrease 
rate=
SPD before treatment – SPD at assessment
X100%
SPD before treatment
Increase 
rate=
SPD at assessment – smallest SPD during the study
X100%
Smallest SPD during the study
6.2.5.2
Complete Remission (CR)
The designation of CR requires the following:
1.
Complete disappearance of all detectable clinical evidence of disease and disease-related 
symptoms if present before therapy. All target nodes must have regressed to 1.5cm in 
the longest diameter (non-measured nodes 1.1-1.5cm in the longest diameter and >1cm in 
the short axis at baseline, must regress to 1cm in the short axis by visual estimation).
2.
The spleen and/or liver, if considered enlarged due to lymphoma (nodules must be 
present) before therapy based on a CT scan and must be considered normal size by 
imaging studies, and nodules related to lymphoma must disappear. However, 
determination of splenic involvement is not always reliable because a spleen considered 
normal in size may still contain lymphoma, whereas an enlarged spleen may reflect 
variations in anatomy, blood volume, the use of hematopoietic growth factors, or causes 
other than lymphoma.
3.
If the bone marrow was involved by lymphoma before treatment, the infiltrate must have 
cleared on repeat bone marrow biopsy. The biopsy sample on which this determination is 
made must be adequate (with a goal of > 20 mm unilateral core). If the sample is 
indeterminate by morphology, it must be negative by immunohistochemistry. A sample 
that is negative by immunohistochemistry but that demonstrates a small population of 
clonal lymphocytes by flow cytometry will be considered a CR until data become 
available demonstrating a clear difference in subject outcome.
6.2.5.3
Partial Remission (PR)
The designation of PR requires all of the following:
1. At least a 50% decrease from baseline in sum of the SPD of target nodes. 
2. The categories of target splenic/hepatic nodules and other extranodal lesions must 
each regress by ≥50% in their SPD compared to baseline. If the category only 
contains a single nodule/lesion, it must regress by ≥50% in the greatest transverse 
diameter compared to baseline.
3. No unequivocal progression must be observed in non-target lesions, liver, or spleen 
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4.
Bone marrow assessment is irrelevant for determination of a PR if the sample was 
positive before treatment. However, if positive, the cell type must be specified (e.g., 
large-cell lymphoma or small neoplastic B cells). Subjects who achieve a CR by the 
above criteria, but who have persistent morphologic bone marrow involvement will 
be considered partial responders. When the bone marrow was involved before 
therapy and a clinical CR was achieved, but with no bone marrow assessment after 
treatment, subjects must be considered partial responders.
5. No new sites of disease must be observed.
6.2.5.4
Stable Disease (SD)
A subject is considered to have SD when he or she fails to attain the criteria needed for a CR 
or PR, but does not fulfill those for PD [Cheson, 2007].
6.2.5.5
Relapsed Disease (after CR)/Progressive Disease (after PR, SD)
Criteria for determining PD for new lesions and target lesions are shown in Table 8.
Table 8
Criteria for determining PD for new lesions and target lesions
Nodes
Extranodal (‘liver/spleen’ & ‘other’ 
categories)
New node/lesiona
A previously normal node (≤1.5 x 
≤1.0 cm), including nodes that were 
not previously visible, must increase 
to >2.0 x ≥1.5 cm.
An unequivocal new lesion at a site 
where there was no disease at 
baseline, provided the lesion cannot 
be attributed to non-lymphoma-related 
causes.
Single node/lesion
Increase in PPD
≥50% increase from nadir in the 
PPD of any target node.  The long 
axis must increase by at least 5 mm 
and to >2.0cm.
≥50% increase from nadir in the PPD 
of any target lesion, and at least a 5
mm increase in either of the axes, and 
the lesion must be >1.5cm x ≥1.5 cm.
Increase in long axis
≥50% increase from nadir in the 
long axis of any target node. The 
long axis must increase by at least 5
mm and to >2.0 cm.
≥50% increase from nadir in the long 
axis of any target lesion, and at least 
a 5 mm increase in the long axis, and 
the lesion must be >1.5 cm x ≥1.5 cm.
Multiple nodes/lesions
Increase in SPD
≥50% increase from nadir in the 
SPD of target nodes and at least 
one node must have a long 
axis >1.5cm.
≥50% increase from nadir in the SPD 
of target lesions and at least one 
lesion must have a long 
axis >1.5cmb.
Abbreviations:  PPD= product of perpendicular diameters; SPD= sum of the products of the greatest diameter. 
a.
Abnormal nodes/extranodal lesions present at baseline that normalize/resolve and then subsequently enlarge/relapse 
are not to be classified as new lesions.
b.
Requiring that one node is > 1.5 cm minimizes the risk of declaring PD based on small artifactual changes.


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Unequivocal progression, as defined in Section 6.2.5, at a site of non-target disease, or 
unequivocal progression of the liver or spleen size (nodules must be present in the organ for 
unequivocal progression to be reported) will fulfill the criteria for PD.  
If the subject achieved a CR on protocol, histological confirmation of relapse is strongly 
recommended.
6.2.6
Independent Review of Disease Response
The study’s primary endpoint is to determine PFS as assessed through an independent review 
of the data based on the RRCML guidelines [Cheson, 2007].  These response criteria are 
described in Section 6.2.  The operation and responsibilities for members that are part of the 
independent review is described in a separate charter.  The final determination of progression 
will be based on the evaluations by the independent reviewer(s) and will be used for the 
study’s efficacy analysis and submission to regulatory agencies.

Imaging confirmed CR must show specified changes as described in Section 6.2.5.2

Imaging to confirm PR has to show specified changes as described in Section 6.2.5.3
6.3
Laboratory Assessments
A detailed description of the procedures for sampling, handling, storage, and shipment of the 
laboratory samples and all material such as test tubes and labels is provided in the SPM or in 
the central laboratory manual.
6.3.1
Flow Cytometry for B Lymphocytes
The number of CD19+ and CD20+ B cells will be assessed by flow cytometry.  This will be 
done in Arm A and in Arm B subjects who receive subsequent ofatumumab monotherapy 
only.  Blood samples for B-cell monitoring will be collected during treatment and during 
follow-up, as defined in Appendix 2 and Appendix 3. See SPM for details. 
6.3.2
Peripheral Blood Sampling for Hematology and Biochemistry
Blood samples will be drawn for analysis inclusive but not limited to the following parameters 
per Appendix 2 and Appendix 3:

Hepatitis B (HBV) and Hepatitis C (HCV) at screening

For subjects that are HBsAg negative, HBcAb positive and HBV DNA negative (see 
Section 4.3) blood samples will be collected for monthly HBV DNA testing on Day 
1 of each cycle depending on the number of cycles administered and samples will be 
collected during FU.  See SPM, and for collection times.

Japan only:  Instructions are in Appendix 8.

Hematology: Complete blood count with differential counts 

Biochemistry:  sodium, potassium, chloride, bicarbonate, calcium, blood urea nitrogen 
(BUN), creatinine, uric acid, total bilirubin*, alkaline phosphatase (ALP),  aspartate 
transaminase (AST), alanine transaminase (ALT), lactic acid dehydrogenase (LDH),  
albumin, glucose (random), and haptoglobulin.  


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*Bilirubin fractionation is recommended if total bilirubin >2 x ULN

A creatinine clearance will be calculated prior to bendamustine administration as 
shown in Appendix 2.  Calculated creatinine clearance will be done at screening and 
can be repeated at the physician’s discretion if there is a significant rise in serum 
creatinine during the treatment phase of the study.  The Cockcroft-Gault formula 
[Cockcroft, 1976] will be used to determine a calculated creatinine clearance:
o
In men:  (140 – age [years]) x weight (kg) / (72 x serum creatinine [mg/dL])
o
In women:  multiply this result by 0.85
6.3.3
Prognostic Factors
Whole blood will be collected at time points defined in Appendix 1 Appendix 2 for later 
analysis of the following prognostic factors:

Follicular lymphoma International Prognostic Index (FLIPI-1, FLIPI-2) See Appendix 6
and [Solal-Celigny, 2004; Federico, 2009]

Absolute Lymphocyte Count (expressed in % and in absolute numbers)

Genetic variation in the FcR gamma 3A

For all patients, Human Anti-Chimeric Antibody (HACA) will be taken at Cycle 1 Day 1 
as defined in Appendix 2.  If receiving ofatumumab following PD in Arm B, HACA will 
be taken as defined in Appendix 3.
6.3.4
Peripheral Blood Sampling for Safety and Disease Status
Peripheral samples will be collected for the analysis of:

Subjects receiving ofatumumab that are Hepatitis B core positive at screening, Hepatitis 
B DNA will be obtained at each cycle visit while on treatment and collected during F/U.  
See SPM, Appendix 2, and Appendix 3 for more details

Screening pregnancy test (HCG) for women of childbearing potential, unless they have 
had a hysterectomy, have undergone tubal ligation within one year before the screening 
visit, or have been postmenopausal for at least one year

Subsequent pregnancy testing in women of child bearing potential will be done as defined 
in Appendix 2 and Appendix 3

Human Anti-Human Antibody (HAHA) will be taken in Arm A as defined in Appendix 2.  
If receiving ofatumumab following PD in bendamustine monotherapy arm, HAHA will 
be taken as defined in Appendix 3

IgA, IgG and IgM will be taken in Arm A as defined in Appendix 2 and Appendix 3


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6.4
Safety Assessments
6.4.1
Liver Interruption/Stopping and Follow- up Criteria
Liver chemistry stopping and follow up criteria are a mandatory part of Novartis studies and 
have been designed to assure subject safety and evaluate liver event etiology.  
NOTE: if serum bilirubin fractionation is not immediately available, study drug should be 
discontinued if ALT > 3xULN and bilirubin > 2xULN. Serum bilirubin fractionation must be 
performed if testing is available. If testing is unavailable, record presence of detectable 
urinary bilirubin on dipstick, indicating direct bilirubin elevations and suggesting liver 
injury.
The Novartis Safety Monitoring Team will review all events which meet liver chemistry 
stopping criteria and determine if the event was due to tumor lysis and to exclude drug 
induced liver injury (DILI) due to ofatumumab.
6.4.1.1
Liver Chemistry Stopping Criteria
The stopping criteria for all subjects are based upon the FDA July 2009 Guidance for 
Industry, Drug-Induced Liver Injury:  Pre-marketing Clinical Evaluation, Section 5, Decision 
to Stop Drug Administration.  The FDA guidance was adapted for oncology ofatumumab 
protocols such that the criteria for stopping dosing are:

ALT>3 times upper limit of normal (ULN) and bilirubin >2 times ULN (>35% direct 
bilirubin; bilirubin fractionation required‡) 

ALT >8 times ULN

ALT >5 times ULN for more than 2 weeks
Compared with the FDA guidance, please note:

International normalized ratio (INR)>1.5 was not included as in an oncology patient 
there may be other valid reasons for this value such as poor nutritional status (due to 
nausea & vomiting).

Criteria 4 was not considered appropriate for an oncology patient as the symptoms 
described may also be attributed to the disease status, concomitant therapies or B-cell 
depletion and cytokine release.

ALT and fractionated bilirubin (if possible) are selected as more specific laboratory 
assessments of liver injury.
6.4.1.2
Liver Chemistry Interruption/Stopping and Follow-up Criteria
Liver chemistry stopping and follow up criteria have been designed to assure subject safety 
and evaluate liver event etiology.  
The Novartis Medical Lead and Global Clinical Safety and Pharmacovigilance (GCSP)
physician in conjunction with the investigator will review all events which meet liver 
chemistry stopping criteria to determine if the event was due to tumor lysis, disease 
related liver involvement, concomitant chemotherapy or other identified cause and to 


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exclude drug induced liver injury (DILI) due to ofatumumab. If the event is determined 
to be due to causes other than ofatumumab DILI and improvement is observed after 
withdrawal of ofatumumab, rechallenge may be attempted if deemed appropriate by the 
Novartis Medical Lead and investigator and in addition to consent of the subject. 
‡ NOTE:  If serum bilirubin fractionation not immediately available, study drug must be 
discontinued if ALT > 3xULN and bilirubin >2xULN pending the results of review by the 
Medical Lead, GCSP physician and the investigator.  Serum bilirubin fractionation must be 
performed if testing is available. If testing unavailable, record presence of detectable urinary 
bilirubin on dipstick, indicating direct bilirubin elevations and suggesting liver injury. 
When any of the liver chemistry stopping criteria is met, do the following:

Immediately stop study treatment

Report the event to Novartis within 24 hours of learning its occurrence

Hold ofatumumab for two weeks, repeat liver chemistry testing at least twice weekly, and 
call the Medical Lead to discuss the possibility of re-challenging with ofatumumab.
Note:  The 2 week time point for stopping medication was chosen because it will 
distinguish from liver function test elevations due to tumor lysis which must have 
resolved within this time period.  Medication is interrupted and it is a clinical and patient 
decision if ofatumumab may be re-started.  The risk:benefit ratio is different in an 
oncology setting and an efficacious therapy may be life-saving.  

Complete the liver event eCRF and SAE data collection tool if the event also meets the 
criteria for an SAE

All events of ALT > 3xULN and bilirubin > 2xULN (>35% direct bilirubin) (or 
ALT>3xULN and INR>1.5, if INR measured; INR measurement is not required and 
the threshold value stated will not apply to subjects receiving anticoagulants), termed 
‘Hy’s Law’, must be reported as an SAE (excluding studies of hepatic 
impairment or cirrhosis).

NOTE: if serum bilirubin fractionation is not immediately available, study treatment 
must be discontinued if ALT > 3xULN and bilirubin > 2xULN. Serum bilirubin 
fractionation must be performed if testing is available. If testing is unavailable, 
record presence of detectable urinary bilirubin on dipstick, indicating direct 
bilirubin elevations and suggesting liver injury.

Complete liver imaging and/or biopsy eCRF(s) if these tests are performed. 

Perform liver chemistry follow-up assessments (see Section 6.4.1.3) and monitor the 
subject until liver chemistries resolve, stabilize or return to baseline values as described 
below. 

In addition, for subject meeting liver stopping criteria 1: 

Make every reasonable attempt to have subjects return to clinical within 24 hours for 
repeat liver chemistries, liver event follow-up assessments (See Section 6.4.1.3) and 
close monitoring


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
A specialist or hepatology consultation is recommended

Monitor subjects twice weekly until liver chemistries (ALT, AST, alkaline 
phosphatase, bilirubin) resolve, stabilize or return to within baseline values.

For subjects meeting criteria 2 or 3: 

Make every reasonable attempt to have subjects return to clinic within 24 to 72 
hours for repeat liver chemistries and liver event follow-up assessments (See Section 
6.4.1.3)

Monitor subjects weekly until liver chemistries (ALT, AST, alkaline phosphatase, 
bilirubin) resolve, stabilize or return to within baseline values.

After holding ofatumumab for two weeks: 

If the treatment is exhibiting efficacy and the subject wants to continue therapy after 
being informed of the results of liver chemistry testing, then the ofatumumab may be 
re-started. 

Liver chemistries and the signs and symptoms listed in liver chemistry follow-up 
assessments must be monitored at a minimum of every 2 weeks until resolution, 
stabilization, or a return to baseline values, at which point monitoring must be 
continued per protocol.
Subjects with ALT >3xULN but <5xULN and bilirubin <2xULN without hepatitis symptoms 
or rash, and who may be monitored weekly for at least 4 weeks, then the following actions 
must be taken:

Subjects can continue ofatumumab. 

Return weekly for repeat liver chemistries until they resolve, stabilize, or return to 
baseline values, then monitor liver chemistries as per protocol assessment schedule.

If at any time the subject meets any of the liver chemistry stopping criteria, then 
proceed as described above.

If after 4 weeks of monitoring, ALT<3xULN and bilirubin<2xULN, monitor twice 
monthly until liver chemistries normalize or return to within baseline values.

Hepatic events should be documented as an AE or an SAE as appropriate (See 
Section 6.5 and Section 6.5.2).
6.4.1.3
Liver Chemistry Follow-up Assessments
For subjects meeting any of the liver chemistry stopping/interruption criteria, make every 
attempt to carry out the liver event follow up assessments described below:
Viral hepatitis serology including:
1. Hepatitis A IgM antibody
2. HBsAg and HBcAb (IgM); 
3. Hepatitis C RNA; 


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4. Cytomegalovirus IgM antibody;  
5. Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, obtain heterophile 
antibody or monospot testing);  
6. Hepatitis E IgM antibody 
7. Blood sample for PK analysis of ofatumumab (if an Arm A subject), obtained as soon as 
possible but no later than 5 months of last dose (approximately 5 half-lives of the drug).  
Record the date/time of the PK sample draw and the date/time of the last dose of 
ofatumumab prior to blood sample draw on the eCRF.  If the date or time of the last dose 
is unclear, provide the best approximation.  If a PK sample cannot be collected in the time 
period indicated above, do not obtain a PK sample.  Instructions for sample handling and 
shipping are in the SPM.  
8. Serum creatine phosphokinase (CPK) and lactate dehydrogenase (LDH)
9. Fractionate bilirubin, if total bilirubin >2xULN
10. Obtain complete blood count with differential to assess eosinophilia
11. Record the appearance or worsening of clinical symptoms of hepatitis, or hypersensitivity, 
fatigue, decreased appetite, nausea, vomiting, abdominal pain, jaundice, fever, or rash as 
relevant on the AE report form
12. Record use of concomitant medications, acetaminophen, herbal remedies, other over the 
counter medications, or putative hepatotoxins, on the concomitant medications report form.
13. Record alcohol use on the liver event alcohol intake form
The following assessments are required for subjects with ALT>3xULN and bilirubin>2xULN 
(.35% direct) but are optional for other abnormal liver chemistries:

Anti-nuclear antibody, anti-smooth muscle antibody, and Type 1 anti-liver kidney 
microsomal antibodies

Serum acetaminophen adduct HPLC assay (quantifies potential acetaminophen 
contribution to liver injury in subjects with definite or likely acetaminophen use in the 
preceding week [James, 2009].

Liver imaging (ultrasound, magnetic resonance, or computerized tomography) to evaluate 
liver disease. 
Only in those with underlying chronic hepatitis B at study entry (identified by positive 
hepatitis B surface antigen): quantitative hepatitis B DNA and hepatitis delta 
antibody. . NOTE: if hepatitis delta antibody assay cannot be performed, it can be replaced 
with a PCR of hepatitis D RNA virus (where needed) – as outlined in: Adverse Events
The investigator or site staff will be responsible for detecting, documenting and reporting 
events that meet the definition of an AE or SAE (Section 6.5 and Section 6.5.2).


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6.5
Adverse Events
The investigator or site staff will be responsible for detecting, documenting and reporting
events that meet the definition of an AE or SAE (Appendix 1 and Appendix 3).
6.5.1
Definition of an AE
Any untoward medical occurrence in a subject or clinical investigation subject, temporally 
associated with the use of a medicinal product, whether or not considered related to the 
medicinal product.
Note: An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the 
use of a medicinal product.  For marketed medicinal products, this also includes failure to 
produce expected benefits (i.e., lack of efficacy), abuse or misuse.
Events meeting the definition of an AE include:

Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition

New conditions detected or diagnosed after investigational product administration even 
though it may have been present prior to the start of the study

Signs, symptoms, or the clinical sequelae of a suspected interaction

Signs, symptoms, or the clinical sequelae of a suspected overdose of either investigational 
product or a concomitant medication (overdose per se will not be reported as an AE/SAE).

“Lack of efficacy” or “failure of expected pharmacological action” per se will not be 
reported as an AE or SAE. However, the signs and symptoms and/or clinical sequelae 
resulting from lack of efficacy will be reported if they fulfill the definition of an AE or 
SAE.  
Events that do not meet the definition of an AE include:

Any clinically significant abnormal laboratory finding or other abnormal safety 
assessments that is associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the subject’s condition. 

The disease/disorder being studied, or expected progression, signs, or symptoms of the 
disease/disorder being studied, unless more severe than expected for the subject’s 
condition

Medical or surgical procedure (e.g., endoscopy, appendectomy); the condition that leads 
to the procedure is an AE

Situations where an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital)

Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or 
detected at the start of the study that do not worsen

B cell depletion due to ofatumumab treatment


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
Events related to the underlying lymphoma and unrelated to the study therapy, unless 
more severe than expected for the condition
6.5.2
Definition of a SAE
6.5.3
Toxicity Assessment of AEs and SAEs
The investigator is required to make an assessment of the toxicity grade of each AE or SAE 
reported.  In this protocol, the maximum toxicity grade of each non-hematologic AE/SAEs 
will be evaluated according to the National Cancer Institute (NCI) Common Terminology
Criteria for Adverse Events (CTCAE) version 4.0 [NCI-CTCAE, 2009].
6.5.4
Laboratory and Other Safety Assessment Abnormalities Reported as 
AEs and SAEs
Any abnormal laboratory test results (hematology, clinical chemistry, or urine analysis) or 
other safety assessments (e.g., ECGs, radiological scans, vital signs measurements), including 
those that worsen from baseline, and felt to be clinically significant in the medical and 
scientific judgment of the investigator are to be recorded as AEs or SAEs.
ALT levels of greater than 3 times the ULN and simultaneous bilirubin levels of greater  than 
2 times ULN (>35% direct bilirubin; bilirubin fractionation required) are to be recorded as 
SAEs. 
However, any clinically significant safety assessments that are associated with the underlying 
disease, unless judged by the investigator to be more severe than expected for the subject’s 
condition, are not to be reported as AEs or SAEs.
B cell depletion due to treatment with ofatumumab not to be reported as an AE or SAE.
Infusion related AEs may lead to a prolonged infusion time. Overnight stay at the hospital due 
to slow infusion rate is not to be reported as a SAE.  
6.5.4.1
Detection and Management of AEs and SAEs of Special Interest
Specific attention will be paid to monitor events of special interest such as infusion reactions, 
tumor lysis syndrome, infections and progressive multifocal leukoencephalopathy (PML).  
Please refer to the SPM and/or the following text for more details.
6.5.4.1.1 Handling Infusion Reactions
Infusion reactions are commonly associated with anti-CD20 antibody therapy. Ofatumumab 
can cause serious infusion reactions manifesting as bronchospasm, dyspnea, laryngeal edema, 
pulmonary edema, flushing, hypertension, hypotension, syncope, cardiac ischemia/infarction, 
back pain, abdominal pain, pyrexia, rash, urticaria, and angioedema. Infusion reactions occur 
more frequently with the first 2 infusions.
The site staff must be prepared to intervene if an infusion reaction occurs. Special caution 
should be taken during the first infusion for each subject and during the infusion for any 
subject who did not tolerate a previous infusion well.  It is recommended that a resuscitation 


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or crash cart/trolley is readily accessible in the event of an emergency. Infusion reactions 
should be treated according to the investigators judgment and best clinical practice.  
Interruption, restart and increasing the rate of the infusion depending on the severity of the AE 
must be according to the description below. An increase of the infusion rate after an 
interruption must not exceed the scheduled amount as described in Table 3 and Table 4 (i.e. 
not more than doubled rate and no earlier than every 30 minutes).  
Mild and Moderate Intensity Adverse Events (Grade 1 and 2)
If the investigator judges the AE to be related to the infusion, the infusion must be temporarily 
slowed or interrupted. When the subject’s condition is stable, the infusion can be restarted 
according to the judgment of the investigator. Upon restart, the infusion rate should be half of 
the infusion rate at the time the infusion was paused. If, however, the infusion rate was 
12mL/hr before the pause, the infusion should be restarted at 12mL/hr.
6.5.4.1.2 Severe Intensity Adverse Events (Grade 3)
If the investigator judges a grade ≥3 AE to be related to the infusion, the infusion must be 
interrupted and the appropriate clinical intervention commenced.  When the AE decreases to 
grade <3, the investigator may restart the infusion. Upon restarting the infusion, the infusion 
rate must be 12mL/hr for the first infusion or 25mL/hr for subsequent infusions, and may 
subsequently be increased according to the judgment of the investigator, as described in 
Section 5.1.2.1 of the protocol (i.e. not more than doubled and no earlier than every 30 
minutes). 
If the severity of the AE does not resolve to grade <3 despite adequate clinical intervention, or 
the same AE increases to grade =3 on three occasions during one infusion, the subject should 
be withdrawn from treatment.
6.5.4.1.3 Handling Tumor Lysis Syndrome
Monitoring and treatment of potential Tumor Lysis Syndrome (TLS) should be performed as 
per oncology standard of care. 
Symptoms of TLS include:

Hyperkalemia, potentially leading to cardiac conduction abnormalities, muscle weakness 
or paralysis

Hyperphosphatemia, potentially leading to renal failure

Hypocalcemia. Symptoms include (but are not limited to):  tetany, seizures, mental 
retardation / dementia, parkinsonian (extrapyramidal) movement disorders, papilledema, 
emotional instability / agitation / anxiety, myopathy


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
Hyperuricemia, potentially leading to renal failure
Risk factors for TLS include a high tumor burden, high concentrations of circulating cells (≥ 
25,000/mm3), hypovolemia, renal insufficiency, elevated pre-treatment uric acid levels and 
elevated lactate dehydrogenase levels. Thus TLS should be suspected in subjects with large 
tumor burden who develop acute renal failure along with hyperuricemia (> 15 mg/dL) or 
hyperphosphatemia (> 8 mg/dL). Acute uric acid nephropathy is associated with little or no 
urine output. The urinalysis may show uric acid crystals or amorphous urates. The 
hypersecretion of uric acid can be detected with a high urine uric acid:creatinine ratio > 1.0, 
compared to a value of 0.6-0.7 for most other causes of acute renal failure.
In those patients considered to be at risk for TLS, management of TLS includes correction of 
electrolyte abnormalities, monitoring of renal function, maintenance of fluid balance (consider 
aggressive hydration i.e. ~3,000 ml/m2/day fluid administered parenterally) and supportive 
care. If signs of TLS occur the investigator can administer rasburicase, allopurinol (e.g. 
Zyloprim, Allohexal, Allosig, Progout, Zyloric), or other drugs used to treat hyperuricemia, 
per prescribing information, if deemed appropriate.  
6.5.4.1.4 Handling Progressive multifocal leukoencephalopathy (PML)
PML is a viral-induced demyelinating disease of the central nervous system usually occurring 
in the immunocompromised individual and has been reported with ofatumumab. JC virus 
(JCV) infection resulting in PML and death has been reported in rituximab-treated subjects 
with hematologic malignancies or with systemic lupus erythematosus, an indication for which 
rituximab has not been approved. Investigators and nurses should pay careful attention for 
signs and symptoms consistent with a diagnosis of PML. Signs and symptoms of PML 
include visual disturbances, ocular movements, ataxia, and changes in mental status such as 
disorientation or confusion. These symptoms are not an exhaustive list, and the investigator 
should exercise judgment in deciding to report signs and symptoms to sponsor promptly.
If a subject develops neurological signs or symptoms consistent with PML, treatment should 
be halted and the subject referred to a neurologist for evaluation. At a minimum, blood JCV 
PCR and/or MRI should be performed; if either test is positive, Cerebrospinal Fluid (CSF) 
JCV PCR should be performed. If blood JCV PCR and MRI are negative, the investigator 
should contact the Sponsor for appropriate action to be taken. If blood JCV PCR and/or MRI 
are positive, the subject should be withdrawn from treatment, proceed to the Follow-Up 
Period, and be followed until resolution. There are no known tests that can reliably determine 
who is at increased risk for developing PML. There are no known interventions that can 
reliably prevent PML or adequately treat PML if it occurs.
The investigator will do the following when reporting a serious infection (including PML) or 
sign/symptom consistent with PML.


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
Refer to Section 6.5.8 of this document for further information and detailed guidance 
for completing and transmitting these and other SAE reports for subjects who 
experience a serious infection, malignancy, death, or sign or symptom of PML.

Provide key source documentation for the Sponsor to assist with the safety evaluation 
process.
Examples of key source documents include but are not limited to: hospitalization records, 
discharge summaries, laboratory evaluations, biopsy results, culture/sensitivity results, death 
certificates, and autopsy reports.
If the subject has not otherwise been withdrawn from the study, then the investigator should 
contact the Sponsor to discuss the appropriate course of action regarding study continuation.
6.5.4.1.5 Monitoring of Hepatitis in patients
In subjects receiving ofatumumab that are Hepatitis B core positive, HBsAg negative, and 
HBV DNA negative (Section 6.3.2 and Section 6.5.7.1), Hepatitis B DNA must be obtained 
on Day 1 of each cycle visit while on treatment and then 1,3,6 months post treatment.
For subjects who require hepatitis monitoring, extra visits outside those defined in the 
protocol may be required.  
If a subject converts to HBV DNA positive during the study, Hepatitis B treatment may be 
initiated by the site investigator after consultation with a physician experienced in the care and 
management of subjects with Hepatitis B and the Novartis Medical Lead.  The risks and 
benefits of continuing ofatumumab or discontinuing ofatumumab must be discussed with the 
Medical Lead before appropriate treatment decisions are made for that individual subject.  
For subjects randomized to the study in Japan, please see Appendix 8 of the protocol for 
additional guidance.
6.5.5
Disease-Related Events and/or Disease-Related Outcomes Not 
Qualifying as SAEs
An event which is part of the natural course of the disease under study (i.e. disease 
progression) is not to be reported as a SAE.  Death from disease progression is also not to be 
reported as an SAE.  However, if the progression of the underlying disease is greater than that 
which would normally be expected for the subject or if the investigator considers that there 
was a causal relationship between treatment with investigational product or protocol 
design/procedures and the disease progression, then this must be reported as a SAE. 
6.5.6
Pregnancy
Any pregnancy that occurs during study participation must be reported using a clinical trial 
pregnancy form.  To ensure subject safety, each pregnancy must be reported to Novartis 
within 24 hours of learning of its occurrence.  The pregnancy must be followed up to 
determine outcome (including premature termination) and status of mother and child.  
Pregnancy complications and elective terminations for medical reasons must be reported as an 
AE or SAE.  Spontaneous abortions must be reported as an SAE.


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Any SAE occurring in association with a pregnancy brought to the investigator’s attention 
after the subject has completed the study and considered by the investigator as possibly 
related to the investigational product, must be promptly reported to Novartis.
The investigator must attempt to collect pregnancy information about a partner of a male 
study subject, who becomes pregnant by a male study subject while he is enrolled in the study. 
Pregnancy information must be reported to Novartis as described above.
6.5.7
Time Period and Frequency of Detecting AEs and SAEs
All SAEs and AEs regardless of relationship to investigational product will be collected from 
the first dose of investigational product to 60 days after the last dose of investigational 
product and will be documented on the eCRF.  All SAEs regardless of causalitywill be 
reported from 61 days after the last dose of investigational product to the end of the follow-up 
period or until initiation of subsequent anti-lymphoma therapy is initiated. Any SAE brought 
to the investigator's attention after the start of subsequent anti-lymphoma therapy and 
considered by the investigator as possibly related to either ofatumumab or bendamustine must 
be reported to Novartis.
From the time a subject consents to participate in and completes the study (See Section 4.4), 
all SAEs assessed as related to study participation (e.g., protocol-mandated procedures, 
invasive tests, or change in existing therapy) will be reported promptly to Novartis as 
indicated in Table 9.
From the time a subject consents to participate in and completes the study or withdraws from 
the study (Section 4.4), all SAEs assessed as related to study participation (e.g., protocol-
mandated procedures, invasive tests, or change in existing therapy) will be recorded.
Discontinuation of ofatumumab is not mandated; however the investigator must consult the 
Novartis Medical Lead to analyze the risk-benefit and determine if appropriate to continue 
ofatumumab therapy in that individual subject. 
Any pre-existing condition or signs and symptoms present prior to investigational product will 
be recorded as medical history.  
Any SAE brought to the investigator’s attention after the subject has completed the study and 
considered by the investigator as possibly related to investigational product must be reported 
to Novartis.
6.5.7.1
Monitoring subjects with Hepatitis B
Subjects that are HBsAG negative, HBcAb positive and HBV DNA negative may be included 
in the study but must undergo HBV DNA monitoring per Appendix 2, Appendix 3, or 
Appendix 8 (for Japan) from the start of treatment during the treatment course and through 
F/U. Consult with a physician experienced in care & management of subjects with hepatitis B 
to manage/treat subjects who are anti-HBc positive. Initiate anti-viral therapy if required. If a 
subject’s HBV DNA becomes positive during the study, notify the Novartis Medical Lead. 
For subjects who have not completed planned ofatumumab therapy, discuss with the Medical 
Lead the risks and benefits of continuing or discontinuing ofatumumab before appropriate 
treatment decisions are made for that individual subject.


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6.5.8
Prompt Reporting of Serious Adverse Events and Other Events to 
Novartis
SAEs and pregnancies and liver chemistries meeting pre-defined stopping criteria will be 
reported promptly to Novartis as described in the following table once the investigator 
determines that the event meets the protocol definition for that event.
Table 9
SAE reporting
Initial Reports
Follow-up Information on a Previous 
Report
Type of Event
Time Frame
Documents
Time Frame
Documents
All SAEs
24 hours
“SAE” data collection 
tool
24 hours
Updated “SAE” data 
collection tool 
Pregnancy
24 hours
Pregnancy 
Notification Form
2 Weeks
Pregnancy Follow up 
Form
Liver chemistry stopping 
criteria (See Section
6.4.1)
24 to 72 hours
Liver event CRFs 
and “SAE” data 
collection tool
24 hours
Updated Liver Event 
CRF and SAE form 
and updated “SAE” 
data collection tool
The method of detecting, recording, evaluating and follow-up of AEs and SAEs plus 
procedures for completing and transmitting SAE reports to Novartis are provided in the SPM.  
Procedures for post-study AEs/SAEs are provided in the SPM.
6.5.9
Regulatory reporting requirements for SAEs
Prompt notification of SAEs by the investigator to Novartis is essential so that legal 
obligations and ethical responsibilities towards the safety of subjects are met.
Novartis has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a product under clinical investigation.  Novartis will 
comply with country specific regulatory requirements relating to safety reporting to the 
regulatory authority, IRB/ IEC and investigators.
Investigator safety reports are prepared for suspected unexpected serious adverse reactions 
according to local regulatory requirements and Novartis policy and are forwarded to 
investigators as necessary.
An investigator who receives an investigator safety report describing a SAE(s) or other 
specific safety information (e.g., summary or listing of SAEs) from Novartis will file it with 
the IB and will notify the IRB/IEC, if appropriate according to local requirements.
6.6
PRO Measures
Subjects will be asked to complete PRO measures in a standardized manner (see description 
below) at baseline, and during treatment or evaluation visits throughout the trial as indicated 
in Appendix 1.  Following completion of questionnaires, site staff will transcribe information 
into eCRFs.  The purpose is to document changes in symptoms and functioning that are 


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important for subjects with indolent lymphoma. The PRO questionnaires for this study are the 
FACT-Lym, EQ-5D and an HCQ. Examples of all PRO questionnaires are included in 
Appendix 5.
For all subjects:

The FACT-Lym and EQ-5D questionnaires will be administered at baseline (screening 
visit) and as described in Appendix 1. The HCQ is not administered at the baseline 
(screening visit), but administered on all other visits as described in Appendix 1.

Subjects will have all the PROs administered at all quarterly evaluations until PD

If a subject demonstrates disease progression, all the measures will be completed at the 
progression visit and again one time after determination of PD.  

If a subject withdraws from the study then all the PRO questionnaires will be administered 
at the point of withdrawal
The importance of completing the PRO questionnaires as fully as possible must be stressed to 
the subjects. 
6.6.1
Functional Assessment of Cancer Therapy - Lymphoma (FACT-Lym) 
Subscale
The FACT-Lym was developed by the FACIT research group and is intended as a lymphoma 
specific additional concerns subscale that is designed to supplement the FACT-G.  The 
subscale consists of 15 items. Subjects respond to the items on a five point Likert scale 
ranging from 0 ‘Not at all’ to 4 ‘Very much’.  Subjects are asked to think back over the past 
week when responding. The FACT-Lym has been validated for reliability, validity and 
sensitivity [Webster, 2005] and it has been shown to have strong internal consistency across 
five different languages [Eremenco, 2004]. The FACT-Lym has recently been shown to be 
sensitive to indolent lymphoma disease activity 
[Pettengel, 2008].
6.6.2
EuroQoL Five-Dimension (EQ-5D)
The EQ-5D is a self-administered, generic, indirect utility measure 
[EuroQoL, 1990] and will be used for health economic analysis. The EQ-5D consists of a 0-
100 Visual Analogue Scale (VAS) on which subjects are asked to rate their current overall 
health status and five single-item dimensions which ask subjects to rate their health in terms 
of mobility, self-care, usual activities, pain/discomfort and anxiety/depression.  The five 
single items can be summed and expressed as a single global index of health-related quality of 
life. For each of the five items subjects must choose between three levels of difficulty in 
accomplishing tasks in that dimension.  The VAS is then used in combination with the 
dimension scores to generate a subject profile.
One response exists per dimension, such that:

Level 1 (no problem) is coded as “1”

Level 2 (some or moderate problems) is coded as “2”


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
Level 3 (unable, or extreme problems) is coded as “3”


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The health states are described in terms of five-digit numbers based on the answers to 
each of the five questions.  The states can then be converted to a single score using a table 
that contains health utility values for the 243 different possible health states.  Thus a 
health utility score is created that can be incorporated into analyses of cost effectiveness.  
Additionally, a three-digit number between 0 and 100 is read off the VAS, from the exact 
point where the subject has marked the scale.  The EQ-5D takes less than five minutes to 
complete.  The EQ-5D has been validated in NHL subjects [Pickard, 2007; 
Doorduijn, 2005; Van Agthoven, 2001], and has been previously used to study the impact 
of FL on subject quality of life [Cheung, 2009].
6.6.3
Health Change Questionnaire
The HCQ used here is a nine item scale that asks the subject to rate change in the health status 
since beginning treatment on this study [Cella, 2002].  Subject response provides an ongoing 
evaluation of perceived progress and satisfaction with treatment services [Juniper, 1994].
The HCQ is valuable to estimate how meaningful change in health status is to subjects, and to 
anchor the scores from the remaining PRO instruments.
6.7
Ofatumumab Pharmacokinetic Sample Collection
6.7.1
Sample Collection for Subjects in Arm A
Blood samples for the quantification of ofatumumab plasma concentrations will be collected 
at the same time as the HAHA samples in subjects receiving ofatumumab in order to 
determine the ofatumumab plasma concentration at that time.  For subjects in Arm A 
(ofatumumab and bendamustine combination), samples will be collected according to 
Appendix 2.  Sample collection, processing, and shipping instructions are provided in the 
SPM.
6.7.2
Sample Collection for Subjects in Arm B Who Receive Ofatumumab 
Monotherapy after Disease Progression
Table 10 provides the pharmacokinetic sample collection schedule for subjects that progress 
on Arm B and select ofatumumab monotherapy (Appendix 3).  The actual date and time of 
each sample collection will be recorded in the eCRF.  Sample collection, processing, and 
shipping instructions are provided in the SPM.


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Table 10
Pharmacokinetic sample collection schedule for subjects that progress in Arm 
B and select ofatumumab monotherapy
Time
Ofatumumab Dose
Sampling time relative to ofatumumab infusion
Week 1
1
Predose
Week 4
4
Predose, EOI
1st monthly dose
5
Predose
5th monthly dose
9
Predose, EOI
6th monthly dose
10
Predose
8th monthly dose
12
Predose, EOI
1 month after last ofatumumab infusion1,2
6 months after last ofatumumab infusion1,2
12 months after last ofatumumab infusion1,2
Abbreviation:  EOI:  end of infusion .  Note:  EOI is within 15 minutes prior to stopping infusion.
1.
Collect sample relative to last dose of ofatumumab regardless of number of doses
2.
Collect sample at any convenient time on study day.


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7
data management
Data Management will identify and implement the most effective data acquisition and 
management strategy for each clinical trial protocol and deliver datasets that support the 
protocol objectives.
For this study, subject data will be entered into the eCRFs, transmitted electronically to 
Novartis and be combined with data provided from other sources (e.g. laboratory data) in a 
validated data system.
Clinical data management will be performed in accordance with applicable standards and data 
cleaning procedures with the objective of resolving errors and inconsistencies in the data 
which would otherwise impact the analysis and reporting objectives, or the credibility of the 
Clinical Study Report. Adverse events and concomitant medications terms will be coded 
using Medical Dictionary for Regulatory Activities (MedDRA) and medication custom drug
dictionary.  In all cases, subject initials will not be collected nor transmitted to Novartis 
according to Novartis policy.
[An appropriate medical dictionary that covers all approved drugs in studies
where Japan is participating will be referenced]. (1 - eDM) "eCRFs (including queries and 
audit trails) will be retained by Novartis, and
copies will be sent to the investigator to maintain as the investigator copy". In
all cases, subject initials will not be collected or transmitted to Novartis according to Novartis 
policy.
8
Data Analysis and Statistical Considerations
8.1
Hypotheses
The primary endpoint is PFS.  The null and alternative hypotheses are designed with the goal 
of demonstrating the superiority of ofatumumab and bendamustine combination therapy over 
bendamustine monotherapy.  Superiority will be determined using the following hypotheses:
H0: PFS curves for ofatumumab + bendamustine and for bendamustine are the same
H1: PFS curves for ofatumumab + bendamustine and for bendamustine are not the same 
8.2
Study Design Considerations
An ‘adaptive-like’ study design is being implemented for this study to take into consideration 
the possibility of a dosing-change recommendation after an independent review for safety and 
tolerability.  Primary efficacy and safety analyses will be conducted on the ‘final’ stage data 
set.  Supplementary efficacy and safety analyses will also be conducted on the cumulative 
data set if a dosing-change recommendation occurs.

Stage 1 will consist of 20 subjects from Arm A and any available data from Arm B to 
be included in the Dose Confirmation Cohort and any additional subjects randomized 
prior to the implementation of an IDMC recommended dosing change.


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
If no IDMC dosing change is implemented, Stage 1 will continue through the 
remainder of the study and will comprise the primary analysis set.

If an IDMC dosing change is implemented, Stage 2 will begin with subjects 
randomized thereafter.  The sample size and event count will restart at this point.   If 
no further dosing change is implemented, subjects enrolled in Stage 2 will comprise 
the primary analysis set.  Analysis of the cumulative set (subjects from Stage 1 and 
Stage 2) will be supplementary.

If an additional IDMC dosing change is implemented, Stage 3 will begin with 
subjects randomized thereafter.  The sample size and event count will restart at this 
point.  Subjects enrolled in stage 3 will comprise the primary analysis set.  Analysis 
of the cumulative set (subjects from Stages 1-3) will be supplementary.
The IDMC met after the first 20 subjects in Arm A received at least 3 cycles of OB.  Based on 
the review of the data available as well as the IDMC charter-defined criteria to alter the dose 
in Arm A, the IDMC recommended that the study can continue without any changes to the 
dosage of Arm A in the study. Consequently, there will be no further IDMC meetings to 
assess dose safety and no further dose modifications other than the protocol-directed dose 
reductions and delays already described.  The safety of subjects enrolled into the study will 
continue to be monitored by Novartis.
Since no IDMC dosing change was implemented, Stage 1 will continue through the remainder 
of the study and will comprise the primary analysis set.
INTERIM ANALYSIS
An Interim Analysis (IA) for efficacy of the primary endpoint, progression free survival, w as 
planned when approximately two thirds (or approximately 172) of the initial total 259 PFS 
events by IRC is achieved.  The interim analysis was planned to be conducted at a 
significance level of 0.012.   At the same time as the IA, a Futility Analysis (FA) was planned.  
The Independent Data Monitoring Committee (IDMC) was expected to review the efficacy 
and futility data at this timepoint.  Further details are specified in the IDMC charter.
The actual significance level at the interim and the primary analysis was planned to be 
updated according tothe actual number of events at the time of analysis - utilizing the 
O’Brien-Fleming boundary.
The IA occurred with 180 PFS events by IRC and the actual alpha spent at IA was calculated 
to be 0.0144.
The IDMC recommended that the study continue without changes.
PRIMARY ANALYSIS
As of Amendment 9, the primary analysis will be performed after approximately 215 PFS 
events by IRC have been observed. This will correspond to a power of approximately 84% to 
detect a 50% improvement in PFS between study arms. The critical boundary to be used at 
primary analysis was recalculated using EAST v6.0 software and was derived from the pre -
specified error spending functions using the actual number of events observed at interim 
analysis (180) and assuming the primary event number is 215 in order to maintain a 


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cumulative type I error smaller than two-sided 5%. Using the interim monitoring function in 
EAST v6.0, the boundary for IA was 0.0144 alpha spent, and the final boundary should be 
0.0483.
If the actual PFS event counts differ for the primary analysis, the significance level (0.0483
for the primary analysis) would be adjusted as appropriate according to the Lan and DeMets 
spending function for the O’Brien-Fleming boundary.  At the time of primary analysis, the 
primary clinical study report will be produced. Following the primary analysis time point, the 
study will remain open. Patients still being followed on the study will continue as per the 
schedule of assessments.
Final Analysis
The study will end once all patients have completed 5 years of follow-up or discontinued 
earlier, and the final analysis of study data will be conducted. All available data from all 
patients up to this cutoff date will be analyzed and final clinical study report will be produced. 
8.2.1
Sample Size Assumptions
The primary endpoint is PFS and the analysis will be conducted using stratified log-rank test.  
The following assumptions were made in the estimation of the required sample size:

Event times are exponentially distributed

Median PFS for bendamustine is 9 months

Median PFS for ofatumumab + bendamustine is 13.5 months

A 1:1 stratified randomization scheme

A 90% chance of successfully declaring a difference in the presence of a true underlying 
difference (power) 

A 5% two-sided risk of erroneously claiming a difference in the presence of no true 
underlying difference 

Accrual rate is 5.1 subjects per month 
Under the above assumptions, approximately 259 total events from both treatment arms 
combined were needed for the study to have 90% power.  With a sample size of 304 subjects, 
the duration of the study was expected to be about 70 months (under H1) to obtain the 259
total events.  Assuming a dropout rate of 12%, the total sample size randomized for both arms 
combined was expected to be 346 subjects, with approximate study duration of 77 months.
Assuming a screening failure rate of 15%, the total number of subjects screened was planned 
to be approximately 408.
Per Amendment 9, the primary analysis will take place after approximately 215 PFS events 
by IRC have been reported which will correspond to approximately 84% power.  The other 
assumptions are not modified. See Section 8.2 - Primary Analysis for details.
As stated, this trial is an event-driven study design with an event-driven sample size of 215
total events and the primary analysis will take place approximately at the time of occurrence 
of the 215th event.


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8.2.2
Sample Size Sensitivity
The robustness and sensitivity of the above sample size calculation is considered in order to 
assess the impact on power if the assumed median PFS varies.  The following table shows the 
estimated power for different median values of PFS for ofatumumab + bendamustine. The 
total number of events is 215.
Table 11
Primary Endpoint power calculation
Median PFS for Ofatumumab  + 
Bendamustine
Median PFS for Bendamustine
Estimated Power
12
9
0.553
13
9
0.763
13.5
9
0.840
14
9
0.895
15
9
0.961
8.2.3
Sample Size Re-estimation
Sample size re-estimation will not be performed.
8.3
Data Analysis Considerations
8.3.1
Analysis Populations
8.3.1.1
Four populations are defined for the analyses:
1.
The Intent-to-Treat (ITT) Population will include subjects in the primary analysis stage 
who are randomized to the study drugs.  This will be the primary population used for all 
efficacy assessments. In the analyses, subjects will be grouped based on how they are 
randomized regardless of which treatment they received. The ITT population will be used 
for all PRO analyses.  The ITT population will also be utilized for the Interim 
Analysis(IA) for efficacy and futility based on the number of subjects randomized at the 
time of the IA.
2.
The Safety Population will include subjects in the primary analysis stage who receive at 
least one dose of a study drug.  This population will be used for all safety measurements. 
In the analyses, subjects will be grouped based on the treatment they receive regardless of 
how they are randomized.
3.
The Safety Population (Dose Confirmation Cohort) will include the first 20 subjects in 
Arm A who receive at least 3 cycles of bendamustine or complete bendamustine therapy 
(if less than 3 cycles are given).  This population will be used to assess the safety and 
tolerability in the Dose Confirmation Cohort analysis of the study by the IDMC.  In the 
analyses, subjects will be grouped based on the treatment they receive regardless of how 
they are randomized.
4.
The Per Protocol (PP) Population will exclude subjects with major protocol deviation that 
will impact the efficacy outcome.  The Per Protocol Population will be used in the 
primary endpoint analysis to check the robustness of the result when using the ITT 


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population.  However, if the number of subjects in the PP population is not more than 
10% smaller than the ITT population, the analysis will not be performed.
8.3.2
Analysis Data Sets
The primary data set for efficacy will be based on the PFS and ORR assessments.  The 
primary data set for safety will be the AEs and the laboratory data sets.
The efficacy response will be assessed by the investigators and by the independent reviewers.  
Data will be summarized for investigator assessed response as well as for independent 
reviewer assessed response. Statistical inference for efficacy claim(s) will be based on the 
PFS and ORR data assessed by the independent reviewers. 
8.3.3
Treatment Comparisons
8.3.3.1
Primary Comparisons of Interest
The primary comparison is performed at IA and at the time of primary analysis. The primary 
treatment comparison of interest will be ofatumumab + bendamustine vs. bendamustine. This 
will be based on comparing the overall PFS using the ITT population.  Refer to Section 8.2
for the timing of the IA and primary analysis.
The primary efficacy endpoint will serve as a gatekeeper for the interpretation of treatment 
comparisons for the ‘inferential’ secondary endpoints.  If H0 is rejected, the conclusion will be 
that there is a treatment difference between ofatumumab in combination with bendamustine 
and bendamustine monotherapy, and the p-value for the ‘inferential’ secondary endpoints may 
be interpreted.
As described in Section 8.2, the significance levels for the interim and final analysis will be 
adjusted as appropriate using the O’Brien-Fleming spending function.
8.3.3.2
Secondary and Other Comparisons of Interest
The secondary comparisons of interest will include ofatumumab + bendamustine vs. 
bendamustine, based on the PFS in patient with follicular lymphoma, ORR in all patients and 
patients with follicular lymphoma, and OS in all patients and patients with follicular 
lymphoma.  These will be considered as “inferential secondary endpoints” and will be tested 
hierarchically only if the primary endpoint, PFS, is significant in all patients.  One spending 
function will be used for each of these hypotheses. Each hypothesis will be tested at the 
remaining alpha level for primary analysis determined based on actual information fraction at 
IA for that hypothesis (assuming that the same alpha level for each hypothesis (i.e. 0.0144)
was spent). This conservative approach ensures strong control of the type I error for the entire 
study, including IA and primary analysis for all comparisons of interest. The following 
sequence of secondary endpoints will be tested, and the subsequent one is tested only if all the 
previous endpoints are tested and deemed statistically significant:
1. PFS in patients with follicular lymphoma
2. ORR in all patients 
3. ORR in patients with follicular lymphoma
4. OS in all patients 


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5. OS in patients with follicular lymphoma
(e.g. only if the PFS in all patients and PFS in patients with follicular lymphoma are 
significant then the ORR in all patients will be tested).
This hierarchical testing procedure ensures a strong type I error control at a two sided 0.05 
level.
The other comparisons of interest will be ofatumumab + bendamustine vs. bendamustine, 
based on the other secondary endpoints.  No multiplicity adjustment will be considered for the 
other secondary endpoints.
Per Amendment 9, the primary analysis will be performed after approximately 215 PFS 
events by IRC have been reported. See Section 8.2 - Primary Analysis for details.
8.3.4
Interim Analysis for Safety
A safety and tolerability analysis was planned after 20 subjects completed 3 cycles (or 
completion of bendamustine therapy) of treatment in Arm A.  This process is described in 
Section 3.1.3 and was further detailed in a charter for the IDMC.
8.3.5
Interim Analysis for Efficacy and Futility
An Interim Analysis (IA) for efficacy was planned when approximately two thirds (or 
approximately 172) of the initial total 259 IRC events is achieved.  The interim analysis for 
PFS was planned to be performed by an IDMC utilizing an O’Brien-Fleming spending 
function with significance level of 0.012 (with 172 events).  Performing this interim analysis 
with an IDMC was planned to allow for an earlier detection of clinical benefit to patients with 
ofatumumab+bendamustine. The interim analysis of the primary endpoint, PFS, was
conducted as described in Section 8.2, and further details of the interim analysis was provided 
in the IDMC Charter.  
The IA occurred with 180 PFS events by IRC and the actual alpha spent at IA was calculated 
to be 0.0144. Per Amendment 9 (See Section 8.2 - Primary Analysis for details), the primary
analysis will be conducted at a significance level of 0.0483 (with 215 events) to maintain an 
overall study significance level of 0.05. This process is further detailed in a charter for the 
IDMC.
8.3.6
Key Elements of Analysis Plan
The primary analysis will take place when the target number of events is reached in the study. 
An event is defined as a subject who either has PD or death due to any cause during the study. 
All available data will be analyzed and the results will be presented in a report.
Released data that are available from later visits will be included as supportive analyses.
Withdrawal
Subjects will be treated until disease progression or withdrawal from study treatment due to 
unacceptable AE(s), consent withdrawal or other reasons.  All data up to time of withdrawal 
will be included in the analysis.  


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Subjects who are withdrawn prematurely from study treatment, but who are not withdrawn 
from the study at the time of analysis, will be included in the analysis, regardless of treatment 
duration.
Missing Data
Since the duration of treatment for a given subject will depend on the efficacy and safety of 
the study drug, the duration of follow-up will vary among subjects.  Consequently, there will 
be no imputation for missing data, with the exception of overall response and PRO scores, for 
which some imputation might be necessary.  Details will be given in the Reporting and 
Analysis Plan (RAP).
The appropriate available data will be summarized over specified intervals using suitable 
summary statistics.  
For PFS endpoint, subjects who are alive and have not progressed at the time of analysis will 
be censored at the date associated with the last visit with adequate assessment.  If a 
progression event occurs after an extensive lost-to-follow-up time (12 weeks or greater), the 
primary analysis will censor those subjects at the date of their last visit with an adequate 
assessment even if subsequent information is available regarding progression or date of death.  
Sensitivity analyses, described in Section 8.3.6.1 will be examined to evaluate the impact of 
the missing assessments.
Derived and Transformed Data
The overall response will be evaluated by the IRC in addition to being evaluated by the 
investigators. All analyses will be based on the IRC assessments.  Details for the evaluation of 
objective response will be provided in RAP.  
Details of the assignments of progression and censoring dates will be provided in the RAP.
Other Issues
Data from all participating centers will be pooled for the analyses.  It is anticipated that 
subject accrual will be spread thinly across centers and summary of data by center would be 
unlikely to be informative, and therefore, will not be conducted.  
Subgroup analyses will be provided by stratification factors and the important baseline 
covariates for supportive purpose.
Subjects that are treated with ofatumumab following PD in the bendamustine monotherapy 
arm will be analyzed as subjects that have a ‘new anti-cancer therapy started’ for efficacy 
analyses.  For safety analyses, subjects will be analyzed based on the treatment course 
received and additional summaries may be required to explore the safety profile for rescued 
subjects. 
Any deviations from, or additions to, the original analysis plan described in this protocol will 
be documented in the RAP and final study report.
8.3.6.1
Efficacy Analyses
Primary Analysis:
Progression-free survival is defined as the time from randomization until progression or death.  
The progression events will be defined by well-documented and verifiable data.  Details of 
censoring will be provided in the RAP.


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An interim analysis of the primary endpoint, PFS, was performed with 180 PFS events by 
IRC .  The interim analysis for PFS was performed by an IDMC. The interim analysis of PFS 
was conducted in the same manner as described for the primary analysis, and further details of 
the interim analysis areprovided in the IDMC Charter.
Per Amendment 9, the primary analysis will take place after approximately 215 PFS events
by IRC.  The primary analysis of PFS will be tested based on a two-sided test, with a 
significance level of 0.0483 (See Section 8.2 - Primary Analysis for details). Survival 
distributions will be estimated using the Kaplan-Meier method, and survival curves will be 
compared using a stratified log-rank test.
In addition to the stratified log-rank test, a Cox regression model will be used and will include 
covariates for treatment, stratification factors (type of last prior rituximab: R-chemo or 
Rituximab alone and by prior exposure to bendamustine: exposed or not exposed) age, gender, 
race, pathology (based on inclusion criteria), FLIPI and ECOG.  Analytical results will 
include the estimated hazard ratios along with 95% confidence intervals, and associated 
probabilities for the effect of treatment, stratification factors and the covariates.  The hazard 
ratio for treatment will express the risk of experiencing disease progression or death for 
‘ofatumumab + bendamustine’ vs. ‘bendamustine’. 
The sensitivity analysis of PFS will be conducted to confirm the robustness of the primary 
PFS analysis.  The assignments of progression and date of censoring for sensitivity analysis of 
PFS are the same as those of  the primary PFS, with the following difference: if a clinical 
progression is proclaimed by the investigator, the outcome is ‘Progressed‘, and the date of the 
progression is the date of the claim or the next scheduled visit (if between visits).
Analyses of PFS (as well as sensitivity analysis of PFS) will be conducted for the independent 
reviewer assessed data.  The statistical inference will be based on the independent reviewer 
assessed data.
The PP population will only be used for the primary endpoint if the difference of total number 
of subjects is greater than 10% of the ITT population.  
Subgroup analyses will be conducted for PFS for the stratification factors.
Inferential Secondary Analyses:

Progression-free survival in patients with follicular lymphoma

Overall response rate in the overall population

Overall response rate in patients with follicular lymphoma
Responders include subjects with CR, PR.  Non-responders include subjects with SD, and PD.  
Subjects with unknown or missing responses will be considered as non-responders.
The number and proportion of subjects with ORR for CR, PR, SD and PD will also be 
provided.  
The exact Cochran-Mantel-Haenszel (CMH) test will be used to compare the proportion of 
subjects with overall response for ofatumumab in combination with bendamustine vs. 
bendamustine, adjusting for stratification factors (type of last prior rituximab: R-
chemotherapy or Rituximab alone and by prior exposure to bendamustine: exposed or not 
exposed).

