A Randomized Study Comparing Maintenance Therapy With Subcutaneous Rituximab Continued Until Progression With Observation Only in Patients With Relapsed or Refractory, Indolent Non-Hodgkin's Lymphoma Who Completed and Responded to Rituximab-based Immunochemotherapy Induction and Initial 2-year Rituximab Maintenance Therapy Administered Subcutaneously
Phase: PHASE3
Conditions: Non-Hodgkin's Lymphoma
Sponsor: Hoffmann-La Roche

 
Official Title: 
A Randomized Study Comparing Maintenance Therapy With 
Subcutaneous Rituximab Continued Until Progression With 
Observation Only In Patients With Relapsed or Refractory, 
Indolent Nonhodgkin’s Lymphoma Who Completed and 
Responded To Rituximab-Based Immunochemotherapy 
Induction and Initial 2-Year Rituximab Maintenance Therapy 
Administered Subcutaneously 
NCT Number: 
NCT 01461928 
Document Date: 
Protocol Amendment Summary, Version 4.0, dated 06-Jul-2017 
Protocol, Version 4.0, 11-Jul-2017 
 
 
 
 

Rituximab - F. Hoffmann-La Roche Ltd 
Protocol MO25455 Version 4.0 
Page 1 of 5 
 
 
SPONSOR: F. HOFFMANN-LA ROCHE LTD 
Grenzacherstrasse 124 
CH-4070 Basel, Switzerland 
 
  
CLINICAL STUDY PROTOCOL 
 
TITLE: 
A 
RANDOMIZED 
STUDY 
COMPARING 
MAINTENANCE THERAPY WITH SUBCUTANEOUS 
RITUXIMAB CONTINUED UNTIL PROGRESSION 
WITH OBSERVATION ONLY IN PATIENTS WITH 
RELAPSED OR REFRACTORY, INDOLENT NON-
HODGKIN’S LYMPHOMA WHO COMPLETED AND 
RESPONDED 
TO 
RITUXIMAB-BASED 
IMMUNOCHEMOTHERAPY 
INDUCTION 
AND 
INITIAL 
2-YEAR 
RITUXIMAB 
MAINTENANCE 
THERAPY ADMINISTERED SUBCUTANEOUSLY 
PROTOCOL NUMBER: MO25455 
VERSION NUMBER: 
4.0 
EUDRACT NUMBER: 
2010-023407-95 
IND NUMBER: 
Not applicable 
TEST PRODUCT: 
Rituximab (RO 045-2294) 
MEDICAL MONITOR: 
Dr. 
 
SPONSOR: 
F. Hoffmann-La Roche Ltd 
DATE FINAL: 
Version 1:  19 April 2011 
DATES AMENDED: 
Version 2:  26 July 2012 
Version 3:  23 September 2012 
Version 4:  06 July 2017 
 
CONFIDENTIAL 
This clinical study is being sponsored globally by F. Hoffmann-La Roche Ltd of Basel, Switzerland.  However, it may be 
implemented in individual countries by Roche’s local affiliates, including Genentech, Inc. in the United States.  The 
information contained in this document, especially any unpublished data, is the property of F. Hoffmann-La Roche Ltd (or 
under its control) and therefore is provided to you in confidence as an investigator, potential investigator, or consultant, for 
review by you, your staff, and an applicable Ethics Committee or Institutional Review Board.  It is understood that this 
information will not be disclosed to others without written authorization from Roche except to the extent necessary to 
obtain informed consent from persons to whom the drug may be administered

5LWX[LPDE)+RIIPDQQ/D5RFKH/WG
3URWRFRO029HUVLRQ
3DJHRI
35272&2/$0(1'0(179(56,21
5$7,21$/(

7KHLQWHQWLRQRIWKHSURWRFROKDVEHHQWRFROOHFWDGYHUVHHYHQW$(DQGVHULRXVDGYHUVH
HYHQW6$(LQIRUPDWLRQIURPSDWLHQWVGXULQJPDLQWHQDQFH,,RQDUPV$DQG%LQRUGHUWR
SHUIRUPDVDIHW\FRPSDULVRQDVSDUWRIWKHVHFRQGDU\REMHFWLYH+RZHYHU7DEOHLQ
SURWRFROYHUVLRQSHUPLWVWKHFHVVDWLRQRI$(DQG6$(GDWDFROOHFWLRQIURPSDWLHQWV
RQDUP%GD\VSRVWWUHDWPHQW3URWRFROYHUVLRQZDVZULWWHQWREDODQFHWKH$(
DQG6$(UHSRUWLQJUHTXLUHPHQWV

•
7DEOHKDVEHHQUHYLVHGWRFODULI\WKH$(DQG6$(UHSRUWLQJGXUDWLRQ

$GGLWLRQDOPLQRUFKDQJHVKDYHEHHQPDGHWRLPSURYHFODULW\DQGFRQVLVWHQF\

•
7KH HQG RI VWXG\ VHFWLRQ LQ WKH V\QRSVLV RI SURWRFRO ZDV UHYLVHG WR FODULI\ WKDW
PDLQWHQDQFH ,, DUP % SDWLHQWV DUH H[SHFWHG WR IROORZ WKH VDPH VFKHGXOH RI
DVVHVVPHQWDVSDWLHQWVRQDUP$

•
3URWRFROFRYHUSDJHSURWRFRODPHQGPHQWDFFHSWDQFHIRUPDQGDSSHQGL[XQGHU
WKHVHFWLRQRIPHGLFDOPRQLWRUFRQWDFWLQIRUPDWLRQIRUDOOVLWHVKDYHEHHQUHYLVHGWR
UHIOHFWWKHQHZ5RFKHPHGLFDOFRQWDFW

•
3URWRFROFRYHUSDJHKDVEHHQUHYLVHGWRUHIOHFWWKHQHZ5RFKHVWDWLVWLFLDQ

•
7KH QXPEHU RI SDWLHQWV VHFWLRQ LQ WKH V\QRSVLV RI SURWRFRO DQG 6HFWLRQ  ZHUH
XSGDWHGWRUHIOHFWWKHILQDOQXPEHURISDWLHQWVUDQGRPL]HGWRPDLQWHQDQFH,,WKHUDS\
DQGWKHHQUROPHQWWLPHOLQH

•
6HFWLRQ7DEOHIRRWQRWHVLDQGWVHFWLRQVHFWLRQVHFWLRQ
VHFWLRQZHUHUHYLVHGWRUHPRYHWKHUHIHUHQFHWRVWDEOHGLVHDVHDWWKHHQGRI
PDLQWHQDQFH,

•
6HFWLRQKDVEHHQUHYLVHGWRFODULI\WKDWWKHWULDOFDQEHVWRSSHGLIWKHWK
3)6HYHQWKDVEHHQUHSRUWHG

•
,Q 7DEOH  IRU WKH ULWX[LPDE WUHDWPHQW DGPLQLVWUDWLRQ URZ WKH IRRWQRWH OLQN LQ WKH
0DLQWHQDQFH,,FROXPQZDVFRUUHFWHG

•
,QWKHQRWHVVHFWLRQIRU7DEOHDQGVHFWLRQFODULILFDWLRQZDVDGGHGUHJDUGLQJ
WKHPRYHPHQWRISDWLHQWVLQWRRIIWUHDWPHQWIROORZXSIROORZLQJWKHHQGRIWUHDWPHQW
RUWKHLUSDUWLFLSDWLRQLQPDLQWHQDQFH,,DUP%

•
6HFWLRQ  KDV EHHQ UHYLVHG UHPRYLQJ WKH JXLGDQFH WR UHFRUG DQG DVVHVV WKH
LQGLYLGXDO V\PSWRPV RI LQIXVLRQ UHODWHG UHDFWLRQV DQG DGPLQLVWUDWLRQ UHODWHG
UHDFWLRQV

•
6SHOOLQJHUURUVZHUHFRUUHFWHGWKURXJKRXWWKHSURWRFRO


7KLVDPHQGPHQWUHSUHVHQWVFXPXODWLYHFKDQJHVWRWKHRULJLQDOSURWRFRO

Rituximab - F. Hoffmann-La Roche Ltd 
Protocol MO25455 Version 4.0 
Page 3 of 5 
PROTOCOL AMENDMENT, VERSION 4.0:  
SUMMARY OF CHANGES 
 
GLOBAL CHANGES  
 
 International Scientific Director has replaced 
 International 
Medical Director as protocol approver and Medical Monitor Contact Information for 
All Sites. 
 
 Statistician has replaced 
 Statistician. 
 
PROTOCOL SYNOPSIS 
 
The protocol synopsis has been updated to reflect the changes to the protocol, 
where applicable. 
 
SECTION 3.1:  OVERVIEW OF STUDY DESIGN 
 
 
Old Text: 
Response assessment will be conducted by the Investigator every 6 months 
during Maintenance I according to the Cheson response criteria for indolent 
lymphoma1 (see Appendix 1) or by the recommendations for Waldenström’s 
macroglobulinemia2 (see Appendix 2). Patients with PD at any time during the study 
will come off study treatment and will start Off-Treatment Follow-Up, being followed 
for survival until the end of the study.  Patients with SD at the end of Maintenance I 
will come off study treatment and will enter Off-Treatment Follow-Up, being followed 
for PD and survival until the end of the study. 
 
SECTION 3.2:  NUMBER OF PATIENTS / ASSIGNMENT TO TREATMENT GROUPS 
 
Old text:  
Approximately 700 enrolled patients are expected to yield a minimum of 330 
randomized patients (Maintenance II).  
 
The estimated recruitment period is approximately 24 months. 
 
New text: 
Approximately 700 enrolled patients were expected to yield a minimum of 330 
randomized patients (maintenance II).  At the conclusion of enrolment and all 
randomizations 694 patients were enrolled and 276 patients were randomized to 
maintenance II.   
 
The recruitment period was expected to be approximately 24 months.  Enrolment 
of the 694 patients required 31 months 
 
TABLE 5:  SCHEDULE OF ASSESSMENTS 
 
In Table 5 for the rituximab treatment administration row the footnote in the 
Maintenance II column was incorrectly associated to footnote (t).  The association 
was corrected to footnote (u). 

Rituximab - F. Hoffmann-La Roche Ltd 
Protocol MO25455 Version 4.0 
Page 4 of 5 
Footnote (i): 
 
Old text: 
Patients with SD at the end of either Induction or Maintenance I will come off study 
treatment and will enter Off-Treatment Follow-Up, being followed every 6 months for 
PD and survival until the end of the study.   
 
Note: 
 
New text: 
After the end-of-treatment or the end of participation in observation arm B all 
patients will enter Off-Treatment Follow-up and be followed for resolution of AEs 
related to SC rituximab induction/maintenance therapy as per Table 14, survival, 
disease status (which might include bone marrow and tumour assessment if PD not 
already documented) and whether a new anti-lymphoma treatment has been started. 
 
SECTION 5.1.3:   Assessments during the Treatment Period 
 
 
Old text: 
Patients with SD at the end of either Induction or Maintenance I will come off study 
treatment and will enter Off-Treatment Follow-Up, being followed every 6 months for 
PD and survival until the end of the study. 
 
SECTION 5.1.3.2:  Maintenance I 
 
 
Old text: 
Patients with PD at any time during the study will come off study treatment and will 
start Off-Treatment Follow-Up, being followed for survival until the end of the study.  
Patients with SD at the end of Maintenance I will come off study treatment and will 
enter Off-Treatment Follow-Up, being followed for PD and survival until the end of 
the study. 
 
SECTION 5.1.5:  End of Treatment Assessments 
 
 
Old text: 
Patients with SD at the end of either Induction or Maintenance I will come off study 
treatment and will enter Off-Treatment Follow-Up, being followed every 6 months for 
PD and survival until the end of the study. 
 
SECTION 5.1.6:  Off-Treatment Follow-up 
 
 
Old text: 
After discontinuation of study treatment patients will enter Off-Treatment Follow-up 
and will be followed every 6 months until the end of the whole study for resolution of 
all SAEs, survival, disease status (which might include bone marrow and tumour 
assessment if PD not already documented) and whether a new anti-lymphoma 
treatment has been started. 
 
 
New text: 
After discontinuation of study treatment or participation in observation Arm B 
patients will enter Off-Treatment Follow-up and will be followed every 6 months until 
the end of the whole study for resolution of all SAEs, survival, disease status (which 

Rituximab - F. Hoffmann-La Roche Ltd 
Protocol MO25455 Version 4.0 
Page 5 of 5 
might include bone marrow and tumour assessment if PD not already documented) 
and whether a new anti-lymphoma treatment has been started. 
 
SECTION 5.2.1:  Tumour Response Criteria 
 
 
Old text: 
At the end of Maintenance I, patients with PD or SD will come off study treatment.  
Patients with PD will start Off-Treatment Follow-Up, being followed for survival until 
the end of the study.  Patients with SD will enter Off-Treatment Follow-Up, being 
followed for PD and survival until the end of the study.  Patients having a CR or PR 
will be randomized and will continue into Maintenance II. 
 
SECTION 5.2.1:  Tumour Response Criteria 
 
 
Old text: 
At the end of Maintenance I, patients with PD or SD will come off study treatment.  
Patients with PD will start Off-Treatment Follow-Up, being followed for survival until 
the end of the study.  Patients with SD will enter Off-Treatment Follow-Up, being 
followed for PD and survival until the end of the study.  Patients having a CR or PR 
will be randomized and will continue into Maintenance II. 
 
Table 14:  Duration of Reporting and Follow-up of Adverse Events 
 
Table 14 has been revised to clarify the AE and SAE reporting duration. 
 
AE row was divided in to two rows – one for AEs grade 1 and 2; a second for AEs ≥ 
grade 3.  Each row contains specific guidance for the grade of AE. 
 
SECTION 7.2.3:  Reporting of Infusion-Related Reactions (IRRs) or Administration- 
Related Reactions (ARRs) 
 
 
Old text: 
IRRs/ARRs must be recorded on the Adverse Event eCRF. In order to capture 
potential differences in terms of clinical relevance of IRRs/ARRs, it is important to 
report and assess the intensity of all individual symptoms of the IRR/ARR.  

 
Rituximab - F. Hoffmann-La Roche Ltd 
Protocol MO25455 v4.0 
2 of 128 
 
TABLE OF CONTENTS 
PROTOCOL AMENDMENT ACCEPTANCE FORM ............................................ 9 
SYNOPSIS OF PROTOCOL MO25455 ............................................................. 10 
STUDY PROCEDURES (SUMMARY) ............................................................... 18 
1. 
BACKGROUND AND RATIONALE ............................................................ 25 
1.1 
Disease Background ............................................................. 25 
1.1.1 
Epidemiology ......................................................................... 25 
1.1.2 
Natural History ....................................................................... 26 
1.1.2.1 
Current management ................................................... 27 
1.2 
Study Drug Background......................................................... 28 
1.2.1 
Clinical Studies with Single-Agent Rituximab 
Induction ................................................................................ 29 
1.2.2 
Rituximab in Combination with Chemotherapy ...................... 30 
1.2.2.1 
Rituximab in combination with other 
chemotherapies and/or other indications ..................... 32 
1.2.3 
Rituximab as Maintenance Therapy ...................................... 32 
1.2.3.1 
Rituximab maintenance therapy following 
chemotherapy induction ............................................... 34 
1.2.3.2 
Rituximab as maintenance therapy 
following rituximab monotherapy induction .................. 34 
1.2.3.3 
Rituximab maintenance therapy following 
rituximab plus chemotherapy induction ........................ 35 
1.2.4 
Clinical Safety of Rituximab ................................................... 38 
1.3 
Regulatory Status .................................................................. 42 
1.4 
Rationale for the Study .......................................................... 44 
2. 
OBJECTIVES .............................................................................................. 46 
2.1 
Primary Objective .................................................................. 46 
2.2 
Secondary Objectives ............................................................ 46 
2.3 
Exploratory Objectives ........................................................... 46 
3. 
STUDY DESIGN ......................................................................................... 46 
3.1 
Overview of Study Design ..................................................... 46 
3.1.1 
Rationale for Study Design .................................................... 48 

 
Rituximab - F. Hoffmann-La Roche Ltd 
Protocol MO25455 v4.0 
3 of 128 
3.1.2 
Rationale for Treatment ......................................................... 49 
3.1.3 
End of Study .......................................................................... 50 
3.2 
Number of Patients/ Assignment to Treatment 
Groups ................................................................................... 50 
3.3 
Centres .................................................................................. 51 
4. 
STUDY POPULATION ................................................................................ 51 
4.1 
Overview ................................................................................ 51 
4.1.1 
Recruitment Procedures ........................................................ 51 
4.2 
Inclusion Criteria .................................................................... 51 
4.3 
Exclusion Criteria ................................................................... 51 
4.4 
Criteria for Prolonged Maintenance (Maintenance 
II) ........................................................................................... 53 
4.5 
Concomitant Medication and Treatment ................................ 54 
4.5.1 
 Permissible Concomitant Medication and      
Treatment .............................................................................. 54 
4.5.1.1 
Prophylaxis of infusion/injection-related 
reactions ......................................................................... 54 
4.5.1.2 
Prophylaxis of nausea and vomiting ............................... 54 
4.5.1.3 
Antimicrobial and antiviral prophylaxis ........................... 54 
4.5.1.4 
Prophylaxis for haemorrhagic cystitis ............................. 54 
4.5.1.5 
Tumour-lysis syndrome prophylaxis ............................... 54 
4.5.1.6 
Hydration, alkalization of urine and 
urostatics .................................................................... 54 
4.5.1.7 
Other Premedication 
 ................ 55 
4.5.2 
Prohibited Concomitant Medication and         
Treatment 
 ................ 55 
4.6 
Criteria for Premature Withdrawal ......................................... 55 
4.7 
Replacement Policy ............................................................... 56 
4.7.1 
For Patients ........................................................................... 56 
4.7.2 
For Centres ............................................................................ 56 
5. 
SCHEDULE OF ASSESSMENTS AND PROCEDURES ............................ 57 
5.1 
Schedule of Assessments ..................................................... 62 
5.1.1 
Screening and baseline Examination and 
Eligibility Screening Form ...................................................... 62 

 
Rituximab - F. Hoffmann-La Roche Ltd 
Protocol MO25455 v4.0 
4 of 128 
5.1.2 
Procedures for Enrolment of Eligible Patients ....................... 63 
5.1.3 
Assessments during the Treatment Period ............................ 63 
5.1.3.1 
Induction .................................................................... 64 
5.1.3.2 
Maintenance I ............................................................ 66 
5.1.3.3 
Maintenance II ........................................................... 68 
5.1.4 
Randomization Procedure ..................................................... 69 
5.1.5 
End of Treatment Assessments ............................................. 69 
5.1.6 
Off-Treatment Follow-up ........................................................ 70 
5.1.6.1 
New anti-lymphoma treatment initiation ..................... 71 
5.2 
Clinical Assessments and Procedures .................................. 71 
5.2.1 
Tumour Response Criteria ..................................................... 71 
5.2.1.1 
Scheduling of tumour assessments ........................... 72 
5.2.2 
Performance status ............................................................... 72 
5.2.3 
Clinical Safety Assessments .................................................. 72 
5.3 
Laboratory Assessments ....................................................... 73 
5.4 
Patient Reported Outcome(s) ................................................ 73 
5.4.1 
Patient Satisfaction with Therapy .......................................... 73 
5.5 
Pharmacoeconomic Assessments ......................................... 74 
5.6 
Post-Study Provisional Care .................................................. 74 
6. 
INVESTIGATIONAL MEDICINAL PRODUCT ............................................. 74 
6.1 
Dose and Schedule of Rituximab .......................................... 74 
6.1.1 
Induction ................................................................................ 74 
6.1.1.1 
Rituximab plus bendamustine (R-Bendamustine) ................... 75 
6.1.1.2 
Rituximab plus CHOP (R-CHOP) ............................... 76 
6.1.1.3 
Rituximab plus CVP (R-CVP) ..................................... 76 
6.1.1.4 
Rituximab plus FCM (R-FCM) .................................... 77 
6.1.1.5 
Rituximab plus MCP (R-MCP) ................................... 77 
6.1.1.6 
Rituximab plus CHVP-IFN (R- CHVP-IFN) ................. 77 
6.1.1.7 
Rituximab plus chlorambucil (R-
Chlorambucil) ................................................................. 77 
6.1.1.8 
Rituximab plus fludarabine (R-Fludarabine) .............................. 78 
6.1.1.9 
Rituximab plus gemcitabine, ifosfamide and 
oxaliplatin (R-GIFOX)....................................................... 78 

 
Rituximab - F. Hoffmann-La Roche Ltd 
Protocol MO25455 v4.0 
5 of 128 
6.1.2 
Maintenance I ........................................................................ 78 
6.1.3 
Maintenance II ....................................................................... 79 
6.1.4 
Dose Modifications, Interruptions and Delays ........................ 79 
6.2 
Preparation and Administration of IMP .................................. 80 
6.2.1 
IV Rituximab Preparation and Administration ........................ 80 
6.2.2 
SC Rituximab Preparation and Administration ....................... 80 
6.3 
Formulation, Packaging and Labelling ................................... 80 
6.3.1 
IV Rituximab .......................................................................... 80 
6.3.2 
SC Rituximab ......................................................................... 81 
6.4 
Blinding and Unblinding ......................................................... 81 
6.5 
Accountability of Rituximab and Assessment of 
Compliance ............................................................................ 81 
6.5.1 
Accountability of Rituximab .................................................... 81 
6.5.2 
Assessment of Compliance ................................................... 82 
6.6 
Destruction of Used Investigational Product .......................... 82 
7. 
SAFETY INSTRUCTIONS AND GUIDANCE .............................................. 83 
7.1 
Adverse Events and Laboratory Abnormalities ...................... 83 
7.1.1 
Clinical Adverse Events ......................................................... 83 
7.1.1.1 
Duration and intensity ................................................ 83 
7.1.1.2 
Drug – adverse event relationship ............................. 84 
7.1.1.3 
 Serious Adverse Events [Immediately 
Reportable to Roche] ................................................. 85 
7.1.1.4 
 Other safety findings requiring expedited 
reporting ..................................................................... 85 
7.1.1.5 
Progression of underlying malignancy ....................... 86 
7.1.1.6 
Deaths ........................................................................ 86 
7.1.2 
Adverse Event Reporting Period and Follow-up .................... 86 
7.1.3 
Procedures for Recording Adverse Events ............................ 88 
7.1.3.1 
Pre-existing medical conditions .................................. 88 
7.1.3.2 
Adverse events secondary to other events ................ 88 
7.1.3.3 
Persistent or recurrent adverse events ....................... 88 
7.1.4 
Laboratory Test Abnormalities ............................................... 89 
7.1.4.1 
Follow-up of abnormal laboratory test 
values ......................................................................... 89 

 
Rituximab - F. Hoffmann-La Roche Ltd 
Protocol MO25455 v4.0 
6 of 128 
7.1.5 
Pregnancy ............................................................................. 89 
7.1.6 
Interactions with other Medicinal Products and 
other Types of Interactions .................................................... 90 
7.2 
Handling of Safety Parameters .............................................. 90 
7.2.1 
Reporting of Serious Adverse Events 
(Immediately Reportable) ...................................................... 90 
7.2.2 
Serious Adverse Events Reporting Timeframe ...................... 90 
7.2.3 
Reporting of Infusion-Related Reactions (IRRs) 
or Administration-Related Reactions (ARRs) ........................ 91 
7.3 
Warnings and Precautions ..................................................... 91 
8. 
STATISTICAL CONSIDERATIONS AND ANALYTICAL PLAN .................. 91 
8.1 
Primary and Secondary Study Endpoints .............................. 91 
8.1.1 
Primary Efficacy Endpoint ...................................................... 91 
8.1.2 
Secondary Efficacy Endpoints ............................................... 91 
8.1.3 
Exploratory efficacy endpoint ................................................. 92 
8.1.4 
Safety Variables .................................................................... 92 
8.2 
Statistical Analyses ................................................................ 92 
8.2.1 
Primary Efficacy Analysis ...................................................... 92 
8.2.2 
Secondary Efficacy Analyses ................................................ 93 
8.2.3 
Exploratory Analyses ............................................................. 93 
8.2.3.1 
Patient Satisfaction with Administration of 
Cancer Therapy (RASQ) ............................................ 93 
8.2.3.2 
Patient Satisfaction with Administration of 
Cancer Therapy (CTSQ) ............................................ 93 
8.2.4 
Analysis Populations ............................................................. 93 
8.2.4.1 
Intent-to-treat populations .......................................... 93 
8.2.4.2 
Per-protocol population .............................................. 94 
8.2.4.3 
Safety population ....................................................... 94 
8.2.5 
Interim Analysis ..................................................................... 94 
8.2.6 
Safety Data Analysis ............................................................. 94 
8.2.7 
Other Analyses ...................................................................... 95 
8.2.7.1 
Pharmacoeconomic analysis ..................................... 95 
8.3 
Sample Size .......................................................................... 95 

 
Rituximab - F. Hoffmann-La Roche Ltd 
Protocol MO25455 v4.0 
7 of 128 
9. 
DATA COLLECTION, MANAGEMENT AND QUALITY 
ASSURANCE .............................................................................................. 96 
9.1 
Assignment of Preferred Terms and Original 
Terminology ........................................................................... 97 
10. STUDY COMMITTEES ............................................................................... 97 
10.1 
Independent Data and Safety Monitoring Board 
(DSMB Committee (iDMC) .................................................... 97 
11. ETHICAL ASPECTS ................................................................................... 98 
11.1 
Local Regulations/Declaration of Helsinki.............................. 98 
11.2 
Informed Consent .................................................................. 98 
11.3 
Independent Ethics Committees (IEC) .................................. 98 
11.4 
Financial Disclosure .............................................................. 99 
12. CONDITIONS FOR MODIFYING THE PROTOCOL................................... 99 
13. CONDITIONS FOR TERMINATING THE STUDY ...................................... 99 
14. STUDY DOCUMENTATION, CRFS AND RECORD KEEPING .................. 99 
14.1 
Investigator's Files / Retention of Documents ........................ 99 
14.2 
Source Documents and Background Data ........................... 100 
14.3 
Protocol Deviations .............................................................. 100 
14.4 
Audits and Inspections......................................................... 100 
14.5 
Electronic Case Report Forms ............................................. 101 
15. MONITORING THE STUDY ..................................................................... 101 
16. CONFIDENTIALITY OF TRIAL DOCUMENTS AND PATIENT 
RECORDS ................................................................................................ 101 
17. CLINICAL STUDY REPORT (CSR) .......................................................... 101 
18. PUBLICATION OF DATA AND PROTECTION OF TRADE 
SECRETS ................................................................................................. 101 
19. APPENDICES ........................................................................................... 103 
Appendix 1. Criteria for Evaluation of Response in Non-
Hodgkin’s Lymphoma1 ......................................................... 103 
Appendix 2. Criteria for Evaluation of Response in 
Waldenström’s Macroglobulinemia2..................................... 105 

 
Rituximab - F. Hoffmann-La Roche Ltd 
Protocol MO25455 v4.0 
8 of 128 
Appendix 3. Follicular Lymphoma Grading System (WHO 
Classification) ...................................................................... 106 
Appendix 4. Common Scales .................................................................. 107 
Eastern Cooperative Oncology Group (ECOG) Performance 
Status..................................................................................................... 107 
Ann Arbor Stage .................................................................................... 107 
FLIPI Score and Nodal Areas ................................................................ 108 
Appendix 5. Formula for Calculation of BSA (Dubois) ............................. 110 
Appendix 6. NCI Common Terminology Criteria for Adverse 
Events  ................................................................................. 111 
Appendix 7. ICH Guidelines for Clinical Safety Data 
Management, Definitions and Standards for 
Expedited Reporting, Topic E2 ............................................ 112 
Appendix 8. Rituximab Patient Satisfaction Questionnaire ...................... 114 
Subcutaneous Administration ................................................................ 114 
Intravenous Administration .................................................................... 116 
Appendix 9. Cancer Therapy Satisfaction Questionnaire ........................ 120 
REFERENCES ................................................................................................. 122 
 

 
Rituximab - F. Hoffmann-La Roche Ltd 
Protocol MO25455 v4.0 
9 of 128 
PROTOCOL AMENDMENT ACCEPTANCE FORM 
TITLE: 
A 
RANDOMIZED 
STUDY 
COMPARING 
MAINTENANCE THERAPY WITH SUBCUTANEOUS 
RITUXIMAB CONTINUED UNTIL PROGRESSION 
WITH OBSERVATION ONLY IN PATIENTS WITH 
RELAPSED OR REFRACTORY, INDOLENT NON-
HODGKIN’S LYMPHOMA WHO COMPLETED AND 
RESPONDED 
TO 
RITUXIMAB-BASED 
IMMUNOCHEMOTHERAPY 
INDUCTION 
AND 
INITIAL 
2-YEAR 
RITUXIMAB 
MAINTENANCE 
THERAPY ADMINISTERED SUBCUTANEOUSLY 
PROTOCOL NUMBER: MO25455 
VERSION NUMBER: 
4.0 
EUDRACT NUMBER: 
2010-023407-95 
IND NUMBER: 
Not applicable 
TEST PRODUCT: 
Rituximab (RO 045-2294) 
MEDICAL MONITOR: 
Dr. 
  
SPONSOR: 
F. Hoffmann-La Roche Ltd 
I agree to conduct the study in accordance with the current protocol. 
 
 
 
Principal Investigator’s Name  (print) 
 
 
 
 
 
Principal Investigator’s Signature 
 
Date 
Please return the signed original of this form as instructed by your local study monitor.  
Please retain a copy for your study files. 
 

 
Rituximab - F. Hoffmann-La Roche Ltd 
Protocol MO25455 v4.0 
10 of 128 
SYNOPSIS OF PROTOCOL MO25455 
TITLE 
A 
randomized 
study 
comparing 
maintenance 
therapy 
with 
subcutaneous rituximab continued until progression with observation 
only in patients with relapsed or refractory, indolent non-Hodgkin’s 
lymphoma who completed and responded to rituximab-based 
immunochemotherapy 
induction 
and 
initial 
2-year 
rituximab 
maintenance therapy administered subcutaneously.  
SPONSOR 
F. Hoffmann-La Roche Ltd 
CLINICAL PHASE 
IIIb 
INDICATION 
Patients with relapsed or refractory CD20+ follicular non-Hodgkin’s 
lymphoma (NHL) Grade 1, 2 or 3a, or other CD20+ indolent NHL 
(Waldenström’s macroglobulinemia or lymphoplasmacytic lymphoma, 
marginal zone lymphoma), according to the WHO classification 
system. 
OBJECTIVES  
Primary objective:  
To evaluate the efficacy of a subcutaneous (SC) formulation of 
rituximab in term of progression-free survival after randomization 
(PFSrand) to either prolonged rituximab maintenance until progression 
(Maintenance II) or observation in patients with relapsed or refractory, 
indolent non-Hodgkin’s lymphoma who responded to Induction and 
initial 2 years maintenance therapy (Maintenance I). 
Secondary objectives: To evaluate the efficacy and safety of SC 
rituximab during Induction, initial 2-year maintenance (Maintenance I) 
and randomized treatment period (Maintenance II). Efficacy will be 
evaluated in terms of Event-Free Survival (EFS), Time to Next 
Lymphoma Treatment (TNLT), Overall survival measured from the first 
Induction dose of rituximab (OSregist) and from the time of 
randomization to Maintenance II (OSrand), Overall Response Rate 
(ORR), Partial Response (PR) to Complete Response (CR) conversion 
rate at the end of Maintenance I, and PFS measured from the first 
Induction dose of rituximab (PFSregist). Safety assessments will include 
frequency of adverse events (AEs), serious adverse events (SAEs), 
and 
infusion/administration-related 
reactions 
(IRRs/ARRs) 
and 
immunoglobulin (Ig) quantification.  
Exploratory objectives: 
 
 
TRIAL DESIGN 
Multicentre, multinational, open label, randomized study 


5LWX[LPDE)+RIIPDQQ/D5RFKH/WG
3URWRFRO02Y
RI
)LJXUH6WXG\6FKHPH

3'
RIIVWXG\
WUHDWPHQW

 
Rituximab - F. Hoffmann-La Roche Ltd 
Protocol MO25455 v4.0 
12 of 128 
NUMBER OF PATIENTS 
Approximately 700 enrolled patients were expected to yield a minimum 
of 330 patients randomized to maintenance II therapy with SC 
rituximab continued until progression or to observation after they 
completed and responded to Induction and initial 2-year maintenance I 
therapy. The final number of patients randomized to maintenance II 
therapy was 276. 
TARGET POPULATION 
The target population will consist of adults with relapsed or refractory 
CD20+ follicular NHL Grade 1, 2 or 3a, or other CD20+ indolent NHL 
(Waldenström’s macroglobulinemia or lymphoplasmacytic lymphoma, 
marginal zone lymphoma) according to the WHO classification system. 
ENROLMENT CRITERIA: 
Patients must fulfil all of the following criteria at enrolment (i.e. prior to 
the first dose of Induction Treatment): 
Inclusion Criteria 
1. Signed, written informed consent form. 
2. Age ≥ 18 years.  
3. Histologically confirmed, CD20+ follicular NHL Grade 1, 2 or 
3a, 
or 
other 
CD20+ 
indolent 
NHL 
(Waldenström’s 
macroglobulinemia or lymphoplasmacytic lymphoma, marginal 
zone lymphoma) according to the WHO classification system. 
4. Patients must have received, and must have relapsed or been 
refractory to, one or more lines of adequate therapy prior to 
enrolment, 
including 
at 
least 
one 
line 
consisting 
of 
immunotherapy and/or chemotherapy and/or radiotherapy.  
Note: Rituximab administration in first line is not mandated, 
but preferred.  
5. Eastern Cooperative Oncology Group (ECOG) performance 
status ≤ 2. 
Exclusion Criteria 
DISEASE-SPECIFIC: 
1. Transformation to high-grade lymphoma. 
2. Patients 
with aggressive lymphoma (e.g. mantle cell 
lymphoma). 
3. Presence or history of central nervous system (CNS) 
lymphomatous 
disease 
(e.g., 
CNS 
lymphoma 
or 
lymphomatous meningitis). 
OTHER MEDICAL CONDITIONS OR TREATMENTS: 
4. Other malignancy within 5 years prior to enrolment, with the 
following exceptions (as long as curatively treated): carcinoma 

 
Rituximab - F. Hoffmann-La Roche Ltd 
Protocol MO25455 v4.0 
13 of 128 
in situ of the cervix, squamous cell carcinoma of the skin, or 
basal cell skin cancer. Cervical carcinoma stage 1B or less, 
breast cancer in situ, or localized prostate cancer stage T1c or 
less may be considered, provided that the patient was treated 
with curative intent and has been relapse- and metastasis-free 
for at least 2 years prior to enrolment. 
5. Inadequate haematological function within 28 days prior to the 
first rituximab induction dose, defined as any of the following 
(unless the abnormality is related to involvement of bone 
marrow by NHL): 
a. Haemoglobin (Hb) < 9.0 g/dL (5.6 mmol/L)  
b. Absolute neutrophil count (ANC) < 1.0 x 109/L  
(1,000/µL) 
c. Platelet count < 100 x 109/L (100,000/µL); lower 
platelet count (but not below 50 x 109/L) is acceptable 
if due to toxicity of previous chemotherapy and not 
accompanied by bleeding. 
6. Patients with severe autoimmune cytopenias as assessed by 
the physician. 
Note: Coombs positive patients without clinical signs of 
autoimmune haemolytic anemia are eligible for enrolment. 
7. Inadequate hepatic function prior to the first rituximab 
induction dose, defined as any of the following:  
a. Total bilirubin > 1.5 times the upper limit of normal 
(ULN).  Note: patients with documented Gilbert 
disease may be enrolled if total bilirubin is ≤ 3.0 x 
ULN. 
b. Alanine aminotransferase (ALT) and/or aspartate 
aminotransferase (AST) > 2.5 times the ULN 
c. Alkaline phosphatase > 2.5 times ULN 
8. Inadequate renal function prior to the first rituximab induction 
dose, defined as creatinine clearance (CrCl) < 30 mL/minute 
or serum creatinine > 2 mg/dL (197 μmol/L). 
9. Known human immunodeficiency virus (HIV) infection  
10. Active and/or severe infection (e.g. tuberculosis, sepsis and 
opportunistic infections, active hepatitis B virus (HBV) or active 
hepatitis C virus (HCV) infection). 
11. Other serious underlying medical conditions, which, in the 
Investigator’s judgment, could impair the ability of the patient 
to participate in the study (e.g., uncontrolled diabetes mellitus, 

 
Rituximab - F. Hoffmann-La Roche Ltd 
Protocol MO25455 v4.0 
14 of 128 
gastric ulcers, active autoimmune disease). 
12. Known or suspected hypersensitivity to components of the 
investigational product, including known hypersensitivity or 
previous anaphylactic reaction to murine antibodies or 
proteins. 
13. Regular corticosteroid use within 28 days prior to the first 
rituximab induction dose, unless administered at a dose 
equivalent to < 20 mg/day prednisone/prednisolone.  
Note: inhaled or topical corticosteroids are permitted. 
14. Major surgery (excluding lymph node biopsy) within 28 days 
prior to the first rituximab induction dose.  
15. Treatment with an investigational product within 30 days prior 
to enrolment. 
GENERAL: 
16. Inability to provide informed consent. 
17. Life expectancy of less than 6 months. 
18. History of poor compliance during previous lines of therapy. 
19. Pregnant or breastfeeding patients. A negative serum 
pregnancy test is required for women of childbearing potential 
within 7 days prior to first rituximab administration or within 14 
days if with a confirmatory urine pregnancy test within 7 days 
prior to the first rituximab administration. Women of 
childbearing potential are defined as pre-menopausal women 
or women who are < 2 years after the onset of menopause 
and are not surgically sterile. 
20. Fertile men or women of childbearing potential who do not 
agree to use a highly effective measure of contraception (such 
as oral contraceptives, intrauterine device or barrier method of 
contraception in conjunction with spermicidal jelly or surgically 
sterile) throughout the study and for at least 12 months after 
the last dose of rituximab.  
 
CRITERIA FOR PROLONGED MAINTENANCE (Maintenance II): 
In addition to the above listed enrolment criteria, patients must fulfil the 
following criteria in order to be randomized: 
1. Completed 
rituximab-based 
Induction 
and 
initial 
2-year 
maintenance therapy with subcutaneous rituximab (Maintenance 
I). 
2. PR or CR as confirmed by computerized tomography (CT) after 
Maintenance I. Response assessment is completed according to 


5LWX[LPDE)+RIIPDQQ/D5RFKH/WG
3URWRFRO02Y
RI
WKH,QWHUQDWLRQDO:RUNLQJ*URXS&KHVRQUHVSRQVHFULWHULD
IRUO\PSKRPDRUE\WKHUHFRPPHQGDWLRQVIRU:DOGHQVWU|P¶V
PDFURJOREXOLQHPLDVHH$SSHQGL[
5DQGRPL]DWLRQ ZLOO RFFXU XVLQJ D FHQWUDOL]HG LQWHUDFWLYH YRLFHZHE
UHVSRQVHV\VWHP,956,:56LQDIDVKLRQVWUDWLILHGDFFRUGLQJWR
LQGROHQW 1+/ VXEW\SH IROOLFXODU O\PSKRPD QRQIROOLFXODU O\PSKRPD
DQG )ROOLFXODU /\PSKRPD ,QWHUQDWLRQDO 3URJQRVWLF ,QGH[ )/,3,
FDWHJRU\ORZULVNLQWHUPHGLDWHULVNKLJKULVN
/(1*7+2)678'<
,WLVH[SHFWHGWKDWDSSUR[LPDWHO\SDWLHQWVZLOOEHHQUROOHG
7KHWRWDOVWXG\GXUDWLRQLVDSSUR[LPDWHO\PRQWKVLQFOXGLQJ
•
PRQWKVHQUROOPHQWSHULRG
•
PRQWKV,QGXFWLRQSHULRG
•
PRQWKVLQLWLDOULWX[LPDE6&PDLQWHQDQFH0DLQWHQDQFH,
•
0LQLPXP  PRQWKV UDQGRPL]HG SHULRG REVHUYDWLRQ RQO\ RU
PDLQWHQDQFH WUHDWPHQW ZLWK 6& ULWX[LPDE FRQWLQXHG XQWLO
SURJUHVVLRQ 0DLQWHQDQFH ,, RU (QG RI 6WXG\ (26 ZKLFKHYHU
RFFXUVILUVW
(1'2)678'<
(QG RI WKH VWXG\ LV GHILQHG DV WKH ODVW SDWLHQW¶V ODVW YLVLW LQ
0DLQWHQDQFH ,,  7KH VWXG\ ZLOO HQG ZKHQ DOO SDWLHQWV UDQGRPL]HG LQ
0DLQWHQDQFH ,, KDYH EHHQ IROORZHG IRU DW OHDVW  PRQWKV DIWHU
UDQGRPL]DWLRQRUHDUOLHULIRQHRIWKHIROORZLQJLVGRFXPHQWHGIRUDOO
SDWLHQWVGLVHDVHUHFXUUHQFHZLWKGUDZDOIURPWKHVWXG\ORVVWRIROORZ
XSRUGHDWK
3DWLHQWV ZLWK SURJUHVVLYH GLVHDVH 3' DW DQ\ WLPH GXULQJ WKH VWXG\
ZLOOFRPHRIIVWXG\WUHDWPHQWDQGVWDUW2II7UHDWPHQW)ROORZ8SEHLQJ
IROORZHG IRU VXUYLYDO XQWLO WKH HQG RI WKH VWXG\  3DWLHQWV ZLWK VWDEOH
GLVHDVH6'DWWKHHQGRI,QGXFWLRQZLOOFRPHRIIVWXG\WUHDWPHQWDQG
ZLOOHQWHU2II7UHDWPHQW)ROORZ8SEHLQJIROORZHGHYHU\PRQWKVIRU
3' DQG VXUYLYDO XQWLO WKH HQG RI WKH VWXG\ 'XULQJ 0DLQWHQDQFH ,,
SDWLHQWVLQWKH6&ULWX[LPDEPDLQWHQDQFHDUPZLOOEHWUHDWHGXQWLO3'
XQDFFHSWDEOHWR[LFLW\ZLWKGUDZDORISDWLHQWFRQVHQWRUXQWLOWKHSULPDU\
HQGSRLQWKDVEHHQUHDFKHG$OOSDWLHQWVLQ$UP$ULWX[LPDEPJ
IL[HGGRVHZHHNO\DQG$UP%REVHUYDWLRQQRWUHDWPHQWZLOOKDYH
HLWKHU WUHDWPHQW RU REVHUYDWLRQ YLVLWV HYHU\  ZHHNV XQWLO GLVHDVH
SURJUHVVLRQRU(26ZKLFKHYHURFFXUVILUVW3DWLHQWVRQERWKDUPVZLOO
EHDFWLYHO\IROORZHGIRUVDIHW\WXPRXUUHVSRQVHSURJUHVVLRQQHZDQWL
O\PSKRPD WUHDWPHQWV DQG VXUYLYDO E\ IROORZLQJ WKH VDPH YLVLW
VFKHGXOHRIDVVHVVPHQWVIRUDWOHDVWPRQWKVDIWHUUDQGRPL]DWLRQ
(QUROOHGSDWLHQWVZKRGRQRWFRPSOHWHWUHDWPHQWSHUSURWRFROIRUDQ\
UHDVRQ ZLOO XQGHUJR WKH HQGRIWUHDWPHQW DVVHVVPHQW DQG HQWHU 2II
7UHDWPHQW)ROORZXS$UP%3DWLHQWVUDQGRPL]HGWRREVHUYDWLRQDUP


5LWX[LPDE)+RIIPDQQ/D5RFKH/WG
3URWRFRO02Y
RI
ZLOOXQGHUJR WKHHQGRIWUHDWPHQWDVVHVVPHQWZLWKLQ  ZHHNVRIODVW
GRVH EXW UHPDLQ RQ WKH VDPH VFKHGXOH RI DVVHVVPHQWV WKDW $UP $
SDWLHQWVDUHIROORZLQJ3DWLHQWVRQREVHUYDWLRQZKRPHHWRQHRUPRUH
RI WKH ZLWKGUDZDO FULWHULD RXWOLQHG LQ VHFWLRQ  ZLOO HQWHU 2II
7UHDWPHQW)ROORZXSVKRXOGWKH\DJUHHWRUHPDLQLQWKHVWXG\
,19(67,*$7,21$/
0(',&$/352'8&76
'26(5287(
5(*,0(1
,QGXFWLRQ
&\FOH,9ULWX[LPDEPJPERG\VXUIDFHDUHD%6$DVDVLQJOH
LQIXVLRQ IROORZHG E\ DGPLQLVWUDWLRQ RI FKHPRWKHUDS\ DV DSSOLFDEOH
VHHEHORZ
&\FOHV  WR  (DFK F\FOH ZLOO FRQVLVW RI D VLQJOH 6& LQMHFWLRQ RI
ULWX[LPDEPJIROORZHGE\DGPLQLVWUDWLRQRIFKHPRWKHUDS\VHH
EHORZDQGUHSHDWHGHYHU\ZHHNVGHSHQGLQJRQWKHFRPELQDWLRQ
FKHPRWKHUDS\UHJLPHQVHOHFWHG
1RWH
•
5LWX[LPDELVDOZD\VDGPLQLVWHUHGSULRUWRFKHPRWKHUDS\ZLWKWKH
H[FHSWLRQRIWKHFRUWLFRVWHURLGFRPSRQHQW
•
3DWLHQWVZKRZHUHQRWDEOHWRUHFHLYHWKHIXOOGRVHRIULWX[LPDEDW
F\FOHDVDUHVXOWRI,55VKRXOGUHFHLYHDOVRWKHVHFRQGULWX[LPDE
GRVHLQWUDYHQRXVO\3DWLHQWVZKRGRQRWH[SHULHQFHJUDGHRU
,55 DIWHU WKH VHFRQG ULWX[LPDE LQIXVLRQ ZLOO UHFHLYH WKH UG
ULWX[LPDEGRVHVXEFXWDQHRXVO\F\FOH3DWLHQWVZLWKJUDGHRU
,55DIWHUWKHVHFRQGULWX[LPDELQIXVLRQ ZLOOEH ZLWKGUDZQIURP
UHFHLYLQJVWXG\WUHDWPHQW
,QLWLDO0DLQWHQDQFH0DLQWHQDQFH,
5LWX[LPDEPJIL[HGGRVHRQH6&LQMHFWLRQHYHU\ZHHNVIRU
 PRQWKV XS WR  LQMHFWLRQV DGPLQLVWHUHG DV GHVFULEHG DERYH
ZLWKRXWFKHPRWKHUDS\0DLQWHQDQFHWKHUDS\ZLWK6&ULWX[LPDEPXVW
VWDUW ZLWKLQ  ZHHNV DIWHU WKH DGPLQLVWUDWLRQ RI WKH ODVW GRVH RI
ULWX[LPDELQWKHLQGXFWLRQWKHUDS\
3URORQJHG0DLQWHQDQFH0DLQWHQDQFH,,
•
$UP $ 5LWX[LPDE  PJ IL[HG GRVH DGPLQLVWHUHG DV
GHVFULEHGDERYHZLWKRXWFKHPRWKHUDS\RQH6&LQMHFWLRQHYHU\
ZHHNVXQWLOGLVHDVHSURJUHVVLRQRU(26ZKLFKHYHURFFXUVILUVW
•
$UP%2EVHUYDWLRQQRWUHDWPHQW
&(175(6
7KLVLVDPXOWLQDWLRQDOPXOWLFHQWUHVWXG\
121,19(67,*$7,21$/
0(',&$/352'8&76
$SSURYHGFRPPHUFLDOO\DYDLODEOHFRPELQDWLRQFKHPRWKHUDS\UHJLPHQV
&203$5$725'58*
'26(5287(
1RDFWLYHFRPSDUDWRUZLOOEHXVHGLQWKHVWXG\

 
Rituximab - F. Hoffmann-La Roche Ltd 
Protocol MO25455 v4.0 
17 of 128 
REGIMEN 
ASSESSMENTS OF: 
- 
EFFICACY 
Tumour assessments will be based on CT scans of the neck (if 
clinically indicated), chest, abdomen and pelvis (if detectable by these 
techniques) to document nodal disease or organ involvement.  Other 
diagnostic means are acceptable for lymphomas that cannot be 
diagnosed radiographically (e.g. gastroscopy in patients with follicular 
lymphoma of the stomach). The CT scan used for eligibility or 
response assessments may be up to 8 weeks old. Response 
assessments during and after the induction period and after 
maintenance therapy will be completed according to the International 
Working Group response (Cheson) criteria for lymphoma (please use 
version of year 1999 for CT scans)1 or by the recommendations 
for Waldenström’s macroglobulinemia2 (see Appendix 2). 
The efficacy of SC rituximab will be evaluated during induction, 
Maintenance I, and Maintenance II in terms of PFSrand and PFSregist 
(from randomization and from the first rituximab induction dose, 
respectively), EFS, TNLT, OSregist and OSrand, ORR, PR to CR 
conversion rate (full restaging, at the end of Maintenance I).   
- 
SAFETY 
All AEs occurring during the course of the study will be captured, 
regardless of their intensity / grading. Grading of AEs will be 
completed according to the National Cancer Institute (NCI) Common 
Terminology Criteria for Adverse Events (CTC-AE), version 4.0.  
Immunoglobulin (IgG, IgM and IgA) quantification will be completed at 
baseline, once a year during Maintenance I (maintenance injections #6 
and #12), once a year during Maintenance II (Arm A) and in case of 
suspicious infections. 
PHARMACOKINETICS/ 
PHARMACODYNAMICS  
N/A 
 
QUALITY OF LIFE (QOL)  
 
 
 
  
PHARMACOECONOMIC
SUB-STUDY 
A Time in Motion pharmacoeconomic sub-study will assess Medical 
Care Utilization (MCU) parameters to enable data collection on time of 
infusion and resource use based on a site protocol at selected sites. 
Details of the sub-study will be described in a separate protocol. 


