Therapy of Nodal Follicular Lymphoma (WHO Grade 1/2) in Clinical Stage I/II Using Response Adapted Involved Site Radiotherapy in Combination With Gazyvaro
Phase: PHASE2
Conditions: Stage II Grade 1 Follicular Lymphoma, Stage II Grade 2 Follicular Lymphoma, Stage I Follicular Lymphoma Grade 1, Stage II Follicular Lymphoma Grade 2
Sponsor: Heidelberg University

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Clinical Trial Protocol 
 
Therapy of Nodal Follicular Lymphoma (WHO grade 1/2) in 
Clinical Stage I/II using Response Adapted Involved Site 
Radiotherapy in Combination with Gazyvaro 
GAZAI Trial 
(GAZyvaro and response Adapted Involved-site Radiotherapy) 
A trial of the German Low Grade Lymphoma Study Group 
 
 
in the Competence Network Malignant Lymphomas 
Code:   
 
GAZAI 
EudraCT No.:  
2016-002059-89 
 
 
Phase:  
non-controlled, open, national multi-center phase II trial 
Version:  
 
1.2 (06.10.2017) 
 
GCP Statement: The study will be conducted in compliance with Good Clinical Practices (ICH-GCP) and the 
Declaration of Helsinki, and in accordance with applicable legal and regulatory requirements, including archiving of 
essential documents. 
 
 
CONFIDENTIAL: This protocol contains confidential information and is intended solely for the guidance of the clinical 
investigation. This protocol may not be disclosed to parties not associated with the clinical investigation or used for any purpose 
without the prior written consent of the Principal Investigator/ Coordinating Investigator. 
 
 
 

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PRINCIPLE INVESTIGATOR / 
COORDINATING INVESTIGATOR 
(LEITER DER KLINISCHEN PRÜFUNG 
(LKP)*) 
*according § 40 Arzneimittelgesetz (AMG) 
SPONSOR 
 
 
Professor Dr. med. Klaus Herfarth 
Universitätsklinikum Heidelberg 
Abteilung Radioonkologie & Strahlentherapie 
Im Neuenheimer Feld 400 
69120 Heidelberg 
phone:  
06221-56 8202 
Fax:   
06221-56 5353 
E-Mail:  
Klaus.Herfarth@med.uni-heidelberg.de 
Ruprecht-Karls-Universität Heidelberg 
Medical Faculty represented by 
University Hospital Heidelberg and its 
Commercial Director Dipl. Volkswirtin  
Irmtraut Gürkan 
Im Neuenheimer Feld 672,  
69120 Heidelberg 
phone:  
06221 / 56-7002 
Fax:   
06221 / 56-4888 
E-Mail:  
Irmtraut.Guerkan@med.uni-heidelberg.de 
 
 
 
 
 
 
BIOMETRICS 
DATA MANAGEMENT 
Professor Dr. Meinhard Kieser 
Christina Klose  
Institut für Medizinische Biometrie und 
Informatik  (IMBI) 
Institut für Medizinische Biometrie und 
Informatik  (IMBI) 
Marsilius-Arkaden - Turm West 
Im Neuenheimer Feld 130.3 
69120 Heidelberg 
Marsilius-Arkaden - Turm West 
Im Neuenheimer Feld 130.3 
69120 Heidelberg 
phone:  
06221-56-4140 
phone:             06221-56-5500 
Fax:   
06221-56-4195  
Fax: 
 
06221-56-4195 
E-Mail:  
meinhard.kieser@imbi.uni-heidelberg.de 
E-Mail:  
klose@imbi.uni-heidelberg.de 
 
 
 
PHARMAKOVIGILANCE 
 
PROJECT MANAGEMENT 
Dr. Jacek Hajda 
Dr. Sabine Gack 
Koordinierungszentrum für Klinische Studien 
(KKS) 
Koordinierungszentrum für Klinische 
Studien (KKS) 
Marsilius-Arkaden - Turm West 
Im Neuenheimer Feld 130.3 
69120 Heidelberg 
Marsilius-Arkaden - Turm West 
Im Neuenheimer Feld 130.3 
69120 Heidelberg 
phone:  
06221/56-34507 
phone:             06221 56 34508 
SAE-Fax:  06221-56 33725 
Fax:   
06221-56 33508 
E-Mail:  
Jacek.Hajda@med.uni-heidelberg.de 
E-Mail:  
sabine.gack@med.uni-heidelberg.de 
 
 
 

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MONITORING 
TRIAL CENTER HEIDELBERG  
Anna-Lena Gamer  
Renate Haselmann 
Leitung Klinisches Monitoring 
 
Koordinierungszentrum für Klinische Studien 
(KKS) Heidelberg am Universitätsklinikum 
Heidelberg 
University Hospital Heidelberg 
Dept. Radiation Oncology 
Marsilius-Arkaden - Turm West 
Im Neuenheimer Feld 130.3 
69120 Heidelberg 
Im Neuenheimer Feld 400; 69120 
Heidelberg 
phone:  
06221/ 56-38613 
phone:  
06221-56-34323 
 
 
(od. 56-8202) 
Fax: 
 
06221-56-33508 
Fax:   
06221/ 56-1979 
E-Mail:  
Anna-Lena.Gamer@med.uni-heidelberg.de 
E-Mail:  
Renate.Haselmann@med.uni-heidelberg.de 
 
 
MANUFACTURER OF IMP 
Contact address in Germany 
Roche Pharma AG 
Emil-Barell-Str. 1 
79639 Grenzach-Wyhlen 
phone:  
07624 - 14-0 
Fax: 
 
07624 - 1019 
 
 
DATA MONITORING COMMITTEE 
(DMC) 
STEERING COMMITTEE 
(SC) 
Prof.  Dr. Ch. Pott 
Prof. Dr. med. M. Dreyling 
II. Medizinische Klinik und Poliklinik 
Medizinische Klinik und Poliklinik III  
Universitätsklinikum Schleswig Holstein 
Campus Kiel  
Langer Segen 8-10, 24105 Kiel 
Ludwigs-Maximilians Universität 
Marchoininistr. 14, 81377 München 
phone:  
0431/ 500-24970 
phone:  
089/ 4400 7-2202 
Fax:   
0431/ 500-24974 
Fax:   
089/ 4400 7-2201 
E-Mail:  
c.pott@med2.uni-kiel.de 
E-Mail:  
martin.dreyling@med.uni-muenchen.de 
 
 
 
 
Prof. Dr. med. F. Sterzing 
Prof. Dr. med. J. Dürig 
Strahlentherapie Kempten 
Klinik für Hämatologie 
Am Klinikum Kempten 
Robert-Weixler-Strasse 50, 87439 Kempten 
Universitätsklinik Essen 
Hufelandstraße 55; 45147 Essen 
phone:  
0831 / 9607940 
phone:  
0201/ 723-2417 
Fax:   
0831 / 9607943456 
Fax:   
0201/ 723-5928 
E-Mail: 
sterzing@st-sued.de 
E-Mail: jan.duerig@uk-essen.de 
 
 
 
 

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Dr. Eva Hoster  
Dr. med. M. Engelhard 
Medizinische Klinik und Poliklinik III  
Klinik für Strahlentherapie  
Ludwigs-Maximilians Universität 
Marchoininistr. 15, 81377 München 
Universitätsklinik Essen 
Hufelandstraße 55; 45147 Essen 
phone:  
089 / 7095-4900 
phone:  
0201/ 723-2056 
Fax:   
089/ 7095-7900 
Fax:   
0201/ 723-5610 
E-Mail: Eva.Hoster@med.uni-muenchen.de 
E-Mail: marianne.engelhard@uni-due.de 
 
 
 
Prof. Dr. med. K. Herfarth 
 
Abt. Radioonkologie & Strahlentherapie 
 
Universitätsklinikum Heidelberg 
INF 400, 69120 Heidelberg   
 
phone:  
06221/ 56 8202 
 
Fax:   
06221/ 56 5353 
 
E-Mail: klaus.herfarth@med.uni-heidelberg.de 
 
 
 
PD Dr. med. K. Hohloch 
 
Abt. Medizinische Onkologie u. Hämatologie  
 
Kantonsspital Graubünden 
Loëstrasse 170, CH-7000 Chur 
  
 
phone:  
+41-81-256 6646 
 
Fax:   
+41-81-256 6668 
 
E-Mail: karin.hohloch@ksgr.ch 
 
 
 
PD Dr. med. A. Viardot 
 
Klinik f. Innere Medizin III 
 
Universitätsklinikum Ulm 
Albert-Einstein-Allee 23, 89081 Ulm 
 
phone:  
0731/500-45501 
 
Fax:   
0731/500-45505 
 
E-Mail: andreas.viardot@uniklinik-ulm.de 
 
 
 
Prof. Dr. med. M. Witzens-Harig 
 
Medizinische Klinik V  
 
INF 410, 69120 Heidelberg 
 
phone:  
06221/ 56 8030 
 
Fax:   
06221/ 56 5813 
 
E-Mail: Mathias.Witzens-Harig@med.uni-
heidelberg.de 
 
 
 
Prof. Dr. sc. hum. Meinhard Kieser 
 
Institut für Medizinische Biometrie und 
Informatik  (IMBI) 
 
Im Neuenheimer Feld 305, 69120 Heidelberg  
 
phone:  
06221-56-4140 
 
Fax:   
06221-56-4195  
 
E-Mail: meinhard.kieser@imbi.uni-
heidelberg.de 

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Central technical facilities to be involved in the conduct of the trial, in which the measurement or 
assessment of the main evaluation criteria are centralised: 
 
CENTRAL FDG-PET/CT ASSESSMENT 
CENTRAL MRD ANALYSIS 
Prof. Dr. U. Haberkorn 
Prof.  Dr. Ch. Pott 
Abt. Nuklearmedizin 
II. Medizinische Klinik und Poliklinik 
Universitätsklinikum Heidelberg 
INF 400 
69120 Heidelberg 
Telefon:  
06221/ 56-7731 
Fax:   
06221/ 56-5473 
Labor für Hämatologische 
Spezialdiagnostik 
Universitätsklinikum Schleswig 
Holstein Campus Kiel 
Langer Segen 8-10 
24105 Kiel 
phone:        0431/ 500-24981 
Sekretariat: 0431/ 500-24970 
Fax:          0431/ 500-24974 
CENTRAL CT ASSESSMENT 
 
Prof. Dr. K. Herfarth 
Abt. Radioonkologie & Strahlentherapie 
Universitätsklinikum Heidelberg 
Im Neuenheimer Feld 400, 69120 Heidelberg 
Tel:  
06221/ 56-8202 
Fax:  06221/ 56-5353 
 
 
 
REFERENCE PHATHOLOGISTS of the 
KML1 
  
Prof. Dr. med. Falko Fend  
Prof. Dr. M. L. Hansmann  
Universitätsklinikum Tübingen  
Universität Frankfurt  
Institut für Pathologie  
Senckenbergisches Inst. f. Pathologie  
Liebermeisterstraße 8 
Theodor-Stern-Kai 7  
72076 Tübingen  
60596 Frankfurt  
phone:  07071 29-80207 
phone:  069/6301-5364  
Fax:  
07071 29-2258 
Fax:  
069/6301-3903  
 
Prof. Dr. P. Möller  
Prof. Dr. W. Klapper 
Universitätsklinikum Ulm  
Inst. für Hämatopathologie  
Inst. f. Pathologie u. Rechtsmedizin  
der Universität Kiel  
Albert-Einstein-Allee 23  
Arnold-Heller Str. 3, Haus 14 
89070 Ulm 
24105 Kiel  
phone:  0731/500-56321 
phone:  0431/ 431-3425  
Fax:  
0731/500-56384 
Fax:  
0431/ 431-4129 
 
Prof. Dr. med. German Ott 
Prof. Dr. med. A. Rosenwald 
Institut für Klinische Pathologie 
Dir. d. Pathologischen Instituts 
Robert-Bosch-Krankenhaus 
der Universität Würzburg 
Auerbachstraße 110 
Josef Schneider Str. 2 
                                                   
1 the actual list of reference sites is available on the homepage of the KML 
(http://www.lymphome.de/Projekte/Referenzpathologie/Institute.jsp) 

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70376 Stuttgart  
97080 Würzburg 
phone:  0711 8101-3619 
phone  0931/ 31-81199 
Fax:  
0711 8101-3619 
Fax:  
0931/ 31-81224 
 
 
Prof. Dr. H. Stein 
 
Pathodiagnostik Berlin 
 
Komturstr. 58-62 
 
12099 Berlin 
 
phone:  0731/500-56321 
 
Fax:  
0731/500-56384 
 
 
 
 
 
 
 

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PARICIPATING SITES  
 
The trial will be conducted in 30 national sites (15 Radiation Oncology; 15 
Hematology&Oncology) at 15 locations. The sites will be specified in a separate document. 

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TABLE OF CONTENT 
SYNOPSIS ................................................................................................................................................................. 11 
STUDY FLOW CHART........................................................................................................................................... 16 
STUDY SCHEDULE ................................................................................................................................................ 17 
LIST OF TABLES .................................................................................................................................................... 20 
ABREVIATIONS ...................................................................................................................................................... 21 
SUMMARY ............................................................................................................................................................... 24 
1 INTRODUCTION .................................................................................................................................................. 24 
1.1 Background.................................................................................................................................................. 24 
1.1.1 Radiation therapy and extension of the target volume .................................................................................................25 
1.1.2 Radiation dose ................................................................................................................................................................25 
1.1.3 Chemotherapy and radiation therapy ............................................................................................................................27 
1.1.4 Immunotherapy using an anti-CD20-Antibody (MabThera / Rituximab) ..................................................................27 
1.1.5 Combination of anti-CD20-antibody and radiation therapy ........................................................................................28 
1.1.6 FDG-PET for staging and response evaluation ............................................................................................................28 
1.2 Rational for the Current Trial Concept ....................................................................................................... 28 
1.3 Benefit-/ Risk-Assessment ............................................................................................................................ 30 
1.4 Additional Scientific Project ........................................................................................................................ 30 
1.5 Committees .................................................................................................................................................. 30 
1.5.1 Data Monitoring Committee (DMC) ............................................................................................................................30 
1.5.2 Steering Committee (SC) ...............................................................................................................................................31 
2. OBJECTIVES AND ENDPOINTS...................................................................................................................... 31 
2.1 Study Objectives .......................................................................................................................................... 31 
2.2 Primary Endpoint ........................................................................................................................................ 31 
2.3 Secondary Endpoints ................................................................................................................................... 31 
2.4 Additional Scientific Program ..................................................................................................................... 31 
2.5 Extended Follow-up Phase (Register Phase) .............................................................................................. 31 
3. TRIAL CONCEPT/ DESIGN .............................................................................................................................. 32 
4. DURATION OF THE TRIAL AND EARLY STOPPING ................................................................................ 32 
4.1 Duration and Time Line .............................................................................................................................. 32 
4.2 Early Stopping of the Trial or Early Stopping of a Trial Site ...................................................................... 32 
5. PARTICIPANTS ................................................................................................................................................... 33 
5.1 Number of Participants ............................................................................................................................... 33 
5.2 Common Criteria for Patient Selection ....................................................................................................... 33 
5.3 Inclusion Criteria ........................................................................................................................................ 33 
5.4 Exclusion Criteria ....................................................................................................................................... 34 
5.5 Criteria of Withdrawal ................................................................................................................................ 34 
5.5.1 Withdrawal of patients from treatment .........................................................................................................................34 
5.5.2 Definition of drop-outs...................................................................................................................................................35 
5.5.3 Replacement of participants ..........................................................................................................................................36 
5.6 Prior and Concomitant Diseases ................................................................................................................. 36 
5.7 Prior and Concomitant Medication ............................................................................................................. 36 
6. STUDY MEDICATION ....................................................................................................................................... 36 
6.1 General Information .................................................................................................................................... 36 
6.2 Characteristics of the Trial Medication....................................................................................................... 37 
6.3 Therapeutic Effects of Gazyvaro ................................................................................................................. 37 
6.4 Known Side Effects ...................................................................................................................................... 38 
6.4.1 Infusion-related reactions (IRRs) ..................................................................................................................................38 
6.4.2 Hypersensitivity reactions including anaphylaxis ........................................................................................................37 
6.4.3 Tumour lysis syndrome (TLS)  .....................................................................................................................................38 
6.4.4 Neutropenia and infections ............................................................................................................................................39 
6.4.5 Thrombocytopenia..........................................................................................................................................................39 
6.4.6 Special populations ........................................................................................................................................................39 