Overall survival in overall population


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
Overall survival in patients with follicular lymphoma
OS is defined as the time from randomization until death.  Analysis methods will be similar to 
those described for the PFS analysis and details of censoring will be provided in the RAP.
Survival distributions will be estimated using the Kaplan-Meier method, and survival curves 
will be compared using a stratified log-rank test.
Efficacy analyses on PFS, ORR and OS will also be performed in the non-FL patients to 
allow an accurate interpretation of the results. 
Other Secondary Analyses
Clinical:

Time to response

Time to response is defined as time from randomization to the first response (CR/ 
PR).  Kaplan-Meier curves will be provided for the treatment arms over time. The 
median time to response along with the associated 95% confidence will be provided 
for ofatumumab in combination with bendamustine and for bendamustine.  Time to 
response will be analysed in all patients, as well as in patients with and without 
follicular lymphoma.

Duration of response

The duration of response is defined as the time from the initial response (CR/ PR) to 
progression or death.  The same analysis will be performed as described for time to 
response analysis. Duration of response will be analysed in all patients, as well as in 
patients with and without follicular lymphoma.

Time to progression

Time to progression (TTP) is defined as the time from randomization until disease 
progression.  The same analysis will be performed as described for time to response 
analysis. Time to progression will be analysed in all patients, as well as in patients 
with and without follicular lymphoma.

Time to next therapy

Time to next therapy is defined as the time from randomization until next line 
treatment.  The same analysis will be performed as described for time to response 
analysis. Time to next therapy will be analysed in all patients, as well as in patients 
with and without follicular lymphoma.

Reduction in tumor size 

Tumor sizes and reduction in tumor size will be measured by the absolute value of, 
and percentage change in the sum of products of the diameters of the largest 
abnormal nodes from baseline to post-baseline. 

Improvement of ECOG performance status 


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
Improvement is defined as a decrease from baseline by at least one step on the 
ECOG performance status scale (yes/no). The same analysis will be performed as 
described for ORR analysis. 

Incidence of grade 3 and 4 infections

The frequency and rate of subjects with grade 3 and 4 infections at the scheduled 
visits will be provided.  A summary by responders and non-responders will also be 
provided.

Human Anti-Chimeric Antibodies (HACA)

The number of subjects with positive HACA in the predose samples will be reported.

HACA results prior to ofatumumab administration will be listed.

Human Anti-Human Antibodies (HAHA)

The number of positive and negative results at each visit will be provided in subjects
who receive ofatumumab.  HAHA results and associated ofatumumab plasma
concentration at each time point will be listed.

Evaluation of myelosuppression (anemia, neutropenia, thrombocytopenia) 

Frequency and percent of subjects with myelosuppression will be provided by 
responders and non-responders.  

IgG, IgA, IgM

Summaries of IgG, IgA, IgM will be provided at scheduled visits.
Disease and Prognostic Markers:

B-cell monitoring

The change of CD19+ or CD20+ from baseline (absolute and percentage) will be 
summarized to assess the treatment effect and to monitor the normal B-cell 
population.  In addition, frequency and percentage with complete B-cell depletion 
will be summarized by responders and non-responders. 

Known and exploratory prognostic markers correlating with clinical response  

Cox regression may be used to explore the relationship between PFS and the 
following explanatory variables: treatment group, FLIPI-1, FLIPI-2, genetic variants 
in FcR, cytogenetics (analyzed by FISH) at baseline, Absolute Lymphocyte Count 
(ALC), thymidine kinase, soluble CD20 at baseline, Human anti-chimeric antibodies 
(HACA) to rituximab. 

Logistic regression will be conducted to explore the relationship between objective 
response and the same set of explanatory variables.   


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8.3.6.2
Safety Analyses
The Safety population will be used for the safety analyses.  For continuous variables, the 
mean, median, standard deviation, minimum, and maximum will be provided in the summary 
tables.  For categorical variables, the frequency and percentage will be provided in the 
summary tables.
Extent of Exposure
The number of subjects administered to each treatment group will be summarized according 
to the duration of treatment.
Adverse Events
AEs will be coded using the standard MedDRA dictionary, and grouped by system organ 
class.  
Events will be summarized by frequency and proportion of subjects by system organ class and 
preferred terms.
If the AE is listed in the NCI CTCAE (version 4.0) table, the maximum grade will be 
summarized.
The incidence of AEs, severity of AE, deaths and the primary cause of death will also be 
provided. 
Clinical Laboratory Evaluations
Hematology and clinical chemistry data will be summarized at each scheduled visit according 
to NCI CTCAE grade (version 4.0).  The proportion of values outside the reference range will 
also be presented.  
Safety Evaluation
After 20 subjects have been treated for 3 cycles (or completion of bendamustine therapy), an 
analysis to assess safety and tolerability will be conducted.  A charter will detail the types of 
analyses, rules for modifying treatment course, and the membership and conduct of the IDMC.
8.3.6.3
PRO Analyses
All PRO measures will be scored as per the developers instructions, with scores created for 
each pre-specified domain.  Details of the scoring methods will be provided in the statistical 
analysis plan.  Each PRO domain will be summarized for each treatment group and the total 
PRO sample at each time point and presented in tabular format as mean, standard deviation, 
median, minimum and maximum. Methods for imputation of missing data will be detailed in 
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Mixed effect model for repeated measures may be used to compare the two treatment arms in 
terms of change from baseline in PRO measures. Details will be specified in the RAP. PRO 
analysis will be performed in all patients and patients with follicular lymphoma.
8.3.6.4
Pharmacokinetic Analyses
The plasma concentrations for individual subjects will be determined using validated 
analytical methods for ofatumumab.  Plasma ofatumumab concentration-time data will be 
summarized and displayed in tabular and graphical form separately for subjects in Arm A and 
for subjects in Arm B who receive ofatumumab following PD.  Individual plasma 
concentrations of ofatumumab will be listed.
Population PK modeling, using non-linear mixed effects modeling will be performed on the 
data for subjects in Arm B who receive ofatumumab following PD using validated software 
such as the computer program NONMEM, if data permit.  Data from this study may be 
combined with data from other studies for analysis.  The aims of this modeling approach are 
to:

Define the structural PK model that characterizes the population time course of plasma 
levels of ofatumumab in this subject population

Describe between-subject variability for PK parameter estimates

Estimate intra-subject variability on predicted concentrations
If possible, the effects of subject characteristics (such as gender, weight, height, disease status, 
etc.) will be investigated in order to account for potential sources of inter-individual 
variability in systemic exposure.  If there are sufficient data for analysis, the details of the 
population PK analyses will be provided in a reporting and analysis plan.
9
Study CONDUCT CONSIDERATIONS
9.1
Regulatory and Ethical Considerations, Including the Informed 
Consent Process
Prior to initiation of a study site, Novartis will obtain approval from the appropriate regulatory 
authority to conduct the study in accordance with applicable country-specific regulatory 
requirements, including those required under a US Investigational New Drug (IND).
The study will be conducted in accordance with all applicable regulatory requirements, IND 
Number 11,465.
The study will be conducted in accordance with Good Clinical Practice (GCP), all applicable 
subject privacy requirements, and the guiding principles of the declaration of Helsinki, 
including, but not limited to:

IRB)/IEC review and approval of study protocol and any subsequent amendments.


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
Subject informed consent.

Investigator reporting requirements.

Novartis will provide full details of the above procedures, either verbally, in writing, or 
both.

Written informed consent must be obtained from each subject prior to participation in the 
study.
9.2
Quality Control (Study Monitoring)
In accordance with applicable regulations, GCP, and Novartis procedures, Novartis (or 
designated Clinical Research Organization) personnel will contact the site prior to the start of the 
study to review with the site staff the protocol, study requirements, and their responsibilities 
to satisfy regulatory, ethical, and Novartis requirements.  When reviewing data collection 
procedures, the discussion will include identification, agreement and documentation of data 
items for which the eCRF will serve as the source document. Novartis will monitor the study 
to ensure that the:

Data are authentic, accurate, and complete.

Safety and rights of subjects are being protected.

Study is conducted in accordance with the currently approved protocol and any other 
study agreements, GCP, and all applicable regulatory requirements.

The investigator and the head of the medical institution (where applicable) agrees to allow 
the Novartis (or designated Clinical Research Organization) personnel direct access to all 
relevant documents.
9.3
Quality Assurance
To ensure compliance with GCP and all applicable regulatory requirements, Novartis may 
conduct a quality assurance audit of the site records, and the regulatory agencies may conduct 
a regulatory inspection at any time during or after completion of the study. In the event of an 
audit or inspection, the investigator (and institution) must agree to grant the auditor(s) and 
inspector(s) direct access to all relevant documents and to allocate their time and the time of 
their staff to discuss any findings/relevant issues.
9.4
Study and Site Closure
Upon completion or termination of the study, the Novartis (or designated Contract Research 
Organization) personnel will conduct site closure activities with the investigator or site staff 
(as appropriate), in accordance with applicable regulations, GCP, and Novartis Standard 
Operating Procedures.
Novartis reserves the right to temporarily suspend or terminate the study at any time for 
reasons including (but not limited to) safety issues, ethical issues, or severe noncompliance.  
If Novartis determines that such action is required, Novartis will discuss the reasons for taking 
such action with the investigator or head of the medical institution (where applicable).  When 


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feasible, Novartis will provide advance notice to the investigator or head of the medical 
institution of the impending action.
If a study is suspended or terminated for safety reasons, Novartis will promptly inform all 
investigators, heads of the medical institutions (where applicable), and/or institutions 
conducting the study.  Novartis will also promptly inform the relevant regulatory authorities 
of the suspension/termination along with the reasons for such action.  Where required by 
applicable regulations, the investigator or head of the medical institution must inform the 
IRB/IEC promptly and provide the reason(s) for the suspension/termination.
9.5
Records Retention
Following closure of the study, the investigator or head of the medical institution (where 
applicable) must maintain all site study records (except for those required by local regulations 
to be maintained elsewhere) in a safe and secure location.  The records must be easily 
accessible when needed (e.g., for a Novartis audit or regulatory inspection) and must be 
available for review in conjunction with assessment of the facility, supporting systems, and 
relevant site staff.
Where permitted by local laws/regulations or institutional policy, some or all of the records 
may be maintained in a format other than hard copy (e.g., microfiche, scanned, electronic); 
however, caution must be exercised before such action is taken.  The investigator must ensure 
that all reproductions are legible and are a true and accurate copy of the original.  In addition, 
they must meet accessibility and retrieval standards, including regeneration of a hard copy, if 
required.  The investigator must also ensure that an acceptable back-up of the reproductions 
exists and that there is an acceptable quality control procedure in place for creating the 
reproductions.
Essential documents (written and electronic) should be retained for a period of not less than 
fifteen (15) years from the completion of the Clinical Trial unless the Sponsor provides 
written permission to dispose of them or, requires their retention for an additional period of 
time because of applicable laws, regulations and/or guidelines.
The investigator must notify Novartis of any changes in the archival arrangements, including, 
but not limited to archival of records at an off-site facility or transfer of ownership of the 
records in the event that the investigator is no longer associated with the site.
9.6
Provision of Study Results and Information to Investigators
Where required by applicable regulatory requirements, an investigator signatory will be 
identified for the approval of the clinical study report.  The investigator will be provided 
reasonable access to statistical tables, figures, and relevant reports and will have the 
opportunity to review the complete study results at a Novartis site or other mutually-agreeable 
location.
Upon completion of the clinical study report, Novartis will ensure public disclosure of the 
clinical trial research results via the Novartis Clinical Trials Register according to the 
Novartis Standard Operating Procedure and provide the investigator with the full summary of 
the study results.  The investigator is encouraged to share the summary results with the study 


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subjects, as appropriate. In addition, upon study completion and finalization of study report, 
Novartis aims to submit results of the study for publication. 
When publication is not feasible, please refer to the Novartis Clinical Trial Results website 
(.novartisclinicaltrials.com) for a summary of the trial results.
9.7
Independent Data Monitoring Committee (IDMC)
9.7.1
Dose Confirmation for Safety and Tolerability
An IDMC will be utilized to ensure external objective medical and/or statistical review of 
safety issues in order to protect the ethical and safety interests of subjects and to protect the 
scientific validity of the study.  The schedule of any planned interim analysis and the analysis 
plan for IDMC review is described in the charter, which is available upon request.
The intended meeting schedule is outlined below:
Twenty subjects in Arm A will comprise an initial dose confirmation cohort.  In addition, 
available data from Arm B will be provided.  The IDMC will assess Arm A (O+B) for the 
safety and tolerability of ofatumumab (1000 mg Day 1; q21 days) and bendamustine (90 
mg/m2 Days 1, 2; q21 days) after completion of 3 cycles (or until completion of bendamustine 
if less than 3 cycles are administered).
The IDMC will confirm or reject the notion that the Arm A utilizes a safe bendamustine dose 
and schedule.  They will base this decision on a rule described in the IDMC charter.  The 
IDMC will have a primary option (in Stage 1) to lengthen the cycle duration from 21 to 28 
days and have a secondary option (Stage 2) to decrease the bendamustine dose in Arm A for 
improved safety and tolerability.
Stage 1:

If the safety and tolerability of Arm A is confirmed by the IDMC (Stage 1), Stage 1 will 
continue throughout the remainder of the study and will comprise the primary analysis set.

If the IDMC decides to modify the bendamustine dosing schedule in Arm A, Stage 2 will 
begin and this modified treatment schedule (bendamustine 90 mg/m2 Days 1 and 2, every 
28 days, up to 8 cycles) will be used in Arm A for the remainder of the study.  
Stage 2:

If an IDMC cycle change is implemented, the sample size and event count will restart at 
this point, and subjects enrolled in Stage 2 will comprise the primary analysis set.  
Analysis of the cumulative set (subjects from Stage 1 and Stage 2) will be supplementary.

If the IDMC modifies the treatment schedule in Arm A, the IDMC will assess the 
modified treatment schedule (bendamustine 90 mg/m2 Days 1 and 2, every 28 days, up to 
8 cycles) after 10 subjects in Arm A are treated at this schedule for 3 cycles (or until 
bendamustine completion, if less than 3 cycles).  If the IDMC confirms the safety of 
bendamustine 90 mg/m2 Days 1 and 2, every 28 days, in Arm A, then Stage 2 will proceed
without further dose modification in Arm A.  

If the IDMC deems that toxicity remains excessive, the IDMC will have the option to 
reduce the bendamustine dose in Arm A to 70 mg/m2; Days 1 and 2, every 28 days (up to 
8 cycles).  This will be Stage 3.


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Stage 3:

The IDMC will then assess the modified treatment schedule (bendamustine 70 mg/m2
Days 1 and 2, every 28 days, up to 8 cycles) after 10 subjects in Arm A are treated at this 
schedule for 3 cycles (or until completion of bendamustine therapy if less than 3 cycles).

If the IDMC deems that bendamustine 70 mg/m2 Days 1 and 2, every 28 days, up to 8 
cycles in Arm A is safe, then no further dose modification in Arm A will occur.

If the IDMC decides that bendamustine 70 mg/m2 Days 1 and 2, every 28 days, up to 8 
cycles, in Arm A is excessively toxic, the IDMC will have the option to close this study.
STAGE 1 RESULTS FROM IDMC DATA REVIEW
The IDMC met after the first 20 subjects in Arm A received at least 3 cycles of OB.  Based on 
their review of the data as well as the IDMC charter defined criteria to alter the dose in Arm A, 
the final recommendation from IDMC was to not change the current dose regimen and 
therefore to allow the study to proceed unchanged [IDMC communication, 2011].  There will 
be no further dose modifications other than the protocol-directed dose reductions and delays 
already described in Section 5.1.3.1 of this protocol.  The safety of subjects enrolled in the 
study will continue to be monitored by Novartis.
9.7.2
Interim Analysis
An IDMC was utilised to review the primary endpoint, progression free survival when 
approximately two thirds of the initial total IRC events has been reached.  The IDMC 
reviewed data from the interim analysis and the futility analysis.
The IDMC met once to review the data and will recommend that the study continue without 
any changes.  
Further details can be found in the IDMC charter.
9.8
Publication Policy
Publications and oral presentations of any results from the study shall be in accordance with 
accepted scientific practice, academic standards and customs and in accordance with the 
specific policy developed for the study. This policy shall be made available to all 
investigators/sites and groups participating in the study.


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10
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Maintenance rituximab after cyclophosphamide, vincristine, and prednisone prolongs 
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effective therapy in patients with rituximab-refractory, indolent B-cell Non-Hodgkin 
Lymphoma: results from a multicenter study  Cancer.  2010; 116:106-114.
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chemotherapy-refractory low-grade or transformed low-grade B-cell non-Hodgkin’s 
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Publication #03-5410.
OFATUMUMAB, Investigator’s Brochure dated 1 March 2012, Version 05
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cancer. Pharmacoeconomics. 2007; 25 (5): 365-384
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Study of Bendamustine Plus Rituximab in Patients With Relapsed Indolent B-Cell and Mantle 
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pathology and genetics of tumours of haematopoietic and lymphoid tissues. Lyon (4rth ed.):  
IARC Press, Washington DC; 2008.


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11
Appendices
11.1
Appendix 1:  Time and Events Table for Treatment and Follow-Up
SCR1
TREATMENT PERIOD25
1M FU Arm A27
Follow Up
Survival/PD F/U23
WD24
Treatment 
Cycle2
1
2
3
4
5
6
7
8
Ofatumumab for 
Arm A (12 total 
infusions)
Every 1M19
F/U121
F/U222
Days within 
Cycle
1
2
1
2
1
2
1
2
1
2
1
2
1
2
1
2
1M
1M
1M
1M
Visit
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
TREATMENT
Ofatumumab
X2
X2
X2
X2
X2
X2
X2
X2
X3
X3
X3
X3
Bendamustine4
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Pre-medication
X5
X6
X6
X6
X6
X6
X6
X6
X6
X6
X6
X6
CLINICAL ASSESSMENTS
Informed 
Consent
X7
Eligibility 
Criteria
X8
Demographics
X
Physical Exam.
X
X
ECG
X
Height
X
Body Wt, 
Constitutional 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X


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SCR1
TREATMENT PERIOD25
1M FU Arm A27
Follow Up
Survival/PD F/U23
WD24
Treatment 
Cycle2
1
2
3
4
5
6
7
8
Ofatumumab for 
Arm A (12 total 
infusions)
Every 1M19
F/U121
F/U222
Days within 
Cycle
1
2
1
2
1
2
1
2
1
2
1
2
1
2
1
2
1M
1M
1M
1M
Visit
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
Symptoms
Medical History
X9
BM/tissue 
biopsy13
X13
Survival 
Assessment
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Next NHL Tx 
and response
X
ECOG PS
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Vitals Signs14
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
AEs
X15
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X16
X16
X16
X16
X16
Concomitant 
Med.
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X17
X17
X17
X17
PRO18
X
X
X
X
X
X
X
X
X
X18
X
CT Scan12
X10,11
Days 84, 168, and 25212,20(+7 days)
X
X
X25
Disease 
Response.
Days 84, 168, and 25212,20 (+7 days)
X
X
X
Lymphoma 
disease 
symptom
assessment26
Days 84, 168, and 25212,20(+7 days)
X26
X26
X26


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Appendix 1: Time and Events Table for Treatment and Follow-Up (Continued)
Abbreviations:  AE= Adverse Events; Assess.= Assessments; B=bendamustine; BM= bone marrow; BP= Blood Pressure; CT= Computed Tomography; ECG= Electrocardiogram; 
Eval.= Evaluation; FLIPI= Follicular lymphoma International Prognostic Index; F/U= Follow-up; IV= intravenous; LN= lymph node; Med.= Medication; M=Months; NHL= Non-Hodgkins 
Lymphoma; ECOG= Eastern Cooperative Oncology Group; O= ofatumumab;  PO= Oral; PD=Progressive Disease; PRO= Patient Reported Outcomes; PS= Performance Status; 
SAE= Severe adverse event; SCR= Screening; Tx= Therapy; SPM= Study procedures manual; WD= Withdrawal; Wt= Weight; YR=Years
1.
Screening is 21 days of dosing for Cycle 1, Day 1, per Section 3.1.1.
2.
During treatment phase, Arm A (OB) will receive:  ofatumumab 1000 mg given on the first day of each cycle and bendamustine (90 mg/m2) given on Days 1, 2 of each cycle.  If 
bendamustine cannot be given on the Day 1, the day of ofatumumab infusion, bendamustine may be administered on Days 2 and 3 of each cycle (see SPM for procedures).  In 
the event the 1st infusion of bendamustine is on Day 2 of a cycle, then assessments required for Day 1 (except HAHA, ofatumumab concentration, Ig, and flow cytometry) will be 
done on Day 2 and the assessments required for Day 2 will now be done on Day 3.  See SPM for more details.  Day 1 of each cycle occurs every 21 days (on or 3 days after).  
See Section 5.1.3.1 and Table 5 for instructions on cycle length in the event of dose reduction. There are a maximum of 8 cycles of OB treatment. If dose delays last longer than 2 
weeks, See Section 5.1.3.1.  In the event a subject cannot complete all scheduled treatments, subjects are expected to come to the clinic for all scheduled assessments until 
study completion.
3.
Ofatumumab monotherapy (1000 mg, q28 days with a +3 day window).  A total of 12 infusions of ofatumumab (1000 mg), including any doses given with bendamustine, will be 
administered in Arm A regardless of the number of OB cycles completed.  In the event a subject in Arm A cannot complete 8 cycles of therapy with bendamustine, subjects must 
come for all scheduled Day 1 assessments (Visits 1-20).
4.
During the treatment phase, Arm B will receive bendamustine 120 mg/m2 (Days 1, 2 of each cycle).  Day 1 of each cycle occurs every 21 days (on or within 3 days after Day 1 of 
each cycle). There are a maximum of 8 cycles of B.  If dose delays last longer than 2 weeks, See Section 5.1.3.1.  In the event a subject in Arm B cannot complete 8 cycles of 
therapy with bednamustine, subjects in Arm B must come for all scheduled Day 1 visits (Visits 1-20) that have assessments without treatment (if it is not tolerated).  Following Visit 
16, subjects will come to the clinic every 28 days, for 4 times and complete scheduled assessments with no treatment.
5.
Administer pre-medication (acetaminophen approximately 1000 mg PO, diphenhydramine or equivalent approximately 50 mg IV, and glucocorticoid approximately 50 mg IV 
prednisolone equivalent) 30 minutes-2 hours before each ofatumumab dose in Arm A.  For Arm B, administration of premedication is not required, but can be administered at the 
investigator’s discretion, per prescribing information.
6.
Administration of premedication in Arm A (OB) will be at investigator discretion if severe infusion reactions did not occur during first infusion.  For Arm B, administration of 
premedication is not required, but can be administered at the investigator’s discretion per the bendamustine prescribing information.
7.
Informed consent can be obtained outside the screening visit window i.e. prior to screening date.
8.
Criteria specified in inclusion and exclusion criteria must be met.  Criteria also include completion of the rituximab refractory worksheet (See Section 3.1.1.1 in protocol for details).  
Subjects will not be enrolled until Novartis verifies this worksheet.  Imaging or documentation verifying rituximab refractory disease requested 30 days following randomization.  In 
the event a CT scan will be used as a baseline CT scan, the CT scan must be submitted per the instructions in Section 6.1.12.
9.
Includes date of initial indolent NHL diagnosis, Ann Arbor stage, FLIPI-1 and FLIPI-2 scores, and medical history.  See Section 6.1.2 in protocol for more details.
10. Documentation worksheet showing dates of CT showing rituximab refractory status while on rituximab are required for inclusion.  See Section 3.1.1.1 in protocol for details. 
11. A CT scan is required at screening if it was not done ≤1 month (+ 7 days) prior to randomization (Section 6.1.12 ).  If CT scan done >1 month (+ 7 days), investigator may contact 
Medical Lead to determine whether scan may be used.


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12. All scheduled visit days requiring a CT scan (+7 days for Days 84, 168, 252) must be completed regardless of the number of completed cycles.  Pertains to both Arm A and Arm B.
13. A sample (further details in Section 3.1.1 and lab manual) will be required at screening unless an appropriate previous sample is available.  A bone marrow biopsy will be 
performed no later than 8 weeks following CR (as judged by investigator) if the BM sample were positive at the start of the study.
14. Includes BP, temperature, and pulse.  Documented at screening and during treatment for both treatment arms, See Section 6.1.9.
15. Only SAEs relating to study procedures or Novartis concomitant medication should be reported.  See Section 6.5
16. All SAEs regardless of causality will be reported from 61 days after the last dose of investigational product to the end of the follow-up period or withdrawal or until initiation of 
subsequent anti-lymphoma therapy is initiated. Any SAE brought to the investigator's attention after the start of subsequent anti-lymphoma therapy and considered by the 
investigator as possibly related to either ofatumumab or bendamustine must be reported to Novartis.  See Section 6.5 for more details.
17. Only steroids, growth factors, transfusions, anticancer, and anti-infectious treatments will be followed from 61 days after the last dose of investigational product to the end of the 
follow-up period or withdrawal or until initiation of subsequent anti-lymphoma therapy..
18. FACT-Lym, EQ-5D, and HCQ (except at screening) paper questionnaires are to be completed at all specified visits.  Sites will transcribe completed questionnaires into eCRFs.If 
PD, then complete on Day 1 of progression determination and once post PD.
19. Monthly ofatumumab dosing begins 28 days after Day 1 of the previous cycle.  Arm B will not receive ofatumumab every 1M, but must come into the clinic for scheduled visits and 
procedures as if they were on the every 1 month (q28 day) schedule following 8 cycles of bendamustine.
20. Subjects in both arms must come for scheduled Day 84, Day 168, and Day 252 visits (+7 days).  See SPM.
21. This is follow-up schedule #1.  The F/U 1 schedule, in both arms, begins on Day 336 (this is 3 months following Day 252) and will continue every 3 months until Month 18 of the 
F/U phase (Table 1).  There will be a ±7 day visit window around each visit.
22. This is follow-up schedule #2 (Table 1).  The F/U 2 schedule comes after the end of F/U 1 and continues until Month 60 in the F/U phase. Visits will occur at least every 12 months 
until Month 54 or earlier if clinical symptoms of progression are suspected.  CT scans must occur every 12 months (but may occur more frequently if clinical symptoms of 
progression are suspected).  The last required yearly CT scan will be done on Month 54 of F/U2.  Following Month 54, subjects will be followed until Month 60 of the F/U phase.  
CT scans will be done to confirm any clinical signs or suspicion of PD throughout the study.  There will be a ±14 day visit window around each day.
23. Subjects that progress in Arm B (bendamustine alone) will have the option to receive ofatumumab monotherapy.  If Arm B subjects select ofatumumab monotherapy, they must 
have PD confirmed by independent radiology review.  If PD confirmed, Appendix 3 assessments will be followed.  They must not continue with Appendix 2 survival assessments.  
See Section 3.1.6 and for more details.  Subjects with PD, as confirmed by CT scan, will be followed for survival.  Survival follow-up visits begin 2 months after PD is confirmed by 
CT scan or start of non-protocol treatment.. Additionally, subjects without PD who stop protocol treatment and begin non-protocol treatment will go into Survival Follow-Up.  
Survival follow-up visits will occur every 3 months (± 7 days) until Month 18 of the F/U phase then every 12 months (± 14 days) until Month 54 of the F/U phase. Refer to Section 
3.1.5.  Following Month 54, subjects will be followed until Month 60.  Table 1 describes this F/U schedule.    Subjects in Arm B with PD may select optional ofatumumab 
monotherapy and are followed up according to Appendix 3.  PD must be confirmed by an independent review prior to receiving ofatumumab monotherapy.  Survival follow-up 
visits may be phone-calls instead of physician office visits. 
24. There are 2 types of withdrawal (WD):  WD from investigational product and WD from study.  See Section 4.4 for details on withdrawal criteria.  If a subject, without PD, 
discontinues or withdraws from treatment (for any reason), the subject remains in the study and completes all scheduled visits that have assessments, but without study drug.  In 
the event a subject WD consent from study, the WD visit must be completed.  CT scan done at WD from study if last CT was >91 days. One month is 28 days when being treated 
in this study.


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25. Treatment is expected to be given on the scheduled days.  A visit window of 3 days following the scheduled day will be allowed between cycles but there is no visit window once 
the subject has entered the cycle (except bendamustine may be administered on either Days 1,2 or Days 2,3 if needed).  There is a minimum 21 day interval between cycles (See 
Section 9.7). 
26. Assess disease symptoms as defined in Section 6.2.4 of protocol on Days 84, 168, and 252 (+7 days), F/U 1, F/U 2 or withdrawal.  Assess disease symptoms during follow-up 
visits.
27. One month following treatment completion in Arm A, regardless of response and regardless of when treatment ended in the study.


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11.2
Appendix 2:  Time and Events Table for Laboratory Assessments
SCR1
TREATMENT PERIOD5,19
1M FU Arm A20
Follow 
Up
Survival/PD F/U15,17
WD16
Treatment 
Cycle
1
2
3
4
5
6
7
8
Ofatumumab for Arm 
A (12 total infusions)
Every 1M5,12
F/U113
F/U214
Days within 
Cycle
1
2
1
2
1
2
1
2
1
2
1
2
1
2
1
2
1M
1M
1M
1M
Visit
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
Hematology
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Biochemistry 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Calculated 
Creatinine 
Clearance2
X2
Flow Cytometry
X1
X3
X3
X3
X3
X3
X3
X8
X8
HAHA
X4,18
X4
X4
X4
X4
X4
HACA11
X18
Ofatumumab PK
samples
X9
X9
X9
X9
X9
X9
HBV6 & HCV,
Pregnancy Test7
X6,7
X7
X6
X7
IgG, IgA, IgM
X3,18
X3
X8
X8
X8
Prognostic 
Markers11,18
X11,18
ß2 micro.11
X18


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APPENDIX 2:  TIME AND EVENTS TABLE FOR LABORATORY ASSESSMENTS (CONTINUED)
Abbreviations:  ALC= absolute lymphocyte count; D=Days; DNA= deoxyribonucleic acid; M=Months; FcR= Fc Gamma Receptor; FLIPI= Follicular lymphoma international prognostic 
index; F/U= Follow -up; PD=Progressive Disease; HAHA= Human anti-Human Antibodies; HACA= Human anti-Chimeric Antibodies; HBV= hepatitis B virus; HBC= Hepatitis C virus; Ig= 
immunoglobulin; micro.= microglobulin; 
; PK= pharmacokinetics; SCR= Screening; SPM= study procedures manual; SLL= Small lymphocytic lymphoma; Tx= 
Therapy; WD= Withdrawal; YR=Years
1.
Screening is ≤21 days of dosing for Cycle 1, Day 1, per Section 3.1.1.  If subjects have SLL, they must have a lymphocyte count of <5000/L. If subjects with SLL have a 
lymphocyte count of ≥5000/L, then flow cytometry must be done.  Subjects with SLL are not eligible if they have a B lymphocyte count of ≥5000/L according to the Central 
Laboratory results (Section 4.2).
2.
Calculated creatinine clearance will be done at screening and can be repeated at the physician’s discretion if there is a significant rise in serum creatinine during the treatment 
phase of the study.  See Section 6.3 and Section 6.4 for details on laboratory tests.
3.
Flow cytometry and IgG, IgA, IgM done in Arm A only. During treatment, collect immunoglobulins (Ig) no later than every 6 months (collection to correspond with a scheduled 
visit).  B-cell flow cytometry for CD19, CD20 (See Section 6.3.1).
4.
HAHA done in Arm A only.  HAHA samples must be collected prior to the start of the ofatumumab infusion on dosing days.  During treatment, collect every 6 months.  During first 
year of follow-up, collect every 6 months for the first year after last ofatumumab infusion.  A HAHA sample must be collected for subjects who withdraw (see footnote 16) or on 
one occasion post-PD for subjects with PD.
5.
In the event a subject in Arm A or Arm B cannot complete 8 cycles of therapy, subjects must come for all scheduled visits (Visits 1-20) that have assessments without treatment 
(i.e., if it is not tolerated).  Following Visit 16, subjects will come to the clinic every 28 days, 4 times, and complete scheduled assessments with no treatment. One month is 28 
days when being treated in this study.
6.
In subjects receiving ofatumumab that are Hepatitis B core positive, HBsAg negative, and HBV DNA negative (Section 6.3.2 and Section 6.5.7.1), Hepatitis B DNA must be 
obtained on Day 1 of each cycle visit while on treatment and then 1,3,6 months post treatment.  If a subject converts to HBV DNA positive during the study, Hepatitis B treatment 
may be initiated by the site investigator after consultation with a physician experienced in the care and management of subjects with Hepatitis B and the Novartis Medical Lead.  
The risks and benefits of continuing ofatumumab or discontinuing ofatumumab must be discussed with the Medical Lead before appropriate treatment decisions are made for that 
individual subject.  Instructions for Japanese subjects are in Appendix 8.
7.
Women of childbearing potential must agree to use a method of birth control approved by the study doctor while during study and for one year after the last dose of treatment.  
Pregnancy testing in women of child bearing potential will be done at Screening then prior to dosing if last test >30 days ago and again 6 months after last dose of ofatumumab.
8.
B-cells and Immunoglobulins (Ig) will be monitored for a period of 2 years after the last ofatumumab infusion in Arm A or until the number of B-cells and circulating IgG, IgM and 
IgA have returned to normal or to within baseline values (according to the central laboratory), whichever is earlier. Monitoring will be done during scheduled F/U visits.  F/U will be 
discontinued in the event the subject is treated with another anti-CD20 therapy, e.g., rituximab or B-cell modifying or depleting agent.
9.
Ofatumumab PK sample collection done for Arm A only. Pharmacokinetic samples must be collected at the time of HAHA sample collection(refer to Footnote 4 in Appendix 2 ).
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12. Ofatumumab monotherapy (1000 mg once every 1 month).  A total of 12 infusions of ofatumumab (1000 mg) will be administered in Arm A regardless of the number of OB cycles 
completed.  Arm B will not receive ofatumumab q1M (this is q28 days), but must come into the clinic for scheduled visits and procedures as if they were on the q1 month schedule 
following 8 cycles of bendamustine. 
13. Follow-up #1, in both arms, will begin on Day 336 (this is 3 months following Day 252) and will continue every 3 months until Month 18 of the F/U phase (Table 1).  There will be a 
±7 day visit window around each day.
14. The follow-up #2 schedule comes after the end of F/U 1 and continues until Month 60 in the entire F/U phase (Table 1).  Visits will occur at least every 12 months until Month 54 or 
earlier if clinical symptoms of progression are suspected.  Following Month 54, subjects will be followed until Month 60 of the F/U phase.  The last required yearly CT scan will be 
done on Month 54 of F/U2.  CT scans will be done to confirm any clinical signs or suspicion of PD throughout the study.  There will be a ±14 day visit window around each day.
15. Subjects with PD, as confirmed by CT scan, will be followed for survival.  Survival follow-up visits begin 2 months after PD is confirmed by CT scan for both arms Subjects who 
stop protocol treatment and begin non-protocol treatment will go into Survival Follow-Up.  Survival follow-up visits will occur every 3 months (± 7 day) until Month 18 of the F/U 
phase following PD confirmation by CT scan.  After Month 18 of the F/U phase, visits will be at least every 12 months (± 14 day) until Month 54.  Following Month 54, subjects will 
have one more survival F/U on Month 60 of the entire F/U phase.  Table 1 describes this F/U visit schedule.  Subjects in Arm B with PD may select optional ofatumumab 
monotherapy.  PD must be confirmed by an independent review prior to receiving ofatumumab monotherapy. Survival follow-up visits may be phone-calls instead of physician 
office visits See Section 3.1.6 for more details.  Subjects with PD or are no longer receiving treatment will be followed for survival.
16. There are 2 types of withdrawal (WD):  WD from investigational product and WD from study.  See Section 4.4 for details on withdrawal criteria.  If a subject, without PD 
discontinues or withdraws from treatment (for any reason) the subject remains in the study and completes all scheduled visits without study drug.  In the event a subject withdraws 
consent from study, the WD visit must be completed.  CT scan done at WD from study if last CT was >91 days.
17. Subjects that progress in Arm B (bendamustine alone) will have the option to receive fatumumab monotherapy.  If Arm B subjects decide to receive ofatumumab monotherapy 
then they must follow Appendix 3 and must not continue with Appendix 2 survival assessments.  See Section 3.1.6 and Appendix 3 for more details.
18. Sample taken prior to first infusion.
19. A visit window of 3 days following the scheduled day will be allowed between cycles but there is no visit window once the subject has entered the cycle (except bendamustine may 
be administered on either Days 1,2 or Days 2,3 if needed).  There is a minimum 21 day interval between cycles.  In the event the 1st infusion of bendamustine is on Day 2 of a 
cycle, then assessments required for Day 1 (except HAHA, ofatumumab plasma concentration, Ig, and flow cytometry) will be done on Day 2 and the assessments required for 
Day 2 will now be done on Day 3.  See SPM for more details.  The protocol must be followed as closely as possible.  If as per local practice, a blood draw for hematology analysis 
prior to the visit date is required, it would be acceptable for hematology analysis, but the blood draw can be taken no more than 3 days ahead of the visit date. Blood draws 
performed by local laboratories (e.g. for quicker pre-dose response assessment or assessment of toxicity) of protocol-required lab assessments are acceptable; however, it is 
important that the sample for the central laboratory analysis is taken at the same time.  Since absolute neutrophil count, platelet count, peripheral blood lymphocytes, and 
hemoglobin results are required to establish if a bendamustine dose reduction and/or treatment delay is required, the results of each of these local laboratory tests must also be 
entered into the eCRF if it is used to manage a dose delay or dose reduction .  Central Laboratory information will also be entered into the eCRF.
20. One month following treatment completion in Arm A, regardless of response and regardless of when treatment ended in the study


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11.3
Appendix 3:  Time and Events:  Ofatumumab Following PD for 
Bendamustine Monotherapy Arm
Phase
TREATMENT PERIOD24
Follow-up
Survival/PD 
confirmation21
WD18
Visit
1
2
3
4
5-12
Week 1 Week 2 Week 3 Week 4
Every1M 
x8 doses17
1M F/U11
F/U119 F/U220
Visit Window 
(Days)
+1
+1
+1
±3
±3
±7
±14
Pre-medication
X1
X2
X2
X2
X2
Ofatumumab
X3
X4
X4
X4
X4
Physical 
examination
X
X
Body weight & 
Constitutional 
Symptoms
X
X
CT Scan5
X
X
Response 
evaluation5
X5
X
Lymphoma 
disease 
symptom 
assessment5
X5
X
Bone marrow 
biopsy6
X6
Survival 
assessment
X
X
X
X
X
X
X
X
X
X
ECOG 
Performance 
Status
X7
X
Vital signs (BP, 
Pulse, temp.)
X
X
X
X
X
X
X
X
X
AE
X
X
X
X
X
X
X, X8
X8
X8
X
Concomitant 
Medication
X
X
X
X
X
X
X9
X9
X9
X
Hematology10
X25
X
X
X
X
X
Biochemistry10
X25
X
X
X
X23
X
Flow 
Cytometry12
X12
X12
X12
X12
HACA
X13
HAHA14
X13,14
X14
X14
X14
X14
Ofatumumab 
PK sample15
X15
X15
X15
X15
X15
X15
X15


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Phase
TREATMENT PERIOD24
Follow-up
Survival/PD 
confirmation21
WD18
Visit
1
2
3
4
5-12
Week 1 Week 2 Week 3 Week 4
Every1M 
x8 doses17
1M F/U11
F/U119 F/U220
Visit Window 
(Days)
+1
+1
+1
±3
±3
±7
±14
IgG, IgA, IgM
X13,14
X12,14
X12,14
X12,14
X12,
14
Hepatitis B16
X16
X16
X16
Pregnancy22
X22


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APPENDIX 3: TIME AND EVENTS:  OFATUMUMAB FOLLOWING PD FOR 
BENDAMUSTINE MONOTHERAPY ARM (CONTINUED)
Abbreviations:  AE= Adverse Events; CR= Complete Remission; CT= Computed Tomography; DNA= deoxyribonucleic acid ; 
ECOG= Eastern Cooperative Oncology Group; F/U= Follow-Up; HBV= Hepatitis B Virus; Ig= immunoglobulin; PD= 
Progressive Disease; PO= oral; M=Months; HAHA= Human anti-Human Antibodies; HACA= Human anti-Chimeric 
Antibodies;IRC=Independent Review Committee; IV= intravenous; SPM= study procedures manual; WD= Withdrawal
1.
Administer pre-medication (acetaminophen approximately 1000 mg PO, diphenhydramine or equivalent approximately 
50 mg IV, and glucocorticoid approximately 50 mg IV prednisolone equivalent) 30 minutes-2 hours before each 
Ofatumumab dose.  
2.
Administration of premedication as indicated (Section 5.1.1) at investigator discretion.  Premedication is administered in 
conjunction with ofatumumab.
3.
Ofatumumab (1000 mg)
4.
Ofatumumab (2000 mg)
5.
PD must be confirmed by an IRR before receiving ofatumumab. The CT scan data confirmed by IRR (or may be a CT 
scan done after IRR confirmation if available) will be used for baseline CT assessments in Appendix 3 .  CT scan, 
response assessment, and assessment of lymphoma-related disease symptoms are done once (+3 days during 1 
month following last ofatumumab infusion).  Lymphoma-related symptoms are described in Section 6.2.4.
6.
A bone marrow biopsy will be performed no later than 8 weeks following CR (as judged by investigator) if bone marrow 
was positive for lymphoma at baseline.
7.
ECOG performance status done once (on last weekly visit for fourth ofatumumab infusion) or withdrawal
8.
All SAEs regardless of causality will be reported from 61 days after the last dose of investigational product to the end of 
the follow-up period or until initiation of subsequent anti-lymphoma therapy is initiated. Any SAE brought to the 
investigator's attention after the start of subsequent anti-lymphoma therapy and considered by the investigator as 
possibly related to either ofatumumab or bendamustine must be reported to Novartis.  See Section 6.5 for more details.
9.
Only steroids, growth factors, transfusions, anticancer, and anti-infectious treatments will be followed from 61 days after 
the last dose of investigational product to the end of the follow-up period or until initiation of subsequent anti-lymphoma 
therapy .
10. See Section 6.3 and Section 6.4 for details on Appendix 3 laboratory tests.  The protocol must be followed as closely as 
possible, but if as per local practice, a blood draw for hematology analysis prior to the visit date is required, it would be
acceptable for hematology analysis, but the blood draw can be taken no more than 3 days ahead of the visit date. Blood 
draws performed by local laboratories (e.g. for quicker pre-dose response assessment or assessment of toxicity) of 
protocol-required lab assessments are acceptable; however, it is important that the sample for the central laboratory 
analysis is taken at the same time.  The local laboratory results of absolute neutrophil count, platelet count, peripheral 
blood lymphocytes, and hemoglobin must also be entered into the eCRF if it is used for a treatment decision.  Central 
Laboratory information will also be entered into the eCRF.
11. One month following treatment completion, regardless of response and regardless of when treatment ended in the 
study.
12. B cell flow cytometry for CD19, CD20 (See Section 6.3.1).  B-cells and immunoglobulins (Ig) will be monitored for a 
period of 2 years after the last ofatumumab infusion or until the number of B-cells and circulating IgG, IgM and IgA have 
returned to normal or to within baseline values (according to the central laboratory), whichever is earlier. Monitoring will 
be done during scheduled F/U visits.  F/U will be discontinued in the event the subject is treated with another anti-CD20 
therapy, e.g., rituximab or B-cell modifying or depleting agent.
13. Table 1 Collect HAHA, HACA, and Immunoglobulin (Ig) samples prior to start of ofatumumab infusion at first dose (Dose 
1).
14. During treatment, collect HAHA and Ig no later than every 6 months (collection to correspond with a scheduled visit).  
During first year of F/U, collect no later than every 6 months (corresponding with a scheduled visit) for the first year after 
the last ofatumumab infusion.  Collect HAHA at withdrawal (see footnote 18 of Appendix 3) or on one occasion post-PD 
for subjects with PD. 
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APPENDIX 3: TIME AND EVENTS:  OFATUMUMAB FOLLOWING PD FOR 
BENDAMUSTINE MONOTHERAPY ARM (CONTINUED
16. In subjects receiving ofatumumab that are Hepatitis B core positive, HBsAg negative, and HBV DNA negative (Section 
6.3.2 and Section 6.5.7.1), Hepatits B DNA must be obtained while on treatment and then 1,3, 6 months post treatment.  
If a subject converts to HBV DNA positive during the study, Hepatitis B treatment may be initiated by the site 
investigator after consultation with a physician experienced in the care and management of subjects with Hepatitis B 
and the Novartis Medical Lead.  The risks and benefits of continuing ofatumumab or discontinuing ofatumumab must be 
discussed with the Medical Lead before appropriate treatment decisions are made for that individual subject.  
Instructions for Japanese subjects are in Appendix 8.
17. First monthly (q28 days) ofatumumab dose (2000 mg) begins 1 month (q28 days) after Week 4 ofatumumab infusion.  
Subsequent ofatumumab infusions occur every 1 month (q28 days) for 8 doses.  There will be a ±3 day visit window 
around each day
18. There are 2 types of withdrawal (WD):  WD from investigational product and WD from study.  See Section 4.4 for details 
on withdrawal criteria (exception: no PRO will be done in Appendix 3).  If a subject, without PD, discontinues or 
withdraws from treatment (for any reason) the subject remains in the study and completes all scheduled visits without 
study drug.  In the event a subject withdraws from study, the WD visit must be completed.  CT scan done at WD from 
study if last CT was >91 days.
19. This is follow-up schedule #1 (schedule frequency shown in Table 1).  F/U 1, in both arms, begins 1 month following last 
infusion of ofatumumab.  Follow-up will continue every 3 months until Month 18 of the F/U phase.  There will be a ±7 
day visit window around each visit.
20. The follow-up #2 schedule comes after the end of F/U 1 and continues until Month 60 of the entire F/U phase (schedule 
frequency shown in Table 1).  Visits will occur every 12 months until Month 54 or earlier if clinical symptoms of 
progression are seen.  Following Month 54, subjects will be followed until Month 60 of the F/U phase.  There will be a 
±14 day visit window around each day.
21. Subjects with PD, as confirmed by CT scan, will be followed for survival.  Additionally, subjects without PD who stop 
protocol treatment and begin non-protocol treatment will go into Survival Follow-Up. Survival follow-up visits occur 
every 3 until Month 18 of F/U 1 then every 12 months until Month 54 of the F/U 2 phase.  Following Month 54, there will 
be one more visit at Month 60 of the F/U phase.  There will be a ± 7 day visit window around visit in F/U 1.  Survival 
follow-up visits begin 2 months after PD is confirmed by CT scan or start of non-protocol treatment.  There will be a ±14 
day visit window around each visit in F/U 2. 
22. Women of childbearing potential must agree to use a method of birth control approved by the study doctor while during 
study and for one year after the last dose of treatment.  Pregnancy testing in women of child bearing potential will be 
done prior to dosing if last test >30 days ago and again 6 months after last dose of ofatumumab.
23. Only for Month 3.
24. One month is 28 days when being treated in this study.
25. To be done prior to first ofatumumab dose only if central laboratory results are not available to confirm eligibility for 
ofatumumab monotherapy following PD in Arm B per Section 3.1.6


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11.5
Appendix 5: Patient Reported Outcome Measures
11.5.1
Functional Assessment of Cancer Therapy - Lymphoma (FACT-Lym, 
version 4)


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11.5.2
EuorQoL Five-Dimension (EQ-5D)


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Health Change Questionnaire


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11.6
Appendix 6:  Follicular Lymphoma International Prognostic 
Index-1 (FLIPI-1)
TABLE I:  THE FIVE PARAMETERS RETAINED FOR BUILDING THE FLIPI
Parameter
Adverse Factor
Age
60 years
Ann Arbor Stage
III-IV
Hemoglobin Level
< 120 g/L
Serum LDH Level
> ULN
Number of Nodal Sites
> 4
Abbreviations:  LDH: lactate dehydrogenase; ULN:  upper limit of normal
1.
See [Solal-Celigny, 2004]
TABLE II:  OUTCOME AND RELATIVE RISK OF DEATH ACCORDING TO RISK GROUP 
AS 
Risk Group
Number 
of 
Factors
Distribution 
of 
Patients, %
5-year 
OS, %(SE)
10-year 
OS, %(SE)
RR
95% CI
Low
0-1
36
90.6 (1.2)
70.7 (2.7)
1.0
NA
Intermediate
2
37
77.6 (1.6)
50.9 (2.7)
2.3
1.9-2.8
High
3
27
52.5 (2.3)
35.5 (2.8)
4.3
3.5-5.3
1.
N= 1795. 
2.
Abbreviations:  OS indicates overall survival; SE, standard error; CI, confidence interval; RR, relative risk (of 
death) and NA, not applicable.
3.
*Factors adversely affecting survival in the FLIPI include age greater than 60 years; Ann Arbor stage III-IV; 
number of nodal sites greater than 4; serum LDH level greater than the upper limit of normal; and hemoglobin level 
less than 120 g/L.
4.
Table II Abbreviations:  OS indicates overall survival; SE, standard error; CI, confidence interval; RR, relative risk 
(of death), and NA, not applicable.
5.
FLIPI, N=1795 [Solal-Celigny, 2004]
6.
FLIPI2, N= 832 [Federico, 2009]


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Appendix 7:  Follicular Lymphoma International Prognostic 
Index-2 (FLIPI-2)
TABLE III:  THE FIVE PARAMETERS RETAINED FOR BUILDING THE FLIPI
Parameter
Adverse Factor
Beta-2-microglobulin
> ULN
LoDLIN
>6cm
Bone marrow involvement presence
yes
Hemoglobin
<120 g/L
Age
>60 years
1.
Abbreviations:  LLoDLIN= longest diameter of the largest involved node; ULN:  upper limit of normal
TABLE IV: OUTCOME AND RELATIVE RISK OF DEATH ACCORDING TO RISK GROUP 
AS DEFINED BY THE FLIPI-2
Risk Group
Number 
of 
Factors
Distribution 
of 
Patients, %
3-year 
PFS, %(SE)
5-year 
OS, %(SE)
RR
95% CI
Low
0
20
90.9 (2.4)
79.5 (5.0)
1.0
NA
Intermediate
1-2
53
69.3 (2.4)
51.2 (5.7)
3.19
2.0-5.15
High
3-5
27
51.3 (3.7)
18.8 (13)
5.76
3.53-9.4
1.
N= 1795. 
2.
Abbreviations:  PFS= indicates Progression Free Survival; SE, standard error; CI, confidence interval; RR, relative 
risk (of death), and NA, not applicable.
[Federico, 2009]


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11.8
Appendix 8:  Instructions for Japanese Hepatitis Testing
These instructions are for patients who enroll on this study in Japan only.
For HBcAb and/or HBsAb positive subjects, to prevent hepatitis B reactivation it is 
recommended that the guidance in the following report be applied: ‘Prevention of 
immunosuppressive therapy or chemotherapy-induced reactivation of hepatitis B virus 
infection -Joint Report of the Intractable Liver Diseases Study Group of Japan and the 
Japanese Study Group of the Standard Antiviral Therapy for Viral Hepatitis’ (Ministry of 
Health, Labour and Welfare in Japan). The report states:

In subjects who are HBV-DNA positive, it is recommended that a nucleoside analogue be 
administered prophylactically.

In subjects who are HBV-DNA negative, but HBsAb and/or HBcAb positive, it is 
recommended that monthly monitoring of HBV-DNA be conducted until 12 months after 
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11.9
Appendix 9: General Protocol Changes for Amendment 1 (16-
November-2009) from Protocol (dated 7-AUG-2009)
WHERE THE AMENDMENT APPLIES
Amendment 1 is applicable to all study sites.
SUMMARY AND RATIONALE FOR AMENDMENT CHANGES
ADMINISTRATIVE CHANGES
Due to administrative changes within GSK, appropriate revisions were made to the Medical 
Monitor contact information to reflect personnel updates and organizational restructuring.
NUMBER OF CYCLES CHANGED FROM 6 TO UP TO 8 CYCLES IN BOTH ARMS
Up to 8 cycles of ofatumumab (O) + bendamustine (B) or B monotherapy will be allowed in 
each study arm.  This reflects the Treanda label [TREANDA, 2008].
OFATUMUMAB DOSING FREQUENCY:  12 INFUSIONS OF OFATUMUMAB IN 
ARM A
A total of 12 ofatumumab infusions will be administered in Arm A (OB) regardless of the 
total number of completed OB therapy cycles.  
Several randomized studies have indicated that extended or maintenance rituximab therapy 
prolongs PFS in relapsed FL, whether after rituximab monotherapy or combination 
chemotherapy [Ghielmini, 2004; Hainsworth, 2003; Hoechster, 2009; van Van Oers, 2006].  
Several schedules have been examined for extended or maintenance dosing of rituximab.  A 
recent meta-analysis, which examined a variety of dosing schedules, suggested that 
maintenance rituximab therapy may improve overall survival (OS) [Vidal, 2009].  Most 
recently, the PRIMA study reportedly showed a significant benefit for rituximab maintenance 
therapy after induction therapy with a rituximab combination regiment in previously untreated 
FL.  Therefore, maintenance monotherapy with rituximab has a role after induction therapy 
with combination chemotherapy in FL.
Study OMB110918 study will examine the role of extended or maintenance ofatumumab 
monotherapy after OB combination therapy in rituximab-refractory FL.  Two points must be 
considered.  First, clearance of ofatumumab may be faster in rituximab-refractory FL patients, 
as they presumably will have greater tumor volume after completing induction therapy than 
patients with more sensitive disease.  Study OMB110918 will enroll rituximab-refractory FL 
patients who are expected to have more disease following OB therapy (and thus, faster 
ofatumumab clearance) and have shorter PFS than the rituximab-sensitive, relapsed FL 
patients in the 920 study.  Thus, more frequent dosing of ofatumumab may be necessary for 
extended dosing in this patient population, similar to the monthly maintenance dosing in CLL 
in the 406 study.  
Recently, Study Hx-CD20-405 reported the results of ofatumumab monotherapy in a 
rituximab refractory patient population.  Study Hx-CD20-405 study indicated a median PFS 


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of 6 months when 500-1000 mg was used.  This suggested that it may be prudent to give the 
maintenance doses more frequently than every 8 weeks to ensure that patients will actually be 
able to receive extended dosing before their FL progresses.  To date, we have no evidence that 
2000 mg is more effective than 1000 mg in FL.  Therefore, we will use 1000 mg as the 
maintenance dose in Study OMB110918 study.  However, we will administer the maintenance 
doses every 4 weeks in anticipation of faster antibody clearance and faster disease progression.
OFATUMUMAB MONOTHERAPY FOR PATIENTS WHO PROGRESS IN ARM B
A study a regimen of ofatumumab 2000 mg weekly for 4 weeks followed by 2000 mg every 4 
weeks for 4 additional doses (total: 8 doses) in rituximab-refractory FL patients who progress 
during or following single agent bendamustine will be offered to subjects with PD in Arm B.  
This study design will allow us to study 1) ofatumumab monotherapy using the 2000 mg dose 
and 2) extended dosing using a monthly schedule in the context of an existing study in 
rituximab-refractory FL.  This is a change from dosing ofatumumab (1000 mg), weekly for 8 
doses.  
To gain information about higher doses of ofatumumab monotherapy in refractory FL, 
patients who progress during or after therapy in Arm B (bendamustine alone) will be offered 
ofatumumab monotherapy.  The only data regarding the dose-response relationship of anti-
CD20 antibody monotherapy in this poor patient population was obtained in Study Hx-CD20-
405, in which patients with rituximab-refractory FL were randomized to single agent 
ofatumumab 500 mg or 1000 mg weekly for 8 doses.  The response rate was approximately 
10%, and median PFS was 6 months, with no difference between the treatment arms.  While 
the study indicated that administering ofatumumab monotherapy at 500-1000 mg weekly was 
not highly effective in rituximab-refractory FL patients, the role of dose intensification is 
unknown in this patient population.  Our experience in chronic lymphocytic leukemia (CLL) 
indicated that increasing the dose intensity of rituximab was able to significantly improve the 
overall response rate from 10-15% to 45%.  Furthermore, ofatumumab showed significant 
clinical activity with an acceptable safety profile in Study Hx-CD20-406 study in fludarabine-
refractory CLL when administered at a dose of 2000 mg.  Therefore, it is reasonable to 
examine the 2000 mg dose in refractory FL.  The optimal duration of therapy in this setting is 
unclear.  The 406 study administered 8 weekly doses of ofatumumab 2000 mg (first dose 300 
mg) followed by 4 monthly doses of 2000 mg.  However, the standard length of weekly 
rituximab therapy in FL is 4 weeks, and there are no convincing data that increasing the 
number of weekly ritxuimab infusions from 4 to 8 is of benefit.  
We will study extended dosing of ofatumumab monotherapy in this patient group, similar to 
our plan in Study OMB113676.  However, Study OMB110918 will enroll rituximab-
refractory, indolent NHL patients who are expected to have more disease following 4 weeks 
of ofatumumab monotherapy (and thus, faster ofatumumab clearance) and have shorter PFS 
than the rituximab-sensitive relapsed FL patients in the 676 study.  Thus, more frequent 
dosing of ofatumumab may be necessary for extended dosing in this patient population, 
similar to the monthly maintenance dosing in CLL in Study Hx-CD20-406.  Therefore, the 
extended dosing will consist of 2000 mg given monthly for 4 doses.