5LWX[LPDE)+RIIPDQQ/D5RFKH/WG
3URWRFRO02Y
RI
678'<352&('85(6VXPPDU\
$IWHUDSDWLHQWKDVFRQVHQWHGWRSDUWLFLSDWHLQWKLVVWXG\WKHIROORZLQJSURFHGXUHVZLOOEHFDUULHG
RXW
• 
%DVHOLQHDVVHVVPHQWZLOOEHSHUIRUPHGDFFRUGLQJWRWKH6FKHGXOHRI$VVHVVPHQWV7DEOH

6HH6HFWLRQIRUGHWDLOVDERXWGRVHPRGLILFDWLRQVLQWHUUXSWLRQVDQGGHOD\VIRUULWX[LPDEDQG
FKHPRWKHUDS\
•
,QGXFWLRQ  F\FOHV RI ULWX[LPDE ZLOO EH DGPLQLVWHUHG LQ FRPELQDWLRQ ZLWK    F\FOHV RI
FKHPRWKHUDS\ EHQGDPXVWLQH &+23 &93 )&0 0&3 &+93,)1 FKORUDPEXFLO RU DQ\
IOXGDUDELQHFRQWDLQLQJ UHJLPHQ LQFOXGLQJ RUDO IOXGDUDELQH 5*,)2; VHOHFWLRQ DW WKH
,QYHVWLJDWRU¶VGLVFUHWLRQ7KHILUVWDGPLQLVWUDWLRQRIULWX[LPDEZLOOEHE\,9LQIXVLRQRQ'D\
RIWKHILUVWLQGXFWLRQF\FOHDWGRVHRIPJP%6$,QWKHDEVHQFHRILQIXVLRQUHODWHGVLGH
HIIHFWVULWX[LPDEZLOOVXEVHTXHQWO\EHDGPLQLVWHUHG6&VWDUWLQJ'D\RIHDFKLQGXFWLRQF\FOH
DW D IL[HG GRVH RI  PJ 3DWLHQWV ZKR H[SHULHQFHG D JUDGH  RU  ,55 DIWHU WKH ILUVW
ULWX[LPDELQIXVLRQ&\FOHEXWZHUHDEOHWRUHFHLYHWKHIXOOGRVHRIULWX[LPDEPXVWUHFHLYH
WKHVHFRQGGRVHRIULWX[LPDE6&&\FOH'D\3DWLHQWVZKRZHUHQRWDEOHWRUHFHLYHWKHLU
IXOO GRVH RI ULWX[LPDE LQIXVLRQ LQ &\FOH  DV D UHVXOW RI ,55 VKRXOG UHFHLYH WKHLU VHFRQG
ULWX[LPDEGRVHDOVR,9,IWKLVVHFRQGULWX[LPDELQIXVLRQLVQRWDVVRFLDWHGZLWKDJUDGHRU
,55WKHSDWLHQWZLOOUHFHLYHKLVKHUWKLUGULWX[LPDEGRVH6&&\FOH'D\3DWLHQWVZLWK
JUDGHRU,55DIWHUWKHVHFRQGULWX[LPDELQIXVLRQZLOOEHZLWKGUDZQIURPWKHVWXG\
R
6WXG\ 9LVLW 6FKHGXOHIRUSDWLHQWVGXULQJWKHLQGXFWLRQWKHUDS\SHULRGZLOORFFXUDW
WKHEHJLQQLQJRIHDFKZHHNRUZHHNWUHDWPHQWF\FOHDFFRUGLQJWRWKH6FKHGXOH
RI$VVHVVPHQWV7DEOH
R
5HVSRQVHDVVHVVPHQWZLOOEHFRQGXFWHGE\WKH,QYHVWLJDWRUDIWHUF\FOHVRUDIWHU
F\FOHVVKRXOG,QGXFWLRQEHFRPSULVHGRIFKHPRWKHUDS\DGPLQLVWUDWLRQVDQGDW
WKHHQGRI,QGXFWLRQLHDIWHUF\FOHVRIULWX[LPDE5HVSRQVHVKRXOGEHDVVHVVHG
DFFRUGLQJWRWKH&KHVRQUHVSRQVHFULWHULDIRULQGROHQWO\PSKRPDVHH$SSHQGL[
RUE\WKHUHFRPPHQGDWLRQVIRU:DOGHQVWU|P¶VPDFURJOREXOLQHPLDVHH$SSHQGL[
3DWLHQWVZLWK3'DWDQ\WLPHGXULQJWKHVWXG\ZLOOFRPHRIIVWXG\WUHDWPHQWDQGZLOO
VWDUW2II7UHDWPHQW)ROORZ8SEHLQJIROORZHGIRUVXUYLYDOXQWLOWKHHQGRIWKHVWXG\
3DWLHQWVZLWK6'DWWKHHQGRI,QGXFWLRQZLOOFRPHRIIVWXG\WUHDWPHQWDQGZLOOHQWHU
2II7UHDWPHQW )ROORZ8S EHLQJ IROORZHG IRU 3' DQG VXUYLYDO XQWLO WKH HQG RI WKH
VWXG\
•
0DLQWHQDQFH ,6&ULWX[LPDEPDLQWHQDQFHWKHUDS\PXVW VWDUWZLWKLQZHHNVDIWHUWKH
DGPLQLVWUDWLRQ RI WKH ODVW GRVH RI ULWX[LPDE LQ WKH LQGXFWLRQ WKHUDS\ ,QLWLDO PDLQWHQDQFH
WKHUDS\ZLOOFRQVLVWRIF\FOHVRIULWX[LPDEDGPLQLVWHUHGDVDVLQJOH6&LQMHFWLRQRI
PJULWX[LPDEHYHU\ZHHNVIRU\HDUV
R
6WXG\9LVLW6FKHGXOHIRUSDWLHQWVGXULQJ0DLQWHQDQFH,ZLOORFFXUDFFRUGLQJWRWKH
6FKHGXOHRI$VVHVVPHQWV7DEOH
•
5HVSRQVH DVVHVVPHQW ZLOO EH FRQGXFWHG E\ WKH ,QYHVWLJDWRU HYHU\  PRQWKV GXULQJ
0DLQWHQDQFH , DFFRUGLQJ WR WKH &KHVRQ UHVSRQVH FULWHULD IRU LQGROHQW O\PSKRPD VHH
$SSHQGL[  RU E\ WKH UHFRPPHQGDWLRQV IRU :DOGHQVWU|P¶V PDFURJOREXOLQHPLD VHH
$SSHQGL[3DWLHQWVZLWK3'DWDQ\WLPHGXULQJWKHVWXG\ZLOOFRPHRIIVWXG\WUHDWPHQWDQG
ZLOO VWDUW 2II7UHDWPHQW )ROORZ8S EHLQJ IROORZHG IRU VXUYLYDO XQWLO WKH HQG RI WKH VWXG\
0DLQWHQDQFH,,DWWKHHQGRI\HDU0DLQWHQDQFH,WXPRXUUHVSRQVHZLOOEHDVVHVVHGDQG
FRPSDUHGWRWKHSDWLHQW¶VEDVHOLQHVWDWXVDQGSDWLHQWVZLWK35RU&5DVGHWHUPLQHGE\WKH
,QYHVWLJDWRUXVLQJWKH&KHVRQUHVSRQVHFULWHULDVHH$SSHQGL[RUE\WKHUHFRPPHQGDWLRQV
IRU:DOGHQVWU|P¶VPDFURJOREXOLQHPLDVHH$SSHQGL[ZLOOEHUDQGRPL]HGWRPDLQWHQDQFH
WUHDWPHQW ZLWK 6& ULWX[LPDE FRQWLQXHG XQWLO SURJUHVVLRQ $UP $ RU REVHUYDWLRQ ZLWK QR
IXUWKHUWUHDWPHQW$UP%3DWLHQWVLQ$UP$ZLOOUHFHLYHRQH6&ULWX[LPDELQMHFWLRQDWDIL[HG


5LWX[LPDE)+RIIPDQQ/D5RFKH/WG
3URWRFRO02Y
RI
GRVHRIPJHYHU\ZHHNVXQWLO3'XQDFFHSWDEOHWR[LFLW\ZLWKGUDZDORISDWLHQWFRQVHQW
RUXQWLO(26
R
6WXG\9LVLW6FKHGXOHIRUSDWLHQWVGXULQJ0DLQWHQDQFH,,ZLOORFFXUDFFRUGLQJWRWKH
6FKHGXOHRI$VVHVVPHQWV7DEOHDQGZLOOLQFOXGHVDIHW\GLVHDVHSURJUHVVLRQQHZ
DQWLO\PSKRPDWUHDWPHQWVDQGVXUYLYDO'LVHDVHSURJUHVVLRQZLOOEHHYDOXDWHGE\WKH
,QYHVWLJDWRU HYHU\  PRQWKV DFFRUGLQJ WR &KHVRQ UHVSRQVH FULWHULD IRU LQGROHQW
O\PSKRPD VHH $SSHQGL[  RU E\ WKH UHFRPPHQGDWLRQV IRU :DOGHQVWU|P¶V
PDFURJOREXOLQHPLDVHH$SSHQGL[3DWLHQWVZLWK3'ZLOOFRPHRIIVWXG\WUHDWPHQW
DQGEHIROORZHGIRUVXUYLYDO

67$7,67,&$/$1$/<6(6
$QDO\VLV3RSXODWLRQV
$OOSDWLHQWVZKRKDYHFRPSOHWHGDEDVHOLQHYLVLWDQGDWOHDVWRQHRQWUHDWPHQWDVVHVVPHQWZLOOEH
LQFOXGHG LQ WKH ,QWHQW7R7UHDW ,77 SRSXODWLRQ VHW 7KH ,77 SRSXODWLRQ ZLOO EH XVHG IRU WKH
DQDO\VLVRIWKHVHFRQGDU\HIILFDF\SDUDPHWHUVDQGEDVHOLQHYDULDEOHV
7KHUHZLOOEHDQDGGLWLRQDO,QWHQW7R7UHDW,77UDQGSRSXODWLRQLQFOXGLQJRQO\UDQGRPL]HGSDWLHQWV
IRUDQDO\VLQJ WKH SULPDU\ HQGSRLQWRI3)6 EH\RQGUDQGRPL]DWLRQ3)6UDQG 0DLQWHQDQFH,, $OO
UDQGRPL]HG SDWLHQWV ZLOO EH LQFOXGHG LQ WKLV ,77UDQG SRSXODWLRQ DQG DQDO\VHG DFFRUGLQJ WR WKH
WUHDWPHQWDUPWKH\ZHUHUDQGRPL]HGWR
(IILFDF\
3ULPDU\HIILFDF\HQGSRLQW3)6UDQG
3)6UDQGZLOOEHPHDVXUHGIURPWKHGD\RIUDQGRPL]DWLRQXQWLOWKHGDWHRIILUVWGRFXPHQWHGGLVHDVH
SURJUHVVLRQRUGHDWKE\DQ\FDXVHZKLFKHYHURFFXUVILUVW
3DWLHQWVZKRKDYHH[SHULHQFHGQRQHRIWKHVHHYHQWVDWWKHWLPHRIDQDO\VLVFOLQLFDOFXWRIIDQG
SDWLHQWVZKRDUHORVWWRIROORZXSZLOOEHFHQVRUHGDWWKHLUODVWFOLQLFDODVVHVVPHQWGDWH
6HFRQGDU\HIILFDF\HQGSRLQWV
•
3)6UHJLVWPHDVXUHGIURPWKHGD\RIILUVWULWX[LPDELQGXFWLRQGRVH
•
()6PHDVXUHGIURPWKHGD\RIILUVWULWX[LPDELQGXFWLRQGRVH
•
71/7PHDVXUHGIURPWKHGD\RIILUVWULWX[LPDELQGXFWLRQGRVH
•
26UHJLVWPHDVXUHGIURPWKHGD\RIILUVWULWX[LPDELQGXFWLRQGRVH
•
26UDQGPHDVXUHGIURPWKHGD\RIUDQGRPL]DWLRQ
•
2YHUDOO5HVSRQVH5DWHPHDVXUHGIURPWKHGD\RIILUVWULWX[LPDELQGXFWLRQGRVHDWWKHHQG
RIWKH,QGXFWLRQ3KDVH
•
35WR&5FRQYHUVLRQUDWHDWWKHHQGRI0DLQWHQDQFH,
([SORUDWRU\HIILFDF\HQGSRLQW
•


0HGLFDO &DUH 8WLOL]DWLRQ GDWD ZLOO EH DQDO\VHG DV SDUW RI D VHSDUDWH 3KDUPDFRHFRQRPLF VXE
VWXG\
6DIHW\
$OOSDWLHQWVZKRKDYHUHFHLYHGDWOHDVWRQHGRVHRI6&ULWX[LPDEZLOOEHLQFOXGHGLQWKH6DIHW\
SRSXODWLRQ7KHVDIHW\DQDO\VLVZLOOEHEDVHGRQWKH6DIHW\SRSXODWLRQ

 
Rituximab - F. Hoffmann-La Roche Ltd 
Protocol MO25455 v4.0 
20 of 128 
Safety assessments will include frequency of AEs, SAEs, and IRRs. Safety data will be analysed 
and described by study period, i.e. Induction, Maintenance I, Maintenance II, as well as overall. 
In addition, IgG, IgM and IgA quantification will be completed once a year during Maintenance I, 
once a year during Maintenance II (Arm A) and in case of suspicious infections. 
Sample Size Calculation  
The sample size of the proposed study has been estimated based on assumptions derived from 
the Phase III randomized EORTC 20981 study of 465 patients with previously treated, advanced-
staged relapsed FL.3 In this study, median PFS from first randomization was 20.2 months after 
CHOP vs. 33.1 months after R-CHOP and rituximab maintenance yielded a median PFS from 
second randomization of 51.5 months vs. 14.9 months with observation. 
In the current study, assuming a median PFS beyond randomization (Maintenance II) of 38 
months in Arm A, and 23 months in Arm B (corresponding to a hazard ratio of approximately 0.6), 
129 events are required to achieve 80% power for the log-rank test at a two-sided significance 
level of 5%.  
In order to see the required events, approximately 300 patients in Maintenance II will be followed 
from randomization (Maintenance II treatment until PD and post-treatment follow-up) for at least 
15 months.  Therefore a total of 700 patients will be enrolled to randomize 330 patients (allowing 
for a 10% drop-out) after the 2.5-year Induction plus Maintenance I treatment period. 
Interim analysis 
There will be no interim analysis for efficacy.
 
 
 
An interim analysis of safety will be performed after approximately 200 patients have been 
enrolled in the study. 
Independent Data Monitoring Committee (iDMC) reports 
An iDMC charter is implemented and describes the frequency of data review, as well as which 
data will be considered. Data outputs prepared for the IDMC may be published.

 
Rituximab - F. Hoffmann-La Roche Ltd 
Protocol MO25455 v4.0 
21 of 128 
 
GLOSSARY OF ABBREVIATIONS 
AE 
Adverse Event 
ALT (SGPT) 
Alanine aminotransferase 
ANC 
Absolute neutrophil count 
ARR 
Administration-related reaction 
AST (SGOT) 
Aspartate aminotransferase 
BSA 
Body Surface Area 
CHOP 
Cyclophosphamide, doxorubicin, vincristine, prednisone/ 
prednisolone (chemotherapy regimen) 
CHVP 
Cyclophosphamide, doxorubicin, etoposide, prednisone/ 
prednisolone (chemotherapy regimen) 
CI 
Confidence interval 
CLL 
Chronic Lymphocytic Leukaemia 
Cmax 
Maximum plasma concentration 
CNS 
Central Nervous System 
Ctrough 
Minimal 
plasma 
concentration 
prior 
to 
next 
drug 
administration 
CR 
Complete Response 
CrCl 
Creatinine clearance 
CRu 
Complete Response, Unconfirmed 
CT 
Computer Tomography or Cancer Therapy 
CTC-AE 
Common Terminology Criteria for Adverse Events 
 
 
CVP 
Cyclophosphamide, vincristine, prednisone/prednisolone 
(chemotherapy regimen) 
DLBCL 
Diffuse Large B-Cell Lymphoma 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic Case Report Form 
EFS 
Event-free survival 
EORTC 
European Organisation for Research and Treatment of 
Cancer 
EOS 
End of Study 
ET 
Expectations of Therapy  
EU 
European Union 
FCM 
Fludarabine, cyclophosphamide, mitoxantrone 
(chemotherapy regimen) 

 
Rituximab - F. Hoffmann-La Roche Ltd 
Protocol MO25455 v4.0 
22 of 128 
FL 
Follicular Lymphoma 
FLIPI 
Follicular Lymphoma International Prognostic Index 
FSE 
Feelings about Side Effects 
GCP 
Good Clinical Practice 
G-CSF 
Granulocyte colony-stimulating factor 
GELA 
Groupe d’etude des lymphomes de l’adulte  
GIFOX 
Gemcitabine, ifosfamide, oxaliplatin (chemotherapy 
regimen) 
GLSG 
German Low Grade Lymphoma Study Group 
GMP 
Good Manufacturing Practices 
HACA 
Human anti-chimeric antibody 
HBV 
Hepatitis B Virus 
HCV 
Hepatitis C Virus 
HIV 
Human Immuno-deficiency Virus 
hpf 
High Power Field (microscopy) 
HR 
Hazard Ratio 
ICH 
International Conference on Harmonization 
ICMJE 
International Committee of Medical Journal Editors 
iDMC 
Independent Data Monitoring Committee 
IEC 
Independent Ethics Committee 
IFN 
Interferon-α 
Ig 
Immunoglobulin 
IgA, IgG, IgM 
Immunoglobulin of type A, G, or M 
IQR 
Interquartile range 
IRR 
Infusion/injection-Related Reaction 
ITT 
Intent to Treat 
IV 
Intravenous 
IVRS/IWRS 
Interactive Voice/Web Response System 
LDH 
Lactate Dehydrogenase 
LPL 
Lymphoplasmacytic Lymphoma 
MCL 
Mantle Cell Lymphoma 
MCP 
Mitoxantrone, chlorambucil, prednisone/prednisolone 
(chemotherapy regimen) 
MCU 
Medical Care Utilization 
MRI 
Magnetic Resonance Image 

 
Rituximab - F. Hoffmann-La Roche Ltd 
Protocol MO25455 v4.0 
23 of 128 
MZL 
Marginal Zone Lymphoma 
NCI 
National Cancer Institute 
NCI-CTCAE 
National Cancer Institute - Common Terminology Criteria 
for Adverse Events 
NHL 
Non-Hodgkin’s lymphoma 
NYHA 
New York Heart Association 
OBS 
Observation 
ORR 
Overall response rate 
OSrand 
Overall survival, from randomization 
OSregist 
Overall survival, from first Induction dose 
PD 
Progressive disease  
PET 
Positron Emission Tomography 
PFS 
Progression-free survival 
PFSrand 
Progression-free survival, from randomization 
PFSregist 
Progression-free survival, from first Induction dose 
PLL 
Prolymphocytic Leukaemia 
PML 
Progressive Multifocal Leukoencephalopathy 
PP 
Per Protocol 
PR 
Partial Response 
 
 
RM 
Rituximab Maintenance 
rHuPH20 
Recombinant Human Hyaluronidase 
R-CHOP 
Rituximab plus CHOP chemotherapy 
R-CVP 
Rituximab plus CVP chemotherapy 
R-CHVP 
Rituximab plus CHVP chemotherapy 
R-FCM 
Rituximab plus FCM chemotherapy 
R-GIFOX 
Rituximab plus GIFOX chemotherapy 
R-MCP 
Rituximab plus MCP chemotherapy 
SAE 
Serious Adverse Event 
SAKK 
Swiss Group for Clinical Cancer Research 
SC 
Subcutaneous 
SD 
Stable Disease 
SEER 
Surveillance, Epidemiology, and End Results 
SLE 
Systemic Lupus Erythematosus 
SLL 
Small Lymphocytic Lymphoma 

 
Rituximab - F. Hoffmann-La Roche Ltd 
Protocol MO25455 v4.0 
24 of 128 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
SWT 
Satisfaction with Therapy  
TLS 
Tumour Lysis Syndrome 
TNF 
Tumour Necrosis Factor 
TNLT 
Time to Next Lymphoma Treatment 
TTF 
Time to Treatment Failure 
TTP 
Time to Tumour Progression 
ULN 
Upper Limit of Normal 
Vs. 
Versus 
WHO 
World Health Organization 
WM 
Waldenström’s Macroglobulinemia 

 
Rituximab - F. Hoffmann-La Roche Ltd 
Protocol MO25455 v4.0 
25 of 128 
PART I: STUDY DESIGN AND CONDUCT 
 
1. 
BACKGROUND AND RATIONALE 
1.1 
DISEASE BACKGROUND 
Non-Hodgkin’s lymphoma (NHL), a group of malignancies arising from lymphoid tissue, 
is one of the leading causes of cancer death in the United States and Europe. As with 
other lymphoid neoplasms, its etiology remains largely unknown, although risk factors 
include certain infections as well as treatments and diseases that cause severe 
immunosuppression. Non-Hodgkin’s lymphoma has been classified into two types: 
aggressive (i.e. fast growing) and indolent (i.e. slow growing).4 Indolent NHL comprises 
a group of incurable, generally slow-growing lymphomas that are highly responsive to 
initial therapy and are characterized by a relapsing and progressive course.  
Follicular lymphoma (FL) is the most common of the indolent NHLs,5 accounting for 20-
25% of all lymphomas. The disease generally manifests with hypertrophy of peripheral 
and deep lymph nodes and splenomegaly, together with bone marrow infiltration. 
Follicular lymphoma is characterized by initial responsiveness to therapy followed by 
repeated relapses and sometimes with histological progression into high-grade NHL.6 In 
the World Health Organization (WHO) classification the histology is further classified into 
Grade 1, 2 or 3 FL, depending on the percentage of large cells seen on high power field 
microscopy (see Appendix 3).7 Grade 3 FL is further subdivided into 3a and 3b, where 
3b may represent a distinct biological entity more similar to diffuse large B-cell 
lymphoma (DLBCL).7 Biologically, FL has been associated with the translocation of 
chromosomes 14 and 18 [t(14;18)], which results in constitutive activation of the bcl-2 
oncogene and the subsequent inhibition of apoptosis of lymphoid cancer cells.8 
Non-follicular indolent subtypes of NHL include chronic lymphocytic leukaemia (CLL), 
small lymphocytic lymphoma (SLL) and marginal zone lymphomas (MZL). They 
represent a diverse group of disorders with different presenting features, behaviour 
patterns and treatment outcomes. Although some subtypes have a prolonged indolent 
course with a good prognosis (e.g. SLL) others (e.g. nodal and splenic MZLs) can 
rapidly evolve into more aggressive subtypes. Universally accepted therapeutic 
guidelines for the treatment of non-follicular indolent NHL do not exist and treatment in 
asymptomatic patients may be deferred until the disease progresses and the patient 
becomes symptomatic.9  
Given that FL is currently incurable with standard treatment options, there is a need to 
improve the clinical outcomes. The use of known active agents such as rituximab may 
be optimised to provide as much clinical benefit as possible. Recently, considerable 
evidence from several randomized phase III studies has reported clinical benefit from 
rituximab maintenance therapy (see Section 1.2.3). This study looks to further 
characterize the efficacy of rituximab maintenance treatment in terms of progression-free 
survival (PFS) and other relevant clinical outcomes and to expand the safety database 
for rituximab maintenance therapy following induction therapy.  
1.1.1 
Epidemiology 
NHLs account for almost 5% of all cancers occurring in the United States, with an 
estimated 56 200 new diagnoses in the year 2001.10 The incidence and mortality rates 
for NHL were reported to have risen steadily in the United States (estimated 50% 

 
Rituximab - F. Hoffmann-La Roche Ltd 
Protocol MO25455 v4.0 
26 of 128 
increase in age-adjusted incidence of NHL from 1970 to 1990) and in other populations 
over several decades. Although further reports suggested that the steep rise in incidence 
may have slowed in the late 1990s, this group of closely related diseases is still an 
important contributor to the overall cancer burden.11,12,13,14  
During 2001 to 2003, a total of 71,762 lymphoid neoplasms were diagnosed among 
residents of the 17 registries of the Surveillance, Epidemiology, and End Results (SEER) 
Program of the National Cancer Institute (NCI). Of these, 87.8% were NHL, 8.5% were 
Hodgkin’s lymphoma, and 3.7% were composite NHL/Hodgkin’s lymphoma or 
unspecified. Among the 62,982 NHLs, B-cell NHL accounted for 90.4%, T-cell NHL 
accounted for 6.8%, and NHL of unknown cell lineage accounted for 2.8%. The major 
NHL subtypes of mature B-cell origin consisted of DLBCL (23.1%), followed by 
CLL/SLL/Prolymphocytic leukaemia (PLL)/Mantle Cell Lymphoma (MCL) (19.4%), 
lymphoplasmacytic lymphoma (LPL)/Waldenström’s macroglobulinemia (2.1%), FL 
(12.0%), MZL (5.7%), Burkitt lymphoma/leukaemia (1.4%), hairy cell leukaemia (1.0%), 
and plasma-cell neoplasms (18.3%), whereas the major NHL subtypes of mature T-cell 
origin consisted of peripheral T-cell lymphoma (3.8%), mycosis fungoides/Sézary 
syndrome (1.5%), and several other rare subtypes (0.4%).15 
FL is the most common form of indolent lymphoma, accounting for about 70% of indolent 
lymphomas and 20% to 25% of all cases of NHL.16 Its incidence is rapidly increasing in 
Western countries and has nearly doubled within the past three decades. Like many 
lymphomas, it is increasing in incidence with over 24,000 new cases diagnosed each 
year. It remains incurable with standard treatment options. 
1.1.2 
Natural History 
Prognosis and selected therapy for indolent lymphoma, which makes up 70% of NHLs, 
are closely related to the extent of the disease at initial diagnosis. Less than 15% – 20% 
of patients with indolent lymphoma are diagnosed at an early stage of the disease (Ann 
Arbor stage I or II), and half of these patients experience long-term disease-free survival 
after radiotherapy.17 However, the vast majority of patients with indolent lymphoma is 
diagnosed with advanced-stage disease (i.e., Ann Arbor stage III or IV) and cannot be 
cured with conventional therapy. 

 
Rituximab - F. Hoffmann-La Roche Ltd 
Protocol MO25455 v4.0 
27 of 128 
The clinical course of indolent NHL is characterized by cycles of relapses and 
remissions, and there are few long-term survivors. Various treatment regimens have 
been shown to produce a high rate of initial response followed inevitably by relapse. 
Subsequent remissions can still be obtained with available salvage regimens but these 
occur at a progressively lower rate and usually with a shorter duration.18,19  Prognoses of 
patients with relapsed disease is poor with a median survival of only 6-10 years.6,20,21 
Histological transformation to more aggressive NHL with poor prognosis has been 
documented to occur in 20-80% of patients over time. In addition, the likelihood of 
progression to resistant lymphoma or occurrence of secondary malignancies such as 
myelodysplastic syndrome or acute myeloid leukaemia increases with time and in 
relation to the number, choice and intensity of previous treatments. 
Several datasets have demonstrated that the overall survival (OS) of patients with 
indolent FL has improved over the past 3 decades, probably because of sequential 
application of different chemotherapy regimens, the use of biologic agents, and 
improved supportive care.6, 22 , 23  A recent report indicates considerable increase in 
relative survival in patients with NHL, from 51% in 1992-1994 to 63% in 2004-2006, 
along with a 10-year survival of 54%.24 
1.1.2.1 
Current management 
The scale of therapeutic options for FL is wide and ranges from a watch-and-wait policy 
to aggressive alternatives, such as hematopoietic stem cell transplant. There are several 
reports of significant improvements in the clinical course of the disease over the past 
decades.23,25 However, the most striking outcome improvement has been achieved with 
the introduction of anti-CD20 monoclonal antibodies in combination with standard 
chemotherapy as demonstrated in several phase III studies 26 , 27 , 28 , 29 , 30 and registry 
data. 31 The combination of rituximab with chemotherapy as first-line treatment has 
become the standard induction therapy. 
Initial 
treatment 
of 
NHL 
with 
chemotherapy 
such 
as 
alkylating 
agents, 
prednisone/prednisolone, anthracyclines, vinca alkaloids, purine analogues, combined 
with interferon or monoclonal antibodies such as rituximab is associated with a high rate 
of clinical response, although typically followed by relapse. Patients with aggressive B-
cell lymphoma are potentially curable when treated with multiagent chemotherapy such 
as cyclophosphamide, doxorubicin, vincristine, and prednisone/prednisolone (CHOP).32 
In 30-70% of the FL cases, the disease eventually transforms to aggressive lymphoma, 
responding only to combination chemotherapies usually employed for aggressive 
disease, such as anthracyclines or cytosine arabinoside-containing regimens or high-
dose chemotherapy with autologous stem cell transplantation.33 The standard of care for 
patients with aggressive lymphoma has changed recently with the implementation of 
therapy with the chimeric anti-CD20 monoclonal antibody rituximab. 34  Combination 
treatment with rituximab and CHOP (R-CHOP) or similar regimens has resulted in 
superior treatment outcomes compared with multiagent chemotherapy alone, making 
combined immunochemotherapy with rituximab the new standard of care for this group 
of 
patients.
35
 The 
combination 
of 
cyclophosphamide, 
vincristine, 
and 
prednisone/prednisolone (CVP) is one of several standard treatment options for 
advanced FL. Similar to other chemotherapeutic regimens; this combination induces 
response rates of 60%-80%, with median response duration of under 2 years. 26 
A recently published large, prospective, longitudinal, observational study to identify 
current patterns of care of FL in the United States (conducted between 2004 and 2007) 
found that amongst the 2728 patients enrolled, the most common initial therapeutic 

 
Rituximab - F. Hoffmann-La Roche Ltd 
Protocol MO25455 v4.0 
28 of 128 
strategy was chemotherapy plus rituximab (51.9%), followed by observation (17.7%), 
rituximab monotherapy (13.9%), clinical trial-related interventions (6.1%), radiation 
therapy (5.6%) and chemotherapy alone (3.2%). Chemotherapy plus rituximab regimens 
were R-CHOP (55.0%), rituximab plus CVP (R-CVP, 23.1%), rituximab plus fludarabine 
based-chemotherapy (15.5%), and other (6.4%). The choice to initiate therapy rather 
than observation only was associated with age, Follicular Lymphoma International 
Prognostic Index (FLIPI), stage, and grade (p < 0.01).36 
Toxicity of rituximab is mild and occurs most frequently during the first infusion. 
Importantly, it does not produce treatment-related cytopenias or severe cumulative 
toxicity. 37 Compared to single-agent cytotoxic therapy, single-agent rituximab was better 
tolerated and had similar efficacy. 38  Several Phase II and Phase III multicentre 
randomized trials demonstrated that the addition of rituximab to various chemotherapy 
regimens in patients with follicular lymphoma significantly improves outcomes when 
compared with standard chemotherapy regimens, without adding significant toxicity.37 In 
clinical trials with rituximab monotherapy given for 4 weeks, haematological 
abnormalities occurred in a minority of patients and were usually mild and reversible. 
Severe (grade 3/4) neutropenia was reported in 4.2%, anaemia in 1.1% and 
thrombocytopenia in 1.7% of the patients. During rituximab maintenance treatment for 
up to 2 years, grade 3/4 leucopoenia (5% vs. 2%, grade 3/4) and neutropenia (10% 
vs.4%, grade 3/4) were reported at a higher incidence when compared to observation. In 
studies with rituximab in combination with chemotherapy, grade 3/4 leucopoenia, 
neutropenia, and pancytopenia were reported higher frequencies when compared to 
chemotherapy alone. However, the higher incidence of neutropenia in patients treated 
with rituximab and chemotherapy was not associated with a higher incidence of 
infections and infestations compared to patients treated with chemotherapy alone and 
the neutropenia was not prolonged in the rituximab group. There were no differences 
reported for the incidence of thrombocytopenia or anaemia. 39 
Rituximab, an anti-CD20 antibody, has had a large impact on the treatment of indolent 
NHL. Its effectiveness as a single agent and in conjunction with known chemotherapy 
regimens has made it a standard of care in the treatment of NHL. Analysis of data 
obtained from NHL clinical trials, as well as data from the NCI, indicate that the OS of 
patients with indolent NHL has improved with the use of rituximab and that given its 
effectiveness and tolerability, rituximab is currently being investigated as a maintenance 
agent with encouraging results.37 
1.2 
STUDY DRUG BACKGROUND 
Rituximab is a chimeric murine/human monoclonal antibody that specific for the B-cell 
antigen CD20.40 In preclinical studies, rituximab was shown to induce both complement-
mediated and antibody-dependent cell mediated lyses of CD20+ cells.41 Rituximab also 
induces apoptosis in vitro of human B-cell lines and sensitizes drug-resistant human B-
cell lymphoma cell lines to the cytotoxic effects of some chemotherapeutic agents.42,43 
The efficacy and safety of rituximab is well established. It had demonstrated clinical 
benefits in combination with chemotherapy and as single agent in the first-line26,30,30,44,45, 
and relapsed setting for induction of remission,38,46 and more recently, as maintenance 
therapy for patients after effective induction.3 Since its preclinical development, many 
studies have been performed to optimize the dose and schedule of rituximab. Rituximab 
is usually given IV at 375 mg/m2, a dose associated with clinical activity and little toxicity. 
Moreover, given its low toxicity and long half-life, there is accumulating evidence 
supporting its use as maintenance therapy.47 

 
Rituximab - F. Hoffmann-La Roche Ltd 
Protocol MO25455 v4.0 
29 of 128 
The main results of clinical experience with rituximab in indolent NHL treatment for 
induction are briefly summarized in Sections 1.2.1 and 1.2.2. The main results for 
rituximab maintenance therapy are summarized in Section 1.2.3 below. Section 1.2.4 
summarizes the safety of rituximab in indolent NHL. 
More detailed information concerning rituximab pre-clinical, dose finding, clinical efficacy 
and safety data can be found in the current version of the Investigator Brochure. 
1.2.1 
Clinical Studies with Single-Agent Rituximab Induction 
Clinical trials evaluating single-agent rituximab as induction treatment in indolent NHL 
have been conducted in patients with first-line disease and relapsed/refractory disease.  
Table 1 MAIN EFFICACY RESULTS FOR RANDOMIZED TRIALS EVALUATING 
SINGLE-AGENT RITUXIMAB INDUCTION THERAPY  
Study / 
Reference 
Population 
Interventions 
PFS 
OS 
Other 
Endpoints 
AEs 
Phase II 
Study 102-05,  
McLaughlin 
et al 199838 
N=166 
Relapsed/ 
refractory low-
grade B-cell 
NHL 
Induction:  
Rituximab 375 
mg/m2, 4 weekly 
infusions  
Median PFS 
(responders, at 
median 11.8 
mo): 13.0 mo 
- 
ORR: 48% 
Grade 3/4: 
12% 
 
Most common 
Grade 1&2: 
Fever, chills 
Phase II 
Study  
Colombat et 
al 200144 
N=50 
1st line CD20+ 
FL 
Induction:  
Rituximab 375 
mg/m2, 4 weekly 
infusions  
 
 
Progression-free 
at 1 year: 31/49 
(63%) 
 
PD at 1 Year:  
15 (1 CR, 9 PR, 
5 SD) 
- 
Day 50 or 78 
(Best response): 
ORR*: 
36/49 
(73%) 
CR: 10, CRu: 3, 
PR: 23, SD: 10, 
PD: 3 
Grade 3/4: 
2 (4%) 
 
Most common 
Grade 1&2: 
headache, fever, 
pain, laryngitis 
Phase II 
Study 102-06, 
Piro et al 
199946 
N=37  
(35 evaluable) 
Relapsed/ 
refractory low-
grade B-cell 
NHL 
Induction + Re-
treatment:  
Rituximab 375 
mg/m2, 8 weekly 
infusions   
Median PFS: 
NR after median 
19.4 mo for 
responders and 
after median 7.7 
mo for the total 
population. 
- 
ORR: 60% 
CR: 5 (14%), PR 
16 (46%) 
 
Grade 3/4: 
10 (27%); 1 Grade 
4 neutropenia 
 
Most common 
Grade 1/2 (IRRs):  
fever (38%), 
chills (35%), 
asthenia (16%),  
nausea (11%) 
headache (8%) 
AE: adverse event; CR: Complete Response; CRu: Complete Response, unconfirmed; DFS: Disease-free Survival; FL: Follicular 
lymphoma; IRR: Infusion-related reaction (within 24 hrs of the infusion); NHL: Non-Hodgkin Lymphoma; NR: not reached; ORR: Overall 
response Rate; OS: Overall Survival; PFS: Progression-free Survival; R: rituximab 
* Primary endpoint in the study 
 
The large multicentre trial by McLaughlin et al (n = 166) served as the basis for approval 
of rituximab in the United States and Europe.38 In the Phase II clinical study by Colombat 
et al, a significant correlation (p < 0.0001) was found between molecular and clinical 
responses: 10 of the 17 patients, who were PCR negative in peripheral blood, were in 
CR/Cru, whereas none of the 13 patients PCR positive in peripheral blood had CR. In 
addition, the study showed that early molecular responses can be sustained for up to 12 
months and that this response is highly correlated with progression-free survival (PFS).44  
In the initial dose finding studies and efficacy trials, the adverse events (AEs) associated 
with single agent rituximab included neutropenia, thrombocytopenia, and asthenia. 

 
Rituximab - F. Hoffmann-La Roche Ltd 
Protocol MO25455 v4.0 
30 of 128 
Some patients with pre-existing cardiac conditions, including arrhythmia and angina, had 
recurrences of these cardiac events during rituximab infusion. 
1.2.2 
Rituximab in Combination with Chemotherapy 
Several Phase II and Phase III multicentre randomized trials have demonstrated that the 
addition of rituximab to first-line therapy for FL significantly improves clinical outcomes 
when compared with standard chemotherapy regimens of varying intensities, without 
adding significant toxicity. The combination chemotherapy regimens used in these trials 
included cyclophosphamide, doxorubicin, vincristine, prednisone/prednisolone (CHOP), 
cyclophosphamide, 
vincristine, 
prednisone/prednisolone 
(CVP), 
mitoxantrone, 
chlorambucil and prednisone/prednisolone (MCP), cyclophosphamide, doxorubicin, 
etoposide, prednisone/prednisolone, interferon-α (CHVP/IFN) and bendamustine; see 
details in Table 2. 
Table 2 MAIN EFFICACY RESULTS FOR RANDOMIZED TRIALS EVALUATING 
RITUXIMAB IN COMBINATION WITH CHEMOTHERAPY  
Study / 
Reference 
Population 
Interventions 
PFS/TTP/ 
EFS/DFS 
OS 
Other 
Endpoints 
AEs 
Phase II Study 
by Czuczman 
et al 199948 
and 200449 
 
OL Single-arm 
N=40 (38 
treated) 
Low-grade or 
follicular B-
cell NHL 
6 cycles of  
R-CHOP 
At 9 yr Follow-up: 
Median TTP:  
82.3 mo 
Median DR:  
83.5 mo 
Remission rate (at 
median 29 mo): 
74% 
- 
ORR: 100% 
CR/CRu: 33 
(87%)  
PR 5 (13%) 
(2 untreated) 
 
Most frequent AEs: 
R: fever, chills, 
pruritus, headache 
(Grade 1&2 IRRs) 
CHOP: alopecia, 
neutropenia, fever  
GLSG Study, 
Hiddemann et 
al 200528,50 
OL RCT 
N=630 (428 
evaluable) 
1st line FL, 
immunocyto-
mas, MCL 
Induction: 
6-8 cycles Q3W: 
R-CHOP, n=223 
CHOP, n=205 
 
 
At median 28 mo: 
Treatment failure: 
R-CHOP: 28 
CHOP: 61 
TTF: 
R-CHOP: NR 
CHOP: 2.6 years 
P<0.001 
DR: P=0.001 
3-yr OS: 
R-CHOP: 
95% 
CHOP: 90% 
P=0.016 
 
ORR: 
R-CHOP: 96% 
CHOP: 90% 
P=0.011 
 
Grade 3/4 
granulocytopenia: 
R-CHOP: 63% 
CHOP: 53% 
P=0.01 
Infections: 
R-CHOP: 5% 
CHOP:7% 
IRRs (R): 7% 
Phase II Study 
by Hainsworth 
et al 200545 
OL Single-arm 
N=86 
1st line 
follicular NHL, 
grade 1&2 
Rituximab 4 
weekly doses, 
followed by  
3 cycles of R-
CHOP or R-CVP 
3-year PFS: 
71% 
4-year PFS: 
62% 
3-year 
survival: 
95% 
ORR: 93% 
CR: 55% 
Grade 3/4 
leukopenia: 
53%, neutropenia 
or fever: 7% 
 
Phase III Study 
M39021  
Marcus et al 
200526 & 200827 
 
OL RCT 
N=321 
1st line 
advanced FL 
8 cycles: 
R-CVP, n=162 
CVP, n=159 
 
 
At median 53 mo: 
Median TTF*:  
R-CVP: 27 mo 
CVP: 7 mo 
P<0.0001 
Median TTP:  
R-CVP: 34 mo 
CVP: 15 mo 
P<0.0001 
Median DFS:  
R-CVP: NR 
CVP: 21 mo 
P=0.0001 
Median DR: 
R-CVP: 38 mo 
CVP: 14 mo 
P<0.0001 
At 48 mo: 
R-CVP: 83% 
CVP: 77% 
P=0.03 
ORR: 
R-CVP: 81% 
CVP: 57% 
P<0.0001 
CR/CRu: 
R-CVP: 41% 
CVP: 10% 
 
Grade 3/4 
neutropenia: 
R-CVP: 24% 
CVP: 14% 
 
Any AEs: 
R-CVP: 97% 
CVP: 95% 
 
IRRs: 
R-CVP: 71% 
CVP: 51% 
Gr 3/4: 9% 
 

 
Rituximab - F. Hoffmann-La Roche Ltd 
Protocol MO25455 v4.0 
31 of 128 
Study / 
Reference 
Population 
Interventions 
PFS/TTP/ 
EFS/DFS 
OS 
Other 
Endpoints 
AEs 
EGSG Study, 
Herold et al 
200351 and 
200729 
 
OL RCT 
N=358 (201 in 
primary 
analysis set) 
Stage III-IV 
indolent FL 
(56%) or MCL 
8 cycles Q4W:  
R-MCP, n=181 
MCP, n=177 
 
Responders: 
maintenance with 
IFN until relapse 
At median 47 mo: 
Median EFS:  
R-MCP: NR (34 
treatment failures) 
MCP: 26 mo (57 
treatment failures) 
P<0.0001 
Median PFS:  
R-MCP: NR (30 
events) 
MCP: 28.8 mo (50 
events) 
P<0.0001 
Median DR:  
R-MCP: NR  
MCP: 35 mo  
P<0.0001 
Median TNLT:  
R-MCP: NR  
MCP: 29.4 mo  
P=0.0002 
4-yr OS: 
R-MCP: 87% 
MCP: 74% 
P=0.01 
Median 
OS 
NR in either 
group. 
 
ORR*: 
R-MCP: 92% 
MCP: 75% 
P=0.0009 
CR: 
R-MCP: 50% 
MCP: 25% 
P=0.004 
 
Grade 3/4 
leukopenia: 
R-MCP: 72% 
MCP: 58% 
 
Grade 3/4 
infections: 
R-MCP: 7% 
MCP: 8% 
 
Any AEs: 
R-MCP: 99% 
MCP: 86% 
 
 
GELA-
GOELAMS 
Study FL2000, 
Salles et al 
200830 
 
OL RCT 
N=358 
1st line FL with 
high tumour 
burden 
R-CHVP, 6 
courses Q4W, + 
IFN for 18 mo, 
n=175 
or 
CHVP+IFN, 6 
courses Q4W + 6 
courses Q8W, 
n=183 
Over 18 mo  
At median 5 yrs: 
Median EFS*:  
R-CHVP+IFN:  
53% 
CHVP+IFN: 37% 
P=0.001 
Median DR (4-yr):  
R-CHVP+IFN:  
64% 
CHVP+IFN: 44% 
P=0.012 
 
 
5-yr OS: 
R-CHVP+IFN: 
84% 
CHVP+IFN: 
79% 
P=0.16 
ORR at 6 mo: 
R-CHVP+IFN: 
94% 
CHVP+IFN: 85% 
CR/Cru, 6 mo: 
R-CHVP+IFN: 
63% 
CHVP+IFN: 34% 
Global P<0.001 
 
ORR at 18 mo: 
R-CHVP+IFN: 
81% 
CHVP+IFN: 72% 
CR/Cru,18 mo: 
R-CHVP+IFN: 
67% 
CHVP+IFN: 50% 
Global P=0.035 
6-mo Induction: 
Grade 3/4 
leukopenia: 
R- CHVP+IFN: 
59% 
CHVP+IFN: 62% 
 
Grade 3/4 
infections: 
R- CHVP+IFN: 2% 
CHVP+IFN: 0% 
 
Phase II Study 
by Rummel et 
al 200552 
N=63 
Relapsed/ 
refractory low-
grade NHL or 
MCL 
R+B, up to 4 
cycles Q4W  
Median PFS: 24 
mo (range 5 to 44+) 
 
Median OS: 
NR  
All patients: 
ORR*: 90% 
CR: 60% 
MCL patients: 
ORR: 75% 
CR: 50% 
Grade 3/4 
leukocytopenia: 
16% 
Grade 3/4 
thrombo-
cytopenia: 3% 
Phase II Study 
by Robinson et 
al 200853 
N=67 (66 
treated) 
Relapsed, 
indolent B-cell 
NHL or MCL  
R+B, 4 - 6 cycles 
Q4W  
Median PFS: 23 
mo (95%CI 20-26) 
Median DR: 21 mo 
(95%CI 18-24) 
 
All patients: 
ORR*: 92% 
CR: 41% 
CRu: 14% 
PR: 38% 
Grade 3/4 
neutropenia: 36% 
Grade 3/4 
thrombo-
cytopenia: 9% 
AE: 
adverse 
event; 
B: 
bendamustine; 
CR: 
Complete 
Response; 
CRu: 
Complete 
Response, 
unconfirmed; 
CHOP: 
cyclophosphamide+doxorubicin+vincristine+prednisone/prednisolone; 
CVP: 
cyclophosphamide+vincristine+ 
prednisone/prednisolone; 
DFS: 
Disease-free Survival; EGSG: East German Study Group; FL: Follicular lymphoma; GLSG: German Low-Grade Lymphoma Study Group; 
GOELAMS: Groupe Ouest Est d’Etude des Leucemies et autres Maladies du Sang; IRR: Infusion-related reaction (within 24 hrs of the infusion); 
MCL: Mantle Cell Lymphoma; MCP: mitoxantrone, chlorambucil and prednisolone/prednisolone; NHL: Non-Hodgkin Lymphoma; NR: not reached; 
OL: open label; ORR: Overall response Rate; OS: Overall Survival; PFS: Progression-free Survival; R: rituximab; RCT: randomized controlled trial; 
TNLT: Time to next lymphoma treatment; TTF: Time to Treatment Failure; TTP: Time to Progression 
* Primary endpoint in the study 
Note: rituximab was administered at the 375 mg/m2 dose in all trials 

 
Rituximab - F. Hoffmann-La Roche Ltd 
Protocol MO25455 v4.0 
32 of 128 
 
1.2.2.1 
Rituximab in combination with other chemotherapies and/or 
other indications  
Data for use of rituximab with other chemotherapies and/or in other indications can be 
found in the current version of the Investigator Brochure. 
1.2.3 
Rituximab as Maintenance Therapy 
Despite the ability of immunochemotherapy to induce high response rates during 
induction in follicular NHL, the pattern of continuous relapse in responding patients 
remains problematic. Rituximab is a potentially attractive candidate for maintenance 
therapy given its lack of cumulative myelotoxicity and evidence that patients previously 
responding to rituximab may respond to a second course of therapy.  
Several randomized studies investigated the benefit of rituximab maintenance therapy 
compared to observation alone. The efficacy results are summarized in Table 3 below. 

 
Rituximab - F. Hoffmann-La Roche Ltd 
Protocol MO25455 v4.0 
33 of 128 
Table 3 MAIN EFFICACY RESULTS FOR RANDOMIZED TRIALS COMPARING 
RITUXIMAB MAINTENANCE THERAPY TO OBSERVATION 
Study / 
Reference 
Population 
Interventions 
PFS 
OS 
Other Endpoints 
Phase II 
Study by 
Hainsworth et 
al 200554 
N=90 
Previously treated 
FL, SLL 
Induction:  
Rituximab 
 
RM: Weekly 
doses for 4 wks, 
repeated Q6M for 
2 yrs 
Median PFS: 
RM: 31.3. mo 
OBS: 7.4 mo 
P=0.007 
- 
ORR: 
RM: 73% 
OBS: 47% 
SAKK 35/98 
Ghielmini et 
al. 200455 
N=151 
(73 RM, 78 OBS) 
1st line & Relapsed/ 
Refractory  
CD20+ FL  
(Grade I-III) 
Induction:  
Rituximab 
 
RM: 
4 Single infusions, 
given Q2M  
Median 
EFS 
at 35 mo: 
RM: 23.2 mo 
OBS: 11.8 mo 
HR 0.61 
P=0.02 
Median 
EFS 
at 9.5 yrs: 
RM: 24 mo 
OBS: 13 mo 
P<0.001 
- 
% event-free at 8 yrs: 
RM: 27%  
   (45% if 1st-line) 
OBS: 5% 
Best Response: 
RM: 38% 
OBS: 31% 
ORR at 24 mo: 
RM: 45% 
OBS: 28% 
ECOG 1496 
Hochster et al 
200456 
Hochster et al 
200757 
N=311 
(153 RM, 158 OBS) 
1st line  
FL (n=282), SLL 
Induction:  
CVP 
 
RM: Weekly 
doses for 4 wks, 
repeated Q6M for 
2 yrs 
3-yr PFS (all): 
RM: 68% 
OBS: 33% 
HR 0.4 
P=4.4x10-10 
 
3-yr PFS (FL): 
RM: 64% 
OBS: 33% 
HR 0.4 
P=9.2x10-8 
OS at 3 yrs: 
RM: 92% 
OBS: 86% 
HR 0.6  
(0.4, 1.1) 
P=0.05 
Improvement in Best 
Response: 
RM: 22% 
  (CR: 16% → 37%) 
OBS: 7% 
  (CR: 16% → 22%) 
P=0.00006 
 
GLSG   
(R-)FCM 
Forstpointner 
et al 200658 
N=195 
162 evaluable 
(80 RM, 82 OBS) 
Relapsed/ 
Refractory  
FL (n=105), MCL 
(n=57), Other 
Induction:  
R-FCM, FCM 
 
RM: Weekly 
doses for 4 wks, 
repeated at 3 mo 
and 9 mo 
- 
OS at 3 yrs: 
RM: 77% 
OBS: 57% 
P=0.1 
Median survival 
not reached. 
Response 
duration 
after med 26 mo): 
RM: 
median 
not 
reached  
OBS: 17 mo 
P=0.0001 
Induction phase: 
ORR: 
R-FCM: 79-86% 
FCM: 58% 
EORTC 20981 
Intergroup 
study 
van Oers et al 
20063 
 
N=334 
(167 RM, 167 OBS) 
Relapsed/ 
Refractory FL 
Induction:  
R-CHOP, CHOP 
 
RM: Single 
infusions, given   
Q3M for 2 yrs 
RM: 51.5 mo 
OBS: 14.9 mo 
HR 0.40 
P<0.0 01 
OS at 3 yrs: 
RM: 85% 
OBS: 77% 
HR 0.52 
P=0.011 
 
OS at 5 yrs: 
RM: 74% 
OBS: 64% 
P=0.07 
Induction phase: 
ORR: 
R-CHOP: 85.1% 
CHOP: 72.3% 
P<0.001 
Median PFS from 1st 
randomization: 
R-CHOP: 33.1 mo 
CHOP: 20.2 mo 
P<0.001 
OS at 3 yrs: 
R-CHOP: 82.5% 
CHOP: 71.9% 
P=0.096 

 
Rituximab - F. Hoffmann-La Roche Ltd 
Protocol MO25455 v4.0 
34 of 128 
Study / 
Reference 
Population 
Interventions 
PFS 
OS 
Other Endpoints 
PRIMA 
Salles et al 
201159 
N=1018 (ITT) 
(505 RM, 513 OBS) 
1st line  
FL (Grade I-IIIa; 
n=994) 
 
Induction:  
R-CHOP, R-CVP, 
or R-FCM 
 
RM: 12 infusions, 
given   Q8W for 2 
yrs 
3-yr PFS: 
RM: 74.9% 
OBS: 57.6% 
HR 0.55 
(0.44, 0.68) 
P<0.0001 
Deaths, 3 yrs: 
RM: 26/505 
OBS: 30/513 
HR 0.87  
(0.51, 1.47) 
CR/CRu at 2 yrs: 
RM: 71.5% 
OBS: 52% 
P=0.0001 
NHL 2-2003 
StiL Group 
Rummel et al. 
201060 
N=219 random.  
(208 analysed, 109 
R-B, 99 R-F) 
RM: N=40  
(23 R-B, 17 R-F) 
 
Relapsed FL, 
indolent or MCL 
Induction:  
R+bendamustine 
R+fludarabine  
 
RM: up to 8 
infusions, given   
Q3M for 2 yrs  
(n=40, 23 R-B, 17 
R-F) 
R-B: 30 mo 
R-F: 11 mo 
HR 0.51 
(0.34, 0.67) 
P’0.0001 
 
PFS (RM vs. 
no mainten.): 
HR 0.27 (0.27, 
0.59) 
P<0.0001 
Deaths after 33 
month median 
follow-up: 
R-B: 42 
R-F: 46 
NSD 
 
OS (RM vs. no 
maintenance): 
HR 0.21 (0.22, 
0.67) 
P=0.0008 
ORR: 
R-B: 83.5% 
R-F: 52.5% 
P’0.0001 
 
CR: 
R-B: 38.5% 
R-F: 16.2% 
P=0.0004 
Abbreviations: CR, complete response; CRu, Complete response, unconfirmed; FL, follicular lymphoma; HR, 
hazard ratio (expressed with 95% confidence interval limits); ITT, intent to treat; MCL, Mantle Cell 
Lymphoma; mo, months; NSD, no significant difference; OBS, observation; ORR, Overall response Rate; 
Q6M, every 6 months;  Q2M, every 2 months; RM, rituximab maintenance; wks, weeks; 
 
1.2.3.1 
Rituximab maintenance therapy following chemotherapy 
induction 
In a large Phase III prospective randomized trial (ECOG1496) by Hochster and 
colleagues,56,57 patients with low-grade NHL achieving a response or stable disease after 
induction treatment with CVP were randomized to receive rituximab maintenance 
therapy (RM, 4 weekly infusions every 6 months, n = 153) over 2 years or no further 
therapy (observation group, OBS, n = 158). The study was terminated early after an 
interim analysis significant superiority of the maintenance arm. After a median follow-up 
of 14 months, the Kaplan-Meier estimate for PFS at 2 years was 74% of patients in the 
RM arm compared with 42% of patients in the OBS arm (p = 0.0008). The median PFS 
for the whole study population was 4.2 years compared to 1.5 years in the OBS arm; 
median follow-up was 18 months. 56,57  Best response improved in 22% of RM patients vs. 
7% of OBS patients (p = 0.00006). Toxicity was minimal in both study arms. Three-year 
PFS after randomization was 68% RM vs. 33% OBS (hazard ratio [HR] 0.4; p = 4.4 x10-
10) in the total population and 64% RM v 33% OBS (HR 0.4; p = 9.2x10-8) in patients with 
FL. There was an advantage for RM regardless of FLIPI score, tumour burden, residual 
disease, or histology. OS at 3 years was 92% RM vs. 86% OBS (HR 0.6; log-rank one-
sided p = 0.05) and, among patients with FL, OS was 91% RM vs. 86% (HR 0.6; log-
rank one-sided p = 0.08).61 
There were differences in neutropenia between the two arms, but overall there were no 
unexpected grade 3/4 toxicities (see Table 4). 
1.2.3.2 
Rituximab as maintenance therapy following rituximab 
monotherapy induction 
Extended rituximab monotherapy (rituximab maintenance therapy) following rituximab 
monotherapy induction was shown to significantly prolong EFS or PFS in previously 
untreated patients with follicular NHL.  