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6.5 Dosage and Dosage Schedule ..................................................................................................................... 41 
6.5.1 Dosage .............................................................................................................................................................................41 
6.5.2 Instruction for dilution ...................................................................................................................................................41 
6.5.3 Administration of Gazyvaro ........................................................................................................................................... 41 
6.5.4 Infusion rate ..................................................................................................................................................................412 
6.5.5 Overdosage .....................................................................................................................................................................43 
6.5.6 Time Window for the Gazyvaro Administration .........................................................................................................43 
6.6 Premedication before Gazyvaro infusion .................................................................................................... 43 
6.7 Subject Number ........................................................................................................................................... 44 
6.8 Packing and Labeling .................................................................................................................................. 44 
6.9 Delivery and Drug Accountability ............................................................................................................... 44 
6.10 Ordering of Gazyvaro ................................................................................................................................ 44 
7 IRRADIATION ...................................................................................................................................................... 45 
7.1 Target volume .............................................................................................................................................. 45 
7.2 LDRT (week 9) ............................................................................................................................................. 46 
7.3 Salvage irradiation (week 20-23) ................................................................................................................ 46 
8. METHODS OF DATA COLLECTION / STUDY VISITS ............................................................................... 46 
8.1 Initial Staging .............................................................................................................................................. 46 
8.1.1 Procedures .......................................................................................................................................................................46 
8.1.2 Risk profile and FLIPI ...................................................................................................................................................47 
8.1.3 Examinations after inclusion and before start of therapy ............................................................................................47 
8.1.4 Examinations during therapy (up to week 18)..............................................................................................................47 
8.1.5 Follow-up examinations month 6, 12, 18, 24 ...............................................................................................................48 
8.1.6 Final examination (month 30) .......................................................................................................................................49 
8.1.7 MRD analysis .................................................................................................................................................................49 
8.1.8 Genetic and molecular testing of the initial lymph node biopsy (additional scientific program) .............................50 
8.2 FDG-PET/CT .............................................................................................................................................. 50 
8.3 Efficacy Parameters .................................................................................................................................... 50 
8.3.1 Criteria of Remission of the FDG-PET (metabolic remission) ...................................................................................50 
8.3.2 Criteria of Remission of CT/MRI .................................................................................................................................51 
8.4 Parameters of safety .................................................................................................................................... 51 
8.5 Additional Parameters ............................................................................................................................... 511 
9. FOLLOW-UP AND POSSIBLE TREATMENTS AFTER END OF TRIAL ................................................. 52 
10. ADVERSE EVENTS ........................................................................................................................................... 52 
10.1 Definitions ................................................................................................................................................. 52 
10.1.1 Adverse Event ..............................................................................................................................................................52 
10.1.2 Serious Adverse Event, SAE .......................................................................................................................................53 
10.1.3 Serious Adverse Reaction, SAR ..................................................................................................................................53 
10.1.4 Expectedness ................................................................................................................................................................53 
10.1.5 Suspected Unexpected Serious Adverse Reaction, SUSAR ...................................................................................533 
10.1.6 AEs of special interest .................................................................................................................................................54 
10.1.7 Grading of AEs .............................................................................................................................................................55 
10.1.8 Relationship and outcome of AEs ...............................................................................................................................56 
10.2 Period of Observation and Documentation ............................................................................................... 57 
10.3 Reporting of Serious Adverse Events by Investigator ................................................................................ 57 
10.4 Expedited Reporting .................................................................................................................................. 58 
10.5 Emergency Treatment ................................................................................................................................ 58 
11. STATISTICAL PROCEDURES ....................................................................................................................... 58 
11.1 Number of Patients .................................................................................................................................... 58 
11.2 Variables of analysis ................................................................................................................................. 59 
11.3 Definition of the Trial Populations ............................................................................................................ 59 
11.4 Statistical Methods .................................................................................................................................... 60 
11.5 Interim Analysis ......................................................................................................................................... 60 
11.6 Definition of Target Variables ................................................................................................................... 60 
12. DATA MANAGEMENT .................................................................................................................................... 60 
12.1 Data Collection ......................................................................................................................................... 60 
12.2 Data Handling ........................................................................................................................................... 61 

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12.3 Archiving of Essential Documents ............................................................................................................. 61 
13. ETHICAL AND LEGAL ASPECTS ................................................................................................................. 62 
13.1 Good Clinical Practice .............................................................................................................................. 62 
13.2 Legal Bases................................................................................................................................................ 62 
13.2.1 Declaration of Helsinki ................................................................................................................................................62 
13.2.2 Other legal bases ..........................................................................................................................................................62 
13.2.3 Approval and trial protocol amendments....................................................................................................................62 
13.2.4 Notification of regulatory authorities ..........................................................................................................................63 
13.3 Subject Information and Informed Consent ............................................................................................... 63 
13.4 Data Protection ......................................................................................................................................... 64 
13.5 Continuous Information to the Ethics Committee and the Competent Authority ....................................... 64 
13.6 Insurance ................................................................................................................................................... 65 
14. QUALITY CONTROL AND QUALITY ASSURANCE................................................................................. 65 
14.1 Direct Access to Source Documents According to ICH GCP .................................................................... 65 
14.2 Monitoring ................................................................................................................................................. 65 
14.3 Inspections and Audits ............................................................................................................................... 66 
14.4 Responsibilities of the Investigator ............................................................................................................ 66 
15. ADMINISTRATIVE AGREEMENTS.............................................................................................................. 66 
15.1 Financing of the Trial ................................................................................................................................ 66 
15.2 Financial Disclosure ................................................................................................................................. 66 
15.3 Reports....................................................................................................................................................... 67 
15.4 Registration of the Trial ............................................................................................................................ 67 
15.5 Publication ................................................................................................................................................ 67 
16 SIGNATURES ...................................................................................................................................................... 68 
17. DECLARATION OF INVESTIGATOR .......................................................................................................... 69 
18. LITERATURE .................................................................................................................................................... 70 
 
 

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SYNOPSIS 
Title 
Therapy of early stage nodal Follicular Non-Hodgkin Lymphoma (WHO grade 1/2) in 
clinical stage I/II using response adapted involved site radiotherapy in combination with 
Gazyvaro 
 
GAZAI trial (Gazyvaro and response Adapted Involved-site Radiotherapy) 
Phase 
Phase II trial 
Sponsor 
Ruprecht-Karls-University Heidelberg, Medical Faculty, represented by the University 
Hospital Heidelberg and its Commercial Director Dipl. Volkswirtin Irmtraut Gürkan, Im 
Neuenheimer Feld 672, 69120 Heidelberg 
Coordinating Principal Investigator / Leiter der klinischen Prüfung 
Prof. Dr. med. Klaus Herfarth, Dept. Radiation Oncology, INF 400, 69120 Heidelberg, 
Germany 
Financing 
Non-commercial clinical investigation under co-funding of the Roche Pharma AG. 
Indication 
Stage I or stage II (Ann Arbor) nodal follicular Non-Hodgkin Lymphoma grade 1 or grade 2  
Study population 
Inclusion criteria 
 Centrally reviewed CD20-positive follicular lymphoma grade 1/2 based on WHO 
classification (2016) 
 Untreated (radiation-, chemo- or immunotherapy) nodal lymphoma (including 
involvement of  Waldeyer´s ring) 
 Age: ≥18 years 
 ECOG: 0-2 
 Stage: clinical stage I or II (Ann Arbor classification) 
 Risk profile: Largest diameter of the lymphoma  7 cm (sectional images) 
 Written informed consent and willingness to cooperate during the course of the trial 
 Adequate hematologic function (unless abnormalities are related to NHL), defined as 
follows: Hemoglobin ≥ 9.0 g/dL;  absolute neutrophil count ≥ 1.5 × 109/L, Platelet 
count ≥ 75 × 109/L 
 Capability to understand the intention and the consequences of the clinical trial 
 Adequate contraception for men and women of child-bearing age during therapy and 18 
months thereafter 
 
Patients with non-active hepatitis B infection (HBsAg neg/HBcAB pos/HBV DNA neg) 
under 1-year require prophylactic anti-viral therapy (e.g. Entecavir®) possible (see also 

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5.6. Prior and Concomitant Disease) 
Exclusion criteria 
 
Extra nodal manifestation 
 
Secondary cancer in the patient’s medical history (exclusion: basalioma, spinalioma, 
melanoma in situ, bladder cancer T1a, non-metastasized solid tumor in constant 
remission, which was diagnosed >3 years ago  
 
Concomitant diseases: congenital or acquired immune-deficiency syndromes, active 
infections including viral hepatitis (serology positive for HBsAg or HBcAb in 
combination positive HBV DNA), uncontrolled concomitant diseases including 
significant cardiovascular or pulmonary disease (see also 5.6. Prior and Concomitant 
Disease) 
 
Severe psychiatric disease 
 
Pregnancy / lactation 
 
Known hypersensitivity against Gazyvaro (Obinutuzumab) or drugs with similar 
chemical structure or any other additive of the pharmaceutical formula of the study 
drug 
 
Participation in another interventional trial or follow-up period of a competing trial 
which can influence the results of this current trial 
 
Creatinine > 1.5 times the upper limit of normal (ULN) (unless creatinine clearance 
normal), or calculated creatinine clearance < 40 mL/min 
 
AST or ALT > 2.5 × ULN 
 
Total bilirubin ≥ 1.5 × ULN 
 
INR > 1.5 × ULN 
 
PTT or aPTT > 1.5 × the ULN 
Background 
Large field radiation therapy has proven to be superior to more limited fields radiation in 
early stage follicular lymphoma in prolonging PFS (ARO 98-01 trial, personal 
communication M. Engelhard) 
The MIR trial showed, that at least in the short time follow-up, the addition of MabThera to 
a small-field radiation therapy in conventional dosage can lead to at least equal results 
concerning the PFS as compared to the historic large field data of the ARO 98-01 trial. 
However, the toxicity has been shown to be lower (Herfarth et al. 2014). 
The metabolic CR rate as demonstrated by FDG-PET was identified as a prognostic marker 
for freedom of recurrence in advanced stage of follicular lymphoma (Trotman et al. 2011 
PRIMA trial).  
Immune modulating radiation therapy alone using a low-dose of 2 x 2 Gy (LDRT) has been 
shown to be effective in inducing CR in about 60% of follicular lymphoma in a prospective 
trial (Haas et al 2003) or 48% in the British FORT trial (Hoskin et al. 2014). It can be 
speculated that a CR-repsonse to LDRT identifies specific subtypes of follicular lymphoma. 
Also, it is not known whether a combination of LDRT with anti-CD20 antibody therapy 
may enhance the CR-rate. 
The goal of the current trial is a further reduction of the radiation dose in patients with a 
good response to a combination of LDRT and anti-CD20 immunotherapy. The shift from 
MabThera to Gazyvaro might lead to an even more effective treatment, which can be 
proven by the morphological response in week 7 and the MRD eradication in comparison to 
the MIR trial. Patients with insufficient response (no metabolic CR) after LDRT will receive 
an additional radiation dose of 36 Gy adding up to the total dose 40 Gy of the MIR trial.  

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Objectives 
Primary 
Evaluation of the rate of metabolic CR after low-dose involved site radiotherapy in 
combination with Gazyvaro (Obinutuzumab) in early stage nodal follicular lymphoma in 
order to avoid conventional full dose IF radiotherapy.  
Secondary 
Efficacy and safety of a response adapted radiation dose treatment schedule. 
Endpoints 
Primary 
 Metabolic complete response (CR) in week 18 in patients with remaining  
macroscopic lymphoma after initial diagnostic biopsy judged by FDG-PET/CT 
Secondary 
 Morphologic CR, PR, SD, PD in week 7, week 18 and month 6 in patients with 
initially remaining lymphoma judged by CT/MRI  
 Historical comparison of the morphologic response with MIR data (using 
MabThera); the comparison of the CR rate in week 7 allow for a comparison of the 
two different anti-CD20 antibodies. Based on the patient numbers a matched pair 
analysis will be not be possible 
 Progression-free survival (PFS) of all treated patients (2 years after individual 
treatment start) 
 Toxicity (NCI-CTC criteria, version 4.03) of all patients 
 Relapse rate and pattern of recurrence of all treated patients at all follow-up visits. 
 Overall survival (OS) of all treated patients (2 years) 
 Quality of life according EORTC QLQ C30 and FACT-Lym questionnaires at 
inclusion and in week 18, month 12, and 24 (all treated patients) 
 MRD response: initially, week 18, months 6, 12, 18 and 24 (all treated patients). 
MRD is evaluated by the laboratory of C. Pott (Kiel) using at least the markers: 
t(14:18) PCR for MBR, 3’mbr, 5’mcr and MCR; clonal IGH rearrangements (FR1-
3); clonal IGL rearrangements (IGK and Kappa-KDE) 
 
Additional Scientific program 
 Genetic profiling of responders and non-responders (coordinated by W. Klapper, 
Kiel) 
Design of the trial 
Open, non-controlled, national multi-center phase II trial 
Study medication: Gazyvaro (Obinutuzumab) 
Duration and dosing: 
1000 mg Obinutuzumab i.v. flat dose weekly in weeks 1-4 and week 8, week 12, week 
16 
(pharmacokinetics based on [1]) 
 
 

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week 
1 
2 
3 
4 
5 
6 
7 
8 
9 
12 
16 
Gazyvaro 
(1000 mg 
i.v.) 
X 
(day 1) 
X  
(day 8) 
X 
(day 
15) 
X 
(day 
22) 
 
 
 
X  
(day 1 of 
week 8) 
 
 
X  
(day 1 of 
week 12) 
X  
(day 1 of 
week 16) 
IS-RT 
 
 
 
 
 
 
 
 
2x2 Gy 
 
 
 
Radiation therapy 
 Involved site radiotherapy of the involved lymph node regions: 2 x 2 Gy in week 9 on 
two consecutive days (after 5th administration of Gazyvaro) 
 Salvage radiotherapy if there is no metabolical CR and  morphological PR/CR at week 
18: additional 18 x 2 Gy (5x2 Gy/week) starting from week 20 (without Gazyvaro) 
Number of patients 
Due to the descriptive character of the trial, no assessment of any formal statistical 
hypotheses is performed. The calculation of the number of patients is primarily based on the 
aspects of practicability and precision of the results. The following calculations are based on 
the intention-to-treat (ITT) population. Since the strength of the results for the primary 
endpoint may be weakened due to early drop-outs (as described later), the number of 
patients needed should be high enough to compensate for potential drop-outs. Primary 
endpoint is the rate of metabolic CR in week 18 in patients with initially remaining 
lymphoma judged by FDG-PET/CT. Based on the morphologic CR rate of 37-84% after 2 x 
2 Gy documented in the literature and in face of a lack of data for metabolic CR after 2x2 
Gy, a CR rate of 60% is assumed. If fifty patients enter the FDG-PET/CT and the observed 
metabolic CR rate amounts to 60%, the half width of the asymptotic two-sided 95% 
confidence interval amounts to about ± 13.5%.  
Based on the experience of the MIR trial, a general drop-out rate of 10% is assumed, and 
about 30% of the included patients will not have remaining lymphoma after initial surgery 
to prove the histology. In addition, we expect an additional drop-out rate of about 15% after 
the initial FDG-PET due to stage-shifting to a stage III/IV disease. 
These considerations lead to the following calculation: 
If 93 patients are being recruited, about 15% will drop out due to a stage-shift to higher 
stages after FDG-PET (79 patients remaining). Of these 79 patients, about 30% will have no 
remaining PET positive lymphoma after initial surgery (according to the experiences in the 
MIR trial). Therefore, 55 patients would start therapy with the goal of reaching the primary 
endpoint assessment. Assuming a drop-out rate of 10%, 50 patients will be available for 
final assessment of the primary endpoint.  
The number of n=93 represents the upper limit of the patients to be included. This number 
of definitively included patients might drop during the trial, if, e.g., less patients show a 
stage-shift or more patients show remaining lymphoma. 
Statistical analysis 
Trial data are evaluated by applying methods of descriptive data analysis: 
Rate of metabolic CR in week 18 after initiation of the therapy of each patient as relative 
frequency including the two-sided 95% confidence interval according to Wilson. (ITT and 
PP populations). 
PFS and OS at 2 years after initiation of the therapy of each patient will be analyzed using 
the Kaplan-Meier method and the two-sided 95% confidence intervals according to 
Greenwood (ITT and PP populations). 
Quality of life will be evaluated according to the evaluation guide of the two questionnaires. 