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OFATUMUMAB DOSING FREQUENCY:  12 INFUSIONS OF OFATUMUMAB IN 
ARM A
Clarification in response criteria (Section 6.2.4, Section 6.2.4.2, Section 6.2.4.3, and Section 
6.2.4.5).  
RESPONSE CRITERIA
Section 6.2 (Efficacy Assessments) updated for clarity
SPECIFIC PROTOCOL CHANGES FOR AMENDMENT 1 (16-NOVEMBER-2009) FROM 
PROTOCOL (DATED 7-AUG-2009)
LIST OF SPECIFIC CHANGES
Note:  deleted language is presented with a strikethrough and added language is printed in 
bold.
EXAMPLE:
Section:
Throughout Document
Original text:
Patient
Text changed to:
Subject
Rationale for Change:
For consistent use of terminology throughout the document.  Amended in appropriate 
document sections.
Section:
Sponsor Information Page
Original text:
Medical Monitor Contact Information:
MD, Ph.D
 – ofatumumab
United Kingdom
Tel: 
Mob: 
Fax: 
Email:


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Text changed to:
Medical Monitor Contact Information:
 MD
 
 USA 
Telephone: 
Fax:  
Email: 
 Contact Information:
Same as above
Rationale for Change:
Information Update.
Section 1.3:
Ofatumumab
Original text:
A Phase I/II dose escalation study of ofatumumab in subjects with relapsed or refractory 
follicular lymphoma tested four weekly doses of ofatumumab at 300, 500, 700, or 1000 mg 
[Study Hx-CD20-001; Hagenbeek, 2008]. Results demonstrated clinical activity with 
reversible Grade 3, 4 adverse events occurring on the day of initial infusion. Those adverse 
events included dyspnea, hypoxia, laryngeal edema, throat tightness, pruritus, and rash. 
Median time to progression (TTP) was 8.8 and 32.6 months, respectively. Median duration of 
response was 29.9 months. Median and maximum follow-up was 9.2 and 38.6 months, 
respectively.  Response did not correlate with ofatumumab dose.
Text changed to:
The Food and Drug Administration (FDA) recently approved ofatumumab (ARZERRA) 
for chronic lymphocytic leukemia (CLL) refractory to fludarabine and alemtuzumab.
A Phase I/II dose escalation study of ofatumumab in subjects with relapsed or refractory 
follicular lymphoma tested four weekly doses of ofatumumab at 300, 500, 700, or 1000 mg 
[Study Hx-CD20-001; Hagenbeek, 2008]. Results demonstrated clinical activity with 
reversible Grade 3, 4 adverse events occurring on the day of initial infusion. Those adverse 
events included dyspnea, hypoxia, laryngeal edema, throat tightness, pruritus, and rash. 
Median time to progression (TTP) was 8.8 and 32.6 months, respectively. Median duration of 
response was 29.9 months. Median and maximum follow-up was 9.2 and 38.6 months, 
respectively.  Response did not correlate with ofatumumab dose.


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A Phase II, open label study in patients with previously-untreated FL compared 
ofatumumab in combination with CHOP vs CHOP.  Patients were randomized into two 
dose groups (N= 29 per group):  300 mg of ofatumumab at the first infusion, followed by 
5 infusions of either 500 or 1000 mg of ofatumumab every 3 weeks in combination with 6 
cycles of CHOP.  Results demonstrated an ORR of 90%, CR of 24%, and 45% Cru  (500 
mg of ofatumumab, N=29).  In patients treated with 1000 mg of ofatumumab (n=29), the 
ORR was 100% including 38% CR, and 17% Cru.  There were no unexpected safety 
findings reported during treatment and within 30 days after last infusion.  The most 
common adverse events of grade 3 or 4 (> 10%) were leukopenia and neutropenia.  
In a single-arm, double-blind study of single-agent ofatumumab, a total of 116 patients 
were treated with two doses of ofatumumab.  The ORR in the total population was 11%.  
This group of patients was highly refractory with 49% refractory to their last 
chemotherapy.  Patients in the study had previously received a median of 4 prior 
treatment regimens.  The 1000 mg dose group (N=86) demonstrated an ORR of 10% 
(included 1 CR, 8 PR).  In addition, 50% (43) of patients in the 1000 mg treatment arm 
had stable disease.  The ORR among patients who were refractory to prior rituximab 
monotherapy (n=27) was 22%.  For patients considered refractory to rituximab in 
combination with chemotherapy the RR was 7% and among patients considered 
refractory to rituximab maintenance the RR was 9%. The median duration of response 
in the 1000 mg treatment arm was 6 months and the PFS was 6 months.  There were no 
unexpected safety findings reported during treatment and within 30 days after last 
infusion. The most common adverse events (> 10%) were rash, urticaria, pruritus, 
fatigue, nausea, pyrexia and cough.
Section 2: Objectives
Original text:
Secondary objectives:

To compare overall response rate, overall survival, time to and duration of response, 
and time to progression in subjects treated with ofatumumab and bendamustine 
combination therapy to those treated with bendamustine monotherapy

To evaluate and compare the safety and tolerability in subjects treated with 
ofatumumab and bendamustine combination therapy to those treated with 
bendamustine alone

To evaluate ofatumumab pharmacokinetics when given with bendamustine 

To evaluate and compare the two treatment arms with respect to changes in subjects’ 
health-related quality of life 

To evaluate and compare prognostic markers and their correlation with clinical 
responses in subjects treated with ofatumumab and bendamustine compared to those 
treated with  bendamustine monotherapy (i.e. ALC, FcR gamma 3, IgVH gene 
rearrangement)


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Text changed to:
Secondary objectives:

To compare overall response rate, overall survival, time to and duration of response, 
and time to progression in subjects treated with ofatumumab and bendamustine 
combination therapy to those treated with bendamustine monotherapy

To evaluate and compare the safety and tolerability in subjects treated with 
ofatumumab and bendamustine combination therapy to those treated with 
bendamustine alone

To evaluate ofatumumab pharmacokinetics when given with bendamustine 

To evaluate and compare the two treatment arms with respect to changes in subjects’ 
health-related quality of life 

To evaluate and compare prognostic markers and their correlation with clinical 
responses in subjects treated with ofatumumab and bendamustine compared to those 
treated with  bendamustine monotherapy (i.e. ALC, FcR gamma 3)

To evaluate the overall response rate to optional ofatumumab monotherapy in 
subjects who are unresponsive to rituximab during or within 6 months of a 
rituximab-containing regimen who progress during or following single-agent 
bendamustine
Section 3.1:
Study Design
Original text:
The study will evaluate, in the first 20 subjects (Stage 1), the safety and tolerability of 
ofatumumab added to bendamustine at 90 mg/m2 bendamustine (Days 1, 2; q21D) after 6
cycles. An independent data safety monitoring board (IDMC) will determine the 
bendamustine dose for the remainder of the trial. If the bendamustine dose in Arm A is not 
changed by the IDMC, Stage 1 will continue throughout the remainder of the study and will 
comprise the final analysis set.  If an IDMC dosing change is implemented, the sample size 
and event count will restart at this point, and subjects enrolled in Stage 2 will comprise the 
final analysis set.  Analysis of the cumulative set (subjects from Stage 1 and Stage 2) will be 
supplementary.
Text changed to:
The study will evaluate, in the first 20 subjects who complete 3 cycles (or complete 
bendamustine therapy with fewer than 3 cycles) cycles in Arm A (Stage 1), the safety and 
tolerability of ofatumumab added to bendamustine at 90 mg/m2 bendamustine (Days 1, 2; q21 
days). Data from Arm B will be made available for review.  An independent data safety 
monitoring board (IDMC) will determine if the bendamustine cycle length should be 
changed to q28 days (Arm A) for the remainder of the trial. If the bendamustine cycle 
length in Arm A is not changed by the IDMC, Stage 1 will continue throughout the remainder 
of the study and will comprise the final analysis set.  If an IDMC cycle change is implemented, 
the sample size and event count will restart at this point, and subjects enrolled in Stage 2 will 
comprise the final analysis set.  Analysis of the cumulative set (subjects from Stage 1 and 
Stage 2) will be supplementary.


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If toxicity remains excessive despite the reduction of the bendamustine dose to 90 mg/m2, 
Days 1, 2, q28 days, the IDMC will assess the next 10 subjects in Arm A who complete 3 
cycles (or complete bendamustine therapy) and have the option to reduce the 
bendamustine dose to 70 mg/m2 (Stage 3), Days 1, 2; q28 days in Arm A in a similar way 
as was done for Stage 1 and Stage 2.  Data from Arm B will be made available each time 
the IDMC assesses Arm A.
Section 3.1:
Figure 1, Figure 2
Original Figure 1:
Randomize 1:1 
(Arm A:Arm B)
IDMC compares
Arm A (N=20) to 
Arm B (N=20) for 
safety and 
tolerability of B.
Arm A 
(Ofatumumab +bendamustine)
Arm B 
(bendamustine)
Primary endpoint= PFS
Follow-Up for q2M for 
3YR; then                 
q6M for 3 YR
If subjects progress while receiving treatment in Arm B (bendamustine monotherapy), they will be 
offered ofatumumab (1000 mg, x8) <120 days following PD diagnosis
Arm B 
(bendamustine)
N=20
Arm A 
(Ofatumumab+bendamustine)
N=20


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Figures changed to:
Figure 1:
Figure 2 added:
Section 3.1.3:
Dose Confirmation for Safety and Tolerability
Original text:
Forty subjects (20 per treatment arm) who enter this study will be part of a dose confirmation 
cohort for evaluation of safety and tolerability of ofatumumab and bendamustine combination 
therapy. Subjects in Arm A will receive ofatumumab, 1000 mg Day 1 followed by 
bendamustine, 90 mg/m2, Days 1,2; every 21 days. The combination will be given in 21-day 
cycles up to 6 cycles.  Subjects in Arm B will receive bendamustine, 120 mg/m2, Days 1,2; 
every 21 days.  Bendamustine monotherapy will be given in 21-day cycles up to 6 cycles. The 
independent data monitoring committee (IDMC) involved in this study will follow a decision 
rule, described in the IDMC charter, to decide whether the dose of bendamustine, in Arm A, 
should remain at 90 mg/ m2, Days 1, 2; every 21 days, or change.  When administered along 
with ofatumumab, the bendamustine dose will not exceed 90 mg/m2 (administered on Days 
Randomize 1:1
(Arm A:Arm B)
Primary endpoint= PFS
Follow-Up for q3M for 
2YR; then                 
q6M for additional 3YR
If subjects in Arm B (bendamustine monotherapy) progress, they will be offered ofatumumab            
<120 days following PD confirmation by CT Scan4
IDMC evaluates
Arm A, 3 cycles 
(N=20) for safety 
and tolerability 
Arm A1,2
Up to 8 cycles of Bendamustine (90 mg/m2 Days 1-2, q21 days) in combination 
with 12 doses of ofatumumab (1000 mg, Day 1). Following completion of OB 
combination, complete 12 doses of  ofatumumab
Arm B2,3
Bendamustine, 120 mg /m2 Days 1,2   q21 days for up to 8 cycles
IDMC evaluates
Arm A, 3 cycles 
(N=10) for safety 
and tolerability 
IDMC evaluates
Arm A, 3 cycles 
(N=10) for safety 
and tolerability 
If q28 day change in Arm A
If dose change in Arm A
Primary endpoint= RR
Follow-Up for q3M for 
3YR; then                 
q6M for additional 3 YR
Ofatumumab (2000 mg),              
once a week x4 followed by              
2000 mg q1M, x8
If subjects in Arm B 
(bendamustine 
monotherapy) 
progress, they will be 
offered ofatumumab            
within 120 days 
following PD


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1,2; every 21 days) in this study.  The IDMC decision rule will take into account and compare 
the nature and severity of serious adverse events and dose-limiting toxicities between Arm A 
and Arm B.  The IDMC will have the option to decrease the bendamustine dose and/or 
lengthen the cycle duration from 21 to 28 days in Arm A for improved safety and tolerability.
Should the IDMC decide to reduce the dose of bendamustine if the nature and severity of 
serious adverse events or dose-limiting toxicities in Arm A exceed those found in Arm B 
(monotherapy bendamustine), then the dose and dose reduction schedule found in the IDMC 
charter will be followed for the remainder of the study.  Also see Section 9.7 for further 
details.
Text changed to:
The IDMC will review safety and tolerability data for Arm A at specific points 
throughout the study as specified in the IDMC charter and summarized in Section 9.7.  
The IDMC will initially review data from the first 20 subjects who complete 3 cycles (or 
complete bendamustine therapy with fewer than 3 cycles) in Arm A to determine 
whether the bendamustine cycle length should be lengthened in to q28 days Arm A or if 
the cycle length should remain as it is.  If cycle length of bendamustine is lengthened in 
Arm A, the IDMC will then review the data to determine whether the dose of 
bendamustine in Arm A should be reduced or if it is appropriate for the dose to remain 
as it is.  If the dose of bendamustine in Arm A is reduced, the IDMC will once more 
review the data to determine if it is appropriate for the study to continue.  For each 
decision the IDMC will follow a decision rule that will be defined in the IDMC charter.  
Arm B data will be made available to the IDMC each time they assess Arm A.
Section 3.1.4:
Treatment Phase
Original text:
Subjects will be followed as described in Appendix 1.  Subjects will be randomized 1:1 to 
receive either:
Arm A: Ofatumumab (1000 mg starting on Day 1 q21 days, Cycles 1-6) followed by 
bendamustine (90 mg/m2, Days 1,2; q21 days, Cycles 1-6)
Arm B:  Bendamustine (120 mg/m2, Days 1, 2; q21 days, Cycles 1-6)
An IDMC will compare the safety and toxicity between Arm A and Arm B.  In the event the 
toxicity in Arm A exceeds Arm B, the IDMC will follow a decision rule for bendamustine 
regimen modification as described in the IDMC charter.  Please see Section 9.7.
Assessments to determine subject response or progression will be performed for both arms 
including:

Physical examination including examination of lymph nodes, spleen and liver

Peripheral blood sample evaluation for complete blood count (CBC) and differential with 
both percent and absolute number of lymphocytes

CT scans for confirmation of response are required (within 10 days) after a subject fulfils 
the Revised Response Criteria for Malignant Lymphoma (RRCML) requirements for CR 
or PR
Text changed to:


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Subjects will be followed as described in Appendix 1.  Subjects will be randomized 1:1 to 
receive either:
Arm A: Up to 8 cycles of bendamustine ( 90 mg/m2, Days 1,2) in combination with 
12 doses of ofatumumab (1000 mg).  Ofatumumab will be given on day 1 
of each cycle of bendamustine as long as patients in Arm A receive 
bendamustine.  Once patients in Arm A complete bendamustine therapy, 
the remaining doses of ofatumumab will be given monthly until all 12 
doses are completed.
Arm B:  Bendamustine (120 mg/m2, Days 1, 2; q21 days, up to 8 cycles)
Subjects in Arm B who cannot complete 8 cycles of therapy must still come in for all 
planned visits (Visits 1-20).
An IDMC will assess the safety and toxicity in Arm A.  In the event of excessive toxicity in
Arm A, the IDMC will follow a decision rule for bendamustine regimen modification as 
described in the IDMC charter.  Please see Section 9.7.
Blood samples are acquired at the start of each cycle, throughout the treatment phase.
Assessments to determine subject response or progression will be performed for both arms 
including:

Physical examination including examination of lymph nodes, spleen and liver

Peripheral blood sample evaluation for complete blood count (CBC) and differential with 
both percent and absolute number of lymphocytes

CT scans will be performed within 3 days of the post randomization Days 84, 168, and 
252 to assess clinical response by the Revised Response Criteria for Malignant 
Lymphoma (RRCML).  Patients who are unable to complete 8 cycles of therapy must 
still have CT scans done on post randomization Days 84, 168, and 252.


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Section 3.1.5:
Follow-up Phase
Original text:
Following study treatment, subjects who have CR, PR or SD will receive regular follow-up 
for 5 years.  Follow-up visits will begin on 3 months after post randomization Day 252 for 
Arm A and Arm B and then continue every 3 months for 2 years, then every 6 months for 3 
years.  Follow-up visits will include survival, and disease status assessments. In addition, 
subjects will be monitored for safety, efficacy, and pharmacokinetics.  See Appendix 1 and 
Appendix 2 for a complete list of follow-up phase procedures.
Text changed to:
Following study treatment, subjects who have CR, PR or SD will receive regular follow-up 
for 5 years in Arm A.  If Arm B subject do decide to receive optional ofatumumab 
monotherapy, they will not follow the schedule described in Section 3.1.5, Appendix 1, 
and Appendix 2, but will receive one End of Treatment visit (EOT) as described in 
Appendix 1, and Appendix 2 and will then follow the schedule described in Section 3.1.6 
and Appendix 3.
Follow-up visits will begin on Day 336 (this is 3 months after post randomization Day 252) 
and then continue every 3 months for 2 years, then every 6 months for 3 years.  One month is 
defined as having 28 days.  Each follow-up visit will have a time window of ± 7 days.  
Follow-up visits will include survival, concomitant medications, and disease status 
assessments. In addition, subjects will be monitored for safety, efficacy, and pharmacokinetics 
as described.  See Appendix 1 and Appendix 2 for a complete list of follow-up phase 
procedures.
Section 3.1.6:
Ofatumumab Following Progressive Disease
Original text:
At the discretion of the physician in consultation with the study subject, ofatumumab may be 
administered to subjects who develop PD during treatment with bendamustine monotherapy 
as defined in Section 6.2.4.5 (See Appendix 3 for follow-up procedures).  Subjects who 
receive ofatumumab following diagnosis of  PD must fulfill the inclusion criteria found in 
Section 4.2 and the exclusion criteria found in Section 4.3 (except for exclusion criteria #7:  
prior bendamustine treatment). 
Follow-up will be considered in days post randomization (Day 1).  
Text changed to:
Follow-up for Progressive Disease
Subjects receiving ofatumumab and bendamustine combination therapy (Arm A) or 
bendamustine monotherapy (Arm B) who experience disease progression, as defined in 
Section 6.2.4.5, will be assessed for safety and followed as described in Appendix 1 and 
Appendix 2 (Survival/PD visits).
Follow-up visits will begin on Day 336 (this is 3 months after Day 252) and continue 
every 3 months for 2 years and then every 6 months for 3 years.  One month is defined 
as having 28 days.  Follow up visits will have a ± 7 day time window.
If an Arm B subject decides to receive optional ofatumumab monotherapy, the subject 
will not follow the schedule described in Section 3.1.5, Appendix 1, and Appendix 2, but 
will receive one End of Treatment visit (EOT) visit as described in Appendix 1, and 


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Appendix 2 and will then follow the treatment and follow-up schedules described in 
Section 3.1.6 and Appendix 3.
Section 3.1.6:
Ofatumumab Following Progressive Disease for Arm B
Follow-up for Progressive Disease
Subjects receiving ofatumumab and bendamustine combination therapy or bendamustine 
monotherapy, who experience disease progression, as defined in Section 6.2.4.5, during 
treatment will be assessed for safety and followed as described in Appendix 1 and Appendix 2. 
Text changed to:
At the discretion of the physician in consultation with the study subject, ofatumumab may be 
administered to subjects who develop PD during or following treatment with bendamustine 
monotherapy in Arm B as defined in Section 6.2.4.5 (See Appendix 3 for follow-up 
procedures).  Subjects with PD in Arm B must have a CT scan done with independent 
radiology review confirmation of PD.  This CT scan will determine measurements of 
pre-ofatumumab disease before exercising the option to receive ofatumumab.
Subjects who receive ofatumumab following diagnosis of  PD must fulfill the inclusion 
criteria found in Section 4.2 and the exclusion criteria found in Section 4.3 (except for 
exclusion criteria #7:  prior bendamustine treatment). Subjects in Arm B who choose to 
receive optional ofatumumab monotherapy receive ofatumumab 2000 mg weekly (±3 
days) for 4 doses followed by 2000 mg every month (±3 days) for 8 additional doses (total: 
12 doses).
The first follow-up visit will occur one month following the last infusion of ofatumumab 
monotherapy and continue every 3 months for 2 years then every 6 months for 3 years 
as described in Appendix 3.
Section 3.1.7:
Study Endpoints
Original text:
Secondary Endpoints

Overall response rate

Overall survival

Time to response and duration of response

Time to progression and time to next therapy

Changes in health-related quality of life (HRQL) measures

Reduction in tumor size

Improvement in ECOG Performance status 

Incidence and severity of adverse events, serious adverse events and other safety 
parameters including frequency of transfusions, development of Human Anti-Human 
Antibodies (HAHA), incidence of 3 and 4 infections, and myelosuppression (anemia,
neutropenia, and thrombocytopenia)


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
Changes in clinical laboratory values

Quantitative assessments of IgG, IgA, IgM

Plasma ofatumumab concentrations

B-cell monitoring (CD19+, CD20+)
KNOWN AND EXPLORATORY PROGNOSTIC MARKERS CORRELATING WITH 
RESPONSE

Baseline FLIPI

Baseline Absolute Lymphocyte Count (ALC)

FcR gamma 3

IgVH gene rearrangement
Text changed to:
Secondary Endpoints

Overall response rate

Overall survival

Time to response and duration of response

Time to progression and time to next therapy

Changes in health-related quality of life (HRQL) measures

Reduction in tumor size

Improvement in ECOG Performance status 

Incidence and severity of adverse events, serious adverse events and other safety 
parameters including frequency of transfusions, development of Human Anti-Human 
Antibodies (HAHA), incidence of 3 and 4 infections, and myelosuppression (anemia, 
neutropenia, and thrombocytopenia)

Overall response rate to optional ofatumumab monotherapy in patients in Arm B 
who progress during or following single-agent bendamustine

Changes in clinical laboratory values

Quantitative assessments of IgG, IgA, IgM

Plasma ofatumumab concentrations

B-cell monitoring (CD19+, CD20+)
KNOWN AND EXPLORATORY PROGNOSTIC MARKERS CORRELATING WITH 
RESPONSE

Baseline FLIPI (FLIPI-1 and FLIPI-2)

Baseline Absolute Lymphocyte Count (ALC)


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
FcR gamma 3
Section 3.2.2:
Ofatumumab Dosing
Original text:
The ofatumumab dose in this study, 1000 mg, was selected based on several considerations:  
preclinical data with ofatumumab and clinical population pharmacokinetic modelling and 
simulation; prior clinical experience with ofatumumab (Study Hx-CD20-001 [Hagenbeek, 
2008]); ongoing clinical experience with ofatumumab (Studies Hx-CD20-405 and Hx-CD20-
409); and prior clinical experience with rituximab.  The proposed schedule is Day 1 of each 
21-day or 28-day cycle, depending upon the IDMC dose recommendation for Stage 2 of the 
study (Section 3.1.3).
Preclinical data suggest that ofatumumab plasma concentrations >10 g/mL are sufficient to
suppress peripheral B-cell recovery in cynomolgus monkeys as well as to suppress tumor cell 
growth in Daudi tumor-bearing SCID mice [Bleeker, 2008].  SCID mice previously 
inoculated with Daudi B-cells received ofatumumab at 0.5 and 50 mg/kg and were observed 
for tumor growth.  Tumor growth was delayed 3-4 weeks after ofatumumab administration, 
with a greater duration of tumor growth inhibition at the higher dose level.  Acceleration of 
tumor growth was observed at the timepoint at which ofatumumab concentrations had 
dropped below 0.4 g/mL.
In the Bleeker study, cynomolgus monkeys received ofatumumab at three dose levels:  1.25, 
6.25, or 12.5 mg daily for four consecutive days (cumulative doses 5, 25, or 50 mg/kg).  A 
profound B-cell depletion was induced both peripherally and in the lymph nodes, with a 
longer time to recovery at higher dose levels.  Ofatumumab concentrations above 50 g/mL 
were sufficient for complete B-cell depletion.  Recovery of CD20+ cells in peripheral blood 
and lymph nodes was detected when plasma ofatumumab concentrations had dropped below 
5-10 g/mL.  Thus, a potential clinical target in developing ofatumumab dosing regimens is 
prolonged maintenance of plasma concentrations >10 g/mL.
Pharmacokinetic data from the Phase I study in subjects with relapsed or refractory follicular 
lymphoma (FL) (Study Hx-CD20-001) were analyzed using a two-compartment model with a 
decrease in clearance after the first dose and assuming a stepped-rate infusion using a 
nonlinear mixed-effects modeling approach (NONMEM).  The resulting model was used to 
simulate concentration-time data for 500 subjects receiving ofatumumab infusions at 1000 mg 
on the first day of each 21-day or 28-day cycle for a total of six cycles.  Based on the 
simulations, the probability of maintaining plasma ofatumumab concentrations >10 µg/mL 
was high with both dosing schedules.  With a 21-day cycle length, the probability of 
maintaining Cp >10 g/mL was >90% after the first cycle and >95% throughout the 
remainder of the six-cycle dosing period and for four weeks after the last dose; the probability 
of Cp >10 µg/mL was approximately 89% at eight weeks after the last dose.  With a 28-day 
cycle length, the probability of maintaining Cp >10 g/mL was 84% after the first cycle 
and >95% throughout the remainder of the six-cycle dosing period and for four weeks after 
the last dose; the probability of Cp >10 g/mL was approximately 85% at eight weeks after 
the last dose.  Thus, a dosing schedule of 1000 mg infusions on Day 1 of each 21-day or 28-
day cycle for six cycles is expected to achieve prolonged maintenance of plasma 
concentrations >10 μg/mL in a high proportion of subjects with follicular lymphoma.


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Prior clinical experience in a Phase I trial of ofatumumab in subjects with relapsed or 
refractory FL suggests that four weekly infusions of 300 mg to 1000 mg are effective.  [Study 
Hx-CD20-001; Hagenbeek, 2008]  Responses were observed in all four dose groups [(300 mg: 
5 of 8 subjects (63%); 500 mg: 3 of 10 subjects (30%); 700 mg: 2 of 10 subjects (20%); and 
1000 mg: 5 of 10 subjects (50%)].  Thus, a regimen using six 1000 mg doses of ofatumumab 
at 21-day or 28-day intervals is expected to be effective.  
There was no apparent difference in the severity and number of adverse events between 
patients with FL receiving ofatumumab at doses ranging from 300 mg to 1000 mg, including 
full ofatumumab doses at first infusion [Study Hx-CD20-001].  Thus, the use of a full 
ofatumumab dose (i.e., 1000 mg) at first infusion is proposed in this study.
In ongoing studies, 1000 mg of ofatumumab has been administered weekly for seven weeks 
after an initial infusion of 300 mg in subjects with FL refractory to rituximab in combination 
with chemotherapy (Study Hx-CD20-405) and administered every three weeks after an initial 
infusion of 300 mg in combination with CHOP for a total of six cycles in subjects with 
previously untreated FL (Study Hx-CD20-409).  Although no efficacy results are currently 
available, no major safety issues have been observed to date [OFATUMUMAB Investigator 
Brochure, 2009].
Prior clinical experience with rituximab suggests that prolonged or maintenance 
administration schedules enhance response duration in subjects with NHL. [reviewed in 
Collins-Burow, 2007; Ghielmini, 2004; Cersosimo, 2003].  The proposed six-cycle dosing 
schedule with doses at 21-day or 28-day intervals increases the duration of ofatumumab 
exposure, which should maintain chemosensitization of FL to concomitant chemotherapy 
while enhancing response duration.
Text changed to:
The ofatumumab dose in this study, 1000 mg, was selected based on several considerations:  
preclinical data with ofatumumab and clinical population pharmacokinetic modelling and 
simulation; prior clinical experience with ofatumumab (Study Hx-CD20-001 [Hagenbeek, 
2008]); ongoing clinical experience with ofatumumab (Studies Hx-CD20-405 and Hx-CD20-
409); and prior clinical experience with rituximab.
A total of 12 doses of ofatumumab will be given in Arm A.  Ofatumumab will be given 
on day 1 of each cycle of bendamustine as long as patients in Arm A receive 
bendamustine (up to 8 cycles).  Once patients in Arm A complete bendamustine therapy, 
additional doses of ofatumumab will be given monthly for a total of 12 ofatumumab 
doses.
Preclinical data suggest that ofatumumab plasma concentrations >10 g/mL are sufficient to 
suppress peripheral B-cell recovery in cynomolgus monkeys as well as to suppress tumor cell 
growth in Daudi tumor-bearing SCID mice [Bleeker, 2008].  SCID mice previously 
inoculated with Daudi B-cells received ofatumumab at 0.5 and 50 mg/kg and were observed 
for tumor growth.  Tumor growth was delayed 3-4 weeks after ofatumumab administration, 
with a greater duration of tumor growth inhibition at the higher dose level.  Acceleration of 
tumor growth was observed at the timepoint at which ofatumumab concentrations had 
dropped below 0.4 g/mL.
In the Bleeker study, cynomolgus monkeys received ofatumumab at three dose levels:  1.25, 
6.25, or 12.5 mg daily for four consecutive days (cumulative doses 5, 25, or 50 mg/kg).  A 


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profound B-cell depletion was induced both peripherally and in the lymph nodes, with a 
longer time to recovery at higher dose levels.  Ofatumumab concentrations above 50 g/mL 
were sufficient for complete B-cell depletion.  Recovery of CD20+ cells in peripheral blood 
and lymph nodes was detected when plasma ofatumumab concentrations had dropped below 
5-10 g/mL.  Thus, a potential target in developing ofatumumab dosing regimens is 
prolonged maintenance of plasma concentrations >10 g/mL.
Pharmacokinetic data from the Phase I study in subjects with relapsed or refractory follicular 
lymphoma (FL) (Study Hx-CD20-001) were analyzed using a two-compartment model with a 
decrease in clearance after the first dose and assuming a stepped-rate infusion using a 
nonlinear mixed-effects modeling approach (NONMEM).  The resulting model was used to 
simulate concentration-time data for 500 subjects receiving ofatumumab infusions at 1000 mg 
on the first day of each 21-day or 28-day cycle for a total of six cycles.  Based on the 
simulations, the probability of maintaining plasma ofatumumab concentrations >10 µg/mL 
was high with both dosing schedules.  With a 21-day cycle length, the probability of 
maintaining Cp >10 g/mL was >90% after the first cycle and >95% throughout the 
remainder of the six-cycle dosing period and for four weeks after the last dose; the probability 
of Cp >10 µg/mL was approximately 89% at eight weeks after the last dose.  With a 28-day 
cycle length, the probability of maintaining Cp >10 g/mL was 84% after the first cycle 
and >95% throughout the remainder of the six-cycle dosing period and for four weeks after 
the last dose; the probability of Cp >10 g/mL was approximately 85% at eight weeks after 
the last dose.  Thus, a dosing schedule of 1000 mg infusions on Day 1 of each 21-day or 28-
day cycle for 12 doses is expected to achieve prolonged maintenance of plasma 
concentrations >10 μg/mL in a high proportion of subjects with follicular lymphoma.
Prior clinical experience in a Phase I trial of ofatumumab in subjects with relapsed or 
refractory FL suggests that four weekly infusions of 300 mg to 1000 mg are effective.  [Study 
Hx-CD20-001; Hagenbeek, 2008]  Responses were observed in all four dose groups (300 mg: 
5 of 8 subjects (63%); 500 mg: 3 of 10 subjects (30%); 700 mg: 2 of 10 subjects (20%); and 
1000 mg: 5 of 10 subjects (50%).  Thus, a regimen using twelve 1000 mg doses of 
ofatumumab at 21-day or 28-day intervals is expected to be effective.  
There was no apparent difference in the severity and number of adverse events between 
patients with FL receiving ofatumumab at doses ranging from 300 mg to 1000 mg, including 
full ofatumumab doses at first infusion [Hagenbeek, 2008].  Thus, the use of a full 
ofatumumab dose (i.e., 1000 mg) at first infusion is proposed in this study.
In ongoing studies in subjects with FL, repeated doses of 500 mg or 1000 mg of 
ofatumumab have been administered.  In Study Hx-CD20-405, ofatumumab was 
administered at 500 mg or 1000 mg weekly for seven weeks after an initial infusion of 300 
mg in subjects with FL refractory to rituximab in combination with chemotherapy; in Study 
Hx-CD20-409, ofatumumab doses of 500 mg or 1000 mg were administered every three 
weeks after an initial infusion of 300 mg in combination with CHOP for a total of six cycles 
in subjects with previously untreated FL.  In these two studies, there were no unexpected 
safety findings reported during treatment and within 30 days of last infusion.  The 
results from these studies suggest that administration of 1000 mg at 21- or 28-day 
intervals is expected to be well tolerated.


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Prior clinical experience with rituximab suggests that prolonged or maintenance 
administration schedules enhance response duration in subjects with NHL. [reviewed in 
Collins-Burow, 2007; Ghielmini, 2004; Cersosimo, 2003].  Prior clinical experience with 
ofatumumab demonstrated longer median duration of response with the addition of four 
infusions at four-week intervals after the end of weekly ofatumumab treatment in 
subjects with fludarabine-refractory CLL (Study Hx-CD20-406).  The proposed regimen 
of twelve ofatumumab six-cycle dosing schedule with doses administered.  The proposed 
ofatumumab regimen of 12 doses administered at 21-day or 28-day intervals increases the 
duration of ofatumumab exposure, which should maintain chemosensitization of FL to 
concomitant chemotherapy while enhancing response duration.
OFATUMUMAB MONOTHERAPY FOR SUBJECTS WHO PROGRESS IN ARM B
Subjects who progress during or after therapy in Arm B (bendamustine alone) will be 
offered ofatumumab monotherapy.  Data regarding ofatumumab monotherapy in this 
population were obtained in Study Hx-CD20-405, in which subjects with rituximab-
refractory FL were randomized to single agent ofatumumab at 500 mg or 1000 mg 
weekly for 7 doses after a 300 mg initial dose (total of 8 doses).  The response rate was 
approximately 10%, and median progression-free survival (PFS) was 6 months, with no 
difference between the dose groups.  Experience in CLL indicates that increasing the 
dose intensity of rituximab was able to mprove the overall response rate significantly 
from 10-15% to 45% (add references); in addition, ofatumumab at a dose of 2000 mg 
showed significant clinical activity with an acceptable safety profile in subjects with 
fludarabine-refractory CLL in Study Hx-CD20-406.  Therefore, it is reasonable to 
examine the 2000 mg dose in refractory FL.  
The optimal duration of therapy in this setting is unclear.  Study Hx-CD20-406 
administered eight weekly doses of ofatumumab 2000 mg (first dose 300 mg) followed by 
four monthly doses of 2000 mg; however, the standard length of weekly rituximab 
therapy in FL is four weeks, and there are no convincing data that increasing the 
number of weekly rituximab infusions from 4 to 8 is of benefit.   
The rituximab-refractory FL population in this study may have more disease (and thus, 
faster clearance) and shorter PFS following four weeks of ofatumumab monotherapy 
than subjects with rituximab-sensitive FL.  Thus, more frequent administration may be 
necessary for extended dosing in this refractory population, similar to the subjects with 
fludarabine-refractory CLL in Study Hx-CD20-406, who received monthly extended 
doses.
Thus, a regimen of 2000 mg ofatumumab for four weekly doses followed by 2000 mg 
ofatumumab every 4 weeks for four additional doses (for a total of 8 doses) will be 
offered to the subjects in Arm B who have progressive disease during or after 
bendamustine monotherapy.
Section 4.1:
Number of Subjects
Original text:


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Subjects who meet all the following inclusion and exclusion criteria will be eligible for 
enrollment into the study.  Approximately 296 subjects will be screened to randomize 266
subjects. See Section 8.2 for further details on assumptions for subject numbers.
Text changed to:
Subjects who meet all the following inclusion and exclusion criteria will be eligible for 
enrollment into the study.  Approximately 376 subjects will be screened to randomize 338
subjects. See Section 8.2 for further details on assumptions for subject numbers.
Rationale for change:
Increased study power from 80% to 90%.
Section 4.3:
Exclusion Criteria
Original text:

Previous autologous stem cell transplant, fludaranine therapy, or Radioimmunotherapy in 
the past 12 months
Text changed to:

Exclusion criterion 3.  Previous autologous stem cell transplant, fludarabine therapy, or 
radioimmunotherapy in the past 12 months

Exclusion criterion 7.  Treatment with anti-CD20 monoclonal antibody within 3 months 
of randomization

Exclusion criterion 14.  Positive serology for Hepatitis B (HB) defined as a positive test 
for HBsAg. In addition, if negative for HBsAg but HBcAb positive (regardless of HBsAb 
status), a HB DNA test will be performed and if positive the subject will be excluded.**

Treatment with anti-CD20 monoclonal antibody or with alemtuzumab within 3 
months of randomization

*Subjects can participate in the study if in the opinion of the investigator and 
medical monitor it is thought not to affect the subject’s safety, the conduct of the 
study or the interpretation of the data.

** If HBV DNA is negative, subject may be included but must undergo HBV DNA 
monitoring (see Section 6.5.7). Prophylactic antiviral therapy may be initiated at 
the discretion of the investigator.
Section 5.1.1:
Ofatumumab
Original text:
Ofatumumab will be infused intravenously on day 1 (1000 mg) of each cycle, followed by 
five more infusions of 1000 mg every 21 or 28 days. Subjects developing progressive disease 
in the bendamustine monotherapy arm will have the option to receive ofatumumab 1000 mg 
once weekly for a maximum of eight infusions. This treatment option will be available within 
120 days following diagnosis of progressive disease.
Text changed to:
In Arm A, ofatumumab 1000 mg will be given on day 1 of each cycle of bendamustine as 
long as patients in Arm A receive bendamustine.  Once patients in Arm A complete 
bendamustine therapy, the remaining doses of ofatumumab will be given monthly until 


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all 12 doses have been administered.  A total of 12 ofatumumab infusion will be 
administered in Arm A regardless of the number of ofatumumab and bendamustine 
cycles completed.
Subjects developing progressive disease in the bendamustine monotherapy arm (Arm B) 
will have the option to receive ofatumumab.  Subjects who choose this option will receive 
ofatumumab 2000 mg once a week for 4 infusions followed by an additional 
ofatumumab (2000 mg) infusions once every month for 8 doses (total: 12 doses).  
Patients in Arm B who choose this option must begin ofatumumab therapy within 120 
days following diagnosis of progressive disease, which can occur at any time during 
treatment or follow-up.
Rational for change:
To reflect updated ofatumumab schedule and randomization post PD.
Section 5.1.2:
Bendamustine
Original text:
Bendamustine (IV) is available as a single-use vial containing 100 mg of bendamustine HCl 
as lyophilized powder.  In the monotherapy arm, the bendamustine dose is 120 mg/m2, given 
on days 1 and 2, every 21 days for 6 cycles.  In the experimental arm, the bendamustine dose 
is 90 mg/m2, given on days 1 and 2, every 21 days for 6 cycles.  Investigators will follow the 
label dose reduction schedule if subjects require lower doses as they advance through 
treatment. The initial dose of bendamustine in Arm A may be lowered on recommendation of 
the IDMC after evaluation of data from the dose confirmation cohort (up to the first 40 
patients).  Detailed instructions for dose reduction and subsequent dose reductions will be in 
the IDMC charter and in Section 9.7 


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Bendamustine may be initiated within 1 day of scheduled start for logistical reasons.  The start 
of Cycles 2-6 may be delayed due to toxicity by up to 2 weeks for medical reasons at the 
investigator’s discretion.  If the subject is medically unable to receive a subsequent cycle of 
treatment after 2 weeks’ delay, a decision will be made about whether the subject will 
withdraw from treatment. Please see Section 5.1.2.1.
Text changed to:
Bendamustine (IV) is available as a single-use vial containing 100 mg of bendamustine HCl 
as lyophilized powder.  In the monotherapy arm, the bendamustine dose is 120 mg/m2, given 
on days 1 and 2, every 21 days for up to 8 cycles.  In the experimental arm, the bendamustine 
dose is 90 mg/m2, given on days 1 and 2, every 21 days for up to 8 cycles.  Investigators will 
follow the label dose reduction schedule if subjects require lower doses as they advance 
through treatment. The initial cycle length and dose of bendamustine in Arm A may be 
lowered on recommendation of the IDMC after evaluation of data from the dose confirmation 
cohorts (up to the first 40 patients).  Detailed instructions for dose reduction and subsequent 
dose reductions will be in the IDMC charter and in Section 9.7 
Bendamustine may be initiated within 1 day of scheduled start for logistical reasons.  The start 
of Cycles 2-8 may be delayed due to toxicity by up to 2 weeks for medical reasons at the 
investigator’s discretion.  If the subject is medically unable to receive a subsequent cycle of 
treatment after 2 weeks’ delay, a decision will be made about whether the subject will 
withdraw from treatment. Please see Section 5.1.2.1.
Rationale for changes:
Reflects changes to number of cycles from 6 to 8.
Section 5.1.2.1:
Bendamustine Dose Reduction
Original text:
The dose of bendamustine will be reduced if, with any cycle, a subject develops grade 4 
hematologic or grade 3/4 non-hematologic toxicities, according to the National Cancer 
Institute Common Toxicity Criteria for Adverse Events (NCI-CTCAE) version 3.0
[NCI-CTCAE, 2006].  This labeled dose reduction will be followed for both arms of the study, 
See Table 4 [TREANDA Prescribing Information, 2007].
Toxicities must be resolved to grade 1 or baseline before beginning the next cycle.  Absolute 
neutrophil count (ANC) must have recovered to at least 1,000 cells/mm3 (1.0 x 109 cells/L) 
and platelets to at least 75,000 cells/mm3 (75 x 109 cells/L) by the start of the next cycle.
If continued toxicities occur beyond reasonable delay for recovery when subjects are dosed 
with 60 mg/m2 of bendamustine in either arm, study treatment will be discontinued (See Table 
4). Subjects in Arm A will stop both ofatumumab and bendamustine and will enter follow up 
as described in Appendix 1 and Appendix 2.


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TABLE 4
BENDAMUSTINE DOSE REDUCTION SCHEDULE 
Bendamustine Dose and 
Schedule 
If Grade 4 Hematologic Toxicity
If Grades 3,4 Nonhematologic 
Toxicity
Dose
Schedule
Dose
Schedule
120 mg/m2, days 1,2 every 
21 days
90 mg/m2
Days 1,2 every 21 
days
90 mg/m2
Days 1,2 every 
21 days
90 mg/m2, days 1,2 every 21 
days
60 mg/m2
Days 1,2 every 21 
days
60 mg/m2
Days 1,2 every 
21 days
60 mg/m2, days 1,2 every 21 
days
Discontinue 
treatment
Discontinue 
treatment
Discontinue 
treatment
Discontinue 
treatment
General Dosing Considerations for both arms:
Delay treatment for Grade 4 hematologic toxicity or clinically significant ≥Grade 2 non-
hematologic toxicity
Toxicities must recover to Grade 1 or baseline before the next administration of treatment. If 
recovery is not met within 2 weeks after the prescribed start of the treatment cycle (i.e., after a 
2 week delay), a decision will be made about continuation in the study. 
If the IDMC decides to reduce the starting dose of bendamustine (in Arm A) from 90 mg/m2, 
Days 1,2; every 21 days to a lower dose or longer treatment cycle, then the dose and dose 
reduction schedule found in the IDMC charter will be followed for the remainder of the study.  
See Section 9.7 for details on the IDMC.
Text changed to:
The dose of bendamustine will be reduced if, with any cycle, a subject develops grade 4 
hematologic or grade 3/4 non-hematologic toxicities, according to the National Cancer 
Institute Common Toxicity Criteria for Adverse Events (NCI-CTCAE) version 4.0
[NCI-CTCAE v4, 2009].  This labelled dose reduction will be followed for bendamustine in
Arm B of the study, See Table 5 [TREANDA Prescribing Information, 2007].  Arm A will 
follow the bendamustine dose reduction described in Table 4.
Toxicities must be resolved to grade 1 or baseline before beginning the next cycle.  Absolute 
neutrophil count (ANC) must have recovered to at least 1,000 cells/mm3 (1.0 x 109 cells/L) 
and platelets to at least 75,000 cells/mm3 (75 x 109 cells/L) by the start of the next cycle.
If continued toxicities occur beyond reasonable delay for recovery, study treatment will be 
discontinued (See Table 4 and Table 5).  In this event, subjects in Arm B will continue to 
come to the clinic for scheduled visits and CT scans (to complete all scheduled visits and 
CT scan Days 84, 168, 252) and subjects in Arm A will stop bendamustine and will 
continue to complete 12 doses of ofatumumab or enter follow-up if the 12 doses of 
ofatumumab are completed, as described in Appendix 1 and Appendix 2.


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TABLE 4
BENDAMUSTINE DOSE REDUCTION SCHEDULE FOR ARM A
Bendamustine Dose and 
Schedule 
If Grade 4 Hematologic Toxicity
If Grades 3,4 Nonhematologic 
Toxicity
Dose
Schedule
Dose
Schedule
90 mg/m2, days 1,2 every 21 
days
90 mg/m2
Days 1,2 every 28 
days
90 mg/m2
Days 1,2 every 
28 days
90 mg/m2, days 1,2 every 28 
days
70 mg/m2
Days 1,2 every 28 
days
70 mg/m2
Days 1,2 every 
28 days
70 mg/m2, days 1,2 every 28 
days
Discontinue 
treatment
Discontinue 
treatment
Discontinue 
treatment
Discontinue 
treatment
TABLE 5
BENDAMUSTINE DOSE REDUCTION SCHEDULE FOR ARM B
Bendamustine Dose and 
Schedule 
If Grade 4 Hematologic Toxicity
If Grades 3,4 Nonhematologic 
Toxicity
Dose
Schedule
Dose
Schedule
120 mg/m2, days 1,2 every 
21 days
90 mg/m2
Days 1,2 every 21 
days
90 mg/m2
Days 1,2 every 
21 days
90 mg/m2, days 1,2 every 21 
days
60 mg/m2
Days 1,2 every 21 
days
60 mg/m2
Days 1,2 every 
21 days
60 mg/m2, days 1,2 every 21 
days
Discontinue 
treatment
Discontinue 
treatment
Discontinue 
treatment
Discontinue 
treatment
General Dosing Considerations for Arm A and Arm B:

Delay treatment for Grade 4 hematologic toxicity or clinically significant ≥Grade 3 
non-hematologic toxicity

Toxicities must recover to Grade 1 or baseline before the next administration of 
treatment. If recovery is not met within 2 weeks after the prescribed start of the 
treatment cycle (i.e., after a 2 week delay), a decision will be made about 
continuation in the study. 
If the IDMC decides to change the cycle length in Arm A from q21 days to q28 days or
reduce the starting dose of bendamustine (in Arm A) from 90 mg/m2, Days 1,2; every 21 days 
to a lower dose or longer treatment cycle, then the dose and dose reduction schedule found in 
the IDMC charter will be followed for the remainder of the study.  See Section 9.7 for details 
on the IDMC.
Rationale for change:
To clarify that this bendamustine dose reduction schedule should be followed for 
bendamustine dose reductions that occur in Arm A and Arm B.  Also updates the remit of the 
IDMC to first alter cycle length then consider altering starting bendamustine dose.


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Section 6.1.12:
Lymph Node and Organ Examination
Original text:
A physical lymph node and organ (spleen and liver) examination will be performed at 
screening and throughout the trial as part of physical examination.
Lymph nodes evaluation requires physical exam recording the diameter in two planes of the 
largest palpable node in each of the following sites: cervical, axillary, supraclavicular, 
inguinal and femoral.  Lymphadenopathy is defined as lymph nodes with the largest diameter 
1.5 cm.
Original text:
A complete physical lymph node and organ (spleen and liver) examination will be performed 
at screening.
Lymphadenopathy is defined as lymph nodes with the largest diameter 1.5 cm.
Liver and spleen size is assessed by physical exam and documented as ‘cm’ below the costal 
margin. 
Section 6.1.13:
Pre-treatment Computed Tomography (CT) Scans
Original text:
All subjects must have a CT-scan with contrast of the thorax, abdomen, and pelvis performed 
during screening.  This will be considered the baseline, CT scan.
Text changed to:
All subjects must have a CT-scan with contrast of the thorax, abdomen, and pelvis performed 
during screening if a CT scan was not done within 1 month prior to randomization.  The 
copy of the CT scan must be adequate to allow comparison to subsequent CT scans for 
response assessment.  This will be considered the baseline CT scan.
Rationale for change:
We will now allow a CT scan done within 1 month prior to randomization as the baseline CT 
scan.
Section 6.1.2:
Disease Characteristics and Medical History
Original text:

Follicular Lymphoma Prognostic Index Score (FLIPI) at screening
Text changed to:

Follicular Lymphoma Prognostic Index Score at screening (FLIPI-1, FLIPI-2)
Section 6.2.2:
CT Scans
Original text:
All subjects must have a CT scan performed before Day 1 of study.  Baseline CT scans will 
be done during the screening period according to the defined standard.


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All subjects must have a CT scan performed within 10 days of both Visit 10 (Day 84) and 
Visit 16 (Day 168) during the treatment period (for both arms) and during follow-up visits, or 
until initiation of alternative indolent lymphoma treatment, See Appendix 1.
Text changed to:
All subjects must have a CT scan performed before Day 1 of study.  Baseline CT scans will 
be done during the screening period according to the defined standard; however, a CT scan 
done within 1 month prior to randomization will be accepted as the baseline CT scan if 
images (which are sufficient for comparison to subsequent CT scans for response 
assessment) are provided.
All subjects must have a CT scan performed within 3 days of Days 84, 168, and 252 post-
randomization, for both arms.  Subjects must come to the clinic for all scheduled visits 
regardless of dose delays.  In the event subjects cannot complete 8 cycles of therapy then 
subjects must come to the clinic for all scheduled visits.  Follow-up visits will begin 3 
months after Day 252, for both arms and continue during follow-up visits, or until 
initiation of alternative indolent lymphoma treatment or WD, See Appendix 1.
Rationale for changes:
To accommodate ofatumumab schedule and administration of B up to 8 cycles.
Section 6.2.4.5:
Relapsed Disease (after CR)/Progressive Disease (after 
PR, SD)
Original text:
Measurable extranodal disease should be assessed in a manner similar to that for nodal disease. 
For these recommendations, the spleen is considered nodal disease. Disease that is only 
assessable (e.g., pleural effusions, bone lesions) will be recorded as present or absent only, 
unless, while an abnormality is still noted by imaging studies or physical examination, it is 
found to be histologically negative.
Text changed to:
Measurable extranodal disease should be assessed in a manner similar to that for nodal disease.  
Because extranodal disease is uncommon in follicular lymphoma and can be difficult to 
measure accurately after treatment, measurable extranodal disease is considered a 
nontarget lesion.  For these recommendations, the spleen is considered nodal disease. 
Disease that is only assessable (e.g., pleural effusions, bone lesions) will be recorded as 
present or absent only, unless, while an abnormality is still noted by imaging studies or 
physical examination, it is found to be histologically negative.
Section 6.3.2:
Peripheral Blood Sampling for Hematology and 
Biochemistry
Original text:
Blood samples will be drawn for analysis inclusive but not limited to the following parameters 
per Appendix 2 and Appendix 3.


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Text changed to:
Blood samples will be drawn for analysis inclusive but not limited to the following parameters 
per Appendix 2 and Appendix 3.

Hepatitis B (HBV) and Hepatitis C (HCV) at screening

For subjects that are HBsAg negative, HBcAb positive and HBV DNA negative (see 
Section 4.3) blood samples will be collected for monthly HBV DNA testing on day 1 
of each cycle  depending on the number of cycles administered and during FU at the 
1M, 3M and 6M post drug visit
Section 6.5.7:
Time Frequency of Detecting AEs and SAEs
Original text:
From the time a subject consents to participate in and completes the study (See Section 4.4), 
all SAEs assessed as related to study participation (e.g., protocol-mandated procedures, 
invasive tests, or change in existing therapy) or related to GSK concomitant medication, will 
be reported promptly to GSK as indicated in Table 7.
SAEs will not be reported after subsequent anti-NHL therapy is initiated.
Specific attention will be paid to monitor infusion reactions, tumor lysis syndrome, infections 
and progressive multifocal leukoencephalopathy (PML) (please refer to the SPM for more 
detail). 
If a subject converts to HBV DNA positive during the study, Hepatitis B treatment may be 
initiated by the site investigator after consultation with the GSK medical monitor.
Text changed to:
From the time a subject consents to participate in and completes the study (See Section 4.4), 
all SAEs assessed as related to study participation (e.g., protocol-mandated procedures, 
invasive tests, or change in existing therapy) or related to GSK concomitant medication, will 
be reported promptly to GSK as indicated in Table 7.
SAEs will not be reported after subsequent anti-NHL therapy is initiated.
Specific attention will be paid to monitor infusion reactions, tumor lysis syndrome, 
infections and progressive multifocal leukoencephalopathy (PML) (please refer to the 
SPM for more detail). 
Subjects that are HBsAG negative, HBcAb positive and HBV DNA negative may be 
included in the study but must undergo HBV DNA monitoring. Prophylactic antiviral 
therapy may be initiated at the discretion of the investigator. If a subjects’ HBV DNA 
becomes positive during the study, the investigator should manage the clinical situation 
as per the standard of care of that institution, and the GSK medical monitor should be 
notified. The risks and benefits of continuing ofatumumab or discontinuing ofatumumab 
should be discussed with the medical monitor before appropriate treatment decisions 
are made for that individual subject.
Rationale for change:  Hepatitis B reactivation may be associated with anti-CD20 mAb 
infusion.  
Section 6.7:
Pharmacokinetics (PK)
Original text:


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Blood samples will be collected from subjects receiving ofatumumab and bendamustine 
combination therapy predose and 0.5 h after the end of the ofatumumab infusion and prior to 
bendamustine administration on Day 2 in treatment Cycle 1 and Cycle 4, if bendamustine is 
administered on Days 2 and 3 in Cycle 1 or Cycle 4, an additional sample should be collected 
prior to bendamustine administration on Day 3.  In addition, predose samples will be collected 
prior to ofatumumab administration at Cycles 2, 3, 5, and 6.  Samples will also be collected at 
1, 3, and 6 months post-treatment.  The actual date and time of each sample collection will be 
recorded in the eCRF.
Table 7 provides the pharmacokinetic sample collection schedule.
TABLE 7
OFATUMUMAB PHARMACOKINETIC SAMPLE COLLECTION SCHEDULE 
(FOR SUBJECTS IN THE OFATUMUMAB-BENDAMUSTINE ARM ONLY)
Cycle
Cycle Day
Sampling time relative to ofatumumab infusion
1
1
Predose, 0.5 h post-end of infusion (EOI)
1
2
Prior to bendamustine administration
1
3
Prior to bendamustine administration1
2
1
Predose
3
1
Predose
4
1
Predose, 0.5 h post-EOI
4
2
Prior to bendamustine administration
4
3
Prior to bendamustine administration1
5
1
Predose
6
1
Predose
1 month after last dose2,3
3 months after last dose2,3
6 months after last dose2,3
1.
Collect sample only if subject receives bendamustine on Day 3 of the cycle
2.
Collect sample at any convenient time on study day.
3.
Collect sample relative to last dose of ofatumumab regardless of number of cycles.
Sample collection, processing, and shipping instructions are provided in the study procedures 
manual.
Text changed to:


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Blood samples will be collected from subjects receiving ofatumumab and bendamustine 
combination therapy predose, at the end of the ofatumumab infusion (immediately prior 
to stopping the infusion, and 1 h after the end of the ofatumumab infusion and prior to 
bendamustine administration on Day 2 in treatment Cycle 1, Cycle 4, and Cycle 7; if 
bendamustine is not administered in Cycle 4 or Cycle 7, the Day 2 ofatumumab 
pharmacokinetic sample may be omitted.  If bendamustine is administered on Days 2 and 3 
in Cycle 1, Cycle 4 or Cycle 7, an additional sample should be collected prior to 
bendamustine administration on Day 3.  In addition, predose samples will be collected prior to 
ofatumumab administration at Cycles 2, 3, 5, 6, 8,9, 10, and 11. Samples will be collected 
prior to and at the end of the ofatumumab infusion at dose 12. Samples will also be 
collected at 1, 3, and 6 months post-treatment.   Samples will also be collected at 1, 3, and 6 
months post-treatment.  The actual date and time of each sample collection will be recorded in 
the eCRF.
Table 7 provides the pharmacokinetic sample collection schedule.


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TABLE 7
OFATUMUMAB PHARMACOKINETIC SAMPLE COLLECTION SCHEDULE 
(FOR SUBJECTS IN THE OFATUMUMAB-BENDAMUSTINE ARM ONLY)
Cycle
Cycle Day
Ofatumumab 
Dose
Sampling time relative to ofatumumab 
infusion
1
1
1
Predose, end of infusion (EOI), 1 h post-
EOI
1
2
Prior to bendamustine administration
1
3
Prior to bendamustine administration1
2
1
2
Predose
3
1
3
Predose
4
1
4
Predose, EOI, 1 h post-EOI
4
2
Prior to bendamustine administration2
4
3
Prior to bendamustine administration1,2
5
1
5
Predose
6
1
6
Predose
7
1
7
Predose, EOI, 1 h post-EOI
7
2
Prior to bendamustine administration2
7
3
Prior to bendamustine administration1,2
8
1
8
Predose
9
Predose
10
Predose
11
Predose
12
Predose, EOI
1 month after last dose3,4
3 months after last dose3,4
6 months after last dose3,4

Collect sample only if subject receives bendamustine on Day 3 of the cycle

Collect sample only if bendamustine is administered

Collect sample at any convenient time on study day.

Collect sample relative to last dose of ofatumumab regardless of number of cycles.
Sample collection, processing, and shipping instructions are provided in the study procedures 
manual.


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Section:  8.2:
Study Design Considerations
Original text:
An ‘adaptive-like’ study design is being implemented for this study to take into consideration 
the possibility of a dosing-change recommendation after an independent review for safety and 
tolerability.  Primary efficacy and safety analyses will be conducted on the ‘final’ stage data 
set.  Supplementary efficacy and safety analyses will also be conducted on the cumulative 
data set if a dosing-change recommendation occurs.

Stage 1 will consist of the 40 subjects included in the Dose Confirmation Cohort and 
any additional subjects randomized prior to the implementation of an IDMC 
recommended dosing change.

If no IDMC dosing change is implemented, Stage 1 will continue through the 
remainder of the study and will comprise the final analysis set.