 
Rituximab - F. Hoffmann-La Roche Ltd 
Protocol MO25455 v4.0 
35 of 128 
The benefit of maintenance rituximab therapy was evaluated in 114 patients with 
relapsed/refractory indolent NHL enrolled in a Phase II study by Hainsworth et al. Of 
the 114 enrolled patients receiving 4 doses of rituximab for induction therapy over 1 
month, 90 (79%) with objective response or stable disease were randomly assigned to 
receive either maintenance rituximab therapy (3 standard 4-week courses administered 
at 6-month intervals) or rituximab re-treatment at the time of lymphoma progression. 
Patients receiving maintenance rituximab had a significantly prolonged PFS (31.3 vs. 7.4 
months; p = 0.007) and higher ORR (73% vs. 47%, respectively) compared to re-
treatment. Duration of rituximab benefit was similar in the maintenance and re-treatment 
groups (31.3 vs. 27.4 months, respectively).54 Both treatment approaches were well 
tolerated; see Table 4).  
The Swiss Group for Clinical Cancer Research (SAKK) 35/98 trial evaluated the 
potential benefits of extended rituximab treatment in a randomized trial comparing the 
standard schedule with prolonged treatment in 202 patients with newly diagnosed or 
refractory/relapsed FL. After all patients received standard treatment consisting of 4 
doses of 375 mg/m2 rituximab weekly, the overall RR was 67% in chemotherapy-naive 
patients and 46% in pre-treated cases (p < 0.01) within in a subset of 185 evaluable 
patients. Responders and patients with stable disease at week 12 (n = 151) were then 
randomized to no further treatment (OBS) or prolonged rituximab administration (four 
375 mg/m2 doses every 2 months). At a median follow-up of 35 months, the median EFS 
was 12 months in the OBS group vs. 23 months in the prolonged treatment arm (p = 
0.02), the difference being particularly notable in chemotherapy-naive (first-line) patients 
(19 vs. 36 months; p = 0.009) and in patients responding to induction treatment (16 vs. 
36 months; p = 0.004).55 A summary of toxicities is provided in Table 4. 
According to a recent update on the SAKK 35/98 study, at a median follow-up of 9.5 
years and with all living patients having been observed for at least 5 years, the median 
EFS was 13 months for the OBS arm and 24 months for the prolonged exposure arm (p 
< 0.001). In the OBS arm, 5% of patients were event-free at 8 years compared to 27% in 
the prolonged exposure arm. The percentage of event-free patients at 8 years was 
highest (45%) amongst previously untreated patients. The only favourable prognostic 
factor for EFS in a multivariate Cox regression analysis was the prolonged rituximab 
schedule (HR 0.59, 95% CI 0.39 to 0.88; p = 0.009), whereas being chemotherapy naive, 
presenting with disease stage lower than IV, and showing a VV phenotype at position 
158 of the Fc-gamma RIIIA receptor were not of independent prognostic value. No long-
term toxicity potentially due to rituximab was observed.62 
1.2.3.3 
Rituximab maintenance therapy following rituximab plus 
chemotherapy induction 
In a phase III EORTC 20981 study (n = 465) evaluating the role of rituximab 
maintenance treatment in relapsed/resistant FL, 334 of the 366 patients achieving PR or 
CR after 6 cycles of induction therapy with CHOP without or with 375 mg/m2 IV rituximab 
underwent a second randomization to maintenance with 375 mg/m2 IV rituximab once 
every 3 months for a maximum of 2 years or to observation alone. Induction with R-
CHOP compared to CHOP yielded a significantly higher overall response rate (85.1% vs. 
72.3%, respectively; p < 0.001) and CR rate (29.5% vs. 15.6%; p < 0.001). Median PFS 
from first randomization was 33.1 months vs. 20.2 months, respectively (HR 0.65; p < 
0.001). Importantly, this was the first trial demonstrating that rituximab maintenance 
significantly prolonged PFS from second randomization (median 51.5 months vs. 14.9 
months with observation alone, HR 0.40; p < 0.001), regardless of whether the induction 
included CHOP (HR 0.30; p < 0.001) or R-CHOP (HR 0.54; p = 0.004). A further 

 
Rituximab - F. Hoffmann-La Roche Ltd 
Protocol MO25455 v4.0 
36 of 128 
important finding of this study is the significant prolongation in 3-year OS from second 
randomization to rituximab maintenance compared to observation alone (85% vs. 77%, 
HR 0.52; p = 0.011).3 The toxicity profile is shown in Table 4).  
A subsequent follow-up indicated that the 5-year OS was 74% in the rituximab 
maintenance arm and 64% in the observation arm (p = 0.07). Of note, after progression, 
a rituximab-containing salvage therapy was given to 59% of patients treated with CHOP 
followed by observation, compared with 26% after R-CHOP followed by rituximab 
maintenance. During rituximab maintenance treatment, neutropenia was the only 
significant toxicity; 11.5% experienced grades 3 to 4 neutropenia in the rituximab 
maintenance arm versus 6.0% in the observation arm. This probably contributed to the 
increased grades 3 to 4 infection rates of 9.7% in the maintenance group and 2.4% 
during observation (p = 0.01). The majority of these infections were in the ear-nose-
throat area and no opportunistic or viral infections were observed. No patient had to be 
withdrawn because of persisting IgG levels less than 3 g/L. Only seven of the 167 
patients withdrew from maintenance treatment because of toxicity. 63 
The data from the pivotal EORTC 20981 Intergroup study has formed the basis for a 
label extension for rituximab to be administered as rituximab maintenance therapy.  
In addition, the GLSG performed a randomized study comparing induction with 4 
courses of FCM or R-FCM in patients with advanced stage relapsed or refractory FL or 
MCL. Responding patients underwent a second randomization to observation alone or to 
rituximab maintenance (RM) comprising 2 further rituximab courses of weekly doses for 
4 weeks, repeated at 3 months and 9 months. The initial randomization was stopped 
after 147 patients due to demonstrated clinical superiority in the R-FCM arm. All 
subsequent patients received R-FCM induction therapy prior to the second 
randomization. Of the 176 evaluable patients at the time of the latest published report, 
138 received R-FCM for remission induction. A total of 184 patients underwent 
randomization to RM or observation alone. After a median observation time of 26 
months (range, 1 - 64 months), a significantly longer response duration was observed for 
the total group of patients on the R-maintenance arm, with the median not being reached 
in this evaluation, compared with an estimated median of 17 months for patients 
receiving no further treatment. In the subgroup of patients receiving R-FCM induction, 
prolonged RM produced a significantly longer response duration, with the median not 
reached vs. an estimated median of 16 months in the observation group (p = 0.001). 
This beneficial effect (RM vs. observation) was also observed when analysing the 
subgroups of patients with FL (p = 0.035) and MCL (p = 0.049) separately.58 
In a randomized phase III study conducted by the German Study Group Indolent 
Lymphomas (Stil) 219 pts with relapsed FL, indolent or MCL were randomized to 
rituximab 375 mg/m2 (day 1) plus either bendamustine 90 mg/m2 (R-B, days 1 and 2) or 
fludarabine 25 mg/m2 (R-F, days 1 to 3) Q4W for a maximum of 6 cycles. The primary 
endpoint was PFS. The protocol was amended in 2006 to allow rituximab maintenance 
therapy (rituximab 375 mg/m2 every 3 months for up to 2 years) in both arms, following 
regulatory approvals in this setting. After a median observation time of 33 months, the 
group receiving R-B, compared to R-F had a significantly prolonged PFS (30 vs. 11 
months, respectively; HR 0.51, 95% CI 0.34 to 0.67; p < 0.0001), ORR (83.5 vs. 52.5%, 
respectively; p < 0.0001), whereas overall survival did not differ significantly between 
arms, with 42 and 46 deaths documented in the two groups, respectively. An exploratory 
analysis showed significantly prolonged overall survival (HR 0.21, 95% CI 0.22 to 0.67; p 
= 0.0008) and PFS (HR 0.27, 95% CI 0.27 to 0.59; p < 0.0001) in the small group of 40 

 
Rituximab - F. Hoffmann-La Roche Ltd 
Protocol MO25455 v4.0 
37 of 128 
patients who received rituximab maintenance treatment (23 B-R, 17 F-R), compared with 
those who did not.60 
The latest data confirming the benefit of rituximab maintenance therapy following 
rituximab plus chemotherapy in first line advanced FL is available from the phase III, 
open-label, randomized PRIMA (Primary Rituximab and Maintenance) study. After 
induction of response with one of 3 rituximab-containing chemotherapy regimens (R-
CHOP, R-CVP, or R-FCM, at the discretion of the treating physician), 1019 of the 1217 
patients with a partial or complete response were randomized to observation alone (n = 
513) or maintenance with 375 mg/m2 rituximab, once every 8 weeks for 2 years (n = 505). 
The primary endpoint was PFS. At a median follow-up of 36 months (interquartile range 
or IQR 30-42), PFS was 74·9% (95% CI 70.9 to 78.9) in the RM group (130 patients 
progressed) and 57.6% (95% CI 53.2 to 62.0) in the observation only group (218 
progressed; HR 0.55, 95% CI 0.44 to 0.68; p < 0·0001). Two years after randomization, 
361 patients (71.5%) in the RM group were in CR or CRu vs. 268 (52.2%) in the 
observation alone group (p = 0.0001). Overall survival did not differ significantly between 
groups (HR 0.87, 95% CI 0.51 to 1.47).59  
Of the 1009 patients assessed for safety, adverse events were reported in 281 of 501 
(56%) patients in the rituximab maintenance group and 189 of 508 (37%) in the 
observation group (risk ratio 1.51, 95% CI 1.32 to 1.73; p < 0·0001). Grade 3 and 4 AEs 
were recorded in 121 patients (24%) in the rituximab maintenance group and 84 (17%) 
in the observation only group (risk ratio 1.46, 95% CI 1.14 to 1.87; p = 0.0026); see 
Table 4. Infections (grades 2-4) were the most common AE, occurring in 197 (39%) and 
123 (24%) patients respectively (risk ratio 1.62, 95% CI 1.35 to 1.96; p < 0.0001). 
Nineteen (4%) and eight (2%) events, respectively, resulted in treatment discontinuation 
(risk ratio 2·41, 1·06 to 5·45; p = 0·029). This study provided first evidence of a 
significant PFS benefit associated with long-term (2-year) maintenance treatment with 
rituximab.59  
Lastly, a systematic review and meta-analysis of randomized controlled trials that 
compared rituximab maintenance therapy with observation or no treatment at relapse 
identified 5 trials comprising 985 adult patients with FL overall and each with adequate 
OS data. Induction therapy used in these trials included three options: chemotherapy 
alone, chemotherapy with or without rituximab, and rituximab alone. In all trials, a dose 
of rituximab consisted of 375 mg/m2/day. The maintenance treatment schedule differed 
among the trials: in three trials, rituximab was administered weekly for 4 consecutive 
weeks (four doses) every 6 months, and in two trials, a single infusion of rituximab was 
administered every 2 – 3 months. The duration of treatment also varied, from 8 – 9 
months to 2 years. Patients treated with RM had statistically significantly better OS than 
patients in the observation only arm or patients treated at relapse (HR 0.60, 95% CI 0.45 
to 0.79). Of note, the survival benefit was significant in the subgroup of patients with 
refractory or relapsed (i.e. previously treated) FL (HR 0.58, 95% CI 0.42 to 0.79), but not 
in previously untreated patients (HR 0.68, 95% CI 0.37 to 1.25). The rate of infection-
related AEs was higher with RM (HR 1.99, 95% CI 1.21 to 3.27). The study results led 
the authors to conclude that maintenance therapy with rituximab, either as 4 weekly 
infusions every 6 months or as a single infusion every 2 - 3 months, should be added to 
standard therapy for patients with relapsed or refractory FL after successful induction 
therapy.64 

 
Rituximab - F. Hoffmann-La Roche Ltd 
Protocol MO25455 v4.0 
38 of 128 
1.2.4 
Clinical Safety of Rituximab  
Comprehensive rituximab safety information is available in the current Investigator 
Brochure. Safety considerations relevant to this study are summarized here. 
Safety data from randomized clinical trials comparing rituximab maintenance therapy 
with observation (no treatment) are summarized in Table 4 below, with focus on Grade 
3/4 toxicities. 

 
Rituximab - F. Hoffmann-La Roche Ltd 
Protocol MO25455 v4.0 
39 of 128 
Table 4 SAFETY SUMMARY OF RANDOMIZED TRIALS COMPARING RITUXIMAB 
MAINTENANCE THERAPY TO OBSERVATION 
Study / 
Reference 
Population, 
Intervention 
Grade 3/4  AEs 
Other AEs 
Phase II Study  
Hainsworth et 
al 200554 
N=90 
Induction:  
Rituximab 
Maintenance: 
RM: Weekly doses 
for 4 wks, repeated 
Q6M for 2 yrs or 
R re-treatment at 
PD 
Grade 3 AEs, n 
RM 
R Re-
treatment 
Grade 3 IRRs 
2 
0 
Neutropenia 
1 
0 
Fatigue 
1 
0 
Anemia 
0 
1 
Dyspnea 
0 
1 
No withdrawals due 
to toxicity. 
 
SAKK 35/98 
Ghielmini et al. 
200455 
N=151 
Induction:  
Rituximab 
RM: 
4 Single infusions, 
given Q2M 
 
IND, N=202 
Non–haematologic, n (%) 
 
  Overall 
19 (10) 
  Hypotension 
5 (3) 
  Asthenia 
8  (4) 
  Other 
13 (6) 
Haematologic, n (%) 
 
  Anemia 
4 (2) 
  Leukocytopenia 
6 (3) 
  Neutropenia 
19 (9) 
  Thrombocytopenia 
8 (4) 
 
MAINT, N=151 
 
RM 
N=73 
OBS 
N=78 
Non-haematologic, n (%) 
7 (10) 
2 (3) 
Haematologic, n (%) 
13 (18) 
13 (17) 
SAEs: 
RM: 9 cases (incl. 2 
infections) 
OBS: 4 cases (incl. 1 
infection) 
 
Late toxicities (1-yr): 
RM: 7% 
OBS: 7% 
Causes: infection (5), 
leucocytopenia (2), 
teeth loss (1), 
asymptomatic 
neutropenia (1), 
cachexia (1). 
 
ECOG 1496 
Hochster et al 
200461 
 
N=311 
Induction:  
CVP 
RM: Weekly doses 
for 4 wks, repeated 
Q6M for 2 yrs 
 
CVP IND 
N=394 
RM 
N=178 
OBS 
N=177 
Neutropenia 
30% 
3% 
1% 
Infection 
7% 
1% 
1% 
Pulmonary 
2% 
1% 
1% 
Other 
N/A 
7% 
4% 
Toxic deaths:   
CF: 8  
RM: 4 
OBS: 1  
Causes:  infection (9) 
liver failure (2) 
CNS gliosis (1)  
GLSG  (R-)FCM 
Forstpointner 
et al 200658 
N=195 
Induction:  
R-FCM, FCM 
RM: Weekly doses 
for 4 wks, repeated 
at 3 mo and 9 mo 
 
 
 
 
RM 
OBS 
Lymphocytopenia 
22% 
16% 
Granulocytopenia 
13% 
6% 
Leukocytopenia 
10% 
5% 
Infection 
4% 
3% 
Fever 
4% 
0 
Thrombocytopenia 
4% 
3% 
Anemia 
3% 
3% 
Cardiac dysfunction 
1% 
0 
Pulmonary toxicity 
1% 
0 
ALT abnormal 
1% 
0 
Withdrawal due to AE 
RM: 1 pt (severe 
allergic reaction) 
OBS: 0 
 
 
EORTC 20981 
Intergroup 
study 
van Oers et al 
20063 
N=334 
Induction:  
R-CHOP, CHOP 
RM: Single 
infusions, given   
Q3M for 2 yrs 
 
 
 
OBS 
RM 
Gr3 
Gr4 
Gr3 
Gr4 
Leucopoenia 
4 (2) 
3 (2) 
10 (6) 
1 (1) 
Granulo-  
cytopenia 
6 (4) 
3 (2) 
11 (7) 
7 (4) 
Infection 
3 (2) 
1 (1) 
12 (7) 
3 (2) 
Cardiac 
7 (4) 
-- 
7 (4) 
3 (2) 
Overall incidence of 
neutropenia: 
RM: 11% 
OBS: 5% 
 
Withdrawals due AE 
RM: 6/167 (6/7 due to 
infections) 

 
Rituximab - F. Hoffmann-La Roche Ltd 
Protocol MO25455 v4.0 
40 of 128 
Study / 
Reference 
Population, 
Intervention 
Grade 3/4  AEs 
Other AEs 
PRIMA 
Salles et al 
201159 
N=1018 (ITT) 
Induction:  
R-CHOP, R-CVP, 
or R-FCM 
RM: 12 infusions, 
given   Q8W for 2 
yrs 
 
OBS 
RM 
 
Gr3/4 
WD 
Gr3/4 
WD 
All AEs 
84 (17) 
8 (2) 
121 
(24) 
19 (4) 
Neoplasia 
17 (3) 
6 (1) 
20 (4) 
5 (1) 
 Neutropenia 
5 (1) 
0 
18 (4) 
0 
Febrile 
neutropenia 
2 (<1) 
0 
1 (<1) 
1 (<1) 
Infections 
5 (1) 
0 
22 (4) 
4 (1) 
CNS 
disorders 
13 (3) 
0 
10 (2) 
0 
Cardiac 
disorders 
5 (1) 
0 
11 (2) 
1 (<1) 
Incidence of AEs: 
RM: 281 (56%) 
OBS: 189 (37%) 
P<0.0001 
 
Most common AEs: 
Gr2-4 infections  
RM: 197 (39%) 
OBS: 123 (24%) 
P<0.0001 
 
Grade 3/4 AEs (RM 
vs OBS): Risk ratio 
1.41, P=0.003 
 
Withdrawal due to AE 
RM: 19 (4%) 
OBS: 8 (2%) 
NHL 2-2003 
StiL Group 
Rummel et al. 
201060 
N=219 random.  
RM: N=40  
Induction:  
R+bendamustine 
R+fludarabine  
RM: up to 8 
infusions,  Q3M for 
2 yrs  
Grade 3/4 neutropenia: 
R-B: 9% 
R-F: 9% 
 
Grade 3/4 leokocytopenia: 
R-B: 12% 
R-F: 12% 
SAEs: 
R-B: 17% 
R-F: 22% 
Abbreviations: AE, adverse event; FL, follicular lymphoma; mo, months; OBS, observation; Q6M, every 6 months;  
Q2M, every 2 months; RM, rituximab maintenance; wks, weeks; WD, (Leading to) Withdrawal 
 
Infusion-related symptoms 
A cluster of signs and symptoms reported during or within 24 hours of rituximab infusion, 
which may be related to the release of cytokines and/or other chemical mediators, has 
been well characterised in pivotal clinical trials in NHL and also from post-marketing 
experience. Signs and symptoms associated with rituximab IRRs included hypotension, 
fever, chills, rigors, urticaria, bronchospasm and angioedema. In addition, some patients 
developed anaphylactic or hypersensitivity reactions due to IV administration of protein 
distinct from the cytokine release effect. In very rare cases these signs and symptoms 
resulted in a fatal outcome. Acute infusion reactions tend to be more frequent and more 
severe with the first infusion.  
In the pivotal rituximab monotherapy trials (IDEC 102-01,65 102-02,66,67 102-05,38 102-
06,46 102-08B,68 and 102-08R69) in relapsed/refractory patients with follicular NHL, the 
incidence of IRRs was 77% (7% grade 3/4) with the first infusion, which decreased to 
approximately 30% (2% grade 3/4) with the fourth infusion and to 14% (no grade 3/4 
events) with the eighth infusion. In pivotal trial (M39021) of first-line treatment of follicular 
NHL, where rituximab was combined with CVP chemotherapy, the incidence of grade 
3/4 acute IRRs was 9%.26 An incidence of 9% for grade 3/4 infusion-related events was 
also reported in patients with diffuse large B-cell lymphoma, when they received their 
first 
rituximab 
infusion 
combined 
with 
CHOP 
chemotherapy 
in 
DLBCL 
(GELA/BO16386).70  
In the U0824n71 non-randomized trial of patients who had not previously been treated 
with systemic therapy for indolent NHL, participants received rituximab weekly for 4 

 
Rituximab - F. Hoffmann-La Roche Ltd 
Protocol MO25455 v4.0 
41 of 128 
weeks. Those who responded then received RM. IRRs (chills/rigors, fever, 
nausea/vomiting and flushing) were observed with the first course of rituximab, 
consistent with the known safety profile of rituximab. It was reported that toxicity 
observed during RM was less than with the first course, but data on the number and type 
of AEs were not provided.  
Thus, patients treated with RM who have previously been exposed to rituximab during 
induction, may have fewer and less severe reactions than patients treated with rituximab 
for the first time. It is unlikely that infusion reactions in the rituximab maintenance setting 
will be any different from those seen during later infusions of induction therapy. During 
this study, rituximab maintenance infusions will be administered in a hospital or 
outpatient clinic by oncologists and their staff, who are familiar with such adverse effects. 
Infection 
Patients with NHL are at risk of infection because of disturbances in immune functions 
as a result of their underlying malignant disease. Treatment with chemotherapeutic 
agents leads to immunosuppression and therefore also may increase the incidence of 
infections. 
Because rituximab depletes B cells, which play an important role in the normal immune 
response, treatment with rituximab may further increase the risk of infection in these 
immunocompromised patients. In two cohorts of patients treated with rituximab 
monotherapy in relapsed/refractory follicular NHL, median immunoglobulin (Ig) G and 
IgA levels remained stable during treatment and during follow-up, but IgM dropped 
below the normal range at 3 months post-treatment with a median time to recovery of 2 
months.72,73 Infections occurred in 30.3% of 356 patients reviewed. Since there was no 
comparator arm in these studies, the contributory role of rituximab in the development of 
these infectious events relative to the underlying NHL and its treatment with other drugs 
could not be determined.  
In Phase III randomized controlled trials comparing the combination of rituximab and 
various chemotherapy regimens (R-CHOP, R-MCP, R-CHVP+IFN) with chemotherapy 
alone (CHOP, MCP, and CHVP+IFN, respectively) in patients with NHL, the incidence of 
grade 3 and 4 infections ranged between 2% and 7% in the combination arms compared 
to 0% to 8% in the chemotherapy arms. 28,29,30 In the pivotal study comparing R-CVP vs. 
CVP alone for first line induction treatment of follicular NHL (M3902126) the overall 
proportion of patients with infections was comparable between treatment groups (33% 
R-CVP, 32% CVP), despite more patients in the R-CVP arm experiencing grade 3/4 
neutropenia (R-CVP 24%, CVP 14%). In the R-CHOP vs. CHOP alone pivotal trial in 
elderly patients with DLBCL (GELA/BO1638670) grade 3 and 4 leucopoenia and 
neutropenia occurred more frequently in the R-CHOP arm than in the CHOP arm (88% 
vs. 79% and 97% vs. 88% respectively), but the incidence of grade 2 to 4 infections was 
only slightly higher (46% in the R-CHOP arm compared to 42% in the CHOP arm). More 
cases of herpes zoster and localized fungal infections were recorded when rituximab 
was added to CHOP chemotherapy in a separate study investigating rituximab in 
aggressive NHL. 70 In the U0824n trial,71 no opportunistic infections were observed 
during rituximab maintenance therapy over 18 months and no patient discontinued from 
the study due to toxicity. 
In two large Phase III randomized controlled trials (EORTC 20981 and PRIMA) up to two 
years of maintenance therapy with rituximab administered every two months was 
associated with higher rates of grade 3 and 4 infections compared to observation (4% to 

 
Rituximab - F. Hoffmann-La Roche Ltd 
Protocol MO25455 v4.0 
42 of 128 
9% compared to 1% to 3%, respectively). 3,59 In the SAKK 35/98 trial, 55 the rate of 
serious infections was 3% in the RM group compared to 1% in the observation group. In 
the RM group, reduction in IgM levels to 86% and 72% of baseline level were observed 
at 3 and 12 months respectively, these changes, however were not associated with an 
increase in the incidence of AEs. The grade 3 and 4 infection rates were comparable 
between the RM and observation arms in other Phase III trials (1% to 4% and 1% to 3%, 
respectively); refer to Table 4 for further details. 58,61  
Other toxicities 
Tumour Lysis Syndrome (TLS) has been reported to occur after the first rituximab 
infusion in patients with a high tumour burden or high numbers of circulating malignant 
lymphocytes during induction treatment.  
Pulmonary events were also reported. They have included hypoxia, pulmonary infiltrates, 
and acute respiratory failure.  
In studies evaluating rituximab in combination with chemotherapy, the incidence of grade 
3 and 4 cardiac arrhythmias, predominantly supraventricular arrhythmias such as 
tachycardia and atrial flutter/fibrillation, was higher in the R-CHOP group (14 patients, 
6.9 %) as compared to the CHOP group (3 patients, 1.5 %). During maintenance 
treatment, the incidence of grade 3 and 4 cardiac disorders was comparable between 
patients treated with rituximab and observation. Cardiac events were reported as serious 
adverse events (including atrial fibrillation, myocardial infarction, left ventricular failure, 
myocardial ischemia) in 3 % of patients treated with rituximab compared to < 1 % on 
observation. 39 
Very rare cases of hepatitis B reactivation, including reports of fulminant hepatitis, have 
been reported in patients receiving rituximab, although these reports are confounded by 
both underlying disease and exposure to other cytotoxic chemotherapy. Patients with a 
history of hepatitis B infection should be carefully monitored for signs of active hepatitis 
B infection when rituximab is used in association with cytotoxic chemotherapy. 
Two spontaneous cases of progressive multifocal leukoencephalopathy (PML) resulting 
in death, have been reported in patients with Systemic Lupus Erythematosus (SLE) 
receiving off-label rituximab. Rituximab is not approved for the treatment of SLE. PML 
has also been reported in SLE patients not treated with rituximab. A causal relationship 
between rituximab and PML has not been established. 
Some other patients who were treated with rituximab and chemotherapy have developed 
gastro-intestinal perforation.  
The safety of immunization with any vaccine following rituximab therapy has not been 
extensively studied. It is recommended that any course of immunization for patients 
should be completed at least 4 weeks before starting rituximab maintenance therapy and 
patients should not receive any vaccinations that contain live or attenuated organisms 
during the study. 
Further information concerning rituximab safety can be found in the current version of 
the Investigator Brochure.74 
1.3 
REGULATORY STATUS 
Rituximab is a chimeric murine/human monoclonal antibody that binds to CD20, a 
hydrophobic transmembrane protein present on B lymphocytes. Rituximab is marketed 


5LWX[LPDE)+RIIPDQQ/D5RFKH/WG
3URWRFRO02Y
RI
XQGHUWKHEUDQGQDPHV0DE7KHUDLQ(XURSHDQGRWKHUFRXQWULHVDQG5LWX[DQLQWKH
86
5LWX[LPDEKDVEHHQDSSURYHGIRUWUHDWPHQWRIUHODSVHGRUFKHPRUHVLVWDQWORZJUDGHRU
IROOLFXODU &' %FHOO1+/ LQ RYHU  FRXQWULHV LQFOXGLQJ WKH (8 DQG 86 DQGIRU
WUHDWPHQWRIUKHXPDWRLGDUWKULWLVLQWKH86DQG(8
,QRQFRORJ\5LWX[DQULWX[LPDELVLQGLFDWHGLQWKH86DVIROORZV
•
5HODSVHGRUUHIUDFWRU\ORZJUDGHRUIROOLFXODU&'%FHOO1+/DVDVLQJOHDJHQW
•
3UHYLRXVO\ XQWUHDWHG IROOLFXODU &' %FHOO 1+/ LQ FRPELQDWLRQ ZLWK ILUVWOLQH
FKHPRWKHUDS\ DQG DV D VLQJOHDJHQW PDLQWHQDQFH WKHUDS\ DIWHU DFKLHYLQJ D
UHVSRQVHWR5LWX[DQLQFRPELQDWLRQZLWKFKHPRWKHUDS\
•
1RQSURJUHVVLQJ LQFOXGLQJ VWDEOH GLVHDVH ORZJUDGH &' %FHOO 1+/ DV D
VLQJOHDJHQWDIWHUILUVWOLQH&93FKHPRWKHUDS\
•
3UHYLRXVO\XQWUHDWHGGLIIXVHODUJH%FHOO&'1+/LQFRPELQDWLRQZLWK&+23RU
RWKHUDQWKUDF\FOLQHEDVHGFKHPRWKHUDS\UHJLPHQV
•
3UHYLRXVO\XQWUHDWHGDQGSUHYLRXVO\WUHDWHG&'SRVLWLYH&//LQFRPELQDWLRQZLWK
IOXGDUDELQHDQGF\FORSKRVSKDPLGH
,QRQFRORJ\0DE7KHUDULWX[LPDELVLQGLFDWHGLQWKH(8DVIROORZV
•
3UHYLRXVO\XQWUHDWHGRUUHODSVHGUHIUDFWRU\&//LQFRPELQDWLRQZLWKFKHPRWKHUDS\
•
3UHYLRXVO\XQWUHDWHGSDWLHQWVZLWKVWDJH,,,,9)/LQFRPELQDWLRQZLWKFKHPRWKHUDS\
•
$VPDLQWHQDQFHWUHDWPHQWIRU)/UHVSRQGLQJWRLQGXFWLRQWKHUDS\
•
&''/%&/LQFRPELQDWLRQZLWK&+23FKHPRWKHUDS\
•
$V PRQRWKHUDS\ VWDJH ,,,,9 )/ FKHPRUHVLVWDQW RU KDV LV LQ VHFRQG RU JUHDWHU
UHODSVHDIWHUFKHPRWKHUDS\
,Q5KHXPDWRORJ\ULWX[LPDELVLQGLFDWHGDVIROORZV
,Q WKH 865LWX[LPDE5LWX[DQUHFHLYHG)RRGDQG'UXJ$GPLQLVWUDWLRQDSSURYDOIRU
UKHXPDWRLG DUWKULWLV LQ )HEUXDU\  DQG LV FXUUHQWO\ LQGLFDWHG LQ FRPELQDWLRQ ZLWK
PHWKRWUH[DWHWRUHGXFHVLJQVDQGV\PSWRPVRIGLVHDVHDQGWRVORZWKHSURJUHVVLRQRI
VWUXFWXUDOGDPDJHLQDGXOWSDWLHQWVZLWKPRGHUDWHWRVHYHUHDFWLYHUKHXPDWRLGDUWKULWLV
ZKR KDYH KDG LQDGHTXDWH UHVSRQVH WR RQH RU PRUH WXPRXU QHFURVLV IDFWRU 71)
DQWDJRQLVWWKHUDSLHV
,Q $SULO  WKH )RRG DQG 'UXJ $GPLQLVWUDWLRQ )'$ DSSURYHG ULWX[LPDE LQ
FRPELQDWLRQ ZLWK IOXFRFRUWLFRLGV IRU WKH WUHDWPHQW RI SDWLHQWV ZLWK DFWLYH VHYHUH
:HJHUQHU¶V*UDQXORPDWRVLVRU0LFURVFRSLF3RO\DQJLLWLV
,QWKH(85LWX[LPDE0DE7KHUDLQFRPELQDWLRQZLWKPHWKRWUH[DWHLVLQGLFDWHGIRUWKH
WUHDWPHQW RI DGXOW SDWLHQWV ZLWK VHYHUH DFWLYH UKHXPDWRLG DUWKULWLV ZKR KDYH KDG DQ
LQDGHTXDWH UHVSRQVH WR LQLWLDO DQWL71) WKHUDS\ )RU UHJXODWRU\ VWDWXV DQG DSSURYHG
LQGLFDWLRQVLQRWKHUFRXQWULHVSOHDVHUHIHUWRWKH,QYHVWLJDWRUV¶%URFKXUHDQGWKHORFDO
3URGXFW,QIRUPDWLRQUHVSHFWLYHO\

 
Rituximab - F. Hoffmann-La Roche Ltd 
Protocol MO25455 v4.0 
44 of 128 
1.4 
RATIONALE FOR THE STUDY  
The efficacy and safety of rituximab is well established. Several phase III trials 
demonstrated that the addition of rituximab to standard induction chemotherapy 
compared to chemotherapy alone significantly improved clinical outcomes in terms of 
OS, PFS, EFS, response duration, particularly in patients with FL. 26,28,29,30,45,48,51,52,53  
Consequently, rituximab-containing regimens have become the standard of care for 
patients suffering from various CD20+ B-cell malignancies, including indolent NHLs. 
More recently, based on two large randomized phase III trials showing significant clinical 
benefits with rituximab maintenance compared to observation in relapsed FL (EORTC 
20981 Study)3 and first-line FL (PRIMA Study), 59 rituximab maintenance has also 
become standard of care in these settings. The EORTC 20981 study (n = 465) was the 
first trial demonstrating that rituximab maintenance significantly prolonged PFS from 
second randomization (median 51.5 months vs. 14.9 months with observation alone, HR 
0.40; p < 0.001) in patients with relapsed/resistant FL, regardless of whether the 
induction included CHOP (HR 0.30; p < 0.001) or R-CHOP (HR 0.54; p = 0.004).3 The 
PRIMA trial (n = 1018) reported a PFS benefit for rituximab induction plus maintenance 
in previously untreated FL patients, along with increased conversion rates from PR to 
CR following rituximab maintenance. After a median follow-up of 25 months from 
randomization (31 months from study entry), 2-year PFS was 82% with rituximab 
maintenance compared to 66% for the observation only group (HR 0.50, 95% CI 0.39 to 
0.64; stratified log-rank, p < 0.0001). 59 
A systematic review and meta-analysis of randomized controlled trials by Vidal et al 64 
that compared RM therapy with observation or no treatment at relapse identified five 
trials including 985 adult patients with FL and adequate OS data. The maintenance 
treatment schedule differed among the trials: in three trials, rituximab was administered 
weekly for 4 consecutive weeks (four doses) every 6 months, and in two trials, a single 
infusion of rituximab was administered every 2 – 3 months. Patients treated with RM had 
statistically significantly better overall survival than patients in the observation arm or 
patients treated at relapse (HR 0.60, 95% CI 0.45 to 0.79). Of note, the survival benefit 
was significant in the subgroup of patients with refractory or relapsed (i.e., previously 
treated) FL (HR 0.58, 95% CI 0.42 to 0.79). 64 
Since its preclinical development, many studies have been performed to optimize the 
dose and schedule of rituximab. In randomized controlled trials completed to date, 
maintenance therapy with rituximab 375 mg/m2 was administered every 2 months for 8 
months, 55 weekly for 4 weeks, repeated every 6 months for 2 years, 54,56  every 3 months 
for 2 years, 3,60 and more recently, every 2 months for 2 years. 59 Current clinical 
investigations aim to determine the optimal duration of rituximab maintenance therapy. 
One currently ongoing study (n = 165 randomized) will compare short maintenance 
consisting of four doses of rituximab (375 mg/m²) every two months with prolonged 
maintenance consisting of rituximab every two months for a maximum of five years or 
until disease progression or unacceptable toxicity, following 4 weekly doses (375 mg/m²) 
of induction therapy. Primary endpoint is event-free survival and preliminary safety data 
indicate that rituximab maintenance beyond two years is feasible without evidence for 
increased toxicity. 75 In the StiL NHL 7-2008 (MAINTAIN) study, patients with FL will 
receive induction therapy with bendamustine plus rituximab, followed by maintenance 
therapy with rituximab every 2 months for 4 years (experimental arm) or rituximab every 
2 months for 2 years (standard arm).76 
Currently, rituximab is administered as an IV infusion over several hours. These long 
infusion times and the side effects related to the infusion were cited by some patients as 

 
Rituximab - F. Hoffmann-La Roche Ltd 
Protocol MO25455 v4.0 
45 of 128 
uncomfortable consequences of the current therapeutic treatment. Furthermore, the 
required procedure to establish IV access is considered invasive and can be painful, 
particularly in patients with malignant diseases who are treated repeatedly. 
Subcutaneous administration could significantly simplify treatment, shorten the 
administration to less than 10 minutes and improve patient satisfaction with the 
treatment.  
Currently, rituximab is administered as an intravenous (IV) infusion over several hours. 
Frequently observed infusion-related reaction may require prolonging the infusion time 
further. For other monoclonal antibodies in other clinical settings the switch from IV 
administration to subcutaneous (SC) administration has resulted in an improved 
tolerability with less infusion-related reactions, an increased patient-convenience and an 
improved cost-effectiveness.
77
,
78  These advantages are anticipated for the 
subcutaneous administration of rituximab as well. However, so far the relatively large 
volume of the established rituximab dose (375 mg/m2) has hindered the subcutaneous 
administration of rituximab. Hence, the development of a rituximab SC formulation 
addresses an unmet medical need. 
The results of a recently presented IV/SC pharmacokinetic/pharmacodynamic (PK/PD) 
cynomolgus monkey study (B cell depletion model) suggest that the SC versus IV dosing 
routes do not influence the pre-clinical efficacy of rituximab. Cynomolgus monkeys were 
treated twice, one week apart, with the rituximab SC formulation or with IV rituximab. 
The SC formulation contained recombinant human hyaluronidase (rHuPH20), which 
transiently degrades the local interstitial matrix component, hyaluronan, at the SC 
injection site, acting as a permeation enhancer and allowing SC administration of high 
volumes. The results indicate similar rituximab trough concentrations in serum as well as 
similar B-cell depletion efficacy in both peripheral blood and distal secondary lymphoid 
tissue after IV and SC dosing.79    
Results from Stage 1 of a two-stage, randomized, open-label, multicentre phase Ib study 
(BP22333) investigating the PK, safety and tolerability of SC rituximab maintenance 
treatment in patients with previously treated or untreated FL (grade 1, 2 or 3a) have 
recently been reported. Eligible patients, who had responded to a rituximab-containing 
induction regimen and had received at least 1 dose of rituximab IV (375 mg/m2) in the 
maintenance setting, were randomized to 1 of 4 rituximab maintenance treatment groups. 
Patients received a single dose of rituximab: 375 mg/m2 IV, 375 mg/m2 SC, 625 mg/m2 
SC, or 800 mg/m2 SC, followed by maintenance rituximab IV every 2 or 3 months for a 
further year. After one year of maintenance therapy and determination of the final fixed 
SC dose (based upon Ctrough levels after a single SC dose compared with IV), patients in 
the SC cohorts could choose to either switch to rituximab SC or continue rituximab IV 
until completion of the 2-year maintenance period. Data from 124 randomized patients 
indicate comparable rituximab concentrations at Ctrough and extent of serum exposure 
(AUC0–57) in patients administered rituximab SC between 625 mg/m2 and 800 mg/m2 and 
those administered rituximab 375 mg/m2 IV. Simulations of mean Ctrough values based on 
body surface area data from 54 patients predicted that a fixed dose of rituximab SC 
1400 mg would be non-inferior to the rituximab IV dose of 375 mg/m2. Treatment with 
SC doses of rituximab was well tolerated with an AE profile comparable to that of 
rituximab IV; of the 4 SAEs reported, none were treatment-related. A total of 157 AEs 
occurred in 65 patients (52%). The most commonly reported AE was local 
administration-associated reactions (n = 30), including rash, erythema and mild 
discomfort; general reactions were very rare. There were no AEs leading to death, 
withdrawal or treatment discontinuation.80  

 
Rituximab - F. Hoffmann-La Roche Ltd 
Protocol MO25455 v4.0 
46 of 128 
It is generally accepted that for monoclonal antibodies undergoing target-mediated drug 
disposition linear pharmacokinetics are observed, once target sites are saturated.81 The 
PK of the currently approved IV dose (375 mg/m2) indicates that target sites are 
saturated in patients with NHL, even at trough concentrations.82 Therefore, achieving the 
same trough concentrations should lead to a comparable saturation of target sites and 
comparable therapeutic effect. A fixed SC dose of 1400 mg has therefore been selected 
for formal Ctrough non-inferiority testing in Stage 2 of the above described trial as well as 
for further clinical testing of maintenance therapy with rituximab SC. Registration studies 
are currently ongoing. 
2. 
OBJECTIVES  
2.1 
PRIMARY OBJECTIVE 
To evaluate the efficacy of a subcutaneous (SC) formulation of rituximab in terms of 
progression-free survival after randomization (PFSrand) to either prolonged rituximab 
maintenance until progression (Maintenance II) or observation in patients with relapsed 
or refractory, indolent non-Hodgkin’s lymphoma who responded to Induction and initial 2 
years maintenance therapy (Maintenance I) at the end of study (EOS). 
2.2 
SECONDARY OBJECTIVES  
Secondary objectives of the study are to evaluate the efficacy and safety of SC rituximab 
during Induction, initial 2-year maintenance (Maintenance I) and randomized treatment 
period (Maintenance II). Efficacy will be evaluated in terms of EFS, Time to Next 
Lymphoma Treatment (TNLT), OS measured from first induction dose of rituximab 
(OSregist) and from the time of randomization to Maintenance II (OSrand), ORR, PR to CR 
Conversion rate (at the end of Maintenance I), and PFS measured from the first 
induction dose of rituximab (PFSregist). Safety assessments will include frequency of AEs, 
SAEs, IRRs/ARRs and immunoglobulin quantification. 
2.3 
EXPLORATORY OBJECTIVES  
 
3. 
STUDY DESIGN 
3.1 
OVERVIEW OF STUDY DESIGN 
This is a multicentre, multinational, open label, randomized study to evaluate 
maintenance therapy with SC rituximab continued until progression compared to 
observation only in patients with relapsed or refractory, indolent NHL who completed and 
responded to Induction and initial 2-year maintenance therapy (see Figure 1). 
The total study duration and active patient participation in the study is approximately 69 
months, including:  
• 
24 months enrollment period 
• 
6 - 8 months Induction period 
• 
24 months initial rituximab SC maintenance (Maintenance I) 
Minimum 15 months randomized period: observation only or maintenance treatment with 
SC rituximab continued until progression (Maintenance II). 


5LWX[LPDE)+RIIPDQQ/D5RFKH/WG
3URWRFRO02Y
RI
$IWHUDSDWLHQWKDVFRQVHQWHGWRSDUWLFLSDWHLQWKLVVWXG\WKHIROORZLQJSURFHGXUHVZLOOEH
FDUULHGRXW
•
%DVHOLQHDVVHVVPHQWZLOOEHSHUIRUPHGDFFRUGLQJWRWKH6FKHGXOHRI$VVHVVPHQWV
7DEOH5HIHUWR6HFWLRQIRUGHWDLOV
6HH 6HFWLRQ  IRU GHWDLOV DERXW GRVH PRGLILFDWLRQV LQWHUUXSWLRQV DQG GHOD\V IRU
ULWX[LPDEDQGFKHPRWKHUDS\
•
,QGXFWLRQF\FOHVRIULWX[LPDEZLOOEHDGPLQLVWHUHGLQFRPELQDWLRQZLWKF\FOHV
RIFKHPRWKHUDS\EHQGDPXVWLQH&+23&93)&00&3&+93,)1FKORUDPEXFLO
RUDQ\IOXGDUDELQHFRQWDLQLQJUHJLPHQLQFOXGLQJRUDOIOXGDUDELQH5*,)2;VHOHFWLRQ
DW WKH ,QYHVWLJDWRU¶V GLVFUHWLRQ 7KH VZLWFK EHWZHHQ GLIIHUHQW FKHPRWKHUDS\
UHJLPHQVLVQRWSHUPLWWHG7KHILUVWDGPLQLVWUDWLRQRIULWX[LPDEZLOOEHE\,9LQIXVLRQ
RQ'D\RIWKHILUVW,QGXFWLRQF\FOHDWGRVHRIPJPERG\VXUIDFHDUHD%6$
,Q WKH DEVHQFH RI LQIXVLRQUHODWHG VLGH HIIHFWV ULWX[LPDE ZLOO VXEVHTXHQWO\ EH
DGPLQLVWHUHG6&VWDUWLQJ'D\RIHDFK,QGXFWLRQF\FOHDWDIL[HGGRVHRIPJ
3DWLHQWVZKRH[SHULHQFHGDJUDGHRU,55DIWHUWKHILUVWULWX[LPDELQIXVLRQ&\FOH
EXWZHUHDEOHWRUHFHLYHWKHIXOOGRVHRIULWX[LPDEFDQUHFHLYHWKHVHFRQGGRVHRI
ULWX[LPDE6&&\FOH'D\3DWLHQWVZKRZHUHQRWDEOHWRUHFHLYHWKHLUIXOOGRVH
RIULWX[LPDE LQIXVLRQ LQ&\FOH  DV D UHVXOW RIDQ ,55 VKRXOG UHFHLYHWKHLU VHFRQG
ULWX[LPDE GRVH DOVR ,9 ,I WKLV VHFRQG ULWX[LPDE LQIXVLRQ LV QRW DVVRFLDWHG ZLWK D
JUDGHRU,55WKHSDWLHQWZLOOUHFHLYHKLVKHUWKLUGULWX[LPDEGRVH6&&\FOH
'D\  3DWLHQWV ZLWKJUDGH  RU ,55 DIWHU WKH VHFRQGULWX[LPDE LQIXVLRQ ZLOO EH
ZLWKGUDZQIURPWKHVWXG\
R 6WXG\9LVLW6FKHGXOHIRUSDWLHQWVGXULQJ,QGXFWLRQZLOORFFXUDWWKHEHJLQQLQJ
RI HDFK ZHHN RU ZHHN WUHDWPHQW F\FOH DFFRUGLQJ WR WKH 6FKHGXOH RI
$VVHVVPHQWV7DEOH5HIHUWR6HFWLRQIRUGHWDLOV
R 5HVSRQVHDVVHVVPHQWVZLOOEHFRQGXFWHGE\WKH,QYHVWLJDWRUDIWHUF\FOHV
RU DIWHU  F\FOHV LQ FDVH WKH ,QGXFWLRQ FRPSULVHG RI  FKHPRWKHUDS\
DGPLQLVWUDWLRQVDQGDWWKHHQGRI,QGXFWLRQLHDIWHUF\FOHVRIULWX[LPDE
5HVSRQVHVKRXOGEHDVVHVVHGDFFRUGLQJWRWKH&KHVRQUHVSRQVHFULWHULDIRU
LQGROHQW O\PSKRPD VHH $SSHQGL[  RU E\ WKH UHFRPPHQGDWLRQV IRU
:DOGHQVWU|P¶VPDFURJOREXOLQHPLDVHH$SSHQGL[3DWLHQWVZLWK3'DWDQ\
WLPH GXULQJ WKH VWXG\ ZLOO FRPH RII VWXG\ WUHDWPHQW DQG ZLOO VWDUW 2II
7UHDWPHQW)ROORZ8SEHLQJIROORZHGIRUVXUYLYDOXQWLOWKHHQGRIWKHVWXG\
3DWLHQWVZLWK6'DWWKHHQGRI,QGXFWLRQZLOOFRPHRIIVWXG\WUHDWPHQWDQGZLOO
HQWHU2II7UHDWPHQW)ROORZ8SEHLQJIROORZHGIRU3'DQGVXUYLYDOXQWLOWKH
HQGRIWKHVWXG\
0DLQWHQDQFH,6&ULWX[LPDEPDLQWHQDQFHWKHUDS\PXVWVWDUWZLWKLQZHHNVDIWHU
WKH DGPLQLVWUDWLRQ RI WKH ODVW GRVH RI ULWX[LPDE LQ WKH LQGXFWLRQ WKHUDS\ 0DLQWHQDQFH
WKHUDS\ZLOOFRQVLVWRIF\FOHVRIULWX[LPDEDGPLQLVWHUHGDVDVLQJOH6&LQMHFWLRQRI
PJULWX[LPDEHYHU\ZHHNVIRU\HDUV6HH6HFWLRQIRUGHWDLOVDERXWGRVH
PRGLILFDWLRQVLQWHUUXSWLRQVDQGGHOD\V
•

R 6WXG\9LVLW6FKHGXOHIRUSDWLHQWVGXULQJ0DLQWHQDQFH,ZLOORFFXUDFFRUGLQJ
WRWKH6FKHGXOHRI$VVHVVPHQWV7DEOH5HIHUWR6HFWLRQIRUGHWDLOV
•
5HVSRQVHDVVHVVPHQWZLOOEHFRQGXFWHGE\WKH,QYHVWLJDWRUHYHU\PRQWKVGXULQJ
0DLQWHQDQFH , DFFRUGLQJ WR WKH &KHVRQ UHVSRQVH FULWHULD IRU LQGROHQW O\PSKRPD

 
Rituximab - F. Hoffmann-La Roche Ltd 
Protocol MO25455 v4.0 
48 of 128 
(see Appendix 1) or by the recommendations for Waldenström’s macroglobulinemia2 
(see Appendix 2). Patients with PD at any time during the study will come off study 
treatment and will start Off-Treatment Follow-Up, being followed for survival until the 
end of the study.  Maintenance II: at the end of the 2-year Maintenance I, tumour 
response will be assessed and compared to the patient’s baseline status and 
patients with PR or CR (as determined by the Investigator using the Cheson 
response criteria,1 see Appendix 1, or by the recommendations for Waldenström’s 
macroglobulinemia,2 see Appendix 2) will be randomized to maintenance treatment 
with SC rituximab continued until progression or until EOS (Arm A) or observation 
with no further treatment (Arm B). Patients in Arm A will receive one SC rituximab 
injection at a fixed dose of 1400 mg every 8 weeks until PD, unacceptable toxicity, 
withdrawal of patient consent or until EOS.  
o Study Visit Schedule for patients during Maintenance II will occur according 
to the Schedule of Assessments (Table 5) and will include safety, disease 
progression, new anti-lymphoma treatments and survival; refers to Section 
5.1.3.3 for details. Disease progression will be evaluated by the Investigator 
every 6 months according to Cheson response criteria for indolent 
lymphoma1 (see Appendix 1) or by the recommendations for Waldenström’s 
macroglobulinemia2 (see Appendix 2). Patients with PD will come off study 
treatment and be followed for survival. 
 