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(ITT and PP populations). 
Toxicity will be evaluated for frequency and intensity (safety population). 
Length of the clinical trial and milestones 
Length of the clinical phase: 
5.5 years (66 months) 
Start of trial preparation: 
Q1 2015 
 
FPI (First Patient In): 
Q4 2017 
 
LPI (Last Patient In): 
Q1 2021 
 
LPO (Last Patient Out): 
Q3 2023 
 
DBL (Data Base Lock): 
Q1 2024 
 
Completion of the statistical analysis: 
Q2 2024 
 
Completion of the trial report: 
Q3 2024 
 
 
 
 

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STUDY FLOW CHART 
Two stage Screening: 
a) 
Histology and CT or MRI: centrally approved follicular lymphoma grade 1/2 in clinical stage I/II (max. 93 
patients) 
b) 
FDG-PET/CT: exclusion of stage III/IV patients (approx.. 15%= 14 patients) 
Inclusion of max 79 patients: ca. 70% (=55 patients with remaining lymphoma); approx. 30% (=24 patients 
with metabolic CR) 
Drop-out-rate: approx. 10% (analyzable for primary endpoint 50 patients with remaining PET positive 
lymphoma) 
 
 
PET-pos (PET+):  PET positive residual lymphoma 
PET-neg. (PET-):  metabolic CR 
W: 
 
week 
FU: 
 
Follow-up examinations 
morph. SD:              morphological SD 
 
 
 

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STUDY SCHEDULE 
 
R/S
* 
Base
line 
Monotherapy  
Gazyvaro 
Staging  
CT 
Combined Therapy 
Gazyvaro +Radiation 
Staging 
FDG-PET/CT 
(Salvage) 
Follow-up 
 
 
 
Week 
Month 
Visits from 1. Gazyvaro  
 
 
1 
2 
3 
4 
7 
8 
9 
12 
16 
18 
20 
21 
22 
23/ 
24 
6 
12 
18 
24 
30 
Window: ± days (d)/weeks (w) 
 
 
 
2d 
2d 
2d 
1w 
3d 
 
3d 
3d 
1w 
1w 
2w 
2w 
2w 
2w 
2w 
Informed consent 
S 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hepatitis11/HIV12/ 
pregnancy testing (serum)20 
R 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy test (serum / 
urine) 22 
 
 
X21 
 
 
X21 
 
X21 
 
X21 
X21 
 
 
 
 
 
 
 
 
 
 
Biopsy(R)/reference 
pathology.(R)7 
R 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Previous medical history 
and current status3  
R 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
X 
X 
X 
X 
ECOG 
S 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
X 
X 
X 
X 
Gazyvaro i.v. 5 
S 
 
X 
X 
X 
X 
 
X 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
Radiation IS6 (2Gy/day) 
S 
 
 
 
 
 
 
 
X6 
 
 
 
 
 
 
 
 
 
 
 
 
Salvage RT 6 (36 Gy) 
S 
 
 
 
 
 
 
 
 
 
 
 
(X 
X 
X 
X) 
 
 
 
 
 
Diff. blood count10 
R 
X 
X2 X2 X2 
 
X 
X2 
 
X2 
X2 
X 
 
 
 
 
X 
X 
X 
X 
X  
Clin. chemistry4; LDH 
R 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
X 
X 
X 
X  
Albumin, immunoglobulins, 
immunefixation15; ß2-
Microglobulin 
R 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
FDG-PET/CT 
S 
X13 
 
 
 
 
 
 
 
 
 
X14 
 
 
 
 
 
 
 
 
 

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R/S
* 
Base
line 
Monotherapy  
Gazyvaro 
Staging  
CT 
Combined Therapy 
Gazyvaro +Radiation 
Staging 
FDG-PET/CT 
(Salvage) 
Follow-up 
 
 
 
Week 
Month 
Visits from 1. Gazyvaro  
 
 
1 
2 
3 
4 
7 
8 
9 
12 
16 
18 
20 
21 
22 
23/ 
24 
6 
12 
18 
24 
30 
Window: ± days (d)/weeks (w) 
 
 
 
2d 
2d 
2d 
1w 
3d 
 
3d 
3d 
1w 
1w 
2w 
2w 
2w 
2w 
2w 
CT/MRI16  
R 
X 
 
 
 
 
CT17 
 
 
 
 
X19 
 
 
 
 
X 
X 
X 
X 
X  
Bone marrow aspiration 
R 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Additional examination 
based on involved sites.8 
R 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
MRD9 
EDTA-blood (10 ml) 
STRECK-tube (10 ml) 
S 
X1 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
X 
X 
X 
 
QLQ (EORTC QLQ-C30; FACT Lym) 
S 
X1 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
X 
 
AEs (CTCAE) 
S/R 
 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X18 
X 
X 
X 
X 
X 
Support medication  
 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
*R = Routine, S = trial specific 
1 before therapy 
2 before each infusion of Gazyvaro 
3 Weight, height, comorbidities, medication, physical examination including lymph node status, FLIPI  
4 Na, K, AST/ALT, Bilirubine total, AP, creatinine: all baseline-values older than 4 weeks before first Gazyvaro infusion. 
5 as described in synopsis 
6 Irradiation: Dosage according ICRU 50 
 
Week 9: IS-Radiation  
Total dose:  
4 Gy 
 
 
 
 
Single dose: 
2 Gy per day on two consecutive days 
 
Salvage RT on remaining lymphoma (after positive FDG-PET/CT week 18) from week 20 (until week 23 or 24): total dose 36 Gy, single dose 2 Gy, 5 fractions per week 
 
There is no salvage RT in case of metabolic CR and morphologic PR  
7 Fine needle aspiration is not acceptable. Biopsy specimens should be sent to the reference pathologists as early as possible. Histology must be not older than 6 months  
8 TSH, fT3/fT4 in case of cervical involvement  
9 MRD-diagnostic via Prof. Dr. Ch. Pott, Kiel 
10 differential blood cell count: hemoglobin, leucocytes, thrombocytes, neutrophils, lymphocytes 
11 HBV-Testing: at least HBsAG-status and HBcAb-status 
12 Hepatitis/HIV screening can be dispensed if values not older than 3 months exists; pregnancy testing in blood serum 

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13 FDG-PET/CT after trial inclusion (initial FDG-PET/CT): it can be dropped if there is an existing FDG-PET/CT not older than 4 months and performed under the requested conditions. 
(central review of these images in Heidelberg) 
14 PET/CT in week 18 if there was initially PET positive remaining lymphoma 
15 Serum electrophoresis: albumin, M-component 
16 CT/MRI: head/neck, thorax/ abdomen/ pelvis incl. inguinal region), if necessary additional ultrasound. staging procedures not older than 4 months. 
17 CT of the involved region as planning CT 
18 in case of salvage RT from week 20 
19 CT/MRI only, in week 18 in patients with PET negative initially enlarged lymph nodes 
20 Pregnancy test (serum) in all women with childbearing potential (including tubal ligation) 
21 Pregnancy test (serum or urine) in all women with childbearing potential (including tubal ligation); In case of a positive urine pregnancy test, dosing will be delayed, until patient’s 
status is determined by a serum pregnancy test. 
22 Additionally, pregnancy test (serum or urine) in all women with childbearing potential (including tubal ligation) if menstruation is overdue more than 2 weeks during the follow up 
period up to month 24.

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LIST OF TABLES 
 
Table 1: Results of radiotherapy in larger patient series with early stage FL (f/u = follow-up; IF = 
Involved field, RF = regional field; EF = Extended field; TLI = total lymphatic irradiation; TNI = total 
nodal irradiation) .......................................................................................................................................... 25 
Table 2: Response (PR/CR) und rate of CR after 2 x 2 Gy IF radiotherapy (based on Luthy et al. [27]
 ....................................................................................................................................................................... 26 
 
 
 

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ABREVIATIONS 
ADCC 
 
 
Antibody-dependent cellular cytotoxicity 
ADCP 
 
 
Antibody-dependent cellular phagocytosis 
AE  
 
 
Adverse Event 
AMG 
 
 
German Drug Law (Deutsches Arzneimittelgesetz) 
ATC 
 
 
Anatomical-Therapeutic-Chemical Code, part of WHO-DRL (Drug  
Reference List) 
BDSG 
 
 
Bundesdatenschutzgesetz 
BfS 
 
 
Bundesamt für Strahlenschutz (Federal Radiation Safety Agency) 
BOB  
 
 
Bundesoberbehörde 
CDC 
 
 
Complement-dependent cytotoxicity 
CLL 
 
 
Chronic lymphocytic leukemia 
CMR 
 
 
Complete Metabolic Response 
CRF 
 
 
Case Report Form 
CR  
 
 
Complete Remission 
CRu 
 
 
unconfirmed Complete Remission 
CS  
 
 
clinical stage 
CT  
 
 
Computer tomography 
CTCAE 
 
 
Common Toxicity Criteria for Adverse Events  
CV 
 
 
Curriculum Vitae 
D  
 
 
Day 
DBL 
 
 
Data Base Lock 
DICOM 
 
 
Digital Imaging and Communications in Medicine 
DMC 
 
 
Data Monitoring Committee 
DSUR 
 
 
Development Safety Update Report 
EC  
 
 
Ethics Committee 
EF  
 
 
Extended field 
ENT 
 
 
Ears nose throat 
EORTC QLQ 
 
European Organization for Research and Treatment of Cancer Quality of 
 
 
 
 
Life questionnaire 
FD  
 
 
Financial Disclosure 
FDG-PET  
 
18F-Fluor-Desoxy-Glucose Positron-Emissions Tomography 
FL  
 
 
Follicular Lymphoma 
FLIPI 
 
 
Follicular lymphoma International Prognostic Index 
FPI 
 
 
First Patient In 
FU  
 
 
Follow-up visit 
GCP 
 
 
Good Clinical Practice 
GCP-V 
 
 
Good Clinical Practice Ordinance (GCP-Verordnung) 
GLSG 
 
 
German Low-Grade Lymphoma Study Group 
Gy  
 
 
Gray, Energy dose (J/kg) 
IB  
 
 
Investigator´s Brochure 
ICH 
International Council on Harmonization of Technical Requirements for 
Registration of Pharmaceuticals for Human Use 

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ICH GCP 
ICH harmonized tripartite guideline on GCP 
ICRU 50  
 
International Committee on Radiation Units and Measurements 50 
ICSR 
 
 
Individual Case Safety Report 
IF  
 
 
Involved field 
IMBI 
 
 
Institute for Medical Biometry and Informatics 
IMP 
Investigational Medicinal Product 
INN 
International Nonproprietary Name 
IRR 
Infusion related reaction 
IS 
Involved site 
ISF 
Investigator Site File 
ISRCTN 
International Standard Randomized Controlled Trial Number 
ITT 
 
 
Intention To Treat 
KKS 
 Coordination Centre for Clinical Trials (Koordinierungszentrum für 
Klinische Studien) 
LDRT 
 Low dose radiation therapy 
LKP 
 
 
Coordinating Investigator according to AMG (Leiter der Klinischen 
 
 
 
 
Prüfung) 
LPO 
 
 
Last Patient Out 
LPI 
 
 
Last Patient In 
MedDRA  
 
Medical Dictionary for Regulatory Activities 
MPD 
 
 
Metabolic Progressive Disease 
MRD 
 
 
minimal residual disease 
MRI 
 
 
Magnetic resonance imaging 
NCI-CTC  
 
National Cancer Institute Common Toxicity Criteria 
NHL 
 
 
Non-Hodgkin Lymphoma 
OS  
 
 
Overall survival 
PD  
 
 
Progressive Disease 
PEI 
 
 
Paul-Ehrlich-Institute 
PFS 
 
 
Progression-free survival 
PI  
 
 
Principal Investigator 
PMR 
 
 
Partial Metabolic Response 
PP  
 
 
per-Protocol 
RF  
 
 
Regional field 
RT  
 
 
Radiotherapy 
SAE 
 
 
Serious Adverse Event 
SAP 
 
 
Statistical analysis plan 
SC  
 
 
Steering Committee 
SmPC 
 
 
Summary of Product Characteristics 
SPD 
 
 
Sum of the products of the greatest diameters 
SUSAR 
 
 
Suspected Unexpected Serious Adverse Reaction 
SUV 
 
 
Standardized Uptake Value 
TLI 
 
 
Total lymphatic irradiation 
TMF 
 
 
Trial Master File 

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TNI 
 
 
Total nodal irradiation 
TSH 
 
 
Thyroid stimulating hormone 
W  
 
 
Week 
WHO 
 
 
World Health Organization 
 
 
 

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SUMMARY 
Extended field or total nodal irradiation had been the gold standard for early stage follicular lymphoma 
for a long time in Germany. An involved field (IF) irradiation has been favored due to the toxicity of 
large field irradiation in other countries (e.g. USA). However, smaller irradiation fields have been 
accompanied with an increased risk of recurrence [2, 3]. A combination of involved field irradiation 
with the anti-CD20 antibody Rituximab (MIR trial) has led to similar efficacy results compared to the 
large field irradiation but with markedly reduced side effects [4]. 
Haas et al. showed in a prospective trial, that a low dose radiation therapy (LDRT) can lead to a 
complete remission in up to 60% in follicular lymphoma [5]. This is presumed to result from immune 
modulatory effects induced by LDRT. The effectiveness of LDRT could also be demonstrated in 
another prospective, randomized British trial (FORT trial [6]: 2 x2 Gy vs. 12 x 2 Gy) with a CR rate of 
40% after 2 x 2 Gy (60% after 12 x 2 Gy). Currently, it is unknown, which patients need a higher 
radiation dose and which not. 
A metabolic complete remission (CR) is an important prognostic marker for progression-free survival. 
According to the results of the PRIMA trial, CR is a very strong predictive parameter if the CR is 
established using FDG-PET [7]. 
In the present GAZAI trial, patients with early stage nodular follicular lymphoma will be treated in a 
combined approach of immunotherapy with an anti-CD20 antibody and small field (involved site) 
irradiation as in the MIR trial. In GAZAI, the fully humanized anti-CD20 antibody Obinutuzumab 
(GAZYVARO) will be used, which showed a high efficacy in combination with bendamustin in 
patients with follicular lymphoma refractory to Rituximab (GADOLIN trial) [8]. In addition, the 
radiation dose will be limited to 2 x2 Gy in responding patients. A dose build-up to a total of 40 Gy 
(dose in the MIR trial) will be performed in case of failure to achieve a complete CR based on a FDG-
PET in week 18. 
Primary endpoint of the trial is the rate of CR (based on FDG-PET/CT) after Obinutuzumab and 2x2 
Gy IS radiotherapy in week 18. Secondary endpoints are the morphological CR rate in week 7, week 
18 and month 6, the PFS, the toxicity, the recurrence rate, the recurrence pattern, overall survival and 
quality of life. 
 
 
1 INTRODUCTION 
 
1.1 Background 
 
Follicular lymphomas (FL) are B cell lymphomas characterized by CD20 expression and quite often 
by a t(14;18)(q32;q21) translocation. Based on the increasing amount of centroblasts, FL is 
categorized in grade 1, 2 or 3. FL grade 3 is a heterogeneous group of lymphomas. Grade 3b FLs 
clinically present more like aggressive lymphomas and are usually treated accordingly. Follicular 
lymphoma is the second most frequent non-Hodgkin lymphoma entity in the US and in Europe (30% 
of all NHL and about 70% of indolent lymphomas). Most patients present with an advanced stage at 
the time of diagnosis. Only about 15-30% of the patients with FL initially present in an early stage 
(stage I or II according to the Ann Arbor classification). The natural course is usually slowly 
advancing with a relatively long survival, especially in the early stages. Due to this behavior, a watch 
and wait concept  (withholding therapy till progression) is being favored for the advanced stages and 
partly also for the early stages [9] [10]. 
 