If an IDMC dosing change is implemented, Stage 2 will begin with subjects 
randomized thereafter.  The sample size and event count will restart at this point.   
Subjects enrolled in stage 2 will comprise the final analysis set.  Analysis of the 
cumulative set (subjects from Stage 1 and Stage 2) will be supplementary.
Text changed to:
An ‘adaptive-like’ study design is being implemented for this study to take into consideration 
the possibility of a dosing-change recommendation after an independent review for safety and 
tolerability.  Primary efficacy and safety analyses will be conducted on the ‘final’ stage data 
set.  Supplementary efficacy and safety analyses will also be conducted on the cumulative 
data set if a dosing-change recommendation occurs.

Stage 1 will consist of the 40 subjects included in the Dose Confirmation Cohort and 
any additional subjects randomized prior to the implementation of an IDMC 
recommended dosing change.

If no IDMC dosing change is implemented, Stage 1 will continue through the 
remainder of the study and will comprise the final analysis set.

If an IDMC dosing change is implemented, Stage 2 will begin with subjects 
randomized thereafter.  The sample size and event count will restart at this point.   If 
no further dosing change is implemented, subjects enrolled in stage 2 will 
comprise the final analysis set.  Analysis of the cumulative set (subjects from Stage 1 
and Stage 2) will be supplementary.

If an additional IDMC dosing change is implemented, Stage 3 will begin with 
subjects randomized thereafter.  The sample size and event count will restart at this 
point.  Subjects enrolled in stage 3 will comprise the final analysis set.  Analysis of 
the cumulative set (subjects from Stages 1-3) will be supplementary.


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Section:  8.2.1:
Sample Size Assumptions
Original text:
The primary endpoint is PFS and the analysis will be conducted using stratified log-rank test.  
The following assumptions are made in the estimation of the required sample size:
Event times are exponentially distributed
A median PFS for bendamustine is 9 months.
A median PFS for ofatumumab + bendamustine is 13.5 months
A 1:1 stratified randomization scheme
A 80% chance of successfully declaring a difference in the presence of a true underlying 
difference (power) 
A 5% two-sided risk of erroneously claiming a difference in the presence of no true 
underlying difference 
Accrual rate is 6 subjects per month 
Under the above assumptions, approximately 192 total events from both treatment arms 
combined are needed for the study to have 80% power.  With a sample size of 238 subjects, 
the duration of the study will be about 51 months (under H1) to obtain the 192 total events.  
Assuming a dropout rate of 10%, the total sample size randomized for both arms combined 
will be 266 subjects, with approximate study duration of 56 months.
Assuming a screening failure rate of 10%, the total number of subjects screened will be 
approximately 296.
As stated, this trial is an event-driven study design with an event-driven sample size of 192
total events and the final analysis will take place at the time of occurrence of the 192nd event. 
The guideline for the study reaching 192 total events with respect to previously stated 
assumptions involve screening of 296 subjects so as to have 266 subjects randomized and to 
have a study duration of about 56 months from the first day of first subject until the time of 
the 192nd event.
Text changed to:
The primary endpoint is PFS and the analysis will be conducted using stratified log-rank test.  
The following assumptions are made in the estimation of the required sample size:

Event times are exponentially distributed

A median PFS for bendamustine is 9 months.

A median PFS for ofatumumab + bendamustine is 13.5 months

A 1:1 stratified randomization scheme

A 90% chance of successfully declaring a difference in the presence of a true underlying 
difference (power) 

A 5% two-sided risk of erroneously claiming a difference in the presence of no true 
underlying difference 

Accrual rate is 6 subjects per month 


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Under the above assumptions, approximately 256 total events from both treatment arms 
combined are needed for the study to have 90% power.  With a sample size of 304 subjects, 
the duration of the study will be about 62 months (under H1) to obtain the 256 total events.  
Assuming a dropout rate of 10%, the total sample size randomized for both arms combined 
will be 338 subjects, with approximate study duration of 68 months.
Assuming a screening failure rate of 10%, the total number of subjects screened will be 
approximately 376.
As stated, this trial is an event-driven study design with an event-driven sample size of 256
total events and the final analysis will take place at the time of occurrence of the 256th event. 
The guideline for the study reaching 256 total events with respect to previously stated 
assumptions involve screening of 376 subjects so as to have 338 subjects randomized and to 
have a study duration of about 68 months from the first day of first subject until the time of 
the 256th event.
Rationale for change:  Reflects increase from 80% to 90% power in study.
Section:  8.2.2:
Sample Size Sensitivity
Original text:
The robustness and sensitivity of the above sample size calculation is considered in order to 
assess the impact on power should the assumed median PFS vary.  The following table shows 
the estimated power for different median values of PFS for ofatumumab + bendamustine. The 
total number of events is 192, and the number of subjects is 238.
TABLE 10
PRIMARY ENDPOINT POWER CALCULATION
Median PFS for Ofatumumab  + 
Bendamustine
Median PFS for Bendamustine
Estimated Power
12
9
0.52
13
9
0.72
13.5
9
0.80
14
9
0.86
15
9
0.93
Text changed to:
The robustness and sensitivity of the above sample size calculation is considered in order to 
assess the impact on power should the assumed median PFS vary.  The following table shows 
the estimated power for different median values of PFS for ofatumumab + bendamustine. The 
total number of events is 256, and the number of subjects is 304.
TABLE 10
PRIMARY ENDPOINT POWER CALCULATION
Median PFS for Ofatumumab  + 
Bendamustine
Median PFS for Bendamustine
Estimated Power
12
9
0.64
13
9
0.83
13.5
9
0.90
14
9
0.94
15
9
0.98


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Rationale for change:  Reflects increase from 80% to 90% power in study.
Section:  8.3.1.1:
Four populations are defined for the analysis
Original text:
1.
The Intent-to-Treat (ITT) Population will include subjects in the final analysis stage 
who are randomized to the study drugs.  This will be the primary population used for 
all efficacy assessments.   In the analyses, subjects will be grouped based on how 
they are randomized regardless of which treatment they received. The ITT 
population will also be used for all Patient Reported Outcomes (PRO) analyses.  
2.
The Safety Population will include subjects in the final analysis stage who receive at 
least one dose of a study drug.  This population will be used for all safety 
measurements. In the analyses, subjects will be grouped based on the treatment they 
receive regardless of how they are randomized.
3.
The Safety Population (Dose Confirmation Cohort) will include the first 40 subjects 
who receive at least one dose of study drug.  This population will be used to assess 
the safety and tolerability in the Dose Confirmation Cohort analysis of the study by 
the IDMC.  In the analyses, subjects will be grouped based on the treatment they 
receive regardless of how they are randomized
4.
The Per Protocol (PP) Population will exclude subjects with major protocol 
deviation that will impact the efficacy outcome.  The Per Protocol Population will be 
used in the primary endpoint analysis to check the robustness of the result when 
using the ITT population.   However, if the number of subjects in the PP population 
is not more than 10% smaller than the ITT population, the analysis will not be 
performed. 
Text changed to:
1.
The Intent-to-Treat (ITT) Population will include subjects in the final analysis stage 
who are randomized to the study drugs.  This will be the primary population used for 
all efficacy assessments.   In the analyses, subjects will be grouped based on how 
they are randomized regardless of which treatment they received. The ITT 
population will also be used for all Patient Reported Outcomes (PRO) analyses.  
2.
The Safety Population will include subjects in the final analysis stage who receive at 
least one dose of a study drug.  This population will be used for all safety 
measurements. In the analyses, subjects will be grouped based on the treatment they 
receive regardless of how they are randomized.
3.
The Safety Population (Dose Confirmation Cohort) will include the first 20 subjects 
in Arm A who complete bendamustine therapy or receive at least 3 cycles of 
bendamustine.  This population will be used to assess the safety and tolerability in 
the Dose Confirmation Cohort analysis of the study by the IDMC.  In the analyses, 
subjects will be grouped based on the treatment they receive regardless of how they 
are randomized. If an additional IDMC review is required, then a second Dose 


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Confirmation Cohort will be created to capture the 20 subjects included in the 
subsequent IDMC review.
4.
The Per Protocol (PP) Population will exclude subjects with major protocol 
deviation that will impact the efficacy outcome.  The Per Protocol Population will be 
used in the primary endpoint analysis to check the robustness of the result when 
using the ITT population.   However, if the number of subjects in the PP population 
is not more than 10% smaller than the ITT population, the analysis will not be 
performed. 
Section 8.3.3.1:
Primary Comparisons of Interest
Original text:
The primary treatment comparison of interest will be ofatumumab + bendamustine vs. 
bendamustine. This will be based on comparing the overall progression-free survival (PFS) 
when the total number of events reaches 192 total events (from both arms) using the ITT 
population.
Text changed to:
The primary treatment comparison of interest will be ofatumumab + bendamustine vs. 
bendamustine. This will be based on comparing the overall progression-free survival (PFS) 
when the total number of events reaches 256 total events (from both arms) using the ITT 
population.
Rationale for change:  Reflects increase from 80% to 90% power in study.
Section 8.3.4:
Interim Analysis
Original text:
A safety and tolerability analysis is planned after 40 subjects have completed 6 cycles of 
treatment and is described in Section 3.1.3.  If a dosing change is required, an additional 
review of safety and tolerability may be conducted after 20 subjects have completed 6 cycles 
of treatment on the new regimen.  This process is described in Section 3.1.3 and will be 
further detailed in a charter for the IDMC.
Text changed to:
A safety and tolerability analysis is planned after 20 subjects have completed 3 cycles (or 
completion of bendamustine therapy) of treatment in Arm A. If a dosing change is 
required, an additional review of safety and tolerability may be conducted after 10 
subjects in Arm A have completed 3 cycles (or completion of bendamustine therapy) on 
the new regimen.  Available data for Arm B may be provided to the IDMC at the time of 
their assessments.  This process is described in Section 3.1.3 and will be further detailed 
in a charter for the IDMC.
Section 8.3.5.2:
Safety Evaluation
Original text:
After 40 subjects have been treated for 6 cycles, an analysis to assess safety and tolerability 
will be conducted.  A charter will detail the types of analyses, rules for modifying treatment 
course, and the membership and conduct of the IDMC.


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Text changed to:
After 20 subjects have been treated for 3 cycles (or completion of bendamustine therapy), 
an analysis to assess safety and tolerability will be conducted.  A charter will detail the types 
of analyses, rules for modifying treatment course, and the membership and conduct of the 
IDMC.
Section 8.3.5.4:
Efficacy Analyses
Original text:
Text changed to:
Section 9.7:
Independent Data Monitoring Committee (IDMC)
Original text:
An IDMC will be utilized in this study to ensure external objective medical and/or statistical 
review of safety issues in order to protect the ethical and safety interests of subjects and to 
protect the scientific validity of the study.  The schedule of any planned interim analysis and 
the analysis plan for IDMC review is described in the in the charter, which is available upon 
request.
Forty subjects (20 per treatment arm) will comprise an initial dose confirmation cohort.  The 
IDMC will compare Arm A (O+B) and Arm B (B) to assess the safety and tolerability of 
ofatumumab (1000 mg Day 1; q21 days) and bendamustine (90 mg/m2 Days 1, 2; q21 days).  
The IDMC will confirm or reject the notion that the Arm A utilizes a safe bendamustine dose.  
They will base this decision on a rule described in the IDMC charter.  This rule will take into 
account observed toxicities associated with bendamustine monotherapy in Arm B.  The IDMC 
will have the option to decrease the bendamustine dose and/or lengthen the cycle duration
from 21 to 28 days in Arm A for improved safety and tolerability.
Text changed to:
An IDMC will be utilized in this study to ensure external objective medical and/or statistical 
review of safety issues in order to protect the ethical and safety interests of subjects and to 
protect the scientific validity of the study.  The schedule of any planned interim analysis and 
the analysis plan for IDMC review is described in the charter, which is available upon request.
Twenty subjects in Arm A will comprise an initial dose confirmation cohort.  In addition, 
available data from Arm B will be provided.  The IDMC will assess Arm A (O+B) for the 
safety and tolerability of ofatumumab (1000 mg Day 1; q21 days) and bendamustine (90 


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mg/m2 Days 1, 2; q21 days), 3 cycles (or completion of bendamustine therapy).  The IDMC 
will confirm or reject the notion that the Arm A utilizes a safe bendamustine dose.  They will 
base this decision on a rule described in the IDMC charter.  The IDMC will have the option to 
decrease the bendamustine dose and/or lengthen the cycle duration from 21 to 28 days in Arm 
A for improved safety and tolerability.
STAGE 1:

If the safety and tolerability of Arm A is confirmed by the IDMC (Stage 1), the 
study will continue to enrol until completion in order to compare progression-
free survival between Arm A and Arm B. 

If the IDMC decides to modify the bendamustine dosing schedule in Arm A, 
Stage 2 will begin and this modified treatment schedule (bendamustine 90 mg/m2
Days 1 and 2, every 28 days, up to 8 cycles) will be used in Arm A for the 
remainder of the study.  
STAGE 2:
a. If an IDMC cycle change is implemented, the sample size and event count will restart 
at this point, and subjects enrolled in Stage 2 will comprise the final analysis set.  
Analysis of the cumulative set (subjects from Stage 1 and Stage 2) will be 
supplementary.
b. If the IDMC modifies the treatment schedule in Arm A, the IDMC will assess the 
modified treatment schedule (bendamustine 90 mg/m2 Days 1 and 2, every 28 days, 
up to 8 cycles) after 10 subjects in Arm A are treated at this schedule for 3 cycles (or 
until bendamustine completion if less than 3 cycles).  If the IDMC confirms the safety 
of bendamustine 90 mg/m2 Days 1 and 2, every 28 days, in Arm A then, Stage 2 will 
proceed without further dose modification in Arm A.  

If the IDMC deems that toxicity remains excessive, the IDMC will have the option to 
reduce the bendamustine dose in Arm A to 70 mg/m2; Days 1 and 2, every 28 days 
(up to 8 cycles).  This will be Stage 3.  


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STAGE 3:

The IDMC will then assess the modified treatment schedule (bendamustine 70 
mg/m2 Days 1 and 2, every 28 days, up to 8 cycles) after 10 subjects in Arm A are 
treated at this schedule for 3 cycles (or until completion of bendamustine therapy if 
less than 3 cycles).  

If the IDMC deems that bendamustine 70 mg/m2 Days 1 and 2, every 28 days, up to 
8 cycles in Arm A is safe, then no further dose modification in Arm A will occur.  

If the IDMC decides that bendamustine 70 mg/m2 Days 1 and 2, every 28 days, up to 
8 cycles, in Arm A is excessively toxic, the IDMC will have the option to close this 
study.
Rationale for change:
Reflects change to using up to 8 cycles of therapy.


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11.10
Appendix 10:  General Protocol Changes for Amendment 2 (12-
May-2010) from Amendment 1 (dated 16-NOV-2009)
WHERE THE AMENDMENT APPLIES
Amendment 2 is applicable to all study sites.
SUMMARY AND RATIONALE FOR AMENDMENT CHANGES 
IMPLEMENTED THROUGHOUT AMENDMENT 2
ADMINISTRATIVE CHANGES
Due to administrative changes within GSK, appropriate revisions were made to the Medical 
Monitor contact information to reflect personnel updates and organizational restructuring.
INITIAL INFUSION FOR OPTIONAL OFATUMUMAB
Subjects in Arm B who choose to receive optional ofatumumab monotherapy will receive 
ofatumumab 1000 mg for the first dose.
VISIT WINDOWS
On Days 84, 168, 252 (±7 days).
Visit window between cycles specified:  ofatumumab and bendamustine must be given 
consecutively.  A visit window of “on or within 7 days after” will be allowed between cycles
In Appendix 3, weekly intervals will be a minimum of 7 days with a ±1 day window around 
each visit.
CT SCANS
CT scans (contrast imaging of neck (when lesion is palpable), thorax, abdomen, pelvis; may 
be whole body CT scan or according to SOC).  Only in the event when whole body CT scan is 
not available, then  contrast imaging of neck, thorax, abdomen, pelvis, and any areas with new 
lesions may be done.
COMPLETE REMISSION
Physical exam of spleen and liver will not be part of this response assessment.
PRO
FACT-G was removed since the questions are incorporated into Version 4 of FACT-Lym.  
FACT-Lym TOI was removed.  This is an analysis that combines 2 different PRO 
questionnaires and does not require a separate questionnaire.  Therefore, it was removed.


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HACA
Test is done at before initial ofatumumab infusion in Arm A and for subjects that select 
optional ofatumumab.  HACA is considered an exploratory prognostic marker.
PK
Additional samples for subjects that select optional ofatumumab.  Reflected in time and 
events table in Appendix 3 and in Section 6.7.
Time and Events Tables, Appendix 1, Appendix 2, and Appendix 3:
Entire tables were updated.  Updated to reflect study changes (HAHA, PK) and to add clarify 
items such as frequency of pregnancy testing, time windows around CT scans, and time 
window between cycles.
Major changes include:
In Appendix 1 and Appendix 2:  If bendamustine cannot be given on the Day 1, the day of 
ofatumumab infusion, bendamustine may be administered on Days 2 and 3 of each cycle.  In 
the event the 1st infusion of bendamustine is on Day 2 of a cycle, then PK (see Table 9 for 
details) and assessments required for Day 1 (except i.e. HAHA, Ig, flow cytometry, etc) will 
be done on Day 2 and the assessments required for Day 2 will now be done on Day 3.  

Appendix 1:

1 month follow-up column added.  Provide more clarity than before where it was 
merely mentioned in a footnote

Time window changes reflected in table

Addition of lymphoma disease symptoms when CT scans are done

Appendix 2:  

Addition of HACA test before the 1st dose of ofatumumab.  Will be a prognostic 
marker

ß2 microglobulin row added.  Provides more clarity than before where it was merely 
mentioned in a footnote and in the protocol text as being part of the FLIPI-2 
prognostic marker

1 month follow-up column added.  Provides more clarity than before where it was 
merely mentioned in a footnote

Frequency of pregnancy testing updated for those with child bearing capacity

Time windows reflected in table

PK and HAHA added at withdraw and PD

Appendix 3:

Time windows changes reflected in table


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
Addition of PK sampling

Addition of HACA test before the 1st dose of ofatumumab.

Initial dose of ofatumumab is 1000 mg and not 2000 mg

Frequency of pregnancy testing updated for those with child bearing capacity

PK and HAHA added at withdraw and PD
STUDY SCHEMATICS UPDATED TO REFLECT PROTOCOL UPDATES
Figure 2 specifies that PD must be confirmed by an IRR before receiving ofatumumab 
following PD in Arm B and 1000 mg will be administered as the first ofatumumab 
monotherapy infusion.
REFERENCES UPDATED
Investigator Brochure update (28 April 2010); Kahl, 2010; Byrd 2001, and Weirda, 2010
references added.  WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues 
updated to 4rth edition, 2008.
SPECIFIC PROTOCOL CHANGES FOR AMENDMENT 2 (12-MAY-2010) FROM 
AMENDMENT 1 (DATED 16-NOV-2009)
LIST OF SPECIFIC CHANGES
Note:  deleted language is presented with a strikethrough and added language is printed in 
bold.
EXAMPLE:
Section:
Throughout Document
Original text:
Patient
Text changed to:
Subject
Rationale for Change:
For consistent use of terminology throughout the document.  Amended in appropriate 
document sections.


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Section:
Sponsor Information Page
Original text:
Medical Monitor Contact Information:
Telephone: 
Text changed to:
Medical Monitor Contact Information:
Telephone: 
Section 1.3:
Ofatumumab
Additional text:
The pivotal trial Study Hx-CD20-406 in subjects with fludarabine-refractory CLL 
[refractory to both fludarabine and alemtuzumab (n=59) or refractory to fludarabine 
and with bulky lymphadenopathy for whom alemtuzumab is not suitable (n=79)] 
evaluated 300 mg + 7 x 2000 mg for eight weekly doses, followed by four monthly 2000 
mg doses.  An objective response rate of 58% consisting of partial responses (PR) was 
achieved in the fludarabine and alemtuzumab refractory group with a median 
progression-free survival of 5.7 months. Similarly, in the bulky fludarabine refractory 
group with a similar unmet medical need, an objective response rate of 47% was 
achieved, including 1 complete response (CR), with all other responses being partial 
responses (PR).  The median PFS in the bulky fludarabine refractory group was 5.9 
months.  In this study, ofatumumab was generally well tolerated.  The most frequently 
reported adverse events (>15% frequency) were pyrexia, diarrhea, fatigue, cough, 
neutropenia, anemia and pneumonia. There were no unexpected safety findings [Wierda, 
2010].  The results of this pivotal study served as the basis for the grant of accelerated 
approval by the FDA for ofatumumab (ARZERRA) for the treatment of patients with 
CLL refractory to fludarabine and alemtuzumab (DR population) in October 2009.
Rationale:  To explain the rationale of using 2000 mg ofatumumab for subjects developing 
progressive disease in the bendamustine monotherapy arm (Arm B)
Deleted text:
Only two subject were treated in the 500 mg group.
Rationale: deleted repeated information.
Section 2: Objectives
Original Text and Text changed to:
Secondary objectives:

To evaluate and compare known and exploratory prognostic markers and their 
correlation with clinical responses in subjects treated with ofatumumab and 
bendamustine compared to those treated with bendamustine monotherapy (i.e. ALC, 
FcR gamma 3A, HACA)


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Section 3.1.1:
Screening Phase
Original Text and Text changed to:

A bone marrow aspirate and biopsy will be required at screening if results are not 
available from a prior bone marrow aspirate and biopsy performed within 8 weeks 
prior to randomization. Results may be provided in the form of a bone marrow 
biopsy report when a previous aspirate and biopsy are not available as long as 
the report was based on the biopsy done within 8 weeks prior to randomization.  
To confirm that disease has not transformed to a Diffuse Large B-cell Lymphoma, an 
incisional or excisional lymph node biopsy of accessible adenopathy is highly 
recommended.  In less accessible lymph nodes, 4 to 8 core biopsies are 
recommended, but not required. If the investigator has clinical suspicion that the 
protocol candidate has transformed disease, the investigator should not consider that 
subject for the trial. 

Bone marrow aspirate, biopsy, and lymph node pathology report including details 
confirming CD20+ tumor status will be sent to GSK along with tissue or slides for 
central review.  Please see SPM for details.

Blood samples, physical examination, and whole body CT imaging (with contrast 
imaging of the neck, thorax, abdomen, and pelvis) (with contrast imaging of 
thorax, abdomen, and pelvis) will be provided to determine baseline disease and 
study eligibility

Rationale:  To provide clarity.
Section 3.17:
Study Endpoints
Additional Text:
Secondary Endpoints
Known and Exploratory Prognostic markers Correlating with Response

Baseline FLIPI (FLIPI-1 and FLIPI-2)

Baseline Absolute Lymphocyte Count (ALC)

FcR gamma 3A

Human Anti-Chimeric Antibodies (HACA),


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SECTION 3.2.2:
OFATUMUMAB DOSING WHEN ADMINISTERED WITH
BENDAMUSTINE
Text Added:
An important safety factor of any antibody therapy concerns infusion reaction, 
particularly following intravenous administration.  Both the proportion of patients 
experiencing infusion reactions to rituximab and the severity of the reactions are higher 
for the first infusion than for subsequent infusions [Chung, 2008]. Early experience with 
ofatumumab showed a similar pattern of infusion reactions [Coiffier, 2008; Hagenbeek, 
2008], and a first infusion dose of 300 mg was therefore adopted in all studies in the 
ofatumumab development program to minimise first dose infusion reaction.  However, 
upon further review of the data collected in the phase I/II study of ofatumumab in 
patients with relapsed or refractory follicular lymphoma grade I-II (Study Hx-CD20-
001), no clinically significant  differences in the severity or frequency of adverse events 
were  observed.  As a result, the median duration of the first infusion and the number of 
infusion reactions between patients with FL receiving ofatumumab at doses of 300 mg, 
500 mg, 700 mg, or 1000 mg, including ofatumumab doses of up to 1000 mg did not 
differ significantly.   [OFATUMUMAB, 2011; Hagenbeek, 2008]. Thus, the use of 1000 
mg at first infusion is proposed in study OMB110918.
Rationale:  Provides additional rationale for 1000 mg initial infusion.  Also clarifies there was 
little difference between dose cohorts regarding infusion time and infusion reactions upon 
initial infusion.
Section 3.2.2.1:
Ofatumumab monotherapy for subjects who progress in 
Arm B
Text Added:
Infusion reactions occur more frequently at the initial infusion. Patients with indolent 
NHL are less likely to have severe infusion toxicity than CLL patients because they do 
not have circulating peripheral blood tumor cells which react with antibody.
To date, no subjects have received 2000 mg as the initial dose, while subjects with 
follicular lymphoma received an initial infusion of 1000 mg in Study Hx-CD20-001.  
Thus, a first dose of 1000 mg will be used in Arm A (Appendix 1, Section 3.1.4) and for 
subjects that progress on Arm B and select optional ofatumumab (Appendix 3, Section 
3.1.6).  Study Hx-CD20-001 infused a 2 mg/mL concentration of ofatumumab at an 
initial rate of 25 mL/hr.  Due to the observed tolerability associated with this 
concentration and rate, Study OMB110918 will infuse ofatumumab (2 mg/mL) at a 
starting rate of 25 mL/hr for infusions that follow the initial infusion for subjects that 
select ofatumumab following PD in Arm B (Appendix 3, Section 3.1.6).
Rationale:  Clarifies rationale for infusion of 2000 mg (2 mg/mL) at 25 mL/hr.
Section 4.2:
Inclusion Criteria
Original Text 
Inclusion criteria 1:  Indolent lymphoma including grades 1-3a follicular, small lymphocytic, 
lymphoplasmacytic, and marginal zone lymphoma; stages III-IV, or bulky disease stage II (i.e. 
as any single mass > 5 cm in any direction) defined according to WHO guidelines [WHO, 
2001]


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Text Changes:
Inclusion criteria 1:  Small lymphocytic, lymphoplasmacytic, marginal zone lymphoma, and 
follicular lymphoma (FL); grades 1, 2 and 3A, defined according to WHO guidelines.

Rationale:  Expands patient population.
Section 4.2:
Inclusion Criteria
Inclusion criteria 2:  Indolent B-cell NHL that remains stable or unresponsive during or 
within 6 months of treatment with rituximab or a rituximab-containing regimen (See Section 
6.2.5.5):

Maintaining stable disease or failure to achieve PR to rituximab-based therapy. (CT 
imaging will support this finding, and will be performed at least 30 60days after the 
last dose of rituximab-based therapy)

or,

disease progression while on rituximab-based therapy (e.g., includes 4 weekly 
courses of rituximab given at 6-week month intervals [Hainsworth, 2005])

or,

disease progression in subjects with stable disease or better response to rituximab-
based therapy <6 months of the last dose of rituximab
Note:  Subjects must have received at least 4 infusions of rituximab (either as monotherapy or 
in combination with any chemotherapy) a minimum of 4 rituximab infusions as 
monotherapy or 3 infusions as part of a rituximab-containing combination regimens.
Rationale: Expands patient population.


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Section 4.3:
Exclusion Criteria
Original Text and Text Change:
Exclusion criteria 3:  Previous autologous stem cell transplant, or fludarabine therapy, or 
radioimmunotherapy in the past 12 last 6 months
Exclusion criteria 5:  High dose steroids ≥ 60 100 mg prednisone/day (or equivalent) for 7 
consecutive days, given as concomitant medication, within 3 months of prior to randomization. 
No more than 10  mg prednisone daily at the time of randomization
Exclusion criteria 7:  Treatment with anti-CD20 monoclonal antibody within 3 months of 
randomization.  Prior treatment with anti-CD20 monoclonal antibody, if 1st dose was 
administered within 60 days prior to randomization. Prior use of any monoclonal antibody 
(other than anti-CD20) within 3 months prior to randomization.
Exclusion criteria 20:  Treatment with anti-CD20 monoclonal antibody within 3 months of 
randomization
Exclusion criteria 15:  Current active liver or biliary disease (subjects with  Gilbert’s 
syndrome or asymptomatic gallstones, liver metastases related to indolent NHL or otherwise 
stable chronic liver disease per investigator assessment)
Exclusion criteria 17:  Screening laboratory values:

platelets < 100 x 109/L (unless due to indolent lymphoma involvement of the bone 
marrow)

neutrophils < 1.5 x 109/L (unless due to indolent lymphoma involvement of the bone 
marrow)

Serum creatinine > 1.5 times the institution’s upper limit of normal (ULN); subjects 
with a serum creatinine > 1.5 ULN will be eligible if the calculated creatinine 
clearance [Cockcroft, 1976] or creatinine clearance from a 24-hour urine collection 
is 40 mL/min.

Total bilirubin > 1.5 times ULN (unless due to liver involvement by FL or Gilbert’s 
disease) 

Transaminases > 3 times ULN.
Exclusion criteria 18:  Previous treatment or known or suspected hypersensitivity to 
ofatumumab, bendamustine, or mannitol
Exclusion criteria 21:         21  “as per local acceptable standards”
Rationale:  Expands patient population.  
For #3, the 12 month interval was overly cautious and would limit population.  The original 
intention of 12 months was to allow for bone marrow recovery.  Six months is sufficient for 
this to occur.
For #5:  30 mg may be administered as part of standard chemotherapy in this population.  We 
should not limit enrollment for those getting standard treatment.
For #7:  All of the subjects in this study will have rituximab prior to study entry.  A three 
month interval between last rituximab and first ofatumumab infusion would severely limit 
accrual.  Further evidence from a previous ofatumumab study (Hx-CD20-405) suggested that 


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the interval between last rituximab and first ofatumumab infusion did not correlate with 
response or lack of response.
For #20:  This criterion repeated #7.
For #15:  Clarification.
For #18:  There may be subjects with known bendamustine and mannitol sensitivity (per 
bendamustine product label).  Bendamustine vials contain mannitol.  We want to limit them 
into our study to minimize subjects who are hypersensitive to these agents.
For#21: To ensure that local acceptable standards are followed.
Section 4.4:
Withdrawal Criteria

Additional Text:  

HAHA and PK (as indicated in Appendix 2 and Appendix 3)
Rationale:  HAHA and PK were added at these time points to determine if HAHA is present 
and to assess if it potentially interfered with ofatumumab therapy.

Section 5.1.1:  Pre-medication

Allows this guidance for subjects receiving bendamustine, in addition to those 
receiving ofatumumab.
Section 5.1.2.1:
Ofatumumab Treatment Schedule

Original Text and Text Change:  

The starting rate of the initial infusion of 1000 mg (Section 3.1.4), or 2000 mg
(Section 3.1.6 and Appendix 3) ofatumumab (1.0 mg/mL) should be 12 mL/hour (hr). 
If no infusion reactions occur the infusion rate should be increased every 30 minutes, 
to a maximum of 400 mL/hr, according to Table 2. If this schedule is followed, the 
1000 mg infusion duration will be approximately 4.5 hours and the 2000 mg infusion 
duration will be approximately 6.5 hours.
Subsequent infusions of ofatumumab
If the previous infusion has been completed without grade ≥ 3 infusion-associated AEs, the 
subsequent infusion 1000 mg (Section 3.1.4, Appendix 1) or 2000 mg (Section 3.1.6 and
Appendix 3) ofatumumab (1.0 mg/mL or 2.0 mg/mL) can start at a rate of 25 mL/hr and 
should be doubled every 30 minutes up to a maximum of 400 mL/hr.
Rationale:  2000 mg dose no longer being used as initial infusion. The 2000 mg dose will be 
utilized for subsequent infusions if Arm B subjects with PD select optional ofatumumab.
Section 6.2.2:
CT Scans
Original Text and Text Change:
Whole body CT scans (with contrast of the neck (when lesion is palpable), thorax,
abdomen, and pelvis) (with contrast of the thorax, abdomen, and pelvis) will be performed
done as part of the efficacy evaluation and after treatment has been completed.  The scans 
must be performed implemented according to a CT scan manual to be provided to GSK as 
mentioned in the SPM.
In situations where progressive disease is apparent through physical examination (such 
as massive lymphadenopathy), only the body area where progressive disease is apparent 
will need to be scanned to confirm progressive disease.


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An Independent Radiology Review (IRR) will review the CT scans will be assessed
according to an independent review.  The independent review will be described in an 
independent review charter an independent radiology review charter, as described.  See
Section 6.2.6 for a description of this independent review.
Follow-up visits will begin on Day 336 (this is 3 months after Day 252) for both arms and 
continue during follow-up visits, or until initiation of alternative indolent lymphoma treatment 
or withdrawal (WD)
Rationale:  Specify preference for whole body CT scans with contrast of particular areas.  
Edited text for independent review for clarity.
Section 6.2.4:
Lymphoma Disease-Related Symptoms:
Entire Section Added:

Assessment for the presence of the following symptoms (done as per Appendix 1 and 
Appendix 3):

Night sweats due to lymphoma (not due to infection or treatment)

Fever due to lymphoma (not due to infection or treatment)

Loss of appetite due to lymphoma (not due to treatment)

Clinically significant weight loss, since the previous disease assessment, which is 
due to lymphoma (not due to treatment)

Fatigue due to lymphoma (not due to treatment)

Other symptoms due to lymphoma (not due to treatment)
Rationale:  Assessment of lymphoma-related symptoms is necessary for CR.  Therefore, these 
assessments must be done when response assessments are done.  These differ from 
constitutional symptoms assessments taken during the study.  Lymphoma disease-related 
symptoms must specifically be due to the lymphoma and cannot be due to infection or therapy.
Section 6.2.5:
Documentation of Target and Non-target Lesions
Added Text:
The definition of unequivocal progression of non-target disease is based on the definition 
applied in RECIST 1.1 [Eisenhauer, 2009] as an overall level of substantial worsening in 
non-target disease such that, even in the presence of SD or PR in target disease, the 
overall tumor burden has increased significantly to merit discontinuation of therapy, or
if therapy has already been completed, commencement of anti-cancer therapy.  A 
modest ‘increase’ in the size of one or more non-target lesions is usually not sufficient to 
qualify for unequivocal progression status.  The designation of progression solely on the 
basis of change in non-target disease in the face of SD or PR of target disease will 
therefore be extremely rare.


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Rationale:  Adds clarity by defining “unequivocal progression”.
Section 6.2.5.2:
Complete Remission (CR)
Original Text and Text Change:
1.
The spleen and/or liver, if considered enlarged due to lymphoma (nodules must be 
present) before therapy on the basis of a physical examination or CT scan should not 
be palpable on physical examination and should be considered normal size by 
imaging studies, and nodules related to lymphoma should disappear. However, 
determination of splenic involvement is not always reliable because a spleen 
considered normal in size may still contain lymphoma, whereas an enlarged spleen 
may reflect variations in anatomy, blood volume, the use of hematopoietic growth 
factors, or causes other than lymphoma.
Rationale:  Spleen and lymph nodes will be assessed by CT scan and not by physical exam.


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Section 6.2.5.5:
Relapsed Disease (after CR)/Progressive Disease (after PR, 
SD)
Original Text and Text Change:
Criteria for determining PD for new lesions and target lesions are shown n Table 7
TABLE 7
CRITERIA FOR DETERMINING PD FOR NEW LESIONS AND TARGET 
LESIONS
Nodes
Extranodal (‘liver/spleen’ & ‘other’ 
categories)
New node/lesiona
A previously normal node (≤1.5 x 
≤1.0 cm), including nodes that were 
not previously visible, must increase 
to >2.0 x ≥1.5 cm.
Any new lesion, irrespective of size, 
will be considered PD An 
unequivocal new lesion at a site 
where there was no disease at 
baseline, provided the lesion cannot 
be attributed to non-lymphoma-related 
causes.
Single node/lesion
Increase in PPD
≥ 50% increase from nadir of any 
previously involved node > 1.5 cm in 
the long axis at baseline  in the 
PPD of any target node.  The long 
axis must increase by at least 5 mm 
and to >2.0cm.
≥50% increase from nadir in the PPD 
of any target lesion, and at least a 5 
mm increase in either of the axes, and 
the lesion must be >1.5cm x ≥1.5 cm.
Increase in long axis
≥50% increase from nadir in the 
long axis of any previously involved 
node > 1.5 cm in the long axis at 
baseline  of any target node. The 
long axis must increase by at least 5 
mm and to >2.0 cm.
≥ 50% increase from nadir in the long 
axis of any target lesion, and at least 
a 5 mm increase in the long axis, and 
the lesion must be >1.5 cm x ≥1.5 cm.
Multiple nodes/lesions
Increase in SPD
≥50% increase from nadir in the 
SPD of target nodes and at least 
one node should have a long 
axis >1.5cm.
≥50% increase from nadir in the SPD 
of target lesions and at least one 
lesion should have a long 
axis >1.5cmb.

Table abbreviations:  PPD= product of perpendicular diameters; SPD= sum of the products of the greatest diameter. 
1.
Abnormal nodes/extranodal lesions present at baseline that normalize/resolve and then subsequently 
enlarge/relapse are not to be classified as new lesions.
2.
Requiring that one node is > 1.5 cm minimizes the risk of declaring PD based on small artifactual changes.
Rationale:  Provides further details.


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Unequivocal progression, as defined in Section 6.2.5, at a site of non-target disease, or 
unequivocal progression of the liver or spleen size (nodules must be present in the organ 
for unequivocal progression to be reported) will fulfill the criteria for PD.  
If the subject achieved a CR on protocol, histological confirmation of relapse is strongly 
recommended.
Section 6.2.6:
Independent Review of Disease Response Committee 
(IRC)
The study’s primary endpoint is to determine PFS as assessed through an independent 
review of the data based on the by the IRC according to the RRCML guidelines [Cheson, 
2007].  These response criteria are described in Section 6.2.  The operation and 
responsibilities for members of that are part of the IRC independent review is described in 
a separate charter.  The final determination of progression will be based on the evaluations by 
the independent reviewer(s) and will be used for the study’s efficacy analysis and submission 
to regulatory agencies.
Rationale:  Clarification.
Section 6.3.2:
Peripheral Blood Sampling for Hematology and 
Biochemistry

Original Text and Text Change:

A creatinine clearance will be calculated prior to drug bendamustine administration on 
Day 1 of each bendamustine cycle. (If a measured creatinine clearance is available, the 
measured creatinine clearance may be used).as shown in Appendix 2.  The Cockcroft-
Gault formula will be used to determine a calculated creatinine clearance:

Rationale:  Clarification when a calculated creatinine clearance will be done.
Section 6.3.4:
Peripheral Blood Sampling for Safety and Disease 
Status
Original Text and Text Changes:

Hepatitis B (HBV) and Hepatitis C (HCV) at screening.  Subjects receiving 
ofatumumab that are Hepatitis B core positive, Hepatitis B DNA should be obtained 
at each cycle visit while on treatment and then at 1,3,6 months post treatment.  See 
SPM for more details.

Screening pregnancy test (HCG) for women of childbearing potential, unless they 
have had a hysterectomy, have undergone tubal ligation within one year before the 
screening visit, or have been postmenopausal for at least one year.

Subsequent pregnancy testing in women of child bearing potential will be done as 
defined in Appendix 2

Human Anti-Human Antibody (HAHA) will be taken as defined in Appendix 2.  If 
receiving ofatumumab following PD in bendamustine monotherapy arm, HAHA will 
be taken as defined in Appendix 3


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
Human Anti-Chimeric Antibody (HACA) will be taken as defined in Appendix 2.  If 
receiving ofatumumab following PD in Arm B, HACA will be taken as defined in 
Appendix 3
Rationale: HACA testing added as part of amendment 2.  Pregnancy test requirements 
clarified.
Section 6.5.4:
Laboratory and Other Safety Assessment Abnormalities 
Reported as AEs and SAEs
Original Text and Text Changes:
B cell depletion, IgG below LLN, low CD19+ count, and hypogammaglobulinemia due to 
treatment with ofatumumab are not to be reported as an AE or SAE.
Rationale:  Ofatumumab mechanism is based on successful B cell depletion with expected B 
cell recovery.
Section 6.6.1:
Functional Assessment of Cancer Therapy – General 
Lymphoma (FACT-G) (FACT-Lym) Subscale
The FACT-G has previously been used to identify quality of life in other studies of indolent 
lymphoma subjects [Witzig, 2002a; Witzig, 2002b]. The FACT-G (FACT-General) was 
developed by the FACIT group for use in adults in a wide range of oncology clinical trial 
populations. The 27 items of the FACT-G are scored in the following domains: Physical 
Well-being (7 items), Social/Family Well-being (7 items), Emotional Well-being (6 items) 
and Functional Well-being (7 items). 
Subjects respond to the items on a five point Likert scale ranging from 0 ‘Not at all’ to 4 
‘Very much’.    Possible ranges of score are from 0 to 108. Subjects are asked to think back 
over the past week when responding to the items. The FACT-G is designed to be self-
administered but has also been validated in an interview format. It has been widely used in 
various oncology populations.  It is available in over 50 languages and higher scores indicate 
better PRO.  The FACT-G is widely used and has been well validated in a number of different 
cancer indications [Overcash, 2001; Winstead, 1997; Cella 1995].
Rationale:  FACT-G was integrated into FACT-Lym questions as part of FACT-Lym version 
4.
Section 6.7:
Added Text:
Section 6.7.1:
Sample Collection for Subjects in Arm A
A pharmacokinetic sample (and a HAHA sample) will be collected with other 
withdrawalwithdraw assessments for subjects who withdraw from treatment.  For subjects 
who experience progressive disease, a pharmacokinetic sample (and a HAHA sample) will be 
collected on one occasion after disease progression.


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Section 6.7.2:
Sample Collection for Subjects in Arm B With Disease 
Progression and Who Receive Ofatumumab Monotherapy
A pharmacokinetic sample (and a HAHA sample) will be collected with other withdrawal 
assessments for subjects who withdraw from treatment.  For subjects who experience 
progressive disease, a pharmacokinetic sample (and a HAHA sample) will be collected on one 
occasion after disease progression.  Table 10 provides a summary of the pharmacokinetic 
sample collection schedule for subjects that progress on Arm B and select ofatumumab 
monotherapy.
TABLE 10
PHARMACOKINETIC SAMPLE COLLECTION SCHEDULE FOR 
SUBJECTS THAT PROGRESS IN ARM B AND SELECT OFATUMUMAB 
MONOTHERAPY
Time
Ofatumumab Dose 
Sampling time relative to ofatumumab infusion
Week 1
1
Predose
Week 4
4
Predose, EOI
1st monthly dose
5
Predose
6th monthly dose
10
Predose, EOI
1 month after last ofatumumab infusion1,2
6 months after last ofatumumab infusion1,2

Note:  EOI is within 15 minutes prior to stopping infusion.
3.
Collect sample relative to last dose of ofatumumab regardless of number of cycles
4.
Collect sample at any convenient time on study day.
Rationale:  Additional HAHA and PK samples will be done at time of PD to determine if 
HAHA may be one potential reason for ofatumumab failure.  These tests will also be done at 
time of withdrawal so that an adequate number of subjects may be assessed for safety and PK 
of ofatumumab.


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Section 8.3.5.1:
Efficacy Analysis
Original Text and Updated Text:

Known and exploratory prognostic markers correlating with clinical response  
Cox regression will be used to explore the relationship between PFS and the following 
explanatory variables: treatment group, cytogenetics (analyzed by FISH) at baseline, Absolute 
Lymphocyte Count (ALC), thymidine kinase, soluble CD20 at baseline, Human anti-
chimeric antibodies (HACA) to rituximab. 

Human Anti-Chimeric Antibodies (HACA)
HACA results prior to ofatumumab administration will be listed.

Human Anti Human Antibodies (HAHA)

The change in HAHA titers from predose to post-baseline visits and the number and 
proportion of positive and negative results at each visit will be provided in patients 
who receive ofatumumab.  HAHA results and associated ofatumumab plasma 
concentration at each timepoint will be listed.  The change in HAHA titers from 
screening to post-baseline visits will be provided.  ANCOVA analysis will be conducted.
Rationale:  HACA testing added to this amendment.


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11.11
Appendix 11: Protocol Changes for Amendment 3 (19 JANUARY 
2012) from Amendment 2 (dated 12 MAY 2010)
General Protocol Changes for Amendment 3 (19-January-2012) from 
Amendment 2 (dated 12-May-2010)
Note:  Appendix 11 is meant to emphasize areas where major changes occurred.  You must 
refer to the final protocol in its entirety to see all final changes in Amendment 3.  The 
information in the protocol will always supercede information presented in Appendix 11.
Where the Amendment Applies
Amendment 3 is applicable to all study sites.
Summary and Rationale for Amendment Changes 
Administrative Changes
Bendamustine (LEVACT) was approved in EU.  This trade name is reflected in document 
along with the European Medicines Agency (EMA) approval.
Minor changes have been made throughout the protocol and the time and events tables for 
spelling, punctuation, general administrative changes, and consistency between sections.
List of Abbreviations
Changed to reflect proper abbreviation spelling.
Recruitment, Screen Failure Rate, and Drop-out Rate
The guideline for the study reaching 256 total events with respect to previously stated 
assumptions involve screening of 408 subjects so as to have 346 subjects randomized and to 
have a study duration of about 69 months from the first day of first subject until the time of 
the 256th event.
This change is reflected throughout the updated protocol.
Study Schematics
Updated to reflect change in study design, including follow-up frequency.
IDMC Decision on Dose Alteration in Arm A
Updates on this decision were made in Section:  3.1, Section 3.1.3, Section 8.2, and Section 
9.7.  Updates were made to reflect output of meeting.
The IDMC met after the first 20 subjects in Arm A received at least 3 cycles of OB.  Based on 
their review of the data as well as the IDMC charter defined criteria to alter the dose in Arm A, 
the final recommendation from IDMC was to not change the current dose regimen and 
therefore to allow the study to proceed unchanged.  Consequently, there will be no further 
IDMC meetings and no further dose modifications other than the protocol-directed dose 
reductions and delays already described in Section 5.1.3.1 of this protocol.  The safety of 
subjects enrolled in the study will continue to be monitored by GSK.
CT Scan Time Window
Updated to be + 7 days not ± 7 days.
Screening Time Window
Updated to be ≤21 days not ≤14 days.
Follow-Up Schedule


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Follow up (F/U) 1 begins on Day 336 post randomization and occurs every 3 months until 
Month 18 of the F/U phase.  F/U 2 follows F/U 1 and occurs every 12 months until Month 54 
of the F/U phase with one more visit on Month 60 of the F/U phase.  The last required CT 
scan will be done on Month 54 of the F/U phase.  Following Month 54, there will be a Month 
60 F/U visit without a required CT scan.   Outside the required CT scans within F/U, 
unscheduled CT scans will be done to confirm clinical signs or suspicion of progression.
This change was made throught the protocol.
References
Updated to reflect current Summary of Product Characteristics (SPC) and Prescribing 
Information (PI)
Clarification text
Clarification of “recommendations” versus “requirements” made throughout protocol. The 
word “should” has been replaced in protocol to offer clarity where needed.
Time and Events Tables (Appendix 1, Appendix 2 and Appendix 3) and other 
General Study Updates throughout Amendment 3

Tables and footnotes updated to reflect changes in protocol:

CT scan time window

No bone marrow aspirate

Screening is 21 days of dosing for Cycle 1, Day 1

Ofatumumab concentration assessed rather than pharmacokinetics (PK)

After 61 days of last treatment, all SAEs, regardless of causality, should be reported 
until the end of follow-up

Monthly ofatumumab dosing begins 28 days after Day 1 of the previous cycle in Arm 
A

CT scan may be whole body or per local practice

The F/U1 schedule, in both arms, begins on Day 336 (this is 3 months following Day 
252) and will continue every 3 months until Month 18 of the F/U phase.  There will be 
a ±7 day visit window around each visit.

The follow-up #2 schedule comes after the end of follow-up schedule #1 and 
continues until Month 54 of F/U phase.  The last required CT scan will be done on 
Month 54 of the F/U phase.  Following Month 54, there will be a Month 60 F/U visit 
without a required CT scan.   Outside the required CT scans within F/U, unscheduled 
CT scans will be done to confirm clinical signs or suspicion of progression

Subjects with PD, as confirmed by CT scan, will be followed for survival.  
Additionally, subjects without PD who stop protocol treatment and begin non-protocol 
treatment will go into Survival Follow-Up.  Survival follow-up visits will occur every 
3 months until Month 18 of F/U 1.  Following F/U 1, survival visits for F/U 2 will 
occur q12 months until Month 54, then one final visit at Month 60 of the F/U phase.  
Survival follow-up visits begin 2 months after PD is confirmed by CT scan or start of 
non-protocol treatment.  Subjects in Arm B with PD may select optional ofatumumab 


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monotherapy.  PD must be confirmed by an independent review prior to receiving 
ofatumumab monotherapy.  There will be a ±7 day visit window around each F/U 1 
visit and a ±14 day visit window around each F/U 2 visit.  

If a subject, without PD, discontinues or withdraws (WD) from treatment (for any 
reason) the subject remains in the study and completes all scheduled visits without 
study drug.  In the event a subject WD from study, the WD visit (as noted in time and 
events tables) must be completed.  CT scan done at WD from study if last CT was >91 
days. 

Treatment is expected to be given on the scheduled days.  A visit window of 3 days 
following the scheduled day will be allowed between cycles but there is no visit 
window once the subject has entered the cycle (except bendamustine may be 
administered on either Days 1,2 or Days 2,3 if needed).  There is a minimum 21 day 
interval between cycles. 

One month follow-up occurs following treatment completion in Arm A, regardless of 
response.

HAHA and ofatumumab concentration (PK sample) sample frequency changed.  
During treatment, collect every 6 months.  During first year of follow-up, collect every 
6 months for the first year after last ofatumumab infusion.  Collect a HAHA sample at 
withdrawal or on one occasion post-PD for subjects with PD.

Ig and vital sign schedules altered in time and events tables

Ofatumumab concentration (PK) only for subjects receiving ofatumumab.

The protocol should be followed as closely as possible.  If as per local practice, a 
blood withdrawal for hematology and biochemistry analysis prior to the visit date is 
required, it would be acceptable for hematology and biochemistry analysis, but the 
blood draw can be taken no more than 3 days ahead of the visit date. Blood draws 
performed by local laboratories (e.g. for quicker pre-dose response assessment or 
assessment of toxicity) of protocol-required lab assessments are acceptable; however it 
is important that the sample for the central laboratory analysis is taken at the same 
time.  Since absolute neutrophil count, platelet count, peripheral blood lymphocytes, 
and hemoglobin results are required to establish if a bendamustine dose reduction 
and/or treatment delay is required, the results of each of these local laboratory tests 
must also be entered into the eCRF if it is used to manage a dose delay or dose 
reduction.  Central Laboratory information will also be entered into the eCRF.

Appendix 3:  visit window now + 1 day


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SPECIFIC PROTOCOL CHANGES FOR AMENDMENT 3 (19-JAN.-2012) FROM 
AMENDMENT 2 (DATED 12-MAY-2010)
List of Specific Changes
Note:  deleted language is presented with a strikethrough and added language is printed in 
bold.  Specific changes do not replicate the entire section that was changed, but merely show 
sentences and/or paragraphs were most of the changes occurred.  Some paragraphs were 
truncated in the following examples.  Specific changes are not shown for every section.  
Specific changes are shown for some sections to highlight extent of change.  These specific 
changes were implemented throughout the protocol even though not shown in this section.  
The final protocol and not this appendix must always be followed when implementing the 
protocol rather these appendices.
Example:
Section:
Throughout Document
Original text:
Patient
Text changed to:
Subject
Rationale for Change:
For consistent use of terminology throughout the document.  Amended in appropriate 
document sections.


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Sections:
Protocol Summary 
Text changed to:
Objectives
The primary objective of the study is to test whether the ofatumumab and bendamustine 
combination therapy will improve disease progression-free survival in subjects with indolent 
B-cell NHLwho had stable disease to, or progressed during or within 6 months of the end 
of a rituximab or rituximab-containing regimen that did not respond (stable disease or 
progressive disease) to rituximab or a rituximab-containing regimen during or within 6 
months of the last rituximab treatment.
Secondary objectives evaluate clinical benefit, changes in health-related quality of life (HRQL) 
measures, safety, tolerability, pharmacokinetics, and exploratory prognostic markers in 
subjects treated with ofatumumab and bendamustine, and ofatumumab pharmacokinetics in 
subjects receiving ofatumumab alone after disease progression.
Study Design
Screening assessments include physical exam, vital signs, biochemistry, and blood samples.  
Blood samples (hematology), vital signs, and biochemistry samples are taken throughout the 
treatment phase.  Follow-up assessments begin on Day 336 (3 months after Day 252), then 
every 3 months for 2 years, and every 6 months for 3 years according to Appendix 1 and 
Appendix 2.  In the event of PD, Survival Follow-Up visits begin 2 months after PD is 
confirmed by CT scan.  A bone marrow examination is required to confirm Complete 
Remission (CR) when a subject fulfills the complete response criteria, based on the Revised 
Response Criteria for Malignant Lymphoma definition of a CR if the subject had bone 
marrow involvement at baseline.  CT imaging is required for confirmation of all responses 
(CR, PR, SD, PD).  During this study, CT imaging of the neck (when lesion is palpable), 
thorax, abdomen, and pelvis will be performed at baseline, and on Days 84, 168, and 252 (+7 
days), regardless of the number of completed cycles of therapy in Arm A and Arm B.
A total of 256 events in a sample size of 304 evaluable subjects (152 subjects per arm) are 
needed for the study to have a 90% power to detect a 50% improvement in progression-free 
survival (PFS) between study arms.  Assuming a dropout rate of 10 12%, the total sample size 
randomized for both arms combined will be 338 346 subjects, with approximate study 


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duration of 68 69 months.  Assuming a screening failure rate of 1015%, the total number of 
subjects screened will be approximately 376 408.
Section 3.1.7
Text changed to:
Known and Exploratory Prognostic Markers Correlating with Response

Baseline FLIPI-1 and FLIPI-2 scoresBaseline Absolute Lymphocyte Count (ALC)

Genetic variation in FcR gamma 3A

Human Anti-Chimeric Antibodies (HACA)
Rationale for Change:
Summary updated to reflect changes in the document.
Section 1.2:
Frontline Treatment
Text changed to:
Bendamustine hydrochloride (RIBOMUSTIN) is currently approved in Germany (i.e., 60 
mg/m² I.V. on days 1-5, vincristine 2 mg I.V. on day 1, prednisone 100 mg/m² I.V. on 
days 1-5; cycle repeated after 3 weeks) for the primary treatment of advanced, indolent 
NHL in combination regimens and as a single agent or combination therapy for multiple 
myeloma and chronic lymphocytic leukemia (CLL) [RIBOMUSTIN Prescribing 
Information Package Insert, 2009; LEVACT SPC, 2010]. Approval for indolent NHL that 
relapsed during or within 6 months of receiving a rituximab-containing regimen is pending in
Europe and Japan. Bendamustine is approved for indolent NHL that relapsed during or 
within 6 months of receiving a rituximab-containing regimen. In the US, bendamustine 
hydrochloride (TREANDA) as a single agent is also approved for the treatment of CLL and 
rituximab-refractory indolent NHL [TREANDA Package Insert, 2010].
Rationale for Change:
Levact approved in EU.


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Section 1.3:
Ofatumumab
Text changed to:
The pivotal trial Study Hx-CD20-406 in subjects with fludarabine-refractory CLL [refractory 
to both fludarabine and alemtuzumab (n=59) or refractory to fludarabine and with bulky 
lymphadenopathy for whom alemtuzumab is not suitable (n=79)] evaluated 300 mg + 7 x 
2000 mg for eight weekly doses, followed by four monthly 2000 mg doses.  An The 
investigator-determined overall objective response rate of patients refractory to 
fludarabine and alemtuzumab was 58 42% with a median duration of response of 6.5 
months consisting of partial responses (PR) was achieved in the fludarabine and 
alemtuzumab refractory group with a median progression-free survival of 5.7 months.  The 
best response was PR.  Similarly, in the bulky fludarabine refractory group with a similar 
unmet medical need, an objective response rate of 47% was achieved, including 1 complete 
response (CR), with all other responses being partial responses (PR).  The median PFS in the 
bulky fludarabine refractory group was 5.9 months.  In this study, ofatumumab was generally 
well tolerated.  Specifically, in the DR group, Tthe most frequently reported adverse events 
(>15% frequency) were pyrexia, diarrhea, fatigue, cough, neutropenia, anemia and pneumonia.
Rationale for Change:
Results updated.
Section 2 Objectives:
Secondary objectives:
Text changed to:

To evaluate ofatumumab pharmacokinetics when ofatumumab is given with as 
monotherapy to subjects who progress during or following single-agent
bendamustine
Rationale for change:
Pharmacokinetic objective is removed from the main body of the study; this objective is being 
addressed appropriately in another study.  This study will assess ofatumumab 
pharmacokinetics in subjects in Arm B who receive ofatumumab monotherapy after disease 
progression.
Section 3.1:
Study Design
Text changed to:
The primary analysis of progression-free survival will use 90% power to detect a 50% 
treatment effect; a 13.5 vs. 9 month improvement in Arm A (ofatumumab and bendamustine 
combination therapy) vs. Arm B (bendamustine monotherapy). A total of 256 events will be 
required in a sample size approximately 304 subjects (152 subjects per arm). With an 
estimated accrural rate of 6 subjects per month, the study treatment duration wil be 
approximately 62 months. However, to meet an assumed 10% drop out rate, 338 subjet will 
be randomized to the study. The study duration increases to approximately 68 months. It is 
also estimated that approximately 10 % of subjects screened may fail screening criteria; 
therefore, approximately 376 subjects may be screened for this study to obtain 338
randomized subjects. This trial is an event-driven study design with an event-driven 
sample size of 256 total events and the final analysis will take place at the time of 


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occurrence of the 256th event. The guideline for the study reaching 256 total events with 
respect to previously stated assumptions involve screening of 376 408 subjects so as to 
have 338 346 subjects randomized and to have a study duration of about 62 69 months 
from the first day of first subject until the time of the 256th event.
Rationale for Change:
Screen failure rate and dropout rate updated to reflect current study status.
Section 3.1.1:
Screening Phase
Text changed to:
Baseline Bone Marrow Sample:
Two types of bone marrow samples will be accepted:
1. An historical bone marrow biopsy sample (obtained at any time prior to study entry) 
may be used to fulfill the study’s needs if:
•
The bone marrow biopsy showed involvement by lymphoma and
•
The subject has received no lymphoma therapy in the intervening time period.
2.
A study specific (screening) sample will be required if any of the following 
points are met: 
1.
The subject has no previous bone marrow biopsy, or
2.
The bone marrow biopsy was taken >1 month prior to randomization and 
showed no involvement by lymphoma, or 
3. The subject has received lymphoma therapy in the intervening time period 
since the prior bone marrow biopsy. 
A screening bone marrow biopsy and aspirate will be required if a prior bone marrow biopsy 
and aspirate results from the previous 8 weeks cannot be provided.
4.
A bone marrow aspirate and biopsy will be required at screening if results are not 
available from a prior bone marrow aspirate and biopsy performed within 8 weeks 
prior to randomization. Results may be provided in the form of a bone marrow 
biopsy report when a previous aspirate and biopsy are not available as long as the 
report was based on the biopsy done within 8 weeks prior to randomization.  Results 
may be provided in the form of a bone marrow biopsy report when a previous 
aspirate and biopsy are not available as long as the report was based on the biopsy 
done within 8 weeks prior to randomization.  If the investigator has clinical suspicion 
that the protocol candidate has transformed to Diffuse Large B-cell Lymphoma 
(DLBCL), the investigator should not consider that subject for the trial unless a 
lymph node biopsy is performed.  To confirm that disease has not transformed to a 
DLBCL, an incisional or excisional lymph node biopsy of accessible adenopathy is 
highly recommended.  In less accessible lymph nodes, 4 to 8 core biopsies are 
recommended, but not required.
Lymph Node Biopsy if Transformation to DLBCL Is Suspected:
If the investigator has clinical suspicion that the protocol candidate has transformed to Diffuse 
Large B-cell Lymphoma (DLBCL), the investigator should not consider that subject for the 
trial unless a lymph node biopsy is performed.  To confirm that disease has not transformed to 


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a DLBCL, an incisional or excisional lymph node biopsy of accessible adenopathy is highly 
recommended.  In less accessible lymph nodes, 4 to 8 core biopsies are recommended, but not 
required.