3.1.1 
Rationale for Study Design  
Although the effectiveness of rituximab as a single agent and in conjunction with known 
chemotherapy regimens has made it a standard of care in the treatment of NHL, there is 
a clear medical need for an optimized route of administration and maintenance schedule. 
9,38 Results of several prospective trials and a recently published systematic review of 
randomized controlled trials suggest that maintenance therapy with rituximab, either as 4 
weekly infusions every 6 months or as a single infusion every 2-3 months, should be 
added to standard therapy for patients with relapsed or refractory (i.e. previously treated) 
FL after successful induction therapy. 64 However, the optimum rituximab maintenance 
regimen, including duration of treatment has not yet been determined.  
The current open label multinational randomized controlled trial will evaluate whether 
continuous maintenance therapy with SC rituximab compared to observation (no 
treatment) will provide additional clinical benefits and be safe in patients with relapsed, 
Grade 1, 2 or 3a CD20+ indolent NHL who responded to induction plus 2-year 
maintenance therapy with rituximab. The randomized controlled design will allow for an 
unbiased treatment allocation. Considering that the continuous maintenance treatment 
with rituximab will be compared with no treatment (observation only), allocation 
concealment is not feasible. PFS is a standard efficacy outcome and commonly selected 
as primary endpoint in clinical trials evaluating maintenance treatment in NHL. 3,59 
Rituximab maintenance therapy after effective induction has been shown to prolong 
progression-free survival, compared with no further treatment until relapse, in 
randomized, prospective phase III clinical trials in FL. In addition, the use of RM therapy 
is likely to have an important psychological and emotional impact for many patients. 
Currently, all patients are expected to relapse eventually following induction treatment: 
the knowledge that they are being actively treated to delay relapse for as long as 
possible may provide significant reassurance and emotional support. Overall, therefore, 

 
Rituximab - F. Hoffmann-La Roche Ltd 
Protocol MO25455 v4.0 
49 of 128 
rituximab maintenance therapy might be expected to improve quality of life for patients 
with FL over and above the observed clinical benefits in PFS.83  
The economic burden of follicular NHL is significant, but available data are generally 
limited to retrospective considerations of hospital-based direct treatment costs, with little 
information available regarding societal cost of illness, and with most direct cost 
information originating from the US. Rituximab is considered cost effective when added 
to induction chemotherapy, and when used as maintenance therapy. 84,85,86,87 However, 
no studies of per-patient or national indirect costs of illness were identified. In most 
studies the focus was on the direct costs of rituximab. 84  Therefore there is a need for 
more real-life cost data, particularly related to the extended maintenance dosing. These 
aspects will be addressed in the Time in Motion pharmacoeconomic sub-study (detailed 
in a separate protocol). 
3.1.2 
Rationale for Treatment 
Induction Treatment 
Given the options available for induction regimens, and varying benefits for each 
according to patient group and line of treatment, no single standard chemotherapy 
regimen has been universally adopted for the treatment of patients with NHL. Therefore 
the chemotherapy to be combined with SC rituximab will not be stipulated in the current 
study, although it will include only approved commercially available products. In keeping 
with current recommendations for induction therapy in the relapsed setting, the first IV 
infusion and 7 SC rituximab administrations will be required during induction in the 
current study before a patient demonstrating initial response (PR or CR) at the end of 
induction can proceed to maintenance treatment with single agent rituximab. Patients 
who were not able to receive their full dose of rituximab infusion in Cycle 1 as a result of 
an IRR should receive their second rituximab dose also IV, as such they will receive 6 
SC administrations (see Section 5.1.3.1). Prior exposure to rituximab induction (and 
maintenance in countries where prescribed) in the first-line setting is preferred as it will 
provide valuable information on the potential benefit and safety profile of rituximab re-
treatment.  
Considering that rituximab is currently not indicated for the treatment of indolent NHL 
other than low-grade malignant lymphoma or follicular lymphoma, the study will not 
mandate that patients with relapsed indolent NHL (other than FL) be previously treated 
with rituximab as first-line treatment. 
Maintenance Treatment  
The pivotal EORTC 20981 Intergroup study,3 the results of which formed the basis for 
submitting an application to the European Medicines Agency (EMA) for a new indication 
of rituximab maintenance therapy in FL used a once every 3-month dosing schedule. 
However, data from several phase II and pharmacokinetic studies reported after the start 
of the EORTC 20981 study suggested that a shorter interval between infusions may be 
more suitable to reach an adequate serum rituximab concentration level for all 
patients. 88 , 89  Data from a phase II study investigating individualised rituximab 
maintenance therapy found that to maintain the level of rituximab above 25 µg/mL after 
two prior rituximab infusions, patients required a repeat bolus at a median of 3 months 
after the second infusion. The range for this estimate was 2 - 4 months, suggesting that 
for some patients, a 3-month dosing interval may be inadequate to maintain rituximab 
serum concentration above 25 µg/mL.88 The scheme of rituximab maintenance therapy 
as one infusion every 8 weeks was further tested in two Phase II clinical trials, enrolling 

 
Rituximab - F. Hoffmann-La Roche Ltd 
Protocol MO25455 v4.0 
50 of 128 
patients with indolent (low-grade or follicular) NHL or patients with MCL. In both studies 
four additional doses of rituximab at 8-week intervals resulted in significantly prolonged 
EFS.55, 90  Consequently, the recently reported phase III randomized PRIMA study, 59 
compared rituximab maintenance therapy administered once every 2 months for 2 years 
to observation alone following a defined rituximab-containing induction therapy (R-CVP, 
R-CHOP or R-FCM) in 1217 patients with previously untreated FL. Maintenance 
rituximab, compared to observation alone, was associated with significantly higher PFS 
(74.9% vs. 57.6% respectively; HR 0.55, 95% CI 0.44 to 0.68; p < 0.0001) after a 
median follow-up of 36 months, and significantly higher CR/Cru rate (71.5% vs. 52.2%; p 
= 0.0001) 2 years after randomization. OS did not significantly differ between the groups.  
Importantly, rituximab maintenance was well tolerated in these studies, with a limited 
number of AEs leading to treatment discontinuation and no unexpected safety findings. 
59,75 
Currently there is one phase Ib randomized, open-label clinical study (BP22333) ongoing 
with rituximab SC in patients with FL. Study BP22333 comprises two stages: dose-
finding stage 1 and dose confirmation stage 2. In stage 2, the final fixed SC dose of 
1400 mg identified in stage 1 is administered to patients randomized to the SC arm until 
the end of maintenance therapy. Results from Stage 1 (n = 124) indicate that SC 
rituximab can be delivered quickly, comfortably and safely while achieving serum 
exposure comparable to the approved IV formulation of rituximab in FL patients during 
maintenance treatment. The study compared a maintenance regimen comprised of a 
single administration of one of four rituximab doses (375 mg/m2 IV, 375 mg/m2 SC, 625 
mg/m2 SC, or 800 mg/m2 SC), followed by rituximab IV every 2 or 3 months for a further 
year. Comparable rituximab concentrations at Ctrough and extent of serum exposure 
(AUC0–57) were achieved in patients administered rituximab SC between 625 mg/m2 and 
800mg/m2 and those administered rituximab 375 mg/m2 IV. Simulations of mean Ctrough 
values based on body surface area data from 54 patients predicted that a fixed dose of 
rituximab SC 1400 mg would be non-inferior to the rituximab IV dose of 375 mg/m2. 
Importantly, treatment with SC rituximab was well tolerated with an AE profile 
comparable to that of rituximab IV; while general reactions were very rare. There were 
no treatment-related SAEs, AEs leading to death, withdrawal or treatment 
discontinuation.80  
The above detailed Stage 1 PK data formed the basis for selecting the 1400 mg fixed 
SC dose testing as maintenance therapy in the current trial. 
3.1.3 
End of Study  
The end of study is defined as the last patient’s last visit in Maintenance II.  The study 
will end when all patients randomized in Maintenance II have been followed for at least 
15 months after randomization, or earlier if the 129th PFS event has been reported or 
one of the following is documented for all patients: disease recurrence, withdrawal from 
the study, loss to follow-up, or death.  
3.2 
NUMBER OF PATIENTS / ASSIGNMENT TO TREATMENT 
GROUPS 
Approximately 700 enrolled patients were expected to yield a minimum of 330 
randomized patients (maintenance II).  At the conclusion of enrolment and all 
randomizations 694 patients were enrolled and 276 patients were randomized to 
maintenance II.   

 
Rituximab - F. Hoffmann-La Roche Ltd 
Protocol MO25455 v4.0 
51 of 128 
The recruitment period was expected to be approximately 24 months.  Enrolment of the 
of 694 patients required 31 months 
3.3 
CENTRES 
This is a multinational, multicentre study, with approximately 190 centres worldwide.  
4. 
STUDY POPULATION 
4.1 
OVERVIEW 
The target population will consist of adults with relapsed or refractory CD20+ indolent 
follicular NHL Grade 1, 2 or 3a, or other CD20+ indolent NHL (Waldenström’s 
macroglobulinemia or lymphoplasmacytic lymphoma, marginal zone lymphoma) 
according to the WHO classification system. 
 
4.1.1 
Recruitment Procedures 
Patients will be identified for potential recruitment using pre-screening enrolment logs; 
Independent Ethics Committee (IEC) approved newspaper/radio advertisements and/or 
mailing lists.  
4.2 
INCLUSION CRITERIA 
Patients must fulfil all of the following criteria at enrolment (i.e. prior to the first dose of 
Induction Treatment): 
1. Signed, written informed consent form.  
2. Age ≥ 18 years.  
3. Histologically confirmed, CD20+ follicular NHL Grade 1, 2 or 3a, or other CD20+ 
indolent 
NHL 
(Waldenström’s 
macroglobulinemia 
or 
lymphoplasmacytic 
lymphoma, marginal zone lymphoma,) according to the WHO classification 
system. 
4. Patients must have received, and must have relapsed or been refractory to, one 
or more lines of adequate therapy prior to enrolment, including at least one line 
consisting of immunotherapy and/or chemotherapy and/or radiotherapy.  
Note: Rituximab administration in first line is not mandated, but preferred.  
5. Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2. 
4.3 
EXCLUSION CRITERIA 
A patient will be excluded if they meet any of the following criteria: 
DISEASE-SPECIFIC: 
1. Transformation to high-grade lymphoma. 
2. Patients with aggressive lymphoma (e.g. MCL). 
3. Presence or history of central nervous system (CNS) lymphomatous disease 
(e.g., CNS lymphoma or lymphomatous meningitis). 

 
Rituximab - F. Hoffmann-La Roche Ltd 
Protocol MO25455 v4.0 
52 of 128 
OTHER MEDICAL CONDITIONS OR TREATMENTS: 
4. Other malignancy within 5 years prior to enrolment, with the following exceptions 
(as long as curatively treated): carcinoma in situ of the cervix, squamous cell 
carcinoma of the skin, or basal cell skin cancer. Cervical carcinoma stage 1B or 
less, breast cancer in situ, or localized prostate cancer stage T1c or less may be 
considered, provided that the patient was treated with curative intent and has 
been relapse- and metastasis-free for at least 2 years prior to enrolment. 
5. Inadequate haematological function within 28 days prior to the first rituximab 
induction dose, defined as any of the following (unless the abnormality is related 
to bone marrow involvement by NHL): 
a. Haemoglobin (Hb) < 9.0 g/dL (5.6 mmol/L)  
b. Absolute neutrophil count (ANC) < 1.0 x 109/L  (1,000/µL) 
c. Platelet count < 100 x 109/L (100,000/µL); lower platelet count (but not 
below 50 x 109/L) is acceptable if due to toxicity of previous 
chemotherapy and not accompanied by bleeding. 
6. Patients with severe autoimmune cytopenias as assessed by the physician. 
Note: Coombs positive patients without clinical signs of autoimmune haemolytic 
anemia are eligible for enrolment. 
7. Inadequate hepatic function prior to the first rituximab induction dose, defined as 
any of the following:  
a. Total bilirubin > 1.5 times the upper limit of normal (ULN).  Note: patients 
with documented Gilbert disease may be enrolled if total bilirubin is ≤ 3.0 
x ULN. 
b. Alanine aminotransferase (ALT) and/or aspartate aminotransferase 
(AST) > 2.5 times the ULN 
c. Alkaline phosphatase > 2.5 times ULN 
8. Inadequate renal function prior to the first rituximab induction dose, defined as 
creatinine clearance (CrCl) < 30 mL/minute or serum creatinine > 2 mg/dL (197 
μmol/L). 
9. Known human immunodeficiency virus (HIV) infection.  
10. Active and/or severe infection (e.g. tuberculosis, sepsis and opportunistic 
infections, active hepatitis B virus (HBV) or active hepatitis C virus (HCV) 
infection). 
11. Other serious underlying medical conditions, which, in the Investigator’s 
judgment, could impair the ability of the patient to participate in the study (e.g., 
uncontrolled diabetes mellitus, gastric ulcers, active autoimmune disease). 
12. Known or suspected hypersensitivity to components of the investigational 
product, including known hypersensitivity or previous anaphylactic reaction to 
murine antibodies or proteins. 

 
Rituximab - F. Hoffmann-La Roche Ltd 
Protocol MO25455 v4.0 
53 of 128 
13. Regular corticosteroid use within 28 days prior to the first rituximab induction 
dose, 
unless 
administered 
at 
a 
dose 
equivalent 
to 
< 
20 
mg/day 
prednisone/prednisolone.  
Note: inhaled or topical corticosteroids are permitted. 
14. Major surgery (excluding lymph node biopsy) within 28 days prior to the first 
rituximab induction dose.  
15. Treatment with an investigational product within 30 days prior to enrolment. 
GENERAL: 
16. Inability to provide informed consent. 
17. Life expectancy of less than 6 months. 
18. History of poor compliance during previous lines of therapy. 
19. Pregnant or breastfeeding patients. A negative serum pregnancy test is required 
for women of childbearing potential within 7 days prior to first rituximab 
administration or within 14 days if with a confirmatory urine pregnancy test within 
7 days prior to the first rituximab administration. Women of childbearing potential 
are defined as pre-menopausal women or women who are < 2 years after the 
onset of menopause and are not surgically sterile. 
20. Fertile men or women of childbearing potential who do not agree to use a highly 
effective measure of contraception (such as oral contraceptives, intrauterine 
device or barrier method of contraception in conjunction with spermicidal jelly or 
surgically sterile) throughout the study and for at least 12 months after the last 
dose of rituximab.  
4.4 
CRITERIA FOR PROLONGED MAINTENANCE (MAINTENANCE 
II) 
In addition to the above listed enrolment criteria, patients must fulfil the following criteria 
in order to be randomized: 
1. Completed rituximab-based Induction and initial 2-year maintenance therapy with 
subcutaneous rituximab (Maintenance I). 
2. PR or CR as confirmed by computerized tomography (CT) after Maintenance I. 
Response assessment is completed according to the International Working Group 
response criteria for lymphoma1 (see Appendix 1) or by the recommendations 
for Waldenström’s macroglobulinemia2 (see Appendix 2). 
Note: Patients enrolled at sites using PET scan as part of their routine response 
assessment must have achieved CR or PR in CT scan according to the International 
Working Group (Cheson) response criteria for lymphoma.1  
Randomization will occur using a centralized interactive voice/web response system 
(IVRS/IWRS) in a 1:1 fashion, stratified according to indolent NHL subtype (FL, non-
follicular lymphoma), and FLIPI category (low risk, intermediate risk, high risk). 
Under no circumstances are patients who enrol in this study permitted to be re-entered 
onto the study for a second course of treatment. 


5LWX[LPDE)+RIIPDQQ/D5RFKH/WG
3URWRFRO02Y
RI

&21&20,7$170(',&$7,21$1'75($70(17
$OOPHGLFDWLRQVSUHVFULSWLRQDQGRYHUWKHFRXQWHUGUXJVWDNHQZLWKLQGD\VSULRUWR
VWXG\VFUHHQLQJPXVWEHUHFRUGHGRQWKHHOHFWURQLFFDVHUHSRUWIRUPH&5),QDGGLWLRQ
DQ\ GLDJQRVWLF WKHUDSHXWLF RU VXUJLFDO SURFHGXUH SHUIRUPHG GXULQJ WKH VWXG\ SHULRG
VKRXOG EH UHFRUGHG LQFOXGLQJ WKH GDWH LQGLFDWLRQ GHVFULSWLRQ RI WKH SURFHGXUHV DQG
DQ\FOLQLFDOILQGLQJV3DWLHQWVVKRXOGUHFHLYHIXOOVXSSRUWLYHFDUHVXFKDV*&6)VXSSRUW
WUDQVIXVLRQVRIEORRGDQGEORRGSURGXFWVDQWLELRWLFVDQWLHPHWLFVHWFZKHUHDSSOLFDEOH
7KH UHDVRQV IRU WUHDWPHQW GRVDJH DQG GDWHV RI WUHDWPHQW PXVW EH UHFRUGHG LQ WKH
H&5)

3HUPLVVLEOH&RQFRPLWDQW0HGLFDWLRQDQG7UHDWPHQW

3URSK\OD[LVRILQIXVLRQLQMHFWLRQUHODWHGUHDFWLRQV
,QRUGHUWRUHGXFHWKHLQFLGHQFHDQGVHYHULW\RILQIXVLRQRULQMHFWLRQUHODWHGUHDFWLRQVLW
LVUHFRPPHQGHGWKDWDOOSDWLHQWVUHFHLYHWKHIROORZLQJSUHPHGLFDWLRQDGPLQLVWHUHG
PLQXWHVSULRUWRHDFKULWX[LPDEDGPLQLVWUDWLRQ
•
SDUDFHWDPRODFHWDPLQRSKHQ
•
GLSKHQK\GUDPLQHK\GURFKORULGHRUDOWHUQDWLYHDQWLKLVWDPLQH
•
VWHURLGVSUHGQLVRQHSUHGQLVRORQH
3UHPHGLFDWLRQ ZLWK JOXFRFRUWLFRLGV VKRXOG EH FRQVLGHUHG LI ULWX[LPDE LV QRW JLYHQ LQ
FRPELQDWLRQ ZLWK JOXFRFRUWLFRLGFRQWDLQLQJ FKHPRWKHUDS\ ,I JLYHQ WKHVH PHGLFDWLRQV
PXVWEHGRFXPHQWHGRQWKH&RQFRPLWDQW0HGLFDWLRQVH&5)
5LWX[LPDE VKRXOG EH DGPLQLVWHUHG RQ 'D\  RI HDFK F\FOH DIWHU LQWUDYHQRXV
DGPLQLVWUDWLRQRIWKHJOXFRFRUWLFRLGFRPSRQHQWRIWKHFKHPRWKHUDS\LIDSSOLFDEOH

3URSK\OD[LVRIQDXVHDDQGYRPLWLQJ
3UHPHGLFDWLRQWRSUHYHQWQDXVHDDQGYRPLWLQJLVDOORZHGDVSHULQVWLWXWLRQDOSUDFWLFH
7KH\ VKRXOG EH DGPLQLVWHUHG SULRUWRWKHFKHPRWKHUDS\ DGPLQLVWUDWLRQDQG VKRXOG EH
GRFXPHQWHGRQWKH&RQFRPLWDQW0HGLFDWLRQVH&5)DFFRUGLQJO\

$QWLPLFURELDODQGDQWLYLUDOSURSK\OD[LV
$QWLPLFURELDODQGDQWLYLUDOSURSK\OD[LVPD\EHXVHGDVSHULQVWLWXWLRQDOSUDFWLFH,IJLYHQ
WKH\PXFKEHGRFXPHQWHGRQWKH&RQFRPLWDQW0HGLFDWLRQVH&5)

3URSK\OD[LVIRUKDHPRUUKDJLFF\VWLWLV
0HVQD0HUFDSWR(WKDQH6XOIRQDWHVRGLXPPD\EHXVHGDVSURSK\OD[LVDFFRUGLQJWR
LQVWLWXWLRQDOSUDFWLFHDQGVKRXOGEHGRFXPHQWHGRQWKH&RQFRPLWDQW0HGLFDWLRQVH&5)

7XPRXUO\VLVV\QGURPHSURSK\OD[LV
7XPRXU O\VLV V\QGURPH 7/6 GHVFULEHV WKH PHWDEROLF GHUDQJHPHQWV WKDW RFFXU ZLWK
WXPRXUEUHDNGRZQIROORZLQJWKHLQLWLDWLRQRIF\WRWR[LFWKHUDS\7KHPHWDEROLWHVUHOHDVHG
LQ 7/6 FDQ RYHUZKHOP WKH ERG\
V QRUPDO KRPHRVWDWLF PHFKDQLVPV FDXVH
K\SHUXULFDHPLDK\SHUNDODHPLDK\SHUSKRVSKDHWHPLDK\SRFDOFDHPLDDQGXUDHPLDDQG
OHDG WR DFXWH UHQDO IDLOXUH 3URSK\OD[LV DJDLQVW 7/6 PD\ EH JLYHQ DV SHU LQVWLWXWLRQDO
SUDFWLFHDQGVKRXOGEHGRFXPHQWHGRQWKH&RQFRPLWDQW0HGLFDWLRQVH&5)DFFRUGLQJO\

+\GUDWLRQDONDOL]DWLRQRIXULQHDQGXURVWDWLFV
7KH PDLQVWD\V RI 7/6 SUHYHQWLRQ LQFOXGH K\GUDWLRQ DQG SURSK\ODFWLF UDVEXULFDVH
UHFRPELQDQW XUDWH R[LGDVH LQ KLJKULVN SDWLHQWV K\GUDWLRQ SOXV DOORSXULQRO RU


5LWX[LPDE)+RIIPDQQ/D5RFKH/WG
3URWRFRO02Y
RI
UDVEXULFDVH IRU LQWHUPHGLDWHULVN SDWLHQWV DQG FORVH PRQLWRULQJ RI HOHFWURO\WH
DEQRUPDOLWLHV IRU ORZULVN SDWLHQWV 3ULPDU\ PDQDJHPHQW RI HVWDEOLVKHG 7/6 LQYROYHV
VLPLODU UHFRPPHQGDWLRQV ZLWK WKH DGGLWLRQ RI DJJUHVVLYH K\GUDWLRQ DQG GLXUHVLV SOXV
DOORSXULQRO
RU
UDVEXULFDVH
IRU
K\SHUXULFHPLD
ZKHUHDV
DONDOLQL]DWLRQ
LV
QRW
UHFRPPHQGHG
5HFHQWO\ IRXU FDVHV RI 6WHYHQV-RKQVRQ6\QGURPH7R[LF HSLGHUPDO QHFURO\VLV
6-67(1 KDYH EHHQ UHSRUWHG LQ SDWLHQWV ZKR ZHUH WUHDWHG ZLWK DOORSXULQRO DQG
EHQGDPXVWLQHZLWKRUZLWKRXWULWX[LPDE7KHUHPD\EHDQLQFUHDVHGULVNRIVHYHUHVNLQ
WR[LFLW\ZKHQEHQGDPXVWLQHDQGDOORSXULQRODUHDGPLQLVWHUHGFRQFRPLWDQWO\$OORSXULQRO
VKRXOGEHXVHGZLWKFDXWLRQDQGRQO\LIGHHPHGQHFHVVDU\E\WKHWUHDWLQJSK\VLFLDQEXW
QRWDVDVWDQGDUGSUHYHQWLYHPHDVXUHIRUSRVVLEOHWXPRXUO\VLVV\QGURPH3UHYHQWLYH
PHDVXUHVLQFOXGHPDLQWDLQLQJDGHTXDWHYROXPHVWDWXVDQGFORVHPRQLWRULQJRIVHUXP
FKHPLVWU\ SDUWLFXODUO\ SRWDVVLXP DQG XULF DFLG OHYHOV ,I SDWLHQWV H[SHULHQFH DQ\ VNLQ
UHDFWLRQV GXULQJ WUHDWPHQW WKH\ VKRXOG EH PRQLWRUHG FORVHO\ DQG LQ FDVH RI DQ\
VXVSLFLRQ RI HYROYLQJ WR D VHULRXV PXFRFXWDQHRXV UHDFWLRQ WUHDWPHQW ZLWK DQ\
VXVSHFWHG GUXJV LQFOXGLQJ EXW QRW OLPLWHG WR EHQGDPXVWLQH ULWX[LPDE DOORSXULQRO DQG
DPR[LFLOOLQVKRXOGEHGLVFRQWLQXHGXQWLOFRPSOHWHUHVROXWLRQRIHYHQW

2WKHU3UHPHGLFDWLRQ
,QVWLWXWLRQV VKRXOG IROORZ WKHLU VWDQGDUG SUHPHGLFDWLRQ SURFHGXUHV UHJDUGLQJ RWKHU
VXSSRUWLYHFDUHLQFOXGLQJWUDQVIXVLRQVRIEORRGDQGEORRGSURGXFWVRUKDHPDWRSRLHWLF
FRORQ\VWLPXODWLQJ IDFWRUV *&6) 5HJXODU DSSOLFDWLRQ RI *&6) LV QRW JHQHUDOO\
UHFRPPHQGHG +RZHYHU LW VKRXOG EH DSSOLHG DFFRUGLQJ WR WKH $6&2 JXLGHOLQHV
HVSHFLDOO\LQFDVHRILQIHFWLRQVDQGSURORQJHGQHXWURSHQLDLQSUHYLRXVF\FOHV

3URKLELWHG&RQFRPLWDQW0HGLFDWLRQDQG7UHDWPHQW
7KHIROORZLQJWUHDWPHQWVDUHSURKLELWHGGXULQJVWXG\WUHDWPHQW
•
,QYHVWLJDWLRQDORUXQOLFHQVHGXQDSSURYHGDJHQWVRIDQ\W\SH
•
2WKHUFRQFRPLWDQWDQWLWXPRXUDJHQWVQRWGHILQHGLQWKLVSURWRFRODVVWXG\WUHDWPHQW
LQFOXGLQJO\PSKRPDWKHUDSHXWLFGRVHVRIJOXFRFRUWLFRVWHURLGV
3DWLHQWVUHFHLYLQJDQ\RIWKHSURKLELWHGWKHUDSLHVZLOOEHGLVFRQWLQXHGDQGIROORZHGIRU
VXUYLYDO 3DWLHQWV ZKRVH VWXG\ WUHDWPHQW LV GLVFRQWLQXHG GXH WR UHDVRQV RWKHU WKDQ
SURJUHVVLYHGLVHDVHZLOOFRQWLQXHWREHIROORZHGXQWLOSURJUHVVLRQRUGHDWK
3DWLHQWVVKRXOGQRWUHFHLYHORQJWHUPWUHDWPHQW!PRQWKZLWKFRUWLFRVWHURLGVRWKHU
WKDQ LQWHUPLWWHQW GH[DPHWKDVRQH WR FRQWURO RU SUHYHQW QDXVHD RU YRPLWLQJ RU
FRUWLFRVWHURLGVIRUQRQLQIHFWLYHH[DFHUEDWLRQVRIDVWKPDRUUHVSLUDWRU\GLVHDVH
1RQVWHURLGDOKRUPRQHVDGPLQLVWHUHGIRUQRQO\PSKRPDUHODWHGFRQGLWLRQVHJLQVXOLQ
IRUGLDEHWHVDUHSHUPLWWHG
,WLVUHFRPPHQGHGWKDWDQ\FRXUVHRILPPXQL]DWLRQIRUSDWLHQWVVKRXOGEHFRPSOHWHGDW
OHDVW ZHHNV EHIRUH VWDUWLQJ ULWX[LPDE ,QGXFWLRQ DQG SDWLHQWV VKRXOG QRW UHFHLYH DQ\
YDFFLQDWLRQVWKDWFRQWDLQOLYHRUDWWHQXDWHGRUJDQLVPVGXULQJWKHVWXG\

&5,7(5,$)2535(0$785(:,7+'5$:$/
3DWLHQWVKDYHWKHULJKWWRZLWKGUDZIURPWKHVWXG\DWDQ\WLPHIRUDQ\UHDVRQ6KRXOGD
SDWLHQWGHFLGHWRZLWKGUDZKHVKHZLOOEHHQFRXUDJHGWRUHWXUQWRWKHVWXG\FHQWUHZLWKLQ
ZHHNVIRUDQHQGRIWUHDWPHQWHYDOXDWLRQVHH6HFWLRQDOOHIIRUWVZLOOEHPDGHWR


5LWX[LPDE)+RIIPDQQ/D5RFKH/WG
3URWRFRO02Y
RI
FRPSOHWHDQGUHSRUWWKHREVHUYDWLRQVSULRUWRZLWKGUDZDODVWKRURXJKO\DVSRVVLEOH7KH
SULPDU\UHDVRQIRUGLVFRQWLQXDWLRQPXVWEHUHFRUGHGRQWKHDSSURSULDWHH&5)SDJH
'LVFRQWLQXLQJ SDWLHQWV VKRXOG DOVR EH DVNHG LI WKH\ FDQ VWLOO EH FRQWDFWHG IRU IXUWKHU
LQIRUPDWLRQ7KHRXWFRPHRIWKDWGLVFXVVLRQVKRXOGEHGRFXPHQWHGLQERWKWKHPHGLFDO
UHFRUGVDQGLQWKHH&5),IORVWWRIROORZXSWKH,QYHVWLJDWRUVKRXOGFRQWDFWWKHSDWLHQW
RU D UHVSRQVLEOH UHODWLYH WR HVWDEOLVK DV FRPSOHWHO\ DV SRVVLEOH WKH UHDVRQ IRU WKH
ZLWKGUDZDO
%HVLGHVGXHWRGLVHDVHSURJUHVVLRQWKH,QYHVWLJDWRUPD\GLVFRQWLQXHVWXG\WUHDWPHQW
DQGRUZLWKGUDZSDWLHQWVIURPWKHVWXG\IRUWKHIROORZLQJUHDVRQV
•
,QWHUFXUUHQWLOOQHVV
•
2FFXUUHQFHRIOLIHWKUHDWHQLQJRUVHYHUHUHDFWLRQV
•
2FFXUUHQFHRI7/6
•
$Q\VLJQLILFDQW$(WKDWFRPSURPLVHVWKHSDWLHQW¶VDELOLW\WRSDUWLFLSDWHLQWKHVWXG\
•
3UHJQDQF\
•
1HHGIRUSURKLELWHGWUHDWPHQWVHH6HFWLRQ
•
/DFNRIFRPSOLDQFHZLWKWKHVWXG\DQGRUVWXG\SURFHGXUHVHJGRVLQJLQVWUXFWLRQV
VWXG\YLVLWV
•
$Q\UHDVRQZKHUHWKHLQYHVWLJDWRUFRQVLGHUVWKDWZLWKGUDZDOLVLQWKHEHVWLQWHUHVWRI
WKHSDWLHQW
$OOHQGRIWUHDWPHQWSURFHGXUHVVKRXOGEHSHUIRUPHGDWWKHWLPHRIGLVFRQWLQXDWLRQ
3DWLHQWV VKRXOG EH LQIRUPHG RI FLUFXPVWDQFHV XQGHU ZKLFK WKHLU SDUWLFLSDWLRQ PD\ EH
WHUPLQDWHGE\WKH,QYHVWLJDWRUZLWKRXWWKHLUFRQVHQW
7KHUHDVRQVIRUWUHDWPHQWGLVFRQWLQXDWLRQDQGRUZLWKGUDZDOPXVWEHGRFXPHQWHGLQ
WKH H&5) ,Q FDVH RI GHDWK RU GLVHDVH SURJUHVVLRQ WKH 'HDWK H&5) RU
3URJUHVVLRQUHODSVH H&5) SDJHV PXVW EH FRPSOHWHG UHVSHFWLYHO\ ,I WKH UHDVRQ IRU
WUHDWPHQWGLVFRQWLQXDWLRQDQGRUZLWKGUDZDOLVDQ$(WKHSULQFLSDOVSHFLILFHYHQWZLOOEH
UHFRUGHG RQ WKH H&5) 7KH SDWLHQW VKRXOG EH IROORZHG XQWLO WKH $( KDV UHVROYHG RU
UHDFKHGDVWDEOHFKURQLFFRQGLWLRQ
$Q H[FHVVLYH UDWH RI ZLWKGUDZDOV FDQ UHQGHU WKH VWXG\ QRQLQWHUSUHWDEOH WKHUHIRUH
XQQHFHVVDU\ ZLWKGUDZDO RI SDWLHQWV VKRXOG EH DYRLGHG 7R WKH H[WHQW IHDVLEOH
GLVFRQWLQXDWLRQV VKRXOG EH OLPLWHG WR WKH VWXG\ WUHDWPHQW RQO\ ZLWK IXUWKHU IROORZXS
FRQWLQXLQJXQWLOWKHHQGRIWKHVWXG\

5(3/$&(0(1732/,&<

)RU3DWLHQWV
3DWLHQWVUDQGRPL]HGLQWRWKHVWXG\ZLOOQRWEHUHSODFHG

)RU&HQWUHV
$FHQWUHPD\EHUHSODFHGIRUWKHIROORZLQJDGPLQLVWUDWLYHUHDVRQV
•
([FHVVLYHO\VORZUHFUXLWPHQW


5LWX[LPDE)+RIIPDQQ/D5RFKH/WG
3URWRFRO02Y
RI
•
3RRUDGKHUHQFHWRWKHSURWRFRORU*RRG&OLQLFDO3UDFWLFHV
•
,QDFFXUDWHLQDSSURSULDWHFOLQLFDOGDWDHQWU\LQWRWKHH&5)V
•
([FHVVLYHO\VORZVXEPLVVLRQRIVWXG\GDWDWRWKH6SRQVRU


6&+('8/(2)$66(660(176$1'352&('85(6
$ VXPPDU\ RI YLVLWV DQG FOLQLFDO SURFHGXUHV LV IRXQG LQ 7DEOH  6FKHGXOH RI
DVVHVVPHQWVDQGSURFHGXUHV


 
Rituximab - F. Hoffmann-La Roche Ltd 
Protocol MO25455 v4.0 
58 of 128 
Table 5 SCHEDULE OF ASSESSMENTS 
 
Study Period  
Screening / 
Baseline 
Visit 
Induction  
Rituximab IV/SC +/- Chemotherapy [a] 
Maintenance I 
Rituximab SC 
Maintenance II 
A: Rituximab SC  
B: Observation 
End of  
Treatment  
Off-Treatment 
Follow-up 
Visit  
 
V1-V4 
Staging 
[b] 
V5-V8 
Staging 
[c] 
V9-V20 
Staging 
[d] 
V21+ 
 
 
Timing / Assessments 
D-28 to D-1 
D1 every 
21-28 days [± 2 
days] 
4 cycles 
 
End  
Cycle 3 or 4 
D1 every 
21-28 days 
[± 2 days] 
4 cycles 
 
End Cycle 
8 
(End of 
induction 
therapy) 
D1 every 8 wks 
[56 ± 7 days]  
12 cycles [2 yrs] 
End 
mainten. 
therapy 
D1 every 8 wks 
[56 ± 7 days] 
until PD or EOS 
Within 4 weeks of 
last dose 
Every 6 months  
until EOS 
[± 14 days] 
Written informed consent [e] 
X 
 
 
 
 
 
 
 
 
 
Demographic data 
X 
 
 
 
 
 
 
 
 
 
NHL diagnosis and Ann Arbor staging [f] 
X 
 
 
 
 
 
 
 
 
 
Bone marrow assessment [g] 
X 
 
If CR and 
baseline 
involvement 
 
If CR and 
baseline 
involveme
nt 
If CR and baseline 
involvement 
If CR and 
baseline 
involvement 
If CR and baseline 
involvement 
 
If CR and 
baseline 
involvement 
Medical history  
X 
 
 
 
 
 
 
 
 
 
Documentation of/testing  for HIV, hepatitis 
and other infections [h] 
X 
 
 
 
 
 
 
 
 
 
12-lead ECG 
X 
 
 
 
 
 
 
 
 
 
Tumour evaluation using CT scan [i] 
X 
 
X 
 
X 
Every 6 months 
(V11, V14,  V17, 
V20) 
X 
Every 6 months 
(V23, V26, V29, 
etc.) 
 
X 
Physical examination, infection assessment, 
vital signs [j] 
X 
X 
 
X 
X 
X 
 
X 
X 
 
Height, weight and BSA 
X 
 
 
 
 
 
 
 
 
 
FLIPI score [k] 
X 
 
 
 
 
 
 
 
 
 
ECOG performance status [l] 
X 
 
X 
 
X 
X 
X 
X 
X 
 
Serum pregnancy test [m] 
X 
 
 
 
 
 
 
 
 
 
Safety laboratory: haematology and 
biochemistry [n]  
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
IgG, IgM and IgA quantification [o] 
X 
 
 
 
X 
Every 12 months 
(V14, V20) 
 
Every 12 months 
(V26, V32, etc.) 
 
 
Review of inclusion / exclusion criteria 
X 
 
 
 
 
 
 
 
 
 

 
Rituximab - F. Hoffmann-La Roche Ltd 
Protocol MO25455 v4.0 
59 of 128 
Study Period  
Screening / 
Baseline 
Visit 
Induction  
Rituximab IV/SC +/- Chemotherapy [a] 
Maintenance I 
Rituximab SC 
Maintenance II 
A: Rituximab SC  
B: Observation 
End of  
Treatment  
Off-Treatment 
Follow-up 
Visit  
 
V1-V4 
Staging 
[b] 
V5-V8 
Staging 
[c] 
V9-V20 
Staging 
[d] 
V21+ 
 
 
Timing / Assessments 
D-28 to D-1 
D1 every 
21-28 days [± 2 
days] 
4 cycles 
 
End  
Cycle 3 or 4 
D1 every 
21-28 days 
[± 2 days] 
4 cycles 
 
End Cycle 
8 
(End of 
induction 
therapy) 
D1 every 8 wks 
[56 ± 7 days]  
12 cycles [2 yrs] 
End 
mainten. 
therapy 
D1 every 8 wks 
[56 ± 7 days] 
until PD or EOS 
Within 4 weeks of 
last dose 
Every 6 months  
until EOS 
[± 14 days] 
Enrolment via eCRF 
Review of criteria for prolonged 
maintenance 
Randomization by IVRS\IWRS 
 
 
 
 
 
 
 
V21 
 
 
Rituximab treatment administration [p]  
 
X 
 
X 
 
X 
 
X [u] 
 
 
Adverse event recording [q]  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant treatments & therapies [r] 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Assessment of disease status, including 
progression [t] 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
Survival 
 
 
 
 
 
 
 
 
 
X 
a. 
Approved commercially available chemotherapy can include bendamustine, CHOP, CVP, FCM, MCP, CHVP-IFN, chlorambucil or any fludarabine-containing regimen including oral 
fludarabine, GIFOX; selection at the Investigator’s discretion 
b. 
Staging assessment performed within 14–28 days after D1 of Visit when the Induction treatment includes 8 cycles of chemotherapy (or within 14–28 days after D1 of Visit 3 when 
the Induction treatment includes 6 cycles of chemotherapy. Refer to Section 6.1.1 for chemotherapy options. 
c. 
Staging assessment performed within 14–28 days after day 1 of the last cycle of rituximab-based Induction. The second tumour staging will occur after the 8th cycle of rituximab-
based Induction treatment. 
d. 
Staging: Post-maintenance assessment performed within 28 days of the last rituximab maintenance dose, with results compared to the patient’s baseline status. The required 
procedures can be performed either at the previous visit or at staging. 
e. 
Signed informed consent must be obtained prior to any baseline assessments or activities. 
f. 
Diagnosis of non-Hodgkin’s lymphoma must have included histological diagnosis and initial CD20 expression confirmation. 
g. 
For patients who have had a previous bone marrow assessment within 6 months prior to enrollment:  1) if bone marrow involvement was documented, these patients are 
considered positive and do not require another bone marrow assessment prior to entering the study; 2) if bone marrow involvement was not documented, another bone marrow 
assessment is only required prior to entering the study if the patient now exhibits signs/symptoms suggesting bone marrow involvement (e.g. anemia without haemolysis, 
thrombocytopenia, etc.).  For patients who had a bone marrow assessment ≥ 6 months prior to enrolment, or who have not had a previous bone marrow assessment, a baseline 

 
Rituximab - F. Hoffmann-La Roche Ltd 
Protocol MO25455 v4.0 
60 of 128 
bone marrow assessment must be done within 28 days prior to the first rituximab induction dose.  In addition, bone marrow assessments are required to confirm any suspected CR 
in patients with bone marrow involvement at baseline. Once the CR is confirmed bone marrow assessment is not needed unless clinically indicated. 
h. 
Patients known to have HIV, Hepatitis C, active Hepatitis B or signs or symptoms of other active and/or severe infection must not be included in the study. Serology should be 
performed according to clinical judgment before and during treatment with rituximab. Patients found to have HIV, Hepatitis C or active Hepatitis B must either not start, or stop 
rituximab induction/maintenance therapy and enter active follow-up. Local guidelines for patient consent to viral testing must be adhered to. 
i. 
Tumour assessments will be based on CT scans with contrast: neck (if clinically indicated), chest, abdomen and pelvis (if detectable by these techniques) to document nodal 
disease or organ involvement.  Other diagnostic means are acceptable for lymphomas that cannot be diagnosed radiographically (e.g. gastroscopy in patients with follicular 
lymphoma of the stomach). The CT scan used for eligibility assessment may be up to 8 weeks old prior to study entry. The on-treatment CT scan used for response assessment 
may be up to 8 weeks old and should be compared to pre-induction CT. The end-of-Induction response assessment including radiology/imaging report must be provided within 8 
weeks of the last Induction cycle. At the end of the 2-year rituximab maintenance period, tumour response will be assessed and compared to the patient’s baseline status.  Patients 
with CR or PR will be randomized. Patients with PD at any time during the study will come off study treatment and will start Off-Treatment Follow-Up, being followed every 6 
months for survival until the end of the study.  Patients with SD at the end of Induction will come off study treatment and will enter Off-Treatment Follow-Up, being followed every 6 
months for PD and survival until the end of the study.  Achievement of CR after initial PR on rituximab maintenance therapy should be recorded. Patients maintaining response 
may continue receiving treatment. Bone marrow assessments are required to confirm any suspected CR in patients with bone marrow involvement at baseline.  In patients not 
progressing at EOS treatment, tumour assessments should be done every 6 months until PD. 
j. 
Patients should be assessed for presence of active infections throughout the treatment periods. Vital signs assessment includes resting heart rate, body temperature and blood 
pressure.  
k. 
FLIPI score determined at baseline (prior to the first Induction dose). Where possible, the baseline FLIPI score should be calculated from the patient notes. Missing FLIPI scores 
will not preclude enrolment or randomization. 
l. 
ECOG performance status needs to be ≤ 2 for inclusion of the patient into the study. 
m. 
Women of childbearing potential (defined as pre-menopausal women or women who are < 2 years after the onset of menopause and not surgically sterile) must undergo serum 
pregnancy test within 7 days prior to first rituximab administration or within 14 days if with a confirmatory urine pregnancy test within 7 days prior to the first rituximab administration.  
n. 
Haematology parameters will include haemoglobin, haematocrit, red blood cell count, white blood cell count with differentials, and platelet count. Biochemistry parameters will 
include sodium, potassium, calcium, phosphate, alanine aminotransferase (ALT/SGPT), total bilirubin, serum creatinine, alkaline phosphatase, albumin, BUN, C-reactive protein 
and Lactate Dehydrogenase (LDH), and if possible aspartate aminotransferase (AST/SGOT). The results from the safety laboratory assessments must be available on the day of 
rituximab administrations. 
o. 
After baseline, IgG, IgM and IgA quantification will be completed once a year during the 2-year rituximab maintenance period (maintenance injections #6 and #12), once a year 
during randomized  rituximab maintenance (Arm A) and in case of suspicious infections. The results from these assessments must be available on the day of the next rituximab 
injection. Samples can be taken up to two weeks before the date of injection. In case the results of the Ig measurements could not be obtained before the planned treatment 
administration, the treatment does not have to be postponed until the Ig results become available. However, the Ig results must be reviewed as soon as possible and a new sample 
for Ig measurement must be drawn before the next injection visit in order to have the new Ig results available for the next injection visit. 
p. 
The first rituximab dose during Induction will be administered as IV infusion on Day 1 of Cycle 1, at a dose of 375 mg/m2 BSA. In the absence of an IRR, subsequent rituximab 
doses will be administered SC, on Day 1 of each Induction cycle at a fixed dose of 1400 mg. Patients who experienced a grade 3 or 4 IRR after the first rituximab infusion (Cycle 1), 
but were able to receive the full dose of rituximab, can receive the second dose of rituximab SC (Cycle 2, Day 1). Patients who were not able to receive their full dose of rituximab 
infusion in Cycle 1 as a result of IRR should receive their second rituximab dose also IV. If this second rituximab infusion is not associated with a grade 3 or 4 IRR, the patient will 
receive his/her third rituximab dose SC (Cycle 3, Day 1). Patients with grade 3 or 4 IRR after the second rituximab infusion will be withdrawn from the study. Induction 
chemotherapy selected by the study Investigator will be administered in accordance with schedules outlined in Section 6.1.1 of the protocol.  The first rituximab maintenance dose 
must be administered within 8 -12 weeks after the administration of the last dose of rituximab in the induction therapy (see Section 6.1.2). The first visit in maintenance II must 
occur 8 weeks (± 7 days) after the administration of the last dose of rituximab in maintenance I (see Section 6.1.2). 
q. 
After ICF signing, but prior to initiation of any study drugs, only SAEs caused by a protocol-mandated intervention (e.g. an invasive procedure such as biopsy or medication 
washout) will be collected.  All AEs reported during the study will be documented and graded using the NCI CTC-AE criteria, version 4.0. Serious adverse events (SAEs) will be 
reported according to the ICH E2 Guideline for Clinical Safety Data Management, Definitions and Standards for Expedited Reporting; refer to Section 7.1.2.  Once a patient has 
permanently discontinued study treatment, all SAEs will continue to be followed until resolution. 


5LWX[LPDE)+RIIPDQQ/D5RFKH/WG
3URWRFRO02Y
RI
U
5HFRUGLQJRIFRQFRPLWDQWWUHDWPHQWV	WKHUDSLHVZLOOLQFOXGHDQ\QHZDQWLO\PSKRPDWUHDWPHQWLQLWLDWHGDIWHUWKHEDVHOLQHYLVLW,QSDWLHQWVZKRKDYHSHUPDQHQWO\GLVFRQWLQXHG
VWXG\WUHDWPHQWRQO\QHZDQWLO\PSKRPDWUHDWPHQWVZLOOEHUHFRUGHG




W
)RUUHTXLUHPHQWVUHJDUGLQJWXPRXUHYDOXDWLRQVUHIHUWRLWHP³K´DERYH&OLQLFDODVVHVVPHQWRIGLVHDVHVWDWXVVKRXOGEHPDGHDWDOOYLVLWVE\,QYHVWLJDWRUVDFFRUGLQJWRORFDO
SUDFWLFH3URJUHVVLRQRIGLVHDVHSK\VLFDOH[DPLQDWLRQLVWREHDVVHVVHGIURP9LVLWRQZDUGV'XULQJWKHUDQGRPL]HGWUHDWPHQWSHULRGSDWLHQWVLQWKHULWX[LPDE6&PDLQWHQDQFH
DUP ZLOO EH WUHDWHG XQWLO 3' XQDFFHSWDEOH WR[LFLW\ ZLWKGUDZDO RI SDWLHQW FRQVHQW RU XQWLO (26 $OO SDWLHQWV LQ $UP $ DQG $UP % ZLOO EH DFWLYHO\ IROORZHG IRU VDIHW\ WXPRXU
UHVSRQVHSURJUHVVLRQQHZDQWLO\PSKRPDWUHDWPHQWVDQGVXUYLYDOIRUDWOHDVWPRQWKVDIWHUUDQGRPL]DWLRQ(QUROOHGSDWLHQWVZKRGRQRWFRPSOHWHWUHDWPHQWSHUSURWRFROIRUDQ\
UHDVRQZLOOXQGHUJRWKHHQGRIWUHDWPHQWDVVHVVPHQWDQGHQWHU2II7UHDWPHQW)ROORZXS3DWLHQWVZLWK3'DWDQ\WLPHGXULQJWKHVWXG\ZLOOFRPHRIIVWXG\WUHDWPHQWDQGZLOOVWDUW
2II7UHDWPHQW)ROORZ8SEHLQJIROORZHGIRUVXUYLYDOXQWLOWKHHQGRIWKHVWXG\3DWLHQWVZLWK6'DWWKHHQGRI,QGXFWLRQZLOOFRPHRIIVWXG\WUHDWPHQWDQGZLOOHQWHU2II7UHDWPHQW
)ROORZ8SEHLQJIROORZHGIRU3'DQGVXUYLYDOXQWLOWKHHQGRIWKHVWXG\
X
1RWDSSOLFDEOHIRUSDWLHQWVLQ$UP%REVHUYDWLRQQRWUHDWPHQW

1RWH
•
$IWHUWKHHQGRIWUHDWPHQWRUWKHHQGRISDUWLFLSDWLRQLQREVHUYDWLRQDUP%DOOSDWLHQWVZLOOHQWHU2II7UHDWPHQW)ROORZXSDQGEHIROORZHGIRUUHVROXWLRQRI$(VUHODWHGWR6&
ULWX[LPDELQGXFWLRQPDLQWHQDQFHWKHUDS\DVSHU7DEOHVXUYLYDOGLVHDVHVWDWXVZKLFKPLJKWLQFOXGHERQHPDUURZDQGWXPRXUDVVHVVPHQWLI3'QRWDOUHDG\GRFXPHQWHGDQG
ZKHWKHUDQHZDQWLO\PSKRPDWUHDWPHQWKDVEHHQVWDUWHG
•
)RUGHWDLOVRQWKHDVVHVVPHQWVRU0HGLFDO&DUH8WLOL]DWLRQSDUDPHWHUVSOHDVHUHIHUWRWKH7LPHLQ0RWLRQSKDUPDFRHFRQRPLF6XEVWXG\SURWRFRO


5LWX[LPDE)+RIIPDQQ/D5RFKH/WG
3URWRFRO02Y
RI

6&+('8/(2)$66(660(176

6FUHHQLQJDQGEDVHOLQH([DPLQDWLRQDQG(OLJLELOLW\6FUHHQLQJ
)RUP
$OOSDWLHQWVPXVWVLJQDQGGDWHWKHPRVWFXUUHQW,(&DSSURYHGZULWWHQLQIRUPHGFRQVHQW
EHIRUHDQ\VWXG\VSHFLILFDVVHVVPHQWVRUSURFHGXUHVDUHSHUIRUPHG$QRULJLQDOVLJQHG
FRQVHQWIRUPZLOOEHUHWDLQHGE\WKH,QYHVWLJDWRUDQGWKHSDWLHQWZLOOUHFHLYHDFRS\WR
WDNHKRPH3RWHQWLDOULVNVZLOOEHH[SODLQHGWRDOOFDQGLGDWHV
$OOWKHIROORZLQJDVVHVVPHQWVPXVWEHSHUIRUPHGZLWKLQGD\VSULRUWRWKHILUVWSODQQHG
GRVHRIVWXG\PHGLFDWLRQ
•
:ULWWHQLQIRUPHGFRQVHQW
•
'HPRJUDSKLFGDWDGDWHRIELUWKJHQGHUUDFHHWKQLFLW\
•
3UHOLPLQDU\UHYLHZRI,QFOXVLRQ([FOXVLRQFULWHULD
•
&RQILUPDWLRQGRFXPHQWDWLRQ RI DGHTXDWH 1+/ GLDJQRVLV VWDJLQJ DQG &'
H[SUHVVLRQDVSHUPHGLFDOKLVWRU\DQGPHGLFDOILOHV
•
$QQ$UERUVWDJLQJVHH$SSHQGL[
•
%RQHPDUURZDVVHVVPHQW
3DWLHQWVZKRKDYHKDGDSUHYLRXVERQHPDUURZDVVHVVPHQWZLWKLQPRQWKVSULRUWR
HQUROPHQW
R ,IERQHPDUURZLQYROYHPHQWZDVGRFXPHQWHGWKHVHSDWLHQWVDUHFRQVLGHUHG
SRVLWLYH DQG GR QRW UHTXLUH DQRWKHU ERQH PDUURZ DVVHVVPHQW SULRU WR
HQWHULQJWKHVWXG\
R ,I ERQH PDUURZ LQYROYHPHQW ZDV QRW GRFXPHQWHG DQRWKHU ERQH PDUURZ
DVVHVVPHQW LV RQO\ UHTXLUHG SULRU WR HQWHULQJ WKH VWXG\ LI WKH SDWLHQW QRZ
H[KLELWVVLJQVV\PSWRPVVXJJHVWLQJERQHPDUURZLQYROYHPHQWHJDQHPLD
ZLWKRXWKDHPRO\VLVWKURPERF\WRSHQLDHWF
)RUSDWLHQWVZKRKDGDERQHPDUURZDVVHVVPHQWıPRQWKVSULRUWRHQUROPHQWRU
ZKRKDYHQRWKDGDSUHYLRXVERQHPDUURZDVVHVVPHQW
R DEDVHOLQHERQHPDUURZDVVHVVPHQWPXVWEHGRQHZLWKLQGD\VSULRUWR
LQLWLDWLRQRIVWXG\WUHDWPHQW
•
&RPSOHWH PHGLFDO KLVWRU\ LQFOXGLQJ FRQILUPDWLRQGRFXPHQWDWLRQ RI DGHTXDWH SULRU
WKHUDS\
R 3DWLHQWVPXVWKDYHUHFHLYHGDQGPXVWKDYHUHODSVHGRUEHHQUHIUDFWRU\WR
RQHRUPRUHOLQHVRIDGHTXDWHLQGXFWLRQWKHUDS\SULRUWRHQUROPHQWLQFOXGLQJ
DWOHDVWRQHOLQHFRQVLVWLQJRILPPXQRWKHUDS\DQGRUFKHPRWKHUDS\
•
&RQILUPDWLRQRIQHJDWLYHKLVWRU\IRU+,9+HSDWLWLV%RU&LQIHFWLRQ+HSDWLWLV%&DQG
+,9VHURORJ\VKRXOGEHSHUIRUPHGDFFRUGLQJWRFOLQLFDOMXGJPHQW
•
OHDG(&*
•
7XPRXUDVVHVVPHQW&XUUHQWGLVHDVHVWDJLQJ


5LWX[LPDE)+RIIPDQQ/D5RFKH/WG
3URWRFRO02Y
RI
R &7 VFDQ ZLWK FRQWUDVW QHFN LI FOLQLFDOO\ LQGLFDWHG FKHVW DEGRPHQ DQG
SHOYLVLIGHWHFWDEOHE\WKHVHWHFKQLTXHVWRGRFXPHQWQRGDOGLVHDVHRURUJDQ
LQYROYHPHQW
R 2WKHU GLDJQRVWLF PHDQV DUH DFFHSWDEOH IRU O\PSKRPDV WKDW FDQQRW EH
GLDJQRVHG UDGLRJUDSKLFDOO\ HJ JDVWURVFRS\ LQ SDWLHQWV ZLWK IROOLFXODU
O\PSKRPDRIWKHVWRPDFK
1RWH
R 7KHEDVHOLQH&7VFDQRUDSSURSULDWHPHDVXUHPHQWVUHSODFLQJUDGLRJUDSKLF
LPDJHVIRUO\PSKRPDVWKDWFDQQRWEHPHDVXUHGE\UDGLRJUDSKLFWHFKQLTXHV
PD\EHSHUIRUPHGXSWRZHHNVSULRUWRILUVWULWX[LPDEDGPLQLVWUDWLRQ
R 'XULQJ WKLV VWXG\ ERQH PDUURZ DVVHVVPHQWV DUH UHTXLUHG WR FRQILUP DQ\
VXVSHFWHG&5LQSDWLHQWVZLWKERQHPDUURZLQYROYHPHQWDWEDVHOLQH
•
3K\VLFDOH[DPLQDWLRQLQIHFWLRQDVVHVVPHQWDQGYLWDOVLJQVUHVWLQJKHDUWUDWHEORRG
SUHVVXUHDQGERG\WHPSHUDWXUH
•
+HLJKWZHLJKWDQG%6$
•
)/,3,LQGH[DVVHVVHGEHIRUH,QGXFWLRQWKHUDS\VHH$SSHQGL[:KHUHSRVVLEOH
WKHEDVHOLQH)/,3,VFRUHVKRXOGEHFDOFXODWHGIURPWKHSDWLHQWQRWHV1RWHPLVVLQJ
)/,3,VFRUHVGRQRWSUHFOXGHHQUROPHQWRUUDQGRPL]DWLRQ
•
(&2*SHUIRUPDQFHVWDWXVVHH$SSHQGL[
•
/DERUDWRU\ DVVHVVPHQWV VHH 6HFWLRQV  DQG  IRU GHWDLOV DERXW LQGLYLGXDO
ODERUDWRU\DVVD\VDQGUHSRUWLQJRUDEQRUPDOLWLHV
R 6HUXP SUHJQDQF\ WHVW ZRPHQ RI FKLOGEHDULQJ SRWHQWLDO RQO\ PXVW EH
SHUIRUPHGZLWKLQGD\VRIWKHILUVWULWX[LPDEDGPLQLVWUDWLRQRUZLWKLQGD\V
LI ZLWK D FRQILUPDWRU\ XULQH SUHJQDQF\ WHVW ZLWKLQ  GD\V SULRU WR WKH ILUVW
ULWX[LPDEGRVHWRUXOHRXWSUHJQDQF\
R 5RXWLQHVDIHW\ODERUDWRU\KDHPDWRORJ\DQGELRFKHPLVWU\LQFOXGLQJ/'+
R ,J*,J0DQG,J$TXDQWLILFDWLRQ
•
)LQDOUHYLHZRI,QFOXVLRQ([FOXVLRQFULWHULDDQGHQUROPHQWYLDH&5)
•
$(UHFRUGLQJVWDUWLQJIURP,QIRUPHG&RQVHQWVLJQDWXUH1RWH6$(VRFFXUULQJDIWHU
LQIRUPHGFRQVHQWEXWSULRUWRLQLWLDWLRQRIDQ\VWXG\PHGLFDWLRQVDUHRQO\FROOHFWHGLI
FDXVHG E\ D SURWRFROPDQGDWHG LQWHUYHQWLRQ HJ LQYDVLYH SURFHGXUHV VXFK DV
ELRSVLHVRUPHGLFDWLRQZDVKRXW
•
&RQFRPLWDQWWUHDWPHQWVDQGWKHUDSLHV