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1.1.1 Radiation therapy and extension of the target volume  
Radiation therapy alone has been the gold standard for patients in the early stages. Long lasting 
remissions and the potential chance for cure were the main arguments supporting this approach. 
However, there was no consensus about the extent of the radiation fields (target volumes). Table 1 
summarizes the results of several international experiences with a longer follow-up [2, 11-22]. These 
are mostly retrospective analyses with only a few exceptions [15, 17, 18]. Involved field, extended 
field and total lymphatic irradiation (TLI) were used in these series. The 10-years freedom-from-
recurrence rates were 38%-72% and the overall survival rates 50%-78% with a median survival of 
more than 12 years. 
 
Table 1: Results of radiotherapy in larger patient series with early stage FL (f/u = follow-up; IF 
= Involved field, RF = regional field; EF = Extended field; TLI = total lymphatic irradiation; 
TNI = total nodal irradiation) 
Autor 
N Median  
f/u [years] 
Proportion
stage I [%]
RF surv 
10 J [%] 
OS 
10 J. [%] 
RT  
Volume 
Soubeyran, 
1988 [12] 
103 
8,3 
44 
49 
56 
IF/RF 
Lawrence, 
1988 [14] 
93 
9 
50 
48 
69 
IF/EF/TLI 
Mac 
Manus, 
1996 [2] 
177 
7,7 
41 
44 
64 
IF/RF/EF/TLI 
Stuschke, 
1997 [18] 
117 
5,5 
51 
59 (5J) 
86 (5J) 
EF/TLI 
Wilder, 
2001 [20] 
80 
19 
41 
72 (I); 
38 (II) 
70 (I); 
58 (II) 
IF/RF/EF 
Ott, 2003 
[21] 
58 
8,75 
40 
64 
69 
IF/EF/TNI/TLI 
Neumann, 
2003 [22] 
103 
4 
61 
48 
51 
IF/EF/TNI 
 
 
A prospective German trial included 117 early stage FL patients between 1986 and 1993. These 
patients were only treated by large field irradiation techniques (EF and TLI). 41% showed a recurrence 
after 8 years of follow-up. Risk for infield-field nodal relapse was significantly lower in adjuvant 
irradiated than in non-irradiated regions at least in stage I patients – suggestive of a necessity to 
evaluate large field irradiation under controlled conditions. However, this kind of treatment was 
accompanied with an increased risk of toxicity: 23% of the patients showed grade 3 / 4 toxicity [18].  
The successor trial ARO98-01 evaluated TLI and a modified EF irradiation in a randomized 
comparison. The recruitment of 202 patients was completed in 2007 and the final results have not been 
published yet. However, interim analyses showed a significant difference of the PFS and most 
recurrences occurred outside the radiation field [3]. 
 
1.1.2 Radiation dose 
Most of the trials listed in Table 1 used radiation doses of 30 Gy or more. In the German trial 

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published by Stuschke 1997, 26 Gy were mandatory for areas of possible microscopic disease and 36 
Gy to macroscopic disease. In a multiviariate analysis, a deviation of more than 20% of this dose 
proved to be a highly significant negative prognostic factor for recurrence [18]. 
In a 2011 published prospective British trial, the dose effect was evaluated in a randomized fashion in 
361 patients with indolent lymphoma [23]. Patients received either 20 x 2 Gy or 12 x 2 Gy involved 
field radiotherapy. There was no difference in the local or systemic lymphoma control reported after 
median follow up of 5 years. However, some reservations have to be made: The patient cohort was 
very heterogeneous regarding the histology (40% non-follicular grade 1/2), the stage and pretreatment 
(30% were treated for recurrence), and the thoroughness of follow-up examinations (radiological and 
only clinical examinations were allowed) [23]. Despite this, 24 Gy has was recommended  as a 
standard dose in England since the results of this study were published[24]. The German radiation 
oncology community is more concerned with the problems of the trial and has more confidence in the 
above mentioned data of Stuschke et al. suggesting a minimal dose of 36 Gy to macroscopic tumor 
sites [18]. 
 
However, low dose radiation therapy (LDRT) has shown long lasting effects. Ganem et al. published 
retrospective data about a low dose radiation therapy of follicular lymphomas in 1994 [25]. Twenty-
seven patients with advanced disease were treated with 2 x 2 Gy over 3 days. A CR was achieved in 
37%. More patients with low-grade lymphoma (according to the Working formulation) were treated 
subsequently using the 2 x2 Gy scheme as published in 2001 by Girinsky et al.: Of 48 patients, 80% 
were pretreated with at least 2 different chemotherapy schedules in their past medical history. A total 
of 135 sites were treated using 2 x 2 Gy and this resulted in a 51% CR rate. Positive predictors were a 
lymphoma <5cm, less previous chemotherapies, and an age < 65 years [26].  
Based on these data, a prospective multicenter phase 2 trial with 109 patients and recurrent indolent 
lymphoma was initiated and published by Haas et al in 2003 [5]. They reported a response rate of 92% 
and a CR rate of 61% (72% in patients without previous therapy). The local PFS in patients who 
achieved a CR was 75% after 2 years. The median local PFS was at 42 months. 
Luthy et al. treated 33 patients with advanced or recurrent indolent lymphoma also using the 2 x 2 Gy 
schedule [27]. They described a CR rate of even 84%. However, they also reported 23% infield 
recurrences after a time of 9 months (median). Achievement of CR was not a positive predictor. 
 
In summary, the CR rates after 2 x 2 Gy irradiation ranged between 37 and 84% (Table 2) 
 
Table 2: Response (PR/CR) und rate of CR after 2 x 2 Gy IF radiotherapy (based on Luthy et al. [27] 
Author 
n 
Total response  [%] 
CR [%] 
Ganem, 1994 [25] 
27 
89 
37 
Sawyer, 1997 [28] 
11 
94 
38 
Girinsky, 2001 [26] 
48 
81 
57 
Johannsson, 2002 [29] 
22 
87 
65 
Haas, 2003 [5] 
109 
92 
61 
Luthy, 2008 [27] 
33 
95 
84 
Hoskin, 2014 [6] 
243 
80 
48 
 
 
The mode of action of 2 x 2 Gy is not completely understood. An induction of the p53 pathway is 
discussed [30]. Knoops et al. looked at lymph node biopsies before and after LDRT. They found an 

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upregulation of p53 expression in 10 of 15 samples. An increase of the p53 immuno-staining from 5% 
to >80% was seen in 7 samples [31]. This effect was observed primarily in the follicular lymphoma 
cells and not in T-cells or endothelial cells visible. In vivo imaging lead to the speculation, that LDRT 
neutralizes anti-apoptotic effects of the characteristic bcl-2 overexpression in follicular lymphoma 
cells [32]. 
The British FORT trial prospectively tested 12 x 2 Gy against 2 x 2 Gy in the treatment of indolent 
lymphomas in a randomized fashion. Recruitment was stopped shortly before the end of the trial was 
reached due to the superiority of the 24 Gy arm (freedom from local progression after 2 years 93.7% 
vs. 80.4%) [33]. The CR rate was 40% after LDRT (total response rate 74%) and 60% after 24 Gy 
(total response rate 81%). For follicular lymphomas, the final results showed a CR rate of 48% after 
LDRT and 68% after 24 Gy (p = 0.0096). There were significantly more recurrences (n=70) in the 
LDRT arm after a median follow-up time of 26 months as compared to the standard 24 Gy arm (21 
recurrences; HR 3.42; p<0.0001) [6]. However, this trial also has some major weaknesses [34]:  
The inferiority regarding the PFS could have been strengthened by a possible imbalance between the 
two arms: There was no differentiation between follicular lymphoma grade 1, 2, 3a or 3b. A central 
review of the pathology confirmed only in 60% a follicular or a marginal zone lymphoma. There was 
no central pathological review in 20% of the patients and other lymphomas (also aggressive 
lymphomas) or no lymphoma at all were diagnosed in the other cases. It was not stratified after the 
size of the lesion. There was also no maximal size limitation and different response rates in relation to 
the size were not discussed. No difference in the PFS was seen in a subgroup analysis of all patients (4 
Gy and 24 Gy), but there was no information about the effect of the different doses in respect to the 
size of the lesion. There was no information about previous and following treatments.  In the staging 
and follow-up procedures, 3D imaging was not mandatory, conventional x-ray and clinical evaluations 
only were also allowed. It is not clear, how many of these patients were evaluated only clinically 
without 3D imaging. Unfortunately, there was also no information about the best response status of the 
patients with recurrence. 
In summary, the FORT trial showed some effectiveness after LDRT, but it is not clear whether the 
difference between LDRT and 24 Gy was as large as published considering the above mentioned 
weaknesses.  
 
1.1.3 Chemotherapy and radiation therapy 
In the 70ties and 80ties, several trials addressed the possibility that relapse control could be improved 
by a combination of radiation therapy with systemic chemotherapy [35-38]. The sequential application 
of COP or CHOP-B and IF radiation therapy showed an improvement of the recurrence-free survival 
but not of the overall survival compared with historical data [39]. An update of the data revealed a 10 
years recurrence free survival of 72%, which is superior to historical controls [40]. However, 22% of 
the patients developed a neutropenia grade IV and there were 14 secondary malignancies. 
 
1.1.4 Immunotherapy using an anti-CD20-Antibody (MabThera / Rituximab) 
In early and advanced stage CD20 positive follicular lymphoma, the use of the anti-CD20 antibody 
Rituximab has been evaluated as monotherapy or in combination with chemotherapy in several trials. 
The effectiveness of Rituximab without chemotherapy was tested in the SAKK 35/09 trial using two 
different dose schedules (4x vs. 8x) [41]. Most of the 202 included patients had an advanced disease, 
only 15% had a clinical stage I or II according to the Ann Arbor classification. Thirty-eight percent of 
the patients of the 8x arm showed a CR during follow-up. The highest CR rate was achieved in 
patients without previous chemotherapy in their medical history and 8 cycles of MabThera (52%) [41]. 
However, there was no plateau of the PFS curve in the long-term follow-up. The above-mentioned best 
subgroup had a PFS of 70% after 2 years and 45% after 5 years (median PFS 43 months) [42]. 

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1.1.5 Combination of anti-CD20-antibody and radiation therapy 
The MIR trial was a multi-center phase II trial investigating the combination of Rituximab with 
involved field radiotherapy in FL stage I/II patients [43]. The recruitment of 85 patients was finished in 
2010. The final clinical results were presented on the annual meeting of the European Society of 
Therapeutic Radiation Oncology (ESTRO) 2014 in Vienna [4]: The effectiveness was comparable 
with the superior arm of the ARO98-01 trial  (TLI) but with a lower morbidity profile. The PFS rate 
after 2 years was 86%. The CR rate after 4 cycles of MabThera (without radiation) was 29% in 
patients with macroscopic disease at inclusion. Best morphologic response was reached at month 6 
with a CR rate of 79%. The final results are going to be published after integration of the scientific 
MRD data.  
 
1.1.6 FDG-PET for staging and response evaluation 
The sensitivity and specificity of a FDG-PET examination for staging purposes is very high [44-46]. 
Tskamoto describes a sensitivity of 91% in 193 regions with involvement of follicular lymphoma [45]. 
Only the involvement of the duodenum in 3 patients was not detected. Elstrom et al. reported of 
similar results (sensitivity 98% in 42 patients) [46]. A sensitivity of 98% and a specificity of 94% were 
presented by Wöhrer et al. in 62 patients with different grades of follicular lymphoma. These were 
lower if conventional staging methods were used (sensitivity 95%, specificity 80%) [44]. Luminari et 
al. looked at the consequences of an FDG-PET in 142 patients of the FOLL05 trial who were primarily 
staged by CT: Based on the FDG-PET, 32% more involved lymph node regions were 
detected(46/146). Less involved regions were diagnosed in 11%. A stage shift into a more advanced 
stage was diagnosed in 11% due to the FDG-PET [47].  
The Cheson criteria of 2007 recommend FDG-PET for response evaluation in patients with Hodgkin`s 
lymphoma or aggressive lymphomas [48, 49]. In these days, there was no statement for the use of 
FDG-PET for staging and response evaluation in indolent lymphomas due to the lack of consequences. 
However, it was recommended for clinical trials if the primary endpoint would be CR [48]. The 
current update from 2014 [50] includes now the use of FDG-PET for staging also for follicular 
lymphomas to avoid an “under staging” (up staging in 8-41%). The 5-PS score is recommended for 
interpretation of the results. The inclusion of FDG PET for staging also for follicular lymphoma was 
also based on the results of the PRIMA trial: A positive FDG-PET in the response evaluation showed 
to be a highly negative predictive value [7, 51]. Patients, who were PET negative after induction 
chemotherapy had a significant higher PFS after 42 months than PET positive patients (71% vs. 33%; 
p<0.001). The PET signal was an independent prognostic marker. Similar observation were made in 
the Italian FOLL05 trial [52]: PET negative patients had a significant superior PFS after 3 years 
compared to PET positive patients (66% vs. 35%, p<0.001). Looking only at the morphologic changes 
via CT, the prognostic difference between CR and non-CR was much weaker (3-years PFS 63% vs. 
51%; p=0.04). The prognostic value was highest in case of a negative FDG-PET and a morphological 
PR in the CT scan [52]. 
 
1.2 Rational for the Current Trial Concept 
The MIR trial has shown that the radiation volumes could be significantly reduced without 
compromising the effectiveness of the historical large field irradiation. The toxicity of the combined 
approach of an anti-CD20 antibody and an involved field radiotherapy was much lower than the 
historical data of large field irradiation. Therefore, the combination of an anti-CD20 antibody with 
small field irradiation of the involved sites will probably become the new standard in the treatment of 
early stage nodal follicular lymphoma grade 1 and grade 2. 
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After the reduction of the radiation field, a marked reduction of the radiation dose should be tested 
prospectively: the combination of an anti-CD20 antibody and low dose radiation therapy (LDRT). 
Although the FORT trial resulted in an inferiority of LDRT compared to higher dose irradiation, it also 
showed effectiveness in part of the patients with follicular lymphoma (CR rate 48%). 
In the GAZAI trial, the concept of LDRT with 2x2 Gy will for the first time be evaluated prospectively 
in a homogenous cohort of newly diagnosed, non-pretreated, and strictly examined FL grade 1 / 2 
stage I/II patients. All diagnoses will be confirmed by central histological review. Involved-site 
irradiation will be combined with immunotherapy with an improved anti-CD20 antibody (Gazyvaro) 
with the aim to control occult systemic disease and prevent distant relapse. Additionally, there will be 
a precisely defined salvage option for those patients who do not achieve CR after the combined LDRT 
and antibody treatment. These patients will receive additional radiation therapy with 36 Gy (5x2 
Gy/week) adding up to a total of 40 Gy which was the established dose of the MIR trial. This salvage 
dose is, therefore, response adapted for those patients who do not sufficiently respond to LDRT. 
Role of FDG-PET 
The routine staging diagnostic procedures using CT/MRI will be augmented by a FDG-PET/CT 
examination in the GAZAI trial. The total radiation dose will then be defined response adapted by a 
second FDG-PET. 
Since the sensitivity and specificity of FDG-PET is higher compared to sole morphological imaging, 
all patients will get an initial FDG-PET/CT. This has to be performed at least 5 weeks after a surgical 
procedure (e.g. lymph node sampling) for minimizing the risk of false positive results. 
LDRT alone of the involved lymph nodes regions results in responses shown in Table 2. However, 
LDRT alone leads less often to a CR than a full dose radiation therapy in these patients (see Table 1 
and 2 and the FORT trial).  
Since a negative FDG-PET is an independent predictive factor regarding PFS [7, 51], the decision for 
or against salvage radiation will be done based on a restaging FDG-PET/CT (FDG-PET positive: 
salvage RT of additional 18 x 2 Gy; FDG-PET negative: no salvage RT). 
Since only patients with initially PET positive lymph nodes are valuable for the evaluation of the 
primary endpoint (metabolic CR rate after LDRT and anti-CD20 antibody), the FDG-PET in week 18 
can be omitted in case of FDG-PET negativity at the initial staging (e.g. all macroscopic pathological 
lymph nodes were surgically removed). 
 