Bone marrow aspirate, biopsy and lymph node pathology report including details 
confirming CD20+ tumor status will be sent along with tissue or slides for central 
review.  Please see SPM for more details.
Review of Materials:
Bone marrow biopsy and tissue pathology report (including details on core and aspirate, 
core alone, or aspirate only) including details confirming CD20+ tumor status will be 
sent along with tissue or slides for central review.  Please see SPM for more details.  
Blood samples, physical examination, and whole body CT imaging (with contrast imaging of 
the neck when lesion is palpable, thorax, abdomen, and pelvis; may be whole body CT scan 
or according to standard of care) will be provided to determine baseline disease and study 
eligibility (See Imaging Acquisition Guidelines). All examinations should be must be 
performed ≤ 14 21 days prior to randomization with the exception of the CT imaging and 
bone marrow biopsy and aspirate as mentioned above.  CT imaging done 1 month prior to 
randomization may be used as the baseline CT scan.  If the investigator would wants to use a 
CT scan done >1 month prior to randomization, the medical monitor may be contacted to 
determine if CT scan can be accepted.
Rationale for Change:
Clarification.
Section 3.1.1.1 Documentation of Indolent B-cell NHL that is stable or has 
progressed during or within six month of the end of treatment 
with rituximab or a rituximab-containing regimen
Text changed to:
A documentation worksheet verifying the investigator’s diagnosis of stable disease following, 
or progression of indolent B-cell NHL during or within 6 months of treatment with rituximab 
or a rituximab-containing regimen will be required at screening.  This documentation 
worksheet must be sent to GSK prior to randomization and will ask for:


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Information about last rituximab therapy:

Dates before and dates after last rituximab-containing regimen

Type of rituximab therapy and regimen (examples: weekly, monthly):
o
Rituximab (includes monotherapy and maintenance), or
o
Rituximab added to chemotherapy

Date and type of response associated with last rituximab-containing regimen

Information regarding imaging:

Copy of the imaging report prior to last rituximab-containing regimen is required (if 
available)

Copy of documentation confirming PD (for example, an imaging report, clinical 
documentation) after subject deemed unresponsive or relapsed to rituximab-based 
regimen is required
Rationale for Change:
Obvious progression could be documented using methods other than imaging.  As long as 
these other methods/documentation can show progression, they may be used to confirm 
rituximab refractory disease.
Section 3.1.4:
Treatment Phase
Text changed to:

Arm A: Up to 8 cycles of bendamustine (90 mg/m2, Days 1, 2; q21 days) in 
combination with 12 doses of ofatumumab (1000 mg).  Beginning in Cycle 2, 
ofatumumab will be given on Day 1 (or within 3 days after Day 1) of each cycle of 
bendamustine as long as subjects in Arm A receive bendamustine.  Once subjects in 
Arm A complete bendamustine therapy, the remaining doses of ofatumumab will be 
given monthly, q28 days (on or 3 days after Day 1 of each month) until all 12 doses 
are completed.  Administer the first dose of ofatumumab monotherapy 28 days 
after Day 1 of the last cycle where combination (ofatumumab+bendamustine) 
was scheduled to be given.

Arm B:  Up to 8 cycles of bendamustine (120 mg/m2, on or 3 days after Days 1, 2; 
q21 days.).
Subjects in Arm B who cannot complete 8 cycles the planned therapy (in Arm A and Arm 
B) must still come in for all planned visits and assessments (Visits 1-20) according to the 
schedule presented in Appendix 1 and Appendix 2.  Also see SPM for more details.  Subjects 
in Arm A and Arm B are required to come for all planned CT scans with corresponding 
assessments for these days (Days 84, 168, 252; ±7 +7 days).
Rationale for Change:
Clarification.


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Section 3.1.5:
Follow-up Phase
Text changed to:
Following study treatment, subjects who have CR, PR or SD will receive regular follow-up 
for 5 years in Arm A.  The last required CT scan will be done on Month 54 (Table 1).  
Unscheduled CT scans will be required in addition to the scheduled CT scans if there 
are clinical signs or suspicion of progression throughout the study.  Arm B will also 
follow this schedule if Arm B subjects do not select ofatumumab monotherapy.
Table 1
Follow-up visit schedule and CT scan requirements
F/U phase1
CT scan3
3 M F/U 12
Required
6 M F/U 1
Required
9 M F/U 1
Required
12 M F/U 1
Required
15 M F/U 1
Required
18 M F/U 1
Required
30 M F/U 2
Required
42 M F/U 2
Required
54 M F/U 2
Required
60 M F/U 2
Not required3
Abbreviations:  Follow-Up 1= F/U 1; Follow-Up 2= F/U 2; Month= M
7.
This schedule is for F/U 1, F/U 2, and the Survival F/U. 
8.
The 3 M F/U 1 visit occurs 336 days after randomization (or 3 months after Day 252) in Arm A and Arm B 
(Appendix 1, Appendix 2).  This 3 M F/U 1 visit occurs 3 months after last ofatumumab monotherapy dose for 
subjects with PD in Arm B who select ofatumumab monotherapy (Appendix 3).
9.
CT scans are required during scheduled F/U 1 and F/U 2 visits with the last required CT scan on Month 54.  CT 
scans will be required to confirm clinical signs or suspicion of progression if observed outside scheduled F/U 1 
and F/U 2 visits.  CT scans are not required for Survival F/U.
Follow-up assessments begin on Day 336 (3 months after Day 252), then according to 
Appendix 1 and Appendix 2 (also see SPM).  In the event of PD, Survival Follow-Up 
visits begin 2 months after PD is confirmed by CT scan.  Follow-up visits will begin on 
Day 336 (this is 3 months after Day 252) and then continue every 3 months for 2 years, then 
every 6 months for 3 years.Each follow-up visit and assessment will have a time window of 
±7 days for Follow-Up Visit #1 and a time window of ±14 days for Follow-Up Visit #2.  
Follow-up visits will include collection of survival status, concomitant medications, and 
response assessments, based on RRCML.  Survival follow-up visits may be phone calls 
instead of physician office visits. In addition, subjects will be monitored for safety, efficacy, 
and pharmacokinetics as described.  See Appendix 1 and Appendix 2 for a complete list of 
follow-up procedures. 
If a subject in Arm B decides to receive ofatumumab monotherapy following PD, they will 
not follow the schedule described in Section 3.1.5, Appendix 1 and Appendix 2, but will be 
monitored according to the follow-up schedule described in Section 3.1.6, Appendix 3, and 
Table 1 (where 3 month F/U begins 3 months after last dose of ofatumumab).


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Rationale for Change:
Follow -up frequency (including CT scans required within these visits) were reduced to 
addresss UK Ethics feedback on the protocol.  The UK Ethics Committee asked that we 
reduce the number of CT scans in this study.  As long as subjects remain on a consistent 
follow up schedule, there is no risk for this new schedule to interfere with data analysis.
Section 3.1.5:
Follow-up for Progressive Disease
Text changed to:
A PD Worksheet will be completed following the CT scan.  Instructions for this 
worksheet are found in the SPM.  
Survival Ffollow-up visits will begin on Day 336 (this is 3 months after Day 252) 2 months 
after PD is confirmed by CT scan as described in Appendix 1 and Appendix 2 and Table 
1 and continue every 3 months for 2 years and then every 6 months for 3 years.  Each follow-
up visit will have a time window of ±7 days for Follow-Up Visit #1 and a time window of 
±14 days for Follow-Up Visit #2.One month is defined as having 28 days.  Each follow up 
visit and assessment will have a time window of ±7 days. Survival follow-up visits may be a 
phone call instead of physician office visit.  
Rationale for Change:
To synchronize follow-up visits after the date of progression in all subjects.
Section 3.1.6:
Ofatumumab Following Progressive Disease for Arm B
Text changed to:
A PD Worksheet must be completed once the decision to begin ofatumumab 
monotherapy following PD in Arm B is taken (See SPM for details).
The first follow-up visit will occur one month following the last infusion of ofatumumab 
monotherapy and continue every 3 months for 2 years then every 6 months for 3 years as 
described in Appendix 3 and Table 1.
Text changed to:
Clarification and reflects change in documentation requirements.
Section 4.2:
Inclusion Criteria
Text changed to:
Inclusion #1:  Small lymphocytic, lymphoplasmacytic, marginal zone lymphoma, and 
follicular lymphoma (FL); grades 1, 2 and 3A, defined according to WHO guidelines.

Tumor verified to be CD20+ positive from a previous or current lymph 
node tissue biopsy.  A bone marrow biopsy is not sufficient for tissue 
diagnosis.

CT imaging in screening phase (based on local evaluation) showing  2 or 
more clearly demarcated lesions with a largest diameter ≥>1.5 cm and 
short axis ≥ 1.0 cm, or 1 clearly demarcated lesion/node with a long axis 
largest diameter ≥>2.0 cm and short axis ≥ 1.0 cm.  CT imaging 
performed at screening as baseline image.
Inclusion #2:  Indolent B-cell NHL with failure to achieve at least a partial response 
lasting 6 months beyond the of treatment with that remains stable or unresponsive during 


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or within 6 months of treatment with rituximab or a rituximab-containing regimen (See 
Section 6.2.5.4- Section 6.2.5.5 for details on response criteria), i.e.:

Stable disease after rituximab or a rituximab-containing regimen (imaging will 
support this finding. NOTE: in cases of stable disease after rituximab 
monotherapy as induction treatment, the minimum time to confirm stable 
disease by imaging is 60 days from start of first rituximab infusion)
or, 

·Disease progression during or within 6 months of treatment with rituximab or 
a rituximab-containing regimen. Imaging must support this finding and will be 
done ≤ 6 months after the last infusion of rituximab. 

Maintaining stable disease or failure to achieve PR to rituximab-based therapy. 
(Imaging will support this finding, and will be performed at least 60 days after the 
last dose of rituximab-based therapy)

or,

disease progression while on rituximab-based therapy (e.g., includes 4 weekly 
courses of rituximab given at 6-month intervals [Hainsworth, 2005])

or,

disease progression in subjects with stable disease or better response to rituximab-
based therapy <6 months of the last dose of rituximab
Note:  Subjects must have received a minimum of 4 rituximab infusions as monotherapy or 3 
infusions as part of rituximab-containing combination regimens
Rationale for Change:
Inclusion Criterion #1:  CD20 staining can be accurately determined from non-lymph node 
tissue (such as bone marrow or splenic tissue). Some patients with splenic marginal zone 
lymphoma may have disease which is primarily non-nodal (or have nodes which are not easily 
accessed), and this change allows such patients to be considered for this study.
Inclusion Criterion #2:  Clarification to accommodate local practices.  Extra examples were
unnecessary to convey criterion.  
Section 4.3:
Exclusion Criteria
Text changed to:
Exclusion Criterion #2:  Previous autologous stem cell transplant or fludarabine therapy, or 
radioimmunotherapy in the last 6 months or previous allogeneic stem cell transplant at any 
time
Prior Exclusion Criterion #4: Previous external beam radiation therapy to the pelvis.  
Previous external beam radiation therapy for bony disease to the cranium, mediastinum, and 
axilla or to more than 3 vertebral bodies
Exclusion Criterion #3:  High dose steroids ≥ 100 mg prednisone/day (or equivalent) for 7 
consecutive days, given as concomitant medication, within 3 months prior to 
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Exclusion Criterion #4:  Prior bendamustine treatment within 1 year of randomization 
not resulting in a CR or PR for at least 6 months
Exclusion Criterion #5: Prior use of any monoclonal antibody (other than CD20) within 3 
months prior to randomization
Prior Exclusion Criterion #7:  Prior treatment with anti-CD20 monoclonal antibody, if 1st
dose was administered within 60 days prior to randomization. Prior use of any monoclonal 
antibody (other than anti-CD20) within 3 months prior to randomization
Rationale for Changes:
No longer excludes fludarabine and radioimmunotherapy:

Previous concern was that prior fludarabine and RI would deplete BM reserve.  We 
wanted BM reserve to recover from these prior therapies before subjects entered the 
OMB110918 study, since bendamustine is myelosuppressive.  Since the inclusion and 
exclusion criteria already require minimum hematological values to safeguard against 
subjects at increased risk of hematologic toxicity from bendamustine, exclusion of prior 
fludarabine and radioimmunotherapy is not necessary.
No longer exclude previous external beam radiation therapy to the pelvis, previous external 
beam radiation therapy for bony disease to the cranium, mediastinum, and axilla or to more 
than 3 vertebral bodies:

Previous concern was that extensive radiation therapy would reduce marrow reserve.  We 
want adequate BM reserve for subjects in the OMB110918 study, since bendamustine is 
myelosuppressive.  Since the I/E criteria already require minimum hematological values 
to safeguard against subjects at increased risk of hematologic toxicity from bendamustine, 
exclusion of patients based on the amount of prior radiation is not necessary.
Removed Exclusion criterion restricting anti-CD20 antibody within the last 60 days:

Since rituximab is included in virtually all treatment regimens for indolent B-NHL and 
refractory patients often have clinically aggressive disease that requires treatment, it is 
not medically feasible to require patients to wait 60 days to begin new therapy if they do 
not respond to their last therapy.
Section 4.4:
Withdrawal Criteria
Text added:
Entire section updated.
Rationale for Change:
Clarification:  text added to explain the difference between “Withdrawal from Investigational 
Product” vs “Withdrawal from study”.
Section 5.1.1:
Pre-Medication, Table footnote


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Text changed to:
Pre-Medication Schedule
Infusion Number
30 minutes to 2 hours prior to treatment
Acetaminophen (PO) ~1000 
mg or equivalent
Antihistamine (IV or PO) 
equivalent to ~50 mg 
diphenhydramine
Glucocorticoid (IV) 
equivalent to ~50 mg 
prednisolone
1st
X
X
X
>11
X1
X1
X1
5.
Administration of steroid premedication in Arm A (and in Arm B, as applicable) will be at investigator discretion if 
severe infusion reactions did not occur during first infusion.
Rationale for Change:
Correction.
Section 5.1.3:
Bendamustine
Text added:
Bendamustine will be given for up to 8 cycles in both Arm A and Arm B.  However, in 
the following instances, bendamustine may be given for fewer than 8 cycles:

If a subject cannot tolerate bendamustine and is unable to receive further 
treatment with bendamustine, the subject may stop bendamustine treatment.  
If this occurs in Arm A:  the subject will continue to receive all 12 doses of 
ofatumumab and continue to attend all scheduled visits on Day 1.  Day 2 visits are 
not required unless the investigator requires additional tests.
If this occurs in Arm B:  the subject will continue to attend all scheduled visits.  
Note:  Subjects will only be required to attend the equivalent of the Day 1 visit.  The 
Day 2 visit is not required unless assessed as necessary by the Investigator.
6.
The number of cycles will be contingent upon the response to the first 4 cycles.  
Subjects achieving CR after 4 cycles in either Arm will be treated with a total of 6 
cycles only, whereas, all other subjects will receive 8 courses of bendamustine as 
monotherapy (Arm B) or in combination with ofatumumab (Arm A).  
2. If this occurs in Arm A:  the subject should continue to receive all 12 
doses of ofatumumab and continue to attend all scheduled visits
3. If this occurs in Arm B:  the subject should continue to attend all 
scheduled visits on Day 1 of each cycle
7.
Subjects with progressive disease at any time during bendamustine 
monotherapy (Arm B) or OB combination therapy (Arm A) will be taken off 
treatment and will continue with survival follow-up (Section 3.1.6 describes 
subjects with PD in Arm B that continue on to ofatumumab monotherapy).


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The initial cycle length or dose of bendamustine in Arm A may be lowered on 
recommendation of the IDMC after evaluation of data from the dose confirmation cohorts.  
Detailed instructions for dose reduction and subsequent dose reductions will be in the IDMC 
charter and summarized in Section 9.7.
Bendamustine may be initiated within 1 day of scheduled start for logistical reasons.  Once 
the first infusion occurs, the second infusion should occur the following day.  The start of 
Cycles 2-8 may be delayed due to toxicity by up to 2 weeks for medical reasons at the 
investigator’s discretion.  
Rationale for Change:
Clarification.
Section 5.1.3.1:
Bendamustine Dose Reduction
Text added:
General Dosing Considerations for Arm A and Arm B:

Delay treatment for Grade 4 hematologic toxicity or clinically significant ≥Grade 3 non-
hematologic toxicity.

Toxicities must recover to Grade 1 or baseline before the next administration of treatment. 
If recovery is not met within 2 weeks after the prescribed start of the treatment cycle (i.e., 
after a 2 week delay), a decision will be made about continuation in the study following 
consultation with medical monitor.

Bendamustine dosage will be delayed in subjects with a serum creatinine > 1.5 
ULN if the calculated creatinine clearance [Cockcroft, 1976] or creatinine 
clearance from a 24-hour urine collection is ≤40 mL/min.

Subjects should be monitored for safety as per local practice.

The protocol should be followed as closely as possible, but if as per local 
practice, a blood draw for hematology analysis prior to the visit date is required, 
it would be acceptable for hematology analysis, but the blood draw can be taken 
no more than 3 days ahead of the visit date.  Blood draws performed by local 
laboratories (e.g. for quicker pre-dose response assessment or assessment of 
toxicity) of protocol-required lab assessments are acceptable; however, it is 
important that the sample for the central laboratory analysis is taken at the 
same time.  The local laboratory results of absolute neutrophil count, platelet 
count, peripheral blood lymphocytes, and hemoglobin must also be entered into 
the eCRF if it is used for a treatment decision.  Central Laboratory data will 
also be entered into the eCRF.
Rationale for Changes:
Taken from Treanda Prescribing Information and added to protocol for clarity.  Also added 
clarification of when and how local laboratory tests may be used in this study.


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Section 6.1.9:
Vital Signs
Text added:
Vital signs including temperature, blood pressure (BP), and pulse are documented per 
Appendix 1 and Appendix 3, at screening and for the remainder of the study in both arms. 
Temperatures for individual subjects must be measured using the same method at all visits.
All subjects must be monitored as per standard of care for changes in blood pressure, 
heart rate, and temperature and for Adverse Events. All recorded values should be 
documented in the subject’s source documentation.
If the subject suffers an adverse event (Grade ≥1) during the infusion (including 
asymptomatic fever, hypotension or tachycardia), which is determined by the 
Investigator to be related to either the study procedures or study treatment, vital sign 
measurements (blood pressure, heart rate and temperature) should be recorded in 
appropriate source documentation AND the blood pressure and heart rate recorded in 
the INFORM eCRF system, for the following time-points:

At the time of event onset.

Then every 30 minutes, or more frequently if clinically indicated, if in the 
Investigator’s opinion the vital sign results at the time of event onset are 
clinically significant. The subject’s vital sign measurements should continue to 
be recorded until they have returned to normal or pre-infusion levels.
Rationale for Change:
Simplification of instructions.
Section 6.2.2:
CT Scans
Text changed to:
Whole body CT scans (with contrast of the neck when lesion is palpable, thorax, abdomen, 
pelvis, may be whole body CT scan or according to standard of care) will be done as part 
of the efficacy evaluation and after treatment has been completed.  The scans must be 
implemented according to a CT scan manual to be provided to GSK (Imaging Acquisition 
Guidelines) as mentioned in the SPM.
In situations where progressive disease is apparent through physical examination (such as 
massive lymphadenopathy), only the body area where progressive disease is apparent must be 
scanned to confirm progressive disease.
All subjects (Arm A and Arm B) must have a CT scan done on Days 84, 168, and 252 (±7 +7 
days).  In the event subjects in Arm B cannot complete 8 cycles of therapy then subjects must 
come to the clinic for all scheduled visits.  Subjects will have CT scans at each follow-up visit
as described in Table 1, Appendix 1, and Appendix 3.  Survival Follow-up visits will 
begin 2 months after PD is confirmed by CT scan.  CT scans will be done to confirm any 
clinical signs or suspicion of PD.  CT scans which are unscheduled and are performed to 
confirm PD in event of clinical signs or suspicion of progression may be done only of the 
suspected body area with progression.  In the event that an unscheduled CT scan does 
NOT show PD, the subject will resume the planned CT scan schedule (i.e. the next CT 
scan will be done based on the date of the last scheduled CT scan and not the day of the 
unscheduled CT scan).  For all other responses, follow-up visits will begin on Day 336 
(this is 3 months after Day 252) for both arms and continue during follow-up visits, or until 


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initiation of alternative indolent lymphoma treatment, PD, or withdrawal (WD), See 
Appendix 1 and Appendix 2 and Appendix 3 for details.  One month is defined as having 28 
days.
CT scans will be assessed according to an independent review.  The independent review will 
be described in an independent review charter.  See Section 6.2.6 for a description of this 
independent review.
Rationale for Change:
Whole body CT imaging is not done at all sites.  All change were made to accommodate 
different global local practices.  Instructions for CT scans in the event of clinical signs of 
progression were added.
Section 6.2.3:
Bone Marrow Examination
Text changed to:
Bone marrow examination (both aspirate smear and biopsy core, if possible) to confirm CR, 
as determined by the clinical and laboratory results listed in Section 6.2.5.2 is required no 
later than 8 weeks following onset of CR if there was disease involvement in the bone 
marrow at baseline.  Samples are to be reviewed in conjunction with the prior pathology. 
Rationale for Change:
Clarification on what is needed for study.
Section 6.2.5:
Documentation of Target and Non-target Lesions
Text changed to:
Eligibility Criterion
CT scan showing at least:

2 or more clearly demarcated lesions/nodes with a long axis >1.5 cm and short axis 
1.0cm and not previously irradiated
OR

1 clearly demarcated lesion/node with a long axis >2.0 cm and short axis 1.0cm and 
not previously irradiated.
Rationale for Change:
If a patient who failed radiation therapy and a lesion which has been previously irradiated is 
the primary site of disease progression, an investigator should be allowed to use that lesion to 
measure response to study therapy without compromising study response.
Section 6.3.2:
Peripheral Blood Sampling for Hematology and 
Biochemistry
Text changed to:

Biochemistry:  sodium, potassium, chloride, bicarbonate, calcium, blood urea nitrogen 
(BUN), creatinine, uric acid, total bilirubin*, alkaline phosphatase (ALP),  aspartate 
transaminase (AST), alanine transaminase (ALT), lactic acid dehydrogenase (LDH),  
albumin, glucose (random), and haptoglobulin.  
o
*bBilirubin fractionation is recommended if total bilirubin >2 x ULN


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
A creatinine clearance will be calculated prior to bendamustine administration as 
shown in Appendix 2.  Calculated creatinine clearance will be done at screening 
and can be repeated at the physician’s discretion if there is a significant rise in 
serum creatinine during the treatment phase of the study.  The Cockcroft-Gault 
formula [Cockcroft, 1976] will be used to determine a calculated creatinine clearance:
Rationale for Change:
Clarification.
Section 6.3.3:
Prognostic Factors
Text changed to:

Genetic variation in the FcR gamma 3A

Human Anti-Chimeric Antibody (HACA) will be taken as defined in Appendix 2.  
If receiving ofatumumab following PD in Arm B, HACA will be taken as defined 
in Appendix 3

HACA
Rationale for Change:
Clarification on the type of FcR gamma 3 A test.
Section 6.3.4:
Peripheral Blood Sampling for Safety and Disease 
Status
Text changed to:

Hepatitis B (HBV) and Hepatitis C (HCV) at screening.  Subjects receiving 
ofatumumab that are Hepatitis B core positive at screening, Hepatitis B DNA should
will be obtained at each cycle visit while on treatment and then at 1,3,6 months post 
treatment.  See SPM for more details.

Human Anti-Chimeric Antibody (HACA) will be taken as defined in Appendix 2.  If 
receiving ofatumumab following PD in Arm B, HACA will be taken as defined in 
Appendix 3
Rationale for Change:
HACA schedule changed and clarification of hepatitis testing.
Section 6.4.1:
Liver Chemistry/Stopping and Follow-up Criteria
This entire section was updated.  See protocol text.
Rationale for Change:
Modified to align to the stopping criteria which has been adopted for all ofatumumab studies 
based upon the FDA July 2009 Guidance for Industry, Drug-Induced Liver Injury:  Pre-
marketing Clinical Evaluation, Section 5, Decision to Stop Drug Administration. Because 
transient elevations in LFTs may be due to tumor lysis which is of clinical benefit, disease 
related liver involvement or due to other chemotherapy rather than drug induced liver injury 
from ofatumumab, the protocol was modified to allow re-challenge with investigational 


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product. Any decision to restart therapy after interruption must be determined by the 
investigator in consultation with the GSK Medical Monitor and the GCSP assigned physician.
Section 6.5.1:
Definition of an AE
Text added:
Events that do not meet the definition of an AE include:

Events related to the underlying lymphoma and unrelated to the study therapy, 
unless more severe than expected for the condition
Rationale for Change:
Clarification.
Section 6.5.7:
Time Period and Frequency of Detecting AEs and SAEs
Text changed to:
All SAEs and AEs regardless of relationship to investigational product will be collected from 
the first dose of investigational product to 60 days after the last dose of investigational 
product and will be documented on the eCRF.  Only SAEs, regardless of causality, will be 
reported from 60 days 61 Days after the last dose of treatment to the end of the follow-up 
period
From the time a subject consents to participate in and completes the study (See Section 4.4), 
all SAEs assessed as related to study participation (e.g., protocol-mandated procedures, 
invasive tests, or change in existing therapy) or related to GSK concomitant medication, will 
be reported promptly to GSK as indicated in Table 8.
SAEs will not be reported after subsequent anti-NHL therapy is initiated.
Rationale for Change:
Clarification and instructions on SAE reporting after NHL therapy.
Section 6.7:
Ofatumumab Pharmacokinetic Sample Collection
Entire section updated.
Rationale for Change:
Removal of the pharmacokinetic objective in the main body of the study resulted in the 
removal of the ofatumumab sample collection in subjects in Arm A related to the assessment 
of ofatumumab pharmacokinetics. The rationale for the removal of the objective is that it is 
being addressed appropriately in another study.
Addition of more extensive HAHA surveillance resulted in the addition of ofatumumab 
sample collection in both Arm A subjects and Arm B subjects who received ofatumumab after 
disease progression related to that surveillance.


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Section 8.3.5.1:
Efficacy Analyses
Other Secondary Analyses
Text changed to:

Human Anti-Chimeric Antibodies (HACA)

HACA results prior to ofatumumab administration will be listed. The number of 
patients with positive HACA in the predose samples will be reported

Human Anti-Human Antibodies (HAHA)

The change in HAHA titers from predose to post-baseline visits and the number and 
proportion of positive and negative results at each visit will be provided in patients 
who receive ofatumumab.  HAHA results and associated ofatumumab plasma 
concentration at each time point will be listed.
Rationale for Change:
Reflects updates in HACA sampling and assessments and planned reporting of HAHA results.
Section 8.3.5.4:
Pharmacokinetic Analyses
The plasma concentrations for individual subjects will be determined using validated 
analytical methods for ofatumumab.  Plasma ofatumumab concentration-time data will be 
summarized and displayed in tabular and graphical form separately for subjects in Arm A and 
for subjects in Arm B who receive ofatumumab following progressive disease.  Individual 
plasma concentrations of ofatumumab will be listed.
Population pharmacokinetic modeling, using non-linear mixed effects modeling will be 
performed on the data for subjects in Arm B who receive ofatumumab following 
progressive disease using validated software such as the computer program NONMEM, if 
data permit.  Data from this study may be combined with data from other studies for analysis.  
The aims of this modeling approach are to:  

Define the structural pharmacokinetic model that characterizes the population time course 
of plasma levels of ofatumumab in this patient population

Describe between-subject variability for pharmacokinetic parameter estimates

Estimate intra-subject variability on predicted concentrations


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If possible, the effects of subject characteristics (such as gender, weight, height, disease status, 
etc.) will be investigated in order to account for potential sources of inter-individual 
variability in systemic exposure.  If there are sufficient data for analysis, the details of the 
population pharmacokinetic analyses will be provided in a reporting and analysis plan.
Rationale for change:
Removal of the pharmacokinetic objective from the main body of the study.
Section 8.3.5.5:
Pharmacokinetic Analyses
Section removed:
 analyses will be performed to determine any potential relationships between 
ofatumumab pharmacokinetics or exposure and B-cell monitoring results or other clinical 
 endpoints, data permitting.  If appropriate, data from all subjects will be 
pooled and analyzed using a population approach.  If there are sufficient data for analysis, the 
details of the PK/PD analyses will be provided in a separate reporting and analysis plan.
Rationale for Change:
Removal of the pharmacokinetic objective from the main body of the study.


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11.12
Appendix 12:  Protocol Changes for Amendment 4 (09-April-2012) 
from Amendment 3 (dated 19-Jan-2012)
Where the Amendment Applies
Amendment 4 is applicable to all study sites.
Important Note”
Appendix 12 describes general, major changes in the protocol and is not all-inclusive of all 
changes.  The protocol Amendment 4 will always supercede items presented in Appendix 12; 
therefore, the protocol Amendment 4 must be consulted for all final guidance.
General Protocol Changes for Amendment 4 (09-April-2012) from Amendment 3 
(dated 19-Jan-2012)

Correction in footnotes to Time and Event Table (Appendix 1):  baseline CT scans 
required ≤1 month of randomization.  Correct to footnotes in time and events tables so that 
premedication reflects text of protocol.

Abbreviations added to abbreviation table.

Clarifications made throughout document specifying subjects who cannot complete 8 
cycles of therapy with bendamustine must still have all planned Day 1 assessments 
including scheduled CT scans on Days 84, 168, 252.

Section 1.3 updated with most recent results for ofatumumab studies.

Removed all references to baseline bone marrow being required within 8 weeks prior to 
randomization.  Refer to Section 3.1.1 for updated details.

Section 3.1.1:  To be consistent with protocol, removed any requirement for a lymph node 
biopsy and require a biopsy if suitable per the instructions in Section 3.1.1

Section 3.1.1.1:  Clarified this section refers to the “qualifying” rituximab regimen and 
when imaging and/or other documentation are required.

Section 3.1.5 Table 1:  Clarified when Survival Follow Up begins and that Survival 
Follow Up timings may not follow Table 1 exactly, but will follow the Table 1 schedule 
(i.e. F/U 1 is every 3 months until Month 18 of F/U and F/U 2 is every 12 months until 
approximately Month 54 of F/U and then Month 60).

Section 3.1.6:  Clarified that the PD Worksheet is required upon diagnosis of PD.

Section 3.2.2 and Section 3.2.2.1:  Upated results based on updated study data.

Inclusion Criterion #1 now specifies that subjects with a diagnosis of SLL who have a 
peripheral blood monoclonal B lymphocyte count of 5,000/L are considered to have CLL 
and are not eligible for this study.

Exclusion Criteria #3:  high dose steroids ≥ 25 mg prednisolone/day (or equivalent) for 7 
consecutive days.  Updated from ≥ 100 mg to ≥ 25 mg.

Section 5.1.3:  Added an example to clarify that subjects in Arm A may have first cycle 
dose of bendamustine initiated on Day 1 or Day 2 of the cycle.


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
Section 5.1.3.1:  Clarified that local laboratory data must be entered into eCRF when a 
dose delay or reduction decision is made based on local laboratory data.

Section 6.3.1:  Clarified the number of CD19+ and CD20+ B cells will be assessed by flow 
cytometry rather than the “surface expression”.

Section 6.3.2, Section 6.3.4, and Time and Events tables (Appendix 2, Appendix 3) 
footnotes:  made consistent to indicate Hepatitis B DNA (if required) will be obtained at 
each cycle and 1,3,6 months after last ofatumumab dose.  

Section 6.5.7:  Clarified that subjects that are HBsAG negative, HBcAb positive and HBV 
DNA negative may be included in the study but must undergo HBV DNA monitoring per 
the time and events tables..  

For Japan only:   additional directions for Hepatitis monitoring added to Appendix 8

Section 6.5.7:  Table 9 is the correct reference.

Section 6.5.7:  Added text:  All SAEs regardless of causality will be reported from 61 days 
after the last dose of investigational product to the end of the follow-up period or until 
initiation of subsequent anti-lymphoma therapy is initiated. Any SAE brought to the 
investigator's attention after the start of subsequent anti-lymphoma therapy and considered 
by the investigator as possibly related to either ofatumumab or bendamustine must be 
reported to GSK.

Follow up for concomitant medications:  after 2 years, only steroids, growth factors, 
transfusions, anticancer, and anti-infectious treatments will be followed from 61 days after 
the last dose of investigational product to the end of the follow-up period or until 
initiation of subsequent anti-lymphoma therapy is initiated

Study Schematic specifies that the IDMC met.

Time and Events Tables updated to be consistent with protocol text and to clarify 
timepoints when needed (example:  clarified that B cells tracking will be done in 
accordance with scheduled follow up visits and no extra visits are required).

Appendix 3:  additional biochemistry testing added for 1, 2, 3, 4, 5, 6, 7, and 8 months
post-Week 4 of treatment, added for the 1 month follow-up visit, and added for the Month 
3 follow-up visit.

Appendix 3:  A 3 day window rather than a ± 3 day window allowed for CT scans.

For immunoglobulin collection (Appendix 2 and Appendix 3):  Flow cytometry and IgG, 
IgA, IgM done in Arm A only.  During treatment, collect immunoglobulins (Ig) no later 
than every 6 months (collection to correspond with a scheduled visit).  B-cells and 
Immunoglobulins (Ig) will be monitored for a period of 2 years after the last ofatumumab 
infusion in Arm A or until the number of B-cells and circulating IgG, IgM and IgA have 
returned to normal or to within baseline values (according to the central laboratory), 
whichever is earlier. Monitoring will be done during scheduled F/U visits/  F/U will be 
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
Appendix 10:  updates made to keep this appendix consistent with changes made in 
Amendment 3.

Minor changes in Time and Events footnotes for protocol consistency.
Administrative Changes
1.
Minor changes have been made throughout the protocol for spelling, grammar, 
punctuation, and for consistency between sections.
2.
Investigator Brochure updated in references
3.
Author list edited.
4.
Reference to IDMC decision letter included.
5.
Title for sponsor signature


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11.13
Appendix 13:  Protocol Changes for Amendment 5 (07-Feb.-2013) 
from Amendment 4 (dated 09-April-2012)
Where the Amendment Applies
Amendment 5 is applicable to all study sites that are required to include information from the 
Study Procedures Manual into Section 6.5.4 of the protocol.
General Protocol Changes for Amendment 5 (07-Feb.-2013) from Amendment 4 
(dated 09-April-2012)
6.
Specific details on how to handle AEs and SAEs such as infusion reactions, tumor 
lysis syndrome, progressive multifocal leukoencephalopathyand hepatitis described
in Section 6.5.4 of the protocol.


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11.14
Appendix 14:  Protocol Changes for Amendment 6 (02-DEC.-2013) 
from Amendment 4 (dated 09-April-2012)
Where the Amendment Applies
Amendment 6 is applicable to all study sites.
Due to country specific requests, some countries were using Amendment 5; whereas, the rest 
of the world were using Amendment 4.  Amendment 6 incorporated changes made in 
Amendment 5.
General Protocol Changes for Amendment 6 (02-DEC.2013) compared to
Amendment 4 (dated 09-April-2012)
If your country was using Amendment 4
7.
Exclusion criteria now specifies that physician experienced in care and management 
of subjects with Hepatitis B to manage/treat subjects who are anti-HBc positive must 
be consulted
8.
Specific details on how to manage AEs and SAEs such as infusion reactions, tumor 
lysis syndrome, progressive multifocal leukoencephalopathyand hepatitis are 
described.
9.
Instructions for monitoring subjects with Hepatitis B
10. Universal Trial Number added per country request
11. Minor grammer, spelling, and administrative edits
If your country was using Amendment 5:
12. Exclusion criteria now specifies that physician experienced in care and management 
of subjects with Hepatitis B to manage/treat subjects who are anti-HBc positive must 
be consulted
13. Instructions for monitoring subjects with Hepatitis B
14. Universal Trial Number added per country request
15. Minor grammer, spelling, and administrative edits


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11.15
Appendix 15:  Protocol Changes for Amendment 7 (07-JUL-2015) 
from Amendment 6 (dated 02-Dec-2013)
Where the Amendment Applies
Amendment 7 is applicable to all study sites.
List of Specific Changes
Note:  deleted language is presented with a strikethrough and added language is printed in 
bold.  
Section: Title Page,Sponsor Information Page and Sponsor Signatory 
Page
Authors, contacts and sponsor signatory updated to reflect current team members and contact 
details.
Section: List of Abbreviations
Text changed to include:
FA: Futility Analysis
IA: Interim Analysis
Section: Protocol Summary: Study Design
Original Text:
A total of 256 events in a sample size of 304 evaluable subjects (152 subjects per arm) are 
needed for the study to have a 90% power to detect a 50% improvement in PFS (PFS) 
between study arms.  Assuming a dropout rate of 12%, the total sample size randomized for 
both arms combined will be 346 subjects, with approximate study duration of 69 months.  
Assuming a screening failure rate of 15%, the total number of subjects screened will be 
approximately 408.
Text changed to:
A total of 256 259 events in a sample size of 304 evaluable subjects (152 subjects per arm) are 
needed for the study to have a 90% power to detect a 50% improvement in PFS (PFS) 
between study arms.  Assuming a dropout rate of 12%, the total sample size randomized for 
both arms combined will be 346 subjects, with approximate study duration of 69 77 months.  
Assuming a screening failure rate of 15%, the total number of subjects screened will be 
approximately 408.
Rationale for Change:
Event count increased slightly from 256 to 259 events to allowfor adding an interim analysis 
and maintaining the overall study alpha-level of 0.05 and 90% power.  The approximate 
duration of the study was increased from 69 months to 77 months as enrollment for the study 
has declined due to the changes in the current management of patients with rituximab-


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refractory iNHL. The original assumption of 6 patients randomized per month has decreased 
to 4 patients per month over the past year
Section: Protocol Summary: Study Design
Text added:
INTERIM ANALYSIS
An Interim Analysis (IA) for efficacy of the primary endpoint, progression free survival, will 
occur when approximately two thirds of the total Independent Radiology Review (IRR) events 
is achieved.  At the same time as the IA, a Futility Analysis (FA) will also occur and an
Independent Data Monitoring Committee (IDMC) will review the data.  Based on the IDMC 
review of the data available the IDMC will recommend that the study continue without any 
changes, be stopped to further enrollment, or be terminated.
Rationale for Change:
An IA and a futility analysis have been added.  The IA may also allow for an earlier detection 
of clinical benefit to patients with the ofatumumab and bendamustine combination.   The 
purpose the IA is to review accumulating safety and efficacy data and to also provide an 
opportunity to terminate the study if there is strong evidence that the ofatumumab and 
bendamustine combination will fail to show superiority if the study is allowed to run to its 
planned completion (stopping for futility).  
Section 3.1: INVESTIGATIONAL PLAN - Study Design
Original Text:
Primary Analysis
The primary analysis of PFS will use 90% power to detect a 50% treatment effect; a 13.5 vs. 9 
month improvement in Arm A (ofatumumab and bendamustine combination therapy) vs. Arm 
B (bendamustine monotherapy).  This trial is an event-driven study design with an event-
driven sample size of 256 total events and the final analysis will take place at the time of 
occurrence of the 256th event. The guideline for the study reaching 256 total events with 
respect to previously stated assumptions will require the screening of 408 subjects to ensure 
346 subjects are randomized and to have a study duration of approximately 69 months from 
the first day of first subject until the time of the 256th event.
Text changed to:
The primary analysis of PFS will use 90% power to detect a 50% treatment effect; a 13.5 vs. 9 
month improvement in Arm A (ofatumumab and bendamustine combination therapy) vs. Arm 
B (bendamustine monotherapy).  This trial is an event-driven study design with an event-
driven sample size of 256 259 total events and the final analysis will take place at the time of 
occurrence of the 256th 259th event. The guideline for the study reaching 256 259 total events 
with respect to previously stated assumptions will require the screening of 408 subjects to 
ensure 346 subjects are randomized and to have a study duration of approximately 6977
months from the first day of first subject until the time of the 256th 259th event.
Rationale for Change:
See rationale above for event count increase and study duration increase.  


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Section 3.1: Investigational Plan – Study Design
Text added:
Interim Analysis 
An Interim Analysis (IA) for efficacy of the primary endpoint, progression free survival, will 
occur when approximately two thirds (or approximately 172) of the total 259 IRR events is 
achieved.  The IA will be conducted at a significance level of 0.012.  At the same time as the 
IA, a Futility analysis (FA) will also occur.  The IDMC will review the efficacy and futility 
data at this timepoint.  
Section 3.1: Investigational Plan - Study Schema
Original Text:
16.
The IDMC met and confirmed the safety and tolerability of the Arm A combination therapy.  No further IDMC meetings 
are required.


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Text changed to:
1.
The IDMC met and confirmed the safety and tolerability of the Arm A combination therapy.  No further IDMC meetins 
are required.  A further IDMC meeting will review the IA and FA data.
Rationale for Change:
Inclusion of an interim analysis.
SECTION 3.1.2  RANDOMIZATION AND STRATIFICATION
Original Text:
Centralized randomization numbers within each stratum will be created for treatment 
assignment using the GSK RandALL randomization system.  The investigator will access the 
GSK Randomization and Medication Ordering System (RAMOS) by telephone to receive the 
subject's randomization number and initial study medication container number.
Text changed to:
Centralized randomization numbers within each stratum will be created for treatment 
assignment to ensure balance, with respect to the number of subjects assigned to each 
treatment group within each stratum, using the GSK RandALL randomization system 
(with randomly permuted blocks within strata).  The investigator will access the GSK 
Randomization and Medication Ordering System (RAMOS) by telephone to receive the 
subject's randomization number and initial study medication container number.
Rationale for Change:
Further clarification of the randomisation process.
IDMC evaluated IA 
Efficacy and 
Futility
4


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Section 3.1.5 Follow-Up Phase
Original Text:
TABLE 1
FOLLOW-UP VISIT SCHEDULE AND CT SCAN REQUIREMENTS FOR 
ARM A AND ARM B
F/U phase1
CT scan3
3 M F/U 12
Required
6 M F/U 1
Required
9 M F/U 1
Required
12 M F/U 1
Required
15 M F/U 1
Required
18 M F/U 1
Required
30 M F/U 2
Required
42 M F/U 2
Required
54 M F/U 2
Required
60 M F/U 2
Not required3
Abbreviations:  Follow-Up 1= F/U 1; Follow-Up 2= F/U 2; Month= M
1.
This time schedule is for F/U 1, F/U 2, and the Survival F/U (begins 2 months after PD, see footnote 2). 
2.
The 3 M F/U 1 visit occurs 336 days after randomization (or 3 months after Day 252) in Arm A and Arm B (Appendix 1, 
Appendix 2).  For subjects with PD in Arm B who select ofatumumab monotherapy (these are subjects who enter ), this 
3 M F/U 1 visit begins 3 months after last ofatumumab monotherapy doseAppendix 3.  Note:  unlike F/U1 and F/U 2, the 
Survival F/U begins 2 months after PD then continues every 3 months until Month 18 of F/U then every 12 months until 
approximately Month 54 of F/U (or 36 months after Month 18 of F/U) and a final visit on Month 60 of F/U.
3.
CT scans are required during scheduled F/U 1 and F/U 2 visits in Arm A and Arm B (Appendix 1) with the last required 
CT scan on Month 54.  CT scans for ofatumumab monotherapy following PD in Arm B will be done according to the 
schedule presented in Appendix 1.  CT scans will be required to confirm clinical signs or suspicion of progression if 
observed outside all scheduled F/U 1 and F/U 2 visits.  CT scans are not required for Survival F/U.  
Follow-up assessments begin on Day 336 (3 months after Day 252), then according to 
Appendix 1 and Appendix 2 (also see SPM).  In the event of PD, Survival Follow-Up visits 
begin 2 months after PD is confirmed by CT scan and will follow the time intervals described 
in Appendix 1. and  Appendix 3.  Survival F/U begins 2 months after PD then follows the F/U 
1 and F/U 2 time intervals described in .  Each follow-up visit and assessment will have a time 
window of ±7 days for Follow-Up Visit #1 and a time window of ±14 days for Follow-Up 
Visit #2.  Follow-up visits will include collection of survival status, concomitant medications, 
and response assessments, based on RRCML.  Survival follow-up visits may be phone calls 
instead of physician office visits.  In addition, subjects will be monitored for safety and 
efficacy as described.  See Appendix 1 and Appendix 2 for a complete list of follow-up 
procedures.


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Text changed to:
TABLE 1
FOLLOW-UP VISIT SCHEDULE AND CT SCAN REQUIREMENTS FOR 
ARM A AND ARM B
F/U phase1
CT scan1
3 M F/U 12
Required
6 M F/U 1
Required
9 M F/U 1
Required
12 M F/U 1
Required
15 M F/U 1
Required
18 M F/U 1
Required
30 M F/U 2
Required
42 M F/U 2
Required
54 M F/U 2
Required
60 M F/U 2
Not required1
Abbreviations:  Follow-Up 1= F/U 1; Follow-Up 2= F/U 2; Month= M

This time schedule is for F/U 1, F/U 2, and the Survival F/U (begins 2 months after PD, see footnote 2). 

The 3 M F/U 1 visit occurs 336 days after randomization (or 3 months after Day 252) in Arm A and Arm B 
(Appendix 1, Appendix 2).  For subjects with PD in Arm B who select ofatumumab monotherapy (these are 
subjects who enter ), this 3 M F/U 1 visit begins 3 months after last ofatumumab monotherapy doseAppendix 3.  
Note:  unlike F/U1 and F/U 2, the Survival F/U begins 2 months after PD then continues every 3 months until Month 
18 of F/U then every 12 months until approximately Month 54 of F/U (or 36 months after Month 18 of F/U) and a 
final visit on Month 60 of F/U.
1.
CT scans are required during scheduled F/U 1 and F/U 2 visits in Arm A and Arm B (Appendix 1) with the last required 
CT scan on Month 54.  CT scans for ofatumumab monotherapy following PD in Arm B will be done according to the 
schedule presented in Appendix 1.  CT scans will be required to confirm clinical signs or suspicion of progression if 
observed outside all scheduled F/U 1 and F/U 2 visits.  CT scans are not required for Survival F/U.  
For patients with SD, PR, or CR, follow-up assessments begin on Day 336 (3 months after 
Day 252), then continue according to Appendix 1, and Appendix 2, and Table 1 (also see 
SPM).  
For patients with In the event of PD during the treatment period, Survival Follow-Up 
visits begin 2 months after PD is confirmed by CT scan and will follow the time intervals 
described in Appendix 1, and Appendix 3 and Table 1, beginning with the 3M F/U visit one 
month after the 2 M F/U visit.  Survival F/U begins 2 months after PD then follows the F/U 
1 and F/U 2 time intervals described in .  
For patients with PD during the follow up period, Survival Follow-Up visits begin 2 
months after PD is confirmed by CT scan.  After the 2M F/U visit they will continue on 
their current follow up schedule according to Appendix 1, Appendix 2 and Table 1.
Each follow-up visit and assessment will have a time window of ±7 days for Follow-Up Visit 
#1 and a time window of ±14 days for Follow-Up Visit #2.  Follow-up visits will include 
collection of survival status, concomitant medications, and response assessments, based on 
RRCML.  Survival follow-up visits may be phone calls instead of physician office visits.  In 
addition, subjects will be monitored for safety and efficacy as described.  See Appendix 1 and 
Appendix 2 for a complete list of follow-up procedures.


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Rationale for Change:
Clarification of instructions for patients moving into Survival Follow-Up
Section 6.4.1: Safety Assessments: Ofatumumab Liver 
Interruption/Stopping and Follow-up Criteria
Original Text:
Title: Ofatumumab Liver Interruption/Stopping and Follow-up Criteria
Text changed to:
Title: Ofatumumab Liver Interruption/Stopping and Follow-up Criteria
Rationale for Change:
Liver stopping criteria should apply to all patients on study, and not just ofatumumab patients 
only (Arm A).  This will assure the safety of all subjects, and the need to evaluate liver event 
etiology.
Section 6.4.1.1: Safety Assessments: Liver Chemistry Stopping Criteria
Original Text:
The stopping criteria for ofatumumab are based upon the FDA July 2009 Guidance for 
Industry, Drug-Induced Liver Injury:  Pre-marketing Clinical Evaluation, Section 5, Decision 
to Stop Drug Administration.  The FDA guidance was adapted for oncology ofatumumab 
protocols such that the criteria for stopping dosing are:
Text changed to:
The stopping criteria for ofatumumab all subjects are based upon the FDA July 2009 
Guidance for Industry, Drug-Induced Liver Injury:  Pre-marketing Clinical Evaluation, 
Section 5, Decision to Stop Drug Administration.  The FDA guidance was adapted for 
oncology ofatumumab protocols such that the criteria for stopping dosing are:
Rationale for Change:
See rationale above for liver stopping criteria.


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Section 6.4.1.3: Safety Assessments: Liver Chemistry Follow-up 
Assessments
Original Text:

Blood sample for PK analysis of ofatumumab, obtained as soon as possible but no later 
than 5 months of last dose (approximately 5 half-lives of the drug).  Record the date/time 
of the PK sample draw and the date/time of the last dose of ofatumumab prior to blood 
sample draw on the eCRF.  If the date or time of the last dose is unclear, provide the best 
approximation.  If a PK sample cannot be collected in the time period indicated above, do 
not obtain a PK sample.  Instructions for sample handling and shipping are in the SPM.  
Text changed to:

Blood sample for PK analysis of ofatumumab (if an Arm A subject), obtained as 
soon as possible but no later than 5 months of last dose (approximately 5 half-lives of 
the drug).  Record the date/time of the PK sample draw and the date/time of the last 
dose of ofatumumab prior to blood sample draw on the eCRF.  If the date or time of 
the last dose is unclear, provide the best approximation.  If a PK sample cannot be 
collected in the time period indicated above, do not obtain a PK sample.  Instructions 
for sample handling and shipping are in the SPM.  
Rationale for Change:
Clarification added as PK analysis of ofatumumab if only required per protocol requirements 
for Arm A patients.
Section 8.2:  Study Design Considerations
Text added to include:
INTERIM ANALYSIS
An Interim Analysis (IA) for efficacy of the primary endpoint, progression free survival, 
will occur when approximately two thirds (or approximately 172) of the total 259 IRR 
events is achieved.  The interim analysis will be conducted at a significance level of 0.012.   
At the same time as the IA, a Futlity Analysis (FA) will also occur.  The Independent 
Data Monitoring Committee (IDMC) will review the efficacy and futility data at this 
timepoint.  Based on the IDMC review of the data available, as well as the IDMC 
charter-defined criteria, the IDMC will recommend that the study continue without any 
changes, be stopped to further enrollment, or be terminated.  Further details are 
specified in the IDMC charter.
The actual significance level at the interim and the final analysis will depend on the 
actual number of events at the time of analysis - utilizing the O’Brien-Fleming boundary.  
Should the interim occur at 172 events then the corresponding significance level is 0.012.  
Additionally, the final analysis (at 259 events) would be tested against 0.046 to maintain 
the overall type I error rate at 5% two-sided. If the actual event counts differ for the 
analysis, modification to the significance levels (0.012 for the interim and 0.046 for the 


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final analysis) would be adjusted as appropriate according to the O’Brien-Fleming 
spending function.
Rationale for Change:
Inclusion of an interim analysis
Section 8.2.1:  Sample Size Assumptions
Original Text:

Accrual rate is 6 subjects per month 
Under the above assumptions, approximately 256 total events from both treatment arms 
combined are needed for the study to have 90% power.  With a sample size of 304 subjects, 
the duration of the study will be about 62 months (under H1) to obtain the 256 total events.  
Assuming a dropout rate of 12%, the total sample size randomized for both arms combined 
will be 346 subjects, with approximate study duration of 69 months.
Assuming a screening failure rate of 15%, the total number of subjects screened will be 
approximately 408.
As stated, this trial is an event-driven study design with an event-driven sample size of 256 
total events and the final analysis will take place at the time of occurrence of the 256th event. 
The guideline for the study reaching 256 total events with respect to previously stated 
assumptions involve screening of 408 subjects so as to have 346 subjects randomized and to 
have a study duration of about 69 months from the first day of first subject until the time of 
the 256th event.
Text changed to:

Accrual rate is 6 5.1 subjects per month 
Under the above assumptions, approximately 256 259 total events from both treatment arms 
combined are needed for the study to have 90% power.  With a sample size of 304 subjects, 
the duration of the study will be about 62 70 months (under H1) to obtain the 256 259 total 
events.  Assuming a dropout rate of 12%, the total sample size randomized for both arms 
combined will be 346 subjects, with approximate study duration of 69 77 months.
Assuming a screening failure rate of 15%, the total number of subjects screened will be 
approximately 408.
As stated, this trial is an event-driven study design with an event-driven sample size of 256
259 total events and the final analysis will take place at the time of occurrence of the 256th
259th event. The guideline for the study reaching 256 259 total events with respect to 
previously stated assumptions involve screening of 408 subjects so as to have 346 subjects 
randomized and to have a study duration of about 69 77 months from the first day of first 
subject until the time of the 256th 259th event.
Rationale for Change:


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See rationale above for event count increase and study duration increase.  
Section 8.2.2:  Sample Size Sensitivity
Original Text:
The robustness and sensitivity of the above sample size calculation is considered in order to 
assess the impact on power if the assumed median PFS varies.  The following table shows the 
estimated power for different median values of PFS for ofatumumab + bendamustine. The 
total number of events is 256, and the number of subjects is 304.
Text changed to:
The robustness and sensitivity of the above sample size calculation is considered in order to 
assess the impact on power if the assumed median PFS varies.  The following table shows the 
estimated power for different median values of PFS for ofatumumab + bendamustine. The 
total number of events is 256 259, and the number of subjects is 304.
Rationale for Change:
See rationale above for event count increase.  
Section 8.3.1.1  Analysis Population - Four Populations are determined 
for the analyses:
Original Text:

The Intent-to-Treat (ITT) Population will include subjects in the final analysis stage 
who are randomized to the study drugs.  This will be the primary population used for 
all efficacy assessments.   In the analyses, subjects will be grouped based on how they 
are randomized regardless of which treatment they received. The ITT population will 
also be used for all PRO analyses.  
Text changed to:

The Intent-to-Treat (ITT) Population will include subjects in the final analysis stage 
who are randomized to the study drugs.  This will be the primary population used for 
all efficacy assessments.   In the analyses, subjects will be grouped based on how they 
are randomized regardless of which treatment they received. The ITT population will
also be used for all PRO analyses.  The ITT population will also be utilized for the 
Interim Analysis(IA) for efficacy and futility based on the number of subjects 
randomized at the time of the IA.
Rationale for Change:
Updated due to addition of the Interim Analysis.  IA will be conducted using an ITT 
population as defined.