3URFHGXUHVIRU(QUROPHQWRI(OLJLEOH3DWLHQWV
2QFH D SDWLHQW KDV EHHQ GHWHUPLQHG WR PHHW WKH VWXG\ HQWU\ FULWHULD KHVKH ZLOO EH
DVVLJQHG D VWXG\ 3DWLHQW (QUROPHQW DQG,GHQWLILFDWLRQ &RGH $ 3DWLHQW(QUROPHQW DQG
,GHQWLILFDWLRQ&RGH/LVW3(,&/PXVWEHPDLQWDLQHGE\WKH,QYHVWLJDWRU

$VVHVVPHQWVGXULQJWKH7UHDWPHQW3HULRG
(OLJLEOHSDWLHQWVZLOOUHFHLYHWUHDWPHQWLQWKUHHSKDVHV


5LWX[LPDE)+RIIPDQQ/D5RFKH/WG
3URWRFRO02Y
RI
•
,QGXFWLRQWRPRQWKVGHSHQGLQJRQWKHFRPELQDWLRQFKHPRWKHUDS\UHJLPHQ
•
0DLQWHQDQFH,PRQWKV
•
0DLQWHQDQFH ,, 6&ULWX[LPDE FRQWLQXHG XQWLO SURJUHVVLRQ RU XQWLO (26>$UP $@ RU
REVHUYDWLRQ>$UP%@PLQLPXPPRQWKV
'XULQJ0DLQWHQDQFH,,SDWLHQWVLQWKHULWX[LPDE6&PDLQWHQDQFHDUPZLOOEHWUHDWHGXQWLO
3'XQDFFHSWDEOHWR[LFLW\ZLWKGUDZDORISDWLHQWFRQVHQWRUXQWLO(26$OOSDWLHQWVLQ$UP
$DQG$UP%ZLOOEHDFWLYHO\IROORZHGHYHU\ZHHNVZLWKWXPRXUDVVHVVPHQWVHYHU\
PRQWKVIRU VDIHW\ WXPRXU UHVSRQVHSURJUHVVLRQ QHZ DQWLO\PSKRPD WUHDWPHQWV DQG
VXUYLYDO IRU DW OHDVW  PRQWKV DIWHU UDQGRPL]DWLRQ (QUROOHG SDWLHQWV ZKR GR QRW
FRPSOHWH WUHDWPHQW SHU SURWRFRO IRU DQ\ UHDVRQ ZLOO XQGHUJR WKH HQGRIWUHDWPHQW
DVVHVVPHQWDQGHQWHU2II7UHDWPHQW)ROORZXS3DWLHQWVZLWK3'DWDQ\WLPHGXULQJWKH
VWXG\ ZLOO FRPH RII VWXG\ WUHDWPHQW DQG ZLOO VWDUW 2II7UHDWPHQW )ROORZ8S EHLQJ
IROORZHGHYHU\PRQWKVIRUVXUYLYDOXQWLOWKHHQGRIWKHVWXG\3DWLHQWVZLWK6'DWWKH
HQGRI,QGXFWLRQZLOOFRPHRIIVWXG\WUHDWPHQWDQGZLOOHQWHU2II7UHDWPHQW)ROORZ8S
EHLQJIROORZHGHYHU\PRQWKVIRU3'DQGVXUYLYDOXQWLOWKHHQGRIWKHVWXG\

,QGXFWLRQ
$WRWDORIWUHDWPHQWYLVLWVDQGWZRVWDJLQJYLVLWVDUHSODQQHGGXULQJ,QGXFWLRQ(LJKW
F\FOHVRIULWX[LPDEZLOOEHDGPLQLVWHUHGLQFRPELQDWLRQZLWKF\FOHVRIFKHPRWKHUDS\
EHQGDPXVWLQH&+23&93)&00&3&+93,)1FKORUDPEXFLORUDQ\IOXGDUDELQH
FRQWDLQLQJUHJLPHQLQFOXGLQJRUDOIOXGDUDELQH5*,)2;VHOHFWLRQDWWKH,QYHVWLJDWRU¶V
GLVFUHWLRQ7KHVZLWFKEHWZHHQGLIIHUHQWFKHPRWKHUDS\UHJLPHQVLVQRWSHUPLWWHG7KH
ILUVWDGPLQLVWUDWLRQRIULWX[LPDEZLOOEHE\,9LQIXVLRQRQ'D\RIWKHILUVW,QGXFWLRQF\FOH
DWGRVHRIPJP%6$,QWKHDEVHQFHRILQIXVLRQUHODWHGVLGHHIIHFWVULWX[LPDEZLOO
VXEVHTXHQWO\EHDGPLQLVWHUHG6&VWDUWLQJ'D\RIHDFK,QGXFWLRQF\FOHDWDIL[HGGRVH
RI  PJ HYHU\ ZHHNVIROORZHG E\ DGPLQLVWUDWLRQ RI FKHPRWKHUDS\ 3DWLHQWV
ZKRH[SHULHQFHGDJUDGHRU,55DIWHUWKHILUVWULWX[LPDELQIXVLRQ&\FOHEXWZHUH
DEOHWRUHFHLYHWKHIXOOGRVHRIULWX[LPDEFDQUHFHLYHWKHVHFRQGGRVHRIULWX[LPDE6&
&\FOH  'D\  3DWLHQWV ZKR ZHUH QRW DEOH WR UHFHLYH WKHLU IXOO GRVH RI ULWX[LPDE
LQIXVLRQLQ&\FOHDVDUHVXOWRI,55VKRXOGUHFHLYHWKHLUVHFRQGULWX[LPDEGRVHDOVR,9
,IWKLVVHFRQGULWX[LPDELQIXVLRQLVQRWDVVRFLDWHGZLWKDJUDGHRU,55WKHSDWLHQWZLOO
UHFHLYHKLVKHUWKLUGULWX[LPDEGRVH6&&\FOH'D\DVVXFKVKHKHZLOOUHFHLYH
6&DGPLQLVWUDWLRQVLQWRWDO3DWLHQWVZLWKJUDGHRU,55DIWHUWKHVHFRQGULWX[LPDE
LQIXVLRQZLOOEHZLWKGUDZQIURPWKHVWXG\
6HH 6HFWLRQ  IRU GHWDLOV DERXW GRVH PRGLILFDWLRQV LQWHUUXSWLRQV DQG GHOD\V IRU
ULWX[LPDEDQGFKHPRWKHUDS\
6WXG\YLVLWVVFKHGXOHGIRUSDWLHQWVGXULQJWKH,QGXFWLRQWKHUDS\SHULRGZLOORFFXUDWWKH
EHJLQQLQJ RI HDFK ZHHN RU ZHHN WUHDWPHQW F\FOH DFFRUGLQJ WR WKH 6FKHGXOH RI
$VVHVVPHQWV7DEOHDQGZLOOLQFOXGHWKHIROORZLQJDVVHVVPHQWV
,QGXFWLRQ&\FOHV±9LVLWVWRDQG±9LVLWVWR
•
3K\VLFDOH[DPLQDWLRQLQIHFWLRQDVVHVVPHQWDQGYLWDOVLJQVUHVWLQJKHDUWUDWHEORRG
SUHVVXUHDQGERG\WHPSHUDWXUH


5LWX[LPDE)+RIIPDQQ/D5RFKH/WG
3URWRFRO02Y
RI
•
/DERUDWRU\ DVVHVVPHQWV VHH 6HFWLRQV  DQG  IRU GHWDLOV DERXW LQGLYLGXDO
ODERUDWRU\DVVD\VDQGUHSRUWLQJRUDEQRUPDOLWLHV
R 5RXWLQHVDIHW\ODERUDWRU\KDHPDWRORJ\DQGELRFKHPLVWU\LQFOXGLQJ/'+
•
6WXG\WUHDWPHQWDGPLQLVWUDWLRQ
•
$(UHFRUGLQJ
•
&RQFRPLWDQWWUHDWPHQWVDQGWKHUDSLHV
•




•
&OLQLFDOHYLGHQFHRIGLVHDVHVWDWXV
6WDJLQJ0LGGOHRI,QGXFWLRQ&\FOHVRUDQG(QGRI,QGXFWLRQ7KHUDS\
•
3K\VLFDOH[DPLQDWLRQLQIHFWLRQDVVHVVPHQWDQGYLWDOVLJQVUHVWLQJKHDUWUDWHEORRG
SUHVVXUHDQGERG\WHPSHUDWXUH(QGRI,QGXFWLRQ7KHUDS\RQO\
•
%RQH PDUURZ DVVHVVPHQWV DUH UHTXLUHG WR FRQILUP DQ\ VXVSHFWHG &5 LQ SDWLHQWV
ZLWKERQHPDUURZLQYROYHPHQWDWEDVHOLQH
•
7XPRXUDVVHVVPHQW&XUUHQWGLVHDVHVWDJLQJ
R &7 VFDQ ZLWK FRQWUDVW QHFN LI FOLQLFDOO\ LQGLFDWHG FKHVW DEGRPHQ DQG
SHOYLVLIGHWHFWDEOHE\WKHVHWHFKQLTXHVWRGRFXPHQWQRGDOGLVHDVHRURUJDQ
LQYROYHPHQW
R 2WKHU GLDJQRVWLF PHDQV DUH DFFHSWDEOH IRU O\PSKRPDV WKDW FDQQRW EH
GLDJQRVHG UDGLRJUDSKLFDOO\ HJ JDVWURVFRS\ LQ SDWLHQWV ZLWK IROOLFXODU
O\PSKRPDRIWKHVWRPDFK
7KH RQWUHDWPHQW &7 VFDQ XVHG IRU UHVSRQVH DVVHVVPHQW PD\ EH XS WR 
ZHHNVROGDQGVKRXOGEHFRPSDUHGWRSUH,QGXFWLRQ&77KHHQGRI,QGXFWLRQ
UHVSRQVH DVVHVVPHQW LQFOXGLQJ UDGLRORJ\LPDJLQJ UHSRUW PXVW EH SURYLGHG
ZLWKLQZHHNVRIWKHODVW,QGXFWLRQF\FOH$OOLPDJLQJSHUIRUPHGVKRXOGEH
GRFXPHQWHG LQ WKH H&5) DQG DQ\ FKDQJHV IURP EDVHOLQH VKRXOG EH
GRFXPHQWHG
5HVSRQVHDVVHVVPHQWVWDJLQJZLOOEHFRQGXFWHGE\WKH,QYHVWLJDWRUDIWHU
F\FOHVRUDIWHUF\FOHVVKRXOG,QGXFWLRQEHFRPSULVHGRIFKHPRWKHUDS\
DGPLQLVWUDWLRQVDQGDWWKHHQGRI,QGXFWLRQLHDIWHUF\FOHVRIULWX[LPDE
DFFRUGLQJ WR WKH &KHVRQ UHVSRQVH FULWHULD IRU LQGROHQW O\PSKRPD VHH
$SSHQGL[

RU
E\
WKH
UHFRPPHQGDWLRQV
IRU
:DOGHQVWU|P¶V
PDFURJOREXOLQHPLD VHH $SSHQGL[  3DWLHQWV ZLWK 3' DW DQ\ WLPH GXULQJ
WKHVWXG\ZLOOFRPHRIIVWXG\WUHDWPHQWDQGZLOOVWDUW2II7UHDWPHQW)ROORZ8S
EHLQJIROORZHGHYHU\PRQWKVIRUVXUYLYDOXQWLOWKHHQGRIWKHVWXG\3DWLHQWV
ZLWK6'DWWKHHQGRI,QGXFWLRQZLOOFRPHRIIVWXG\WUHDWPHQWDQGZLOOHQWHU
2II7UHDWPHQW)ROORZ8SEHLQJIROORZHGHYHU\PRQWKVIRU3'DQGVXUYLYDO
XQWLOWKHHQGRIWKHVWXG\


5LWX[LPDE)+RIIPDQQ/D5RFKH/WG
3URWRFRO02Y
RI
%RQH PDUURZ DVVHVVPHQWV DUH UHTXLUHG WR FRQILUP DQ\ VXVSHFWHG &5 LQ
SDWLHQWVZLWKERQHPDUURZLQYROYHPHQWDWEDVHOLQH
•
(&2*SHUIRUPDQFHVWDWXVVHH$SSHQGL[
•
/DERUDWRU\ DVVHVVPHQWV VHH 6HFWLRQV  DQG  IRU GHWDLOV DERXW LQGLYLGXDO
ODERUDWRU\DVVD\VDQGUHSRUWLQJRUDEQRUPDOLWLHV
R 5RXWLQHVDIHW\ODERUDWRU\KDHPDWRORJ\DQGELRFKHPLVWU\/'+
R ,J*,J0DQG,J$TXDQWLILFDWLRQ(QGRI,QGXFWLRQ7KHUDS\RQO\
•
$(UHFRUGLQJ
•
&RQFRPLWDQW WUHDWPHQWV DQG WKHUDSLHV LQFOXGLQJ QHZ DQWLO\PSKRPD WUHDWPHQW LI
DSSOLFDEOH
•
&OLQLFDOHYLGHQFHRIGLVHDVHVWDWXV

0DLQWHQDQFH,
$ WRWDO RI  WUHDWPHQW YLVLWV IROORZHG E\ RQH VWDJLQJ YLVLW DUH SODQQHG GXULQJ
0DLQWHQDQFH , 0DLQWHQDQFH WKHUDS\ ZLWK 6& ULWX[LPDE PXVW VWDUW ZLWKLQ  ZHHNV
DIWHU WKH DGPLQLVWUDWLRQ RI WKH ODVW GRVH RI ULWX[LPDE LQ WKH LQGXFWLRQ WKHUDS\
0DLQWHQDQFHWKHUDS\ZLOOFRQVLVWRIF\FOHVRIULWX[LPDEDGPLQLVWHUHGDVDVLQJOH6&
LQMHFWLRQRIPJULWX[LPDEHYHU\ZHHNVIRU\HDUV
6HH6HFWLRQIRUGHWDLOVDERXWGRVHPRGLILFDWLRQVLQWHUUXSWLRQVDQGGHOD\V
6WXG\YLVLWVIRUSDWLHQWVGXULQJ0DLQWHQDQFH,ZLOORFFXUDWWKHEHJLQQLQJRIHDFKZHHN
WUHDWPHQWF\FOHDFFRUGLQJWRWKH6FKHGXOHRI$VVHVVPHQWV7DEOHDQGZLOOLQFOXGHWKH
IROORZLQJDVVHVVPHQWV
0DLQWHQDQFH,&\FOHV±9LVLWVWR
•
%RQH PDUURZ DVVHVVPHQWV DUH UHTXLUHG WR FRQILUP DQ\ VXVSHFWHG &5 LQ SDWLHQWV
ZLWKERQHPDUURZLQYROYHPHQWDWEDVHOLQH
•
7XPRXUDVVHVVPHQWFRQGXFWHGHYHU\PRQWKVDW9LVLWVDQG
R &7 VFDQ ZLWK FRQWUDVW QHFN LI FOLQLFDOO\ LQGLFDWHG FKHVW DEGRPHQ DQG
SHOYLVLIGHWHFWDEOHE\WKHVHWHFKQLTXHVWRGRFXPHQWQRGDOGLVHDVHRURUJDQ
LQYROYHPHQW
R 2WKHU GLDJQRVWLF PHDQV DUH DFFHSWDEOH IRU O\PSKRPDV WKDW FDQQRW EH
GLDJQRVHG UDGLRJUDSKLFDOO\ HJ JDVWURVFRS\ LQ SDWLHQWV ZLWK IROOLFXODU
O\PSKRPDRIWKHVWRPDFK
7KH &7 VFDQ PD\ EH XS WR  ZHHNV ROG $OO LPDJLQJ SHUIRUPHG VKRXOG EH
GRFXPHQWHGLQWKHH&5)DQGDQ\FKDQJHVIURPEDVHOLQHVKRXOGEHGRFXPHQWHG
5HVSRQVHDVVHVVPHQWVWDJLQJZLOOEHFRQGXFWHGE\WKH,QYHVWLJDWRUDFFRUGLQJ
WRWKH&KHVRQUHVSRQVHFULWHULDIRULQGROHQWO\PSKRPDVHH$SSHQGL[RUE\
WKHUHFRPPHQGDWLRQVIRU:DOGHQVWU|P¶VPDFURJOREXOLQHPLDVHH$SSHQGL[
3DWLHQWVZLWK3'DWDQ\WLPHGXULQJWKHVWXG\ZLOOFRPHRIIVWXG\WUHDWPHQWDQG
ZLOOVWDUW2II7UHDWPHQW)ROORZ8SEHLQJIROORZHGIRUVXUYLYDOXQWLOWKHHQGRIWKH
VWXG\


5LWX[LPDE)+RIIPDQQ/D5RFKH/WG
3URWRFRO02Y
RI
•
3K\VLFDOH[DPLQDWLRQLQIHFWLRQDVVHVVPHQWDQGYLWDOVLJQVUHVWLQJKHDUWUDWHEORRG
SUHVVXUHDQGERG\WHPSHUDWXUH
•
(&2*SHUIRUPDQFHVWDWXVVHH$SSHQGL[
•
/DERUDWRU\ DVVHVVPHQWV VHH 6HFWLRQV  DQG  IRU GHWDLOV DERXW LQGLYLGXDO
ODERUDWRU\DVVD\VDQGUHSRUWLQJRUDEQRUPDOLWLHV
R 5RXWLQHVDIHW\ODERUDWRU\KDHPDWRORJ\DQGELRFKHPLVWU\LQFOXGLQJ/'+
R ,J*,J0DQG,J$TXDQWLILFDWLRQHYHU\PRQWKVDW9LVLWVDQG
•
6WXG\WUHDWPHQWDGPLQLVWUDWLRQ
•
$(UHFRUGLQJ
•
&RQFRPLWDQWWUHDWPHQWVDQGWKHUDSLHVLQFOXGLQJQHZDQWLO\PSKRPDWUHDWPHQWLI
DSSOLFDEOH
•




•
&OLQLFDOHYLGHQFHRIGLVHDVHVWDWXV
6WDJLQJ(QGRI\HDU0DLQWHQDQFH7KHUDS\
$WWKHHQGRIWKH\HDUULWX[LPDEPDLQWHQDQFHSHULRGWXPRXUVWDWXVZLOOEHDVVHVVHG
DQGFRPSDUHGWRWKHSDWLHQW¶VEDVHOLQHVWDWXV
•
%RQH PDUURZ DVVHVVPHQWV DUH UHTXLUHG WR FRQILUP DQ\ VXVSHFWHG &5 LQ SDWLHQWV
ZLWKERQHPDUURZLQYROYHPHQWDWEDVHOLQH
•
7XPRXUDVVHVVPHQW&XUUHQWGLVHDVHVWDJLQJ
R &7 VFDQ ZLWK FRQWUDVW QHFN LI FOLQLFDOO\ LQGLFDWHG FKHVW DEGRPHQ DQG
SHOYLVLIGHWHFWDEOHE\WKHVHWHFKQLTXHVWRGRFXPHQWQRGDOGLVHDVHRURUJDQ
LQYROYHPHQW
R 2WKHU GLDJQRVWLF PHDQV DUH DFFHSWDEOH IRU O\PSKRPDV WKDW FDQQRW EH
GLDJQRVHG UDGLRJUDSKLFDOO\ HJ JDVWURVFRS\ LQ SDWLHQWV ZLWK IROOLFXODU
O\PSKRPDRIWKHVWRPDFK
7KH&7VFDQXVHGIRUUHVSRQVHDVVHVVPHQWPD\EHXSWRZHHNVROG$OO
LPDJLQJ SHUIRUPHG VKRXOG EH GRFXPHQWHG LQ WKH H&5) DQG DQ\ FKDQJHV
IURP WKH SDWLHQW¶V EDVHOLQH DVVHVVPHQW VKRXOG EH GRFXPHQWHG 5HVSRQVH
DVVHVVPHQWVWDJLQJZLOOEHFRQGXFWHGE\WKH,QYHVWLJDWRUDFFRUGLQJWRWKH
&KHVRQUHVSRQVHFULWHULDIRULQGROHQWO\PSKRPDVHH$SSHQGL[RUE\WKH
UHFRPPHQGDWLRQVIRU:DOGHQVWU|P¶VPDFURJOREXOLQHPLD VHH $SSHQGL[ 
3DWLHQWVZLWK3'DWDQ\WLPHGXULQJWKHVWXG\ZLOOFRPHRIIVWXG\WUHDWPHQW
DQG ZLOO VWDUW 2II7UHDWPHQW )ROORZ8S EHLQJ IROORZHG IRU VXUYLYDO XQWLO WKH
HQG RI WKH VWXG\  %RQH PDUURZ DVVHVVPHQWV DUH UHTXLUHG WR FRQILUP DQ\
VXVSHFWHG&5LQSDWLHQWVZLWKERQHPDUURZLQYROYHPHQWDWEDVHOLQH
•
(&2*SHUIRUPDQFHVWDWXVVHH$SSHQGL[


5LWX[LPDE)+RIIPDQQ/D5RFKH/WG
3URWRFRO02Y
RI
•
/DERUDWRU\ DVVHVVPHQWV VHH 6HFWLRQV  DQG  IRU GHWDLOV DERXW LQGLYLGXDO
ODERUDWRU\DVVD\VDQGUHSRUWLQJRUDEQRUPDOLWLHV
R 5RXWLQHVDIHW\ODERUDWRU\KDHPDWRORJ\DQGELRFKHPLVWU\LQFOXGLQJ/'+
•
$(UHFRUGLQJ
•
&RQFRPLWDQW WUHDWPHQWV DQG WKHUDSLHV LQFOXGLQJ QHZ DQWLO\PSKRPD WUHDWPHQW LI
DSSOLFDEOH
•
&OLQLFDOHYLGHQFHRIGLVHDVHVWDWXV

0DLQWHQDQFH,,
$WWKHHQGRI0DLQWHQDQFH,WXPRXUUHVSRQVHZLOOEHDVVHVVHGDQGFRPSDUHGWRWKH
SDWLHQW¶VEDVHOLQHVWDWXVDQGSDWLHQWVZLWK35RU&5DVGHWHUPLQHGE\WKH,QYHVWLJDWRU
XVLQJWKH&KHVRQUHVSRQVHFULWHULDZLOOEHUDQGRPL]HGWR
•
$UP$PDLQWHQDQFHWUHDWPHQWZLWK6&ULWX[LPDEFRQWLQXHGXQWLOSURJUHVVLRQRU
XQWLO(26
•
$UP%REVHUYDWLRQRQO\ZLWKQRIXUWKHUWUHDWPHQW
3DWLHQWVLQ$UP $ZLOOUHFHLYHRQH6&ULWX[LPDELQMHFWLRQDWDIL[HGGRVHRIPJ
HYHU\ZHHNVXQWLO3'XQDFFHSWDEOHWR[LFLW\ZLWKGUDZDORISDWLHQWFRQVHQWRUXQWLO(26
6HH6HFWLRQIRUGHWDLOVDERXWGRVHPRGLILFDWLRQVLQWHUUXSWLRQVDQGGHOD\V
6WXG\YLVLWVIRUSDWLHQWVGXULQJ0DLQWHQDQFH,,ZLOORFFXUDFFRUGLQJWRWKH6FKHGXOHRI
$VVHVVPHQWV7DEOHDQGZLOOLQFOXGHWKHIROORZLQJDVVHVVPHQWV
0DLQWHQDQFH,,9LVLWV$VVHVVPHQWVIRU$UP$	$UP%
•
%RQH PDUURZ DVVHVVPHQWV DUH UHTXLUHG WR FRQILUP DQ\ VXVSHFWHG &5 LQ SDWLHQWV
ZLWKERQHPDUURZLQYROYHPHQWDWEDVHOLQH
•
7XPRXUDVVHVVPHQWFRQGXFWHGHYHU\PRQWKVDW9LVLWVHWFXQWLO3'
R &7 VFDQ ZLWK FRQWUDVW QHFN LI FOLQLFDOO\ LQGLFDWHG FKHVW DEGRPHQ DQG
SHOYLVLIGHWHFWDEOHE\WKHVHWHFKQLTXHVWRGRFXPHQWQRGDOGLVHDVHRURUJDQ
LQYROYHPHQW
R 2WKHU GLDJQRVWLF PHDQV DUH DFFHSWDEOH IRU O\PSKRPDV WKDW FDQQRW EH
GLDJQRVHG UDGLRJUDSKLFDOO\ HJ JDVWURVFRS\ LQ SDWLHQWV ZLWK IROOLFXODU
O\PSKRPDRIWKHVWRPDFK
7KH &7 VFDQ PD\ EH XS WR  ZHHNV ROG $OO LPDJLQJ SHUIRUPHG VKRXOG EH
GRFXPHQWHGLQWKHH&5)DQGDQ\FKDQJHVIURPEDVHOLQHVKRXOGEHGRFXPHQWHG
7XPRXU UHVSRQVH LQFOXGLQJ GLVHDVH SURJUHVVLRQ ZLOO EH HYDOXDWHG E\ WKH
,QYHVWLJDWRUDFFRUGLQJWR&KHVRQUHVSRQVHFULWHULDIRUO\PSKRPDVHH$SSHQGL[
 RU E\ WKH UHFRPPHQGDWLRQV IRU :DOGHQVWU|P¶V PDFURJOREXOLQHPLD VHH
$SSHQGL[
•
3K\VLFDOH[DPLQDWLRQLQIHFWLRQDVVHVVPHQWDQGYLWDOVLJQVUHVWLQJKHDUWUDWHEORRG
SUHVVXUHDQGERG\WHPSHUDWXUH
•
(&2*SHUIRUPDQFHVWDWXVVHH$SSHQGL[


5LWX[LPDE)+RIIPDQQ/D5RFKH/WG
3URWRFRO02Y
RI
•
/DERUDWRU\ DVVHVVPHQWV VHH 6HFWLRQV  DQG  IRU GHWDLOV DERXW LQGLYLGXDO
ODERUDWRU\DVVD\VDQGUHSRUWLQJRUDEQRUPDOLWLHV
R 5RXWLQHVDIHW\ODERUDWRU\KDHPDWRORJ\DQGELRFKHPLVWU\LQFOXGLQJ/'+
R ,J*,J0DQG,J$TXDQWLILFDWLRQHYHU\PRQWKVDW9LVLWVHWF
•
$(UHFRUGLQJUHIHUWRFKDSWHU$GYHUVH(YHQW5HSRUWLQJ3HULRGDQG)ROORZXS
SDJH
•
&RQFRPLWDQW WUHDWPHQWV DQG WKHUDSLHV LQFOXGLQJ QHZ DQWLO\PSKRPD WUHDWPHQW LI
DSSOLFDEOH
•
&OLQLFDOHYLGHQFHRIGLVHDVHVWDWXV
'XULQJ0DLQWHQDQFH,,SDWLHQWVLQWKHULWX[LPDE6&PDLQWHQDQFHDUPZLOOEHWUHDWHGXQWLO
3'XQDFFHSWDEOHWR[LFLW\ZLWKGUDZDORISDWLHQWFRQVHQWRUXQWLO(26
$OO SDWLHQWV LQ $UP $ DQG $UP % ZLOO EH DFWLYHO\ IROORZHG XS IRU VDIHW\ WXPRXU
UHVSRQVHSURJUHVVLRQ QHZ DQWLO\PSKRPD WUHDWPHQWV DQG VXUYLYDO IRU DW OHDVW 
PRQWKVDIWHUUDQGRPL]DWLRQ

5DQGRPL]DWLRQ3URFHGXUH
3DWLHQWV FDQQRW EH UDQGRPL]HG XQOHVV DOO HQWU\ FULWHULD DUH IXOILOOHG 8QGHU QR
FLUFXPVWDQFHVZLOOSDWLHQWVZKRZHUHUDQGRPL]HGDUHSHUPLWWHGWREHUHUDQGRPL]HGLQ
WKHVWXG\
3DWLHQWVZLOOEHDVVLJQHGWRWUHDWPHQWJURXSVYLDDFHQWUDO,956,:56LQDIDVKLRQ
3DWLHQWQXPEHUUDQGRPL]DWLRQQXPEHUGDWHRIUDQGRPL]DWLRQDQGVWUDWLILFDWLRQIDFWRUV
ZLOOEHUHFRUGHG5DQGRPL]DWLRQZLOOEHVWUDWLILHGDFFRUGLQJWRWKHIROORZLQJIDFWRUV
•
,QGROHQW1+/VXEW\SH)/QRQIROOLFXODUO\PSKRPDDQG
•
)/,3,ORZULVNLQWHUPHGLDWHULVNKLJKULVNQRWDSSOLFDEOH
$OOSDWLHQWLGHQWLILFDWLRQZLOOEHXQLTXHDFURVVWKHVWXG\

(QGRI7UHDWPHQW$VVHVVPHQWV
(QUROOHG SDWLHQWV ZKR GR QRW FRPSOHWH WUHDWPHQW SHU SURWRFRO IRU DQ\ UHDVRQ ZLOO
XQGHUJRWKHHQGRIWUHDWPHQWDVVHVVPHQWDQGHQWHU2II7UHDWPHQW)ROORZXS3DWLHQWV
ZLWK 3' DW DQ\ WLPH GXULQJ WKH VWXG\ ZLOO FRPH RII VWXG\ WUHDWPHQW DQG ZLOO VWDUW 2II
7UHDWPHQW )ROORZ8S EHLQJ IROORZHG HYHU\  PRQWKV IRU VXUYLYDO XQWLO WKH HQG RI WKH
VWXG\3DWLHQWVZLWK6'DWWKHHQGRI,QGXFWLRQZLOOFRPHRIIVWXG\WUHDWPHQWDQGZLOO
HQWHU2II7UHDWPHQW)ROORZ8SEHLQJIROORZHGHYHU\PRQWKVIRU3'DQGVXUYLYDOXQWLO
WKHHQGRIWKHVWXG\
$OOSDWLHQWVGLVFRQWLQXLQJVWXG\WUHDWPHQWVIRUDQ\UHDVRQUHJDUGOHVVRIWKHWUHDWPHQW
SHULRG VKRXOG XQGHUJRHQGRIWUHDWPHQW DVVHVVPHQW ZLWKLQ  ZHHNV RI WKH ODVW VWXG\
GUXJDGPLQLVWUDWLRQDVGHWDLOHGLQ6FKHGXOHRI$VVHVVPHQWV7DEOH
7KH(QGRI7UHDWPHQW9LVLWZLOOLQFOXGHWKHIROORZLQJDVVHVVPHQWV
•
3K\VLFDOH[DPLQDWLRQLQIHFWLRQDVVHVVPHQWDQGYLWDOVLJQVUHVWLQJKHDUWUDWHEORRG
SUHVVXUHDQGERG\WHPSHUDWXUH
•
(&2*SHUIRUPDQFHVWDWXVVHH$SSHQGL[


5LWX[LPDE)+RIIPDQQ/D5RFKH/WG
3URWRFRO02Y
RI
•
/DERUDWRU\ DVVHVVPHQWV VHH 6HFWLRQV  DQG  IRU GHWDLOV DERXW LQGLYLGXDO
ODERUDWRU\DVVD\VDQGUHSRUWLQJRUDEQRUPDOLWLHV
R 5RXWLQHVDIHW\ODERUDWRU\KDHPDWRORJ\DQGELRFKHPLVWU\LQFOXGLQJ/'+
•
$(UHFRUGLQJ
•
&RQFRPLWDQW WUHDWPHQWV DQG WKHUDSLHV LQFOXGLQJ QHZ DQWLO\PSKRPD WUHDWPHQW LI
DSSOLFDEOH
3DWLHQWV ZKR H[SHULHQFH WROHUDQFH RU WR[LFLW\ SUREOHPV UHODWHG WR ULWX[LPDE
DGPLQLVWUDWLRQVDQGZLWKRXWHYLGHQFHRIGLVHDVHSURJUHVVLRQZLOOQRWEHFRQVLGHUHGDV
SDWLHQWVZLWKDVWXG\RXWFRPHHYHQWXQOHVVDQHZDQWLO\PSKRPDWUHDWPHQWLVLQVWLWXWHG
VHH6HFWLRQ

2II7UHDWPHQW)ROORZXS
$IWHUGLVFRQWLQXDWLRQRIVWXG\WUHDWPHQWRUSDUWLFLSDWLRQLQREVHUYDWLRQ$UP%SDWLHQWVZLOO
HQWHU2II7UHDWPHQW)ROORZXSDQGZLOOEHIROORZHGHYHU\PRQWKVXQWLOWKHHQGRIWKH
ZKROHVWXG\IRUUHVROXWLRQRIDOO6$(VVXUYLYDOGLVHDVHVWDWXVZKLFKPLJKWLQFOXGHERQH
PDUURZDQGWXPRXUDVVHVVPHQWLI3'QRWDOUHDG\GRFXPHQWHGDQGZKHWKHUDQHZDQWL
O\PSKRPDWUHDWPHQWKDVEHHQVWDUWHG
2QJRLQJIROORZXSZLOOLQFOXGHWKHIROORZLQJDVVHVVPHQWV
•
%RQH PDUURZ DVVHVVPHQWV DUH UHTXLUHG WR FRQILUP DQ\ VXVSHFWHG &5 LQ SDWLHQWV
ZLWKERQHPDUURZLQYROYHPHQWDWEDVHOLQH
•
7XPRXUDVVHVVPHQWLQSDWLHQWVZKHUH3'QRW\HWGRFXPHQWHG
R &7 VFDQ ZLWK FRQWUDVW QHFN LI FOLQLFDOO\ LQGLFDWHG FKHVW DEGRPHQ DQG
SHOYLVLIGHWHFWDEOHE\WKHVHWHFKQLTXHVWRGRFXPHQWQRGDOGLVHDVHRURUJDQ
LQYROYHPHQW
R 2WKHU GLDJQRVWLF PHDQV DUH DFFHSWDEOH IRU O\PSKRPDV WKDW FDQQRW EH
GLDJQRVHG UDGLRJUDSKLFDOO\ HJ JDVWURVFRS\ LQ SDWLHQWV ZLWK IROOLFXODU
O\PSKRPDRIWKHVWRPDFK
7KH &7 VFDQ PD\ EH XS WR  ZHHNV ROG $OO LPDJLQJ SHUIRUPHG VKRXOG EH
GRFXPHQWHGLQWKHH&5)DQGDQ\FKDQJHVIURPEDVHOLQHVKRXOGEHGRFXPHQWHG
7XPRXU UHVSRQVH LQFOXGLQJ GLVHDVH SURJUHVVLRQ ZLOO EH HYDOXDWHG E\ WKH
,QYHVWLJDWRUDFFRUGLQJWR&KHVRQUHVSRQVHFULWHULDIRUO\PSKRPDVHH$SSHQGL[
 RU E\ WKH UHFRPPHQGDWLRQV IRU :DOGHQVWU|P¶V PDFURJOREXOLQHPLD VHH
$SSHQGL[
•
$OO6$(VZLOOFRQWLQXHWREHIROORZHGXQWLOUHVROXWLRQ
•
1HZDQWLO\PSKRPDWUHDWPHQWLIDSSOLFDEOH
•
&OLQLFDOHYLGHQFHRIGLVHDVHVWDWXV
•
6XUYLYDO
)RUDOOYLVLWVDGD\RIIWUHDWPHQWZLQGRZZLOOEHSHUPLWWHGLHGD\VWRDOORZ
IOH[LELOLW\GXHWRKROLGD\VDQGSDWLHQWVWUDYHODUUDQJHPHQWV


5LWX[LPDE)+RIIPDQQ/D5RFKH/WG
3URWRFRO02Y
RI

1HZDQWLO\PSKRPDWUHDWPHQWLQLWLDWLRQ
1HZ DQWLO\PSKRPD WUHDWPHQW LV GHILQHG DV VWDUW RI DQ\ UDGLDWLRQ WKHUDS\ HYHQ IRFDO
UDGLDWLRQFKHPRWKHUDS\RULPPXQRWKHUDS\DORQHRULQDQ\FRPELQDWLRQRIWKHPZKLFK
LV LQVWLWXWHG IRU WKH WUHDWPHQW RI O\PSKRPD $Q\ QHZ DQWLO\PSKRPD WUHDWPHQW QRW
SODQQHGLQWKHSURWRFROZLOOEHFRQVLGHUHGDVDVWXG\RXWFRPHHYHQW
1HZ DQWLO\PSKRPD WUHDWPHQW VKRXOG EH VWDUWHG DW DQ\ WLPH RI GRFXPHQWHG GLVHDVH
SURJUHVVLRQLIWKLVSURJUHVVLRQLVV\PSWRPDWLFDQGRULIWKH,QYHVWLJDWRUFRQVLGHUVWKDWD
QHZ WUHDWPHQW LV QHFHVVDU\ IRU WKH SDWLHQW¶V EHQHILW 'LVHDVH SURJUHVVLRQ VKRXOG EH
GRFXPHQWHG ,I WKH QHZ DQWLO\PSKRPD WUHDWPHQW ZDV LQLWLDWHG GXULQJ WKH ULWX[LPDE
EDVHG,QGXFWLRQRU0DLQWHQDQFH,WKHSDWLHQWZLOOXQGHUJRHQGRIWUHDWPHQWDVVHVVPHQW
DQGFRPHRIIVWXG\WUHDWPHQW(QUROOHGSDWLHQWVVWDUWLQJQHZDQWLO\PSKRPDWUHDWPHQW
ZLOOXQGHUJRHQGRIWUHDWPHQWDVVHVVPHQWDQGZLOOVWDUW2II7UHDWPHQW)ROORZ8SEHLQJ
IROORZHGIRUVXUYLYDOXQWLOWKHHQGRIWKHVWXG\
'DWDRQWUHDWPHQWDWSURJUHVVLRQZLOOEHUHFRUGHGLQWKHH&5),IDQHZDQWLO\PSKRPD
WUHDWPHQW KDV EHHQ VWDUWHG WKH WKHUDS\ XVHG DQG WKH UHVSRQVHWR WKHUDS\ VKRXOG EH
GRFXPHQWHGLQWKHH&5)

&/,1,&$/$66(660(176$1'352&('85(6

7XPRXU5HVSRQVH&ULWHULD
&OLQLFDOWXPRXUDVVHVVPHQWVZLOOLQFOXGHWKHIROORZLQJ
•
&OLQLFDODVVHVVPHQWRIO\PSKDGHQRSDWK\
•
/LYHUDQGVSOHHQVL]HE\SK\VLFDOH[DPLQDWLRQ
•
&7VFDQVZLWKFRQWUDVWQHFNLIFOLQLFDOO\LQGLFDWHGFKHVWDEGRPHQDQGSHOYLVLI
GHWHFWDEOHE\WKHVHWHFKQLTXHVWRGRFXPHQWQRGDOGLVHDVHRURUJDQLQYROYHPHQW
2WKHU GLDJQRVWLF PHDQV DUH DFFHSWDEOH IRU O\PSKRPDV WKDW FDQQRW EH GLDJQRVHG
UDGLRJUDSKLFDOO\ HJ JDVWURVFRS\ LQ SDWLHQWV ZLWK IROOLFXODU O\PSKRPD RI WKH
VWRPDFK
•
%RQH PDUURZ DVVHVVPHQWV DUH UHTXLUHG WR FRQILUP DQ\ VXVSHFWHG &5 LQ SDWLHQWV
ZLWKERQHPDUURZLQYROYHPHQWDWEDVHOLQH
1RWH3DWLHQWVZLWKERQHPDUURZLQYROYHPHQWDWEDVHOLQHZLOOEHUHTXLUHGWRUHFHLYH
D ERQH PDUURZ ELRSV\ WR FRQILUP D VXVSHFWHG &5 RQ VWXG\  3DWLHQWV ZLWK ERQH
PDUURZLQYROYHPHQWDWEDVHOLQHZLOOEHDVVHVVHGDV35LIWKHERQHPDUURZELRSV\DW
ILQDODVVHVVPHQWLVPLVVLQJ
7XPRXU UHVSRQVH DVVHVVPHQW ZLOO EH FRQGXFWHG E\ WKH ,QYHVWLJDWRU DFFRUGLQJ WR
&KHVRQ UHVSRQVH FULWHULD IRU LQGROHQW O\PSKRPD VHH $SSHQGL[  RU E\ WKH
UHFRPPHQGDWLRQVIRU:DOGHQVWU|P¶VPDFURJOREXOLQHPLDVHH$SSHQGL[
3DWLHQWVHQUROOHGDWVLWHVXVLQJ3(7VFDQDVSDUWRIWKHLUURXWLQHUHVSRQVHDVVHVVPHQW
PXVWKDYHDFKLHYHG&535RU6'LQ&7VFDQDFFRUGLQJWRWKH,QWHUQDWLRQDO:RUNLQJ
*URXSUHVSRQVHFULWHULDIRUO\PSKRPD3DWLHQWVZLWK:DOGHQVWU|P¶VPDFURJOREXOLQHPLD
VKRXOGEHDVVHVVHGIRUUHVSRQVHXVLQJWKHGHILQLWLRQVSURYLGHGLQ$SSHQGL[
$FKLHYHPHQW RI &5 DIWHU LQLWLDO 35 RQ ULWX[LPDE PDLQWHQDQFH WKHUDS\ VKRXOG EH
UHFRUGHGLQWKHH&5)


5LWX[LPDE)+RIIPDQQ/D5RFKH/WG
3URWRFRO02Y
RI
$WWKHHQGRI,QGXFWLRQSDWLHQWVZLWK3'RU6'ZLOOFRPHRIIVWXG\WUHDWPHQW3DWLHQWV
ZLWK3'ZLOOVWDUW2II7UHDWPHQW)ROORZ8SEHLQJIROORZHGIRUVXUYLYDOXQWLOWKHHQGRIWKH
VWXG\3DWLHQWVZLWK6'ZLOOHQWHU2II7UHDWPHQW)ROORZ8SEHLQJIROORZHGIRU3'DQG
VXUYLYDO XQWLO WKH HQG RI WKH VWXG\  3DWLHQWV KDYLQJ D &5 RU 35 ZLOO FRQWLQXH LQWR
0DLQWHQDQFH,
$WWKHHQGRI0DLQWHQDQFH,SDWLHQWVZLWK3'ZLOOFRPHRIIVWXG\WUHDWPHQW3DWLHQWV
ZLWK3'ZLOOVWDUW2II7UHDWPHQW)ROORZ8SEHLQJIROORZHGIRUVXUYLYDOXQWLOWKHHQGRIWKH
VWXG\  3DWLHQWV KDYLQJ D &5 RU 35 ZLOO EH UDQGRPL]HG DQG ZLOO FRQWLQXH LQWR
0DLQWHQDQFH,,
1RWH$WDOOWLPHVGXULQJWKHFRXUVHRIWKHVWXG\GLVHDVHSURJUHVVLRQGLDJQRVHGEDVHG
RQFOLQLFDOH[DPLQDWLRQKDVWREHFRQILUPHGE\&7VFDQDVVRRQDVIHDVLEOHPD[LPXP
ZLWKLQZHHNVDQGSULRUWRLQVWLWXWLQJQRQSURWRFRODQWLO\PSKRPDWKHUDS\

6FKHGXOLQJRIWXPRXUDVVHVVPHQWV
7XPRXUDVVHVVPHQWVDUHSHUIRUPHGZLWKWKHIROORZLQJIUHTXHQF\GXULQJWKHVWXG\
•
$WEDVHOLQHZLWKLQZHHNVSULRUWRWKHILUVWGRVHRIULWX[LPDE
•
$WWKHHQGRI&\FOHRU&\FOHDQGHQGRIWKHODVW,QGXFWLRQWUHDWPHQW
•
(YHU\PRQWKVGXULQJ0DLQWHQDQFH,DVVHVVPHQWV
•
(YHU\PRQWKVGXULQJ0DLQWHQDQFH,,ZLWKFRUUHVSRQGLQJPRQWKO\DVVHVVPHQWV
IRUSDWLHQWVLQWKHREVHUYDWLRQJURXS$UP%
,I D SDWLHQW LQDGYHUWHQWO\ PLVVHV D SUHVFULEHG WXPRXU HYDOXDWLRQ RU D WHFKQLFDO HUURU
SUHYHQWV WKH HYDOXDWLRQ WKH SDWLHQW PD\ FRQWLQXH WUHDWPHQW XQWLO WKH QH[W VFKHGXOHG
DVVHVVPHQW XQOHVV VLJQV RI FOLQLFDO SURJUHVVLRQ DUH SUHVHQW ,I WKHUH LV VXVSLFLRQ RI
GLVHDVHSURJUHVVLRQEDVHGRQFOLQLFDORUODERUDWRU\ILQGLQJVEHIRUHWKHQH[WVFKHGXOHG
DVVHVVPHQWDQXQVFKHGXOHGDVVHVVPHQWVKRXOGEHSHUIRUPHG

3HUIRUPDQFHVWDWXV
3HUIRUPDQFH6WDWXVZLOOEHPHDVXUHGXVLQJWKH(&2*3HUIRUPDQFH6WDWXV6FDOHVHH
$SSHQGL[,WLVUHFRPPHQGHGZKHUHSRVVLEOHWKDWDSDWLHQW¶VSHUIRUPDQFHVWDWXVZLOO
EHDVVHVVHGE\WKHVDPHSHUVRQWKURXJKRXWWKHVWXG\
(&2* SHUIRUPDQFH VWDWXV ZLOO EH DVVHVVHG DW EDVHOLQH DW HDFK WUHDWPHQW YLVLW
WKURXJKRXWWKHVWXG\DQGDWWKHHQGRIWUHDWPHQWYLVLW

&OLQLFDO6DIHW\$VVHVVPHQWV
7KH1&,&RPPRQ7HUPLQRORJ\&ULWHULDIRU$GYHUVH(YHQWV&7&$(YHUVLRQZLOOEH
XVHG WR HYDOXDWH WKH FOLQLFDO VDIHW\ RI WKH WUHDWPHQW LQ WKLV VWXG\ VHH $SSHQGL[ 
3DWLHQWVZLOOEHDVVHVVHGIRU$(VDWHDFKFOLQLFDOYLVLWDQGDVQHFHVVDU\WKURXJKRXWWKH
VWXG\
$ FRPSOHWH PHGLFDO KLVWRU\ LQFOXGLQJ GHPRJUDSKLFV DQG SULRU WUHDWPHQW RI WKH
XQGHUO\LQJFRQGLWLRQZLOOEHSHUIRUPHGDWVFUHHQLQJEDVHOLQH
$ SK\VLFDO H[DPLQDWLRQ ZLOO EH SHUIRUPHG DW HDFK WUHDWPHQW YLVLW DQG DW WKH HQG RI
WUHDWPHQWYLVLW


5LWX[LPDE)+RIIPDQQ/D5RFKH/WG
3URWRFRO02Y
RI

/$%25$725<$66(660(176
1RUPDOUDQJHVIRUWKHVWXG\ODERUDWRU\SDUDPHWHUVPXVWEHVXSSOLHGWR5RFKHEHIRUH
WKHVWXG\VWDUWV$OOVDIHW\ODERUDWRU\DVVHVVPHQWVZLOOEHSHUIRUPHGORFDOO\
•
+DHPDWRORJ\KDHPRJORELQKDHPDWRFULWUHGEORRGFHOOFRXQWZKLWHEORRGFHOOFRXQW
ZLWKGLIIHUHQWLDOOHXNRF\WHFRXQWVSODWHOHWFRXQW
•
%LRFKHPLVWU\ VRGLXP SRWDVVLXP FDOFLXP SKRVSKDWH WRWDO ELOLUXELQ VHUXP
FUHDWLQLQH DONDOLQH SKRVSKDWDVH DOEXPLQ %81 /'+ &UHDFWLYH SURWHLQ $/7
6*37DQGLISRVVLEOH$676*27
•
,J*,J0DQG,J$TXDQWLILFDWLRQ$IWHUEDVHOLQH,J*,J0DQG,J$TXDQWLILFDWLRQZLOO
EHFRPSOHWHGRQFHD\HDUGXULQJWKH0DLQWHQDQFH,PDLQWHQDQFHLQMHFWLRQVDQG
 RQFH D \HDU GXULQJ 0DLQWHQDQFH ,, $UP $ DQG LQ FDVH RI VXVSLFLRXV
LQIHFWLRQV 7KH UHVXOWV IURP WKHVH DVVHVVPHQWV PXVW EH DYDLODEOH RQ WKH GD\ RI
ULWX[LPDE LQMHFWLRQV 6DPSOHV FDQ EH WDNHQ XS WR WZR ZHHNV EHIRUH WKH GDWH RI
LQMHFWLRQ,QFDVHWKHUHVXOWVRIWKH,JPHDVXUHPHQWVFRXOGQRWEHREWDLQHGEHIRUH
WKHSODQQHGWUHDWPHQWDGPLQLVWUDWLRQWKHWUHDWPHQWGRHVQRWKDYHWREHSRVWSRQHG
XQWLOWKH,JUHVXOWVEHFRPHDYDLODEOH+RZHYHUWKH,JUHVXOWVPXVWEHUHYLHZHGDV
VRRQDVSRVVLEOHDQGDQHZVDPSOHIRU,JPHDVXUHPHQWPXVWEHGUDZQEHIRUHWKH
QH[WLQMHFWLRQYLVLWLQRUGHUWRKDYHWKHQHZ,JUHVXOWVDYDLODEOHIRUWKHQH[WLQMHFWLRQ
YLVLW
1RWH SDWLHQWV ZKR KDYH FOLQLFDOO\ VLJQLILFDQW UHGXFWLRQV LQ ,J* OHYHOV VKRXOG EH
FRQVLGHUHG IRU ,J* UHSODFHPHQW DFFRUGLQJ WR ORFDO SURFHGXUHV IRU LPPXQRJOREXOLQ
UHSODFHPHQW 3DWLHQWV ZLWK SURIRXQG SURORQJHG RU UHSHDWHG UHGXFWLRQV LQ
LPPXQRJOREXOLQOHYHOVVKRXOGEHWUHDWHGZLWK,9LPPXQRJOREXOLQVDFFRUGLQJWRWKH
ORFDOSROLFLHV
•
,I FOLQLFDOO\ LQGLFDWHG QHJDWLYH VHURORJ\ IRU KHSDWLWLV % DQG & DQG +,9 PXVW EH
GHPRQVWUDWHGDWEDVHOLQH
•
6HUXPSUHJQDQF\WHVWIRUZRPHQRIFKLOGEHDULQJSRWHQWLDOZLWKLQGD\VSULRUWRWKH
ILUVWULWX[LPDEDGPLQLVWUDWLRQRUZLWKLQGD\VLIZLWKDFRQILUPDWRU\XULQHSUHJQDQF\
WHVWFRPSOHWHGZLWKLQGD\VSULRUWRWKHILUVWULWX[LPDEGRVH

3$7,(175(3257('287&20(6














 
Rituximab - F. Hoffmann-La Roche Ltd 
Protocol MO25455 v4.0 
74 of 128 
 
 
 
 
 
  
 
 
5.5 
PHARMACOECONOMIC ASSESSMENTS 
Selected sites will also participate in the Time in Motion pharmacoeconomic sub-study 
that will assess Medical Care Utilization parameters. Details of the sub-study will be 
described in a separate protocol. 
5.6 
POST-STUDY PROVISIONAL CARE 
Not applicable. 
6. 
INVESTIGATIONAL MEDICINAL PRODUCT 
6.1 
DOSE AND SCHEDULE OF RITUXIMAB 
See Section 6.1.4 for details about dose modifications, interruptions and delays. 
6.1.1 
Induction 
Each participating Investigator has to decide before treatment initiation which 
chemotherapy regimen should be used in combination with rituximab for an individual 
patient. During Induction, 8 cycles of rituximab will be administered in combination with 6 
- 8 cycles of approved, commercially available chemotherapy (bendamustine, CHOP, 
CVP, FCM, MCP, CHVP-IFN, chlorambucil or any fludarabine-containing regimen 
including oral fludarabine, R-GIFOX; selection at the Investigator’s discretion). The 
switch between different chemotherapy regimens is not permitted. 
Cycle 1: During the first cycle, rituximab will be administered as a single IV infusion at a 
standard dose of 375 mg/m2 BSA, followed by administration of chemotherapy (see 
below).  
IV rituximab should be given as a slow infusion through a dedicated line with an IV 
infusion pump and must not be administered as an IV push or bolus. The recommended 
initial rate for infusion is 50 mg/hour; after the first 30 minutes it can be escalated in 50 
mg/hour increments every 30 minutes, to a maximum of 400 mg/hour.  
In the absence of IRRs, rituximab will subsequently be administered SC starting Day 1 of 
each Induction cycle at a fixed dose of 1400 mg.  Patients who experienced a grade 3 or 
4 IRR after the first rituximab infusion (Cycle 1), but were able to receive the full dose of 
rituximab, must receive the second dose of rituximab SC (Cycle 2, Day 1). Patients who 
were not able to receive their full dose of rituximab infusion in Cycle 1 as a result of IRR 
should receive their second rituximab dose also IV. If this second rituximab infusion is 
not associated with a grade 3 or 4 IRR, the patient will receive his/her third rituximab 
dose SC (Cycle 3, Day 1). Patients with grade a 3 or 4 IRR after the second rituximab 
infusion will be withdrawn from the study. 
Cycles 2 to 8: Each cycle will consist of a single SC injection of rituximab 1400 mg, 
followed by administration of chemotherapy (see below) and repeated every 3 - 4 weeks, 
depending on the combination chemotherapy regimen selected. 