Obitunuzumab (Gazyvaro) 
The additional use of Rituximab in the radiation treatment of the early stages of nodular follicular 
lymphomas has been successfully proven in the MIR trial. However, Rituximab is a chimeric antibody 
and known to induce allergic reactions. One patient in the MIR trial could not complete the treatment 
due to an allergic reaction to Rituximab. It will, therefore, be useful to use a third generation 
humanized antibody instead. 
Obinutuzumab is a humanized anti-CD20 antibody, which has already been approved for the treatment 
of CLL: Obinutuzumab showed superior results compared to Rituximab in an interim analysis of a 
prospective randomized trial [53, 54]. 
In follicular lymphoma, Obinutuzumab showed improved response rates in phase II trials if compared 
to Rituximab [55, 56]. A prospective randomized trial comparing Rituximab and Obinutuzumab in 
combination with a chemotherapy has completed recruitment. Just recently, primary results of the 
GADOLIN trial for Rituximab in refractory or fast recurrent follicular lymphoma resulted in the EMA 
registration of Gazyvaro in combination with Bendamustin chemotherapy. The combination of 
Bendamustin with Gazyvaro resulted in a 52% risk reduction for recurrence or death compared to 
Bendamustin alone [8, 57]. 

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Based on these results, it can be assumed that the use of Obinutuzumab may induce a higher CR rate 
compared to the Rituximab data of the MIR trial. It might be, therefore, an ideal partner for LDRT and 
should reduce the portion of patients who need salvage RT. Additionally, QLQ data and MRD data 
can be used for historical comparison with the use of Rituximab in the MIR trial. 
 
1.3 Benefit-/ Risk-Assessment 
The standard treatment for the early stages of follicular lymphoma is under permanent discussion. 
Treatment recommendations range from watch & wait (with deferement of treatment until 
progression) to large field irradiations. The combination of involved-field irradiation and use of 
MabThera becomes more and more popular after the successful completion of the MIR trial. This 
includes an off-label use of MabThera, which is only accredited in the combination with chemotherapy 
for the treatment of follicular lymphoma. 
The actual trial offers the chance of a substantial reduction of the radiation time (2 instead of 20 
fractions in the best case) and the radiation dose (10% of the radiation dose in the best case). In any 
case, no patient will receive a higher radiation treatment dose compared to the dose of the MIR trial. 
In addition to and in comparison with the MIR trial, the patients are treated with a humanized CD20 
antibody with less allergic potential, receive only 7 instead of 8 administrations, and a potentially more 
efficent antibody as shown in CLL. 
The use of LDRT has a higher risk of recurrence compared to a higher radiation dose according to the 
FORT trial. This risk will be minimized by additional salvage radiation up to the ”full dose” in case of 
a failure to reach a complete remission. The use of FDG-PET/CT strengthens the initial staging and the 
evaluation of the response. The remaining risk of a late in-field recurrence after Obinutuzumab and 
LDRT has to be balanced against the substantially reduced radiation dose to the patent. In addition, 
“full dose” radiation therapy is still possible in case of a late recurrence.  
 
1.4 Additional Scientific Project 
The members of the pathology panel of the GLSG will conduct the pathological scientific add-on 
project. Genetic and molecular examinations of the already excised lymphoma specimen will be tested 
for different subgroups, which might result in the generation of new hypothesis [58, 59]. The genetic 
and molecular research strictly limited to all aspects of the lymphoma disease. The detection of certain 
genetic profiles, which might predict the response to LDRT is one of the goals of these studies. 
 
1.5 Committees 
The following committees were initiated to control certain aspects during the course of the trial: 
 
1.5.1 Data Monitoring Committee (DMC) 
The DMC consists of independent experts in the treatment of malignant lymphomas. The DMC should 
evaluate the conduct of the trial, the safety, and the achievements of the major endpoints. The duty of 
the DMC is to secure the ethically correct conduct of the trial and to protect the interests of safety for 
the patients. 
The DMC will meet on a regular basis (GLSG annual meetings). The DMC will give 
recommendations to the LKP regarding modifications, stopping or continuation of the clinical trial. 
Those recommendations should be send to the LKP in written form within 2 months after the meeting. 
The DMC will get the annual DSURs. 
The members of the DMC are listed in the protocol. 
 

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1.5.2 Steering Committee (SC) 
The steering committee is comprised of the coordinating investigator and his supporting co-
investigators, clinical experts not directly involved in the clinical trial, and the responsible 
biometrician. The steering committee is responsible for the scientific integrity of the study protocol, 
the quality of the study conduct as well as for the quality of the final study report. The Steering 
committee will decide on the recommendations made by the DMC. Members of the steering 
committee are listed in the protocol. 
 
 
2. OBJECTIVES AND ENDPOINTS 
2.1 Study Objectives 
The rate of metabolic CR after low-dose radiotherapy in combination with Gazyvaro (Obinutuzumab) 
for early stage nodal follicular lymphoma will be assessed. In addition, the feasibility of a response 
adapted approach using FDG-PET/CT regarding success (PFS, rates of remission, analysis of 
recurrences) and safety in combination with Gazyvaro will be assessed. 
The results will be historically compared to the results of the MIR trial regarding morphologic 
response in week 7 and the quality of life (secondary endpoints). Additional secondary endpoints are 
PFS, the site of recurrences in the three subgroups (1. PET negative after initial staging; 2. PET 
negative in week 18; 3. PET positive in week 18). 
 
2.2 Primary Endpoint 
 Metabolic complete response (CR) in week 18 in patients with initially remaining lymphoma 
judged by FDG-PET/CT 
 
2.3 Secondary Endpoints 
 Morphologic CR, PR, SD, PD in week 7, week 18 and month 6 in patients with initially 
remaining lymphoma judged by CT/MRI  
 Historical comparison of the morphologic response with MIR data (using MabThera); The 
comparison of the CR rate in week 7 will allow for a comparison of the two different CD20 
antibodies. Due to the restricted patient numbers no matched pair analysis will be possible 
 Progression free survival (PFS) of all treated patients (2 years after individual treatment start) 
 Toxicity (NCI-CTC criteria, version 4.03) of all patients 
 Relapse rate and pattern of recurrence of all treated patients at all follow-up visits. 
 Overall survival (OS) of all treated patients (2 years) 
 Quality of life according EORTC QLQ C30 and FACT-Lym questionnaires at inclusion and in 
week 18, month 12, and 24 (all treated patients) 
 MRD response in peripheral blood: initially, week 18, months 6, 12, 18 and 24 (all treated 
patients). MRD is evaluated by the laboratory of C. Pott (Kiel) using at least the markers: 
t(14:18) PCR for MBR, 3’mbr, 5’mcr and MCR; clonal IGH rearrangements (FR1-3); clonal 
IGL rearrangements (IGK and Kappa-KDE) 
 
2.4 Additional Scientific Program 
 Genetic and molecular profiling of responders and non-responders (coordinated by W. Klapper, 
Kiel) 
 
2.5 Extended Follow-up Phase (Register Phase) 
The GAZAI trial ends 30 months after the first Gazyvaro infusion for each individual patient. Further 
follow-up will be performed according to the standards of each participating center. The patients will 

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be asked to allow the transfer of this follow-up data to the trial center in Heidelberg to enable the 
collection and evaluation of long-time follow-up (PFS, OS, etc.) of this patient group. 
 
 
3. TRIAL CONCEPT/ DESIGN 
GAZAI is a prospective, open, nationally multi-center phase II trial for evaluation of LDRT in 
combination with Gazyvaro (Obinutuzumab) in patients with early stage nodal follicular lymphoma 
grade 1/2. Patients will get a completion of the “full” radiation dose in case of not reaching a sufficient 
response (metabolic CR AND morphologic PR/CR) after LDRT. 
 
4. DURATION OF THE TRIAL AND EARLY STOPPING  
 
4.1 Duration and Time Line  
The individual duration for each participant is 30 months. Patients may enter in a succeeding register 
phase without trial specific appointments or examinations. 
 
Initial therapy phase: 3 months 
Week 1-4 and week 8: 1 x weekly Gazyvaro (1000mg flat dose) 
Week 9: Radiation therapy: 2x2 Gy involved-site 
Week 12, 16: 1x weekly Gazyvaro (1000mg flat dose) 
Week 18: Re-Staging (if applicable) 
Week 20-23: Radiation therapy 18 x 2 Gy involved-site (if applicable) 
Follow-up Phase: Month 6 – month 30 months (every 6 months) 
 
The trial (FPI – LPO) will last approximately 5.5 years. The duration of patient recruitment is 
estimated with 3.5 years and starts in Q4 2017. 
Length of the clinical phase: 
5.5 years (66 months) 
Start of trial preparation: 
Q1 2015 
 
FPI (First Patient In): 
Q4 2017 
 
LPI (Last Patient In): 
Q1 2021 
 
LPO (Last Patient Out): 
Q3 2023 
 
DBL (Data Base Lock): 
Q1 2024 
 
Completion of the statistical analysis: 
Q2 2024 
 
Completion of the trial report: 
Q3 2024 
 
4.2 Early Stopping of the Trial or Early Stopping of a Trial Site 
The trial can be stopped by the LKP if the DMC detects an unexpected accumulation of side effects 
(each grade 5, 2 succeeding grade 4 or 3 succeeding grade 3 CTC side effects), has new information 
about the effect-risk ratio of the investigated therapy or the used methods of examination. The trial can 
also be stopped by the LKP if recruitment is below the expectations and cannot be improved. 
All investigators have to be informed immediately about a stopping or a permanent ending of the trial. 
The participating sites must accept the decision. 

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All study material has to be returned to the LKP in case of early stopping of the trial. 
A participating site can also be closed early by the LKP if the site does not act according to ICH-GCP 
or according to the trial protocol or the recruitment or the quality of the data is below the expectations. 
If the DMC suggests an interruption or an ending of the trial due to SAE evaluations or other reasons, 
the ethical board and the authorities (BOB and sate authority) have to be informed. The Ethical Board 
and the authorities can also decide about an interruption or an ending of the trial. 
 
5. PARTICIPANTS 
5.1 Number of Participants 
As described in the chapter Sample Size Calculation, a maximum of 93 patients will be included in the 
trial. 
The recruitment will be stopped, if (whatever occurs first) 
 79 patients will have a FDG-PET/CT confirmed stage I/II follicular lymphoma and a trial 
specific therapy has been initiated or 
 55 patients had a second restaging FDG-PET/CT in week 18 or 
 93 patients were included 
Recruitment and treatment of the participating patients will be performed in 15 locations/30 sites (each 
location consists of a radiation oncology site and a hemato-oncology site). 
The sites should have experience in the treatment of early stage follicular lymphoma (min. 5 patients / 
year). The sites should have the infrastructure for execution and documentation of a clinical trial 
according the AMG, Röntgenverordnung and Strahlenschutzverordnung. There must be the possibility 
to conduct a FDG-PET/CT. 
 
Each location should include 6-7 patients. All sites, which successfully recruited and completely 
documented the therapy and follow-up of at least 4 patients will be considered for authorship in the 
final publication. 
 
5.2 Common Criteria for Patient Selection 
Patients (≥18 yrs) with histologically proven and centrally histologically reviewed nodal follicular 
lymphoma grade 1 or grade 2 in the clinical stage I or II (Ann Arbor classification) should be included. 
The biopsy must be performed within the last 6 months and the complete staging must be within the 
last 4 months. A fine needle biopsy is not sufficient for a qualified diagnosis. The diagnosis must be 
centrally verified by one of the reference pathologists of the GLSG. 
 
Gender 
According to the MIR data, no gender specific effects regarding the efficacy or the safety are 
anticipated. It is expected that the distribution of gender in the trial mirrors the natural distribution of 
the disease. 
 
5.3 Inclusion Criteria 
 Centrally reviewed CD20-positive follicular lymphoma grade 1/2 based on WHO classification 
(2008) 
 Untreated (radiation-, chemo- or immunotherapy) nodal lymphoma (including involvement of  
Waldeyer´s ring) 
 Age: ≥18 years 
 ECOG: 0-2 

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 Stage: clinical stage I or II (Ann Arbor classification) 
 Risk profile: Largest diameter of the lymphoma  7 cm (sectional images) 
 Written informed consent and willingness to cooperate during the course of the trial 
 Adequate hematologic function (unless abnormalities are related to NHL), defined as follows: 
Hemoglobin ≥ 9.0 g/dL;  absolute neutrophil count ≥ 1.5 × 109/L, Platelet count ≥ 75 × 109/L 
 Adequate bone marrow capacity: ANC ≥ 1.5 x 103/ml, thrombocytes ≥ 100000 x 10 3/ml, 
hemoglobin ≥ 10 g/dL 
 Capability to understand the intention and the consequences of the clinical trial 
 Adequate contraception for men and women of child-bearing age during therapy and 18 months 
thereafter 
 Patients with non-active hepatitis B infection (HBsAg neg/HBcAB pos/HBV DNA neg) under 1-
year prophylactic anti-viral therapy (e.g. Entecavir®) possible (see also 5.6. Prior and Concomitant 
Disease) 
 
5.4 Exclusion Criteria 
 
Extra nodal manifestation 
 
Secondary cancer in the patient’s medical history (exclusion: basalioma, spinalioma, melanoma 
in situ, bladder cancer T1a, non-metastasized solid tumor in constant remission, which was 
diagnosed >3 years ago  
 
Concomitant diseases: congenital or acquired immune-deficiency syndromes, active infections 
including viral hepatitis (serology positive for HBsAg or HBcAb in combination positive HBV 
DNA), uncontrolled concomitant diseases including significant cardiovascular or pulmonary 
disease (see also 5.6. Prior and Concomitant Disease) 
 
Severe psychiatric disease 
 
Pregnancy / lactation 
 
Known hypersensitivity against Gazyvaro (Obinutuzumab) or drugs with similar chemical 
structure or any other additive of the pharmaceutical formula of the study drug 
 
Participation in another interventional trial or follow-up period of a competing trial which can 
influence the results of this current trial 
 
Creatinine > 1.5 times the upper limit of normal (ULN) (unless creatinine clearance normal), or 
calculated creatinine clearance < 40 mL/min 
 
AST or ALT > 2.5 × ULN 
 
Total bilirubin ≥ 1.5 × ULN 
 
INR > 1.5 × ULN 
 
PTT or aPTT > 1.5 × the ULN 
 
No patient must be included more than once. 
 
5.5 Criteria of Withdrawal 
5.5.1 Withdrawal of patients from treatment 
Any patient can withdraw from the treatment at any time without personal disadvantages and without 
having to give a reason. Patients who discontinue participation in the clinical study on their own or 
patients who are withdrawn by the investigator, for reasons other than disease progression (i.e. in case 
of AEs, protocol violations, …), will be defined as premature withdrawals. Premature withdrawals will 
not be replaced. 
The investigator can also discontinue the study after considering the risk-to-benefit ratio, if he/she no 
longer considers the further treatment of the patient according to study protocol justifiable. The date of 
and the primary reason for the withdrawal, as well as the observations available at the time of 
withdrawal are to be documented on the CRF. Reasons leading to the withdrawal of a patient can 
include the following (one primary reason must be determined): 

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 Lack of efficacy of the study medication, e.g. 
– 
Progress of study disease compared to baseline  
– 
Need for a prohibited concomitant medication for the treatment of study disease 
 Intolerable adverse events 
 Lack of patient’s cooperation, e.g. 
– 
Patient’s request to withdraw 
– 
Lack of compliance, patient fails to attend the interim visits as agreed  
– 
Existing or intended pregnancy, lactation 
 Other reasons (noting reason), e.g. 
– 
Other diagnosis than study disease 
– 
Did not meet major in-/exclusion criteria (coming to light after inclusion) 
In all patients who finish the study prematurely, a withdrawal examination at least with respect to the 
primary endpoint should be carried out. The patient must be asked to consent to this last examination. 
The withdrawal examination must be documented in the CRF. 
In case of a drop-out, all ongoing AEs or SAEs should be monitored until there are no more signs or 
symptoms or until the participant shows a stable condition.  
 