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Section 8.3.3.1 Treatment Comparisons - Primary Comparisons of 
Interest
Original Text:
The primary treatment comparison of interest will be ofatumumab + bendamustine vs. 
bendamustine. This will be based on comparing the overall PFS when the total number of 
events reaches 256 total events (from both arms) using the ITT population.
The primary efficacy endpoint will serve as a gatekeeper for the interpretation of treatment 
comparisons for the ‘inferential’ secondary endpoints.  If H0 is rejected at the 0.05 level, the 
conclusion will be that there is a treatment difference between ofatumumab in combination 
with bendamustine and bendamustine monotherapy, and the p-value for the ‘inferential’ 
secondary endpoints may be interpreted.
Text Changed to:
The primary treatment comparison of interest will be ofatumumab + bendamustine vs. 
bendamustine. This will be based on comparing the overall PFS when the total number of 
events reaches 256 events (from both arms) 172 events for the interim analysis or 259 
events for the final analysis using the ITT population.
The primary efficacy endpoint will serve as a gatekeeper for the interpretation of treatment 
comparisons for the ‘inferential’ secondary endpoints.  If H0 is rejected at the 0.05 0.012 level 
for the interim analysis or 0.046 level for the final analysis, the conclusion will be that 
there is a treatment difference between ofatumumab in combination with bendamustine and 
bendamustine monotherapy, and the p-value for the ‘inferential’ secondary endpoints may be 
interpreted.
As described in Section 8.2, the significance levels for the interim and final analysis will 
be adjusted as appropriate using the O’Brien-Fleming spending function.
Rationale for Change:
Inclusion of an interim analysis.
Section 8.3.3.2 Treatment Comparisons Secondary and Other 
Comparisons of Interest
Original Text:
The secondary comparisons of interest will be ofatumumab + bendamustine vs. bendamustine, 
based on the ORR and OS.  The ORR and OS will be considered as “inferential secondary 
endpoints” and will be tested hierarchically only if the primary endpoint, PFS, is significant.  
Each hypothesis will be tested at alpha level 0.05.  If the PFS is significant then the ORR will 
be tested and if significant, then the OS will be tested.
The other comparisons of interest will be ofatumumab + bendamustine vs. bendamustine, 
based on the other secondary endpoints at alpha level 0.05.  No multiplicity will be considered 
in the other secondary endpoints and any p-value that is 0.05 will be identified as nominally 
significant.
Text Changed to:
The secondary comparisons of interest will be ofatumumab + bendamustine vs. bendamustine, 
based on the ORR and OS.  The ORR and OS will be considered as “inferential secondary 
endpoints” and will be tested hierarchically only if the primary endpoint, PFS, is significant.  
Each hypothesis will be tested at alpha level 0.05 0.012 for the interim analysis or 0.046 for 


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the final analysis.  If the PFS is significant then the ORR will be tested and if significant, 
then the OS will be tested.
The other comparisons of interest will be ofatumumab + bendamustine vs. bendamustine, 
based on the other secondary endpoints at alpha level 0.05 0.012 for the interim analysis or 
0.046 for the final analysis.  No multiplicity will be considered in the other secondary 
endpoints and any p-value that is 0.05  0.012 for the interim analysis and 0.046 for 
the final analysis will be identified as nominally significant.
Rationale for Change:
Inclusion of an interim analysis
Section 8.3. Data Analysis Considerations:
Text added:
8.3.5 INTERIM ANALYSIS FOR EFFICACY AND FUTILITY
An Interim Analysis (IA) for efficacy will occur when approximately two thirds (or 
approximately 172) of the total 259 IRR events is achieved.  The interim analysis for PFS 
will be performed by an IDMC utilizing an O’Brien-Fleming spending function with 
significance level of 0.012 (with 172 events).  Performing this interim analysis with an 
IDMC may allow for an earlier detection of clinical benefit to patients with
ofatumumab+bendamustine and if this analysis is positive, may support a submission 
that enables earlier access to patients. The interim analysis of the primary endpoint, PFS, 
will be conducted as described in Section 5.1.3.1, and further details of the interim 
analysis will be provided in the IDMC Charter.  The final analysis will be conducted at a 
significance level of 0.046 (with 259 events) to maintain an overall study significance 
level of 0.05.  At the same time as the IA, a Futlity Analysis (FA) will also occur.  This 
process is further detailed in a charter for the IDMC.
Rationale for Change:
Inclusionof an interim analysis.
Section 8.3.6.1  Efficacy Analyses
Primary Analysis
Original text:
Progression-free survival is defined as the time from randomization until progression or death.  
The progression events will be defined by well-documented and verifiable data.  Details of 
censoring will be provided in the RAP.
PFS will be tested based on a two-sided test, with a significance level of 0.05.  Survival 
distributions will be estimated using the Kaplan-Meier method, and survival curves will be 
compared using a stratified log-rank test.
Text changed to:
Progression-free survival is defined as the time from randomization until progression or death.  
The progression events will be defined by well-documented and verifiable data.  Details of 
censoring will be provided in the RAP.


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An interim analysis of the primary endpoint, PFS, will be performed when two thirds of 
the total number of events have occurred (172 events).  The interim analysis for PFS will 
be performed by an IDMC utilizing a significance level of 0.012.   The interim analysis of 
PFS will be conducted in the same manner as described for the final analysis, and 
further details of the interim analysis will be provided in the IDMC Charter. 
The final analysis of PFS will be tested based on a two-sided test, with a significance level of
0.05 0.046.  Survival distributions will be estimated using the Kaplan-Meier method, and 
survival curves will be compared using a stratified log-rank test.
Rationale for change:
Inclusion of an interim analysis
Section 8.3.6.1  Efficacy Analyses
Original text:
Inferential Secondary Analyses:

Overall survival 
OS is defined as the time from randomization until death.  Analysis methods will be similar to 
those described for the PFS analysis and details of censoring will be provided in the RAP.
OS will be tested on a two sided test, with a significance level of 0.05. Survival distributions 
will be estimated using the Kaplan-Meier method, and survival curves will be compared using 
a stratified log-rank test.
Text changed to:
Inferential Secondary Analyses:

Overall survival 
OS is defined as the time from randomization until death.  Analysis methods will be similar to 
those described for the PFS analysis and details of censoring will be provided in the RAP.
OS will be tested on a two sided test, with a significance level of 0.05. Survival distributions 
will be estimated using the Kaplan-Meier method, and survival curves will be compared using 
a stratified log-rank test.
Rationale:
Updated to avoid duplication with other sections.
Section 9.7  Independent Data Monitoring Committee (IDMC):
Sub-headings added:
9.7.1  Dose Confirmation for Safety and Tolerability
9.7.2  Interim Analysis


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Section 9.7  Independent Data Monitoring Committee (IDMC):
Original text:
STAGE 1 RESULTS FROM IDMC DATA REVIEW
The IDMC met after the first 20 subjects in Arm A received at least 3 cycles of OB.  Based on 
their review of the data as well as the IDMC charter defined criteria to alter the dose in Arm A, 
the final recommendation from IDMC was to not change the current dose regimen and 
therefore to allow the study to proceed unchanged [IDMC communication, 2011].  
Consequently, there will be no further IDMC meetings and no further dose modifications 
other than the protocol-directed dose reductions and delays already described in Section 
5.1.3.1of this protocol.  The safety of subjects enrolled in the study will continue to be 
monitored by GSK.
Text changed to:
STAGE 1 RESULTS FROM IDMC DATA REVIEW
The IDMC met after the first 20 subjects in Arm A received at least 3 cycles of OB.  Based on 
their review of the data as well as the IDMC charter defined criteria to alter the dose in Arm A, 
the final recommendation from IDMC was to not change the current dose regimen and 
therefore to allow the study to proceed unchanged [IDMC communication, 2011].  
Consequently There will be no further IDMC meetings and no further dose modifications 
other than the protocol-directed dose reductions and delays already described in Section 
5.1.3.1of this protocol.  The safety of subjects enrolled in the study will continue to be 
monitored by GSK.
Rationale for Change:
Inclusion of an interim analysis.
Section 9.7  Independent Data Monitoring Committee (IDMC):
Text added:
9.7.2  Interim Analysis
An IDMC will be utilised to review the primary endpoint, progression free survival 
when approximately two thirds of the total IRR events has been reached.  The IDMC 
will review data from the interim analysis and the futility analysis.
The IDMC will meet once to review the data and will recommend that the study 
continue without any changes, be stopped to further enrolment, or be terminated.  
Further details can be found in the IDMC charter.
Rationale for Change:
Inclusion of an interim analysis


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11.16
Appendix 16:  Protocol Changes for Amendment 8 (18-MAR-2016) 
from Amendment 7 (dated 07-JUL-2015)
Where the Amendment applies:
Ammendment 8 is applicable to all study sites.
Global Changes:
Section(s)
Change
Rationale
Header/Footer
Changed as per Novartis 
requirements
Change in study sponsorship from 
GSK to Novartis
Title Page
Title page replaced as per 
Novartis requirements
Change in study sponsorship from 
GSK to Novartis
Sponsor 
Information Page
The GSK contact information 
replaced with Novartis 
contact information
Change in study sponsorship from 
GSK to Novartis
Sponsor 
signatory
Change of sponsor signatory
Change in study sponsorship from 
GSK to Novartis
Multiple
The term ‘medical monitor’ 
replaced with ‘Medical Lead’
Change in study sponsorship from 
GSK to Novartis
Multiple
References to GSK or its staff 
replaced with that of Novartis 
and its authorized agents
To align with the change of 
sponsorship from GSK to Novartis
Multiple
References to GSK tools, 
departments, and concomitant 
medication deleted
To align with the change of 
sponsorship from GSK to Novartis
Appendices
References to GSK in figures 
changed to Novartis
To align with the change of 
sponsorship from GSK to Novartis
In addition, several typographical and format changes have been made throughout the 
protocol, but not listed individually. 
List of Specific Changes
Note: deleted language is presented with a strikethrough and added language is printed in 
bold.
Section: Title Page, Sponsor Information Page, and Sponsor Signatory 
Page
Authors, contacts and sponsor signatory updated to reflect the curren team members and 
contact details. Also, necessary changes are made to reflect the study transfer from GSK to 
Novartis.
Section: List of Abbreviations
List has been updated as required.
Trademark information deleted to align with Novartis processes and procedures.


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Protocol Summary: 
Study Design: Dose Confirmation Cohort
Original text:
The safety of subjects enrolled into the study will continue to be monitored by 
GlaxosmithKline (GSK).
Text changed to:
The safety of subjects enrolled into the study will continue to be monitored by 
GlaxosmithKline (GSK) Novartis.
Rationale for change:
The rationale for the change is deletion or replacement of all references to GSK or its staff 
with that of Novartis and its authorized agents to align with the change of sponsorship and 
make administrative changes to align with Novartis processes and procedures.
Section 3.1: Study Design
Original text:
The safety of subjects enrolled into the study will continue to be monitored by 
GlaxosmithKline (GSK).
Text changed to:
The safety of subjects enrolled into the study will continue to be monitored by 
GlaxosmithKline (GSK) Novartis.
Rationale for change:
The rationale for the change is deletion or replacement of all references to GSK or its staff 
with that of Novartis and its authorized agents to align with the change of sponsorship and 
make administrative changes to align with Novartis processes and procedures.
Section 3.1.1: Screening Phase
Original text:
Review of Materials: 
If the investigator wants to use a CT scan done >1 month (+7 days) prior to randomization, 
the medical monitor must be contacted to determine if CT scan can be accepted.
Text changed to:
If the investigator wants to use a CT scan done >1 month (+7 days) prior to randomization, 
the medical monitor Medical Lead must be contacted to determine if CT scan can be 
accepted.
Rationale for change:
The rationale for the change is deletion or replacement of all references to GSK or its staff 
with that of Novartis and its authorized agents to align with the change of sponsorship and 
make administrative changes to align with Novartis processes and procedures.


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Section 3.1.1.1: Documentation of indolent B-cell NHL that is stable or 
has progressed during or within six months of the end of treatment with 
rituximab or a rituximab–containing regimen
Original text:
A documentation worksheet verifying the investigator’s diagnosis of SD following, or 
progression during or within 6 months of treatment with rituximab or a rituximab-containing 
regimen will be required at screening.  This documentation worksheet must be sent to GSK 
prior to randomization and will ask for:
Information about last qualifying rituximab therapy:

Dates before and dates after last qualifying rituximab-containing regimen

Type of rituximab therapy and regimen (examples: weekly, monthly):

Rituximab (includes monotherapy and maintenance), or

Rituximab added to chemotherapy

Date and type of response associated with last qualifying rituximab-containing regimen
Information regarding imaging:

Copy of documentation (for example, an imaging report, clinical documentation) prior to 
last qualifying rituximab-containing regimen is required (if available)

Copy of documentation confirming PD (for example, an imaging report, clinical 
documentation) after subject deemed unresponsive or relapsed to rituximab-based 
regimen is requiredAssurance of an ability to submit, for each subject 

imaging or other documentation showing disease status before the start of the last 
qualifying rituximab-containing regimen is requested

imaging or other documentation confirming unresponsive or relapse following the 
last qualifying rituximab regimen is required

CT imaging is performed at screening
Subjects will not be enrolled in the study unless the investigator or designate verifies SD 
following, or progression during or within six months of treatment with rituximab or a 
rituximab–containing regimen.  Submission of the subject’s imaging is expected be sent to 
GSK within one month following randomization.
Text changed to:
A documentation worksheet verifying the investigator’s diagnosis of SD following, or 
progression during or within 6 months of treatment with rituximab or a rituximab-containing 
regimen will be required at screening.  This documentation worksheet must be sent to GSK
Novartis prior to randomization and will ask for:
Information about last qualifying rituximab therapy:

Dates before and dates after last qualifying rituximab-containing regimen

Type of rituximab therapy and regimen (examples: weekly, monthly):

Rituximab (includes monotherapy and maintenance), or


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
Rituximab added to chemotherapy

Date and type of response associated with last qualifying rituximab-containing regimen
Information regarding imaging:

Copy of documentation (for example, an imaging report, clinical documentation) prior to 
last qualifying rituximab-containing regimen is required (if available)

Copy of documentation confirming PD (for example, an imaging report, clinical 
documentation) after subject deemed unresponsive or relapsed to rituximab-based 
regimen is required

Assurance of an ability to submit, for each subject 

imaging or other documentation showing disease status before the start of the last 
qualifying rituximab-containing regimen is requested

imaging or other documentation confirming unresponsive or relapse following the 
last qualifying rituximab regimen is required

CT imaging is performed at screening
Subjects will not be enrolled in the study unless the investigator or designate verifies SD 
following, or progression during or within six months of treatment with rituximab or a 
rituximab–containing regimen.  Submission of the subject’s imaging is expected be sent to 
GSK Novartis within one month following randomization.
Rationale for change:
The rationale for the change is deletion or replacement of all references to GSK or its staff 
with that of Novartis and its authorized agents to align with the change of sponsorship and 
make administrative changes to align with Novartis processes and procedures.
Section 3.1.2: Randomization and Stratification
Original text:
Centralized randomization numbers within each stratum will be created for treatment 
assignment to ensure balance, with respect to the number of subjects assigned to each 
treatment group within each stratum, using the GSK RandALL randomization system (with 
randomly permuted blocks within strata).  The investigator will access the GSK 
Randomization and Medication Ordering System (RAMOS) by telephone to receive the 
subject's randomization number and initial study medication container number.
Text changed to:
Centralized randomization numbers within each stratum will be created for treatment 
assignment to ensure balance, with respect to the number of subjects assigned to each 
treatment group within each stratum, using the GSK RandALL a randomization system (with 
randomly permuted blocks within strata).  The investigator will access the GSK 
Randomization and Medication Ordering System (RAMOS) Interactive Voice Response 
System by telephone to receive the subject's randomization number and initial study 
medication container number.
Rationale for change:


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The rationale for the change is deletion or replacement of all references to GSK or its staff 
with that of Novartis and its authorized agents to align with the change of sponsorship and 
make administrative changes to align with Novartis processes and procedures.
Section 3.1.3: Dose Confirmation for Safety and Tolerability
Original text:
Update:  Decision from IDMC Meeting (Stage 1):
The safety of subjects enrolled into the study will continue to be monitored by GSK.
Text changed to:
The safety of subjects enrolled into the study will continue to be monitored by GSK Novartis.
Rationale for change:
The rationale for the change is deletion or replacement of all references to GSK or its staff 
with that of Novartis and its authorized agents to align with the change of sponsorship and 
make administrative changes to align with Novartis processes and procedures.
Section 4.3: Exclusion Criteria
Original text:
11. Significant concurrent, uncontrolled medical condition that in the opinion of the 
investigator or GSK medical monitor contraindicates participation this study
Subjects can participate in the study if in the opinion of the investigator and medical monitor 
it is thought not to affect the subject’s safety, the conduct of the study or the interpretation of 
the data
Text changed to:
11. Significant concurrent, uncontrolled medical condition that in the opinion of the 
investigator or GSK medical monitor Novartis Medical Lead contraindicates participation 
this study
Subjects can participate in the study if in the opinion of the investigator and medical monitor
Medical Lead it is thought not to affect the subject’s safety, the conduct of the study or the 
interpretation of the data
Rationale for change:
The rationale for the change is deletion or replacement of all references to GSK or its staff 
with that of Novartis and its authorized agents to align with the change of sponsorship and 
make administrative changes to align with Novartis processes and procedures.
Section 5.1: Investigational Product and Reference Therapy
Original text:
A Material Safety Data Sheet (MSDS) describing the occupational hazards and recommended 
handling precautions will be provided to site staff if required by local laws or will otherwise 
be available from GSK upon request.
Text changed to:
A Material Safety Data Sheet (MSDS) describing the occupational hazards and recommended 
handling precautions will be provided to site staff if required by local laws or will otherwise 
be available from GSK Novartis upon request.
Rationale for change:


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The rationale for the change is deletion or replacement of all references to GSK or its staff 
with that of Novartis and its authorized agents to align with the change of sponsorship and 
make administrative changes to align with Novartis processes and procedures.
Section 5.1.3.1: Bendamustine Dose Reduction
Original text:
Toxicities must recover to Grade 1 or baseline before the next administration of treatment. If 
recovery is not met within 2 weeks after the prescribed start of the treatment cycle (i.e., after a 
2 week delay), a decision will be made about continuation in the study following consultation 
with medical monitor.
Text changed to:
Toxicities must recover to Grade 1 or baseline before the next administration of treatment. If 
recovery is not met within 2 weeks after the prescribed start of the treatment cycle (i.e., after a 
2 week delay), a decision will be made about continuation in the study following consultation 
with medical monitor Medical Lead.
Rationale for change:
The rationale for the change is deletion or replacement of all references to GSK or its staff 
with that of Novartis and its authorized agents to align with the change of sponsorship and 
make administrative changes to align with Novartis processes and procedures.
Section 5.4: Product Accountability
Original text:
In accordance with local regulatory requirements, the investigator, designated site staff,
or head of the medical institution (where applicable) must document the amount of 
bendamustine and GSK investigational product administered to study subjects and the amount 
received from and returned to GSK, when applicable. Product accountability records must be 
maintained throughout the course of the study.
Text changed to:
In accordance with local regulatory requirements, the investigator, designated site staff,
or head of the medical institution (where applicable) must document the amount of 
bendamustine and GSK Novartis investigational product administered to study subjects and 
the amount received from and returned to GSK Novartis, when applicable. Product 
accountability records must be maintained throughout the course of the study.
Rationale for change:
The rationale for the change is deletion or replacement of all references to GSK or its staff 
with that of Novartis and its authorized agents to align with the change of sponsorship and 
make administrative changes to align with Novartis processes and procedures.
Section 6.2.2: CT Scans
Original text:
The scans must be implemented according to a CT scan manual to be provided to GSK 
(Imaging Acquisition Guidelines) as mentioned in the SPM.
Text changed to:
The scans must be implemented according to a CT scan manual to be provided to GSK
Novartis (Imaging Acquisition Guidelines) as mentioned in the SPM.


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Rationale for change:
The rationale for the change is deletion or replacement of all references to GSK or its staff 
with that of Novartis and its authorized agents to align with the change of sponsorship and 
make administrative changes to align with Novartis processes and procedures.
Section 6.4.1: Liver Interruption/Stopping and Follow-up Criteria
Original text:
Liver chemistry stopping and follow up criteria are a mandatory part of GSK studies and have 
been designed to assure subject safety and evaluate liver event etiology.
The GSK Safety Review Team will review all events which meet liver chemistry stopping 
criteria and determine if the event was due to tumor lysis and to exclude drug induced 
liver injury (DILI) due to ofatumumab.
Text changed to:
Liver chemistry stopping and follow up criteria are a mandatory part of GSK Novartis studies 
and have been designed to assure subject safety and evaluate liver event etiology.
The GSK Novartis Safety Review Monitoring Team will review all events which meet 
liver chemistry stopping criteria and determine if the event was due to tumor lysis and 
to exclude drug induced liver injury (DILI) due to ofatumumab.
Rationale for change:
The rationale for the change is deletion or replacement of all references to GSK or its staff 
with that of Novartis and its authorized agents to align with the change of sponsorship and 
make administrative changes to align with Novartis processes and procedures.
Section 6.4.1.2: Liver Chemistry Interruption/Stopping and Follow-up 
Criteria
Original text:
The GSK Medical Monitor and Global Clinical Safety and Pharmacovigilance (GCSP) 
physician in conjunction with the investigator will review all events which meet liver 
chemistry stopping criteria to determine if the event was due to tumor lysis, disease 
related liver involvement, concomitant chemotherapy or other identified cause and to 
exclude drug induced liver injury (DILI) due to ofatumumab. If the event is determined 
to be due to causes other than ofatumumab DILI and improvement is observed after 
withdrawal of ofatumumab, rechallenge may be attempted if deemed appropriate by the 
GSK Medical Monitor and investigator and in addition to consent of the subject. 
‡ NOTE:  If serum bilirubin fractionation not immediately available, study drug must be 
discontinued if ALT > 3xULN and bilirubin >2xULN pending the results of review by the 
Medical Monitor, GCSP physician and the investigator.  Serum bilirubin fractionation must 
be performed if testing is available. If testing unavailable, record presence of detectable 
urinary bilirubin on dipstick, indicating direct bilirubin elevations and suggesting liver 
injury.
When any of the liver chemistry stopping criteria is met, do the following:

Immediately stop study treatment

Report the event to GSK within 24 hours of learning its occurrence


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Hold ofatumumab for two weeks, repeat liver chemistry testing at least twice weekly, and call 
the Medical Monitor to discuss the possibility of re-challenging with ofatumumab.
Text changed to:
The GSK Novartis Medical Monitor Lead and Global Clinical Safety and 
Pharmacovigilance (GCSP) physician in conjunction with the investigator will review all 
events which meet liver chemistry stopping criteria to determine if the event was due to 
tumor lysis, disease related liver involvement, concomitant chemotherapy or other 
identified cause and to exclude drug induced liver injury (DILI) due to ofatumumab. If 
the event is determined to be due to causes other than ofatumumab DILI and 
improvement is observed after withdrawal of ofatumumab, rechallenge may be 
attempted if deemed appropriate by the GSK Novartis Medical Monitor Lead and 
investigator and in addition to consent of the subject. 
‡ NOTE:  If serum bilirubin fractionation not immediately available, study drug must be 
discontinued if ALT > 3xULN and bilirubin >2xULN pending the results of review by the 
Medical Monitor Lead, GCSP physician and the investigator.  Serum bilirubin fractionation 
must be performed if testing is available. If testing unavailable, record presence of detectable 
urinary bilirubin on dipstick, indicating direct bilirubin elevations and suggesting liver 
injury.
When any of the liver chemistry stopping criteria is met, do the following:

Immediately stop study treatment

Report the event to GSK Novartis within 24 hours of learning its occurrence
Hold ofatumumab for two weeks, repeat liver chemistry testing at least twice weekly, and call 
the Medical Monitor Lead to discuss the possibility of re-challenging with ofatumumab.
Rationale for change:
The rationale for the change is deletion or replacement of all references to GSK or its staff 
with that of Novartis and its authorized agents to align with the change of sponsorship and 
make administrative changes to align with Novartis processes and procedures.
Section 6.5.4.1.5: Monitoring of Hepatitis in patients
Original text:
If a subject converts to HBV DNA positive during the study, Hepatitis B treatment may be 
initiated by the site investigator after consultation with a physician experienced in the care and 
management of subjects with Hepatitis B and the GSK medical monitor. The risks and 
benefits of continuing ofatumumab or discontinuing ofatumumab must be discussed with the 
medical monitor before appropriate treatment decisions are made for that individual subject.
Text changed to:
If a subject converts to HBV DNA positive during the study, Hepatitis B treatment may be 
initiated by the site investigator after consultation with a physician experienced in the care and 
management of subjects with Hepatitis B and the GSK medical monitor Novartis Medical 
Lead. The risks and benefits of continuing ofatumumab or discontinuing ofatumumab must 
be discussed with the medical monitor Medical Lead before appropriate treatment decisions 
are made for that individual subject.
Rationale for change:


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The rationale for the change is deletion or replacement of all references to GSK or its staff 
with that of Novartis and its authorized agents to align with the change of sponsorship and 
make administrative changes to align with Novartis processes and procedures.
Section 6.5.6: Pregnancy
Original text:
To ensure subject safety, each pregnancy must be reported to GSK within 2 weeks of learning 
of its occurrence.
Any SAE occurring in association with a pregnancy brought to the investigator’s attention 
after the subject has completed the study and considered by the investigator as possibly 
related to the investigational product, must be promptly reported to GSK.
The investigator must attempt to collect pregnancy information about a partner of a male 
study subject, who becomes pregnant by a male study subject while he is enrolled in the study. 
Pregnancy information must be reported to GSK as described above.
Text changed to:
To ensure subject safety, each pregnancy must be reported to GSK Novartis within 2 weeks
24 hours of learning of its occurrence.
Any SAE occurring in association with a pregnancy brought to the investigator’s attention 
after the subject has completed the study and considered by the investigator as possibly 
related to the investigational product, must be promptly reported to GSK Novartis.
The investigator must attempt to collect pregnancy information about a partner of a male 
study subject, who becomes pregnant by a male study subject while he is enrolled in the study. 
Pregnancy information must be reported to GSK Novartis as described above.
Rationale for change:
The rationale for the change is deletion or replacement of all references to GSK or its staff 
with that of Novartis and its authorized agents to align with the change of sponsorship and 
make administrative changes to align with Novartis processes and procedures.
Section 6.5.7: Time Period and Frequency of Detecting AEs and SAEs
Original text:
Any SAE brought to the investigator's attention after the start of subsequent anti-lymphoma 
therapy and considered by the investigator as possibly related to either ofatumumab or 
bendamustine must be reported to GSK.
From the time a subject consents to participate in and completes the study (See Section 4.4), 
all SAEs assessed as related to study participation (e.g., protocol-mandated procedures, 
invasive tests, or change in existing therapy) or related to GSK concomitant medication, will 
be reported promptly to GSK as indicated in Table 9.
From the time a subject consents to participate in and completes the study or withdraws from 
the study (Section 4.4), all SAEs assessed as related to study participation (e.g., protocol-
mandated procedures, invasive tests, or change in existing therapy) or related to concomitant 
medication, will be recorded.
Discontinuation of ofatumumab is not mandated; however the investigator must consult the 
GSK medical monitor to analyze the risk-benefit and determine if appropriate to continue 
ofatumumab therapy in that individual subject. 


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Any pre-existing condition or signs and symptoms present prior to investigational product will 
be recorded as medical history.  
Any SAE brought to the investigator’s attention after the subject has completed the study and 
considered by the investigator as possibly related to investigational product must be reported 
to GSK.
Text changed to:
Any SAE brought to the investigator's attention after the start of subsequent anti-lymphoma 
therapy and considered by the investigator as possibly related to either ofatumumab or 
bendamustine must be reported to GSK Novartis.
From the time a subject consents to participate in and completes the study (See Section 4.4), 
all SAEs assessed as related to study participation (e.g., protocol-mandated procedures, 
invasive tests, or change in existing therapy) or related to GSK concomitant medication, will 
be reported promptly to GSK Novartis as indicated in Table 9.
From the time a subject consents to participate in and completes the study or withdraws from 
the study (Section 4.4), all SAEs assessed as related to study participation (e.g., protocol-
mandated procedures, invasive tests, or change in existing therapy) or related to concomitant 
medication, will be recorded.
Discontinuation of ofatumumab is not mandated; however the investigator must consult the 
GSK medical monitor Novartis Medical lead to analyze the risk-benefit and determine if 
appropriate to continue ofatumumab therapy in that individual subject. 
Any pre-existing condition or signs and symptoms present prior to investigational product will 
be recorded as medical history.  
Any SAE brought to the investigator’s attention after the subject has completed the study and 
considered by the investigator as possibly related to investigational product must be reported 
to GSK Novartis.
Rationale for change:
The rationale for the change is deletion or replacement of all references to GSK or its staff 
with that of Novartis and its authorized agents to align with the change of sponsorship and 
make administrative changes to align with Novartis processes and procedures.
Section 6.5.7.1: Monitoring subjects with Hepatitis B
Original text:
If a subject’s HBV DNA becomes positive during the study, notify the GSK medical monitor. 
For subjects who have not completed planned ofatumumab therapy, discuss with the medical 
monitor the risks and benefits of continuing or discontinuing ofatumumab before appropriate 
treatment decisions are made for that individual subject.
Text changed to:
If a subject’s HBV DNA becomes positive during the study, notify the GSK medical monitor 
Novartis Medical Lead. For subjects who have not completed planned ofatumumab therapy, 
discuss with the medical monitor Medical Lead the risks and benefits of continuing or 
discontinuing ofatumumab before appropriate treatment decisions are made for that individual 
subject.
Rationale for change:


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The rationale for the change is deletion or replacement of all references to GSK or its staff 
with that of Novartis and its authorized agents to align with the change of sponsorship and 
make administrative changes to align with Novartis processes and procedures.
Section 6.5.8: Prompt Reporting of Serious Adverse Events and Other 
Events to GSK Novartis
Original text:
SAEs and pregnancies and liver chemistries meeting pre-defined stopping criteria will be 
reported promptly to GSK as described in the following table once the investigator determines 
that the event meets the protocol definition for that event.
Table 12
SAE reporting
Initial Reports
Follow-up Information on a Previous 
Report
Type of Event
Time Frame
Documents
Time Frame
Documents
All SAEs
24 hours
“SAE” data collection 
tool
24 hours
Updated “SAE” data 
collection tool 
Pregnancy
2 Weeks
Pregnancy 
Notification Form
2 Weeks
Pregnancy Follow up 
Form
Liver chemistry stopping 
criteria (See Section 
6.4.1)
24 to 72 hours
Liver event CRFs 
and “SAE” data 
collection tool
24 hours
Updated Liver Event 
CRF and SAE form 
and updated “SAE” 
data collection tool
The method of detecting, recording, evaluating and follow-up of AEs and SAEs plus 
procedures for completing and transmitting SAE reports to GSK are provided in the SPM.  
Procedures for post-study AEs/SAEs are provided in the SPM.
Text changed to:
SAEs and pregnancies and liver chemistries meeting pre-defined stopping criteria will be 
reported promptly to GSK Novartis as described in the following table once the investigator 
determines that the event meets the protocol definition for that event.
Table 13
SAE reporting
Initial Reports
Follow-up Information on a Previous 
Report
Type of Event
Time Frame
Documents
Time Frame
Documents
All SAEs
24 hours
“SAE” data collection 
tool
24 hours
Updated “SAE” data 
collection tool 
Pregnancy
2 Weeks 24 
hours
Pregnancy 
Notification Form
2 Weeks
Pregnancy Follow up 
Form
Liver chemistry stopping 
criteria (See Section 
6.4.1)
24 to 72 hours
Liver event CRFs 
and “SAE” data 
collection tool
24 hours
Updated Liver Event 
CRF and SAE form 
and updated “SAE” 
data collection tool


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The method of detecting, recording, evaluating and follow-up of AEs and SAEs plus 
procedures for completing and transmitting SAE reports to GSK Novartis are provided in the 
SPM.  Procedures for post-study AEs/SAEs are provided in the SPM.
Rationale for change:
The rationale for the change is deletion or replacement of all references to GSK or its staff 
with that of Novartis and its authorized agents to align with the change of sponsorship and 
make administrative changes to align with Novartis processes and procedures.
Section 6.5.9: Regulatory reporting requirements for SAEs
Original text:
Prompt notification of SAEs by the investigator to GSK is essential so that legal obligations 
and ethical responsibilities towards the safety of subjects are met.
GSK has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a product under clinical investigation.  GSK will 
comply with country specific regulatory requirements relating to safety reporting to the 
regulatory authority, IRB/ IEC and investigators.
Investigator safety reports are prepared for suspected unexpected serious adverse reactions 
according to local regulatory requirements and GSK policy and are forwarded to investigators 
as necessary.
An investigator who receives an investigator safety report describing a SAE(s) or other 
specific safety information (e.g., summary or listing of SAEs) from GSK will file it with the 
IB and will notify the IRB/IEC, if appropriate according to local requirements.
Text changed to:
Prompt notification of SAEs by the investigator to GSK Novartis is essential so that legal 
obligations and ethical responsibilities towards the safety of subjects are met.
GSK Novartis has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a product under clinical investigation.  GSK Novartis
will comply with country specific regulatory requirements relating to safety reporting to the 
regulatory authority, IRB/ IEC and investigators.
Investigator safety reports are prepared for suspected unexpected serious adverse reactions 
according to local regulatory requirements and GSK Novartis policy and are forwarded to 
investigators as necessary.
An investigator who receives an investigator safety report describing a SAE(s) or other 
specific safety information (e.g., summary or listing of SAEs) from GSK Novartis will file it 
with the IB and will notify the IRB/IEC, if appropriate according to local requirements.
Rationale for change:
The rationale for the change is deletion or replacement of all references to GSK or its staff 
with that of Novartis and its authorized agents to align with the change of sponsorship and 
make administrative changes to align with Novartis processes and procedures.
Section 7: DATA MANAGEMENT
Original text:
For this study, subject data will be entered into GSK defined eCRFs, transmitted 
electronically to GSK and combined with data provided from other sources (e.g. laboratory
data) in a validated data system.


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Clinical data management will be performed in accordance with applicable GSK standards 
and data cleaning procedures with the objective of removing errors and inconsistencies in the 
data which would otherwise impact the analysis and reporting objectives, or the credibility of 
the Clinical Study Report. Adverse events and concomitant medications terms will be coded 
using Medical Dictionary for Regulatory Activities (MedDRA) and GSKDrug, an internal 
validated medication dictionary.  In all cases, subject initials will not be collected nor 
transmitted to GSK according to GSK policy.
[An appropriate medical dictionary that covers all approved drugs in studies
where Japan is participating will be referenced].  [Select one of the following 2 options:
(1 - eDM) "eCRFs (including queries and audit trails) will be retained by GSK, and
copies will be sent to the investigator to maintain as the investigator copy" or (2- paper)
“Original CRFs will be retained by GSK, while the investigator will retain a copy”.] In
all cases, subject initials will not be collected or transmitted to GSK according to GSK policy.
Text changed to:
For this study, subject data will be entered into GSK defined the eCRFs, transmitted 
electronically to GSK Novartis and be combined with data provided from other sources (e.g. 
laboratory data) in a validated data system.
Clinical data management will be performed in accordance with applicable GSK standards 
and data cleaning procedures with the objective of removing resolving errors and 
inconsistencies in the data which would otherwise impact the analysis and reporting 
objectives, or the credibility of the Clinical Study Report. Adverse events and concomitant 
medications terms will be coded using Medical Dictionary for Regulatory Activities 
(MedDRA) and GSKDrug, an internal validated medication custom drug dictionary.  In all 
cases, subject initials will not be collected nor transmitted to GSK Novartis according to GSK
Novartis policy.
[An appropriate medical dictionary that covers all approved drugs in studies
where Japan is participating will be referenced].  [Select one of the following 2 options:
(1 - eDM) "eCRFs (including queries and audit trails) will be retained by GSK Novartis, and
copies will be sent to the investigator to maintain as the investigator copy". or (2- paper)
“Original CRFs will be retained by GSK, while the investigator will retain a copy”.] In
all cases, subject initials will not be collected or transmitted to GSK Novartis according to 
GSK Novartis policy.
Rationale for change:
The rationale for the change is deletion or replacement of all references to GSK or its staff 
with that of Novartis and its authorized agents to align with the change of sponsorship and 
make administrative changes to align with Novartis processes and procedures.
Section 8.2: Study Design Considerations
Original text:
The safety of subjects enrolled into the study will continue to be monitored by GSK.
Text changed to:


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The safety of subjects enrolled into the study will continue to be monitored by GSK Novartis.
Rationale for change:
The rationale for the change is deletion or replacement of all references to GSK or its staff 
with that of Novartis and its authorized agents to align with the change of sponsorship and 
make administrative changes to align with Novartis processes and procedures.
Section 8.3.6.2: Safety Analyses
Original text:
Adverse Events
AEs will be coded using the standard GSK MedDRA dictionary, and grouped by system 
organ class.
Text changed to:
AEs will be coded using the standard GSK MedDRA dictionary, and grouped by system 
organ class.
Rationale for change:
The rationale for the change is deletion or replacement of all references to GSK or its staff 
with that of Novartis and its authorized agents to align with the change of sponsorship and 
make administrative changes to align with Novartis processes and procedures.
Section 9.1: Regulatory and Ethical Considerations, Including the 
Informed Consent Process
Original text:
Prior to initiation of a study site, GSK will obtain approval from the appropriate regulatory 
authority to conduct the study in accordance with applicable country-specific regulatory 
requirements, including those required under a US Investigational New Drug (IND).
The study will be conducted in accordance with all applicable regulatory requirements, IND 
Number 11,465.
The study will be conducted in accordance with Good Clinical Practice (GCP), all applicable 
subject privacy requirements, and the guiding principles of the declaration of Helsinki, 
including, but not limited to:

IRB/IEC review and approval of study protocol and any subsequent amendments.

Subject informed consent.

Investigator reporting requirements.

GSK will provide full details of the above procedures, either verbally, in writing, or both.
Text changed to:
Prior to initiation of a study site, GSK Novartis will obtain approval from the appropriate 
regulatory authority to conduct the study in accordance with applicable country-specific 
regulatory requirements, including those required under a US Investigational New Drug 
(IND).
The study will be conducted in accordance with all applicable regulatory requirements, IND 
Number 11,465.


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The study will be conducted in accordance with Good Clinical Practice (GCP), all applicable 
subject privacy requirements, and the guiding principles of the declaration of Helsinki, 
including, but not limited to:

IRB/IEC review and approval of study protocol and any subsequent amendments.

Subject informed consent.

Investigator reporting requirements.

GSK Novartis will provide full details of the above procedures, either verbally, in writing, 
or both.
Rationale for change:
The rationale for the change is deletion or replacement of all references to GSK or its staff 
with that of Novartis and its authorized agents to align with the change of sponsorship and 
make administrative changes to align with Novartis processes and procedures.
Section 9.2: Quality Control (Study Monitoring)
Original text:
In accordance with applicable regulations, GCP, and GSK procedures, monitors will contact 
the site prior to the start of the study to review with the site staff the protocol, study 
requirements, and their responsibilities to satisfy regulatory, ethical, and GSK requirements.  
When reviewing data collection procedures, the discussion will include identification, 
agreement and documentation of data items for which the eCRF will serve as the source 
document. GSK will monitor the study to ensure that the:

Data are authentic, accurate, and complete.

Safety and rights of subjects are being protected.

Study is conducted in accordance with the currently approved protocol and any other 
study agreements, GCP, and all applicable regulatory requirements.

The investigator and the head of the medical institution (where applicable) agrees to allow 
the monitor direct access to all relevant documents.
Text changed to:
In accordance with applicable regulations, GCP, and GSK Novartis procedures, Novartis (or 
designated Clinical Research Organization) personnel monitors will contact the site prior to 
the start of the study to review with the site staff the protocol, study requirements, and their 
responsibilities to satisfy regulatory, ethical, and GSK Novartis requirements.  When 
reviewing data collection procedures, the discussion will include identification, agreement and 
documentation of data items for which the eCRF will serve as the source document. GSK
Novartis will monitor the study to ensure that the:

Data are authentic, accurate, and complete.

Safety and rights of subjects are being protected.

Study is conducted in accordance with the currently approved protocol and any other 
study agreements, GCP, and all applicable regulatory requirements.


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
The investigator and the head of the medical institution (where applicable) agrees to allow 
the Novartis (or designated Clinical Research Organization) personnel monitor direct 
access to all relevant documents.
Rationale for change:
The rationale for the change is deletion or replacement of all references to GSK or its staff 
with that of Novartis and its authorized agents to align with the change of sponsorship and 
make administrative changes to align with Novartis processes and procedures.
Section 9.3: Quality Assurance
Original text:
To ensure compliance with GCP and all applicable regulatory requirements, GSK may 
conduct a quality assurance audit of the site records, and the regulatory agencies may conduct 
a regulatory inspection at any time during or after completion of the study.
Text changed to:
To ensure compliance with GCP and all applicable regulatory requirements, GSK Novartis
may conduct a quality assurance audit of the site records, and the regulatory agencies may 
conduct a regulatory inspection at any time during or after completion of the study.
Rationale for change:
The rationale for the change is deletion or replacement of all references to GSK or its staff 
with that of Novartis and its authorized agents to align with the change of sponsorship and 
make administrative changes to align with Novartis processes and procedures.
Section 9.4: Study and Site Closure
Original text:
Upon completion or termination of the study, the GSK monitor will conduct site closure 
activities with the investigator or site staff (as appropriate), in accordance with applicable 
regulations, GCP, and GSK Standard Operating Procedures.
GSK reserves the right to temporarily suspend or terminate the study at any time for reasons 
including (but not limited to) safety issues, ethical issues, or severe noncompliance.  If GSK 
determines that such action is required, GSK will discuss the reasons for taking such action 
with the investigator or head of the medical institution (where applicable).  When feasible, 
GSK will provide advance notice to the investigator or head of the medical institution of the 
impending action.
If a study is suspended or terminated for safety reasons, GSK will promptly inform all 
investigators, heads of the medical institutions (where applicable), and/or institutions 
conducting the study.  GSK will also promptly inform the relevant regulatory authorities of 
the suspension/termination along with the reasons for such action.  Where required by 
applicable regulations, the investigator or head of the medical institution must inform the 
IRB/IEC promptly and provide the reason(s) for the suspension/termination.
Text changed to:
Upon completion or termination of the study, the GSK monitor Novartis (or designated 
Contract Research Organization) personnel will conduct site closure activities with the 
investigator or site staff (as appropriate), in accordance with applicable regulations, GCP, and 
GSK Novartis Standard Operating Procedures.


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GSK Novartis reserves the right to temporarily suspend or terminate the study at any time for 
reasons including (but not limited to) safety issues, ethical issues, or severe noncompliance.  
If GSK Novartis determines that such action is required, GSK Novartis will discuss the 
reasons for taking such action with the investigator or head of the medical institution (where 
applicable).  When feasible, GSK Novartis will provide advance notice to the investigator or 
head of the medical institution of the impending action.
If a study is suspended or terminated for safety reasons, GSK Novartis will promptly inform 
all investigators, heads of the medical institutions (where applicable), and/or institutions 
conducting the study.  GSK Novartis will also promptly inform the relevant regulatory 
authorities of the suspension/termination along with the reasons for such action.  Where 
required by applicable regulations, the investigator or head of the medical institution must 
inform the IRB/IEC promptly and provide the reason(s) for the suspension/termination.
Rationale for change:
The rationale for the change is deletion or replacement of all references to GSK or its staff 
with that of Novartis and its authorized agents to align with the change of sponsorship and 
make administrative changes to align with Novartis processes and procedures.
Section 9.5: Records Retention
Original text:
Following closure of the study, the investigator or head of the medical institution (where 
applicable) must maintain all site study records (except for those required by local regulations 
to be maintained elsewhere) in a safe and secure location.  The records must be easily 
accessible when needed (e.g., for a GSK audit or regulatory inspection) and must be available 
for review in conjunction with assessment of the facility, supporting systems, and relevant site 
staff.
Where permitted by local laws/regulations or institutional policy, some or all of the records 
may be maintained in a format other than hard copy (e.g., microfiche, scanned, electronic); 
however, caution must be exercised before such action is taken.  The investigator must ensure 
that all reproductions are legible and are a true and accurate copy of the original.  In addition, 
they must meet accessibility and retrieval standards, including regeneration of a hard copy, if 
required.  The investigator must also ensure that an acceptable back-up of the reproductions 
exists and that there is an acceptable quality control procedure in place for creating the 
reproductions.
GSK will inform the investigator of the time period for retaining the site records in order to 
comply with all applicable regulatory requirements.  The minimum retention time will meet 
the strictest standard applicable to a particular site, as dictated by local laws/regulations, GSK 
standard operating procedures, and/or institutional requirements.
The investigator must notify GSK of any changes in the archival arrangements, including, but 
not limited to archival of records at an off-site facility or transfer of ownership of the records 
in the event that the investigator is no longer associated with the site.
Text changed to:
Following closure of the study, the investigator or head of the medical institution (where 
applicable) must maintain all site study records (except for those required by local regulations 
to be maintained elsewhere) in a safe and secure location.  The records must be easily 
accessible when needed (e.g., for a GSK Novartis audit or regulatory inspection) and must be 


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available for review in conjunction with assessment of the facility, supporting systems, and 
relevant site staff.
Where permitted by local laws/regulations or institutional policy, some or all of the records 
may be maintained in a format other than hard copy (e.g., microfiche, scanned, electronic); 
however, caution must be exercised before such action is taken.  The investigator must ensure 
that all reproductions are legible and are a true and accurate copy of the original.  In addition, 
they must meet accessibility and retrieval standards, including regeneration of a hard copy, if 
required.  The investigator must also ensure that an acceptable back-up of the reproductions 
exists and that there is an acceptable quality control procedure in place for creating the 
reproductions.
GSK will inform the investigator of the time period for retaining the site records in order to 
comply with all applicable regulatory requirements.  The minimum retention time will meet 
the strictest standard applicable to a particular site, as dictated by local laws/regulations, GSK 
standard operating procedures, and/or institutional requirements.
Essential documents (written and electronic) should be retained for a period of not less 
than fifteen (15) years from the completion of the Clinical Trial unless the Sponsor 
provides written permission to dispose of them or, requires their retention for an 
additional period of time because of applicable laws, regulations and/or guidelines.
The investigator must notify GSK Novartis of any changes in the archival arrangements, 
including, but not limited to archival of records at an off-site facility or transfer of ownership 
of the records in the event that the investigator is no longer associated with the site.
Rationale for change:
The rationale for the change is deletion or replacement of all references to GSK or its staff 
with that of Novartis and its authorized agents to align with the change of sponsorship and 
make administrative changes to align with Novartis processes and procedures.
Section 9.6: Provision of Study Results and Information to Investigators
Original text:
Where required by applicable regulatory requirements, an investigator signatory will be 
identified for the approval of the clinical study report.  The investigator will be provided 
reasonable access to statistical tables, figures, and relevant reports and will have the 
opportunity to review the complete study results at a GSK site or other mutually-agreeable 
location.
Upon completion of the clinical study report, GSK will ensure public disclosure of the clinical 
trial research results via the GSK Clinical Trials Register according to the GSK Standard 
Operating Procedure and provide the investigator with the full summary of the study results.  
The investigator is encouraged to share the summary results with the study subjects, as 
appropriate.
Text changed to:
Where required by applicable regulatory requirements, an investigator signatory will be 
identified for the approval of the clinical study report.  The investigator will be provided 
reasonable access to statistical tables, figures, and relevant reports and will have the 
opportunity to review the complete study results at a GSK Novartis site or other mutually-
agreeable location.


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Upon completion of the clinical study report, GSK Novartis will ensure public disclosure of 
the clinical trial research results via the GSK Novartis Clinical Trials Register according to 
the GSK Novartis Standard Operating Procedure and provide the investigator with the full 
summary of the study results.  The investigator is encouraged to share the summary results 
with the study subjects, as appropriate. In addition, upon study completion and finalization 
of study report, Novartis aims to submit results of the study for publication. 
When publication is not feasible, please refer to the Novartis Clinical Trial Results 
website (...novartisclinicaltrials.com) for a summary of the trial results.
Rationale for change:
The rationale for the change is deletion or replacement of all references to GSK or its staff 
with that of Novartis and its authorized agents to align with the change of sponsorship and 
make administrative changes to align with Novartis processes and procedures.
Section 9.7.1: Dose Confirmation for Safety and Tolerability
Original text:
Stage 1 Results from IDMC Data Review
The safety of subjects enrolled in the study will continue to be monitored by GSK.
Text changed to:
The safety of subjects enrolled in the study will continue to be monitored by GSK Novartis.
Rationale for change:
The rationale for the change is deletion or replacement of all references to GSK or its staff 
with that of Novartis and its authorized agents to align with the change of sponsorship and 
make administrative changes to align with Novartis processes and procedures.
Section 11: Appendices
Text changed to:
All references to GSK and medical monitor has been replaced with Novartis and Medical 
Lead in the relevant sections, respectively.
Rationale for change:
The rationale for the change is deletion or replacement of all references to GSK or its staff 
with that of Novartis and its authorized agents to align with the change of sponsorship and 
make administrative changes to align with Novartis processes and procedures.
Section 11.4: Appendices 1, 2, 3, and 4
Text changed to:
All references to GSK has been replaced with Novartis.
Rationale for change:
The rationale for the change is deletion or replacement of all references to GSK or its staff 
with that of Novartis and its authorized agents to align with the change of sponsorship and 
make administrative changes to align with Novartis processes and procedures.

SAP_001.pdf: 
CONFIDENTIAL
Protocol ID: COMB157E2301 / NCT01077518
1
Division: Oncology Global Development
Information Type: Statistical Analysis Plan
Title:
A Randomized, Open Label Study of Ofatumumab
and 
Bendamustine 
Combination 
Therapy 
Compared 
with 
Bendamustine Monotherapy in Indolent B-cell Non-Hodgkin’s 
Lymphoma Unresponsive to Rituximab or a Rituximab-
Containing Regimen During or Within Six Months of Treatment
Compound Number:
OMB157/GSK1841157
Version
Amendment 1.0
Effective Date:  
23-Apr-2018
Description: 
This document provides a detailed statistical analysis plan for study 
OMB157E2301, a randomized, open label study of Ofatumumab and Bendamustine 
Combination Therapy compared with Bendamustine Monotherapy in Indolent B-cell 
Non-Hodgkin’s Lymphoma unresponsive to Rituximab or a Rituximab-Containing 
regimen during or within six months of treatment.
Subject: Statistical Analysis Plan for Indolent Non-Hodgkin’s Lymphoma study 
OMB157E2301
Author’s Name, Title and Functional Area:
All rights reserved.  Unauthorized copying or use of this information is prohibited.