5LWX[LPDE)+RIIPDQQ/D5RFKH/WG
3URWRFRO02Y
RI
6&ULWX[LPDELQMHFWLRQVZLOOEHDGPLQLVWHUHGXVLQJFRQYHQWLRQDOV\ULQJHVDQGDJDXJH
LQMHFWLRQQHHGOHLQVHUWHGXVLQJVWHULOHWHFKQLTXHLQWKH6&VSDFHLQWKHDEGRPHQ7KH
LQMHFWLRQVKRXOGEHPDQXDOO\SXVKHGDWDIORZUDWHRIDSSUR[LPDWHO\P/PLQWKHUHIRUH
DQDGPLQLVWUDWLRQYROXPHRIP/FRUUHVSRQGLQJWRWKHPJGRVHVKRXOGWDNH
DSSUR[LPDWHO\EHWZHHQDQGPLQXWHV
3DWLHQWVVKRXOGEHREVHUYHGDIWHU6&DGPLQLVWUDWLRQDVGHVFULEHGLQWKHFXUUHQWYHUVLRQ
RIWKH,QYHVWLJDWRU%URFKXUH
'XULQJF\FOHVWRRI,QGXFWLRQULWX[LPDEZLOOEHDGPLQLVWHUHGLQFRPELQDWLRQZLWKRQH
RIWKHIROORZLQJFKHPRWKHUDS\UHJLPHQVVHOHFWLRQDWWKH,QYHVWLJDWRU¶VGLVFUHWLRQ
•
%HQGDPXVWLQH
•
&+23&\FORSKRVSKDPLGHGR[RUXELFLQYLQFULVWLQHSUHGQLVRQHSUHGQLVRORQH
•
&93&\FORSKRVSKDPLGHYLQFULVWLQHSUHGQLVRQHSUHGQLVRORQH
•
)&0)OXGDUDELQHF\FORSKRVSKDPLGHPLWR[DQWURQH
•
0&30LWR[DQWURQHFKORUDPEXFLOSUHGQLVRQHSUHGQLVRORQH
•
&+93,)1 F\FORSKRVSKDPLGH   GR[RUXELFLQ  HWRSRVLGH  SUHGQLVRQH
SUHGQLVRORQHLQWHUIHURQĮ
•
&KORUDPEXFLO
•
$Q\IOXGDUDELQHFRQWDLQLQJUHJLPHQLQFOXGLQJRUDOIOXGDUDELQH
•
*,)2;JHPFLWDELQHLIRVIDPLGHR[DOLSODWLQ
1RWH
•
5LWX[LPDELVDOZD\VDGPLQLVWHUHGSULRUWRFKHPRWKHUDS\ZLWKWKHH[FHSWLRQRIWKH
FRUWLFRVWHURLGFRPSRQHQW
•
)RUDOO,QGXFWLRQWUHDWPHQWYLVLWVDGD\WUHDWPHQWZLQGRZZLOOEHSHUPLWWHGLH
GD\VWRDOORZIOH[LELOLW\GXHWRKROLGD\VDQGSDWLHQWVWUDYHODUUDQJHPHQWV
6HH6HFWLRQIRUGHWDLOVDERXWGRVHPRGLILFDWLRQVLQWHUUXSWLRQVDQGGHOD\V

5LWX[LPDESOXVEHQGDPXVWLQH5%HQGDPXVWLQH
:KHUHWKH,QYHVWLJDWRUVHOHFWVEHQGDPXVWLQHDVFRPELQDWLRQFKHPRWKHUDS\WKHSDWLHQW
ZLOOUHFHLYHF\FOHVRIULWX[LPDEFRPELQHGZLWKF\FOHVRIEHQGDPXVWLQHDVVKRZQLQ
7DEOH
7DEOH5%(1'$0867,1('26,1*6&+('8/(&<&/(6(9(5<:((.6
0HGLFDWLRQ
'RVH
0RGH
'
'
'
5LWX[LPDE
&\FOH
&\FOHV

PJP
PJ

,9
6&

•
•


%HQGDPXVWLQH
&\FOHV

PJP

,9


•

•


5LWX[LPDE)+RIIPDQQ/D5RFKH/WG
3URWRFRO02Y
RI
2Q'D\5LWX[LPDEPXVWEHJLYHQILUVWIROORZHGE\%HQGDPXVWLQH$FFRUGLQJWR
ORFDO SUDFWLFH %HQGDPXVWLQH PD\ DOVR EH JLYHQ RQ 'D\  IROORZLQJ 5LWX[LPDE
DGPLQLVWUDWLRQWKHQRQ'D\
1RWH$OORSXULQROVKRXOGEHXVHGZLWKFDXWLRQSOHDVHUHIHUWR6HFWLRQ

5LWX[LPDESOXV&+235&+23
:KHUH WKH ,QYHVWLJDWRU VHOHFWV &+23 DV FRPELQDWLRQ FKHPRWKHUDS\ WKH SDWLHQW ZLOO
UHFHLYHF\FOHVRIULWX[LPDEFRPELQHGZLWKF\FOHVRIVWDQGDUG&+23DVVKRZQLQ
7DEOH
7DEOH5&+23'26,1*6&+('8/(&<&/(6(9(5<:((.6
0HGLFDWLRQ
'RVH
0RGH
'
'
'
'
'
5LWX[LPDE
&\FOH
&\FOHV

PJP
PJ

,9
6&

•
•




&+23&\FOHV±







&\FORSKRVSKDPLGH
PJP
,9
•




'R[RUXELFLQ
PJP
,9
•




9LQFULVWLQH
PJP
DEVROXWHPJ
PD[
,9
•




3UHGQLVRQH
SUHGQLVRORQH
PJ
32
•
•
•
•
•


5LWX[LPDESOXV&935&93
:KHUH WKH ,QYHVWLJDWRU VHOHFWV &93 DV FRPELQDWLRQ FKHPRWKHUDS\ WKH SDWLHQW ZLOO
UHFHLYHF\FOHVRIVWDQGDUG&93DVVKRZQLQ7DEOH
7DEOH5&93'26,1*6&+('8/(&<&/(6(9(5<:((.6
0HGLFDWLRQ
'RVH
0RGH
'
'
'
'
'
5LWX[LPDE
&\FOH
&\FOHV±

PJP
PJ

,9
6&

•
•




&93&\FOHV±







&\FORSKRVSKDPLGH
PJP
,9
•




9LQFULVWLQH
PJP
DEVROXWH
PJPD[
,9
•




3UHGQLVRQH
SUHGQLVRORQH
PJP
32
•
•
•
•
•



5LWX[LPDE)+RIIPDQQ/D5RFKH/WG
3URWRFRO02Y
RI

5LWX[LPDESOXV)&05)&0
:KHUH WKH ,QYHVWLJDWRU VHOHFWV )&0 DV FRPELQDWLRQ FKHPRWKHUDS\ WKH SDWLHQW ZLOO
UHFHLYH  DGPLQLVWUDWLRQV RI ULWX[LPDE JLYHQ LQ  F\FOHV LQ F\FOH  DQG F\FOH  WZR
DGPLQLVWUDWLRQVRIULWX[LPDEDUHJLYHQ7KHDGPLQLVWUDWLRQVRIULWX[LPDEDUHFRPELQHG
ZLWKF\FOHVRIVWDQGDUG)&0DVVKRZQLQ7DEOH
7DEOH5)&0'26,1*6&+('8/(&<&/(6(9(5<:((.6
0HGLFDWLRQ
'RVH
0RGH
'
'
'
'
5LWX[LPDE
&\FOH±'D\
&\FOH±'D\
&\FOH
&\FOH
&\FOH

PJP
PJ
PJ
PJ
PJ

,9
6&
6&
6&
6&

•

•
•
•




•

•

)&0&\FOHV±






)OXGDUDELQH
PJP
,9
•
•
•

&\FORSKRVSKDPLGH
PJP
32
•
•
•

0LWR[DQWURQH
PJP
,9
•



3DWLHQWVZKRZHUHQRWDEOHWRUHFHLYHWKHLUIXOOGRVHRIULWX[LPDELQIXVLRQLQ&\FOHDVDUHVXOWRI,55VKRXOG
UHFHLYHWKHLUVHFRQGULWX[LPDEGRVH'D\&\FOHDOVR,9

5LWX[LPDESOXV0&350&3
:KHUHWKH,QYHVWLJDWRUVHOHFWV0&3DVFRPELQDWLRQFKHPRWKHUDS\ZLWKULWX[LPDEWKH
SDWLHQWZLOOUHFHLYHF\FOHVRIULWX[LPDEFRPELQHGZLWKF\FOHVRI0&3DVVKRZQLQ
7DEOH
7DEOH50&3'26,1*6&+('8/(&<&/(6(9(5<:((.6
0HGLFDWLRQ
'RVH
0RGH
'
'
'
'
'
'
'
5LWX[LPDE
&\FOH
&\FOHV

PJP
PJ

,9
6&

•
•







0&3 &\FOHV
±









0LWR[DQWURQH
PJP
,9


•




&KORUDPEXFLO
[PJP
32


•
•
•
•
•
3UHGQLVRQH
SUHGQLVRORQH
PJP
32


•
•
•
•
•

5LWX[LPDESOXV&+93,)15&+93,)1
,QFDVHWKH,QYHVWLJDWRUVHOHFWV&+93,)1DVFRPELQDWLRQFKHPRWKHUDS\ZLWKULWX[LPDE
WKH SDWLHQW ZLOO UHFHLYH  F\FOHV RI ULWX[LPDE FRPELQHG ZLWK  F\FOHV RI &+93,)1
WUHDWPHQWHYHU\ZHHNVDVSHUVWDQGDUGLQVWLWXWLRQDOSUDFWLFHRIWKHVWXG\FHQWUH

5LWX[LPDESOXVFKORUDPEXFLO5&KORUDPEXFLO
,Q FDVH WKH ,QYHVWLJDWRU VHOHFWV FKORUDPEXFLO DV FRPELQDWLRQ FKHPRWKHUDS\ ZLWK
ULWX[LPDE WKH SDWLHQW ZLOO UHFHLYH  F\FOHV RI ULWX[LPDE FRPELQHG ZLWK &KORUDPEXFLO


5LWX[LPDE)+RIIPDQQ/D5RFKH/WG
3URWRFRO02Y
RI
WUHDWPHQW HYHU\  ZHHN DV SHU VWDQGDUG LQVWLWXWLRQDO SUDFWLFH RI WKH VWXG\ FHQWUH
DFFRUGLQJWRWKHORFDOODEHO

5LWX[LPDESOXVIOXGDUDELQH5)OXGDUDELQH
:KHUHWKH,QYHVWLJDWRUVHOHFWVDQ\IOXGDUDELQHUHJLPHQDVFRPELQDWLRQFKHPRWKHUDS\
ZLWKULWX[LPDEWKHSDWLHQWZLOOUHFHLYHF\FOHVRIULWX[LPDEFRPELQHGZLWKF\FOHVRI
IOXGDUDELQHDVVKRZQLQ7DEOH
7DEOH5)/8'$5$%,1('26,1*6&+('8/(&<&/(6(9(5<:((.6
0HGLFDWLRQ
'RVH
0RGH
'
'
'
'
'
5LWX[LPDE
&\FOH
&\FOHV

PJP
PJ

,9
6&

•
•




)OXGDUDELQH
&\FOHV
PJP

PJPGD\
,9

RUDO
•

•
•

•
•

•


•


•
1RWHLQFDVHVRIVHYHUHJUDQXORF\WRSHQLD*&6)XVHLVSHUPLWWHG
)OXGDUDELQH PD\ DOVR EH DGPLQLVWHUHG RUDOO\ LQ FRPELQDWLRQ ZLWK ULWX[LPDE 7KH RUDO
UHJLPHQLQFOXGHVGDLO\GRVHVRIIOXGDUDELQHPJPRQGD\VWRRIHDFKZHHN
F\FOHIRUF\FOHVFRPELQHGZLWKF\FOHVRIULWX[LPDE

5LWX[LPDESOXVJHPFLWDELQHLIRVIDPLGHDQGR[DOLSODWLQ5
*,)2;
:KHUH WKH ,QYHVWLJDWRUVHOHFWVJHPFLWDELQH LIRVIDPLGH DQG R[DOLSODWLQ DV FRPELQDWLRQ
FKHPRWKHUDS\ZLWKULWX[LPDEWKHSDWLHQWZLOOUHFHLYHF\FOHVRIULWX[LPDEFRPELQHGZLWK
F\FOHVRIFKHPRWKHUDS\DVVKRZQLQ7DEOH
7DEOH5*,)2;'26,1*6&+('8/(&<&/(6(9(5<:((.6
0HGLFDWLRQ
'RVH
0RGH
'
'
'
5LWX[LPDE
&\FOH
&\FOHV

PJP
PJ

,9
6&

•
•


*HPFLWDELQH
&\FOHV
PJP
,9

•

2[DOLSODWLQ
&\FOHV
PJP
,9


•
,IRVIDPLGH
&\FOHV
JP
KU
LQIXVLRQ



•
1RWHLQFDVHVRIVHYHUHJUDQXORF\WRSHQLD*&6)XVHLVSHUPLWWHG

0DLQWHQDQFH,
'XULQJ0DLQWHQDQFH,SDWLHQWVZLOOUHFHLYHLQMHFWLRQVRI6&ULWX[LPDEDWDIL[HG
PJ GRVH DGPLQLVWHUHG HYHU\  ZHHNV DFFRUGLQJ WR WKH 6& DGPLQLVWUDWLRQ PHWKRG
GHVFULEHGDERYH


5LWX[LPDE)+RIIPDQQ/D5RFKH/WG
3URWRFRO02Y
RI
6HH6HFWLRQIRUGHWDLOVDERXWGRVHPRGLILFDWLRQVLQWHUUXSWLRQVDQGGHOD\V)RUDOO
WUHDWPHQW YLVLWV D GD\ WUHDWPHQW ZLQGRZ ZLOO EH SHUPLWWHG LH   GD\V WR DOORZ
IOH[LELOLW\GXHWRKROLGD\VDQGSDWLHQWVWUDYHODUUDQJHPHQWV

0DLQWHQDQFH,,
7KHILUVWYLVLWLQPDLQWHQDQFH,,PXVWRFFXUZHHNVGD\VDIWHUWKHDGPLQLVWUDWLRQRI
WKHODVWGRVHRIULWX[LPDELQPDLQWHQDQFH,'XULQJ0DLQWHQDQFH,,SDWLHQWVUDQGRPL]HG
WRWKHH[SHULPHQWDODUPZLOOFRQWLQXHWKH6&ULWX[LPDEPDLQWHQDQFHWUHDWPHQWVHYHU\
ZHHNVXQWLOGLVHDVHSURJUHVVLRQXQDFFHSWDEOHWR[LFLW\ZLWKGUDZDORISDWLHQWFRQVHQWRU
XQWLO (26 ZKHUHDV SDWLHQWV LQ WKH FRQWURO DUP ZLOO UHFHLYH QR WUHDWPHQW REVHUYDWLRQ
RQO\DVIROORZV
•
$UP $ SURORQJHG PDLQWHQDQFHWUHDWPHQWULWX[LPDE6&PJIL[HGGRVH
RQH LQMHFWLRQ HYHU\  ZHHNV DGPLQLVWHUHG DFFRUGLQJ WR WKH 6& DGPLQLVWUDWLRQ
PHWKRGGHVFULEHGDERYH
•
$UP%REVHUYDWLRQRQO\QRIXUWKHUWUHDWPHQW
6HH6HFWLRQIRUGHWDLOVDERXWGRVHPRGLILFDWLRQVLQWHUUXSWLRQVDQGGHOD\V)RUDOO
YLVLWVLQ0DLQWHQDQFH,,DGD\WUHDWPHQWZLQGRZZLOOEHSHUPLWWHGLHGD\VWR
DOORZIOH[LELOLW\GXHWRKROLGD\VDQGSDWLHQWVWUDYHODUUDQJHPHQWV
(QUROOHG SDWLHQWV ZKR GR QRW FRPSOHWH WUHDWPHQW SHU SURWRFRO IRU DQ\ UHDVRQ ZLOO
XQGHUJRWKHHQGRIWUHDWPHQWDVVHVVPHQWDQGHQWHU2II7UHDWPHQW)ROORZXS3DWLHQWV
ZLWK 3' DW DQ\ WLPH GXULQJ WKH VWXG\ ZLOO FRPH RII VWXG\ WUHDWPHQW DQG ZLOO VWDUW 2II
7UHDWPHQW )ROORZ8S EHLQJ IROORZHG HYHU\  PRQWKV IRU VXUYLYDO XQWLO WKH HQG RI WKH
VWXG\

'RVH0RGLILFDWLRQV,QWHUUXSWLRQVDQG'HOD\V
%HIRUHVWDUWLQJDQHZWUHDWPHQWF\FOHWR[LFLW\UHODWHGWRWKHSUHYLRXVF\FOHPXVWKDYH
UHVROYHG
3DWLHQWV ZKR H[SHULHQFH D GHOD\ LQ WKH LQLWLDWLRQ RI WKH QH[W SODQQHG WUHDWPHQW F\FOH
FDXVHGE\XQUHVROYHGJUDGHRU$(VZLOOHQWHU2II7UHDWPHQW)ROORZXS
• 
,QGXFWLRQZHHNV
• 
0DLQWHQDQFH,	,,ZHHNV
3DWLHQWVZKRH[SHULHQFHDWRWDOGHOD\LQWKHLQLWLDWLRQRIWKHQH[WSODQQHGWUHDWPHQWF\FOH
IRUDQ\UHDVRQRWKHUWKDQJUDGHRU$(VZLOOHQWHU2II7UHDWPHQW)ROORZXS
• 
,QGXFWLRQZHHNV
• 
0DLQWHQDQFH,	,,ZHHNV
'HOD\V ORQJHU WKDQ WKRVH VSHFLILHG DERYH IRU VWXG\GUXJUHODWHG WR[LFLWLHV UHTXLUH
GLVFRQWLQXDWLRQ IURP VWXG\ WUHDWPHQW XQOHVV WKH VSRQVRU DJUHHV WKH EHQHILWULVN
DVVHVVPHQWVXSSRUWVFRQWLQXHGWUHDWPHQW
1R GRVH PRGLILFDWLRQ VKRXOG EH GRQH IRU ULWX[LPDE ,9 RU ULWX[LPDE 6& 'RVH
PRGLILFDWLRQVFDQEHGRQHIRUFKHPRWKHUDS\LIQHFHVVDU\,IFKHPRWKHUDS\LVGHOD\HG
ULWX[LPDEDGPLQLVWUDWLRQPXVWDOVREHGHOD\HG,IDSDWLHQWDFKLHYHV&5DFFRUGLQJWR
$SSHQGL[  SULRU WR FRPSOHWLQJ WKH IXOO FKHPRWKHUDS\ UHJLPHQ WKHQ WKH


5LWX[LPDE)+RIIPDQQ/D5RFKH/WG
3URWRFRO02Y
RI
FKHPRWKHUDS\ FDQ EH VWRSSHG EXW WKH IXOO  F\FOHV RI ULWX[LPDE PXVW VWLOO EH
DGPLQLVWHUHG

35(3$5$7,21$1'$'0,1,675$7,212),03

,95LWX[LPDE3UHSDUDWLRQDQG$GPLQLVWUDWLRQ
'HWDLOVUHJDUGLQJWKHSUHSDUDWLRQDQGDGPLQLVWUDWLRQRI,9ULWX[LPDEZLOOEHSURYLGHGLQD
VHSDUDWH*XLGDQFH'RFXPHQW6HHDOVRWKHULWX[LPDE,QYHVWLJDWRU¶V%URFKXUH
3DWLHQWVUHFHLYLQJ,9ULWX[LPDEZLOOEHDGPLQLVWHUHGDGRVHRIPJPZLWKSRVVLEOH
URXQGLQJWRWKHQHDUHVWPJ7KHDSSURSULDWHDPRXQWRIVROXWLRQWREHZLWKGUDZQIURP
WKHYLDOZLOOEHFDOFXODWHGDVIROORZV
9ROXPHP/
 

%6$P[GRVHPJP
FRQFHQWUDWLRQRIUHFRQVWLWXWHGVROXWLRQPJP/
PJP/DQGRUPJP/

,QVWUXFWLRQVIRUFDOFXODWLQJWKH%6$LVSURYLGHGLQ$SSHQGL[
5LWX[LPDEZLOOEHDGPLQLVWHUHG,9LQDQRXWSDWLHQWVHWWLQJLISRVVLEOH
,QRUGHUWRUHGXFHWKHLQFLGHQFHDQGVHYHULW\RILQIXVLRQLQMHFWLRQUHODWHGUHDFWLRQVLWLV
UHFRPPHQGHGWKDWDOOSDWLHQWVUHFHLYHWKHIROORZLQJSUHPHGLFDWLRQDGPLQLVWHUHG
PLQXWHVSULRUWRHDFKULWX[LPDEDGPLQLVWUDWLRQ
•
SDUDFHWDPRODFHWDPLQRSKHQ
•
GLSKHQK\GUDPLQHK\GURFKORULGHRUDOWHUQDWLYHDQWLKLVWDPLQH
•
VWHURLGVSUHGQLVRQHSUHGQLVRORQH
3UHPHGLFDWLRQ ZLWK JOXFRFRUWLFRLGV VKRXOG EH FRQVLGHUHG LI ULWX[LPDE LV QRW JLYHQ LQ
FRPELQDWLRQ ZLWK JOXFRFRUWLFRLGFRQWDLQLQJ FKHPRWKHUDS\ ,I JLYHQ WKHVH PHGLFDWLRQV
PXVWEHGRFXPHQWHGRQWKH&RQFRPLWDQW0HGLFDWLRQVH&5)
,QVWLWXWLRQVVKRXOGIROORZWKHLUVWDQGDUGSUHPHGLFDWLRQSURFHGXUHVUHJDUGLQJDQWLHPHWLFV
DQGK\GUDWLRQ
$OO$(VUHJDUGOHVVRILQWHQVLW\WKDWFRPPHQFHGXULQJRUVKRUWO\ZLWKLQKRXUVDIWHU
WKH ULWX[LPDE LQIXVLRQLQMHFWLRQ VKRXOG EH FDSWXUHG LQ WKH H&5) DV ,55V$55V
0HGLFDWLRQVWRWUHDWWKHVHHYHQWVVKRXOGDOVREHUHFRUGHG

6&5LWX[LPDE3UHSDUDWLRQDQG$GPLQLVWUDWLRQ
'HWDLOVUHJDUGLQJWKHSUHSDUDWLRQDQGDGPLQLVWUDWLRQRI6&ULWX[LPDEZLOOEHSURYLGHGLQD
VHSDUDWH*XLGDQFH'RFXPHQW6HHDOVRWKHULWX[LPDE,QYHVWLJDWRU¶V%URFKXUH
3DWLHQWVUHFHLYLQJ6&ULWX[LPDEZLOOEHDGPLQLVWHUHGDWDIL[HGGRVHRIPJ

)2508/$7,213$&.$*,1*$1'/$%(//,1*

,95LWX[LPDE
5LWX[LPDEIRUWKH,9DGPLQLVWUDWLRQ0DE7KHUD,95RZLOOEHSURYLGHGDV
PJ P/ OLTXLG ILOOHG YLDOV ZLWK D QRPLQDO FRQWHQW RI  PJP/ ULWX[LPDE 7KH GUXJ
SURGXFW FRQWDLQV VRGLXP DFHWDWH EXIIHU VRGLXP FKORULGH WRQLFLW\ DGMXVWPHQW DQG

 
Rituximab - F. Hoffmann-La Roche Ltd 
Protocol MO25455 v4.0 
81 of 128 
polysorbate 80 (surfactant) in water for injection at a pH of 6.5. The drug product is a 
sterile, colourless to pale yellow liquid.  
6.3.2 
SC Rituximab  
Rituximab for the subcutaneous administration (MabThera SC; Ro 045-2294) is supplied 
as a ready to use liquid formulation with a nominal content of 120 mg/mL rituximab in an 
11.7 mL vial and must not be diluted prior to administration. The drug product contains 
2,000 U/mL rHuPH20 (manufactured in a CHO cell line) acting as a permeation 
enhancer, histidine/histidine-HCl (buffer), α,α-trehalose (bulking agent), methionine 
(stabilizer), and polysorbate 80 (surfactant) in water for injection at a pH of 5.5. The drug 
product is a sterile, colourless to yellowish, clear to opalescent liquid in colourless 11.7 
mL vials.  
Study drug packaging will be overseen by the Roche clinical trial supplies department 
and bear a label with the identification required by local law, the protocol number, drug 
identification and dosage. The packaging and labelling of the study medication will be in 
accordance with Roche standards and local regulations. All the requirements of Annex 
13 of the Good Manufacturing Practices guideline for labelling investigational drug will be 
fulfilled. 
The study drug must be stored in a refrigerator, at temperature between 2° and 8°C. For 
additional storage requirements refer to the drug label.  It is highly recommended that 
the study medication will not be withdrawn from the vial until at the time of administration. 
For further information please refer to the most current version of the Investigator 
Brochure. 
Upon arrival of investigational products at the site, site personnel should check them for 
damage and verify proper identity, quantity, integrity of seals and temperature conditions, 
and report any deviations or product complaints to the monitor upon discovery. 
6.4 
BLINDING AND UNBLINDING 
Not applicable, this is an open label study. 
6.5 
ACCOUNTABILITY OF RITUXIMAB AND ASSESSMENT OF 
COMPLIANCE 
The Investigator is responsible for the control of drugs under investigation.  Adequate 
records for the receipts (e.g. Drug Receipt Record) and disposition (e.g. Drug Dispensing 
Log) of the study drug must be maintained.  Accountability and patient compliance will be 
assessed by maintaining adequate drug dispensing and return records. 
6.5.1 
Accountability of Rituximab 
IV and SC rituximab will be supplied by F. Hoffmann-La Roche Ltd and shipped to the 
pharmacist of each centre by the local Roche affiliate.  
In accordance with the requirements of national regulatory agencies and of local health 
authorities, the Investigator or the responsible local pharmacist will sign a receipt for the 
vials of rituximab, and will be held accountable for proper storage and dispensing. All drug 
supplies that will be used in the study must be maintained securely. The disposal will be 
the responsibility of the local Roche Affiliate in accordance with local regulations. 
All drugs shall be dispensed in accordance with the Investigator's prescription. The site 
pharmacy must not release rituximab if the patient’s enrolment number is not on the 
prescription received. Under no circumstances will the Investigator supply study drug to a 


5LWX[LPDE)+RIIPDQQ/D5RFKH/WG
3URWRFRO02Y
RI
WKLUGSDUW\RUDOORZWKHVWXG\GUXJWREHXVHGGHVWUR\HGRUGLVSRVHGLQRWKHUZD\VWKDQ
DVGLUHFWHGE\WKLVSURWRFRO
$FFXUDWH UHFRUGV PXVW EH NHSW IRU HDFK VWXG\ GUXJSURYLGHG E\ WKH 6SRQVRU 7KHVH
UHFRUGVPXVWFRQWDLQWKHIROORZLQJLQIRUPDWLRQ
•
'RFXPHQWDWLRQRIGUXJVKLSPHQWVUHFHLYHGIURPWKH6SRQVRUGDWHUHFHLYHGEDWFK
QXPEHUDQGTXDQWLW\
•
'LVSRVLWLRQRIXQXVHGVWXG\GUXJQRWGLVSHQVHGWRSDWLHQW
$OOUHFRUGVDQGGUXJVXSSOLHVPXVWEHDYDLODEOHIRULQVSHFWLRQE\WKH0RQLWRUDWHYHU\
PRQLWRULQJYLVLW$OOVXSSOLHVLQFOXGLQJSDUWLDOO\XVHGRUHPSW\FRQWDLQHUVDQGFRSLHVRI
WKHGLVSHQVLQJ	LQYHQWRU\ORJVPXVWEHUHWXUQHGWRWKH0RQLWRUDWWKHHQGRIWKHVWXG\
XQOHVV DOWHUQDWH GHVWUXFWLRQ KDV EHHQ DXWKRUL]HG E\ 5RFKH RU UHTXLUHG E\ ORFDO RU
LQVWLWXWLRQDOUHJXODWLRQV6HFWLRQ
7KH H&5) DQG FOLQLF UHFRUGV ZLOO EH FKHFNHG IRU FRQVLVWHQF\ ZLWK VLWHDGPLQLVWHUHG
FKHPRWKHUDS\DJHQWVXVHGGXULQJ,QGXFWLRQ

$VVHVVPHQWRI&RPSOLDQFH
7KH,QYHVWLJDWRULVUHVSRQVLEOHIRUHQVXULQJWKDWGRVLQJLVDGPLQLVWHUHGLQFRPSOLDQFH
ZLWKWKHSURWRFRO$Q\GHOHJDWLRQRIWKLVWDVNPXVWEHFOHDUO\GRFXPHQWHGDQGDSSURYHG
E\WKH,QYHVWLJDWRU
3DWLHQW FRPSOLDQFH ZLOO EH DVVHVVHG E\ PDLQWDLQLQJ DGHTXDWH VWXG\ GUXJ GLVSHQVLQJ
UHFRUGV$'UXJ'LVSHQVLQJ/RJPXVWEHNHSWFXUUHQWDQGVKRXOGFRQWDLQWKHIROORZLQJ
LQIRUPDWLRQ
•
WKHLGHQWLILFDWLRQRIWKHSDWLHQWWRZKRPWKHVWXG\PHGLFDWLRQZDVGLVSHQVHG
•
WKH GDWHV EDWFK QXPEHU DQG TXDQWLW\ RI WKH VWXG\ PHGLFDWLRQ GLVSHQVHG WR WKH
SDWLHQW
$WHDFKULWX[LPDEDGPLQLVWUDWLRQWKH,QYHVWLJDWRUZLOOUHFRUGWKHGDWHGHOLYHU\UDWHDQG
DPRXQWRIVWXG\GUXJDGPLQLVWHUHGLQWKHH&5)

'(6758&7,212)86(',19(67,*$7,21$/352'8&7
/RFDO RU LQVWLWXWLRQDO UHJXODWLRQV PD\ UHTXLUH LPPHGLDWH GHVWUXFWLRQ RI XVHG
LQYHVWLJDWLRQDO SURGXFW IRU VDIHW\ UHDVRQV HJ F\WRWR[LFLW\  ,Q WKHVH FDVHV LW PD\ EH
DFFHSWDEOH IRU LQYHVWLJDWLRQDO VLWH VWDII WR GHVWUR\ GLVSHQVHG LQYHVWLJDWLRQDO SURGXFW
EHIRUHDPRQLWRULQJLQVSHFWLRQSURYLGHGWKDWVRXUFHGRFXPHQWYHULILFDWLRQLVSHUIRUPHG
RQWKHUHPDLQLQJLQYHQWRU\DQGUHFRQFLOHGDJDLQVWWKHGRFXPHQWDWLRQRITXDQWLW\VKLSSHG
GLVSHQVHG UHWXUQHG DQG GHVWUR\HG :ULWWHQ DXWKRUL]DWLRQ PXVW EH REWDLQHG IURP WKH
6SRQVRUDWVWXG\VWDUWXSEHIRUHGHVWUXFWLRQ
:ULWWHQGRFXPHQWDWLRQRIGHVWUXFWLRQPXVWFRQWDLQWKHIROORZLQJ
•
,GHQWLW\EDWFKQXPEHUVDQGSDWLHQWQXPEHUVRILQYHVWLJDWLRQDOSURGXFWVGHVWUR\HG
•
4XDQWLW\RILQYHVWLJDWLRQDOSURGXFWVGHVWUR\HG
•
'DWH RI GHVWUXFWLRQ GDWH GLVFDUGHG LQ GHVLJQDWHG KD]DUGRXV FRQWDLQHU IRU
GHVWUXFWLRQ


5LWX[LPDE)+RIIPDQQ/D5RFKH/WG
3URWRFRO02Y
RI
•
0HWKRGRIGHVWUXFWLRQWKHVLWHPXVWSURYLGHWKH6SRQVRUZLWKGRFXPHQWDWLRQRIWKHLU
LQVWLWXWLRQDOSROLF\DQGSURFHGXUHVIRUKDQGOLQJDQGGLVSRVLQJRIKD]DUGRXVGUXJV
•
1DPHDQGVLJQDWXUHRIUHVSRQVLEOHSHUVRQZKRGLVFDUGHGWKHLQYHVWLJDWLRQDOSURGXFW
LQDKD]DUGRXVFRQWDLQHUIRUGHVWUXFWLRQ

6$)(7<,16758&7,216$1'*8,'$1&(

$'9(56((9(176$1'/$%25$725<$%1250$/,7,(6

&OLQLFDO$GYHUVH(YHQWV
$FFRUGLQJ WR WKH ,QWHUQDWLRQDO &RQIHUHQFH RQ +DUPRQL]DWLRQ ,&+ DQ $( LV DQ\
XQWRZDUG PHGLFDO RFFXUUHQFH LQ D SDWLHQW RU FOLQLFDO LQYHVWLJDWLRQ RI D SDWLHQW
DGPLQLVWHUHGDSKDUPDFHXWLFDOSURGXFWDQGZKLFKGRHVQRWQHFHVVDULO\KDYHDFDXVDO
UHODWLRQVKLS ZLWK WKLV WUHDWPHQW  $Q $( FDQ WKHUHIRUH EH DQ\ XQIDYRXUDEOH DQG
XQLQWHQGHG VLJQ LQFOXGLQJ DQ DEQRUPDO ODERUDWRU\ ILQGLQJ V\PSWRP RU GLVHDVH
WHPSRUDOO\ DVVRFLDWHG ZLWK WKH XVH RI DPHGLFLQDO SURGXFW ZKHWKHU RU QRW FRQVLGHUHG
UHODWHG WR WKH PHGLFLQDO SURGXFW  3UHH[LVWLQJ FRQGLWLRQV ZKLFK ZRUVHQ RU FKDQJH LQ
FKDUDFWHUGXULQJDVWXG\DUHWREHUHSRUWHGDV$(V
,QYHVWLJDWRUVZLOOVHHNLQIRUPDWLRQRQ$(VDQG6$(VDWHDFKSDWLHQWFRQWDFWE\VSHFLILF
TXHVWLRQLQJ DQG DV DSSURSULDWH E\ FOLQLFDO H[DPLQDWLRQ $OO $(V DQG 6$(V ZKHWKHU
VSRQWDQHRXVO\UHSRUWHGE\WKHSDWLHQWRUQRWHGE\DXWKRUL]HGVWXG\SHUVRQQHOZLOOEH
UHFRUGHGLQWKHSDWLHQW¶VPHGLFDOUHFRUGDQGRQWKH$(H&5)

'XUDWLRQDQGLQWHQVLW\
(DFKUHFRUGHG$(RU6$(ZLOOEHGHVFULEHGE\LWVGXUDWLRQLHVWDUWDQGHQGGDWHV
VHYHULW\ UHJXODWRU\ VHULRXVQHVV FULWHULD LI DSSOLFDEOH VXVSHFWHG UHODWLRQVKLS WR WKH
LQYHVWLJDWLRQDOSURGXFWDQGDFWLRQVWDNHQ
,QWHQVLW\RIDOO$(VZLOOEHJUDGHGDFFRUGLQJWRWKH 1&,&7&$(YRQDILYHSRLQW
VFDOH*UDGHWRDQGUHSRUWHGLQGHWDLOLQWKHH&5)
$(VQRWOLVWHGLQWKH&7&$(VKRXOGEHJUDGHGDVGHWDLOHGLQ7DEOH
7DEOH*UDGLQJRI$GYHUVH(YHQWVQRWOLVWHGLQWKH1&,&7&$(


5LWX[LPDE)+RIIPDQQ/D5RFKH/WG
3URWRFRO02Y
RI
&7&*UDGH
(TXLYDOHQW7R
'HILQLWLRQ
*UDGH
0LOG
$V\PSWRPDWLF RU PLOG V\PSWRPV FOLQLFDO RU GLDJQRVWLF
REVHUYDWLRQVRQO\LQWHUYHQWLRQQRWLQGLFDWHG
*UDGH
0RGHUDWH
0LQLPDO ORFDO RU QRQLQYDVLYH LQWHUYHQWLRQ LQGLFDWHG OLPLWLQJ
DJHDSSURSULDWH LQVWUXPHQWDO DFWLYLW\ RI GDLO\ OLYLQJ LQFOXGLQJ
SUHSDULQJ PHDOV VKRSSLQJ IRU JURFHULHV RU FORWKHV XVLQJ WKH
WHOHSKRQHPDQDJLQJPRQH\HWF
*UDGH
6HYHUH
6HYHUH RU PHGLFDOO\ VLJQLILFDQW EXW QRW LPPHGLDWHO\ OLIH
WKUHDWHQLQJ KRVSLWDOL]DWLRQ RU SURORQJDWLRQ RI KRVSLWDOL]DWLRQ
LQGLFDWHGGLVDEOLQJOLPLWLQJVHOIFDUHDFWLYLW\RIGDLO\OLYLQJZLWK
LQDELOLW\ WR SHUIRUP EDWKLQJ GUHVVLQJ DQG XQGUHVVLQJ IHHGLQJ
VHOIXVLQJWKHWRLOHWWDNLQJPHGLFDWLRQVEXWQRWEHGULGGHQ
*UDGH
/LIH WKUHDWHQLQJ
GLVDEOLQJ
$QLPPHGLDWHWKUHDWWROLIHRUOHDGLQJWRDSHUPDQHQWPHQWDORU
SK\VLFDO FRQGLWLRQV WKDW SUHYHQWV ZRUN RU SHUIRUPLQJ QRUPDO
GDLO\ DFWLYLWLHVWUHDWPHQWRUPHGLFDO LQWHUYHQWLRQ LVUHTXLUHGLQ
RUGHUWRPDLQWDLQVXUYLYDO
*UDGH
'HDWK
$(UHVXOWLQJLQGHDWK


'UXJ±DGYHUVHHYHQWUHODWLRQVKLS
7KHFDXVDOLW\UHODWLRQVKLSRIVWXG\GUXJWRWKHDGYHUVHHYHQWZLOOEHDVVHVVHGE\WKH
,QYHVWLJDWRUDVHLWKHU<HVRU1R
,IWKHUHLVDUHDVRQDEOHVXVSHFWHGFDXVDOUHODWLRQVKLSWRWKHVWXG\PHGLFDWLRQLHWKHUH
DUH IDFWV HYLGHQFH RU DUJXPHQWV WR VXJJHVW D FDXVDO UHODWLRQVKLS WKH GUXJHYHQW
UHODWLRQVKLSVKRXOGEHDVVHVVHGDV<HV
7KHIROORZLQJFULWHULDVKRXOGEHFRQVLGHUHGLQRUGHUWRDVVHVVWKHUHODWLRQVKLSDV<HV
•
5HDVRQDEOHWHPSRUDODVVRFLDWLRQZLWKGUXJDGPLQLVWUDWLRQ
•
,WPD\RUPD\QRWKDYHEHHQSURGXFHGE\WKHSDWLHQW¶VFOLQLFDOVWDWHHQYLURQPHQWDO
RUWR[LFIDFWRUVRURWKHUPRGHVRIWKHUDS\DGPLQLVWHUHGWRWKHSDWLHQW
•
.QRZQUHVSRQVHSDWWHUQWRVXVSHFWHGGUXJ
•
'LVDSSHDUVRUGHFUHDVHVRQFHVVDWLRQRUUHGXFWLRQLQGRVH
•
5HDSSHDUVRQUHFKDOOHQJH
7KHIROORZLQJFULWHULDVKRXOGEHFRQVLGHUHGLQRUGHUWRDVVHVVWKHUHODWLRQVKLSDV1R
•
,WGRHVQRWIROORZDUHDVRQDEOHWHPSRUDOVHTXHQFHIURPDGPLQLVWUDWLRQRIWKHGUXJ
•
,WPD\UHDGLO\KDYHEHHQSURGXFHGE\WKHSDWLHQW¶VFOLQLFDOVWDWHHQYLURQPHQWDORU
WR[LFIDFWRUVRURWKHUPRGHVRIWKHUDS\DGPLQLVWHUHGWRWKHSDWLHQW
•
,WGRHVQRWIROORZDNQRZQSDWWHUQRIUHVSRQVHWRWKHVXVSHFWHGGUXJ
•
,WGRHVQRWUHDSSHDURUZRUVHQZKHQWKHGUXJLVUHDGPLQLVWHUHG


5LWX[LPDE)+RIIPDQQ/D5RFKH/WG
3URWRFRO02Y
RI
1RWHGXULQJ,QGXFWLRQIRUSDWLHQWVUHFHLYLQJULWX[LPDESOXVFKHPRWKHUDS\WKHWHVWGUXJ
UHODWLRQVKLSLVDVVHVVHGIRUWKHULWX[LPDEFKHPRWKHUDS\FRPELQDWLRQ,IWKHHYHQWLVDQ
6$(PRUHVSHFLILFLQIRUPDWLRQZLOOEHUHTXLUHGRQWKH6$()RUP

6HULRXV$GYHUVH(YHQWV>,PPHGLDWHO\5HSRUWDEOHWR5RFKH@
5RFKH FRQILUPV WKDW WKH SURSRVHG VWXG\ ZLOO FRPSO\ ZLWK DOO ORFDO UHJXODWRU\
UHTXLUHPHQWV 7KH VWXG\ ZLOO DGKHUH WR WKH IXOO UHTXLUHPHQWV RI ,&+ *XLGHOLQHV IRU
&OLQLFDO 6DIHW\ 'DWD 0DQDJHPHQW 'HILQLWLRQV DQG 6WDQGDUGVIRU ([SHGLWHG 5HSRUWLQJ
7RSLF(ZLOOEHDGKHUHGWRVHH$SSHQGL[
$Q6$(LVDQ\DGYHUVHHYHQWWKDW
•
,VIDWDOUHVXOWVLQGHDWK
1RWHGHDWKLVDQRXWFRPHQRWDQHYHQW
•
,VOLIHWKUHDWHQLQJ
1RWH WKH WHUP OLIHWKUHDWHQLQJ UHIHUV WR DQ HYHQW LQ ZKLFK WKH SDWLHQW ZDV DW
LPPHGLDWHULVNRIGHDWKDWWKHWLPHRIWKHHYHQWLWGRHVQRWUHIHUWRDQHYHQWZKLFK
FRXOGK\SRWKHWLFDOO\KDYHFDXVHGDGHDWKKDGLWEHHQPRUHVHYHUH
•
5HTXLUHVLQSDWLHQWKRVSLWDOL]DWLRQRUSURORQJDWLRQRIH[LVWLQJKRVSLWDOL]DWLRQ
•
5HVXOWVLQSHUVLVWHQWRUVLJQLILFDQWGLVDELOLW\LQFDSDFLW\
•
,VDFRQJHQLWDODQRPDO\ELUWKGHIHFW
•
,V PHGLFDOO\ VLJQLILFDQW HJ VHFRQGDU\ PDOLJQDQFLHV RU UHTXLUHV LQWHUYHQWLRQ WR
SUHYHQWRQHRURWKHURIWKHRXWFRPHVOLVWHGDERYH
$OO$(VWKDWGRQRWPHHWDQ\RIWKHFULWHULDIRU6$(VKRXOGEHUHJDUGHGDVQRQVHULRXV
$(V
7KHWHUPV³VHYHUH´DQG³VHULRXV´DUHQRWV\QRQ\PRXV6HYHULW\UHIHUVWRWKHLQWHQVLW\RI
DQ$(DVLQPLOGPRGHUDWHRUVHYHUHSDLQWKHHYHQWLWVHOIPD\EHRIUHODWLYHO\PLQRU
PHGLFDOVLJQLILFDQFHVXFKDVVHYHUHKHDGDFKH³6HULRXV´LVDUHJXODWRU\GHILQLWLRQDQG
LVEDVHGRQSDWLHQWRUHYHQWRXWFRPHRUDFWLRQFULWHULDXVXDOO\DVVRFLDWHGZLWKHYHQWV
WKDWSRVHDWKUHDWWRDSDWLHQW¶VOLIHRUYLWDOIXQFWLRQV6HULRXVQHVVQRWVHYHULW\VHUYHV
DVWKHJXLGHIRUGHILQLQJUHJXODWRU\UHSRUWLQJREOLJDWLRQV
6HYHULW\DQGVHULRXVQHVVVKRXOGEHLQGHSHQGHQWO\DVVHVVHGZKHQUHFRUGLQJ$(VDQG
6$(VRQWKHH&5)

2WKHUVDIHW\ILQGLQJVUHTXLULQJH[SHGLWHGUHSRUWLQJ
2WKHUVDIHW\ILQGLQJVPD\UHTXLUHH[SHGLWHGUHSRUWLQJGHSHQGLQJRQORFDOOHJLVODWLRQHJ
DPDMRUVDIHW\ILQGLQJIURPDQHZO\FRPSOHWHGDQLPDOVWXG\VXFKDVFDUFLQRJHQLFLW\


5LWX[LPDE)+RIIPDQQ/D5RFKH/WG
3URWRFRO02Y
RI

3URJUHVVLRQRIXQGHUO\LQJPDOLJQDQF\
3URJUHVVLRQ RU GHWHULRUDWLRQ RI WKH PDOLJQDQF\XQGHUVWXG\LQFOXGLQJQHZOHVLRQV
DQG GHDWK GXH WR GLVHDVH SURJUHVVLRQ ZLOO EH SDUW RI WKH HIILFDF\ DVVHVVPHQW DQG
VKRXOG127EHUHSRUWHGDVDQ$(RU6$(
6LJQVDQGV\PSWRPVFOHDUO\DVVRFLDWHGZLWKWKHPDOLJQDQF\XQGHUVWXG\VKRXOG127
EHUHSRUWHGDVDQ$(RU6$(XQOHVV
• 
1HZO\HPHUJHQWLHQRWSUHVHQWDWEDVHOLQHDQGDVVRFLDWLRQZLWKWKHXQGHUO\LQJ
PDOLJQDQF\DQGROGQHZPHWDVWDWLFOHVLRQVLVXQFOHDU
• 
WKH ,QYHVWLJDWRU DWWULEXWHG GHWHULRUDWLRQ RI PDOLJQDQF\DVVRFLDWHG VLJQV DQG
V\PSWRPVGLUHFWO\WRWKHVWXG\GUXJ
6KRXOGWKHUHEHDQ\XQFHUWDLQW\UHJDUGLQJWKHDWWULEXWLRQRIWKHPDOLJQDQF\XQGHUVWXG\
WRDQ$(LWVKRXOGEHUHSRUWHGDVDQ$(RUD6$(DFFRUGLQJO\

'HDWKV
'HDWKVWKDWRFFXUGXULQJWKHSURWRFROVSHFLILHG$(UHSRUWLQJSHULRGWKDWDUHDWWULEXWHGE\
WKH ,QYHVWLJDWRU VROHO\ WR SURJUHVVLRQ RI 1+/ ZLOO EH UHFRUGHG RQO\ RQ WKH 6WXG\
'LVFRQWLQXDWLRQH&5)SDJH$OORWKHURQVWXG\GHDWKVUHJDUGOHVVRIDWWULEXWLRQZLOOEH
UHFRUGHG RQ DQ $( H&5) SDJH DQG H[SHGLWLRXVO\ UHSRUWHG WR WKH 6$( UHVSRQVLEOH
UHSRUWHU
:KHQUHFRUGLQJDGHDWKRQDQ$(H&5)SDJHWKHHYHQWRUFRQGLWLRQWKDWFDXVHGRU
FRQWULEXWHGWRWKHIDWDORXWFRPHVKRXOGEHUHFRUGHGDVWKHVLQJOHPHGLFDOFRQFHSW RQ
WKH$(H&5)SDJH,IWKHFDXVHRIGHDWKLVXQNQRZQDQGFDQQRWEHDVFHUWDLQHGDWWKH
WLPHRIUHSRUWLQJUHFRUG³8QH[SODLQHG'HDWK´RQWKH$(H&5)SDJH
1RWH
6HULRXV$GYHUVH(YHQW5HSRUWVFRQWDLQLQJWKH6$(WHUPV³'HDWK8QH[SODLQHG´³'HDWK
&DXVH 8QNQRZQ´ RU ³'HDWK 126´ ZLOO EH FRQVLGHUHG XQH[SHFWHG IRU DOO 6DIHW\
5HIHUHQFH 'RFXPHQWV ,W LVWKXV LPSRUWDQW WKDW,QYHVWLJDWRUV GLIIHUHQWLDWH EHWZHHQ WKH
6$( WHUPV³'HDWK 8QH[SODLQHG´ DQG ³6XGGHQ 'HDWK´ ZKHQ FRPSOHWLQJ6$( UHSRUWLQJ
IRUPV7KHWHUP³VXGGHQ GHDWK´ VKRXOG EH XVHG RQO\ ZKHQ WKH FDXVHLV RI D FDUGLDF
RULJLQDVSHUVWDQGDUGGHILQLWLRQ7KHWHUPVGHDWKDQGVXGGHQGHDWKDUHFOHDUO\GLVWLQFW
DQGPXVWQRWEHXVHGLQWHUFKDQJHDEO\³6XGGHQGHDWK´LVFRQVLGHUHGDVEHLQJODEHOOHG
OLVWHGRUH[SHFWHGLIPHQWLRQHGLQWKHVDIHW\UHIHUHQFHGRFXPHQW³'HDWKFDXVHXQNQRZQ´
RU³'HDWK8QH[SODLQHG´VKRXOGEHXVHGDVWKH6$(WHUPRQO\ZKHQWKHFDXVHRIGHDWKLV
QRWNQRZQDWWKHWLPHRIUHSRUWLQJWKH6$(WR5RFKH
0RQLWRUV VKRXOG HQVXUH WKDW ,QYHVWLJDWRUV XQGHUVWDQG WKH ZD\ LQ ZKLFK WKH 6$(
UHSRUWLQJ IRUPV IRU VXFK GHDWKV VKRXOG EH FRPSOHWHG DQG VKRXOG XUJHQWO\ IROORZXS
³'HDWK8QH[SODLQHG´6$(VWRHQVXUHWKDWWKH,QYHVWLJDWRUSURYLGHVIXUWKHULQIRUPDWLRQ
UHJDUGLQJ WKH FDXVH RI GHDWK DV VRRQ DV SRVVLEOH 7KH 5RFKH *XLGDQFH 1RWHV IRU
&RPSOHWLQJ WKH 6$( UHSRUWLQJ IRUP JFSBIRU SURYLGHV IXUWKHU FODULILFDWLRQ
UHJDUGLQJWKHUHSRUWLQJRIGHDWKDVDQ6$(

$GYHUVH(YHQW5HSRUWLQJ3HULRGDQG)ROORZXS
6HULRXV $GYHUVH (YHQWV RFFXUULQJ GXULQJ WKH VWXG\ PXVW EH UHSRUWHG WR 5RFKH RU
GHVLJQHHLPPHGLDWHO\LHZLWKLQKRXUVRIWKHLQYHVWLJDWRUEHFRPLQJDZDUHRIWKH
HYHQW$IWHUREWDLQLQJLQIRUPHGFRQVHQWEXWSULRUWRLQLWLDWLRQRIVWXG\PHGLFDWLRQVRQO\
6$(VFDXVHGE\DSURWRFROPDQGDWHGLQWHUYHQWLRQZLOOEHFROOHFWHGHJ6$(VUHODWHGWR

 
Rituximab - F. Hoffmann-La Roche Ltd 
Protocol MO25455 v4.0 
87 of 128 
invasive procedures such as biopsies, or medication washout). Once study treatments 
commence, the site must enter the SAE into the eCRF.  
Patients will be followed for new or worsening AEs as detailed in Table 14. 
Resolution of AEs and SAEs including dates should be documented on the AE/SAE 
eCRF and in the patient’s medical record to facilitate source data verification. Unrelated 
AEs and SAEs occurring in an off-study patient who has started a new anti-cancer 
treatment do not need to be reported. 
Table 14 Duration of Reporting and Follow-up of Adverse Events 
 
Related 
Unrelated 
 
Reporting Period 
Follow-up 
Reporting Period 
Follow-up 
AEs 
grade 
1 and 
2 
From signing of ICF until 
28 days post-treatment 
Until resolution, 
stabilization, death 
or patient lost to 
follow-up 
From signing of ICF until 
28 days post-treatment 
Until 28 days 
post-treatment 
AEs 
≥ 
grade 
3 
From signing of ICF up 
to 6 months after the 
last dose on arm A, or 
the last observation visit 
on arm B, or EOS 
whichever comes first. 
 