5.5.2 Definition of drop-outs 
 
Term 
Definition 
Drop-out, study  
Participation terminated completely, including follow-up 
Possible reasons: 
 Patient withdraws consent: Withdrawal 
 Patient moved/cannot be contacted 
 Follow-up-interventions cannot be performed due to medical 
reasons 
 Non-compliance of patient 
Drop-out after completion of study intervention: Lost to follow-up 
FU-CRF-forms need to be marked as invalid.  
Final examination will be performed, if patient agrees. Study-
Completion/ Withdrawal-form will be completed. 
Drop-out, study 
intervention 
Termination of study intervention, follow-up as per protocol. 
Screening-failure 
Exclusion criteria given prior to screening / enrolment: 
Patient will be recorded at screening list, but will not be provided with 
a patient number. 
(Depending on sponsor a screening CRF may have to be completed) 
Protocol deviation 
Drop-out to study and drop-out to study intervention are both protocol 
deviations.  
It needs to be predefined, how to manage each type of protocol 
deviation. 
 
Major deviations: 

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If exclusion criteria become evident after enrolment, and safety of the 
participant is affected, or if the diagnosis does not any more relate to 
the indication listed in the protocol affecting the benefit/risk 
negatively, the participant has to be excluded from study intervention. 
FU-examinations may still be performed. 
 
Minor deviations: 
Other protocol deviations (errors in timing of visits/ missing samples/ 
missing examinations) do not result in exclusion 
 
 
5.5.3 Replacement of participants 
Drop-outs will not be replaced.  
 
5.6 Prior and Concomitant Diseases 
Relevant additional diseases present at the time of informed consent are regarded as concomitant 
diseases and will be documented on the appropriate pages of the case report form (CRF). Included are 
conditions that are seasonal, cyclic, or intermittent (e.g. seasonal allergies; intermittent headache). 
Abnormalities, which appear for the first time or worsen (intensity, frequency) during the trial are 
adverse events (AEs) and must be documented on the appropriate pages of the CRF. 
 
5.7 Prior and Concomitant Medication 
The treatment of accompanying illnesses not subject to the exclusion criteria is permissible if this is 
not expected to have any effect on the outcome measures used in this study and to interfere with the 
trial medication. 
If concomitant drugs are administered, these must be recorded in the patient file and in the CRF. 
All patients must get a Hepatitis B testing before treatment with Gazyvaro. At least the HBsAg status 
and the HBcAb status should be assessed and can be added by other markers according to the local 
recommendations. In case of HBsAg negative/HBcAb positive status, also serology for HBV DNA has 
to be done. Patients suffering from an active Hepatitis B infection (all HBsAg positive and all HBcAb 
positive/HBV-DNA positive) must not be treated with Gazyvaro and have to be excluded. 
Patients with HBcAb positive / HBV DNA negative status should be referred to a hepatologist or 
gastroenterologist before start of treatment and should be monitored and managed following local 
standards to prevent hepatitis reactivation. It is recommended to do a 1-year prophylaxis with 
antiretroviral medication (e.g. Entecavir®). If there is no chance of prophylaxis, the patient must be 
excluded. 
 
 
6. STUDY MEDICATION 
6.1 General Information 
Roche Pharma AG will provide the quantity of trial medication required for the clinical trial. The 
medication provided must be used only in the context of this clinical trial. Careful records will be kept 
of the trial medication supplied to the centers and distributed to the patients. At the end of the study, all 
unused medication will be returned to manufacturer. If deficiencies of the trial medication are noticed, 
the monitor, the project manager and the LKP must be informed immediately. 

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The order and delivery of the mediation includes the local pharmacy of each site. The order fax for 
each patient will be faxed by the site to the study trial center.  
 
6.2 Characteristics of the Trial Medication 
Obinutuzumab (also known as RO5072759, GA101, GAZYVA®, GAZYVAROTM) is a humanized 
glycoengineered type II anti-CD20 monoclonal antibody (mAb). Obinutuzumab was derived by 
humanization of the parental B-Ly1 mouse antibody and subsequent glycoengineering leading to the 
following characteristics: high-affinity binding to the CD20 antigen, high antibody-dependent cellular 
cytotoxicity (ADCC), and antibody-dependent cellular phagocytosis (ADCP); low complement-
dependent cytotoxicity (CDC) activity; and high direct cell death induction.  
 
Proprietary name: 
GAZYVARO® 
International 
Nonproprietary Name 
(INN):  
Obinutuzumab 
ATC code, if officially 
registered: 
L01XC15  
Manufacturer: 
Roche Pharma AG 
Pharmaceutical 
formulation: 
Obinutuzumab is provided as a single 1000 mg dose liquid 
concentrate with a strength of 25 mg/mL. It is supplied in 50 
mL glass vials containing 40 mL of the 25 mg/mL liquid 
concentrate. In addition to the antibody, the liquid also contains 
histidine/histidine-HCl, trehalose, poloxamer 188 and HPW.  
Mode of administration: iv infusion 
Batch no.: 
 
Storage instructions: 
Store in a refrigerator (2 °C-8 °C). Do not freeze. Keep the vial 
in the outer carton in order to protect from light. 
From a microbiological point of view, the prepared infusion 
solution should be used immediately. If not used immediately, 
in-use storage times and conditions prior to use are the 
responsibility of the user and would normally not be longer 
than 24 hours at 2°C-8°C, unless dilution has taken place in 
controlled and validated aseptic conditions.  
 
 
6.3 Therapeutic Effects of Gazyvaro 
(Cited from IB, September 2014) 
Non-clinical in vitro studies show that Obinutuzumab mediates superior induction of direct cell death 
and effector cell-mediated ADCC and ADCP on a panel of NHL cell lines as compared to the type I 
CD20 antibodies rituximab and Ofatumumab. Its potency to mediate CDC is significantly reduced as 
compared to these two antibodies. In ex vivo autologous whole blood B-cell depletion studies with 
blood from healthy volunteers as well as CLL patients, Obinutuzumab mediated superior B-cell 

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depletion when compared with rituximab.  
These properties of Obinutuzumab translated into superior anti-tumor efficacy in direct comparison to 
Rituximab against a number of aggressive subcutaneous (SC) and disseminated NHL xenograft 
models. The efficacious and optimal dose range of Obinutuzumab in xenograft models was in the 
range of 10-30 mg/kg, corresponding to trough levels of 300-600 μg/mL. Treatment with 
Obinutuzumab resulted in potent and superior depletion of B-cells in the peripheral blood and in 
lymphoid tissues of hCD20 transgenic mice and cynomolgus monkeys. Vaccination studies in 
cynomolgus monkeys and human CD20 transgenic mice showed that the enhanced efficacy in terms of 
B-cell depletion of Obinutuzumab translated into suppression of de novo antibody responses, but left 
the protective humoral memory responses intact.  
The data generated to date imply that Obinutuzumab represents a novel therapeutic CD20 antibody 
with outstanding efficacy compared to classical Type I and non-ADCC enhanced CD20 antibodies, 
such as Rituximab and Ofatumumab. 
 
6.4 Known Side Effects 
(Cited from ANEX I. package leaflet amended by the GADOLIN data [8]) 
Important risks identified in clinical investigations with Obinutuzumab were: IRRs (infusion related 
reactions, TLS (tumor lysis syndrome), thrombocytopenia (including acute thrombocytopenia), 
neutropenia (including prolonged and late onset neutropenia), prolonged B-cell depletion, infections 
(including hepatitis B reactivation and PML), worsening of pre-existing cardiac conditions and GI 
perforation.  
6.4.1 Infusion-related reactions (IRRs)  
The incidence of IRRs was higher in the Gazyvaro plus chlorambucil arm compared to the Rituximab 
plus chlorambucil arm. The incidence of IRRs was 65% with the infusion of the first 1,000 mg of 
Gazyvaro (20% of patients experiencing a Grade 3-4 IRR, with no fatal events reported). Overall, 7% 
of patients experienced an IRR leading to discontinuation of Gazyvaro. The incidence of IRRs with 
subsequent infusions was 3% with the second 1,000 mg dose and 1% thereafter. No Grade 3-5 IRRs 
were reported beyond the first 1,000 mg infusions of Cycle 1.  
IRRs grade 3-5 occurred in 11% of the patients in the Bendamustin/Obinutuzumab arm compared to 
6% in the Bendamustin only arm in the GADOLIN trial [8]. 
Most frequently reported symptoms associated with an IRR were nausea, chills, hypotension, pyrexia, 
vomiting, dyspnea, flushing, hypertension, headache, tachycardia, and diarrhea. Respiratory and 
cardiac symptoms such as bronchospasm, larynx and throat irritation, wheezing, laryngeal edema and 
atrial fibrillation have also been reported.  
6.4.2 Hypersensitivity reactions including anaphylaxis  
Anaphylaxis has been reported in patients treated with Gazyvaro. Hypersensitivity may be difficult to 
distinguish from IRRs. If a hypersensitivity reaction is suspected during infusion (e.g. symptoms 
typically occurring after previous exposure and very rarely with the first infusion), the infusion must 
be stopped and treatment permanently discontinued. Patients with known IgE mediated 
hypersensitivity to obinutuzumab must not be treated. 
6.4.3 Tumour lysis syndrome (TLS)  
Tumour lysis syndrome (TLS) has been reported with Gazyvaro. Patients who are considered to be at 
risk of TLS (e.g. patients with a high tumour burden and/or a high circulating lymphocyte count [> 25 
x 109/L] and/or renal impairment [CrCl <70 mL/min]) should receive prophylaxis. Prophylaxis should 

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consist of adequate hydration and administration of uricostatics (e.g. allopurinol), or a suitable 
alternative such as a urate oxidate (e.g. rasburicase) starting 12-24 hours prior to the infusion of 
Gazyvaro as per standard practice (see section 4.2). All patients considered at risk should be carefully 
monitored during the initial days of treatment with a special focus on renal function, potassium, and 
uric acid values. Any additional guidelines according to standard practice should be followed. For 
treatment of TLS, correct electrolyte abnormalities, monitor renal function and fluid balance, and 
administer supportive care, including dialysis as indicated. 
6.4.4 Neutropenia and infections  
The incidence of neutropenia was higher in the Gazyvaro plus chlorambucil arm compared to the 
rituximab plus chlorambucil arm with the neutropenia resolving spontaneously or with use of 
granulocyte-colony stimulating factors. The incidence of infection was 38% in the Gazyvaro plus 
chlorambucil arm and 37% in the rituximab plus chlorambucil arm (with Grade 3-5 events reported in 
12% and 14%, respectively and fatal events reported in < 1% in both treatment arms). Cases of 
prolonged neutropenia (2% in the Gazyvaro plus chlorambucil arm and 4% in the rituximab plus 
chlorambucil arm) and late onset neutropenia (16% in the Gazyvaro plus chlorambucil arm and 12% in 
the rituximab plus chlorambucil arm) were also reported. 
Concerning treatment of follicular lymphoma in the GADOLIN trial, the grade 3-5 neutropenia 
reached 33% in the Bendamustin/Obinutuzumab arm compared to 26% in the Bendamustin only arm. 
Serious (grade 3-5) infections were reported in 18% or 17%, respectively [8] 
6.4.5 Thrombocytopenia  
The incidence of thrombocytopenia was higher in the Gazyvaro plus chlorambucil arm compared to 
the rituximab plus chlorambucil arm especially during the first cycle. Four percent of patients treated 
with Gazyvaro plus chlorambucil experienced acute thrombocytopenia (occurring within 24 hours 
after the Gazyvaro infusion). The overall incidence of hemorrhagic events was similar in the Gazyvaro 
treated arm and in the rituximab treated arm. The number of fatal hemorrhagic events was balanced 
between the treatment arms; however, all of the events in patients treated with Gazyvaro were reported 
in Cycle 1. A clear relationship between thrombocytopenia and hemorrhagic events has not been 
established.  
The reported thrombocytopenia (grade 3-5) in the GADOLIN trial was 11% in the arm with 
Obinutuzumab and 16% in the Bendamustin only arm [8] 
6.4.6 Special populations  
Elderly  
In the pivotal study, 46% (156 out of 336) of patients with CLL treated with Gazyvaro plus 
chlorambucil were 75 years old or older (median age was 74 years). These patients experienced more 
serious adverse events and adverse events leading to death than those patients < 75 years of age.  
Renal impairment  
In the pivotal study, 27% (90 out of 336) of patients with CLL treated with Gazyvaro plus 
chlorambucil had moderate renal impairment (CrCl < 50 mL/min). These patients experienced more 
serious adverse events and adverse events leading to death than those with CrCl ≥50 mL/min.  
Additional safety information from clinical studies experience  
Progressive multifocal leukoencephalopathy (PML)  
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Gazyvaro. The diagnosis of PML should be considered in any patient presenting with new-onset or 
changes to pre-existing neurologic manifestations. The symptoms of PML are unspecific and can vary 
depending on the affected region of the brain. Motor symptoms with corticospinal tract findings (e.g. 
muscular weakness, paralysis and sensory disturbances), sensory abnormalities, cerebellar symptoms, 
and visual field defects are common. Some signs/symptoms regarded as “cortical” (e.g. aphasia or 
visual-spatial disorientation) may occur. Evaluation of PML includes, but is not limited to, 
consultation with a neurologist, brain magnetic resonance imaging (MRI), and lumbar puncture 
(cerebrospinal fluid testing for John Cunningham viral DNA). Therapy with Gazyvaro should be 
withheld during the investigation of potential PML and permanently discontinued in case of confirmed 
PML. Discontinuation or reduction of any concomitant chemotherapy or immunosuppressive therapy 
should also be considered. The patient should be referred to a neurologist for the evaluation and 
treatment of PML.  
Hepatitis B reactivation  
Hepatitis B virus (HBV) reactivation, in some cases resulting in fulminant hepatitis, hepatic failure and 
death, can occur in patients treated with anti-CD20 antibodies including Gazyvaro. Hepatitis B virus 
screening should be performed in all patients before initiation of treatment with Gazyvaro. At a 
minimum this should include hepatitis B surface antigen (HBsAg) status and hepatitis B core antibody 
(HBcAb) status. These can be complemented with other appropriate markers as per local guidelines. 
Patients with active hepatitis B disease (all HBsAg positive and all HBcAb positive/HBV DNA 
positive) must not be treated with Gazyvaro. Patients with HBcAb positive/HBV-DNA negative status 
should consult liver disease experts before start of treatment and should be monitored and managed 
following local medical standards to prevent hepatitis reactivation (e.g. Entecavir®).  
Worsening of pre-existing cardiac conditions  
Cases of arrhythmias (such as atrial fibrillation and tachyarrhythmia), angina pectoris, acute coronary 
syndrome, myocardial infarction and heart failure have occurred when treated with Gazyvaro. These 
events may occur as part of an IRR and can be fatal.  
Laboratory abnormalities  
Transient elevation in liver enzymes (aspartate aminotransferase [AST], alanine aminotransferase 
[ALT], alkaline phosphatase) has been observed shortly after the first infusion of Gazyvaro.  
The most frequently observed identified risk in patients receiving Obinutuzumab was IRRs; these 
occurred predominantly during the first infusion/first cycle. In patients with CLL as observed in study 
BO21004, the incidence and severity of infusion related symptoms decreased substantially with 
subsequent infusions, with most patients having no IRRs during the second and subsequent 
administrations of Obinutuzumab. In patients with NHL as observed in study GAO4753g, the 
incidence of IRRs was highest during the first cycle (55.2%), and gradually decreased during 
subsequent cycles (24.3%, 21.8%, 13.7%, 14.8%, 10.3% during Cycles 2, 3, 4, 5, and 6, respectively). 
The commonly experienced IRRs are characterized by nausea, fatigue, chills, hypotension, fever, 
vomiting, dyspnea, flushing, hypertension, headache, tachycardia, dizziness, diarrhea amongst other 
symptoms. Respiratory and cardiac symptoms, such as bronchospasm, larynx and throat irritation, 
wheezing, laryngeal edema and atrial fibrillation have also been reported. In the majority of patients, 
IRRs were mild or moderate and could be managed by the slowing or temporary halting the first 
infusion but severe IRRs requiring symptomatic treatment have also been reported. IRRs may be 
clinically indistinguishable from IgE-mediated allergic reactions (e.g. anaphylaxis). Patients with a 
high tumor burden (e.g. high peripheral lymphocyte count in CLL [> 25 × 10
9/L]) may be at increased 
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Risks associated with prolonged B-cell depletion 
B-cell depletion by itself is not an adverse outcome in patients with B-cell malignancies. It reflects 
drug efficacy. However, B-cell depletion could increase the risk of infection, including serious 
infections, and/or reactivation of latent viral infections. Overall, although Obinutuzumab has a potent 
and prolonged effect on B-cell depletion; the AEs observed in trials did not suggest any clinically 
relevant effect. Potentially B-cell depletion can be associated with the risk of PML and Hepatitis B 
reactivation (which are analyzed and described separately). In addition, immunization with live or 
attenuated viral vaccines, following Obinutuzumab treatment has not been studied, therefore the 
vaccination with live vaccines is not recommended during treatment and until B-cell recovery. 
Postponing vaccination with live vaccines should be considered for infants born to mothers who have 
been exposed to Obinutuzumab during pregnancy until the infants’ B-cell levels are within normal 
ranges. 
 