CONFIDENTIAL
OMB157E2301
2
Date
Version 
number
Summary of changes
5-Jul-2017
1.0
First final version
23-Apr-
2018
Amendment 
1.0
Section 2.3: Derivation rule details are added for FLIPI-1 
and FLIPI-2 scores 
Section 8.3: Text for subgroup analysis is updated to be 
more consistent with data collection
Section 9.2.7: Text is added to clarify the definition of 
baseline for the optional ofatumumab period for subjects 
taking optional ofatumumab in Arm B.
Section 11.1: Text is modified to make the Cox model 
for sensitivity analysis  more consistent with the Cox 
model in the primary analysis. Text for subgroup 
analysis is updated to be more consistent with data 
collection
Section 11.2.11: Text for B-cell monitoring was updated 
to be more consistent with data collection
Section 11.2.12: Text for subgroup analysis is updated to 
be more consistent with data collection
Section 13.1: Text is added to clarify what scores will be 
analyzed for PRO


CONFIDENTIAL
OMB157E2301
3
TABLE OF CONTENTS
PAGE
1.
INTRODUCTION......................................................................................................8
2.
STUDY OBJECTIVES AND ENDPOINTS................................................................8
2.1.
Statistical Hypotheses...................................................................................8
2.2.
Study Objectives...........................................................................................9
2.3.
Study Endpoints..........................................................................................10
3.
STUDY DESIGN ....................................................................................................12
3.1.
Treatment Phase ........................................................................................12
3.2.
Follow-up Phase.........................................................................................13
3.3.
Post PD follow-up .......................................................................................13
3.4.
Ofatumumab Salvage Following Progressive Disease for Arm B................14
4.
PLANNED ANALYSES ..........................................................................................14
4.1.
Interim Analyses .........................................................................................14
4.2.
Primary Analysis.........................................................................................14
4.3.
Final Analyses ............................................................................................15
5.
SAMPLE SIZE CONSIDERATIONS.......................................................................15
5.1.
Sample Size Assumptions ..........................................................................15
5.2.
Sample Size Sensitivity...............................................................................16
5.3.
Sample Size Re-estimation.........................................................................16
6.
ANALYSIS POPULATIONS ...................................................................................16
6.1.
Intent-to-Treat Population ...........................................................................17
6.2.
Safety Population........................................................................................17
6.3.
Per Protocol Population ..............................................................................17
6.4.
Optional Ofatumumab Population ...............................................................18
6.5.
Pharmacokinetic Population........................................................................18
6.6.
Analysis Datasets .......................................................................................18
7.
TREATMENT COMPARISONS..............................................................................18
7.1.
Primary Comparisons of Interest.................................................................18
7.2.
Secondary and other Comparisons of Interest............................................19
7.3.
Data Display Treatment and Other Subgroup Descriptors ..........................19
8.
GENERAL CONSIDERATIONS FOR DATA ANALYSES.......................................21
8.1.
Multicenter Studies .....................................................................................22
8.2.
Other Strata and Covariates .......................................................................22
8.3.
Examination of Subgroups..........................................................................22
8.4.
Multiple Comparisons and Multiplicity .........................................................23
9.
DATA HANDLING CONVENTIONS .......................................................................24
9.1.
Premature Withdrawal and Missing Data ....................................................24
9.2.
Derived and Transformed Data...................................................................24


CONFIDENTIAL
OMB157E2301
4
9.2.1.
Reference Dates..........................................................................24
9.2.2.
Study Day for Safety Measures ...................................................25
9.2.3.
Study Day for Efficacy..................................................................25
9.2.4.
Duration and Elapsed Time .........................................................26
9.2.5.
Imputation of Partial Dates...........................................................26
9.2.6.
Imputation of Missing Exposure End Dates..................................33
9.2.7.
Baseline Definition.......................................................................34
9.2.8.
Change from baseline..................................................................34
9.2.9.
Multiple Assessments ..................................................................34
9.2.10.
Actual Treatment .........................................................................35
9.2.11.
Treatment Cycle ..........................................................................35
9.2.12.
Extended Loss to Follow-up or Extended Time without an 
Adequate Assessment.................................................................36
9.3.
Study Time Periods ....................................................................................36
9.3.1.
Time in Relation to Treatment......................................................36
9.3.2.
Study Time Periods for Concomitant Medications and 
Blood and Blood Supportive Care Products.................................37
9.4.
Values of Potential Clinical Importance.......................................................38
9.4.1.
Laboratory Parameters ................................................................38
9.4.2.
Vital Signs....................................................................................38
10. STUDY POPULATION...........................................................................................39
10.1.
Disposition of Subjects................................................................................39
10.2.
Protocol Deviations.....................................................................................39
10.3.
Demographic and Baseline Characteristics.................................................39
10.4.
Treatment Compliance................................................................................40
10.5.
Concomitant Medications............................................................................41
10.6.
Subsequent Anti-Cancer Therapies ............................................................42
11. EFFICACY .............................................................................................................42
11.1.
Primary Efficacy Analysis............................................................................42
Progression-free survival (PFS)..................................................................42
11.2.
Secondary Efficacy Analyses......................................................................46
11.2.1.
Overall Response Rate (ORR).....................................................46
11.2.2.
Overall Survival (OS) ...................................................................47
11.2.3.
Time to response.........................................................................47
11.2.4.
Duration of response ...................................................................47
11.2.5.
Time to progression.....................................................................48
11.2.6.
Time to next therapy....................................................................48
11.2.7.
Reduction in tumor size ...............................................................48
11.2.8.
Improvement in ECOG performance status .................................48
11.2.9.
Constitutional Symptoms (or B-Symptoms)..................................49
11.2.10. Organ Examination......................................................................49
11.2.11. Disease Markers..........................................................................49
B-cell Monitoring..........................................................................49
11.2.12. Prognostic and biological markers correlating with clinical 
response......................................................................................50
 
50


CONFIDENTIAL
OMB157E2301
5
11.2.14. Optional Ofatumumab – Investigator-Assessed Response 
Rate.............................................................................................50
11.3.
Other Efficacy Analyses..............................................................................50
11.3.1.
Concordance Analysis of Overall Response Rate........................50
11.3.2.
Concordance Analysis of PFS .....................................................51
51
12. SAFETY ANALYSES .............................................................................................51
12.1.
Extent of Exposure .....................................................................................51
12.2.
Adverse Events...........................................................................................52
12.3.
AEs of Special Interest................................................................................53
12.4.
Deaths and Serious Adverse Events...........................................................56
12.5.
Adverse Events Leading to Discontinuation of Investigational 
Product and/or Withdrawal from the Study and Other Significant 
Adverse Events...........................................................................................56
12.6.
Pregnancies................................................................................................57
12.7.
Clinical Laboratory Evaluations...................................................................57
12.7.1.
Analyses of Liver Function Tests .................................................57
12.8.
Other Safety Measures...............................................................................58
12.8.1.
Vital Signs....................................................................................58
12.8.2.
ECG.............................................................................................58
12.8.3.
Liver Events.................................................................................59
12.8.4.
Frequency of transfusions............................................................59
12.8.5.
Human Anti-Human Antibodies (HAHA).......................................59
12.8.6.
Human Anti-Chimeric Antibodies (HACA) ....................................59
12.8.7.
Quantitative IgG, IgA, IgM............................................................60
13. HEALTH OUTCOMES ANALYSES........................................................................60
13.1.
Functional Assessment of Cancer Therapy - Lymphoma (FACT-
Lym) ...........................................................................................................62
13.2.
EuroQoL Five-Dimension (EQ-5D)..............................................................66
13.3.
Health Change Questionnaire.....................................................................67
14. PHARMACOKINETIC ANALYSES.........................................................................68
14.1.
Drug Concentration Measures ....................................................................68
14.2.
Statistical Analyses.....................................................................................69
15. PHARMACOKINETIC/PHARMACODYNAMIC ANALYSES ...................................69
16. REFERENCES.......................................................................................................69
17. ATTACHMENTS ....................................................................................................70
17.1.
Table of Contents for Data Display Specifications.......................................70


CONFIDENTIAL
OMB157E2301
6
ABBREVIATIONS
ADaM
Analysis Data Model
AE
Adverse Event
ALC
Absolute Lymphocyte Count
ALT
alanine transaminase
ALP
alkaline phosphatase
AST
aspartate transaminase
ATC
Anatomical Therapeutic Chemical
AUC
Area under the curve
BUN
blood urea nitrogen
CBC
Complete Blood Count
CDISC
Clinical Data Interchange Standards Consortium
Cmax
Maximum observed plasma concentration
CR
Complete Remission
DNA
Deoxyribonucleic Acid
eCRF
Electronic Case Report Form
ECOG
Eastern Cooperative Oncology Group
EOI
End of Infusion
EQ-5D
EuroQoL Five Dimension
FACT-Lym
Functional Assessment of Cancer Therapy – Lymphoma
FA
Futility Analysis
FISH
Fluorescent in-situ Hybridization
FL
Follicular Lymphoma
GSK
GlaxoSmithKline
HACA
Human Anti-chimeric Antibodies
HAHA
Human Anti-Human Antibodies
HARP
Harmonization (Analysis and Reporting) Programmed
HCQ
Health Change Questionnaire
HRQL
Health Related Quality of Life 
IA
Interim Analysis
IDMC
Independent Data Monitoring Committee
IDSL
Independent Data Standards Library
INHL
Indolent Non-Hodgkin’s Lymphoma
IRC
Independent Review Committee
IR
Independent Review(er)
IRR
Independent Radiological Review
LLN
Lower Level of Normal
NHL
Non-Hodgkin’s Lymphoma
ORR
Overall Response Rate
OS
Overall Survival
PD
Progressive Disease
PFS
Progression-Free Survival


CONFIDENTIAL
OMB157E2301
7
PK
Pharmacokinetic(s)
PML
Progressive multifocal leukoencephalopathy
POP
Data set with indicators for different study populations
PR
Partial Remission
PRO
Patient Reported Outcome
RAMOS
Registration and Medication Ordering System
RAP
Report and Analysis Plan
RRCML
Revised Response Criteria for Malignant Lymophoma
SAE
Serious Adverse Event
SD
Stable Disease; Standard Deviation
SDTM
Study Data Tabulation Model
SMT
Safety Monitoring Team
SPM
Study Procedures Manual
SRT
Safety Review Team
t½
Terminal phase half-life
tmax
Time of maximum observed plasma concentration
TLS
Tumor Lysis Syndrome
TTP
Time To Progression
ULN
Upper Level of Normal
Vss
Volume of distribution at steady state
Trademark Information
Trademarks of the Novartis group of 
companies
Trademarks 
not 
owned 
by 
the 
Novartisgroup of companies
ARZERRA
NONMEM
SAS


CONFIDENTIAL
OMB157E2301
8
1.
INTRODUCTION
This statistical analysis plan (SAP) details planned analyses for a Clinical Study Report 
(primary analysis) to support a possible regulatory submission of study OMB157E2301.  
This is a phase III, randomized, open label, multi-center trial to evaluate the efficacy and 
safety of ofatumumab in combination with bendamustine versus bendamustine 
monotherapy in subjects with indolent Non-Hodgkin’s Lymphoma (iNHL) that is 
unresponsive to rituximab or a rituximab-containing regimen during or within six months 
of treatment.
Initially, this study was planned with an adaptive-like design - to allow a potential change 
to the dosing regimen of Bendamustine in combination with Ofatumumab based on 
tolerability of the combination. Upon the first planned review of the data, the IDMC 
recommended no change was required to the dosing of Bendamustine.  Therefore, the 
study continued with the original dosing regimen and an adaptive approach was no longer 
necessary for this study. 
The IDMC review of  an Interim Analysis for efficacy and futility occurred (22Feb2016) 
after 180 PFS events by IRC were reached (31Oct2015). The IDMC recommended to 
continue the study without any changes. The interim analysis of PFS was performed by 
an independent Statistical Data Analysis Centre. As per the IDMC charter, unblinded 
results were not communicated to the sponsor in order to maintain the integrity of the 
trial. The protocol defined randomization of 346 patients was achieved as of 16May2016.
For further information on the study design, see Protocol Amendment 09, dated 13-Apr-
2017.
The content of this SAP is based on protocol OMB157E2301 Amendment 09. All 
decisions regarding final primary endpoint analysis, as defined in this SAP document, 
have been made prior to SDTM Database Freeze of the study data. The planned analyses 
are specified in Section 4.
Analyses of the 
 biomarker components of the study will be
provided in separate documents as appropriate.
2.
STUDY OBJECTIVES AND ENDPOINTS
2.1.
Statistical Hypotheses
The primary endpoint is progression-free survival (PFS) as assessed by the IRC.  The 
primary efficacy analysis will be the comparison of the distribution of PFS between the 
two treatment groups. Assuming proportional hazards for PFS, the following statistical 
hypothesis will be tested to address the primary efficacy objective:
H: θ = 1 vs. H: θ ≠1


CONFIDENTIAL
OMB157E2301
9
where θ is the PFS  hazard ratio (ofatumumab + bendamustine arm vs  bendamustine 
arm). 
2.2.
Study Objectives
Primary Objective:

To establish effectiveness of ofatumumab in combination with bendamustine in 
subjects with indolent B-cell NHL disease refractory to rituximab-containing 
therapy
Secondary Objectives:

To establish effectiveness of ofatumumab in combination with bendamustine in 
subjects with follicular lymphoma (FL) refractory to rituximab-containing therapy

To evaluate and compare ORR, OS, time to and duration of response, and time to 
progression (TTP) in subjects treated with ofatumumab and bendamustine 
combination therapy to those treated with bendamustine alone

To evaluate and compare ORR, OS, time to and duration of response, and time to 
progression (TTP) in subjects with follicular lymphoma treated with ofatumumab 
and bendamustine combination therapy to those treated with bendamustine alone

To evaluate and compare the safety and tolerability in subjects treated with 
ofatumumab and bendamustine combination therapy to those treated with 
bendamustine alone

To evaluate and compare the two treatment arms with respect to changes in 
subjects’ health-related quality of life

To evaluate and compare the two treatment arms with respect to changes in 
subjects’ health-related quality of life in patients with follicular lymphoma

To evaluate and compare known and exploratory prognostic markers and their 
correlation with clinical responses in subjects treated with ofatumumab and 
bendamustine compared to those treated with bendamustine monotherapy (i.e. 
absolute lymphocyte count (ALC), FcR gamma 3A genetic variants, human anti-
chimeric antibody [HACA])

To evaluate the ORR to ofatumumab monotherapy in subjects who progress 
during or following single-agent bendamustine

To evaluate ofatumumab pharmacokinetics (PK) when given as monotherapy to 
subjects who progress during or following single-agent bendamustine


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2.3.
Study Endpoints
Primary Endpoint:

Progression-free survival (PFS) as assessed by the IRC, defined as the time 
interval between randomization until disease progression or death (due to any 
cause). Investigator-assessed PFS will be supportive.
Secondary Endpoints:
Clinical

Overall response rate (ORR) in all patients and patients with follicular lymphoma
- for both IRC and Investigator assessments

Overall survival (OS) in all patients and patients with follicular lymphoma

Time to response and duration of response – for both IRC and Investigator 
assessments in all patients and patients with follicular lymphoma

Time to progression in all patients and patients with follicular lymphoma - for 
both IRC and Investigator assessments 

Time to next therapy (defined as time to next therapy or death) in all patients and 
patients with follicular lymphoma

Changes in health-related quality of life (HRQL) measures in all patients and 
patients with follicular lymphoma

Reduction in tumor size

Improvement in Eastern Cooperative Oncology Group (ECOG) Performance 
status 

Incidence and severity of AEs, serious adverse events (SAEs) and other safety 
parameters including frequency of transfusions, development of Human Anti-
Human Antibodies (HAHA), incidence of grade 3 infections, and 
myelosuppression (anemia, neutropenia, and thrombocytopenia)

Overall response rate (ORR) to optional ofatumumab monotherapy in subjects 
who progress during or following single-agent bendamustine

Changes in clinical laboratory values

Quantitative assessments of immunoglobulins G, A and M (IgG, IgA, IgM)

Plasma ofatumumab concentrations

B-cell monitoring (CD19+, CD20+)


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Known and Exploratory Prognostic Markers Correlating with Response
to 
ofatumumab:

Baseline Follicular Lymphoma International Prognostic Index (FLIPI score)

Baseline Absolute Lymphocyte Count (ALC)

Genetic variation in FcR gamma 3A
Human Anti-Chimeric Antibodies (HACA)
Table for the Five Parameters Retained for Building the FLIPI-1
Parameter
Adverse Factor
Source
Age
60 years
Screening value
Ann Arbor Stage
III-IV
Screening value
Hemoglobin Level
< 120 g/L
Baseline value (likely to be from Cycle 
1 Day 1)
Serum LDH Level
> ULN
Baseline value (likely to be from Cycle 
1 Day 1)
Number of Nodal 
Sites
> 4
From screening assessment by 
investigator
Abbreviations: LDH: lactate dehydrogenase; 
ULN: upper limit of normal
Table for the Five Parameters Retained for Building the FLIPI-2
Parameter
Adverse 
Factor
Source
Beta-2-microglobulin
> ULN
Baseline value (likely to be from Cycle 
1 Day 1)
LoDLIN
>6cm
From screening assessment by 
investigator
Bone marrow involvement 
presence
yes
From screening assessment from 
central lab 
Hemoglobin
<120 g/L
Baseline value (likely to be from Cycle 
1 Day 1)
Age
>60 
Screening value


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years
Abbreviations: LLoDLIN= longest diameter of the largest involved node; ULN: upper limit of 
normal
3.
STUDY DESIGN
This randomized, open label, two-arm, Phase III study consists of two treatment groups:  
ofatumumab and bendamustine combination therapy (Arm A) or bendamustine 
monotherapy (Arm B).  Subjects in Arm B may be offered optional Ofatumumab
monotherapy after progressive disease (PD) has been reported.
Randomization and Stratification
Subjects were randomized to receive treatment arm A or B in a 1:1 ratio for the duration 
of treatment period.
Assignment of study drug was stratified according to two stratification factors (i) type of 
last prior rituximab therapy:  rituximab plus chemotherapy or rituximab alone (either in 
maintenance or monotherapy) and (ii) prior exposure to bendamustine: exposed or not 
exposed.
Centralized randomization numbers within each stratum were created for treatment 
assignment to ensure balance, with respect to the number of subjects assigned to each 
treatment group within each stratum, using the GSK RandALL randomization system.  
The investigator accessed the GSK Randomization and Medication Ordering System 
(RAMOS) (or the Clinphone system after study transfer to Novartis) by telephone to 
receive the subject's randomization number and initial study medication container 
number.  (The transfer to the ClinPhone system occurred on 13May16.  Previously, 245 
of the 246 patients were randomized with the RAMOS system.  Only one subject was 
randomized after transfer to the ClinPhone system.)
3.1.
Treatment Phase
Subjects randomized to treatment arm A received ofatumumab in combination with 
bendamustine and subjects randomized to arm B received bendamustine. 
Treatment Arm A:


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Up to 8 cycles of bendamustine (90 mg/m2 Days 1 and 2, every 21 days) given in 
combination with 12 doses of ofatumumab (1000 mg).  Ofatumumab will be given on 
Day 1 of each cycle of bendamustine as long as subjects in Arm A receive bendamustine.  
Once subjects in Arm A complete bendamustine therapy, the remaining doses of 
ofatumumab will be given monthly (q28 days) until all 12 doses are completed.
OR
Treatment Arm B:
Bendamustine (120 mg/m2 Days 1 and 2, every 21 days, up to 8 cycles). 
Subjects in Arm A and Arm B who cannot complete 8 cycles of therapy with 
bendamustine must still have all planned Day 1 assessments (Visits 1-20) done including 
scheduled CT scans and assessments that occur on Days 84, 168, and 252.
At the discretion of the investigator, ofatumumab will be offered to those with 
progressive disease (PD) in Arm B.  If these subjects select ofatumumab, therapy must 
begin 120 days following PD.  PD must be verified by CT scan.  This CT scan must be 
confirmed by an independent radiologist before ofatumumab therapy begins.  Subjects 
will receive ofatumumab (1000 mg for the first infusion on Week 1 followed by 2000 mg, 
one infusion every week for a total of 3 infusions (Weeks 2-4) followed by 2000 mg, one 
infusion every month for 8 infusions, total: 12 doses).
3.2.
Follow-up Phase
Following study treatment, subjects who have CR, PR or SD will receive regular follow-
up for 5 years – every 3 months to 18 months then every 12 months.  
Subjects demonstrating disease progression will be followed for survival status until 
study completion. 
PRO measures (FACT-Lym, EQ-5D, HCQ) will be administered for completion by the 
subjects at all follow-up visits.
3.3.
Post PD follow-up
Follow-up assessment for subjects experiencing disease progression during the treatment 
phase will include a 1 month post-treatment safety assessment and subsequent follow up 
visits to assess survival status and date of next iNHL therapy. 
Subjects demonstrating disease progression during the follow up phase require a 
complete follow-up visit. In subsequent visits the subject will continue to be followed as 
per the post PD follow up schedule, for survival status, until the end of the 5 years.
Patient Reported Outcomes (PRO) measures (FACT-Lym, EQ-5D, HCQ) will be 
administered for completion by the subjects Post PD follow-up.  If a subject demonstrates 


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disease progression, all the measures will be completed at the progression visit and again 
one time after determination of PD. If a subject withdraws from the study then all the 
PRO questionnaires will be administered at the point of withdrawal.
3.4.
Ofatumumab Salvage Following Progressive Disease for 
Arm B
At the discretion of the physician in consultation with the study subject, ofatumumab may 
be administered to subjects within 120 days who develop PD during or following 
treatment with bendamustine monotherapy in Arm B. Subjects with PD in Arm B must 
have a CT scan done with Independent Reviewer confirmation of PD.  
Subjects in Arm B who choose to receive optional ofatumumab monotherapy will receive 
ofatumumab, 1000 mg for the first infusion (Week 1) followed by 2000 mg weekly (+1 
day) for 3 doses (Weeks 2-4), followed by 2000 mg every month (±3 days; q28 days) for 
8 additional doses (total: 12 doses).
The first follow-up visit will occur one month following the last infusion of ofatumumab 
monotherapy and continue every 3 months to month 18, then every 12 months to Month 
54.  The 1 month follow-up visit will include CT-scan and response evaluation.  All 
follow-up visits will include survival follow-up and safety assessments.
4.
PLANNED ANALYSES
4.1.
Interim Analyses
An Interim Analysis (IA) for efficacy of the primary endpoint, progression free survival, 
was planned when approximately two thirds (or approximately 172) of the initial total 
259 PFS events by IRC is achieved.  The interim analysis was planned to be conducted 
at a significance level of 0.012.  At the same time as the IA for efficacy, a Futility 
Analysis (FA) was planned. The Independent Data Monitoring Committee (IDMC) was 
expected to review the efficacy and futility data at this timepoint.  Further details are 
specified in the IDMC charter.
The actual significance level at the interim and the primary analysis was planned to be 
updated according to the actual number of events at the time of analysis - utilizing the 
O’Brien-Fleming boundary.    
The IA occurred with 180 PFS events by IRC and the actual alpha spent at IA was 
calculated to be 0.0144. The IDMC recommended that the study continue without 
changes.
4.2.
Primary Analysis
As described in Protocol Amendment 9, the primary analysis will be performed after 
approximately 215 PFS events confirmed by IRC have been observed. This will 
correspond to a power of approximately 84% to detect a 50% improvement in PFS 
between study arms. The critical boundary to be used at primary analysis was recalculated 


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using EAST v6.0 software and was derived from the pre-specified error spending functions 
using the actual number of events observed at interim analysis (180) and assuming the 
primary event number is 215 in order to maintain a cumulative type I error smaller than two-
sided 5%. Using the interim monitoring function in EAST v6.0, the boundary for IA was
0.0144 alpha spent, and the final boundary should be 0.0483.
If the actual PFS event counts differ for the primary analysis, the significance level 
(0.0483 for the primary analysis) would be adjusted as appropriate according to the Lan 
and DeMets spending function for the O’Brien-Fleming boundary.  At the time of 
primary analysis, the primary clinical study report will be produced. Following the 
primary analysis time point, the study will remain open. Patients still being followed on 
the study will continue as per the schedule of assessments described in the protocol.
4.3.
Final Analyses
The study will end once all patients have completed 5 years of follow-up or discontinued 
earlier, and the final analysis of study data will be conducted at that time. All available 
data from all patients up to this cutoff date will be analyzed, and the final clinical study 
report will be produced.
5.
SAMPLE SIZE CONSIDERATIONS
5.1.
Sample Size Assumptions
The primary endpoint is PFS (as assessed by the IRC) and the analysis will be conducted 
using stratified log-rank test.  The following assumptions are made in the estimation of 
the required sample size:

Event times are exponentially distributed

Median PFS for bendamustine is 9 months

Median PFS for ofatumumab + bendamustine is 13.5 months

A 1:1 stratified randomization scheme

A 90% chance of successfully declaring a difference in the presence of a true 
underlying difference (power) 

A 5% two-sided risk of erroneously claiming a difference in the presence of no 
true underlying difference 

Accrual rate is 5.1 subjects per month 
Under the above assumptions, approximately 259 total events from both treatment arms 
combined were needed for the study to have 90% power.  With a sample size of 304 
subjects, the duration of the study was expected to be about 70 months (under H1) to 
obtain the 259 total events.  Assuming a dropout rate of 12%, the total sample size 
randomized for both arms combined was expected to be 346 subjects, with approximate 
study duration of 77 months.


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Assuming a screening failure rate of 15%, the total number of subjects screened was 
planned to be approximately 408.
Per Protocol Amendment 9, the primary analysis will take place after approximately
215 PFS events confirmed by IRC have been reported which will correspond to
approximately 84% power.  The other assumptions are not modified. See Section 4.2 -
Primary Analysis for details.
As stated, this trial uses an event-driven study design. A cut-off date will be established
after the targeted number of events (approximately 215 PFS events confirmed by IRC) 
for the planned primary analysis has been documented. All statistical analyses will be 
performed using all data collected in the database up to the data cut-off date.
5.2.
Sample Size Sensitivity
The robustness and sensitivity of the above sample size calculation is considered in order 
to assess the impact on power if the assumed median PFS varies.  The following table 
shows the estimated power for different median values of PFS for ofatumumab + 
bendamustine. The total number of events is 215.
Primary Endpoint power calculation
Median PFS for Ofatumumab  + 
Bendamustine
Median PFS for Bendamustine
Estimated Power
12
9
0.553
13
9
0.763
13.5
9
0.840
14
9
0.895
15
9
0.961
5.3.
Sample Size Re-estimation
Sample size re-estimation will not be performed for this study.
6.
ANALYSIS POPULATIONS
Analysis populations in the protocol made reference to analysis ‘stage’, assuming an 
adaptive-like design would be implemented.  Since multiple stages were not required, this 
text has been removed from the population definitions.
The protocol also makes reference to a Safety Population (Dose Confirmation Cohort).  
This population was utilized for the IDMC tolerability analyses and is not planned for 
any further presentation.


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6.1.
Intent-to-Treat Population
The Intent-to-Treat (ITT) population will include subjects who are randomized in the 
study.  This will be the primary population used for evaluation of the efficacy data for all 
efficacy assessments.  In the analyses, subjects will be grouped according to the treatment 
and strata to which they were randomized. The ITT population will also be used for all 
PRO analyses.
6.2.
Safety Population
The Safety population will include all subjects who receive at least one dose of a study 
drug. This population will be used for evaluation of all safety measurements. In the 
analyses, subjects will be grouped based on the treatment they received regardless of how 
they are randomized.  
The subjects’ actual treatment will be derived from exposure data.  If a subject’s actual 
treatment is the same as the assigned treatment at least once, then actual treatment is the
assigned treatment. If a subject receives a study treatment that is different from the 
assigned treatment for the entire time of treatment, then actual treatment is the different 
treatment (the treatment actually received).
Patients receiving Bendamustine and any Ofatumumab (not Optional Ofatumumab) will 
be included in the Ofatumumab + Bendamustine group.  Patients receiving only 
Bendamustine will be included in the Bendamustine group.  Patients receiving 
Bendamustine and Optional Ofatumab salvage therapy will be summarized with the 
Bendamustine group up to the time of administration of Optional Ofatumumab. Data 
collected  after the administration of Optional Ofatumumab will be reported separately.
6.3.
Per Protocol Population
The Per-Protocol (PP) population will comprise all randomized subjects and will exclude 
subjects with important protocol deviations that will impact the efficacy outcome.  The 
Per Protocol Population will be used in the primary endpoint analysis to check the 
robustness of the results when using the ITT population.  However, if the difference 
between the ITT and the Per-Protocol population is 10% or less, then the Per-Protocol 
analysis will not be performed.
Subjects who meet the following conditions will be excluded from the Per Protocol 
Population:

Subject did not meet definition of Indolent B-cell Non-Hodgkin’s Lymphoma 
(Inclusion Criteria 1 violation)

Subject did not meet response criteria to previous therapy (Inclusion Criteria 2 
violation)

Subject has transformed aggressive Lymphoma (Exclusion Criteria 1 violation)

Subject is taking high dose steroids (Exclusion Criteria 3 violation)

Prohibited therapy or procedure


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
Subjects who are exposed to less than <80 % or >120% of planned total dose 
(during the whole treatment phase) for both of the study drugs, unless due to 
adverse events and/or protocol defined dose reductions criteria for each planned 
cycle.
6.4.
Optional Ofatumumab Population
The Optional Ofatumumab Population will consist of all subjects in the ITT population 
for whom at least one dose of optional ofatumumab salvage therapy (for patients in Arm 
B) was administered.
6.5.
Pharmacokinetic Population
The Pharmacokinetic Population includes all subjects who provide at least one evaluable
PK concentration. For a concentration to be evaluable, subjects are required to:

take a dose of Ofatumumab within -1 to +2 weeks of the planned 28 day cycle during 
which the PK was collected

(for pre-dose samples): have the sample collected before the start of the next infusion 

(for EOI samples): have the sample collected after the end of infusion
6.6.
Analysis Datasets
The primary data set for efficacy will be based on the response assessments.  The primary 
data set for safety will be the adverse events and the laboratory data sets.
The response will be assessed by the investigators and by the Independent Review
Committee (IRC).  Data will be summarized for investigator assessed response as well as 
for IRC assessed response, unless specified otherwise.  Statistical inference for efficacy 
claim(s) will be based on the data assessed by the IRC.
7.
TREATMENT COMPARISONS
7.1.
Primary Comparisons of Interest
The primary efficacy analysis will be the comparison of the distribution of PFS between 
the two treatment groups performed at the time of primary analysis using the ITT 
population. . Refer to Section 4.2 - Primary Analysis for the timing of the IA and primary 
analysis.
The primary efficacy endpoint will serve as a gatekeeper for the interpretation of 
treatment comparisons for the ‘inferential’ secondary endpoints.  If H0 is rejected, the
conclusion will be that there is a treatment difference between ofatumumab in 
combination with bendamustine and bendamustine monotherapy, and the p-value for the 
‘inferential’ secondary endpoints may be interpreted.


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As described in section 4.1, the significance levels for the primary analysis will be 
adjusted as appropriate using the O’Brien-Fleming spending function.
7.2.
Secondary and other Comparisons of Interest
The secondary comparisons of interest will include ofatumumab + bendamustine vs. 
bendamustine, based on the PFS in patients with follicular lymphoma, ORR in all 
patients and patients with follicular lymphoma, and OS in all patients and patients with 
follicular lymphoma.  These will be considered as “inferential secondary endpoints” and 
will be tested hierarchically only if the primary endpoint, PFS, is significant in all 
patients.  One spending function will be used for each of these hypotheses. Each 
hypothesis will be tested at the remaining alpha level for primary analysis determined
based on actual information fraction at IA for that hypothesis (assuming that the same 
alpha level for each hypothesis [i.e. 0.0144] was spent). This conservative approach 
ensures strong control of the type I error for the entire study, including IA and primary 
analysis for all comparisons of interest. The following sequence of secondary endpoints 
will be tested, and the subsequent one will be tested only if all the previous endpoints are 
tested and deemed statistically significant:
1. PFS in patients with follicular lymphoma
2. ORR in all patients 
3. ORR in patients with follicular lymphoma
4. OS in all patients 
5. OS in patients with follicular lymphoma
(e.g. only if the PFS in all patients and PFS in patients with follicular lymphoma are 
significant then the ORR in all patients will be tested. This hierarchical testing procedure 
ensures a strong type I error control at a two sided 0.05 level).
The other comparisons of interest will be ofatumumab + bendamustine vs. bendamustine, 
based on PRO assessments.
Per Protocol Amendment 9, the primary analysis will be performed after approximately 
215 PFS events confirmed by IRC have been reported. See Section 4.2 - Primary 
Analysis for details.
7.3.
Data Display Treatment and Other Subgroup Descriptors
For tabulations comparing treatment groups “ofatumumab + bendamustine” and 
“bendamustine” will be presented.  
For patients taking “optional ofatumumab” following progression after bendamustine 
monotherapy - separate efficacy tables for response after optional ofatumumab will be 
presented to display data for this single treatment group.  The safety data collected after 
administration of optional ofatumumab will be displayed as a separate treatment column 
on the safety displays.
All listings will be presented by individual treatment arm.


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Efficacy Data:
The following treatment descriptors will be used on all applicable efficacy displays
except displays summarizing response after administration of optional ofatumumab:
Treatment Group
Data Display
Order 
of 
Treatment 
Groups
Code
Description
A
Ofatumumab + Bendamustine combination  
followed by Ofatumumab monotherapy
Ofatumumab+ 
Bendamustine
1st 
 
treatment 
column
B
Bendamustine monotherapy
Bendamustine
2nd 
 
treatment 
column
For efficacy tables assessing ‘Optional Ofatumumab Salvage’ after progression on 
Treatment Arm B (Bendamustine monotherapy), a single treatment column displaying 
‘Optional Ofatumumab’ will be presented.
The following treatment descriptors will be used on displays summarizing response after 
administration of optional ofatumumab:
Treatment Group
Data 
Display
Order 
of 
Treatment 
Groups
Code
Description
B
Optional Ofatumumab (administered after 
progression on Bendamustine monotherapy)
Optional 
Ofatumumab
1st 
 
treatment 
column
Safety Data:
The following treatment descriptors will be used on all applicable safety displays:
Treatment Group
Data Display
Order 
of 
Treatment 
Groups
Code
Description
A
Ofatumumab + Bendamustine combination  
followed by Ofatumumab monotherapy
Ofatumumab+ 
Bendamustine
1st 
 
treatment 
column
B
Bendamustine monotherapy
Bendamustine
2nd 
 
treatment 
column
B*
Optional Ofatumumab (administered after 
progression on Bendamustine monotherapy)
Optional 
Ofatumumab
3rd 
 
treatment 
column
B/B* = Patients receiving Bendamustine and Optional Ofatumab will be summarized 
with the Bendamustine group up to the time of administration of Optional Ofatumumab. 


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Data collected  after the administration of Optional Ofatumumab will be reported 
separately in the Optional Ofatumumab group.
It is anticipated that only a small number of subjects, approximately 25, will receive 
optional ofatumumab during the study. 
If there appears to be an imbalance in the follow-up periods for adverse events, due to 
differing follow-up after treatment, exploratory analyses may be conducted to further 
investigate this, such as a supplementary analysis using ‘patient years’ as the 
denominator.
Stratification factors and other subgroups are specified in Section 8.3 and will be used for 
subgroup analyses if sample size permits.
Pharmacokinetic Data:
For pharmacokinetic analyses, only data from the Ofatumumab+Bendamustine arm (Arm 
A) will be displayed as only results corresponding to Ofatumumab dosing will be 
collected.  Patients in Arm B taking Bendamustine will not be assessed, unless the patient 
receives Optional Ofatumumab. Data after receiving Optional Ofatumumab will not be 
summarized, but will be included in the data listings.
The following treatment descriptors will be used on all applicable pharmacokinetic 
displays:
Treatment Group
Data Display
Order 
of 
Treatment 
Groups
Code
Description
A
Ofatumumab + Bendamustine combination  
followed by Ofatumumab monotherapy
Ofatumumab+ 
Bendamustine
1st 
 
treatment 
column
Data listings will display all pharmacokinetic data available including data that may be 
collected from patients taking optional ofatumumab.
8.
GENERAL CONSIDERATIONS FOR DATA ANALYSES
Analysis datasets will be created according to CDISC/ADaM standards, and data will be 
listed and summarized according to GSK Integrated Data Standards Library (IDSL)
reporting standards. Formatting for dates, times, and decimal places will follow GSK 
standards except where specified.
The currently supported version of SAS (Version 9.3) will be used to perform all data 
analyses and to generate tables, listings, and figures.  All data in the database will be 
presented in subject data listings.  Data displays will follow the agreements proposed by 
the IDSL where possible.


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Unless otherwise stated, continuous variables will be summarized with the following 
statistics: mean, median, standard deviation, minimum, and maximum.  Categorical 
variables will be summarized with frequency counts and percentages.
All data up to the time of study completion/withdrawal from study will be included in the 
analysis, regardless of duration of treatment.
All confidence intervals will be two-sided and will use a 95% confidence level.
In the protocol and other study-related documents the terms Independent Review 
Committee (IRC), Independent Radiological Review (IRR) and Independent Reviewer 
(IR) have been used to represent the blinded indpendent assessment of the efficacy 
response data.  For this document and the supporting displays, the terminology IRC will 
be used throughout.
Deviations from the analyses in the SAP will be identified in the CSR.
8.1.
Multicenter Studies
Data from all participating centers will be pooled prior to analysis.  It is anticipated that 
subject accrual will be spread thinly across centers and summaries of data by center 
would not be informative and will not be provided.  However, a summary of enrollment 
by center will be provided.
8.2.
Other Strata and Covariates
Prior to randomization, eligible subjects were stratified according to the following 
stratification factors:

Last prior rituximab therapy (rituximab plus chemotherapy vs. rituximab alone)

Prior exposure to bendamustine (exposed vs. not exposed)
For analysis purposes, subjects will be analyzed based on the stratification details entered 
at randomization, e.g. the data as recorded in RAMOS (Registration and Medication 
Ordering System).
A sensitivity analysis of the primary endpoint (PFS based on IRC assessment) using 
stratification according to the actual data recorded in the eCRF will also be provided.  
Hence, if any misallocations took place in the stratification, the actual data will be used to 
determine the stratification of the subject rather than the data as recorded at 
randomization in RAMOS. If the eCRF data is missing or incomplete, the stratification 
item(s) will be populated with the randomization details recorded in RAMOS.
8.3.
Examination of Subgroups
Summary tables for PFS as assessed by the IRC will be provided by  stratification factors
as noted in section 8.2.


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Other subgroups of interest may include age (<65 vs 65), gender (male vs female), race 
(white vs non-white), geographic distribution (North America, European Union, Asia-
Pacific, and Emerging Markets),  Ann Arbor Stage (I-II vs III-IV), FLIPI Score (0-2 vs 3-
5), ECOG (0-1 vs 2), baseline absolute lymphocyte count/ALC (<LLN vs LLN), FcR 
gamma 3A variation (G/G, G/T and T/T), FcR gamma 2A variation (T/T, T/C and C/C) 
and Human Anti-Chimeric Antibodies/HACA status (positive vs negative).  
For geographic region, countries will be assigned as follows:

North America: Canada, United States

European Union & Neighbors: Austria, Belgium, France, Germany, Greece, Italy, 
Poland, Slovakia, United Kingdom, Russia, Ukraine

Emerging Markets & Asia-Pacific (EMAP): Argentina, Hong Kong, Japan
For the regulatory requirements in Japan, efficacy, safety and pharmacokinetic analysis 
for Japanese and non-Japanese subgroups will be performed. TFLs necessary for the 
Japanese subgroup are described in the TFL TOC.
8.4.
Multiple Comparisons and Multiplicity
To control the overall type I error rate, a hierarchical testing procedure will be applied to 
the primary endpoint (PFS assessed by the IRC) and inferential secondary endpoints (PFS 
in patients with follicular lymphoma, ORR in all patients, ORR in patients with follicular 
lymphoma, OS in all patients, OS in patients with follicular lymphoma) analyses.
The detailed procedure is specified in Section 7.2.
As described in Section 4.1 and 4.2, the significance levels for the interim and primary
analysis will be adjusted as appropriate using the O’Brien-Fleming spending function and 
the actual number of events for the analysis.
Assuming ~70% of the patients enrolled in the study had FL, the boundaries used in the 
primary analysis for each endpoint are shown in the table below.
Sample size
Boundary for primary 
analysis
(# of events for PFS/OS and 
# of patients randomized for 
ORR)
IA
Final
Final
PFS 
180
215
0.0483
PFS in FL
126
151
0.0483
ORR
331
346
0.0500
ORR in FL
235
239
0.0500


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OS
115
145
0.0474
OS in FL
81
102
0.0475
The actual boundaries to be used for primary analysis will be updated according to the 
actual number of events observed in subgroups of interest.
9.
DATA HANDLING CONVENTIONS
9.1.
Premature Withdrawal and Missing Data
Because study treatment is dependent on the study endpoints (e.g., progression, rather 
than a fixed treatment duration), the length of treatment for each subject will depend on 
the efficacy and toxicity of the treatment, so the duration of treatment will vary across 
subjects. Similarly, the duration of follow up will also vary. All available data will be 
analyzed using suitable statistical methods; subjects with shorter treatment and follow-up 
due to the natural history of their disease or medical necessities of the treatment of their 
disease will not be considered to have missing data. For endpoints which determine the 
percentage of responders, subjects with not evaluable or missing best overall response 
will be assumed to be non-responders, and will be included in the denominator when 
calculating the percentages. 
Missing data occurs when any requested data are not provided, leading to blank fields on 
the collection instrument. These data will be indicated by the use of a “blank” in subject 
listing displays. Answers such as “Not applicable” and “Not evaluable” are not 
considered to be missing data and should be displayed as such.
Subjects with the designation of treatment relationship for adverse events (AEs) and 
serious adverse events (SAEs) missing will have the worst case assumed to impute the 
relationship: if relationship to study treatment is missing it will be assumed to be “Yes”. 
There will be no other imputation for missing data other than what is described in Section 
9.2 for partial dates and for missing exposure end dates.
9.2.
Derived and Transformed Data
The following sections provide a general description of the derived and transformed 
variables used to describe and analyze the data. Separate analysis dataset specifications
provide full details on all data derivations and transformations including descriptions of 
core standard algorithms and standard Oncology algorithms. The analysis dataset 
specifications will clearly communicate the content and source of the datasets supporting 
the statistical analyses.
9.2.1.
Reference Dates
There are four reference dates:

The reference date for age is the date of screening.


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
The safety reference date is the treatment start date, and will be used to calculate 
study day for safety measures.  

The efficacy reference date is the date of randomization and will be used to calculate 
study day for efficacy measures and baseline characteristics (such as time since initial 
diagnosis), as well as efficacy durations.

The last contact reference date is derived for patients not known to have died at the 
analysis cut-off using the latest complete date on the database.
o
The following dates will be considered for the latest complete date: date of 
treatment assignment; start/last date of study treatment; all assessment dates 
(e.g. assessment date of vital signs or performance status, and assessment date 
in third-party data such as tumor imaging, central laboratory, ECG, etc.); 
adverse event dates including start and stop date of AEs; medication dates 
including study medication, concomitant medications, blood products, next 
anti-cancer therapy, etc.; last known date patient was alive from survival or 
end of study eCRF page; date of discontinuation from treatment or study.
o
Only dates associated with patient visits or actual examinations of the patient 
will be used in the derivation.  Dates associated with a technical operation 
unrelated to patient status such as the date a blood sample was processed, will 
not be used.
o
An imputed partial date will not be used to derive the last contact date.
o
The assessment dates after the cutoff date will not be applied to derive the last 
contact date.
o
The last contact date will be used for censoring of patients in the analysis of 
overall survival and time to next therapy. 
9.2.2.
Study Day for Safety Measures
If the date of interest occurs on or after the safety reference date, then the safety study 
day will be calculated as (date of interest - safety reference date) + 1. If the date of 
interest occurs before the safety reference date, then the safety study day will be 
calculated as (date of interest – safety reference date). There is no safety study day 0.
9.2.3.
Study Day for Efficacy
If the date of interest occurs on or after the efficacy reference date, then efficacy study 
day will be calculated as (date of interest - efficacy reference date) + 1. If the date of 
interest occurs prior to the efficacy reference date, then efficacy study day will be 
calculated as (date of interest – efficacy reference date). There is no efficacy study day 0. 


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9.2.4.
Duration and Elapsed Time
Durations (e.g., the duration of an adverse event, duration of exposure, etc.) are 
calculated as the stop date minus the start date plus one.
For elapsed time (e.g., the time since initial diagnosis):

If the reference date is on or after the event date, then the elapsed time is the 
reference date minus the event date + 1.

If the reference date is before the event date, then the elapsed time is the reference 
date minus the event date.
When reporting time to event (TTE) durations [e.g. PFS, time to next treatment, overall 
survival] in months, divide the number of days by 30.4375; to report in weeks divide the 
number of days by 7; to report in years divide the number of days by 365.25. These
algorithms for time to event return decimal numbers, and ignore the actual numbers of 
days in the months or years between start date and stop date. The "year" used in these 
algorithms is 365.25 days long, and the "month" is one twelfth of that year.
The algorithms above for age and duration return whole numbers for months and years, 
accurately accounting for the actual numbers of days in the months or years between the 
start date and the stop date.
9.2.5.
Imputation of Partial Dates
Imputed partial dates will not be used to derive study day, duration (e.g., duration of 
adverse events), or elapsed time variables. In addition, imputed dates are not used for 
deriving the last contact date (as noted in Section 9.2.1) in overall survival analysis 
dataset.
With the exception of new anti-cancer start date on the time to event analysis dataset and 
exposure end date in the Exposure analysis dataset, imputed dates will also not be stored 
in datasets. 
Imputed dates will not be displayed in listings. However, where necessary, display 
macros may impute dates as temporary variables for the purpose of sorting data in listings 
only. In addition partial dates may be imputed for ‘slotting’ data to study time periods 
(see Section 9.3) or for specific analysis purposes as outlined below.
The partial date imputation will follow ADaM conventions. The ADaM approach is to 
populate the numeric date variables with the imputed date and add a flag variable to the 
dataset that indicates the level of imputation. 
The flag variable can contain the values: blank, 'D', 'M', 'Y'. 
blank: indicates that no imputation was done
D='Day': indicates that the day portion of the date is imputed


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M='Month': indicates that the month and day portions of the date are imputed
Y='Year': indicates that the entire date (year, month, and day) is imputed
Example of Date Variables: 
XYZD_ - character date variable
XYZDT - numeric date variable
XYZDTFL - flag variable
Details on imputing partial dates for specific datasets are outlined below.
Adverse Events (AE):
Imputations in the adverse events dataset are used for slotting events to the appropriate 
study time periods and for sorting in data listings.
Dataset
Date
Missing 
Element
Rule
Adverse 
Events 
(AE)
Start 
Date
day, 
month, 
and year

No Imputation for completely missing dates
day, 
month

If study treatment start date is missing (i.e. subject did 
not start study treatment), then set start date = January 1. 

Else if study treatment start date is not missing: 
o
If year of start date = year of study treatment start 
date then 

If stop date contains a full date and 
stop date is earlier than study 
treatment start date then set start date 
= January 1. 

Else set start date = study treatment 
start date. 
o
Else set start date = January 1.


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Dataset
Date
Missing 
Element
Rule
day

If study treatment start date is missing (i.e. subject did 
not start study treatment), then set start date = 1st of 
month. 

Else if study treatment start date is not missing: 
o
If month and year of start date = month and year 
of study treatment start date then 

If stop date contains a full date and 
stop date is earlier than study 
treatment start date then set start 
date= 1st of month. 

Else set start date = study treatment 
start date.
o
Else set start date = 1st of month.
End 
Date

No imputation for partial end dates will be performed
Anti-Cancer Therapy and Radiotherapy:
Start and end dates are generally not imputed. If start or end dates need to be imputed for 
an analysis (e.g., to calculate duration or elapsed time as covariates for efficacy analyses), 
the rules for imputation will be defined within the algorithm of the derived covariate.
Additionally, post treatment anti-cancer therapy and radiotherapy start dates may be 
imputed to determine date of new anti-cancer therapy. In this case only, the date of new 
anti-cancer therapy (not all anti-cancer therapy and radiotherapy start dates) will be 
stored on appropriate efficacy datasets. Imputed partial dates will not be used to derive 
time since most recent prior therapy. In addition, the cancer therapy treatment status 
variable, and not any variables that use imputed partial dates, will be used to differentiate 
prior and follow-up anti-cancer therapy and radiotherapy. 


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Dataset
Date
Missing 
Element
Rule
Anti-Cancer 
Therapy 
Radiotherapy 
Start 
Date
day, 
month, 
and year

No Imputation for completely missing dates
day, 
month

If partial date contains a year only set to January 
1st.
day

If partial date contains a month and year set to the 
1st of the month.
End 
Date

No imputation for partial end dates will be 
performed
Surgery:
The date of surgery or procedure is generally not imputed. If the date of surgery or 
procedure needs to be imputed for an analysis (e.g., to calculate duration or elapsed time 
as covariates for efficacy analyses), the rules for imputation will be defined within the 
algorithm of the derived covariate. Additionally, post treatment surgery or procedure 
dates maybe imputed (where applicable) to determine date of new anti-cancer therapy. In 
this case only, the date of new anti-cancer therapy (not specific surgery or procedure 
date) will be stored on appropriate efficacy datasets. The category for surgical procedure 
variable, and not any variables that use imputed partial dates, will be used to differentiate 
prior, on, and follow-up surgical procedure data. The derived time in relation to treatment 
variables are not needed for reporting of data because the category for surgical procedure 
variable can be used. Therefore, imputed dates are not needed for derivation of time in 
relation to treatment.
Dataset
Missing 
Element
Rule
Surgical 
Procedures
day, 
month, 
and year

No Imputation for completely missing dates
day, month

If partial date contains a year only set to January 
1st.
day

If partial date contains a month and year set to the 
1st of the month
Concomitant Medication and Blood and Blood Supportive Care Products:


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Impute start and end dates for use in derivation of the reference variables concomitant 
medication start and end relative to treatment and blood and blood supportive care start 
and end relative to treatment, but do not permanently store the imputed start and end 
dates in the analysis datasets. The reference variables will be used to differentiate before, 
during and after for the concomitant medication or blood or blood supportive care start 
and end dates. The derived time in relation to treatment variables are not needed for 
reporting of these data.
Dataset
Date
Missing 
Element
Rule
Concomitant 
Medication
Blood 
and 
Blood 
Supportive 
Care 
Products 
Start 
Date
day, 
month, 
and year

No Imputation for completely missing dates
day, 
month

If study treatment start date is missing (i.e. 
subject did not start study treatment), then set 
start date = January 1. 

Else if study treatment start date is not missing: 
o
If year of start date = year of study 
treatment start date then 

If stop date contains a full date and 
stop date is earlier than study 
treatment start date then set start 
date = January 1. 

Else set start date = study 
treatment start date. 
o
Else set start date = January 1.
day

If study treatment start date is missing (i.e. 
subject did not start study treatment), then set 
start date = 1st of month. 

Else if study treatment start date is not missing: 
o
If month and year of start date = month 
and year of study treatment start date then 

If stop date contains a full date and 
stop date is earlier than study 
treatment start date then set start 
date= 1st of month. 

Else set start date = study 
treatment start date.


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Dataset
Date
Missing 
Element
Rule
o
Else set start date = 1st of month.
End 
Date
day, 
month, 
and year

No Imputation for completely missing dates
day, 
month

If partial end date contains year only, set end date 
= earliest of December 31 or date of last contact. 
day

If partial end date contains month and year, set 
end date = earliest of last day of the month or date 
of last contact.
Time to Event, Overall Response, and Overall Response for Independent Review: 
Start dates for follow-up anti-cancer therapy, radiotherapy (where applicable), and 
surgical procedures (where applicable) will be temporarily imputed in order to define 
event and censoring rules for progression-free survival, response rate, or duration of 
response (i.e., start date for new anti-cancer therapy). Dates will only be imputed when a 
month and year are available but the day is missing. The imputed date(s) will not be 
stored on the anti-cancer therapy, or radiotherapy, datasets. The following rules will be 
used to impute the date when partial start dates are present on anti-cancer therapy 
radiotherapy, and/or surgical procedures dataset[s]:
Dataset
Date
Missing 
Element
Rule
Anti-Cancer 
Therapy 
Where 
applicable: 
Radiotherapy 
Surgical 
Procedures
Start 
Date
day, month, 
and year

No Imputation for completely missing dates
day, month

No imputation for missing day and month 
(note the eCRF should only allow for 
missing day)
day

If partial date falls in the same month as the 
last dose of study treatment, then assign to 
earlier of (date of last dose of study 


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Dataset
Date
Missing 
Element
Rule
treatment+1, last day of month). 

If partial date falls in the same month as the 
subject’s last assessment and the subject’s 
last assessment is PD, then assign to earlier 
of (date of PD+1, last day of month). 

If both rules above apply, then assign to 
latest of the 2 dates 

Otherwise, impute missing day to the first of 
the month.
End 
Date

No imputation for partial end dates will be 
performed
The date of new anti-cancer therapy is derived as the earliest date of new anti-cancer 
therapy (e.g., chemotherapy), radiotherapy (where applicable), or cancer related surgical 
procedure (where applicable) and will include imputed dates. If the date of new anti-
cancer therapy is an imputed date, then the date of new anti-cancer therapy flag variable 
is assigned the value of 'D' to indicate that the day portion of the date is imputed 
(following ADaM convention). 
As multiple dates are used to derive the date of new anti-cancer therapy ensure that the 
date of new anti-cancer therapy flag is only set to ‘D’ if the derived date is imputed. For 
example if the date of new radiotherapy is imputed but the date of new anti-cancer 
therapy is prior to date of new radiotherapy and the new anti-cancer therapy date is not a 
partial date then the flag should be set to missing as the date used for the new anti-cancer 
therapy is not an imputed date.
Covariates:
The following imputation rules are the standard rules to be used when algorithms for 
covariates require date imputations.
Variable 
Example of when to impute
Rule
Prior 
anti-cancer 
therapy start date
Prior 
radiotherapy 
start date

Impute to derive duration 
o
Duration of prior 
Therapy

Only impute when a month 
and year are available but 
the day is missing. 

Impute to first day of the 
month. 

Do not store imputed date 


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Variable 
Example of when to impute
Rule

Use 
only 
for 
relevant 
efficacy analyses (i.e. not to 
be 
used 
for 
general 
radiotherapy or anti-cancer 
therapy summaries)
Prior 
anti-cancer 
therapy 
end 
date
Prior 
radiotherapy 
end date

Impute to derive elapsed 
time and duration 
o
Duration of prior 
Therapy 
o
Time 
from 
Last 
dose 
of 
prior 
therapy 
to 
Randomization

Only impute when a month 
and year are available but 
the day is missing. 

Impute to last day of the 
month, also must be prior to 
'start' 
o
if 'start' is the first of 
the month assign to 
'start', else assign to 
'start'-1), where 'start' 
is either the date of 
randomization or the 
start 
of 
study 
treatment. 

Do not store imputed date 

Use 
only 
for 
relevant 
efficacy analyses (i.e. not to 
be 
used 
for 
general 
radiotherapy or anti-cancer 
therapy summaries)
Any 
disease 
characteristic dates. 
For example: 

Date of initial 
diagnosis 

Date 
of 
last 
recurrence

Date 
of 
last 
progression

Impute to derive elapsed 
time 
o
Time from initial 
diagnosis 
to 
randomization 
for 
use as a covariate 
o
Time 
from 
progression on last 
therapy 
until 
randomization 
for 
use as a covariate

If both month and day are 
missing, impute to January 
1st 

else if day is missing, impute 
to first day of the month. 

Do not store imputed date 

Use 
only 
for 
relevant 
efficacy analyses (i.e. not to 
be used for general disease 
characteristic summaries)
9.2.6.
Imputation of Missing Exposure End Dates
In general, completely missing dates are not imputed. However, subjects in oncology 
trials may still be on study treatment when analyses are performed and so may have 
missing exposure end dates. For subjects with missing exposure end dates at the time of 
data cutoff, the exposure end date will be imputed to the earliest of: the date of the 


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clinical cutoff, the date of withdrawal from the study, or the death date. The imputed 
exposure end date will be used to calculate cumulative dose and exposure duration. The 
imputed exposure end date will be stored in the exposure analysis dataset and an 
exposure end date imputation flag variable will be derived indicating which exposure end 
date records are imputed. Imputed exposure end dates will also be stored on the study 
treatment end date variable.
For subjects who have missing end dates in their last exposure record because they are 
still on study treatment, the on-therapy indicator variables (time in relation to study 
treatment) are assigned to on-therapy for all records where the 'dataset'.'date' is after or on 
the study treatment start date.
9.2.7.
Baseline Definition
Baseline will be defined as the most recent, non-missing value prior to or on the first 
study treatment dose date. For laboratory data, baseline will be defined as the most recent, 
non-missing value from a central laboratory prior to or on the first study treatment dose 
date.
For subjects taking optional ofatumumab in Arm B, another baseline is defined for the 
optional ofatumumab period as the the most recent, non-missing value prior to or on the 
first optional ofatumumab dose date.
For subjects who did not receive study treatment during the study, baseline will be 
defined as the latest, non-missing collected value.
9.2.8.
Change from baseline
Change from baseline will be presented for safety data. 
Change from baseline is calculated as:

For records occurring after baseline: (visit value) – baseline value.
Percent change from baseline is calculated as:

For records occurring after baseline: ((change from baseline) / baseline value) * 100
If either the baseline or visit value is missing, the change from baseline and/or percent 
change from baseline is set to missing as well.
9.2.9.
Multiple Assessments
Summaries of by visit safety data include data from scheduled assessments only. 
Unscheduled data are included only in summary sections labeled “worst case”.  Data 
from all assessments (scheduled and unscheduled), including multiple assessments, will 
be included in listings


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9.2.10.
Actual Treatment 
The subjects’ actual treatment will be derived from exposure data.  If a subject’s actual 
treatment is the same as the assigned treatment at least once, then actual treatment is the
assigned treatment. If a subject receives a study treatment that is different from the 
assigned treatment for the entire time of treatment, then actual treatment is the different 
treatment (the treatment actually received).
9.2.11.
Treatment Cycle
In order to differentiate cycle variables based on the “assessment” cycle 
(timeslicing/eCRF collected) versus actual treatment cycle variables based on exposure 
cycle start dates, treatment cycle, treatment cycle description, day with treatment cycle, 
day of start within treatment cycle, and day of end within treatment cycle, as appropriate, 
will be added to adverse events, blood and blood supportive care products, ECG, 
laboratory, and vital sign analysis datasets.
Treatment cycle:

For non-planned visits/assessments select the cycle record for each subject where the 
dataset date variable is greater than or equal to cycle start date and less than or equal 
to cycle end date.

For planned visits/assessments where Day 1 assessments are assumed to be done 
prior to dosing, add 1 to the cycle start date and cycle end date from the cycle dataset. 
For each subject, select the cycle record where the dataset date variable is greater 
than or equal to the cycle start date and less than or equal to the cycle end date. 
Treatment cycle description:

Set treatment cycle description to the cycle dataset cycle description where the cycle 
dataset cycle is equal to the dataset treatment cycle.
Day within treatment cycle:

For each subject, dataset date variable minus the cycle start date from the cycle 
dataset + 1 where the dataset date variable is greater than or equal to the cycle 
dataset start date and less than or equal to the cycle end date and the cycle dataset 
cycle is equal to the dataset treatment cycle.
Day of start within treatment cycle:

For each subject, dataset start date variable minus the cycle start date from the cycle 
dataset + 1 where the dataset start date variable is greater than or equal to the cycle 
dataset start date and less than or equal to the cycle end date and the cycle dataset 
cycle is equal to the dataset treatment cycle.
Day of end within treatment cycle:


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
For each subject, dataset end date variable minus the cycle start date from the cycle 
dataset + 1 where the dataset end date variable is greater than or equal to the cycle 
dataset start date and less than or equal to the cycle end date and the cycle dataset 
cycle is equal to the dataset treatment cycle.
9.2.12.
Extended Loss to Follow-up or Extended Time without an 
Adequate Assessment
If two or more scheduled disease assessments are missed and are then followed by an 
assessment of PD or death, PFS will be censored at the last adequate assessment prior to 
PD or death. For example, when the scheduled disease assessment is every 4 weeks, a 
window of 70 days (8 weeks + 14 day window) will be used to determine whether there 
was an extended time without adequate assessment. That is, if the time difference 
between PD/death and last adequate assessment is more than 70 days, then PFS will be 
censored at the last adequate assessment prior to PD/death.
9.3.
Study Time Periods
9.3.1.
Time in Relation to Treatment
Adverse events, concomitant medications, blood product, death, subject disposition, 
ECOG, laboratory, image data, vital signs, constitutional symptoms, lymph node 
examination, organ examination, biomarker, and questionnaire data (FACT-Lym and EQ-
5D) will be assigned to the treatment periods defined below.  Flag variables indicating 
the treatment period will be added to these datasets. 
Pre-therapy is defined as the time prior to the subject’s first dose of study treatment.  
On-treatment is defined as the time from start date/time of study treatment until the 
earlier of the end date/time of the study treatment + 60 days and the date prior to start 
date/time of the optional ofatumumab for subjects in Arm B (if applicable).  The start 
date of the on-treatment phase is the earlier date of the first dose for each study drug. The 
end of study treatment is defined as the last dose of planned treatment which includes the 
latter date of the last dose for each study drug in the regimen for combination trials. 
There are specific rules to handle the cases where start date/time is equal to start 
date/time of study treatment or the start date/time is missing for different classes of data 
sets:

For interventions and events, including adverse event, concomitant medications, 
blood product, death, and disposition, i.e., if the date/time is equal to start date/time of 
study treatment or time is not available and the date is equal to start date of study 
treatment, the flag will be set to on-treatment.  If the start date is missing, and the end 
date/time is before start date/time of study treatment, the flag will be set to pre-
treatment. If start date is missing and end date/time is not before the start date/time of 
study treatment, or both start date and end date are missing, the flag will be set to on-
treatment. 


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
For findings including ECOG status, laboratory data, imaging data , vital signs, 
constitutional symptoms, lymph node examination,  organ examination, and 
biomarker if the date/time is equal to start date/time of study treatment, the flag will 
be set to pre-treatment. If time is not available and the date is equal to start date of 
study treatment, the flag will be set to pre-treatment. If the date is missing, the flag 
will be set to on-treatment. 
Post-treatment is defined as any time beyond the on-treatment period.
9.3.2.
Study Time Periods for Concomitant Medications and Blood and 
Blood Supportive Care Products
Concomitant Medication and Blood and Blood Supportive Care Product start and end 
dates will be assigned to study time periods in relation to first dose of study treatment as 
defined below. The start date references time flag variables and end date reference time 
flag variables will be added to the concomitant medications and blood and blood 
supportive products datasets, respectively.

Start relative to treatment: Assign to 'BEFORE' if start date is prior to study 
treatment start date or if subject has not taken any study treatment or (start date is 
missing and end date is before study treatment start date). Else assign to 'DURING' if 
the start date falls into the on-therapy period as defined above or if subject is ongoing 
(not all study treatment discontinuation records completed) or start date is missing. 
Else assign to 'AFTER' if start date is after the on-therapy period.

End relative to treatment: Assign to 'BEFORE' if end date is prior to study treatment 
start date or if subject has not taken any study treatment. Else assign to 'DURING' if 
start date falls into the on-therapy period or if subject is ongoing (not all study 
treatment discontinuation records completed) or (end date is missing and start 
relative to treatment not 'AFTER'). Else assign to 'AFTER' if start date is after the 
on-therapy period or (end date is missing and start relative to treatment='AFTER').
Only on-therapy blood and blood supportive care products that start after the start of 
study treatment are included in the Blood Products and Blood Supportive Care Product 
summaries. Therefore, for summary tables, include blood and blood supportive care 
product records where start relative to treatment in ('DURING') and end relative to 
treatment in ('DURING','AFTER'). All data will be reported in listings.
Concomitant medication start relative to treatment and end relative to treatment flags are 
used to select data to include in the Concomitant Medication summaries as follows:

Summary of Concomitant Medications: This summary will contain medications 
including those with start date prior to study treatment start date and continue 
(missing end date or end date after study treatment start date) on therapy. Note that 
any medications with start date and end date prior to study treatment start date will be 
excluded. In addition, any medication that was started during post-therapy will be 
excluded. 


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9.4.
Values of Potential Clinical Importance
9.4.1.
Laboratory Parameters
Reference ranges for all laboratory parameters collected throughout the study are 
provided by the laboratory. A laboratory value that is outside the reference range is 
considered either high abnormal (value above the upper limit of the reference range) or 
low abnormal (value below the lower limit of the reference range). Note: a high abnormal 
or low abnormal laboratory value is not necessarily of clinical concern. The laboratory 
reference ranges will be provided on the listings of laboratory data. Clinical laboratory 
test results outside of the reference range will be flagged in the listings.
A summary of values outside the normal range will be provided.
9.4.2.
Vital Signs
To identify heart rate values of potential clinical importance, NCI-CTCAE v4.0 will be 
used to assign categories that align with the grades for ‘Sinus bradycardia’, ‘Sinus 
tachycardia’, ‘Supraventricular tachycardia’, and ‘Ventricular tachycardia’.
The following criteria will be used to flag vital sign values that are values of potential 
clinical importance:
Vital Sign Parameter
Potential Clinical Importance (PCI) Range
Unit
Decrease from baseline 
Heart Rate
Decrease to <60
bpm
Increase from baseline 
Heart Rate
Increase to >100
bpm
To identify blood pressure values of potential clinical importance, NCI-CTCAE v4.0 will 
be used to assign categories that align with the grades for ‘Hypertension’.
Vital Sign Parameter
Potential Clinical Importance (PCI) Range
Unit
Increase from baseline 
Systolic Blood Pressure
120 to <140 (Grade 1)
140 to <160 (Grade 2)
160 (Grade 3)
mmHg
Increase from baseline 
Diastolic Blood Pressure
80 to <90 (Grade 1)
90 to <100 (Grade 2)
100 (Grade 3)
mmHg
To identify temperature values of potential clinical importance, NCI-CTCAE v4.0 will be 
used to assign categories that align with the grades for ‘Hypothermia’ and ‘Fever’.