Until resolution, 
stabilization, death 
or patient lost to 
follow up 
From signing of ICF up 
to 6 months after the 
last dose on arm A or 
the  last observation 
visit on arm B,  or  until 
the start of new anti-
lymphoma treatment, , 
or EOS whichever 
comes first. 
Until resolution, 
stabilization, death 
or patient lost to 
follow up 
SAEs 
From signing of ICF 
onwards.* 
Note: After ICF signing, 
but prior to initiation of 
any study drugs, only 
SAEs caused by a 
protocol-mandated 
intervention (e.g., an 
invasive procedure such 
as biopsy or medication 
washout) will be 
collected. 
Once study treatment 
has been permanently 
discontinued, all related 
SAEs should continue to 
be reported, regardless 
when they occur, in 
particular any second 
primary malignancy. 
Until resolution, 
stabilization, death 
or patient lost to 
follow-up 
From signing of ICF until 
6 months after the last 
dose on arm A, or the 
last observation visit on 
arm B, or until the start 
of new anti-lymphoma 
treatment, or EOS 
whichever comes first. 
Note: After ICF signing, 
but prior to initiation of 
any study drugs, only 
SAEs caused by a 
protocol-mandated 
intervention (e.g., an 
invasive procedure such 
as biopsy or medication 
washout) will be 
collected. 
Until resolution, 
stabilization, death 
or patient lost to 
follow-up 
AE = adverse event, ICF = informed consent form, SAE = serious adverse event. 
* The Investigator should also notify the study Sponsor of any other SAEs occurring at any time after a 
patient terminated study participation if felt to be related to prior study treatment. 

 
Rituximab - F. Hoffmann-La Roche Ltd 
Protocol MO25455 v4.0 
88 of 128 
It is encouraged that any second primary malignancy events are reported, regardless of 
causal relationship to study drug, occurring at any time following study treatment 
permanent discontinuation. 
For some SAEs, the Sponsor or its designee may follow-up by telephone, fax, electronic 
mail, and/or a monitoring visit to obtain additional case details deemed necessary to 
appropriately evaluate the SAE report (e.g., hospital discharge summary, consultant 
report, or autopsy report). 
7.1.3 
Procedures for Recording Adverse Events 
Adverse Events should be recorded on an AE eCRF page. Investigators should use 
correct medical terminology/concepts when recording AEs or SAEs on the eCRF. 
Colloquialisms and abbreviations should be avoided. Only one event should be recorded 
in the event field on the AE eCRF page. 
If known, a diagnosis should be recorded on the eCRF rather than individual signs and 
symptoms (e.g., record only liver failure or hepatitis rather than jaundice and elevated 
transaminases). However, if a constellation of signs and/or symptoms cannot be 
medically characterized as a single diagnosis or syndrome at the time of reporting, each 
individual event should be recorded as an AE or SAE on the eCRF. If a diagnosis is 
subsequently established, it should be reported as follow-up information. 
7.1.3.1 
Pre-existing medical conditions 
A pre-existing medical condition is one that is present at the start of the study. Such 
conditions should be recorded on the appropriate General Medical History and Baseline 
Conditions eCRF forms. 
A pre-existing medical condition should be recorded as an AE or SAE only if the 
frequency, severity, or character of the condition worsens during the study. When 
recording such events on an AE eCRF page, it is important to convey the concept that 
the pre-existing condition has changed by including applicable descriptors (e.g., “more 
frequent headaches”). 
7.1.3.2 
Adverse events secondary to other events 
In general, AEs occurring secondary to other events should be identified by their primary 
cause. For example, if severe diarrhea is known to have resulted in dehydration, it is 
sufficient to record only diarrhea as an AE or SAE on the eCRF.  
However, medically significant AEs occurring secondary to an initiating event that are 
separated in time should be recorded as independent events on the eCRF. For example, 
if a severe gastrointestinal haemorrhage leads to renal failure, both events should be 
recorded separately on the eCRF. 
7.1.3.3 
Persistent or recurrent adverse events  
A persistent AE is one that extends continuously, without resolution between patient 
evaluation time points. Such events should only be recorded once in the eCRF unless 
their severity increases. If a persistent AE becomes more severe, it should be recorded 
again on an AE eCRF page. 
A recurrent AE is one that occurs and resolves between patient evaluation time points 
and subsequently recurs. All recurrent AEs should be recorded on an AE eCRF page. 


5LWX[LPDE)+RIIPDQQ/D5RFKH/WG
3URWRFRO02Y
RI

/DERUDWRU\7HVW$EQRUPDOLWLHV
/DERUDWRU\ WHVWUHVXOWVZLOO EH UHFRUGHG RQWKHODERUDWRU\ UHVXOWV H&5) RU DSSHDU RQ
HOHFWURQLFDOO\SURGXFHGODERUDWRU\UHSRUWVVXEPLWWHGGLUHFWO\IURPWKHFHQWUDOODERUDWRU\
DVDSSOLFDEOH
2QO\FOLQLFDOO\VLJQLILFDQWODERUDWRU\DEQRUPDOLWLHVWKDWUHTXLUHDFWLYHPDQDJHPHQWZLOOEH
UHFRUGHGDV$(VRU6$(VRQWKHH&5)HJDEQRUPDOLWLHVWKDWUHTXLUHGLVFRQWLQXDWLRQ
RIVWXG\WUHDWPHQWPRUHIUHTXHQWDVVHVVPHQWVIXUWKHUGLDJQRVWLFLQYHVWLJDWLRQHWF,I
WKHFOLQLFDOO\VLJQLILFDQWODERUDWRU\DEQRUPDOLW\LVDVLJQRIDGLVHDVHRUV\QGURPHHJ
DONDOLQHSKRVSKDWDVHDQGELOLUXELQ[WKHXSSHUOLPLWRIQRUPDO8/1DVVRFLDWHGZLWK
FKROHF\VWLWLV RQO\ WKH GLDJQRVLV HJ FKROHF\VWLWLV QHHGV WR EH UHFRUGHG RQ WKH $(
H&5)SDJH
,IWKHFOLQLFDOO\VLJQLILFDQWODERUDWRU\DEQRUPDOLW\LVQRWDVLJQRIDGLVHDVHRUV\QGURPH
WKH DEQRUPDOLW\ LWVHOI VKRXOG EH UHFRUGHG DV DQ $( RU 6$( RQ WKH H&5)  ,I WKH
ODERUDWRU\DEQRUPDOLW\FDQEHFKDUDFWHUL]HGE\DSUHFLVHFOLQLFDOWHUPWKHFOLQLFDOWHUP
VKRXOGEHUHFRUGHGDVWKH$(RU6$()RUH[DPSOHDQHOHYDWHGVHUXPSRWDVVLXPOHYHO
RIP(T/VKRXOGEHUHFRUGHGDV³K\SHUNDODHPLD´
2EVHUYDWLRQVRIWKHVDPHFOLQLFDOO\VLJQLILFDQWODERUDWRU\DEQRUPDOLW\IURPYLVLWWRYLVLW
VKRXOGQRWEHUHSHDWHGO\UHFRUGHGDV$(VRU6$(VRQWKHH&5)XQOHVVWKHLUVHYHULW\
VHULRXVQHVVRUHWLRORJ\FKDQJHV
$Q\ODERUDWRU\UHVXOWDEQRUPDOLW\IXOILOOLQJWKHFULWHULDIRUDVHULRXVDGYHUVHHYHQW6$(
VKRXOGEHUHSRUWHGDVVXFKLQDGGLWLRQWREHLQJUHFRUGHGDVDQ$(LQWKH&5)
$Q\ WUHDWPHQWHPHUJHQW DEQRUPDO ODERUDWRU\ UHVXOW ZKLFK LV FOLQLFDOO\ VLJQLILFDQW LH
PHHWLQJ RQH RU PRUH RI WKH IROORZLQJ FRQGLWLRQV VKRXOG EH UHFRUGHG DV D VLQJOH
GLDJQRVLVRQWKHDGYHUVHHYHQWSDJHLQWKHH&5)
•
$FFRPSDQLHGE\FOLQLFDOV\PSWRPV
•
/HDGLQJ WR D FKDQJH LQ VWXG\ PHGLFDWLRQ HJ GRVH PRGLILFDWLRQ LQWHUUXSWLRQ RU
SHUPDQHQWGLVFRQWLQXDWLRQ
•
5HTXLULQJ D FKDQJH LQ FRQFRPLWDQW WKHUDS\ HJ DGGLWLRQ RI LQWHUUXSWLRQ RI
GLVFRQWLQXDWLRQ RI RU DQ\ RWKHU FKDQJH LQ D FRQFRPLWDQW PHGLFDWLRQ WKHUDS\ RU
WUHDWPHQW

)ROORZXSRIDEQRUPDOODERUDWRU\WHVWYDOXHV
,Q WKH HYHQW RI PHGLFDOO\ VLJQLILFDQW XQH[SODLQHG DEQRUPDO ODERUDWRU\ WHVW YDOXHV WKH
WHVWVVKRXOGEHUHSHDWHGDQGIROORZHGXSXQWLOWKH\KDYHUHWXUQHGWRWKHQRUPDOUDQJH
DQGRU DQ DGHTXDWH H[SODQDWLRQ RI WKH DEQRUPDOLW\ LV IRXQG ,I D FOHDU H[SODQDWLRQ LV
HVWDEOLVKHGLWVKRXOGEHUHFRUGHGRQWKHH&5)

3UHJQDQF\
,IDIHPDOHSDWLHQWEHFRPHVSUHJQDQWZKLOHUHFHLYLQJLQYHVWLJDWLRQDOWKHUDS\RUXSWR
PRQWKVDIWHUWKHODVWGRVHRILQYHVWLJDWLRQDOSURGXFWDSDSHU3UHJQDQF\5HSRUWLQJ)RUP
VKRXOGEHFRPSOHWHGDQGID[HGLPPHGLDWHO\LHZLWKLQ  KRXUVRIWKHLQYHVWLJDWRU
EHFRPLQJ DZDUH RI WKH SUHJQDQF\ 7KH FRPSOHWHG 3UHJQDQF\ 5HSRUWLQJ )RUP DQG
3UHJQDQF\)D[&RYHU6KHHWVKRXOGEHID[HGWRWKH5RFKH'UXJ6DIHW\'HSDUWPHQWRU
WKH5RFKHGHVLJQHH$Q\DFWLRQVSHUWDLQLQJWRVXEVHTXHQWVWXG\GUXJDGPLQLVWUDWLRQV
ZLOOEHDWWKH,QYHVWLJDWRU¶VGLVFUHWLRQLQFRQVXOWDWLRQZLWKWKHSDWLHQW


5LWX[LPDE)+RIIPDQQ/D5RFKH/WG
3URWRFRO02Y
RI
0DOH SDWLHQWV PXVW DOVR EH LQVWUXFWHG WR LPPHGLDWHO\ LQIRUP WKH ,QYHVWLJDWRU LI WKHLU
SDUWQHUEHFRPHVSUHJQDQWGXULQJWKHVWXG\RUZLWKLQPRQWKVDIWHUWKHODVWGRVHRI
LQYHVWLJDWLRQDO SURGXFW ,I VXFK DQ HYHQW RFFXUV D SDSHU 3UHJQDQF\ 5HSRUWLQJ )RUP
VKRXOGEHFRPSOHWHGDQGID[HGLPPHGLDWHO\LHZLWKLQ  KRXUVRIWKHLQYHVWLJDWRU
EHFRPLQJ DZDUH RI WKH SUHJQDQF\ 7KH FRPSOHWHG 3UHJQDQF\ 5HSRUWLQJ )RUP DQG
3UHJQDQF\)D[&RYHU6KHHWVKRXOGEHID[HGWRWKH5RFKH'UXJ6DIHW\'HSDUWPHQWRU
WKH5RFKHGHVLJQHH
$ERUWLRQZKHWKHUWKHUDSHXWLFRUVSRQWDQHRXVLQDIHPDOHSDWLHQWRUIHPDOHSDUWQHURID
PDOH SDWLHQW H[SRVHG WR WKH LQYHVWLJDWLRQDO SURGXFW VKRXOG DOZD\V EH FODVVLILHG DV
VHULRXVDVWKH6SRQVRUFRQVLGHUVWKHVHPHGLFDOO\VLJQLILFDQWUHFRUGHGRQDQ$(H&5)
SDJHDQGH[SHGLWLRXVO\UHSRUWHGWRWKH6SRQVRU
$Q\FRQJHQLWDODQRPDO\ELUWKGHIHFWLQDFKLOGERUQWRDIHPDOHSDWLHQWRUIHPDOHSDUWQHU
RIDPDOHSDWLHQWH[SRVHGWRWKHLQYHVWLJDWLRQDOSURGXFWVKRXOGEHUHFRUGHGDQGUHSRUWHG
DVDQ6$(RQDQ$(H&5)SDJH

,QWHUDFWLRQVZLWKRWKHU0HGLFLQDO3URGXFWVDQGRWKHU7\SHVRI
,QWHUDFWLRQV
)RUPDOGUXJLQWHUDFWLRQVWXGLHVKDYHEHHQSHUIRUPHGZLWKULWX[LPDE7KHWROHUDELOLW\RI
WKHVLPXOWDQHRXVRUVHTXHQWLDOFRPELQDWLRQRIULWX[LPDEZLWKFKHPRWKHUDS\DJHQWVWKDW
DUHOLDEOHWRFDXVHGHSOHWLRQRIQRUPDO%FHOOVLVZHOOGHILQHG
3DWLHQWV ZLWK KXPDQ DQWL±PRXVH DQWLERG\ RU KXPDQ DQWL±FKLPHULF DQWLERG\ +$&$
WLWUHV PD\ GHYHORS DOOHUJLF RU K\SHUVHQVLWLYLW\ UHDFWLRQV ZKHQ WUHDWHG ZLWK RWKHU
GLDJQRVWLFRUWKHUDSHXWLFPRQRFORQDODQWLERGLHV,QWKHLQWHJUDWHGUHYLHZRIGDWDIURP
SDWLHQWVSDWLHQWVGHYHORSHGD+$&$UHVSRQVHIROORZLQJWUHDWPHQW7ZRRIWKHVH
SDWLHQWV ZHUH UHWUHDWHG ZLWKRXW SUREOHPV 1R FRUUHODWLRQ ZDV VHHQ EHWZHHQ +$&$
UHVSRQVHDQGORVVRIRULQWHUIHUHQFHZLWKUHVSRQVHWRWUHDWPHQW

+$1'/,1*2)6$)(7<3$5$0(7(56

5HSRUWLQJRI6HULRXV$GYHUVH(YHQWV,PPHGLDWHO\5HSRUWDEOH
7KLV VWXG\ DGKHUHV WR WKH GHILQLWLRQ DQG UHSRUWLQJ UHTXLUHPHQWV RI ,&+ *XLGHOLQH IRU
&OLQLFDO 6DIHW\ 'DWD 0DQDJHPHQW 'HILQLWLRQV DQG 6WDQGDUGVIRU ([SHGLWHG 5HSRUWLQJ
7RSLF(&RPSOHWHLQIRUPDWLRQFDQEHIRXQGLQ$SSHQGL[
$Q\FOLQLFDODGYHUVHHYHQWRUDEQRUPDOODERUDWRU\WHVWYDOXHWKDWLVVHULRXVDQGZKLFK
RFFXUVGXULQJWKHFRXUVHRIWKHVWXG\DVGHILQHGLQ6HFWLRQDERYHUHJDUGOHVV
RIWKHWUHDWPHQWDUPPXVWEHUHSRUWHGWR5RFKHLPPHGLDWHO\LHZLWKLQKRXUVRI
WKH,QYHVWLJDWRUEHFRPLQJDZDUHRIWKHHYHQW7KH,QYHVWLJDWRUPXVWFRPSOHWHWKH6$(
5HSRUWLQJ)RUPDQGIRUZDUGLWWRWKHGHVLJQDWHG6$(&RQWDFW

6HULRXV$GYHUVH(YHQWV5HSRUWLQJ7LPHIUDPH
5HODWHG6HULRXV$GYHUVH(YHQWV0867EHFROOHFWHGDQGUHSRUWHGUHJDUGOHVVRIWKHWLPH
HODSVHGIURPWKHODVWVWXG\GUXJDGPLQLVWUDWLRQHYHQLIWKHVWXG\KDVEHHQFORVHG
$Q$(TXDOLILHVDV6XVSHFWHG8QH[SHFWHG6HULRXV$GYHUVH5HDFWLRQ686$5ZKHQDOO
WKHIROORZLQJFRQGLWLRQVDUHPHW
•
7KHHYHQWLVVHULRXV6$(
•
7KHUHPXVWEHDFHUWDLQGHJUHHRISUREDELOLW\WKDWWKHHYHQWLVDQDGYHUVHUHDFWLRQWR
WKHVWXG\GUXJ


5LWX[LPDE)+RIIPDQQ/D5RFKH/WG
3URWRFRO02Y
RI
•
7KH DGYHUVH UHDFWLRQ PXVW EH XQH[SHFWHG LH QRW IRUHVHHQ LQ WKH ,QYHVWLJDWRU¶V
%URFKXUH
686$5VDUHUHSRUWHGWR,QYHVWLJDWRUVDWHDFKVLWHDQGWKHLUDVVRFLDWHG,(&V
8QUHODWHG6HULRXV$GYHUVH(YHQWVPXVWEHFROOHFWHGDQGUHSRUWHGGXULQJWKHVWXG\DQG
IRU XS WR  PRQWKV DIWHU WKH ODVW GRVH RI VWXG\ PHGLFDWLRQ RU LQLWLDWLRQ RI QHZ DQWL
O\PSKRPDWUHDWPHQWZKLFKHYHURFFXUVILUVW

5HSRUWLQJRI,QIXVLRQ5HODWHG5HDFWLRQV,55VRU
$GPLQLVWUDWLRQ5HODWHG5HDFWLRQV$55V
6SHFLDODWWHQWLRQVKRXOGEHJLYHQWRLQIXVLRQUHODWHGUHDFWLRQV,55VDGPLQLVWUDWLRQ
UHODWHGUHDFWLRQV$55V$Q\$(VRFFXUULQJZLWKLQKRXUVDIWHUDGPLQLVWUDWLRQRI,9
ULWX[LPDEDQGFRQVLGHUHGUHODWHGWRWKHVWXG\GUXJZLOOEHFRQVLGHUHGDV,55V$Q\$(V
RFFXUULQJZLWKLQKRXUVDIWHUDGPLQLVWUDWLRQRI6&ULWX[LPDEDQGFRQVLGHUHGUHODWHGWR
WKHVWXG\GUXJZLOOEHFRQVLGHUHGDV$55V
,55V$55VFDQSUHVHQWZLWKRQHRUPRUHRIWKHIROORZLQJV\PSWRPVDOOHUJLFUHDFWLRQ
DUWKUDOJLD EURQFKRVSDVP FKLOOV FRXJK GL]]LQHVV G\VSQHD KHDGDFKH K\SHUWHQVLRQ
K\SRWHQVLRQP\DOJLDQDXVHDSUXULWXVS\UH[LDUDVKWDFK\FDUGLDXUWLFDULDOYRPLWLQJ

:$51,1*6$1'35(&$87,216
1RHYLGHQFHDYDLODEOHDWWKHWLPHRIWKHDSSURYDORIWKLVVWXG\SURWRFROLQGLFDWHGWKDW
VSHFLDOZDUQLQJVRUSUHFDXWLRQVZHUHDSSURSULDWHRWKHUWKDQWKRVHQRWHGLQWKHFXUUHQW
ULWX[LPDE,QYHVWLJDWRUV¶%URFKXUH

67$7,67,&$/&216,'(5$7,216$1'$1$/<7,&$/3/$1

35,0$5<$1'6(&21'$5<678'<(1'32,176

3ULPDU\(IILFDF\(QGSRLQW
7KHSULPDU\HIILFDF\HQGSRLQWRIWKHVWXG\LV3)6UDQG,WLVGHILQHGDVWKHWLPHIURPGD\RI
UDQGRPL]DWLRQWRWKHILUVWGRFXPHQWHGGLVHDVHSURJUHVVLRQRUGHDWKZKLFKHYHURFFXUV
ILUVW 3URJUHVVLRQ ZLOO EH EDVHG RQ WXPRXU DVVHVVPHQW PDGH E\ WKH LQYHVWLJDWRU
DFFRUGLQJWRWKH&KHVRQUHVSRQVHFULWHULDIRULQGROHQWO\PSKRPD
,Q WKLV WULDO 3)6UDQG ZLOO EH XVHG WR HYDOXDWH ZKHWKHU ULWX[LPDE PDLQWHQDQFH WKHUDS\
EH\RQG\HDUVIXUWKHULPSURYHVWKHUHVSRQVHWRWUHDWPHQW

6HFRQGDU\(IILFDF\(QGSRLQWV
7KHVHFRQGDU\HIILFDF\HQGSRLQWVDUH3URJUHVVLRQIUHHVXUYLYDO3)6PHDVXUHGIURP
WKH GD\ RIILUVWULWX[LPDE ,QGXFWLRQ GRVH 3)6UHJLVW (YHQWIUHH VXUYLYDO ()67LPH WR
QH[WO\PSKRPDWUHDWPHQW71/72YHUDOOVXUYLYDOPHDVXUHGIURPGD\RIILUVWULWX[LPDE
,QGXFWLRQGRVH26UHJLVWDQGIURPUDQGRPL]DWLRQ26UDQG2YHUDOO5HVSRQVH5DWH255
DW WKH HQG RI WKH ,QGXFWLRQ 3KDVH DQG 35 WR &5 FRQYHUVLRQ UDWH DW WKH HQG RI
0DLQWHQDQFH,
3URJUHVVLRQ)UHH 6XUYLYDO 3)6UHJLVW 3)6UHJLVW ZLOOEHPHDVXUHGIURPWKHGD\RIILUVW
ULWX[LPDE,QGXFWLRQGRVHXQWLOWKHGDWHRIILUVWGRFXPHQWHGGLVHDVHSURJUHVVLRQRUGHDWK
E\ DQ\ FDXVH 3DWLHQWV ZKR KDYH H[SHULHQFHG QRQH RI WKHVH HYHQWV DW WKH WLPH RI
DQDO\VLVFOLQLFDOFXWRIIDQGSDWLHQWVZKRDUHORVWWRIROORZXSZLOOEHFHQVRUHGDWWKHLU
ODVWFOLQLFDODVVHVVPHQWGDWH

 
Rituximab - F. Hoffmann-La Roche Ltd 
Protocol MO25455 v4.0 
92 of 128 
Event-Free Survival (EFS, time to treatment failure): EFS will be measured from the 
day of first rituximab Induction dose until the date of any treatment failure, including 
disease progression, or discontinuation of treatment for any reason (e.g. disease 
progression, toxicity, patient preference, initiation of new anti-lymphoma treatment, or 
death). Patients who have experienced none of these events by the end of the study and 
patients who are lost to follow-up will be censored at their last clinical assessment date. 
Overall Response Rate (ORR): ORR will be determined by tumour response according 
to the Cheson response criteria for indolent lymphoma1, and will be assessed at the end 
of Induction.   A responder is defined as patient experiencing either a CR or PR by these 
criteria.  
Overall Survival (OS): OS will be determined 1) from the day of first rituximab Induction 
dose until the date of death irrespective of cause (OSregist) and 2) from the day of 
randomization until the date of death irrespective of cause (OSrand). In both cases, 
patients who have not died at the time of end of the study, and patients who are lost to 
follow-up, will be censored at the date of the last contact. 
Time to Next Lymphoma Treatment (TNLT): TNLT will be measured from the day of 
first rituximab Induction dose to the date of first documented intake of any new anti-
lymphoma treatment (chemotherapy, radiotherapy, immunotherapy, etc.). Responding 
patients, and patients who are lost to follow-up, will be censored at their last visit where 
the start of new medication was assessed. Patients, who do not have documentation 
that a new anti-lymphoma treatment has started and patients who are lost to follow-up, 
will be censored at their last visit where the assessment for start of any new lymphoma 
medication was actually made. 
PR to CR conversion rate: Conversion rate will be assessed at end of Maintenance I. 
The percentage of patients with PR prior to rituximab maintenance therapy who achieve 
CR while on rituximab maintenance I therapy will be assessed. Response assessment 
will be conducted by the Investigator according to the Cheson response criteria for 
indolent lymphoma1 (see Appendix 1) or by the recommendations for Waldenström’s 
macroglobulinemia2 (see Appendix 2). 
8.1.3 
Exploratory efficacy endpoint 
 
  
 
8.1.4 
Safety Variables 
Safety of the treatment will be evaluated by: AEs, laboratory tests, vital signs, 
concomitant medications, new anti-lymphoma treatments and physical examination. In 
addition, IgG, IgM and IgA quantification will be completed once a year during the 2-year 
rituximab maintenance period, once a year during randomized  rituximab maintenance 
(Arm A) and in case of suspicious infections. 
8.2 
STATISTICAL ANALYSES 
8.2.1 
Primary Efficacy Analysis 
The PFSrand will be graphically presented using the Kaplan-Meier curves. The median 
PFSrand with 95% confidence interval will be reported for each treatment arm. Patients 

 
Rituximab - F. Hoffmann-La Roche Ltd 
Protocol MO25455 v4.0 
93 of 128 
who have not experienced an event at data cut-off date or patients who are withdrawn 
from the study without documented progression will be censored at the date of the last 
tumour assessment when the patient was known to be progression free. 
Patients without post baseline tumour assessments but known to be alive will be 
censored at the time of randomization.  
The difference in PFSrand between the two treatment arms (Arm A versus Arm B) will be 
tested with a stratified log-rank test using the stratification factors as defined in Section 
5.1.4. 
Furthermore, for the primary endpoint PFSrand a Cox regression model will be used to 
estimate the hazard ratio. 
8.2.2 
Secondary Efficacy Analyses 
The analysis of the secondary efficacy variables PFSregist, EFS, OSregist, OSrand and TNLT 
will be performed the same way as described for the primary variable PFSrand.  
Descriptive statistics and Kaplan-Meier curves will be presented for non-randomized 
patients and for the two randomized treatment groups. 
ORR (comprising CR and PR) at the end/completion of Induction treatment (measured 
from the day of first dose of rituximab induction dose) will be analysed in frequency 
tables including 95% two-sides Pearson-Clopper confidence intervals by treatment 
group.  
Logistic regression analysis will be performed to assess the influence of baseline 
covariates in an exploratory manner. 
The PR to CR conversion rate at the end of Maintenance I will be summarized.  
All tests will be performed at a 5% alpha level. No adjustments for multiplicity will be 
made during the analysis of the secondary efficacy variables. 
More details regarding the efficacy analyses and statistical models used will be defined 
in the Statistical Analysis Plan (SAP). 
8.2.3 
Exploratory Analyses 
8.2.3.1 
 
 
 
 
 
8.2.4 
Analysis Populations 
8.2.4.1 
Intent-to-treat populations 
All patients who have completed a baseline visit and at least one on-treatment 
assessment will be included in the Intent-To-Treat (ITT) population set. The ITT 
population will be used for the analysis of the secondary efficacy parameters and 
baseline variables. 


5LWX[LPDE)+RIIPDQQ/D5RFKH/WG
3URWRFRO02Y
RI
7KHUHZLOOEHDQDGGLWLRQDO,QWHQW7R7UHDW,77UDQGSRSXODWLRQLQFOXGLQJRQO\UDQGRPL]HG
SDWLHQWV IRU DQDO\VLQJ WKH SULPDU\ HQGSRLQW SURJUHVVLRQIUHH VXUYLYDO EH\RQG
UDQGRPL]DWLRQ$OOUDQGRPL]HGSDWLHQWVZLOOEHLQFOXGHGLQWKLV,77UDQGSRSXODWLRQ
,QERWK,77SRSXODWLRQVSDWLHQWVZLOOEHDVVLJQHGWRWUHDWPHQWJURXSVDVUDQGRPL]HGIRU
DQDO\VLVSXUSRVHV

3HUSURWRFROSRSXODWLRQ
$SHUSURWRFRO33UDQGDQDO\VLVSDWLHQWVIURPWKH,77UDQGSRSXODWLRQQRWKDYLQJDQ\PDMRU
SURWRFROYLRODWLRQVZLOODOVREHSHUIRUPHG
7KHSULPDU\HIILFDF\DQDO\VLVZLOOEHUHSHDWHGEDVHGRQWKH33UDQGSRSXODWLRQWRFRQILUP
WKHRYHUDOOVWXG\UHVXOWV

6DIHW\SRSXODWLRQ
$OOSDWLHQWVZKRUHFHLYHGDWOHDVWRQHGRVHRIULWX[LPDEZLOOEHLQFOXGHGLQWKHVDIHW\
SRSXODWLRQ3DWLHQWVZLOOEHDVVLJQHGWRWUHDWPHQWJURXSVDVWUHDWHG

,QWHULP$QDO\VLV
7KHUHZLOOEHQRLQWHULPDQDO\VLVIRUHIILFDF\+RZHYHUDIWHUWKHILUVWSDWLHQWVKDYH
FRPSOHWHGWKHLUULWX[LPDEEDVHG,QGXFWLRQDQH[SORUDWRU\DQDO\VLVRISDWLHQWDVVHVVHG
VDWLVIDFWLRQDQGFRQYHQLHQFHZLWKFKHPRWKHUDS\DGPLQLVWUDWLRQEDVHGRQWKH5$64ZLOO
EHSHUIRUPHG
$Q LQWHULP DQDO\VLV RI VDIHW\ ZLOO EH SHUIRUPHG DIWHU DSSUR[LPDWHO\  SDWLHQWV KDYH
EHHQHQUROOHGLQWKHVWXG\

6DIHW\'DWD$QDO\VLV
$OOSDWLHQWVZKRKDYHUHFHLYHGDWOHDVWRQHGRVHRI6&ULWX[LPDEZLOOEHLQFOXGHGLQWKH
6DIHW\SRSXODWLRQ7KHVDIHW\DQDO\VLVZLOOEHEDVHGRQWKH6DIHW\SRSXODWLRQ
$OOVDIHW\SDUDPHWHUVZLOOEHVXPPDUL]HGDQGSUHVHQWHGLQWDEOHVE\VWXG\SHULRGLH
,QGXFWLRQ0DLQWHQDQFH,0DLQWHQDQFH,,DVZHOODVRYHUDOO
5HSRUWHG $( WHUPV ZLOO EH FRGHG DFFRUGLQJ WR WKH 0HGLFDO 'LFWLRQDU\ IRU 'UXJ
5HJXODWRU\$IIDLUV0HG'5$
$OO $(V DQG ODERUDWRU\ SDUDPHWHUV ZLOO EH DVVHVVHG DFFRUGLQJ WR WKH 1&,&7&$(
YHUVLRQJUDGLQJV\VWHP
$(V ZLOO EH SUHVHQWHG LQ IUHTXHQF\ WDEOHV RYHUDOO E\ LQWHQVLW\ DQG E\ UHODWLRQVKLS WR
VWXG\WUHDWPHQWE\V\VWHPRUJDQFODVV
7KHLQFLGHQFHRI$(VZLOOEHUHSRUWHGDORQJZLWK3HDUVRQ&ORSSHU&,V
)UHTXHQF\WDEOHVZLOOEHJHQHUDWHGIRU
•
$(V
•
6$(V
•
*UDGH$(V
•
$(VOHDGLQJWRWUHDWPHQWGLVFRQWLQXDWLRQ
•
,55V$55V

 
Rituximab - F. Hoffmann-La Roche Ltd 
Protocol MO25455 v4.0 
95 of 128 
Changes in the NCI CTC-AE grades from laboratory parameters assessed at baseline of 
will be summarized by shift tables by treatment group. An additional analysis will be 
performed to examine the distribution of AEs over the course of the study (i.e. Induction, 
Maintenance I, Maintenance II as well as overall).  
Safety laboratory abnormalities will be presented in summary tables and as shift tables 
from baseline tables, as applicable. In addition, IgG, IgM and IgA quantification will be 
completed once a year during Maintenance I, once a year during Maintenance I (Arm A) 
and in case of suspicious infections. 
Vital signs will be summarized over time by treatment period and arm (Maintenance II). 
Concomitant medication will be coded according to the WHO DRUG dictionary and 
tabulated in summary tables. 
Further anti-lymphoma treatment data (chemotherapy, radiotherapy, immunotherapy) 
recorded in the eCRF (e.g. type of chemotherapy or site of radiotherapy) will be 
presented in summary tables.  
The Statistical Analysis Plan (SAP) will describe the safety analyses in more detail. 
8.2.7 
Other Analyses 
Major protocol deviations will be summarised. 
8.2.7.1 
Pharmacoeconomic analysis  
For details on the assessments or Medical Care Utilization parameters, refer to the Time 
in Motion pharmacoeconomic Sub-study protocol. 
8.3 
SAMPLE SIZE 
The sample size of the proposed study has been estimated based on assumptions 
derived from the Phase III randomized EORTC 20981 study of 465 patients with 
previously treated, advanced-staged, relapsed FL.3 In this study, patients were first 
randomized to 6 cycles of CHOP or R-CHOP. Those with an objective response 
underwent a second randomization to 2 years maintenance treatment with IV rituximab 
(375 mg/m2 once every 3 months) or observation (without maintenance treatment). 
Median PFS from first randomization was 20.2 months after CHOP vs. 33.1 months after 
R-CHOP (HR 0.65; p < 0.001). Rituximab maintenance yielded a median PFS from 
second randomization of 51.5 months vs. 14.9 months with observation alone (HR 0.40; 
p < 0.001). 
In the current study, all patients will undergo rituximab-based Induction followed by a SC 
rituximab maintenance period of 2 years (Maintenance I). After this approximately 2.5-
year treatment period, patients will be randomized to Arm A: further receive rituximab 
SC until progression vs. Arm B: observation only (Maintenance II). Assuming around 1.5 
year of enrolment, the last patient would be randomized around 4 years after first patient 
enrolled. Patients with PR or CR after Maintenance I can be randomized, whereas 
patients with PD or SD will come off study treatment and enter Off-Treatment Follow-Up.  
Assuming a median PFS beyond randomization of 38 months in arm A, and 23 months 
in arm B (corresponding to a HR of approximately 0.6), then 129 events are required to 
achieve 80% power for the log-rank test at a two-sided significance level of 5%.  
In order to see the required events, approximately 300 patients in Maintenance II will be 
followed from randomization (Maintenance II treatment until PD and Off-Treatment 

 
Rituximab - F. Hoffmann-La Roche Ltd 
Protocol MO25455 v4.0 
96 of 128 
Follow-Up) for at least 15 months. Allowing for a drop-out rate of 10%, 330 patients 
should be randomized.  
In total, 700 patients need to be enrolled in order to have 330 patients randomized after 
the 2.5-year Induction plus Maintenance I treatment period. The assumptions regarding 
the drop-out rates in each study phase are presented in the scheme below. 
 
Figure 2 Estimated attrition rates during the pre-randomization phase 
  
 
 
 
 
 
 
 
 
 
 
 
A summary of the sample size assumptions can be found in Table 15 below. 
Table 15 SAMPLE SIZE ASSUMPTIONS 
Estimated 
HR 
 
Estimated 
Median PFS 
beyond 
randomization 
Duration of 
Follow-up 
Post-
randomization 
Total 
Number of 
Events 
needed 
Number of 
patients 
randomized* 
Total Number 
of Patients 
Enrolled 
(% reaching 
randomization) 
 0.6 
 
  A: 38 months 
  B: 23 months 
Minimum  
15 months 
129 
330 
700 (47%) 
* Includes a +10% adjustment for post-randomization dropouts 
A: Rituximab maintenance until PD 
B: Observation (no treatment) after 2.5 years of rituximab-based Induction plus Maintenance I 
 
9. 
DATA COLLECTION, MANAGEMENT AND QUALITY 
ASSURANCE 
The overall procedures for quality assurance of clinical study data are described in the 
Roche Standard Operational Procedures. 
Data for this study will be recorded via an Electronic Data Capture system (EDC) using 
electronic Case Report Forms (eCRF). Site personnel will transcribe data from the paper 
source documents onto the eCRF. In no case is the eCRF to be considered as source 
data for this trial. Accurate and reliable data collection will be assured by verification and 
cross-check of the CRFs against the Investigator’s records by the study monitor (source 
document verification), and the maintenance of a Drug Dispensing Log by the 
700 patients enrolled 
20% PD and other reasons 
560 patients entering 2-year initial maintenance 
Approximately 330 patients randomized 
30% PD or SD at end Maintenance I 
10% dropout due to other reasons 


5LWX[LPDE)+RIIPDQQ/D5RFKH/WG
3URWRFRO02Y
RI
,QYHVWLJDWRU$FRPSUHKHQVLYHYDOLGDWLRQFKHFNSURJUDPXWLOL]LQJIURQWHQGFKHFNVLQWKH
&5)DQGEDFNHQGFKHFNVLQWKH5RFKHGDWDEDVHZLOOYHULI\WKHGDWDDQGGLVFUHSDQFLHV
ZLOOEHJHQHUDWHGDFFRUGLQJO\7KHVHDUHWUDQVIHUUHGHOHFWURQLFDOO\WRWKH&5)DWWKHVLWH
IRU UHVROXWLRQ E\ WKH ,QYHVWLJDWRU (&5)V DQG FRUUHFWLRQ GRFXPHQWDWLRQ ZLOO EH
PDLQWDLQHGLQWKH('&V\VWHP¶VDXGLWWUDLO6\VWHPEDFNXSVIRUGDWDVWRUHGZLWK6SRQVRU
DQG UHFRUGV UHWHQWLRQ IRU WKH VWXG\ GDWD ZLOO EH FRQVLVWHQW ZLWK 6SRQVRU¶V VWDQGDUG
SURFHGXUHV
7KH6SRQVRUZLOOEHUHVSRQVLEOHIRUWKHGDWDPDQDJHPHQWRIWKLVWULDOLQFOXGLQJTXDOLW\
FKHFNLQJRIWKHGDWDDFFRUGLQJWRWKH('&6WXG\6SHFLILFDWLRQGRFXPHQW7KURXJKRXW
WKHVWXG\WKH6WXG\0DQDJHPHQW7HDPZLOOUHYLHZGDWDDFFRUGLQJWRWKH5RFKH'DWD
0DQDJHPHQW3ODQDVGHVFULEHGLQWKH'DWD4XDOLW\3ODQ&HQWUDOODERUDWRU\DQGRWKHU
HOHFWURQLF GDWD ZLOO EH VHQW GLUHFWO\ WR WKH 6SRQVRU XVLQJ WKH 6SRQVRU¶V VWDQGDUG
SURFHGXUHVWRKDQGOHDQGSURFHVVWKHHOHFWURQLFWUDQVIHURIWKHVHGDWD

$66,*10(172)35()(55('7(506$1'25,*,1$/
7(50,12/2*<
)RU FODVVLILFDWLRQ SXUSRVHV SUHIHUUHG WHUPV ZLOO EH DVVLJQHG E\ WKH 6SRQVRU WR WKH
RULJLQDOWHUPVHQWHUHGRQWKHH&5)XVLQJWKHPRVWXSWRGDWHYHUVLRQRIWKH0HG'5$
WHUPLQRORJ\IRUDGYHUVHHYHQWVDQGGLVHDVHDQGWKH,QWHUQDWLRQDO1RQSURSULHWDU\1DPH
,11'UXJ7HUPVDQG3URFHGXUHV'LFWLRQDU\IRUWUHDWPHQWVDQGVXUJLFDODQGPHGLFDO
SURFHGXUHV

678'<&200,77((6

,1'(3(1'(17'$7$$1'6$)(7<021,725,1*%2$5'
'60%&200,77((L'0&
$Q,QGHSHQGHQW'DWD0RQLWRULQJ&RPPLWWHHL'0&ZLOOEHIRUPHGDQGFRPSRVHGRI
PHPEHUVLQFOXGLQJDVWDWLVWLFLDQ7KHL'0&ZLOOUHYLHZDOOVDIHW\GDWDSHUWDLQLQJWRWKH
VWXG\GUXJRQDUHJXODUEDVLVDWOHDVWRQFHD\HDURUDW)+RIIPDQQ/D5RFKH/WG¶V
UHTXHVW
7KH &RPPLWWHH ZLOO EH UHVSRQVLEOHIRUPRQLWRULQJ RQ DQ RQJRLQJ EDVLV DOO VLJQLILFDQW
VDIHW\HYHQWV66(V
$66(LVGHILQHGDVDQ\RIWKHIROORZLQJ
•
*HQHUDOWR[LFLW\1&,&7&JUDGHDQGJUDGH$(V6$(V
•
$Q\$(WKDWUHTXLUHVGRVHLQWHUUXSWLRQUHGXFWLRQRUGLVFRQWLQXDWLRQRIWKHVWXG\GUXJ
•
$SDWLHQWGHDWK
)ROORZLQJHDFKPHHWLQJWKH&RPPLWWHHZLOOUHFRPPHQGWRWKH6SRQVRUWKDWWKHVWXG\
FRQWLQXHV DFFRUGLQJ WR WKH SURWRFRO RU VXJJHVW FKDQJHV WR WKH SURWRFRO EDVHG RQ WKH
RXWFRPH RI WKH GDWD UHYLHZ ,Q H[FHSWLRQDO FDVHV WKH &RPPLWWHH PD\ UHFRPPHQG
VWRSSLQJWKHVWXG\GXHWRVDIHW\UHDVRQV)XUWKHUGHWDLOVDERXWWKHGHILQLWLRQDQGWKH
UROHDVZHOODVWKHUHVSRQVLELOLW\RIWKHL'0&ZLOOEHSURYLGHGLQDVHSDUDWHGRFXPHQW
WKHL'0&&KDUWHU

 
Rituximab - F. Hoffmann-La Roche Ltd 
Protocol MO25455 v4.0 
98 of 128 
PART II: ETHICS AND GENERAL STUDY ADMINISTRATION 
11. 
ETHICAL ASPECTS 
11.1 
LOCAL REGULATIONS/DECLARATION OF HELSINKI 
The Investigator will ensure that this study is conducted in full conformance with the 
principles of the “Declaration of Helsinki” or with the laws and regulations of the country 
in which the research is conducted, whichever affords the greater protection to the 
individual.  The study must fully adhere to the principles outlined in “Guideline for Good 
Clinical Practice” ICH Tripartite Guideline [January 1997] or with local law if it affords 
greater protection to the patient. For studies conducted in the EU/EEA countries, the 
Investigator will ensure compliance with the EU Clinical Trial Directive [2001/20/EC].   
In other countries where “Guideline for Good Clinical Practice” exists, Roche and the 
Investigators will strictly ensure adherence to the stated provisions. 
11.2 
INFORMED CONSENT  
It is the responsibility of the Investigator, or a person designated by the Investigator (if 
acceptable by local regulations), to obtain signed informed consent from each patient 
prior to participating in this study after adequate explanation of the aims, methods, 
anticipated benefits, and potential hazards of the study. The Investigator or designee 
must also explain that the patients are completely free to refuse to enter the study or to 
withdraw from it at any time, for any reason.   
The eCRFs for this study contain a section for documenting patient informed consent, 
and this must be completed appropriately.  If new safety information results in significant 
changes in the risk/benefit assessment, the consent form should be reviewed and 
updated if necessary. All patients (including those already being treated) should be 
informed of the new information, given a copy of the revised form and give their consent 
to continue in the study. 
For the patient not qualified or incapable of giving legal consent, written consent must be 
obtained from the legally acceptable representative.  In the case where both the patient 
and his/her legally acceptable representative are unable to read, an impartial witness 
should be present during the entire informed consent discussion.  After the patient and 
representative have orally consented to participation in the trial, the witness’ signature 
on the form will attest that the information in the consent form was accurately explained 
and understood.   
11.3 
INDEPENDENT ETHICS COMMITTEES (IEC)  
The protocol, informed consent and any accompanying material provided to the patient 
will be submitted to an IEC for review.  For EEA member states, the Sponsor will submit 
to the Competent Authority and IEC, the protocol and any accompanying material 
provided to the patient. In the EEA member states, the accompanying material may 
include patient information sheets, descriptions of the study used to obtain informed 
consent and terms of any compensation given to the patient as well as advertisements 
for the trial. 
An approval letter or certificate (specifying the protocol number and title) from the IEC 
must be obtained before study initiation by the Investigator specifying the date on which 
the committee met and granted the approval. This applies whenever subsequent 
amendments/modifications are made to the protocol. 

 
Rituximab - F. Hoffmann-La Roche Ltd 
Protocol MO25455 v4.0 
99 of 128 
Any modifications made to the protocol, informed consent or material provided to the 
patient after receipt of the IEC  approval must also be submitted by the Investigator or by 
the Sponsor (in the EEA member states) in accordance with local procedures and 
regulatory requirements. 
When no local review board exists, the Investigator is expected to submit the protocol to 
a regional committee.  If no regional committee exists, Roche will assist the Investigator 
in submitting the protocol to the European Ethics Review Committee. 
Roche shall also submit an Annual Safety Report once a year to the IEC and Competent 
Authorities (CAs) according to local regulatory requirements and timelines of each 
country participating in the study. 
11.4 
FINANCIAL DISCLOSURE 
The Investigator(s) will provide the Sponsor with sufficient accurate financial information 
(PD35) to allow the Sponsor to submit complete and accurate financial certification or 
disclosure statements to the appropriate regulatory authorities. The Investigator is 
responsible to promptly update any information provided to the Sponsor if relevant 
changes occur in the course of the investigation and for 1 year following the completion 
of the study (last patient, last visit). 
12. 
CONDITIONS FOR MODIFYING THE PROTOCOL 
Requests from Investigators to modify the protocol to ongoing studies will be considered 
only by consultation between an appropriate representative of the sponsor and the 
Investigator (or Investigator representative[s]).  Protocol modifications must be prepared 
by a representative of the sponsor and initially reviewed and approved by the Lead 
Scientific Responsible and Biostatistician. 
All protocol modifications must be submitted to the appropriate Independent Ethics 
Committee for information and approval in accordance with local requirements, and to 
Regulatory Agencies if required. Approval must be obtained before any changes can be 
implemented, except for changes necessary to eliminate an immediate hazard to trial 
patients, or when the change[s] involves only logistical or administrative aspects of the trial 
(e.g. change in monitor[s], change of telephone number[s]). 
13. 
CONDITIONS FOR TERMINATING THE STUDY 
Both the sponsor and the Investigator reserve the right to terminate the study at any time.  
Should this be necessary, both parties will arrange the procedures on an individual study 
basis after review and consultation.  In terminating the study, Roche and the Investigator 
will assure that adequate consideration is given to the protection of the patient’s interests. 
The appropriate IEC and Regulatory Agencies should be informed accordingly. 
14. 
STUDY DOCUMENTATION, CRFS AND RECORD KEEPING 
14.1 
INVESTIGATOR'S FILES / RETENTION OF DOCUMENTS 
The Investigator must maintain adequate and accurate records to enable the conduct of 
the study to be fully documented and the study data to be subsequently verified. These 
documents should be classified into two different separate categories: 1) Investigator's 
Study File, and 2) patient clinical source documents. 

 
Rituximab - F. Hoffmann-La Roche Ltd 
Protocol MO25455 v4.0 
100 of 128 
The Investigator's Study File will contain the protocol/amendments, eCRF/DCS and 
schedule of assessments, Independent Ethics Committee/Institutional Review Board and 
governmental approval with correspondence, sample informed consent, drug records, 
staff 
curriculum 
vitae 
and 
authorization 
forms 
and 
other 
appropriate 
documents/correspondence, etc. In addition at the end of the study the investigator will 
receive the patient data, which includes an audit trail containing a complete record of all 
changes to data, query resolution correspondence and reasons for changes, in human 
readable format on CD which also has to be kept with the Investigator’s Study File. 
Patient clinical source documents [usually defined by the project in advance to record 
key efficacy/safety parameters independent of the eCRFs] would include patient 
hospital/clinic records, physician's and nurse's notes, appointment book, original 
laboratory reports, ECG, EEG, X-ray, pathology and special assessment reports, signed 
informed consent forms, consultant letters, and patient screening and enrollment logs. 
The Investigator must keep the two categories of documents as described above 
(including the archival CD) on file for at least 15 years after completion or discontinuation 
of the study. After that period of time the documents may be destroyed, subject to local 
regulations. 
Should the Investigator wish to assign the study records to another party or move them 
to another location, Roche must be notified in advance. 
If the Investigator cannot guarantee this archiving requirement at the investigational site 
for any or all of the documents, special arrangements must be made between the 
Investigator and Roche to store these in a sealed container[s] outside of the site so that 
they can be returned sealed to the Investigator in case of a regulatory audit. Where 
source documents are required for the continued care of the patient, appropriate copies 
should be made for storing outside of the site. 
ICH GCP guidelines require that Investigators maintain information in the study patient’s 
records which corroborate data collected on the eCRF(s). 
14.2 
SOURCE DOCUMENTS AND BACKGROUND DATA 
The investigator shall supply the sponsor on request with any required background data 
from the study documentation or clinic records. This is particularly important when errors 
in data transcription are suspected. In case of special problems and/or governmental 
queries or requests for audit inspections, it is also necessary to have access to the 
complete study records, provided that patient confidentiality is protected. 
14.3 
PROTOCOL DEVIATIONS 
The investigator should document and explain any protocol deviations.  The investigator 
should promptly report any deviations that might have an impact on patient safety and 
data integrity to the Sponsor and to the IRB/EC in accordance with established IRB/EC 
policies and procedures. 
14.4 
AUDITS AND INSPECTIONS 
The investigator should understand that source documents for this trial should be made 
available to appropriately qualified personnel from Roche, or its designees, or to health 
authority inspectors after appropriate notification. The verification of the eCRF data must 
be by direct inspection of source documents. 

 
Rituximab - F. Hoffmann-La Roche Ltd 
Protocol MO25455 v4.0 
101 of 128 
14.5 
ELECTRONIC CASE REPORT FORMS   
Data for this study will be captured via an Electronic Data Capture (EDC) system by 
using eCRFs. For each patient enrolled, an eCRF must be completed and electronically 
signed by the principal investigator or authorized delegate from the study staff. This also 
applies to records for those patients who fail to complete the study. If a patient withdraws 
from the study, the reason must be noted on the eCRF. If a patient is withdrawn from the 
study because of a treatment-limiting AE, thorough efforts should be made to clearly 
document the outcome. 
The investigator should ensure the accuracy, completeness and timeliness of the data 
reported to the sponsor in the eCRFs and in all required reports. 
15. 
MONITORING THE STUDY 
It is understood that the responsible monitor will contact and visit the investigator 
regularly and will be allowed, on request, to inspect the various records of the trial [CRFs 
and other pertinent data] provided that patient confidentiality is maintained in accord with 
local requirements. 
It will be the monitor's responsibility to inspect the CRFs at regular intervals throughout 
the study, to verify the adherence to the protocol and the completeness, consistency and 
accuracy of the data being entered on them. The monitor must verify that the patient 
received the study drug assigned by the randomization centre (by controlling the written 
confirmation of the randomization by IVRS/IWRS). The monitor should have access to 
laboratory test reports and other patient records needed to verify the entries on the CRF. 
The investigator [or deputy] agrees to cooperate with the monitor to ensure that any 
problems detected in the course of these monitoring visits are resolved. 
16. 
CONFIDENTIALITY OF TRIAL DOCUMENTS AND PATIENT 
RECORDS 
The investigator must assure that patients’ anonymity will be maintained and that their 
identities are protected from unauthorized parties. On CRFs or other documents 
submitted to the sponsor, patients should not be identified by their names, but by an 
identification code. The investigator should keep a patient enrollment log showing codes, 
names and addresses. 
The investigator should maintain documents not for submission to Roche, e.g., Roche 
already maintains rigorous confidentiality standards for clinical studies by “coding” (i.e. 
assigning a unique patient ID number at the investigator site) all patients enrolled in 
Roche clinical studies.  This means that patient names are not included in data sets that 
are transmitted to any Roche location. 
17. 
CLINICAL STUDY REPORT (CSR) 
A clinical study report will be written and distributed to Health Authorities as required by 
applicable regulatory requirements.   
18. 
PUBLICATION OF DATA AND PROTECTION OF TRADE 
SECRETS 
Roche will comply with the requirements for publication of study results. 

 
Rituximab - F. Hoffmann-La Roche Ltd 
Protocol MO25455 v4.0 
102 of 128 
The results of this study may be published or presented at scientific meetings. If this is 
foreseen, the investigator agrees to submit all manuscripts or abstracts to Roche prior to 
submission. This allows the sponsor to protect proprietary information and to provide 
comments based on information from other studies that may not yet be available to the 
investigator.   
In accordance with standard editorial and ethical practice, Roche will generally support 
publication of multicentre trials only in their entirety and not as individual centre data. In 
this case, a coordinating investigator will be designated by mutual agreement. 
Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors (ICMJE) authorship requirements.  Any formal 
publication of the study in which input of Roche personnel exceeded that of conventional 
monitoring will be considered as a joint publication by the investigator and the 
appropriate Roche personnel.  
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of data from this study will become and remain the exclusive and unburdened 
property of the Sponsor, except where agreed otherwise. 
  