6.5 Dosage and Dosage Schedule 
 
6.5.1 Dosage 
The recommended dose of Gazyvaro is 1,000 mg.  
6.5.2 Instruction for dilution  
Gazyvaro should be prepared by a healthcare professional using aseptic technique. Do not shake the 
vial.  
Withdraw 40 mL of concentrate from the vial and dilute in polyvinyl chloride (PVC) or non-PVC 
polyolefin infusion bags containing 250 mL sodium chloride 9 mg/mL (0.9%) solution for injection.  
After dilution, chemical and physical stability have been demonstrated in sodium chloride 9 mg/mL 
(0.9%) solution for injection at concentrations of 0.4 mg/mL to 20 mg/mL for 24 hours at 2°C to 8°C 
followed by 48 hours (including infusion time) at ≤ 30°C.  
From a microbiological point of view, the prepared infusion solution should be used immediately. If 
not used immediately, in-use storage times and conditions prior to use are the responsibility of the user 
and would normally not be longer than 24 hours at 2°C-8°C, unless dilution has taken place in 
controlled and validated aseptic conditions. 
Do not use other diluents such as glucose (5%) solution.  
The bag should be gently inverted to mix the solution in order to avoid excessive foaming. The diluted 
solution should not be shaken or frozen.  
Parenteral medicinal products should be inspected visually for particulates and discoloration prior to 
administration. 
 
6.5.3 Administration of Gazyvaro 
Gazyvaro has to be administered as an intravenous infusion by experienced medical oncologists in a 
medical institution and with direct access to emergency facility, where emergency situations can be 
handled immediately. The administration can be done in an out-patient setting, if these preconditions 
are fulfilled. 
After the end of administration patients should be monitored around ≥ 1 hours with remaining catheter 
to give the possibility for administration of drugs if required. If no reactions occur during this period of 
observation, the patients may be discharged. Patients with pre-existing cardiac or pulmonary disease 

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should be carefully monitored during the infusion and afterwards (as described in the Investigator 
Brochure).  
 
6.5.4 Infusion rate 
Standard infusion rate in the absence of infusion reactions/hypersensitivity  
Cycle  
Day of treatment  
Rate of infusion  
Cycle 1  
Day 1 (1000 mg)  
Administer at 50 mg/hr. The rate of the infusion can be 
escalated in increments of 50 mg/hr every 30 minutes to a 
maximum rate of 400 mg/hr.  
Cycles 2-7 
Day 1 (1000 mg) 
If there were no infusion related side effects during 
previous administrations, infusions can be started at a rate 
of 100 mg/hr and increased by 100 mg/hr increments every 
30 minutes to a maximum of 400 mg/hr.  
 
Management of IRRs may require temporary interruption, reduction in the rate of infusion, or 
treatment discontinuations of Gazyvaro as outlined below.  
• Grade 4 (life threatening): Infusion must be stopped and therapy must be permanently discontinued.  
• Grade 3 (severe): Infusion must be temporarily stopped and symptoms treated. Upon resolution of 
symptoms, the infusion can be restarted at no more than half the previous rate (the rate being 
used at the time that the IRR occurred) and, if the patient does not experience any IRR 
symptoms, the infusion rate escalation can resume at the increments and intervals as 
appropriate for the treatment dose (see above). The infusion must be stopped and therapy 
permanently discontinued if the patient experiences a second occurrence of a Grade 3 IRR.  
• Grade 1-2 (mild to moderate): The infusion rate must be reduced and symptoms treated. Infusion 
can be continued upon resolution of symptoms and, if the patient does not experience any IRR 
symptoms, the infusion rate escalation can resume at the increments and intervals as 
appropriate for the treatment dose (see Table 3)..  
Patients must not receive further Gazyvaro infusions if they experience:  
• acute life-threatening respiratory symptoms,  
• a Grade 4 (i.e. life threatening) IRR or,  
• a second occurrence of a Grade 3 (prolonged/recurrent) IRR (after resuming the first infusion or 
during a subsequent infusion). Patients who have pre-existing cardiac or pulmonary conditions 
should be monitored carefully throughout the infusion and the post-infusion period. Hypotension 
may occur during Gazyvaro intravenous infusions. Therefore, withholding of antihypertensive 
treatments should be considered for 12 hours prior to and throughout each Gazyvaro infusion and 
for the first hour after administration. Patients at acute risk of hypertensive crisis should be 
evaluated for the benefits and risks of withholding their anti-hypertensive medicine. 
 
 

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6.5.5 Overdosage 
No experience with overdose is available from human clinical studies. In clinical studies with 
Gazyvaro, doses ranging from 50 mg up to and including 2,000 mg per infusion have been 
administered. The incidence and intensity of adverse reactions reported in these studies did not appear 
to be dose dependent.  
Patients who experience overdose should have immediate interruption or reduction of their infusion 
and be closely supervised. Consideration should be given to the need for regular monitoring of blood 
cell count and for increased risk of infections while patients are B cell depleted.  
 
6.5.6 Time Window for the Gazyvaro Administration 
Therapy starts after inclusion of the patient and reconfirmation of stage I/II disease by the initial FDG-
PET/CT. Gazyvaro should be administered weekly (every 7 days) for the first 4 weeks (week 1 – week 
4). A deviation of +/- 2 days is defined as conform to the protocol. Additional infusions are scheduled 
for week 8, 12 and 16 (every 28 days). A deviation of  +/- 4 days is defined as conform to the protocol. 
The LDRT (2x2 Gy) is scheduled for week 9 (after the 5. Gazyvaro infusion in week 8) 
 
6.6 Premedication before Gazyvaro infusion 
Day of 
treatment cycle  
Patients requiring 
premedication  
Premedication  
Administration  
Cycle 1   
All patients  
Intravenous corticosteroid 
(recommended) 1  
Completed at least 1 hour 
prior to Gazyvaro 
infusion  
Oral analgesic/anti-pyretic2  
At least 30 minutes 
before Gazyvaro infusion  
Anti-histaminic medicine3  
Cycle 2-7    
All patients without 
IRR during 
previous 
administrations 
Oral analgesic/anti-pyretic2 
At least 30 minutes 
before Gazyvaro infusion 
Patients with IRR 
grade 1 or 2 during 
previous 
administrations 
Oral analgesic/anti-pyretic2 
At least 30 minutes 
before Gazyvaro infusion 
Anti-histaminic medicine3 
Patients with IRR 3 
during previous 
administrations OR  
Patients with 
lymphocytes > 25 x 
109 before next 
administration 
Intravenous corticosteroid 1  
Completed at least 1 hour 
prior to Gazyvaro 
infusion 
Oral analgesic/anti-pyretic2  
At least 30 minutes 
before Gazyvaro infusion 
Anti-histaminic medicine3 
1100 mg prednisone/prednisolone or 20 mg dexamethasone or 80 mg methylprednisolone. Hydrocortisone should not be 

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used as it has not been effective in reducing rates of IRR. 
2 e.g. 1,000 mg acetaminophen/paracetamol 
3e.g. 50 mg diphenhydramine  
 
 
6.7 Subject Number 
Trial medication must only be used for participants of the clinical trial. 
All patients who might be suitable for inclusion and are under screening get a screening number. If the 
patient fits into the study in respect of the inclusion and exclusion criteria and if the patient agrees to 
participate in the trial (signed informed consent), the patient receives a running patient number. 
Patients who were excluded from the trial keep their screening and patient number. New participants 
always receive a new identification code (ID code). 
The ID code will be locally assigned (by the site, which includes the patients (hemato-oncology or 
radiation oncology) and is composed of the site number and the running patient number with the prefix 
GAZ (e.g. GAZ-01-03). Each recruiting site keeps their own identification list. The same ID will be 
used by the treating hemato-oncology site and radiation oncology site. 
 
6.8 Packing and Labeling 
The trial medication will be packed by Roche Pharma AG. 
One vial of 40 mL concentrate contains 1,000 mg obinutuzumab, corresponding to a concentration 
before dilution of 25 mg/mL.  
The trial medication will be provided free of charge by Roche Pharma AG (Roche Pharma AG, 
Postfach 1270, D-79630 Grenzach-Wyhlen) and will be delivered to the trial site or the pharmacy of 
the trial site. 
The trial medication will be labeled by Roche Pharma AG according to § 5 of GCP-V. 
 
 
6.9 Delivery and Drug Accountability 
The investigator will confirm correct receipt of the trial medication in writing and ensure that the 
medication is stored safely and correctly. The trial medication must be carefully stored in accordance 
with manufacturer’s instructions at 2-8 °C and dry at the study sites in a locked area with restricted 
access, separately from other drugs, and kept out of the reach and sight of children. The investigator 
will document the distribution and return of the trial medication to the patient with the date, recording 
the quantity distributed and used on the forms provided for this purpose. The site monitor will 
periodically check the supplies of trial medication held by the investigator to ensure the correct 
accountability of all trial medication used. At the end of the trial, all unused trial medication and all 
medication containers will be completely returned to Roche Pharma AG. It will be assured that a final 
report of the drug accountability is prepared and maintained by the investigator. 
The medication must not be used after the expiry date, which is stated on the carton after EXP. The 
expiry date refers to the last day of that month.  
 
6.10 Ordering of Gazyvaro 
Each new patient will be reported to the trial center in Heidelberg by using the inclusion fax form send 
together with the order form for study medication. The inclusion fax will be send forward to the trial 
monitor at the KKS and the data manager at the IMBI. 

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The information on the inclusion form also includes the anticipated date of the FDG-PET/CT. 
• 
After the FDG-PET/CT, following items should be send by mail to the trial center in 
Heidelberg: 
• 
Imaging of the staging (CT/MRI) on a CD in DICOM format 
• 
Data of the FDG-PET/CT in DICOM format 
• 
Gazyvaro order form including the patients trial ID and the delivery address 
Studiensekretariat  
Radioonkologie & Strahlentherapie 
z.Hd. Frau Renate Haselmann 
Universitätsklinik Heidelberg 
INF 400 
69120 Heidelberg 
Tel.: 06221/56 38613 (od. 06221-56 8202) 
Fax: 06221/56 1979 
E-mail: Renate.Haselmann@med.uni-heidelberg.de 
 
All images will be centrally reviewed by the LKP, an experienced radiologist (CT/MRI) and specialist 
for nuclear medicine (PET). 
If the central review confirms an early stage, the order fax will be send forward to Roche Pharma AG 
and the trial site will be informed. The delivery of all vials necessary for the patient will be carried out 
directly to the address of the site, which is noted on the order form. The delivery usually lasts 3 days.  
The trial center will inform the monitor about the order. 
 
Gazyvaro is labeled as trial medication and must not be given to patients other than within the trial. An 
early notification and good internal communication within the trial site (pharmacist, physician and 
investigator) is mandatory for a smooth order. 
 
7 IRRADIATION 
The CT for 3D treatment planning is scheduled for week 7 and should be done using appropriate 
positioning devices (e.g. thermoplastic masks etc.). The response to the first 4 Gazyvaro 
administrations is also assessed using this CT. The irradiation occurs in week 9 after der fifth 
Gazyvaro administration (week 8).  
 
7.1 Target volume 
A 3D treatment planning is mandatory. The target volume should be assigned as involved site 
according to the guidelines of the International Lymphoma Radiation Group (ILROG) [60]: 
The clinical target volume (CTV) encompasses the original GTV (at study inclusion). Normal 
structures such as lungs, kidneys, and muscles that were clearly uninvolved, though previously 
displaced by the GTV, should be excluded from the CTV according to clinical judgment. Potential 
subclinical involvement should also be considered. Therefore, the CTV should also include at least 
adjacent lymph nodes in that site and a generous margin dictated by the clinical situation. If there are 
questions about the delineation of the target volume the trial center in Heidelberg should be contacted. 
Although a LDRT with 2x2 Gy will be carried out initially, the treatment plan should be prepared for a 
dose of 40 Gy in 20 fractions and the usual normal tissue constraints should be accepted for this dose. 
If a salvage irradiation is necessary after the FDG-PET/CT in week 18, the same irradiation plan 
should be used.  
 

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7.2 LDRT (week 9) 
The irradiation in week 9 is a LDRT using 2x2 Gy on two succeeding days (no start on a Friday or 
before a holiday). The dose delivery should be according ICRU50. The irradiation delivery may 
include photons, electrons and protons. 
 
7.3 Salvage irradiation (week 20-23) 
All patients with PET positive lymphoma before the first Gazyvaro administration (initial FDG-
PET/CT), will get an additional FDG-PET/CT in week 18 which should be sent to the trial center in 
Heidelberg. All of those patients who do not show a morphologic CR/PR or do not have a metabolic 
CR will get a salvage irradiation starting in week 20. 
The target volume is identical to the initial LDRT irradiation in week 9. The dose is 18 x 2 Gy (ICRU 
50).  The same positioning devices, the same planning CT and the same treatment plan as for the 
LDRT should be used (see above). 
 
 
8. METHODS OF DATA COLLECTION / STUDY VISITS 
8.1 Initial Staging 
The extent of the lymphoma manifestation will be assessed according the Ann-Arbor classification 
system and using 3D imaging and bone marrow aspiration. A pathological staging is not necessary. 
8.1.1 Procedures 
 
Medical history (incl. of B-symptoms) 
Current medication 
Clinical examination (including palpation of lymph node regions) 
Shipping of the biopsy tissue to a reference pathologist of the GLSG 
Laboratory testing: 
- Differential blood cell count (hemoglobin, leucocytes, thrombocytes, neutrophils, 
lymphocytes)  
- Clinical chemistry (sodium, potassium, AST/ALT, total bilirubin, alkaline phosphatase, 
creatinine) 
- LDH 
- albumin, immunoglobulins, immunefixation 
- ß2 microglobuline 
- Peripheral blood (10 ml EDTA) for MRD analysis and STRECK tube (10 ml) for cell-free 
DNA collection 
- Hepatitis- und HIV – serology (not applicable if there are values < 3 months ) 
- Pregnancy test (serum) for all women with childbearing potential (including tubal ligation)  
CT or MRI (</= 4 months), if necessary: additional ultrasound  
- head&neck* 
- thorax* 
- abdomen* 
- pelvis including inguinal region* 
*These regions must be screened using 3D sectional imaging and should also be scanned during the 
follow-up examinations from months 6 on. Ultrasound can be used additionally, but it cannot replace a 
CT or MRI since the morphological remission criteria are based on 3D sectional imaging. A FDG-
PET/CT of these regions can be used instead of CT or MRI. 