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Vital Sign Parameter
Potential Clinical Importance (PCI) Range
Unit
Increase from baseline 
Temperature
Increase to 38
Degrees 
C
Decrease from baseline
Temperature
Decrease to 35
Degrees 
C
10.
STUDY POPULATION
Unless otherwise stated, all tables and listings in this section will be based on the ITT 
population and all summaries and data listings will use treatment labels specified in 
Section 7.
10.1.
Disposition of Subjects
A summary of the number of subjects in each of the analysis populations described in 
Section 6. will be provided. In addition, the number of subjects enrolled by investigator 
will be summarized by treatment group using the ITT population. A listing of subjects 
excluded from analysis populations will also be provided.
A summary of subject status and reason for study withdrawal will be provided. This 
display will show the number and percentage of subjects who withdrew from the study,
including primary reasons for study withdrawal. Reasons for study withdrawal will be 
presented in the order they are displayed in the eCRF. 
A summary of study treatment status will be provided. This display will show the number 
and percentage of subjects who have completed the study treatment, are ongoing, or have 
discontinued study treatment and a summary of the primary reasons for discontinuation 
of study treatment. Reasons for study treatment discontinuation will be presented in the 
order they are displayed in the eCRF. A listing of study treatment discontinuation will be 
generated. The listing will include last dose date, and reasons for study treatment 
discontinuation. 
10.2.
Protocol Deviations
All important protocol deviations as collected per the Protocol Deviation Management 
Plan (PDMP) will be summarized and listed and will include inclusion/exclusion criteria 
deviations as well as other deviations. Protocol deviations will be classified as 
‘Deviations that require exclusion from per-protocol population’ (as described in section 
6.3) and ‘Deviations that do not require exclusion from per-protocol population’.
A separate summary and listing of inclusion/exclusion deviations will also be provided.
10.3.
Demographic and Baseline Characteristics
The demographic characteristics (e.g., age, race, ethnicity, sex, baseline height, and 
baseline weight) will be summarized and listed. Age, height and weight will be 


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summarized using the mean, standard deviation, minimum, median, and maximum. In 
addition, age will also be categorized and summarized for the following categories:

<18, 18-64, 65-74, and 75 

<65 and 65 years.
The count and percentage will be presented for sex and ethnicity.
Race and racial combinations will be summarized and listed.
The number of subjects enrolled by country and by site will be summarized.
The disease history and characteristics at screening will be summarized. The summaries 
of disease characteristics at initial diagnosis will also be provided. Medical conditions 
present at screening will be listed and will be summarized, along with liver and spleen 
organ examination, physical lymph node examination, anti-cancer therapies, and 
concomitant medications.
Prior anti-cancer therapy will be coded using the WHODrug coding dictionary, then 
summarized by type of therapy and listed. A listing of prior anti-cancer therapy will show 
the relationship between ATC Class (e.g. ATC Level 1), Preferred Term (e.g. Ingredient), 
and verbatim text. A summary of the best response to the most recent prior anti-cancer 
therapy will be provided. A summary of the number of prior anti-cancer therapy regimens 
will also be produced. 
A summary of pre-medications required prior to infusion will also be provided. Prior 
anti-cancer radiotherapy will be summarized and listed. Prior cancer and non-cancer 
related surgeries will be summarized.
The baseline stratification factors, will be summarized. A cross-tabulation showing the 
differences between stratification based on the randomization (RAMOS/RANDALL) and 
stratification based on the eCRF data will be provided.
Summaries of baseline covariates included in Cox proportional hazards model regression 
analyses (see Section 11.1.) will be provided. 
The summaries will be produced in all patients using ITT population as well as in 
patients with and without FL.
10.4.
Treatment Compliance
A listing of planned and actual treatments will be produced.
A listing of drug accountability data (date, actual dose, total volume infused) will be 
produced.


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A summary and listing of overall study medication compliance will be produced for 
ofatumumab.  Compliance will be based on the total dose of ofatumumab received (mg) 
divided by the total dose (mg) expected taking into account withdrawal from treatment.  
Therefore, the denominator is based on the total dose received during the time that a 
subject is actually eligible to receive drug.  
For example, if the dosing period for a study is 6 cycles and during that 6 cycles, a 
subject received 100 mg of drug each cycle, then the denominator (total dose expected) 
would be 600 mg as a total dose, if the subject was actually in the study for the 6 cycles.  
However, if the subject discontinued treatment at the end of the 3 cycles, then total dose 
in mg expected for this case would be 300 mg.
Overall Compliance = (total dose in mg received / total dose in mg expected) * 100
Overall compliance will be categorized into the following intervals:  <80%, 80% -
<100%, 100%, >100% - < 120%, and 120%.
Overall compliance will also be provided for bendamustine, using the same formula as 
ofatumumab.
In addition, summaries of study treatment exposure and dose modifications (e.g., number 
of dose reductions, number of dose interruptions) will further characterize compliance. 
These analyses are described in Section 12.1, ‘Extent of Exposure’.
10.5.
Concomitant Medications
Concomitant medications will be coded using WHODrug coding dictionary, summarized, 
and listed. The summary of concomitant medications will show the number and 
percentage of subjects taking concomitant medications by Ingredient. Multi-ingredient 
products will be summarized by their separate ingredients rather than as a combination of 
ingredients. 
In the summary of concomitant medications, each subject is counted once within each 
unique ingredient. For example, if a subject takes Amoxycillin on two separate occasions, 
the subject is counted only once under the ingredient “Amoxycillin”.
In the summary of concomitant medications, the ingredients will be summarized by the 
base only (and will not be shown separately for different base + salt combinations).
Blood products or blood supportive care products with onset date within the on-therapy 
window will be included in the summary tables. The frequency and percentage of 
subjects using blood products and blood supportive care products after the start of study 
medication will be provided. Supporting listings will also be provided


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10.6.
Subsequent Anti-Cancer Therapies
The number and percentage of subjects that received chemotherapy, immunotherapy, 
hormonal therapy, biologic therapy, radioactive therapy, and small molecule targeted 
therapy as post study treatment anti-cancer therapy, including the optional ofatumumab
for subjects in Arm B, will be summarized. Time from study treatment discontinuation to 
the first post study treatment anti-cancer therapy will also be included in this summary 
table. 
Follow-up anti-cancer therapy will be coded using the WHODrug coding dictionary, then
summarized by ingredient. A listing of the type of follow-up anti-cancer therapy received 
(chemotherapy, immunotherapy, hormonal therapy, biologic therapy, radioactive therapy, 
small molecule targeted therapy) for each subject will be provided.
11.
EFFICACY
All efficacy analyses, with the exception of analyses of response after optional 
ofatumumab, will be based on the ITT population as defined in Section 6, unless 
otherwise 
specified. 
 
Analyses 
will 
be 
presented 
by 
treatment 
arm: 
ofatumumab+bendamustine vs. bendamustine. 
Analyses of response after optional ofatumumab salvage therapy will be based on the 
Optional Ofatumumab Population as defined in Section 6.  Analyses will be presented by 
a single treatment arm: optional ofatumumab.
The Revised Response Criteria for Malignant Lymphoma [RRCML] guidelines (Cheson, 
2007) will be used to assess clinical activity and disease status. IRC assessments will be 
considered as primary assessments.  Investigator assessments will be considered as 
supplementary.
11.1.
Primary Efficacy Analysis
Progression-free survival (PFS)
The primary endpoint, progression-free survival (PFS), is defined as the interval of time 
(in months) between the date of randomization and the earlier of the date of disease 
progression or death due to any cause.  The IRC assessment of response will be used for 
the primary analysis. 
The date of documented disease progression will be defined as the date of disease 
progression based on imaging data.  The date of death should be taken from the Record 
of Death page.  Death on study due to any cause will be included as an event for 
calculation of PFS.
If there is no adequate baseline assessment, the subjects will be censored at their date of 
randomization.  Subjects without any adequate post-baseline assessments will be 
censored at the date of randomization.


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Subjects who progressed or died after an extended period without an adequate assessment 
will be censored at their date of last adequate assessment prior to progression or death 
even if subsequent information is available regarding progression or death.  An adequate 
assessment is defined as an assessment where the IRC determined response is CR, PR, or 
SD. The date of response at that assessment will be used for censoring. As the assessment 
schedule may change through the course of the protocol, specific rules for identifying 
extended loss to follow-up or extended time without an adequate assessment are provided 
in Section 9.
For subjects who receive subsequent anti-cancer therapy, the following rules will apply:

If the start date of the anti-cancer therapy is partial (i.e. either missing the day but has 
the month and year available or missing both day and month) the imputation rules 
described in Section 9 will be applied.  No imputation will be made for completely 
missing dates.

If anti-cancer therapy is started without documented disease progression or is started 
prior to documented disease progression, then PFS will be censored at the date of the 
last adequate assessment that is no later than the date of initiation of anti-cancer 
therapy (i.e. if an assessment occurs on the same day as the start of new anti-cancer 
therapy the assessment will be used as it will be assumed the assessment occurred 
prior to the administration of new anti-cancer therapy).  The date of response at the 
last adequate assessment will be used as the censoring value.

If a subject has only a baseline visit or does not have an adequate assessment that is 
not later than the date of initiation of anti-cancer therapy, PFS will be censored at the 
date of randomization.
If a subject has not progressed, has not died and has not started new-anti-cancer therapy, 
then PFS will be censored at the date of the last adequate assessment defined as an 
assessment where the IRC determined response is CR, PR, SD. The date of response will 
be used as the censoring date.  
A summary of the assignments for progression and censoring dates for PFS are specified 
in the following table.
Table 1
Assignments for Progression and Censoring Dates for PFS Analysis
Situation
Date 
of 
Event 
(Progression/Death) 
or 
Censoring
Outcome 
Event (Progression/Death) 
or Censored
No (or inadequate) baseline 
assessment and the subject 
has not died 
Randomization
Censored
No post-baseline response Randomization
Censored


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assessments and the subject 
has not died
Progression 
documented 
between scheduled visits
Date 
of 
assessment 
of 
progression
Event
No progression (or death)
Date 
of 
last 
adequate 
assessment of response1
Censored
New anticancer treatment 
started (prior to documented 
disease progression)2
Date 
of 
last 
adequate 
assessment of response1 (on 
or prior to starting anti-
cancer therapy)
Censored
Death 
before 
first 
PD 
assessment (or Death at 
baseline or prior to any 
adequate assessments)
Date of death
Event
Death 
between 
adequate 
assessment visits with no 
PD
Date of death
Event
Death or progression after 
more than one missed visit
Date 
of 
last 
adequate 
assessment 
of 
response 
(prior 
to 
missed 
assessments)3
Censored
1An adequate assessment is defined as an assessment where the Independent Reveiwerer determined response is 
CR, PR, or SD. 
2If PD and new anti-cancer therapy occur on the same day, assume that progression was documented first (i.e. 
outcome is progression and the date is the date of the assessment of progression).  If anti-cancer therapy is started 
prior to any adequate assessments, censoring date should be the date of randomization.
3For the rare case where a subject dies after more than 1 missed visit, and there are no post-baseline response 
assessments, the date of censoring will be defined as the randomization date.
An interim analysis of the primary endpoint, PFS confirmed by IRC, was planned to be
performed when approximately 2/3 of the initial number of PFS events confirmed by IRC 
occurred (172 PFS events by IRC).  The interim analysis for PFS was planned to be 
reviewed by an IDMC utilizing a significance level of 0.012 (for 172 events or adjusted 
as appropriate using an O’Brien-Fleming spending function). The interim analysis of PFS 
was conducted in the same manner as described for the primary analysis.  Details of the 
interim analysis are also provided in the IDMC Charter. The IA occurred with 180 PFS 
events by IRC and the actual alpha spent at IA was calculated to be 0.0144.
The primary analysis of PFS was planned to be based on a two-sided test with a 
significance level of 0.046. The primary analysis will be conducted at a significance level 
of 0.0483 (with 215 events) to maintain an overall study significance level of 0.05 (See 
Section 4.2 - Primary Analysis for details). The survival distributions will be estimated 
using Kaplan-Meier survival curves and will be compared using a log-rank test stratified 


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by randomization stratification factors. 
A Cox regression model stratified by 
randomization stratification factors will be used to estimate the hazard ratio (HR) of PFS, 
along with 95% CI based on the Wald test.
If there are a sufficient number of progressions or deaths, median PFS, first and third 
quartiles and 95% CI, will be estimated using the Brookmeyer-Crowley method 
[Brookmeyer, 1982]. A figure and listing of progression-free survival time will also be 
provided.
A supplementary table showing the details of the number at risk, number of events, and 
number censored with the event time will also be produced.  
A Cox regression model stratified by randomization stratification factors will be used as 
supportive analysis and will include covariates for treatment and other baseline data 
deemed appropriate including age, gender, race, Ann Arbor stage at screening, histology 
at screening, FLIPI score, and ECOG. The hazard ratio for treatment will represent the 
risk of experiencing disease progression or death for ‘ofatumumab+bendamustine’ vs 
‘bendamustine’.
PFS will be evaluated for the ITT population.  If the ITT population and Per Protocol 
population differ by more than 10%, then PFS will also be evaluated for the Per-Protocol 
population to check the robustness of the result.
Sensitivity Analyses for PFS
Five sensitivity analyses of PFS will be performed.  All sensitivity analyses will be 
performed as described for the primary analysis of PFS.  If the primary efficacy analysis 
is not significant, the supportive and sensitivity analyses will be considered exploratory 
in nature. The sensitivity analyses are specified as follows:

The first sensitivity analysis will be conducted using the Investigator assessed 
response data.  

The second sensitivity analysis will be conducted using stratification based on the 
eCRF data rather than stratification based on randomization details (see Section 
8.2).

The third sensitivitity will treat all progressions and deaths as events, regardless 
of whether they occurred after starting new anti-cancer therapy, including the 
optional ofatumumab for subjects in Arm B.

The fourth sensitivitity will treat all progressions and deaths as events, regardless 
of whether they occurred after starting new anti-cancer therapy or after 2 or more 
missed scheduled assessments.


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
The fifth sensitivity analysis will treat progression, death and new anti-cancer 
therapy, whichever occurs earlier, as events.
Subgroup Analyses for PFS
If the primary efficacy analysis is statistically significant, the primary endpoint of PFS  
will be summarized for the subgroups specified in Section 8.3 (FL subgroup, gender, age 
group, race, geographic region, Ann Arbor Stage, FLIPI Score, ECOG, ALC, FcR
gamma 3A, FcR gamma 2A and HACA status) and using the same conventions as for the 
primary analysis, provided subgroups are large enough to result in meaningful analyses.  
Figures displaying the survival curves will also be provided by treatment arms as well as 
for each of the stratification factors.  PFS will also be summarized by stratification 
factors provided the subgroups are large enough to result in a meaningful analysis.
Efficacy analyses in subgroups are intended to explore the consistency (homogeneity) of 
treatment effect. Forest plot (including sample size/number of events and HR with 95% 
CI) will be produced to graphically depict the treatment effect estimates in different 
subgroups. No inferential statistics (p-values) will be produced for the subgroups
11.2.
Secondary Efficacy Analyses
A hierarchical testing procedure will be applied to inferential secondary endpoints (PFS 
in patients with follicular lymphoma, ORR in all patients, ORR in patients with follicular 
lymphoma, OS in all patients, OS in patients with follicular lymphoma) analyses should 
the analysis of primary endpoint show significant results (see section 8.3 for further 
details).
11.2.1.
Overall Response Rate (ORR)
Overall Response Rate (ORR) is defined as the percentage of subjects achieving a CR or 
PR from the start of randomization until disease progression or the start of new anti-
cancer therapy, including the optional ofatumumab for subjects in Arm B.  This will be 
based on responses from the IRC assessment of best overall response using the Revised 
Response Criteria for Malignant Lymophoma (RRCML) with response criteria defined as 
CR, PR, SD, PD or  NE.  The best response data will be summarized by treatment arm in 
all patients using ITT population as well as in patients with and without FL.
Subjects with Not Evaluable (NE) or missing response will be treated as non-responders; 
i.e., they will be included in the denominator when calculating the percentage.
The 95% CI for response rates in each arm will be calculated and responses rates will be 
compared between treatment arms using a chi-square test adjusting for stratification 
factors (last prior rituximab therapy and prior exposure to bendamustine). 95% CI for the 
difference in response rates will be calculated.
All data relating to response from the IRC will be listed (including individual response 
assessments and best response).


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The Investigator determined best response data will also be summarized by treatment arm.
11.2.2.
Overall Survival (OS)
Overall Survival (OS) is defined as the interval of time (in months) between the date of 
randomization and the date of death due to any cause.  For subjects who are alive, time of 
death will be censored at the date of last contact (as defined in Section 9.2.1).  The date 
of death should be taken from that recorded on the Record of Death page.  
Survival will be summarized using the Kaplan-Meier method, and survival curves will be 
compared using a stratified log-rank test by randomization stratification factors along 
with 95% Confidence Intervals (CI).  In addition, for each treatment group, the Kaplan-
Meier estimates for the median overall survival time, the first and third quartiles will be 
presented, along with approximate 95% CIs if there are a sufficient number of deaths.
The analysis will be performed based on all patients using ITT population as well as for
patients with and without FL.
A graph of survival curves and a listing of survival times will also be provided.
Analyses will be conducted at the time of the primary endpoint PFS analysis as well as at 
the end of the study.
11.2.3.
Time to response
Time to response is defined as time from randomization to the first response (CR/ PR).  If 
no CR/PR value is present data will be censored at last adequate assessment. Kaplan-
Meier estimates will be provided for the treatment arms over time. The median time to 
response along with the associated 95% confidence will be provided by treatment group.
The analysis will be performed in all patients using ITT population as well as in patients 
with and without FL.
Both IRC assessed and Investigator assessed time to response will be provided.
11.2.4.
Duration of response
The duration of response is defined as the time (in months) from the initial response 
(CR/PR) to first documented sign of disease progression or death due to any cause.  If 
sample size permits, the median duration of response will be calculated from the Kaplan-
Meier estimates.  First and third quartiles will also be calculated along with associated 
95% confidence intervals if there are a sufficient number of responders who subsequently 
progress or die due to any cause.  Censoring rules will follow those of the primary PFS 
analysis defined in Section 11.1. No treatment comparison will be provided for duration 
of response. The subset of ITT (subjects who are responders) will be used for this 
analysis. The analysis will be performed in all patients as well as in patients with and 
without FL.
Both IRC assessed and Investigator assessed duration of response will be provided.


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A listing of duration of response will be provided. 
11.2.5.
Time to progression
Time to progression is defined as the time from randomization until disease progression.  
The same analysis will be performed as described for time to response analysis. The 
analysis will be performed in all patients using ITT population as well as in patients with 
and without FL.
Both IRC assessed and Investigator assessed time to progression will be provided.
11.2.6.
Time to next therapy
Type and time to next therapy will be provided.  Time to next therapy is defined as the 
time (in months) from randomization date to the date of receiving the next line treatment
as collected on the “Follow up anti-cancer therapy” CRF page (including all therapy 
types) or death (due to any cause).  Next line treatments given after a PD or those given 
without a PD are both considered.  For subjects who do not receive another next line 
therapy or die, time of next therapy will be censored at the date of last contact.  The same 
analysis will be conducted as described for the primary endpoint, PFS.
Patients taking optional Ofatumumab will be considered to have received next therapy.
Both the ITT population and a subset of the ITT (subjects who take next therapy) will be 
used for this analysis. The data structure for treatment comparisons used in PFS will also 
be applied. The analysis will be performed in all patients as well as in patients with and 
without FL.
11.2.7.
Reduction in tumor size
Tumor sizes and reduction in tumor size will be measured by the absolute value of, and 
percentage change in the sum of products of the diameters of the largest abnormal nodes 
from baseline to post-baseline.
11.2.8.
Improvement in ECOG performance status
Improvement is defined as a decrease from baseline by at least one step on the ECOG 
performance status scale (improvement categorized as yes or no).  The proportion of 
subjects with improvement will be compared between treatment groups with the 
Cochran-Mantel-Haenszel test adjusting for stratification factors.
ECOG performance status will also be summarized at baseline and the worst-case post-
baseline. Summaries will present the frequency and percentage of subjects with worst-
case changes during the study (improved, no change, deteriorated). 
A supporting listing will also be provided. 


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11.2.9.
Constitutional Symptoms (or B-Symptoms)
A summary of the number and percentage of subjects with any constitutional 
symptom/B-symptom will be displayed at each assessment time during the study.  A 
summary of improvement at each post-baseline assessment will also be provided. 
A plot of proportion of subject with B-symptoms by visit will also be provided.
11.2.10.
Organ Examination
The number and percentage of subjects with normal or enlarged organs based on liver 
and spleen examination by palpation/CT scan will be summarized by scheduled visits.
A supporting listing will also be provided. 
11.2.11.
Disease Markers
B-cell Monitoring
The change and percent change of CD45+CD19+ and CD45+CD20+ from baseline will be 
summarized to assess the treatment effect, to monitor the normal B-cell population, and 
to follow their recovery.  In addition, frequency and percentage of subjects with complete 
B-cell depletion and near-complete B-cell depletion will be summarized.  Complete B-
cell depletion is defined as the absolute value of CD45+CD19+ and CD45+CD20+ both 
equal to zero cells/uL.   Near complete B-cell depletion is defined as the sum of the 
absolute value of CD45+CD19+   and CD45+CD20+  <5 cells/uL.
Tables that will be provided are: 

Summary of CD45+CD19+ counts over time

Summary of CD45+CD20+ counts over time

Summary of CD45+CD19+ change from baseline (counts and percentage)

Summary of CD45+CD20+ percent change from baseline (counts and percentage)

Summary of CD45+CD19+  change from baseline (counts and percentage)

Summary of CD45+CD20+ percent change from baseline (counts and percentage)

Summary of subjects with near-complete B-cell depletion 

Summary of subjects with complete B-cell depletion 

Summary of subjects with complete B-cell depletion by IRC assessed responder
(CR or PR)
Summaries for CD45+CD19+ will use ITT population while CD45+CD20+ will use safety 
population (since this requires subjects to be on treatment to have an effect).


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11.2.12.
Prognostic and biological markers correlating with clinical 
response
Univariate regression analyses will be used to assess the relationship between PFS as 
assessed by the IRC and the following prognostic factors: Stratfication Factors (previous 
rituximab and prior bendamustine exposure), age, gender, race, Ann Arbor stage, FLIPI 
score, ECOG, Baseline Absolute Lymphocyte count (ALC), , FcR gamma 3A, and 
Human Anti-chimeric Antibodies (HACA) at baseline including the factor and treatment 
in the model.
Logistic regression will be conducted to explore the relationship between IRC assessed 
overall response and the same set of variables specified above. 
11.2.14.
Optional Ofatumumab – Investigator-Assessed Response Rate 
Investigator-Assessed Response Rate is defined as the percentage of subjects achieving a 
CR or PR one month after last dose of optional ofatumumab.  The best response data will 
also be summarized.  
Subjects with Not Evaluable (NE) or missing response will be treated as non-responders; 
i.e., they will be included in the denominator when calculating the percentage.
Only subjects receiving optional ofatumumab will be included in the analysis. 
A data listing of the individual response data will also be provided.
11.3.
Other Efficacy Analyses
11.3.1.
Concordance Analysis of Overall Response Rate
An assessment of the concordance between IRC assessment and Investigator Assessment
of the Best Overall Response for each subject will be provided, overall and by treatment
group.  A summary by responder (CR or PR) and non-responder status and a separate 


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summary showing agreement of each individual response category (CR, PR, SD, PD, NE, 
missing) will be provided.
The calculation will be based on the percent agreement (the proportion of response 
outcomes that agree or match across both IRC and Investigator Assessments):
Percent Agreement = (Number of matched responders + Number of matched non-
responders) /Total number of subjects assessed.
11.3.2.
Concordance Analysis of PFS
A cross-tabulation will be produced displaying the Progression-free survival timings for 
the Investigator data compared to the IRC data. For progression assessments, the 
frequency and percent of subjects with complete agreement, progression later, 
progression earlier, and cases where progression was called by one method and censored 
by the other will be displayed.  Similarly, if censoring was recorded, the frequency and 
percent of subjects with complete agreement, censoring called later, censoring called 
earlier, and cases where censoring was called by one method and progression was called 
by the other method will be displayed.
This summary will be displayed overall and by treatment group.
A figure may also be produced displaying the PFS assessment for Investigator data 
overlaid with the PFS assessment from the IRC to provide a visual display to assess 
discordance.
12.
SAFETY ANALYSES
Unless otherwise specified, all the safety analyses will be based on the Safety population 
as defined in Section 6 and summaries will include all events or assessments collected 
during the study. All the analyses will be performed by treatment arm.
12.1.
Extent of Exposure
Extent of exposure to study drugs will be summarized separately.
The Ofatumumab exposure (mg) and Bendamustine exposure (mg) by cycle will be 
provided. 
The dose (mg) and duration of exposure to treatment will be summarized by each 
infusion using summary statistics mean, standard deviation, median, minimum value, and 


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maximum. The total number of infusions administered will also be summarised with 
mean, median, standard deviation, minimum, and maximum. The number and percentage 
of subjects who received infusions will be reported.
The frequency of infusion interruptions and incomplete infusions will also be provided.
Listings will also be provided for all exposure data.
The number of subjects discontinuing study treatment will also be summarized and listed 
along with the reasons for discontinuation.
12.2.
Adverse Events
An overview summary of AEs, including counts and percentages of subjects with any AE, 
AEs related to study treatment, AEs leading to permanent discontinuation of study 
treatment, AEs leading to dose reductions, delays or interruptions, SAEs, SAEs related to 
study treatment, fatal SAEs, and fatal SAEs related to study treatment will be produced.
A summary of all non-serious AEs  will be provided. The summary will be displayed by 
SOC and PT.
The relationship between MedDRA SOC, PT, and Verbatim Text will be displayed.
Adverse events (AEs) will be graded according to the CTCAE (Version 4.0). Adverse 
events will be coded to the preferred term (PT) level using the Medical Dictionary for 
Regulatory Affairs (MedDRA dictionary, using the latest version available at the time of 
database release). 
A summary of number and percentage of subjects with any adverse events by maximum 
grade will be produced. AEs will be sorted by Preferred term (PT) in descending order of
the ‘Ofatumumab + Bendamustine’ arm. The summary will use the following algorithms 
for counting the subject:

Preferred term row: Subjects experiencing the same AE preferred term several 
times with different grades will only be counted once with the maximum grade.

Any event row: Each subject with at least one adverse event will be counted only 
once at the maximum grade no matter how many events they have.
In addition, the frequency and percentage of AEs (all grades) will be summarized and 
displayed in two ways: 1) in descending order of incidence in ‘Ofatumumab + 
Bendamustine’ arm by PT only and 2) in descending order of incidence in ‘Ofatumumab
+ Bendamustine’ arm by System Organ Classes (SOC) and PT. In the SOC row, the 
number of subjects with multiple events under the same system organ class will be 
counted once. 
A separate summary will be provided for study treatment-related AEs. A study treatment-
related AE is defined as an AE for which the investigator classifies the relationship to 


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study treatment as “Yes”. A worst case scenario approach will be taken to handle missing 
relatedness data, i.e. the summary table will include events with the relationship to study 
treatment as ‘Yes’ or missing. The summary table will be displayed in descending order 
of incidence in ‘Ofatumumab + Bendamustine’ arm by PT only.
For the legal requirements of ClinicalTrials.gov and EudraCT, two required tables 
adverse events which are not serious adverse events with an incidence and serious 
adverse events and SAE suspected to be related to study treatment will be provided by 
system organ class and preferred term on the safety set population.
If for a same patient, several consecutive AEs (irrespective of study treatment causality, 
seriousness and severity) occurred with the same SOC and PT:

a single occurrence will be counted if there is ≤ 1 day gap between 
the end date of the preceding AE and the start date of the 
consecutive AE

more than one occurrence will be counted if there is > 1 day gap 
between the end date of the preceding AE and the start date of the 
consecutive AE
For occurrence, the presence of at least one SAE / SAE suspected to be related to study 
treatment / non SAE has to be checked in a block e.g., among AE's in a ≤ 1 day gap block, 
if at least one SAE is occurring, then one occurrence is calculated for that SAE.
All AEs will be listed. Additionally, a listing of subject IDs for each individual AE will 
be produced. 
Summaries based on the following subgroups: FL subgroup, gender, age, race, and 
geographic region (as defined in Section 8.3) will be provided for all AEs.
12.3.
AEs of Special Interest
A comprehensive list of MedDRA terms based on clinical review will be used to identify 
each type of event. Changes to the MedDRA dictionary may occur between the start of 
the study and the time of reporting and/or emerging data from on-going studies may 
highlight additional adverse events of special interest, therefore the list of terms to be 
used for each event of interest and the specific events of interest will be based on the 
safety monitoring team (SMT) agreements in place at the time of reporting. 
The events of special interest include:

Infusion related AEs

Infections

Myelosuppression Events (anemia, neutropenia, thrombocytopenia)

Progressive multifocal leukoencephalopathy (PML)


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
Tumor Lysis Syndrome (TLS)

Mucotaneous Reactions

Reactivation of Hepatitis B

Cardiac events

Bowel Obstruction

Neoplasms
Summaries of the number and percentage of subjects with these events will be provided
for each type of event separately.
Infusion related AEs
Infusion reactions will be summarized using the preferred terms from the AE dataset.  
The process for defining and reporting the infusion reactions is the following:
1) Select the candidate AEs
For each infusion, only AEs occur during and within 24 hours following the end of 
infusion will be included as candidate AEs. 
If the AE onset date is available but the onset time is missing, then the AE will be 
included if it occurs on the same day as the infusion and the day following the infusion.
2) The list of candidate events based on the above criteria will be reviewed by the clinical 
and safety review team to select the final set of terms for inclusion in the analysis tables.  
This will be conducted at the Preferred Term (PT) level. 
Infections
Summaries of infections will be based on treatment period and follow-up period pooled 
together by each grade and will be provided for grade 3, 4 and 5, respectively, as well as 
all infections regardless of grades.
In addition, the following summaries will be presented:
1) Summary of worst-grade infections 
2) Summary of type of infections by all infections, all respiratory tract infections, lower 
respiratory tract infections, upper respiratory tract infections, sepsis and other infections.   
3) Summary for drug-related infections 
4) Summary of infections for subjects with baseline neutropenia.


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The number and percentage of subjects with grade 3,4, and 5 infections  will also be 
provided by responders and non-responders.
Myelosuppression events
A summary of AEs associated with anemia, neutropenia, and thrombocytopenia will be 
provided combined and separately. The frequency and percent of subjects with 
myelosuppression will also be provided by responders and non-responders.
A subject listing of all events will be provided.
Progressive multifocal leukoencephalopathy (PML)
A summary of AEs associated with progressive multifocal leukoencephalopathy (PML) 
will be provided.
A subject listing of all events will be provided.
Tumor Lysis Syndrome (TLS)
A summary of AEs associated with progressive multifocal leukoencephalopathy (PML) 
will be provided.  Candidate events include: hyperuricemia, hyperphosphatemia, 
hyperkalemia, hypocalemia, and acute kidney injury. 
A subject listing of all events will be provided.
Mucotaneous Reactions
A summary of AEs associated with mucotaneous reactions will be provided.
A subject listing of all events will be provided.
Reactivation of Hepatitis B
A summary of AEs associated with reactiviation of Hepatitis B will be provided.
A subject listing of all events will be provided.
Cardiac Events
A summary of AEs associated with cardiac events will be provided.
A subject listing of all events will be provided.
Bowel Obstruction
A summary of AEs associated with Bowel obstruction will be provided.
A subject listing of all events will be provided.
Neoplasms


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A summary of AEs associated with Neoplasms will be provided.
A subject listing of all events will be provided
12.4.
Deaths and Serious Adverse Events
No programming will be done to validate or remove death data from the dataset. All 
deaths will be summarised based on the number and percentage of subjects. This 
summary will classify subjects by time of death (on treatment, “<= 60 days after last 
dose”, “> 60 days after last dose”) and primary cause of death. A supportive listing will 
be generated to provide subject-specific details on subjects who died. 
All SAEs will be tabulated based on the number and percentage of subjects who 
experienced the event. Separate summaries will also be provided for study treatment-
related SAEs, fatal SAEs and study treatment related fatal SAEs. The summary tables 
will be displayed in descending order of incidence in ‘ofatumumab + bendamustine’ arm 
by PT only.
A study treatment-related SAE is defined as an SAE for which the investigator classifies 
the relationship to study treatment as “Yes”. A worst case scenario approach will be
taken to handle missing data, i.e. the summary table will include events with the 
relationship to study treatment as ‘Yes’ or missing. 
SAEs are included in the listing of all adverse events. Separate supportive listings with 
subject-level details will be generated for

Fatal SAEs 

Non-Fatal SAEs.
A summary of all serious adverse events and deaths will also be provided.
12.5.
Adverse 
Events 
Leading 
to 
Discontinuation 
of 
Investigational Product and/or Withdrawal from the Study and Other 
Significant Adverse Events
The following categories of AEs will be summarized separately in descending order of 
‘ofatumumab + bendamustine’ arm by PT only and separate supportive listings will be 
generated with subject level details for those subjects:

AEs Leading to Discontinuation of Study Treatment 

AEs Leading to Dose Interruptions/Delay

AEs Leadings to Dose Reductions


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12.6.
Pregnancies
While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy for medical reasons will be recorded 
as an AE or SAE as described in the protocol. If subjects become pregnant while on the 
study, the information will be included in the narratives and no separate table or listing 
will be produced.
12.7.
Clinical Laboratory Evaluations
Summaries of worst case grade increase (shift) from baseline grade will be provided for 
all the lab tests that are gradable by CTCAE v4.0. The summary will include the baseline 
grade vs. worst-case post-baseline grade. Categories will be displayed as Grade 0, 1, 2, 3, 
4, or missing. For laboratory tests that are graded for both low and high values, 
summaries will be done separately and labeled by direction, e.g., sodium will be 
summarized as hyponatremia and hypernatremia.
For lab tests that are not gradable by CTCAE v4.0, summaries of worst case changes 
(shifts) from baseline with respect to normal range will be generated. The summary will 
include the baseline grade vs. worst-case post-baseline grade. Worst-case (Extreme) 
Categories will be displayed as Low, Normal, High, High & Low, or missing.. 
Separate summary tables for hematology and chemistry laboratory tests will be produced.
A supporting listing of laboratory data for subjects with abnormalities of potential clinical 
concern (grade 3 or 4 toxicities) will be provided. A separate listing of laboratory data 
with character values will also be provided.
Detailed derivation of baseline assessment is specified in Section 9.2.7.
Unless otherwise specified, the denominator in percentage calculation at each scheduled 
visit will be based on the number of subjects with non-missing value at each particular 
visit.
Figures for median hemoglobin/neutrophil count/platelet count for all subjects, and for all 
subjects excluding those who received blood supportive care products over time will also 
be generated.
12.7.1.
Analyses of Liver Function Tests
Summaries of hepatobiliary laboratory events including possible Hy’s law cases will be 
provided. 
Possible Hy’s law cases are defined as (ALT>3×ULN or AST>3xULN) and Total 
Bilirubin>2×ULN and Alkaline Phosphatase <2xULN.


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12.8.
Other Safety Measures
Unless otherwise specified, the denominator in percentage calculation at each scheduled 
visit will be based on the number of subjects with non-missing value at each particular 
visit.
12.8.1.
Vital Signs
Summary statistics of values and changes from baseline at worst value for the study will 
include count, mean, median, standard deviation, minimum, and maximum.  Baseline is 
defined as the assessment closest to but prior to first dose without time (e.g., Day 1 if 
available otherwise screening).
Summaries of the number and percentage of subjects with increases in each vital sign for 
the worst-case post baseline value will be produced.  Increases will be categorized as 
follows:

Systolic Blood Pressure:  ‘Any Grade Increase’, ‘Increase to Grade 2 (140-159)’ and 
‘Increase to Grade 3 (160)’

Diastolic Blood Pressure: ‘Any Grade Increase’, , ‘Increase to Grade 2 (90-99)’, 
‘Increase to Grade 3 (100)’  

Heart Rate: ‘Decrease to <60’, ‘Increase to > 100’  

Temperature: ‘Decrease to 35’, ‘Increase to 38’  
Summaries of shift from baseline values for the worst-case post baseline will be provided 
for all vital signs.  Shifts will be categorized at baseline and worst-case assessment times 
as follows:

Systolic Blood Pressure:  ‘<120’, ’120-139’, ‘140-159’, ‘160’

Diastolic Blood Pressure: ‘<80’, ‘80-89’, ‘90-99’, ‘100’

Heart Rate: ‘<60’, ‘60-100’, ‘>100’

Temperature: ‘35’, ‘36-37’, 38’
Vital signs (blood pressure, heart rate, temperature, respiration rate, and weight) will be 
listed for each subject. 
12.8.2.
ECG
A summary of the number and percentage of subjects who had normal and abnormal 
(clinically significant and not clinically significant) ECG findings at screening/baseline 
will be provided. 
A supporting listing will also be provided. 


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12.8.3.
Liver Events
Any liver events occurring during the study will be summarized based on data recorded 
on the Liver Events eCRF pages.  Timing of the event will be summarized (while on 
treatment, after stopping treatment) and summary statistics for time from first dose to 
start of liver event and time from last dose to start of liver event will be provided.  A
summary table for subjects who meet the liver event stopping criteria will also be 
provided.
The following listings will be provided:

Listing of liver event results and time of event relative to treatment.   

Listing of liver chemistry laboratory for subjects with at least one liver event

Listing of ofatumumab concentration and time relative to liver event for subjects with 
at least one liver event.
12.8.4.
Frequency of transfusions
The number and percentage of subjects who receive blood transfusions during the study 
will be provided by treatment group.
12.8.5.
Human Anti-Human Antibodies (HAHA)
Human Anti-Human Antibodies (HAHA) sample analysis will be conducted by a 
contract research organization using a validated assay. The number and percentage of 
subjects with positive and negative HAHA results will be provided for each HAHA 
timepoint.  A summary table with the overall HAHA assessment for each subject, 
considering ofatumumab concentration at the time of each HAHA sample collection, will 
be provided.  A listing of HAHA results with the ofatumumab concentration at that time 
will be provided.    
12.8.6.
Human Anti-Chimeric Antibodies (HACA)
Human Anti-Chimeric Antibodies (HACA) sample analysis will be conducted by a 
contract research organization using a validated assay. The number and percentage of 
subjects with positive and negative HACA results will be provided for each HACA 
timepoint.  
A summary table with the number of subjects with positive HACA in the pre-dose 
samples will be reported.
HACA results prior to ofatumumab administration will be listed.


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12.8.7.
Quantitative IgG, IgA, IgM
Summaries of IgG, IgA, and IgM will be provided at scheduled visits for actual values as 
well as for change from baseline.
Plots of this data over time will also be provided as appropriate.
13.
HEALTH OUTCOMES ANALYSES
All analyses described in this section will be performed using the ITT population, and the 
same analysis will be repeated in patients with FL. Summaries will be presented by 
treatment group.  A data listing with individual subject data for each questionnaire will 
also be provided.
The FACT-Lym and EQ-5D should be administered at the screening visit and at all post-
baseline visits per protocol. The Health Change Questionnaire (HCQ) should be 
administered at all post-screening visits.  If a subject demonstrates disease progression, 
the measures should be completed at the progression visit and again one time after the 
determination of the progression.  If a subject withdraws from the study then the
questionnaires should be administered at the point of withdrawal. 
PRO analysis will be performed in all patients and patients with follicular lymphoma
based on ITT population. No formal statistical test will be performed and hence no 
multiplicity adjustment will be applied.
All PRO measures will be scored as per the developers instructions, with scores created 
for each pre-specified domain.  Each PRO domain will be summarized by treatment 
group and time point, which will be presented in tabular format as mean, standard 
deviation, median, minimum and maximum. 
A mixed-model repeated measurement (MMRM) for longitudinal data will be used to 
compare the two treatment arms in terms of the domain scores over time. This 
longitudinal model will include terms for treatment, the randomization stratification 
factors, time of visit, baseline value and an interaction term for treatment by time as fixed 
effects, and time will be treated as the repeated variable within subject. This analysis will 
be restricted to patients with an evaluable baseline score and at least one evaluable post-
baseline score. Time will be considered as a continuous variable in this analysis. As a 
first approach, an unstructured correlation matrix will be used to model the correlation 
within patients, if the model fitting is inadequate, AR(1) structure will be experimented.
Nominal p-values will be presented without any statistical inference since there is no 
adjustment for multiplicity.
For the model considered, the SAS code will therefore be:
PROC MIXED data=dataset method=reml;
     CLASS subject trt timeC strat_factors;


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     MODEL score = trt strat_factors time score_B 
trt*time / noint s ddfm=kr;
     REPEATED timeC / subject=subject type=AR(1);
RUN;
/* score refers to the observed scores after Baseline
score_B refers to the baseline score
trt is the treatment variable
timeC refers to the time window as class variable
time refers to the time window
method=reml
specifies that the restricted Maximum Likelihood 
Estimation method used
type=
AR(1) specifies
that the first order autoregressive 
covariance matrix is used */
Handling of missing data
Missing items data in a scale will be handled based on each instrument manual. No 
imputation will be applied if the total or subscale scores are missing at a visit, since all 
available data during the study will be used in the repeated measures model analyses 
which assume that the missing scores at any time point are missing-at-random.
Time Windows for PRO analyses
If more than one assessment is available in the same time window, the assessment closest 
to the planned date will be considered. If two assessments are obtained with the same 
time difference compared to the scheduled visit day, the assessment obtained prior to visit 
will be considered. The assessment at end of treatment visit will be considered as a 
scheduled time-point and in the time window definition if collected within 28 days of the 
last date of study treatment in the treatment phase, before crossover and before the start 
of any further anti-neoplastic therapies based on the definitions in table below. 
The same time window definitions will be used for assessing the compliance rates over 
time-points for the PRO scores.  A patient will be considered as eligible for a time-point 
assessment if the lower bound of the time window for that scheduled time point is within 
28 days of the last date of study treatment in the treatment phase, before crossover and 
start date of new antineoplastic therapy. 
Table Time Windows for PRO
Scheduled Time point
Planned Visit Timing 
Time Window Definition
On treatment – includes assessment visits when treatment is ongoing and within 28 days of last 
dose
Screening (Baseline, except for 
HCQ) 
On or before Day 1*
≤ Study Day 1


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Cycle 1 Day 1
Day 1
Day 1 - 22
Cycle x Day 1 (starting from 
Cycle 3 Day 1, every 2 cycles, 
till Cycle 7 Day 1)
Day (x-1)*21+1
Day (x-1)*21+1-20 to 
(x-1)*21+1+21
Cycle 9 Day 1
Day 169
Day 149 to 197
Cycle 11 Day 1
Day 225
Day 198 to 253
Follow-up Cycle 1 Day 1
Day 
(8*21)+(4*28)+28*2+1=337
Day 254 to 379
Follow-up 
Cycle 
x 
Day 
1 
(starting from Follow-up Cycle 4 
Day 1, every 3 cycles, till 
Follow-up Cycle 16 Day 1)
Day 337+(x-1)*28
Day 337+(x-1)*28-28*1.5+1 to 
337+(x-1)*28+28*1.5
Follow-up Cycle 30 Day 1
Day 337+30*28 = 1177
Day 800 to 1345
Follow-up Cycle 42 Day 1
Day 337+42*28 = 1513
Day 1346 to 1681
Follow-up Cycle 54 Day 1
Day 337+54*28 = 1849
Day 1682 to 2017
* Day 1 =  date of randomization
13.1.
Functional Assessment of Cancer Therapy - Lymphoma
(FACT-Lym)
Background:
The FACT-Lym is comprised of a 5 dimension health status measure: physical well-
being (7 items); social/family well-being (7 items); emotional well-being (6 items); 
functional well-being (7 items); and additional concerns (15 items). Subjects respond to 
the individual questions within a dimension on a five point Likert scale ranging from 0
‘Not at all’ to 4 ‘Very much’ and are asked to think back over the past 7 days when 
responding to each of the items.
Summaries and Analyses:
Instructions for FACT-Lymphoma Scoring Guidelines:
1. Record answers in "item response" column. If missing, mark with an X
2. Perform reversals as indicated, and sum individual items to obtain a score.
3. Multiply the sum of the item scores by the number of items in the subscale, then 
divide by the  number of items answered.  This produces the subscale score.
4. Add subscale scores to derive total scores 
5. The higher the score, the better the QOL.
Subscale
  Item Code    Reverse item?       Item response        
Item Score
PHYSICAL
GP1
4
-
________
=________
WELL-BEING
GP2
4
-
________
=________


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   (PWB)
GP3
4
-
________
=________
      
GP4
4
-
________
=________
      
GP5
4
-
________
=________
      
GP6
4
-
________
=________
      
GP7
4
-
________
=________
              Sum individual item scores: ________  
                      Multiply by 7: ________
             Divide by number of items answered: ________=PWB 
subscale score
SOCIAL/FAMILY
GS1
0
+
________
=________
WELL-BEING
GS2
0
+
________
=________
    (SWB)
GS3
0
+
________
=________
      
GS4
0
+
________
=________
      
GS5
0
+
________
=________
   
GS6
0
+
________
=________
      
GS7
0
+
________
=________
             Sum individual item scores: ________  
                     Multiply by 7: ________
            Divide by number of items answered: ________=SWB 
subscale score
EMOTIONAL
GE1
4
-
________
=________
WELL-BEING
GE2
0
+
________
=________
    (EWB)
GE3
4
-
________
=________
      
GE4
4
-
________
=________
     
GE5
4
-
________
=________
GE6
4
-
________
=________
             Sum individual item scores: ________  
                     Multiply by 6: ________
Score range: 0-28
Score range: 0-28
Score range: 0-24


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            Divide by number of items answered: ________=EWB 
subscale score
FUNCTIONAL  
GF1
0
+
________
=________
WELL-BEING 
GF2
0
+
________
=________
     (FWB)
GF3
0
+
________
=________
      
GF4
0
+
________
=________
      
GF5
0
+
________
=________
      
GF6
0
+
________
=________
      
GF7
0
+
________
=________
             Sum individual item scores: ________  
                     Multiply by 7: ________
            Divide by number of items answered: ________=FWB 
subscale score
Subscale
         Item Code       Reverse item?            Item response        
Item Score
LYMPHOMA
P2
4
-
________
=________
SUBSCALE
LEU1
4
-
________
=________
   (LYMS)
BRM3
4
-
________
=________
        
ES3
4
-
________
=________
        
LYM1
4
-
________
=________
        
LYM2
4
-
________
=________
        
BMT6
4
-
________
=________
        
C2
4
-
________
=________
        
GA1
4
-
________
=________
        
HI8
4
-
________
=________
        
N3
4
-
________
=________
        
LEU6
4
-
________
=________
        
LEU7
4
-
________
=________
        
BRM9
4
-
________
=________
Score range: 0-28
Score range: 0-60


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LEU4
4
-
________
=________
              Sum individual item scores:________  
                   Multiply by 15: ________
            Divide by number of items answered: ________=LYM 
Subscale score
To derive a FACT-Lymphoma Trial Outcome Index (TOI):
__________ + __________ + __________ =________=FACT-Lymphoma TOI
(PWB score)   (FWB score)   (LymS score)  
To Derive a FACT-G total score:
__________ + __________ + __________ + __________=________=FACT-G Total score
(PWB score)    (SWB score)   (EWB score)  (FWB score)
To Derive a FACT-Lymphoma total score:
_________ + __________ + __________ + __________ + __________ =________=FACT-Lymphoma Total 
(PWB score)  (SWB score)   (EWB score)   (FWB score)    (LymS score)                    score
Handling missing items for FACT-Lym
If there are missing items, subscale scores can be prorated.  This is done by multiplying 
the sum of the subscale by the number of items in the subscale, then dividing by the 
number of items actually answered.  This can be done on the scoring guide or by using 
the formula below:
Prorated subscale score = [Sum of item scores] x [N of items in subscale] [N of items 
answered] 
When there are missing data, prorating by subscale in this way is acceptable as long as 
more than 50% of the items were answered (e.g., a minimum of 4 of 7 items, 4 of 6 items, 
etc).  The total score is then calculated as the sum of the un-weighted subscale scores.  
The FACT scale is considered to be an acceptable indicator of patient quality of life as 
long as overall item response rate is greater than 80% (e.g., at least 22 of 27 FACT-G 
items completed).  This is not to be confused with individual subscale item response rate, 
which allows a subscale score to be prorated for missing items if greater than 50% of 
items are answered. In addition, a total score should only be calculated if ALL of the 
component subscales have valid scores.
The analyses will be prepared by domain and will be summarized as follows:
Score range: 0-116
Score range: 0-108
Score range: 0-168


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
Summary of raw score and change from baseline by domain (PWB score, SWB score, 
EWB score, FWB score, LymS score, as well as FACT-Lymphoma TOI, FACT-G 
Total score FACT-Lymphoma Total), by time point and treatment group 

Summary of MMRM (PWB score, SWB score, EWB score, FWB score, LymS score, 
as well as FACT-Lymphoma TOI, FACT-G Total score FACT-Lymphoma Total)
13.2.
EuroQoL Five-Dimension (EQ-5D)
Background:
The EQ-5D is comprised of a 5-item health status measure and a visual analogue rating
scale/feeling thermometer. These components are administered independently which
results in the derivation of two utility measures. It is a simple, effective, validated and
globally accepted generic instrument which is being used in this study as a two part
measure (part one is the five dimensional Health State Classification and part two is the
visual analogue scale 'Thermometer') [EuroQol, 1990] .
The first utility value will be derived from the five domains of the EQ-5D and the second 
utility value will be derived from the feeling thermometer.
Summaries and Analyses:
Using the five dimensional Health State Classification [EQ-5D User Guide,1992], 
subjects are asked to respond to five questions on different aspects of their health status 
that assess mobility, self-care, usual activities, pain/discomfort and anxiety/depression. 
Each question is responded to on a three-point scale which indicates the level of 
impairment (level 1 = no problem; level 2 = some or moderate problem(s) and level 3 = 
unable, or extreme problems). This generates a unique description of the subjects' health 
status, which is valued between zero (representing death) and one (representing perfect 
health). Negative health status describes health state worse than death. Details of the 
method for calculating this score are provided below.
In addition to completing the five dimensional Health State Classification to generate a
single health status index and a health profile, subjects are asked to rate their current
health status using the visual analogue scale 'Thermometer'. The 'Thermometer' has
endpoints of 100 (best imaginable health state) and 0 (worse imaginable health state).
The subject rates their current health state by drawing a line from the box marked 'Your
health state today' to the appropriate point on the 'Thermometer' scale. 
Tariff for the 243 health states defined by the EuroQoL classification are calculated from 
regression coefficients which have been used to derive the decrements shown in the
following table.
Table for EuroQoL Health State Decrements


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EuroQoL Health State
Level 2
Level 3
Mobility (A)
0.069
0.314
Self-care (B)
0.104
0.214
Usual activity (C)
0.036
0.094
Pain/discomfort (D)
0.123
0.386
Anxiety/depression (E)
0.071
0.236
Constant=0.081
N3=0.269
The arithmetic needed to recover the estimated value for any health state from this table
of decrements is shown in the following equation:
Tariff (utility score) = Full health tariff – constant – A level – B level – C level – D level 
– E level – N3
where:

full health has a state of 1 1 1 1 1 and a tariff of 1.0,

a level of 1 for any question has a decrement of 0,

the constant is only subtracted if at least one state has level 2 or level 3 and

N3 is only subtracted if at least one state has level 3
For example:
Overall Health state 1 1 2 2 3
where:
Level
Subtract
Mobility
1
0
Self-care
1
0
Usual activity
2
0.036
Pain/discomfort
2
0.123
Anxiety/depression
3
0.236
The estimated tariff (utility score) is therefore: 1.0 – 0.081 – 0.036 – 0.123 - 0.236 –
0.269 = 0.255
The following summary tables will be provided:

Summary of utility score and change from baseline score in EQ-5D by time point 
and treatment group

Summary of Visual Analog Scale (VAS) and change from baseline score in EQ-
5D by time point and treatment group

Summary of MMRM on utility score and VAS
13.3.
Health Change Questionnaire
The Health Change Questionnaire (HCQ) used is a nine item scale that asks the patient to 
rate change in status since beginning treatment on this study.  Scale choices are :


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
A great deal better

Moderately better

A little better 

Almost the same, hardly any better

Unchanged

Almost the same, hardly any worse

A little worse

Moderately worse

A great deal worse
A summary of the percentage of subjects in each category will be provided by time point 
and treatment group.
14.
PHARMACOKINETIC ANALYSES 
The reconciliation of the pharmacokinetic Case Report Form (CRF) and Pharmacokinetic 
(PK) data will be performed by, or under the direct auspices of, Data Sciences -
Oncology, Novartis.
The merge of pharmacokinetic concentration data and CRF data to generate a dataset 
with actual blood sampling times, actual time relative to dosing, and concentrations will 
be performed after DBF by, or under the direct auspices of, Novartis Oncology Clinical 
Data Review and Reporting.  Analysis datasets will be created according to 
CDISC/ADaM standards.
Derivation of pharmacokinetic parameters will be performed by Novartis Oncology 
Clinical Pharmacology.  A population pharmacokinetic approach will be used to estimate 
ofatumumab pharmacokinetic parameters. The details of the analysis will be included in a 
separate analysis plan, and the results will be reported in a separate Population 
Pharmacokinetic report.  
Unless otherwise stated, all tables, figures and listings in this section will be based on the 
Pharmacokinetic population, and all summaries, figures and data listings will use 
treatment labels as specified in Section 7.
14.1.
Drug Concentration Measures
Concentrations of ofatumumab in plasma will be listed by actual relative time and 
summarized by nominal time. Standard summary statistics will be calculated (i.e., mean, 
standard deviation, median, minimum and maximum). Refer to the PK Guidance 
“Pharmacokinetic / Pharmadynamic Analysis Manual” document for more information 
regarding the handling of ofatumumab plasma concentration data.
Below the limit of quantitation (BLQ) values will be set to zero by the Bioanalyst, and 
will be displayed in the listings as zero and flagged. BLQ values will be treated as 
missing for the calculation of the geometric means and geometric CV%.


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Individual plasma concentration-time profiles and median/mean profiles by treatment 
group will be plotted using actual elapsed time for individual plots and nominal time for 
median/mean profiles. Each of the figures will contain one plot on the untransformed 
scale (i.e., a linear plot) and one plot on the log-transformed scale (i.e., log-linear plot). 
Any concentration falling outside of pharmacokinetic sample collection windows will be 
excluded from summary tables and figures.
14.2.
Statistical Analyses
Only data for patients taking Ofatumumab will be analyzed.  Summary data will only be 
reported for patients on Arm A (Ofatumumab + Bendamustine).  Data Listings will 
include all data, including data for patients taking Optional Ofatumumab.
The following tables and listings will be created:

Summary of Plasma Ofatumumab Concentration -Time Data

Listing of Plasma Ofatumumab Concentration -Time Data
Additionally, the figures listed below will also be provided:

Mean Plasma Ofatumumab Concentration –Time Plot

Median Plasma Ofatumumab Concentration –Time Plot

Individual Plasma Ofatumumab Concentration –Time Plots
15.
PHARMACOKINETIC/PHARMACODYNAMIC ANALYSES
If data permit, 
 analyses may be performed by Novartis Oncology Clinical 
Pharmacology as part of the Population Pharmacokinetic analyisis.  Any 
Pharmacokinetic/Pharmacodynamic (PK/PD) analyses will be described in the Population 
Pharmacokinetic Analysis Plan, and will be reported as part of the Population 
Pharmacokinetic Report, which will be issued separately.
16.
REFERENCES
Brookmeyer R, Crowley J. A confidence interval for the median survival time. 
Biometrics, 1982; 38:29-41.
Cheson BD, Pfistner B, Juweid ME, Gascoyne RD, Specht L, Horning SJ et al. Revised 
Response Criteria for Malignant Lymphoma. J Clin Oncol. 2007;25:579-586. 
Cox. Regression Models and Life-Tables. Journal of the Royal Statistical Society. Series 
B (Methodological), Vol. 34, No. 2. (1972), pp. 187-220.


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Eremenco S, Webster K, Kutikova L, Kutikova L, Bowman L, and Cella D. Development 
and multilingual validation of the FACT-LYM. Presented at ISOQOL Annual 
Conference 17th October 2004. Qual Life Res. 2004; 13(9): 1495–1603.
EuroQoL Group. Health Policy 1990; 16(3):199-208. 
EuroQol -. A new facility for the measurement of health-related quality of life. Health 
Policy. 1990;16:199-208. 
EuroQol EQ-5D User Guide. Cumulative Illness Rating Scale-Geriatric : Miller et al, 
Psychiatry Res, 41, 237-48, 1992.
National Cancer Institute, Common Terminology Criteria for Adverse Events (NCI-
CTCAE) v4.0 Cancer Therapy Evaluation Program. DCTD, NCI, NIH, DHHS, USA; 
2009. NIH Publication #03-5410.
Pettengell R, Donatti C, Hoskin P, Poynton C, Kettle PJ, Hancock B, et al. The impact of 
follicular lymphoma on health-related quality of life. Ann Oncol. 2008; 19(3):570-600.
Webster K, Cashy D, Cella D, Kutikova L, Gauthier J, Liepa A, Bowman L, Gregory S, 
et al. Measuring quality of life (QOL) in subjects with non-hodgkin’s lymphoma (NHL): 
the Functional Assessment of Cancer Therapy-Lymphoma (FACT-LYM). Qual Life Res
2005; 14: 1650.
17.
ATTACHMENTS
17.1.
Table of Contents for Data Display Specifications
The table of contents for the data displays as well as the data display specifications will 
be available as a separate document from the SAP.