 
Rituximab - F. Hoffmann-La Roche Ltd 
Protocol MO25455 v4.0 
103 of 128 
19. 
APPENDICES 
APPENDIX 1. 
CRITERIA FOR EVALUATION OF RESPONSE IN NON-
HODGKIN’S LYMPHOMA1 
 
Complete Response (CR) 
A complete response requires the following: 
1. Complete disappearance of all detectable clinical and radiographic evidence of 
disease and disappearance of all disease-related symptoms if present before 
therapy, and normalization of those biochemical abnormalities [e.g., lactate 
dehydrogenase (LDH)] definitely assignable to Non-Hodgkin’s Lymphoma (NHL). 
2. All lymph nodes and nodal masses must have regressed to normal size (≤1.5 cm in 
their greatest transverse diameter for nodes ≥1.5 cm before therapy). Previously 
involved nodes that were 1.1 to 1.5 cm in their greatest transverse diameter before 
treatment must have decreased to < 1 cm in their greatest transverse diameter after 
treatment, or by more than 75% in the sum of the products of the greatest diameters 
(SPD). 
3. The spleen, if considered to be enlarged before therapy on the basis of a CT scan, 
must have regressed in size and must not be palpable on physical examination. 
Similarly, other organs considered to be enlarged before therapy due to involvement 
by lymphoma, such as liver and kidneys, must have decreased in size. 
4. Bone marrow, if positive at baseline, must be histologically negative for lymphoma. 
 
Partial Response (PR) 
A partial response requires the following: 
1. ≥ 50% decrease in SPD of the six largest dominant nodes or nodal masses. These  
nodes or masses should be selected according to the following features: (a) they 
should be clearly measurable in at least two perpendicular dimensions, (b) they 
should be from as disparate regions of the body as possible, and (c) they should 
include mediastinal and retroperitoneal areas of disease whenever these sites are 
involved. 
2. No increase in the size of the other nodes, liver, or spleen 
3. Splenic and hepatic nodules must regress by at least 50% in the SPD. 
4. With the exception of splenic and hepatic nodules, involvement of other organs is 
considered assessable and not measurable disease. 
5. No new sites of disease. 
 

 
Rituximab - F. Hoffmann-La Roche Ltd 
Protocol MO25455 v4.0 
104 of 128 
Stable Disease (SD) 
Stable disease is defined as less than a PR (as described above) but not progressive 
disease (see below). 
 
Progressive Disease (PD) 
Progressive Disease is defined as follows: 
- 
≥ 50% increase from nadir in the SPD of any previously identified abnormal node 
- 
Appearance of any new lesion during or at the end of therapy. 
 


5LWX[LPDE)+RIIPDQQ/D5RFKH/WG
3URWRFRO02Y
RI
$33(1',;
&5,7(5,$)25(9$/8$7,212)5(63216(,1
:$/'(1675g0¶60$&52*/2%8/,1(0,$

'HILQLWLRQVRI5HVSRQVH
7KH
XSGDWHG
UHFRPPHQGDWLRQV
IRU
DVVHVVLQJ
UHVSRQVH
LQ
:DOGHQVWU|P¶V
0DFURJOREXOLQHPLDDUHDVIROORZV
•
&RPSOHWH UHVSRQVH &5 FDWHJRUL]HG E\ D GLVDSSHDUDQFH RI VHUXP DQG XULQH
PRQRFORQDO SURWHLQ GHWHUPLQHG E\ LPPXQRIL[DWLRQ DEVHQFH RI PDOLJQDQW FHOOV LQ
ERQH
PDUURZ
GHWHUPLQHG
E\
KLVWRORJLF
HYDOXDWLRQ
UHVROXWLRQ
RI
DGHQRSDWK\RUJDQRPHJDO\FRQILUPHGE\FRPSXWHGWRPRJUDSK\>&7@VFDQDQGQR
VLJQVRUV\PSWRPVDWWULEXWDEOHWR:DOGHQVWU|P¶VPDFURJOREXOLQHPLD5HFRQILUPDWLRQ
RIWKH&5VWDWXVLVUHTXLUHGZHHNVODWHUZLWKDVHFRQGLPPXQRIL[DWLRQ
•
3DUWLDO UHVSRQVH FDWHJRUL]HG E\   UHGXFWLRQ RI VHUXP PRQRFORQDO ,J0
FRQFHQWUDWLRQ GHWHUPLQHG E\ SURWHLQ HOHFWURSKRUHVLV   GHFUHDVH LQ
DGHQRSDWK\RUJDQRPHJDO\ RQ SK\VLFDO H[DPLQDWLRQ RU RQ &7 VFDQ DQG QR QHZ
V\PSWRPVRUVLJQVRIDFWLYHGLVHDVH
•
0LQRU UHVSRQVHFDWHJRUL]HG E\   EXW  UHGXFWLRQ RI VHUXPPRQRFORQDO
,J0GHWHUPLQHGE\SURWHLQHOHFWURSKRUHVLVDQGQRQHZV\PSWRPVRUVLJQVRIDFWLYH
GLVHDVH
•
6WDEOH GLVHDVH FDWHJRUL]HG E\   UHGXFWLRQ DQG   LQFUHDVH RI VHUXP
PRQRFORQDO
,J0
GHWHUPLQHG
E\
HOHFWURSKRUHVLV
ZLWKRXW
SURJUHVVLRQ
RI
DGHQRSDWK\RUJDQRPHJDO\F\WRSHQLDVRUFOLQLFDOO\VLJQLILFDQWV\PSWRPVFDXVHGE\
GLVHDVHDQGRUVLJQVRI:DOGHQVWU|P¶VPDFURJOREXOLQHPLD
•
3URJUHVVLYH GLVHDVHFDWHJRUL]HG E\  LQFUHDVH LQ VHUXPPRQRFORQDO ,J0 E\
SURWHLQ HOHFWURSKRUHVLV FRQILUPHG E\ D VHFRQG PHDVXUHPHQW RU SURJUHVVLRQ RI
FOLQLFDOO\ VLJQLILFDQW ILQGLQJV FDXVHG E\ GLVHDVH HJ DQHPLD WKURPERF\WRSHQLD
OHXNRSHQLD RU EXON\ DGHQRSDWK\RUJDQRPHJDO\ RU V\PSWRPV HJ XQH[SODLQHG
UHFXUUHQWIHYHU&GUHQFKLQJQLJKWVZHDWVZHLJKWORVVK\SHUYLVFRVLW\
QHXURSDWK\ RU V\PSWRPDWLF FU\RJOREXOLQHPLD DWWULEXWDEOH WR :DOGHQVWU|P¶V
PDFURJOREXOLQHPLD
•
1RWHYDOXDEOHGHOD\HGUHVSRQVHLQVRPHFDVHVWKHUHLVLQVXIILFLHQWGDWDDQGRUWLPH
IRU D GHWHUPLQDWLRQ RI UHVSRQVH WR WUHDWPHQW $ GHOD\HG UHVSRQVH PLJKW EH VHHQ
SDUWLFXODUO\ DIWHU SXULQH DQDORJXH RU PRQRFORQDO DQWLERG\ WKHUDS\ 7KH SDQHO
UHFRPPHQGHGWKDWSDWLHQWVPXVWKDYHEHHQIROORZHGIRUPRQWKVDIWHUWUHDWPHQW
LQLWLDWLRQWREHFRQVLGHUHGXQUHVSRQVLYHWRWKHUDS\,QDGGLWLRQWKHEHVWUHVSRQVHLV
RIWHQH[KLELWHGVHYHUDOPRQWKVDIWHUWUHDWPHQWGLVFRQWLQXDWLRQ


 
Rituximab - F. Hoffmann-La Roche Ltd 
Protocol MO25455 v4.0 
106 of 128 
APPENDIX 3. 
FOLLICULAR LYMPHOMA GRADING SYSTEM (WHO 
CLASSIFICATION) 
 
Follicular Cell Lymphomas: Grading and Variants96 
 
Grade 
1 
 
0-5 centroblasts/hpf (high power field [microscopy]) 
Grade 
2 
 
6-15 centroblasts/hpf 
Grade 
3 
 
15 centroblasts/hpf 
 
3a  
15 centroblasts, but centrocytes are still present 
 
3b  
Centroblasts form solid sheets with no residual centrocytes 
 
Variants 
 
Cutaneous follicle centre lymphoma 
 
Diffuse follicle centre lymphoma 
 
 
Grade 1 0-5 CB/hpf 
 
 
Grade 2 6-15 CB/hpf 
 
 
 

 
Rituximab - F. Hoffmann-La Roche Ltd 
Protocol MO25455 v4.0 
107 of 128 
APPENDIX 4. 
COMMON SCALES 
 
Eastern Cooperative Oncology Group (ECOG) Performance Status 
 
GRADE 
PERFORMANCE STATUS – WHO CLASSIFICATION 
0 
Able to carry out all normal activity without restriction 
1 
Restricted in physically strenuous activity but ambulatory and 
able to carry out light work 
2 
Ambulatory and capable of all self-care but unable to carry out 
any work; up and about more 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 out any self-care; totally 
confined to bed and chair. 
 
Ann Arbor Stage 
 
Stage I: 
 I = Involvement of a single lymph node region. 
 
 IE = Localized involvement of a single extralymphatic organ or site. 
 
Stage II: 
 II = Involvement of 2 or lymph node regions on the same side of the 
diaphragm. 
 IIE = Localized involvement of a single associated extralymphatic organ or 
site and its regional lymph nodes with or without other lymph node regions 
on the same side of the diaphragm. 
 
Stage III:  III = Involvement of lymph node regions on both sides of the diaphragm. 
 IIIE = Involvement of lymph node regions on both sides of the diaphragm 
accompanied by localized involvement of an extralymphatic organ or site. 
 IIIS = Involvement of lymph node regions on both sides of the diaphragm 
accompanied by involvement of the spleen*. 
 IIIS+E = Both IIIS+IIIE *. 
(*Of note, in FLIPI, spleen involvement is categorized as stage IV) 
 
Stage IV:  IV = Disseminated (multifocal) involvement of 1 or more extralymphatic sites 
with 
or 
without 
associated 
lymph 
node 
involvement 
or 
isolated 
extralymphatic organ involvement with distant (non-regional) nodal 
involvement. 
 IVE = Extranodal lymphoid malignancies arise in tissues separate from, but 
near, the major lymphatic aggregates. 

 
Rituximab - F. Hoffmann-La Roche Ltd 
Protocol MO25455 v4.0 
108 of 128 
FLIPI Score and Nodal Areas 
 
Follicular Lymphoma International Prognostic Index (FLIPI)97 
 
 
 
The Follicular Lymphoma International Prognostic Index, or FLIPI, is a standardized 
guide on prognosis of survival rates of follicular lymphoma patients based on certain risk 
factors. As patients of Waldenström’s macroglobulinemia or lymphoplasmacytic 
lymphoma, marginal zone lymphoma are non-FL patients, thus the FLIPI is not 
applicable. 
 
Five adverse prognostic factors were selected: 
1. Age (> 60 vs. ≤ 60) 
2. Ann Arbor Stage (III-IV vs. I-II) 
3. Haemoglobin level (< 12 g/dl vs. ≥ 12 d/dl) 
4. Number of nodal areas (> 4 vs. ≤ 4) 
5. Serum LDH level (> normal vs. ≤ normal) 
Three risk groups were defined: 

 
Rituximab - F. Hoffmann-La Roche Ltd 
Protocol MO25455 v4.0 
109 of 128 
1. LOW RISK (0-1 adverse factor) 
2. INTERMEDIATE RISK (2 adverse factors) 
3. HIGH RISK (≥ 3 adverse factors) 
 


5LWX[LPDE)+RIIPDQQ/D5RFKH/WG
3URWRFRO02Y
RI
$33(1',;
)2508/$)25&$/&8/$7,212)%6$'8%2,6


%6$Pð [+HLJKWP[:HLJKWNJ

8QLW&RQYHUVLRQ
•
NJ OEV
•
LQFK FP
([DPSOH%6$RIDVXEMHFWEHLQJPWDOODQGZHLJKLQJNJ
•
%6$Pð [P[NJ
•
%6$Pð [[ 
7KHVXEMHFW¶VVWDQGLQJKHLJKWZLOOEHPHDVXUHGLQEDUHIHHWVWDQGLQJZLWKKLVKHUKHHOV
DQGEDFNLQFRQWDFWZLWKWKHYHUWLFDOEDURIDZDOOPRXQWHGPHDVXULQJGHYLFH7KHKHDG
LVKHOGVRWKHVXEMHFWORRNVVWUDLJKWIRUZDUG$OHYHOZLOOEHSODFHGRQWKHVXEMHFW¶VKHDG
WR HQVXUH WKDW WKH VXEMHFW LV ORRNLQJ VWUDLJKW IRUZDUG 7KH SRLQW DW ZKLFK WKH ORZHU
VXUIDFH RI WKH OHYHO LQWHUVHFWV ZLWK WKH YHUWLFDO PHDVXULQJ GHYLFH ZLOO EH WKH VWDQGLQJ
KHLJKW



 
Rituximab - F. Hoffmann-La Roche Ltd 
Protocol MO25455 v4.0 
111 of 128 
APPENDIX 6. 
NCI COMMON TERMINOLOGY CRITERIA FOR ADVERSE 
EVENTS 
 
In the present study, toxicities will be recorded according to the National Cancer 
Institute (of the United States of America, NCI) Common Terminology Criteria for 
Adverse Events (CTC-AE), version 4.0. 
At the time this protocol was issued, the full CTC document was available on the 
NCI site, at the following address: http://ctep.cancer.gov  
Investigators who do not have access to Internet can contact the Data Centre to 
receive a hard copy of this document by mail. 
 
 
 


5LWX[LPDE)+RIIPDQQ/D5RFKH/WG
3URWRFRO02Y
RI
$33(1',;
,&+*8,'(/,1(6)25&/,1,&$/6$)(7<'$7$
0$1$*(0(17'(),1,7,216$1'67$1'$5'6)25
(;3(',7('5(3257,1*723,&(
$ VHULRXV DGYHUVH HYHQW 6$( LV DQ\ H[SHULHQFH WKDW VXJJHVWV D VLJQLILFDQW KD]DUG
FRQWUDLQGLFDWLRQVLGHHIIHFWRUSUHFDXWLRQ,WLVDQ\$(WKDWDWDQ\GRVHIXOILOVDWOHDVW
RQHRIWKHIROORZLQJFULWHULD
•
LVIDWDO>UHVXOWVLQGHDWK@>127(GHDWKLVDQRXWFRPHQRWDQHYHQW@
•
LV/LIH7KUHDWHQLQJ>127(WKHWHUP/LIH7KUHDWHQLQJUHIHUVWRDQHYHQWLQZKLFK
WKHSDWLHQWZDVDWLPPHGLDWHULVNRIGHDWKDWWKHWLPHRIWKHHYHQWLWGRHVQRWUHIHUWR
DQHYHQWZKLFKFRXOGK\SRWKHWLFDOO\KDYHFDXVHGDGHDWKKDGLWEHHQPRUHVHYHUH@
•
UHTXLUHGLQSDWLHQWKRVSLWDOL]DWLRQRUSURORQJDWLRQRIH[LVWLQJKRVSLWDOL]DWLRQ
•
UHVXOWVLQSHUVLVWHQWRUVLJQLILFDQWGLVDELOLW\LQFDSDFLW\
•
LVDFRQJHQLWDODQRPDO\ELUWKGHIHFW
•
LV PHGLFDOO\ VLJQLILFDQW RU UHTXLUHV LQWHUYHQWLRQ WR SUHYHQW RQH RU RWKHU RI WKH
RXWFRPHVOLVWHGDERYH
0HGLFDO DQG VFLHQWLILF MXGJPHQW VKRXOG EH H[HUFLVHG LQ GHFLGLQJ ZKHWKHU H[SHGLWHG
UHSRUWLQJ WR WKH VSRQVRU LV DSSURSULDWH LQ RWKHU VLWXDWLRQV VXFK DV LPSRUWDQW PHGLFDO
HYHQWVWKDWPD\QRWEHLPPHGLDWHO\OLIHWKUHDWHQLQJRUUHVXOWLQGHDWKRUKRVSLWDOL]DWLRQ
EXW PD\ MHRSDUGL]H WKH SDWLHQW RU PD\ UHTXLUH LQWHUYHQWLRQ WR SUHYHQW RQH RI WKH
RXWFRPHV OLVWHG LQ WKH GHILQLWLRQV DERYH 7KHVH VLWXDWLRQV VKRXOG DOVR XVXDOO\ EH
FRQVLGHUHGVHULRXV
([DPSOHVRIVXFKHYHQWVDUHLQWHQVLYHWUHDWPHQWLQDQHPHUJHQF\URRPRUDWKRPHIRU
DOOHUJLFEURQFKRVSDVPEORRGG\VFUDVLDVRUFRQYXOVLRQVWKDWGRQRWUHVXOWLQKRVSLWDOL]DWLRQ
RUGHYHORSPHQWRIGUXJGHSHQGHQF\RUGUXJDEXVH
$Q XQH[SHFWHG $( LV RQH WKH QDWXUH RU VHYHULW\ RI ZKLFK LV QRW FRQVLVWHQW ZLWK WKH
DSSOLFDEOHSURGXFWLQIRUPDWLRQ
&DXVDOLW\LVLQLWLDOO\DVVHVVHGE\WKHLQYHVWLJDWRU)RU6HULRXV$GYHUVH(YHQWVSRVVLEOH
FDXVHVRIWKHHYHQWDUHLQGLFDWHGE\VHOHFWLQJRQHRUPRUHRSWLRQV&KHFNDOOWKDWDSSO\
•
3UHH[LVWLQJ8QGHUO\LQJGLVHDVHVSHFLI\
•
6WXG\WUHDWPHQW±VSHFLI\WKHGUXJVUHODWHGWRWKHHYHQW
•
2WKHUWUHDWPHQWFRQFRPLWDQWRUSUHYLRXV±VSHFLI\
•
3URWRFROUHODWHGSURFHGXUH
•
2WKHUHJDFFLGHQWQHZRULQWHUFXUUHQWLOOQHVVVSHFLI\
7KHWHUPVHYHUHLVDPHDVXUHRILQWHQVLW\WKXVDVHYHUH$(LVQRWQHFHVVDULO\VHULRXV)RU
H[DPSOH QDXVHD RI VHYHUDO KRXUV
 GXUDWLRQ PD\ EH UDWHG DV VHYHUH EXW PD\ QRW EH
FOLQLFDOO\VHULRXV
$VHULRXVDGYHUVHHYHQWRFFXUULQJGXULQJWKHVWXG\RUZKLFKFRPHVWRWKHDWWHQWLRQRI
WKHLQYHVWLJDWRUZLWKLQGD\VDIWHUVWRSSLQJWKHWUHDWPHQWRUGXULQJWKHSURWRFROGHILQHG
IROORZXSSHULRGLIWKLVLVORQJHUZKHWKHUFRQVLGHUHGWUHDWPHQWUHODWHGRUQRWPXVWEH

 
Rituximab - F. Hoffmann-La Roche Ltd 
Protocol MO25455 v4.0 
113 of 128 
reported.  In addition, a serious adverse event that occurs after this time, if considered 
related to test “drug”, should be reported. 
Such preliminary reports will be followed by detailed descriptions later which will include 
copies of hospital case reports, autopsy reports and other documents when requested 
and applicable. 
For serious adverse events, the following must be assessed and recorded on the AEs 
page of the CRF: intensity, relationship to test substance, action taken, and outcome to 
date. 
The investigator must notify the Ethics Review Committee/Institutional Review Board of 
a serious adverse event in writing as soon as is practical and in accordance with 
international and local laws and regulations. 
ROCHE LOCAL COUNTRY CONTACT for SAEs: Local Monitor  
See attached Protocol Administrative and Contact Information & List of Investigators 
Form, for details of administrative and contact information. 
ROCHE HEADQUARTERS CONTACT for SAEs and other medical emergencies: 
Clinical Operations/Clinical Science 
See attached Protocol Administrative and Contact Information & List of Investigators 
form, for details of administrative and contact information  
24 HOUR MEDICAL COVERAGE 
To ensure the safety of study patients, an Emergency Medical Call Centre Help Desk will 
access the Roche Medical Emergency List, escalate emergency medical calls, provide 
medical translation service (if necessary), connect the investigator with the Roche 
medical contact for this study and track all calls. The Emergency Medical Call Centre 
Help Desk will be available 24 hours per day, 7 days a week. Toll free numbers for the 
Help Desk and Medical Monitor contact information will be distributed to all investigators 
(see “Protocol Administrative and Contact Information & List of Investigators"). The Help 
Desk will be used for medical emergencies outside regular business hours. 
 
Medical Monitor Contact Information for All Sites: 
Medical Monitor: 
 
Dr 
 
Email (preferred contact): 
 
Telephone No.: 
 
 
Mobile Telephone No.:  
 
 
 

 
Rituximab - F. Hoffmann-La Roche Ltd 
Protocol MO25455 v4.0 
114 of 128 
APPENDIX 8. 
  
 
 
 
 
 
 
 

 
Rituximab - F. Hoffmann-La Roche Ltd 
Protocol MO25455 v4.0 
115 of 128 
 

 
Rituximab - F. Hoffmann-La Roche Ltd 
Protocol MO25455 v4.0 
116 of 128 
 
 
 
 
 
  
 
 

 
Rituximab - F. Hoffmann-La Roche Ltd 
Protocol MO25455 v4.0 
117 of 128 

 
Rituximab - F. Hoffmann-La Roche Ltd 
Protocol MO25455 v4.0 
118 of 128 
 
 
 
 
 

 
Rituximab - F. Hoffmann-La Roche Ltd 
Protocol MO25455 v4.0 
119 of 128 
 

 
Rituximab - F. Hoffmann-La Roche Ltd 
Protocol MO25455 v4.0 
120 of 128 
APPENDIX 9. 
  
 

 
Rituximab - F. Hoffmann-La Roche Ltd 
Protocol MO25455 v4.0 
121 of 128 
 
 
 
 
 
 
 
 
 

 
Rituximab - F. Hoffmann-La Roche Ltd 
Protocol MO25455 v4.0 
122 of 128 
REFERENCES 
                                            
 
 
1 Cheson BD, Horning SJ, Coiffier B, Shipp MA, Fisher RI, Connors JM, Lister TA, Vose J, Grillo-
López A, Hagenbeek A, Cabanillas F, Klippensten D, Hiddemann W, Castellino R, Harris NL, 
Armitage JO, Carter W, Hoppe R, Canellos GP. Report of an international workshop to 
standardize response criteria for non-Hodgkin's lymphomas. NCI Sponsored International 
Working Group. J Clin Oncol. 1999 Apr;17(4):1244. 
2 Kimby E, Treon SP, Anagnostopoulos A et al.  Update on recommendations for assessing 
response from the Third International Workshop on Waldenstrom's Macroglobulinemia. Clin 
Lymphoma Myeloma. 2006 Mar;6(5):380-3. 
3 van Oers MH, Klasa R, Marcus RE, Wolf M, Kimby E, Gascoyne RD, Jack A, Van't Veer M, 
Vranovsky A, Holte H, van Glabbeke M, Teodorovic I, Rozewicz C, Hagenbeek A. Rituximab 
maintenance improves clinical outcome of relapsed/resistant follicular non-Hodgkin’s lymphoma 
in patients both with and without rituximab during induction: results of a prospective randomized 
phase 3 intergroup trial. Blood. 2006 Nov 15;108(10):3295-301. 
4 Landis SH, Murray T, Bolden S, Wingo PA. Cancer Statistics, 1999. CA Cancer J Clin 1999 
Jan-Feb;49(1):8-31,1. 
5 Friedberg JW. Treatment of follicular non-Hodgkin's lymphoma: the old and the new. Semin 
Hematol. 2008 Jul;45(3 Suppl 2):S2-6. 
6 Horning SJ. Natural history of and therapy for the indolent non-Hodgkin’s lymphomas. Semin 
Oncol 1993;20 Suppl 5:75-88. 
7 Nathwani BN, Harris NL, Weisenburger D, Isaacson P, Piris MA, Berger F, Müller-Hermelink HK, 
Swerdlow SH. Follicular Lymphoma. In Jaffe ES, Harris NL, Stein H and Vardiman JW (Eds): 
World Health Organization Classification of Tumors. Pathology and Genetics of Tumors of 
Haematopoietic and Lymphoid Tissues. IARC Press: Lyon 2001; p 162-7. 
8 Bordeleau L, Berinstein NL. Molecular diagnostics in follicular non-Hodgkin's lymphoma: a 
review. Semin Oncol. 2000; 27 (Suppl 12):42-52. 
9  Landgren O, Tilly H. Epidemiology, pathology and treatment of non-follicular indolent 
lymphomas. Leuk Lymphoma. 2008;49 Suppl 1:35-42. 
10 American Cancer Society. Cancer facts and figures 2001. Atlanta: American Cancer Society, 
2001. 
11 Morton LM, Wang SS, Devesa SS et al. Lymphoma incidence patterns by WHO subtype in the 
United States, 1992-2001. Blood. 2006 January 1; 107(1): 265–276. 
12 Cartwright RA. Time trends in incidence of haematological malignancies and related conditions. 
Br J Haematol. 1999;106: 281-295. 
13 Eltom MA, Jemal A, Mbulaiteye SM, Devesa SS, Biggar RJ. Trends in Kaposi's sarcoma and 
non-Hodgkin's lymphoma incidence in the United States from 1973 through 1998. J Natl Cancer 
Inst. 2002;94: 1204-1210. 
14 Clarke CA, Glaser SL. Changing incidence of non-Hodgkin’s lymphomas in the United States. 
Cancer. 2002;94: 2015-2023. 
15 Morton LM, Turner JJ, Cerhan JR et al. Proposed classification of lymphoid neoplasms for 
epidemiologic research from the Pathology Working Group of the International Lymphoma 
Epidemiology Consortium (InterLymph). Blood. 2007 July 15; 110(2): 695–708. 
16 The Non-Hodgkin’s Lymphoma Classification Project. A clinical evaluation of the International 
Lymphoma Study Group classification of non-Hodgkin’s lymphoma. Blood. 1997;89:3909-3918. 

 
Rituximab - F. Hoffmann-La Roche Ltd 
Protocol MO25455 v4.0 
123 of 128 
                                                                                                                                  
 
 
17 Gallagher CJ, Gregory WM, Jones AE, Stansfeld AG, Richards MA, Dhaliwal HS, et al. 
Follicular lymphoma: prognostic factors for response and survival. J Clin Oncol 1986;4:1470-80. 
18 Gallagher CJ, Gregory WM, Jones AE, Stansfeld AG, Richards MA, Dhaliwal HS, Malpas JS, 
Lister TA. Follicular lymphoma: prognostic factors for response and survival. J Clin Oncol. 1986; 
4:1470-80. 
19 Johnson PW, Rohatiner AZ, Whelan JS, Price CG, Love S, Lim J, Matthews J, Norton AJ, 
Amess JA, Lister TA. Patterns of survival in patients with recurrent follicular lymphoma: a 20-year 
study from a single center. J Clin Oncol. 1995; 13:140-7. 
20 Solal-Celigny PH. Management of histologically indolent non-Hodgkin’s lymphomas. Baillie` 
re’s Clin Hematol. 1996;9:669-687. 
21 Aisenberg AC. Coherent view of non-Hodgkin’s lymphoma [review]. Clin Oncol. 1995;13:2656-
2675. 
22 Liu Q, Fayad L, Cabanillas F, Hagemeister FB, Ayers GD, Hess M, et al. Improvement of 
overall and failure-free survival in stage IV follicular lymphoma: 25 years of treatment experience 
at The University of Texas M.D. Anderson Cancer Center. J Clin Oncol 2006;24:1582-9. 
23  Swenson WT, Wooldridge JE, Lynch CF, Forman-Hoffman VL, Chrischilles E, Link BK. 
Improved survival of follicular lymphoma patients in the United States. J Clin Oncol 
2005;23:5019-26. 
24 Ellison LF, Wilkins K. An update on cancer survival. Health Rep. 2010 Sep;21(3):55-60. 
25 Fisher RI, LeBlanc M, Press OW, et al: New treatment options have changed the survival of 
patients with follicular lymphoma. J Clin Oncol 2005;23:8447-8452. 
26 Marcus R, Imrie K, Belch A, et al. CVP chemotherapy plus rituximab compared with CVP as 
first-line treatment for advanced follicular lymphoma. Blood. 2005;105:1417-1423. 
27 Marcus R, Imrie K, Solal-Celigny P, Catalano JV, Dmoszynska A, Raposo JC, Offner FC, 
Gomez-Codina J, Belch A, Cunningham D, Wassner-Fritsch E, Stein G. Phase III study of R-CVP 
compared with cyclophosphamide, vincristine, and prednisone alone in patients with previously 
untreated advanced follicular lymphoma. J Clin Oncol. 2008 Oct 1;26(28):4579-86. 
28 Hiddemann W, Kneba M, Dreyling M, et al: Frontline therapy with rituximab added to the 
combination of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) significantly 
improves the outcome for patients with advanced-stage follicular lymphoma compared with 
therapy with CHOP alone: Results of a prospective randomized study of the German Low-Grade 
Lymphoma Study Group. Blood. 2005;106:3725-3732. 
29 Herold M, Haas A, Srock S, et al: Rituximab added to first-line mitoxantrone, chlorambucil, and 
prednisolone chemotherapy followed by interferon maintenance prolongs survival in patients with 
advanced follicular lymphoma: An East German Study Group Hematology and Oncology Study. J 
Clin Oncol. 2007 May 20;25(15):1986-92. 
30  Salles G, Mounier N, de Guibert S, et al: Rituximab combined with chemotherapy and 
interferon in follicular lymphoma patients: Results of the GELA-GOELAMS FL2000 study. Blood. 
2008;112:4824-4831. 
31 Pulte D, Gondos A, Brenner H: Ongoing improvement in outcomes for patients diagnosed as 
having Non-Hodgkin’s lymphoma from the 1990s to the early 21st century. Arch Intern Med 
2008;168:469-476. 
32 Fisher RI, Gaynor ER, Dahlberg S, Oken MM, Grogan TM, Mize EM, et al . Comparison of a 
standard regimen (CHOP) with three intensive chemotherapy regimens for advanced non-
Hodgkin’s lymphoma . N Engl J Med 1993;328:1002-6. 

 
Rituximab - F. Hoffmann-La Roche Ltd 
Protocol MO25455 v4.0 
124 of 128 
                                                                                                                                  
 
 
33  Lossos IS. Higher-grade transformation of follicular lymphoma - a continuous enigma. 
Leukemia. 2005; 19(8): 1331-3. 
34 Boye J, Elter T, Engert A. An overview of the current clinical use of the anti-CD20 monoclonal 
antibody rituximab . Ann Oncol 2003;14:520-35. 
35 Feugier P, Van Hoof A, Sebban C, Solal-Celigny P, Bouabdallah R, Ferme C, et al. Long-term 
results of the R-CHOP study in the treatment of elderly patients with diffuse large B-cell 
lymphoma: a study by the Groupe d’Etude des Lymphomes de l’Adulte. J Clin Oncol 
2005;23:4117-26. 
36  Friedberg JW, Taylor MD, Cerhan JR, Flowers CR, Dillon H, Farber CM, Rogers ES, 
Hainsworth JD, Wong EK, Vose JM, Zelenetz AD, Link BK. Follicular lymphoma in the United 
States: first report of the national LymphoCare study. J Clin Oncol. 2009 Mar 10;27(8):1202-8. 
Epub 2009 Feb 9. 
37 Sousou T, Friedberg J. Rituximab in indolent lymphomas. Semin Hematol. 2010 Apr;47(2):133-
42. 
38 McLaughlin P, Grillo-López AJ, Link BK, et al. Rituximab chimeric anti-CD20 monoclonal 
antibody therapy for relapsed indolent lymphoma: half of patients respond to a four-dose 
treatment program. J Clin Oncol. 1998; 16: 2825-33. 
39 Rituximab Summary of Product Characteristics 
40 Tedder TF, Engel P. CD20: a regulator of cell-cycle progression of B lymphocytes. Immunol 
Today 1994; 15:450–4. 
41 Reff ME, Carner K, Chambers KS, Chinn PC, Leonard JE, Raab R, et al. Depletion of B cells in 
vivo by a chimeric mouse human monoclonal antibody to CD20. Blood 1994; 83:435–45. 
42 Maloney D, Smith B, Appelbaum F. The anti-tumor effect of monoclonal anti-CD20 antibody 
(MAB) therapy includes direct anti-proliferative activity and induction of apopthosis in CD20 
positive non-Hodgkin’s Lymphoma (NHL) cell lines. Blood 1996; 88:637a. 
43 Demidem A, Lam T, Alan S, Hariharan K, Hanna N, Bonavida B. Chimeric anti-CD20 (IDEC-
C2B8) monoclonal antibody sensitizes a B cell lymphoma cell line to cell killing by cytotoxic drugs. 
Cancer Biotherapy and Radiopharmaceuticals 1997; 12:177-86. 
44 Colombat P, Salles G, Brousse N et al. Rituximab (anti-CD20 monoclonal antibody) as single 
first-line therapy for patients with follicular lymphoma with a low tumor burden: clinical and 
molecular evaluation. Blood. 2001 Jan 1;97(1):101-6. 
45 Hainsworth JD, Litchy S, Morrissey LH et al. Rituximab plus short-duration chemotherapy as 
first-line treatment for follicular non-Hodgkin's lymphoma: a phase II trial of the minnie pearl 
cancer research network. J Clin Oncol. 2005 Mar 1;23(7):1500-6. 
46 Piro LD, White CA, Grillo-López AJ, et al. Extended rituximab (anti-CD20 monoclonal antibody) 
therapy for relapsed or refractory low-grade or follicular non-Hodgkin’s lymphoma. Ann. Oncol. 
1999; 10:655-61. 
47 Moccia A, Ghielmini M. Monoclonal antibodies for the treatment of hematologic malignancies: 
schedule and maintenance therapy. Semin Hematol. 2008 Apr; 45(2):75-84. 
48 Czuczman MS, Grillo-Lopez AJ, White CA, Saleh M, Gordon L, LoBuglio AF, et al. Treatment 
of patients with low-grade B-cell lymphoma with the combination of chimeric anti-CD20 
monoclonal antibody and CHOP chemotherapy. J Clin Oncol 1999; 17:268–76. 
49 Czuczman MS, Grillo-Lopez AJ, LoBuglio AI, Gordon LI, Starostik P, Dowden S, Alkuzweny B, 
Allen RS. Prolonged clinical and molecular remission in patients with low-grade or follicular non-

 
Rituximab - F. Hoffmann-La Roche Ltd 
Protocol MO25455 v4.0 
125 of 128 
                                                                                                                                  
 
 
Hodgkin's lymphoma treated with rituximab plus CHOP chemotherapy: 9-year follow-up. Journal 
of Clinical Oncology, 2004;Vol 22, No 23 (December 1): 4711-4716. 
50 Lenz G, Dreyling M, Hoster E, Wörmann B, Dührsen U, Metzner B, Eimermacher H, Neubauer 
A, Wandt H, Steinhauer H, Martin S, Heidemann E, Aldaoud A, Parwaresch R, Hasford J, 
Unterhalt M, Hiddemann W. Immunochemotherapy With Rituximab and Cyclophosphamide, 
Doxorubicin, Vincristine, and Prednisone Significantly Improves Response and Time to Treatment 
Failure, But Not Long-Term Outcome in Patients With Previously Untreated Mantle Cell 
Lymphoma: Results of a Prospective Randomized Trial of the German Low Grade Lymphoma 
Study Group (GLSG). J Clin Oncol. 2005; 23(9): 1984-92. 
51 Herold M, Dölken G, Fiedler F et al. Ongoing clinical studies – randomized phase III study for 
the treatment of advanced indolent NHL and MCL: chemotherapy versus chemotherapy plus 
Rituximab. Ann Hematol. 2003; 82:77–9. 
52 Rummel MJ, Al-Batran SE, Kim SZ, et al. Bendamustine plus rituximab is effective and has a 
favorable toxicity profile in the treatment of mantle cell and low-grade non-Hodgkin’s lymphoma. J 
Clin Oncol. 2005;23:3383–3389. 
53 Robinson KS, Williams ME, van der Jagt RH, Cohen P, Herst JA, Tulpule A, Schwartzberg LS, 
Lemieux B, Cheson BD. Phase II multicenter study of bendamustine plus rituximab in patients 
with relapsed indolent B-cell and mantle cell non-Hodgkin's lymphoma. J Clin Oncol. 2008 Sep 
20;26(27):4473-9. 
54  Hainsworth JD, Litchy S, Shaffer DW, Lackey VL, Grimaldi M, Greco FA. Maximizing 
therapeutic benefit of rituximab: maintenance therapy versus re-treatment at progression in 
patients with indolent non-Hodgkin's lymphoma--a randomized phase II trial of the Minnie Pearl 
Cancer Research Network. J Clin Oncol. 2005 Feb 20;23(6):1088-95. Epub 2005 Jan 18. 
55 Ghielmini M, Hsu Schmitz SF, Cogliatti SB, Pichert G, Hummerjohann J, Waltzer U, Fey MF, 
Betticher DC, Martinelli G, Peccatori F, Hess U, Zucca E, Stupp R, Kovacsovics T, Helg C, Lohri 
A, Bargetzi M, Vorobiof D, Cerny T. Prolonged treatment with rituximab in patients with follicular 
lymphoma significantly increases event-free survival and response duration compared with the 
standard weekly x 4 schedule. Blood. 2004; 103(12): 4416-23. 
56 Hochster HS, Weller E, Ryan T, et al. Results of E1496: A phase III trial of CVP with or without 
maintenance rituximab in advanced indolent lymphoma (NHL) [abstract]. Proc Am Soc Clin 
Oncol.2004;23:556. 
57 Hochster H, Weller E, Gascoyne R, et al. Cyclophosphamide and fludarabine (CF) in advanced 
indolent lymphoma: results from the ECOG/CALGB intergroup E1496 trial. J Clin Oncol (ASCO 
Annual Meeting Proceedings Part I). 2007;25(18S):8004 
58 Forstpointner R, Unterhalt M, Dreyling M, Böck HP, Repp R, Wandt H, Pott C, Seymour JF, 
Metzner B, Hänel A, Lehmann T, Hartmann F, Einsele H, Hiddemann W; German Low Grade 
Lymphoma Study Group (GLSG). Maintenance therapy with rituximab leads to a significant 
prolongation of response duration after salvage therapy with a combination of rituximab, 
fludarabine, cyclophosphamide, and mitoxantrone (R-FCM) in patients with recurring and 
refractory follicular and mantle cell lymphomas: Results of a prospective randomized study of the 
German Low Grade Lymphoma Study Group (GLSG). 2.Blood. 2006 Dec 15;108(13):4003-8. 
59 Salles G, Seymour JF, Offner F, López-Guillermo A, Belada D, Xerri L, Feugier P, Bouabdallah 
R, Catalano JV, Brice P, Caballero D, Haioun C, Pedersen LM, Delmer A, Simpson D, Leppa S, 
Soubeyran P, Hagenbeek A, Casasnovas O, Intragumtornchai T, Fermé C, da Silva MG, Sebban 
C, Lister A, Estell JA, Milone G, Sonet A, Mendila M, Coiffier B, Tilly H. Rituximab maintenance 
for 2 years in patients with high tumour burden follicular lymphoma responding to rituximab plus 

 
Rituximab - F. Hoffmann-La Roche Ltd 
Protocol MO25455 v4.0 
126 of 128 
                                                                                                                                  
 
 
chemotherapy (PRIMA): a phase 3, randomised controlled trial. Lancet. 2011 Jan 
1;377(9759):42-51. 
60 Rummel MJ, Kaiser U, Balser C et al. Bendamustine Plus Rituximab Versus Fludarabine Plus 
Rituximab In Patients with Relapsed Follicular, Indolent and Mantle Cell Lymphomas – Final 
Results of the Randomized Phase III Study NHL 2–2003 on Behalf of the StiL (Study Group 
Indolent Lymphomas, Germany). Blood (ASH Annual Meeting Abstracts) 2010 116: Abstract 856. 
61 Hochster H, Weller E, Gascoyne RD, Habermann TM, Gordon LI, Ryan T, Zhang L, Colocci N, 
Frankel S, Horning SJ. Maintenance rituximab after cyclophosphamide, vincristine, and 
prednisone prolongs progression-free survival in advanced indolent lymphoma: results of the 
randomized phase III ECOG1496 Study. J Clin Oncol. 2009 Apr 1;27(10):1607-14.  
62 Martinelli G, Schmitz SF, Utiger U, Cerny T, Hess U, Bassi S, Okkinga E, Stupp R, Stahel R, 
Heizmann M, Vorobiof D, Lohri A, Dietrich PY, Zucca E, Ghielmini M. Long-term follow-up of 
patients with follicular lymphoma receiving single-agent rituximab at two different schedules in 
trial SAKK 35/98. J Clin Oncol. 2010 Oct 10;28(29):4480-4. 
63 van Oers MH, Van Glabbeke M, Giurgea L, Klasa R, Marcus RE, Wolf M, Kimby E, van t Veer 
M, Vranovsky A, Holte H, Hagenbeek A. Rituximab maintenance treatment of relapsed/resistant 
follicular non-Hodgkin's lymphoma: long-term outcome of the EORTC 20981 phase III 
randomized intergroup study. J Clin Oncol. 2010 Jun 10;28(17):2853-8. 
64 Vidal L, Gafter-Gvili A, Leibovici L, Dreyling M, Ghielmini M, Hsu Schmitz SF, Cohen A, 
Shpilberg O.Rituximab maintenance for the treatment of patients with follicular lymphoma: 
systematic review and meta-analysis of randomized trials. J Natl Cancer Inst. 2009 Feb 
18;101(4):248-55. Epub 2009 Feb 10. 
65 Maloney DG, Liles TM, Czerwinski DK, Waldichuk C, Rosenberg J, Grillo-Lopez A, et al. Phase 
I clinical trial using escalating single-dose infusion of chimeric anti-CD20 monoclonal antibody 
(IDEC-C2B8) in patients with recurrent B-cell lymphoma. Blood 1994; 84:2457–66. 
66 Maloney DG, Grillo-Lopez AJ, Bodkin DJ, White CA, Liles TM, Royston I, et al. IDEC-C2B8: 
results of a phase I multiple-dose trial in patients with relapsed non-Hodgkin’s lymphoma. J Clin 
Oncol 1997 (a); 15:3266–74. 
67 Maloney DG, Grillo-Lopez AJ, White CA, Bodkin D, Schilder RJ, Neidhart JA, et al. IDEC-C2B8 
(Rituximab) anti-CD20 monoclonal antibody therapy in patients with relapsed low-grade non-
Hodgkin’s lymphoma. Blood 1997 (b); 90:2188–95. 
68 Davis TA, White CA, Grillo-Lopez AJ, Velasquez WS, Link B, Maloney DG, Dillman RO, 
Williams ME, Mohrbacher A, Weaver R, Dowden S, Levy R. Single-agent monoclonal antibody 
efficacy in bulky non-Hodgkin's lymphoma: results of a phase II trial of rituximab. J Clin Oncol. 
1999; 17(6):1851-7. 
69 Davis TA, Grillo-Lopez AJ, White CA, McLaughlin P, Czuczman MS, Link BK, et al. Rituximab 
anti-CD20 monoclonal antibody therapy in non-Hodgkin's lymphoma: safety and efficacy of re-
treatment. J Clin Oncol. 2000; 18(17): 3135-43. 
70 Coiffier B, Lepage E, Briere J, Herbrecht R, Tilly H, Bouabdallah R, Morel P, Van Den Neste E, 
Salles G, Gaulard P, Reyes F, Lederlin P, Gisselbrecht C. CHOP chemotherapy plus rituximab 
compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma. N Engl J Med. 
2002; 346:235-242. 
71 Hainsworth JD, Litchy S, Burris HA 3rd, Scullin DC Jr, Corso SW, Yardley DA, Morrissey L, 
Greco FA. Rituximab as first-line and maintenance therapy for patients with indolent non-
Hodgkin's lymphoma. J Clin Oncol. 2002; 20: 4261-7. 

 
Rituximab - F. Hoffmann-La Roche Ltd 
Protocol MO25455 v4.0 
127 of 128 
                                                                                                                                  
 
 
72 Weaver R, Eldredge E, Alkuzweny B. Integrated summary of efficacy and safety of rituximab, 
September 27, 1999. 
73  IDEC Pharmaceuticals Corporation, Rituxan® Biologic License Application Supplement, 
October 19, 1999. 
74 Investigator Brochure MabThera®, Rituxan®, Fifteenth Edition, July 2010 (Rituximab IV), and 
Second Edition, October 2010 (Rituximab SC). 
75 Taverna CJ, Bassi S, Hitz F, Mingrone W, Pabst T, Cevreska L, del Giglio A, Vorobiof DA, 
Simcock M and Ghielmini M. Rituximab Maintenance Treatment for a Maximum of 5 Years In 
Follicular Lymphoma: Safety Analysis of the Randomized Phase III Trial SAKK 35/03. ASH 2010, 
December 4, Poster Board I-782, Abstract 1802. 
76 Rummel M. Reassessing the standard of care in indolent lymphoma: a clinical update to 
improve clinical practice. J Natl Compr Canc Netw. 2010 Sep;8 Suppl 6:S1-14. 
77 Stilgenbauer S, Zenz T, Winkler D, Bühler A, Schlenk RF, Groner S, Busch R, Hensel M, 
Dührsen U, Finke J, Dreger P, Jäger U, Lengfelder E, Hohloch K, Söling U, Schlag R, Kneba M, 
Hallek M, Döhner H; German Chronic Lymphocytic Leukemia Study Group. Subcutaneous 
alemtuzumab in fludarabine-refractory chronic lymphocytic leukemia: clinical results and 
prognostic marker analyses from the CLL2H study of the German Chronic Lymphocytic Leukemia 
Study Group J Clin Oncol. 2009 Aug 20;27(24):3994-4001. Epub 2009 Jul 13.  
78 Wynne C, Harvey V, Schwabe C, Waaka D, McIntyre C, Bittner B. The development of a 
formulation of trastuzumab for subcutaneous administration. Ann Oncol 2010;21(8):viii 78 – viii 95, 
Abstract 218PD. 
79 Del Nagro CJ, Mao CP, Brovarney M, Dabbagh K, Birnboeck H,  Richter WF. Comparison of B 
Cell Depletion Mediated by Intravenous (IV) Rituxan® and Rituxan Given Subcutaneous (SC) In 
Cynomolgus Monkeys. Presented at 52nd Annual ASH Meeting and Exposition, Monday, 
December 6, 2010, Poster Session: Molecular Pharmacology, Drug Resistance, Poster Board III-
759, Abstract 3980.  
80 Salar A, Bouabdallah R, McIntyre C, Sayyed P, Bittner B. A Two-Stage Phase Ib Study to 
Investigate the Pharmacokinetics, Safety and Tolerability of Subcutaneous Rituximab in Follicular 
Lymphoma as Part of Maintenance Treatment. Presented at 52nd Annual ASH Meeting and 
Exposition, Monday, December 5, 2010, Poster Session: Lymphoma - Therapy with Biologic 
Agents, excluding Pre-Clinical Models; Poster Board II-738, Abstract 2858. 
81 Mager DE, Jusko WJ. General pharmacokinetic model for drugs exhibiting target-mediated 
drug disposition. J Pharmacokinet Pharmacodyn. 2001 Dec;28(6):507-32.  
82 Regazzi MB, Iacona I, Avanzini MA, Arcaini L, Merlini G, Perfetti V, Zaja F, Montagna M, Morra 
E, Lazzarino M.  Pharmacokinetic behavior of rituximab: a study of different schedules of 
administration for heterogeneous clinical settings. Ther Drug Monit. 2005 Dec;27(6):785-92.  
83 Ghielmini M. Patient benefits of maintenance immunotherapy. Leuk Res. 2006 Mar;30 Suppl 
1:S22-6. 
84 Foster T, Miller JD, Boye ME, Russell MW. Economic burden of follicular non-Hodgkin's 
lymphoma. Pharmacoeconomics. 2009;27(8):657-79. 
85 Deconinck E, Miadi-Fargier H, Pen CL, Brice P. Cost effectiveness of rituximab maintenance 
therapy 
in 
follicular 
lymphoma: 
long-term 
economic 
evaluation. 
Pharmacoeconomics. 
2010;28(1):35-46. 

 
Rituximab - F. Hoffmann-La Roche Ltd 
Protocol MO25455 v4.0 
128 of 128 
                                                                                                                                  
 
 
86 Kasteng F, Erlanson M, Hagberg H, Kimby E, Relander T, Lundkvist J.Cost-effectiveness of 
maintenance rituximab treatment after second line therapy in patients with follicular lymphoma in 
Sweden. Acta Oncol. 2008;47(6):1029-36. 
87 Knight C, Maciver F.The cost-effectiveness of rituximab in non-Hodgkin's lymphoma. Expert 
Rev Pharmacoecon Outcomes Res. 2007 Aug;7(4):319-26. 
88 Gordan LN, Grow WB, Pusateri A, Douglas V, Mendenhall NP, Lynch JW. Phase II trial of 
individualized rituximab dosing for patients with CD20-positive lymphoproliferative disorders. J 
Clin Oncol. 2005 Feb 20;23(6):1096-102. Epub 2005 Jan 18. 
89 Kahl BS, Williams ME, Hong F, Gascoyne R, Horning SJ. Preliminary pharmacokinetic (PK) 
analysis of Eastern Cooperative Oncology Group Protocol E4402: Rituximab extended schedule 
or re-treatment trial (RESORT). Blood 2007; 110: 3420 (abstr). 
90 Ghielmini M, Rufibach K, Salles G, Leoncini-Franscini L, Léger-Falandry C, Cogliatti S, Fey M, 
Martinelli G, Stahel R, Lohri A, Ketterer N, Wernli M, Cerny T, Schmitz SF. Single agent rituximab 
in patients with follicular or mantle cell lymphoma: clinical and biological factors that are predictive 
of response and event-free survival as well as the effect of rituximab on the immune system: a 
study of the Swiss Group for Clinical Cancer Research (SAKK). Ann Oncol. 2005 
Oct;16(10):1675-82.  
91 Cairo M & Bishop M. Tumor lysis syndrome: new strategies and classification. Br J Hematol, 
2004. 127(1): 3-11. 
92 Coiffier B, Altman A, Pui CH, Younes A, Cairo MS. Guidelines for the management of pediatric 
and adult tumor lysis syndrome: an evidence-based review. J Clin Oncol. 2008 Jun 
1;26(16):2767-78. 
93 Smith TJ, Khatcheressian J, Lyman GH, Ozer H, Armitage JO, Balducci L, Bennett CL, Cantor 
SB, Crawford J, Cross SJ, Demetri G, Desch CE, Pizzo PA, Schiffer CA, Schwartzberg L, 
Somerfield MR, Somlo G, Wade JC, Wade JL, Winn RJ, Wozniak AJ, Wolff AC.  2006 update of 
recommendations for the use of white blood cell growth factors: an evidence-based clinical 
practice guideline. J Clin Oncol. 2006 Jul 1;24(19):3187-205. 
94 Mulligan SP, Gill DS, Renwick WEP, Sulda ML, Best OG, Kuss BJ, Seymour JF. The Safety 
and Tolerability of Oral Fludarabine, ±oral Cyclophosphamide and Iv Rituximab Therapy In 
Previously Untreated Patients with Chronic Lymphocytic Leukaemia (CLL) Aged  65 Years – 
Interim Analysis From the Australasian Leukaemia and Lymphoma Group (ALLG) and CLL 
Australian Research Consortium (CLLARC) CLL5 Study. Blood (ASH Annual Meeting Abstracts) 
2010 116: Abstract 699. 
95 Kornbrot B, Kobayashi RH, Singer A, et al. Hypersensitivity to therapeutic murine monoclonal 
antibodies. Nebrascan Medical Journal 1994;79(12):393-8. 
96 Harris LH, Jaffe ES, Kiebold J, et al. World Health Organization classification of neoplastic 
diseases of the hematopoietic and lymphoid tissues: report of the Clinical Advisory Committee 
Meeting-Airlie House, Virginia, November 1997. J Clin Oncol. 1999;17:3835-49. 
97 Solal-Celigny P, Roy P, Colombat P, White J, Armitage JO, Arranz-Saez R, Au WY, Bellei M, 
Brice P, Caballero D, Coiffier B, Conde Garcia E, Doyen C, Federico M, Fisher RI, Garcia-Conde 
JF, Guglielmi C, Hagenbeek A, Haioun C, LeBlanc M, Lister AT, Lopez-Guillermo A, Mc Laughlin 
P, Milpied N, Morel P, Mounier N, Proctor SJ, Rohatiner A, Smith P, Soubeyran P, Tilly H, Vitolo 
U, Zinzani PL, Zucca E, Montserrat E. Follicular lymphoma international prognostic index. Blood. 
2004 Sep 1;104(5):1258-65.