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Site-specific examinations:  
Thyroid testing in case of cervical or supraclavicular lymphoma (TSH, fT3/fT4) 
Consultation of a head&neck in case of supra-diaphragmal lymphoma  
 
8.1.2 Risk profile and FLIPI 
 
A risk profile according to the "Follicular lymphoma International Prognostic Index (FLIPI)" [61] and 
additional potential risk factors should be recorded.  
General condition ECOG 0, 1 or 2 
Age  40, 41 - 60, > 60 years 
Largest lymphoma < 3 cm or  3 cm in max. diameter (sectional imaging) 
Morphologically macroscopic tumor remaining after surgical intervention for proof of histology  
stage I or II  
Serum-LDH normal or elevated 
Serum-ß2 microglobulin (ß2m) normal or elevated 
Hemoglobin ≥ or < 12 g/dl 
 
The actual concomitant medication should be checked at each visit and should be documented in the 
patient chart and the CRF. 
8.1.3 Examinations after inclusion and before start of therapy 
 
FDG-PET/CT incl. central review  
(not applicable if already done for initial staging (see above)) 
EORTC QLQ-C30 and FACT-Lym questionnaires 
 
8.1.4 Examinations during therapy (up to week 18) 
 
 before each Gazyvaro administration:  
Differential 
blood 
cell 
count 
(hemoglobin, 
leucocytes, 
thrombocytes, 
neutrophils, 
lymphocytes) 
Assessment of AEs 
Pregnancy test (serum or urine) in premenopausal female patients before Gazyvaro 
administration in week 1, week 4, week 8, week 12 and week 16. In case of a positive urine 
pregnancy test, dosing will be delayed, until patient’s status is determined by a serum 
pregnancy test 
 
 week  7:  
CT imaging of the involved lymphoma region for radiation planning and response assessment  
Palpation of the lymphatic region 
Laboratory testing: 
- Differential blood cell count (hemoglobin, leucocytes, thrombocytes, neutrophils, 
lymphocytes) 
- clinical chemistry (sodium, potassium, AST/ALT, total bilirubin, alkaline phosphatase, 
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- LDH 
Assessment of AEs 
 
 week 18 
Medical history 
Clinical examination (including palpation of lymph node regions, skin reaction in the radiation 
area) 
ECOG-Performance status 
Laboratory testing: 
- Differential blood cell count (hemoglobin, leucocytes, thrombocytes, neutrophils, 
lymphocytes) 
- clinical chemistry (sodium, potassium, AST/ALT, total bilirubin, alkaline phosphatase, 
creatinine) 
- LDH 
EORTC QLQ-C30, FACT-Lym questionnaires 
In dependence of the initial FDG-PET/CT before the first Gazyvaro administration: 
• 
FDG-PET/CT of the initially involved region for response evaluation (central review) 
for patients with initially PET positive remaining lymphoma  
• 
Contrast enhanced CT/MRI for patients with initially PET negative remaining 
lymphoma 
• 
No imaging for patients without initially remaining macroscopic lymphoma after 
surgical intervention for proof of histology 
Peripheral blood (10 ml EDTA) for MRD analysis and STRECK tube (10 ml) for cell-free 
DNA collection 
Assessment of AEs 
 
8.1.5 Follow-up examinations month 6, 12, 18, 24 
 
Medical history (incl. assessment of B-symptoms) 
Clinical examination (including palpation of lymph node regions, skin reaction in the radiation 
area) 
ECOG-Performance status 
Laboratory testing: 
- Differential blood cell count (hemoglobin, leucocytes, thrombocytes, neutrophils, 
lymphocytes)  
- Clinical chemistry (sodium, potassium, calcium, AST/ALT, total bilirubin, alkaline 
phosphatase, creatinine) 
- LDH 
- Total protein, protein-electrophoresis 
CT or MRI (</= 4 months), if necessary: additional ultrasound  
- head&neck 
- thorax 
- abdomen 
- pelvis including inguinal region 
Peripheral blood (10 ml EDTA) for MRD analysis and STRECK tube (10 ml) for cell-free 
DNA collection 
EORTC QLQ-C30 und FACT –Lym questionnaires  (only month 12, 24) 
Assessment of AEs 
 

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Independent of the follow-up examinations: Pregnancy test (serum or urine) in all women with 
childbearing potential (including tubal ligation) if menstruation is overdue more than 2 weeks up to 
month 24 
8.1.6 Final examination (month 30) 
 
Medical history (incl. assessment of B-symptoms) 
Clinical examination (including palpation of lymph node regions, skin reaction in the radiation 
area) 
ECOG-Performance status 
Laboratory testing: 
- Differential blood cell count (hemoglobin, leucocytes, thrombocytes, neutrophils, 
lymphocytes)  
- Clinical chemistry (sodium, potassium, calcium, AST/ALT, total bilirubin, alkaline 
phosphatase, creatinine) 
- LDH 
- Total protein, protein-electrophoresis 
- ß2 microglobuline 
CT or MRI (</= 4 months), if necessary: additional ultrasound  
- head&neck 
- thorax 
- abdomen 
- pelvis including inguinal region 
Site specific examinations: 
Thyroid testing in case of cervical or supraclavicular lymphoma (TSH, fT3/fT4) 
Assessment of AEs 
 
 
8.1.7 MRD analysis 
 
10 ml EDTA-blood and 10 ml STRECK tube for cell-free DNA collection (STRECK tubes will be 
provided by the Laboratory of Prof. Pott in Kiel). 
Time points: 
 Before the first administration of Gazyvaro 
 Week 18 
 Month 6 /12 / 18 / 24 
All samples will be pseudonymized using the patient ID code and send to the analyzing laboratory in 
Kiel. The shipment can be performed any time using the regular mail.  
Hämatologie Labor Kiel 
Medizinischen Klinik II 
Universitätsklinikum Schleswig-Holstein, Campus Kiel 
Langer Segen 8-10 
24105 Kiel 
phone:        0431/ 500-24981 
Sekretariat: 0431/ 500-24970 
Fax:          0431/ 500-24974 

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8.1.8 Genetic and molecular testing of the initial lymph node biopsy (additional scientific 
program) 
Genetic and molecular investigations (e.g. p53 mutations, bcl2 transformation, genetic profiling testing 
for mutations on several sites) in relation to lymphoma disease are planned on the initial biopsy 
specimen as additional scientific program. These investigations are planned and coordinated by the 
pathology panel of the GLSG. All investigations should serve the increase of knowledge about origin, 
expansion and therapy of malignant lymphomas. There might be new scientific questions/methods 
concerning the aim of the study, which cannot be addressed today (e.g. knowledge of a new genetic 
mutation in follicular lymphomas, new measurement tools, which allow a more sensitive evaluation of 
MRD,…). For this reason, blood and tissue samples should be stored for an unlimited time or until the 
draw back of the patients consent. 
 
8.2 FDG-PET/CT 
The FDG-PET/CT within the trial should be performed according to the recommendations of Juweid 
et al.[49] 
 There should be at least 5 weeks interval after a surgical intervention (e.g. lymph node 
extirpation) 
 No use of „non attenuation PET scans“ 
 FDG dosage 3.5 – 8 MBq/kg body weight with a minimal dose of 185 MBq 
 4 hours fasting before FDG injection 
 Glucose level < 200 mg/dL at the time of injection 
 Primary staging FDG-PET/CT: Whole body scanning 60 +/- 10 minutes after FDG injection;  
Week 18: Whole body PET scanning, CT scanning of the initially involved regions 
 contrast enhancing agents are not mandatory for the CT imaging  
 Oral contrast agent might be used for better differentiation of bowel and other structures  
 
The interpretation of the initial staging PET should be done using visual assessment, with PET/CT 
images scaled to fixed SUV display and color table [50] 
 
 
8.3 Efficacy Parameters 
8.3.1 Criteria of Remission of the FDG-PET (metabolic remission) 
The metabolic remission criteria of the PET scan is according to the revised Cheson criteria of 2014 
under the use of the 5-PS score [50, 62].  
The 5-PS scores the most intense uptake in a site of initial disease, if present, as follows: 
● Score 1: No uptake 
● Score 2: Uptake ≤ mediastinum 
● Score 3: Uptake ≥ mediastinum but ≤ liver 
● Score 4: Uptake moderately higher than liver 
● Score 5: Uptake markedly higher than liver and/or new lesions 
● Score X: New areas of uptake unlikely to be related to lymphoma 
 
Complete Metabolic Response (CMR) 
Score 1 and score 2. 
Partial Metabolic Response (PMR) 
Score 3, 4 or 5 with reduced uptake compared with baseline and residual mass(es) of any size 
 

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Metabolic Treatment Failure / Metabolic Progressive Disease (MPD) 
An increase in FDG uptake to a score of 5, score 5 with no decrease in uptake, and new FDG-avid foci 
consistent with lymphoma 
 
 
8.3.2 Criteria of Remission of CT/MRI 
The morphologic remission is according to the NCI criteria [63].  
Complete Response (CR) 
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). 
 
Complete Response/unconfirmed (CRu) 
A residual lymph node mass greater than 1.5 cm in greatest transverse diameter that has regressed by 
more than 75% in the SPD. Individual nodes that were previously confluent must have regressed by 
more than 75% in their SPD compared with the size of the original mass. 
 
Partial Response (PR) 
≥ 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. 
 
Stable Disease (SD) 
Stable disease is defined as less than a PR but is not progressive disease 
 
Progressive Disease (PD) 
• ≥ 50% increase from nadir in the SPD of any previously identified abnormal node for PRs or 
non-responders. 
• 
Appearance of any new lesion during or at the end of therapy. 
 
8.4 Parameters of safety 
Clinical examination and medical history, blood values at the above mentioned visits. The 
classification of side effects is according to the NCI-CTC criteria version 4.03 
 
8.5 Additional Parameters 
The quality of life is assessed on a longitudinal time line using the EORTC QLQ-C30 questionnaire 
and the FACT-Lym questionnaire. 
 
 

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9. FOLLOW-UP AND POSSIBLE TREATMENTS AFTER END OF TRIAL 
Follow-up procedures and possible further treatments after the trial (early ending or after month 30) 
should be performed according to local standard procedures at each site. The results of this extended 
follow-up should be collected with the consent of the patient as in a register. It is the goal to analyze 
these long time follow-up data retrospectively in the future. 
 
In case of a recurrence at the primary involved site after 2x2 Gy, it should be respected, that a 
“full dose” up to the target dose of the MIR trial (40 Gy) should still be possible. 
 
 
10. ADVERSE EVENTS 
 
10.1 Definitions 
 
10.1.1 Adverse Event 
According to GCP, an adverse event (AE) is defined as follows: Any untoward medical occurrence in 
a subject administered a pharmaceutical product and which does not necessarily have a causal 
relationship with this treatment. An AE can therefore be any unfavourable and unintended sign 
(including an abnormal laboratory finding), symptom, or disease temporally associated with the use of 
a medicinal (investigational) product, whether or not related to the medicinal (investigational) product. 
An AE may be: 
- New symptoms/ medical conditions 
- New diagnosis 
- Changes of laboratory parameters 
The criteria that should be considered when determining whether an abnormal test finding should be 
reported as adverse event are as follows: 
- Test result is associated with accompanying symptoms, and/or 
- Test result require diagnostic testing or medical/surgical intervention, and/or 
- Test result lead to a change in trial dosing outside the protocol-stipulated dose adjustments, or 
discontinuation from the trial, significant additional concomitant drug treatment, or other therapy, 
and/or 
- Test result is considered clinically relevant at the discretion of the investigator or sponsor 
- Intercurrent diseases and accidents 
- Worsening of medical conditions/ diseases existing before clinical trial start 
- Recurrence of disease 
- Increase of frequency or intensity of episodic diseases. 
A pre-existing disease or symptom will not be considered an adverse event unless there will be an 
untoward change in its intensity, frequency or quality. This change will be documented by an 
investigator. 
Surgical procedures themselves are not AEs; they are therapeutic measures for conditions that require 
surgery. The condition for which the surgery is required may be an AE. Planned surgical measures 
permitted by the clinical trial protocol and the condition(s) leading to these measures are not AEs, if 
the condition leading to the measure was present prior to inclusion into the trial. In the latter case the 
condition should be reported as medical history. 
AEs are classified as "non-serious" or "serious". 

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10.1.2 Serious Adverse Event, SAE 
 
A serious adverse event (SAE) is an AE that regardless of the dosage of the IMP (GAZYVARO) or by 
irradiation: 
- Results in death 
- Is life-threatening (the term life-threatening refers to an event in which the subject was at risk of 
death at the time of event and not to an event which hypothetically might have caused death if it 
was more severe) 
- Requires hospitalisation or prolongation of existing hospitalisation* 
- Results in persistent or significant disability/ incapacity**  
- Is a congenital anomaly/ birth defect or 
- Is otherwise medically relevant 
* Hospitalisation for performing protocol-required procedures or administration of study treatment is not classified as an 
SAE. Hospitalisations for disease-related procedures (surgery, imaging, laboratory tests) or any procedures planned before 
entry into the study are not considered SAEs. Hospitalisations for social reasons in the absence of an adverse event are not 
classified as SAEs either.  
** Persistent or significant disability or incapacity means that there is a substantial disruption of a person's ability to carry 
out normal life functions. The irreversible injury of an organ function (e.g. paresis, diabetes, cardiac arrhythmia) fulfils this 
criterion. 
Medical and scientific judgement should be exercised in deciding whether expedited reporting is 
appropriate in other situations - such as important medical events that may not be immediately life 
threatening or result in death or hospitalisation but may jeopardise the patient or may require 
intervention to prevent one of the other outcomes listed above. These should also usually be 
considered serious (examples of such events are intensive treatment in an emergency room or at home 
for allergic bronchospasm; blood dyscrasias or convulsions that do not result in hospitalisation; or 
development of drug dependency or drug abuse). 
Progression of the malignancy under treatment needs not to be reported as an adverse event.  
 
10.1.3 Serious Adverse Reaction, SAR 
SAEs that potentially may be attributed to the investigational medicinal product (IMP; Gazyvaro) are 
to be classified as Serious Adverse Reactions (SARs). This terminology is also used in the context of 
side effects due to irradiation. 
 
10.1.4 Expectedness 
An ‘unexpected’ adverse reaction is one the nature or severity of which is not consistent with the 
applicable product information, the Investigator’s Brochure (IB). Furthermore, reports, which add 
significant information on specificity or severity of a known adverse reaction constitute ‘unexpected’ 
events.  
 
10.1.5 Suspected Unexpected Serious Adverse Reaction, SUSAR 
SAEs that are both ‘suspected’, i.e., possibly related to the study drug (investigational medicinal 
product (IMP)) and ‘unexpected’, i.e., the nature and/ or severity of which is not consistent with the 
applicable product information are to be classified as Suspected Unexpected Serious Adverse 
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In case, either the investigator who primary reported the SAE or the second assessor, classifies the 
SAE as ‘suspected’ and the SAE is unexpected it will be categorised as a SUSAR. 
All SUSARs are subject to an expedited reporting to the responsible ethics committee(s), the 
competent authority and to all participating investigators 
 
10.1.6 AEs of special interest 
 
The following AEs of special interest (AESI) will be reported as AE and SAE, considered an 
“Important Medical Event” even if no other criteria for seriousness apply, on the appropriate pages of 
the CRF and in the source documents: 
- 
Non-drug specific Drug induced liver injury (DILI) 
The drug causes hepatocellular injury, generally shown by more frequent 3-fold or greater 
elevations above the upper limits of normal (ULN) of ALT or AST than the 
(nonhepatotoxic) control agent or placebo. Among subjects showing such aminotransferase 
(AT) elevations, often with ATs much greater than 3 x ULN, some subjects also show 
elevation of serum total bilirubin (TBL) to ≥ 2 x ULN, without initial findings of 
cholestasis (serum alkaline phosphatase (ALP) activity  < 2 x ULN). No other reason can 
be found to explain the combination of increased AT and serum TBL, such as viral hepatitis 
A, B, or C, preexisting or acute liver disease, or another drug capable of causing the 
observed injury.) 
 
- 
Progressive multifocal leucoencephalophathy (PML) 
PML is a disease that is always serious, and that is fatal or severely debilitatingin the large 
majority of patients. There is a potential risk that B-cell depletion may have an impact on 
the incidence and severity of infections. Rituximab has been associated with serious viral 
infections including PML. As obinutuzumab is more potent in terms of B-cell depletion 
than rituximab, there may be an increased risk of infections with obinutuzumab compared 
to rituximab. PML occurs almost exclusively in immunocompromised patients with deficits 
in the humoral or cellular immune response or both. PML has been observed most 
frequently in subjects with hematological malignancies (e.g. NHL and CLL) as well as 
subjects with liver transplants and autoimmune disease (e.g. SLE) [66]. 
 
- 
Suspected transmission of an infectious agent (STIAMP) 
The definition of STIAMP is any organism, virus or infectious particle (e.g. prion protein 
transmitting Transmissible Spongiform Encephalopathy), pathogenic or non-pathogenic, is 
considered an infectious agent. A transmission of an infectious agent may be suspected from 
clinical symptoms or laboratory findings indicating an infection in a patient exposed to a 
medicinal product. As in the case of suspected adverse reactions and adverse reactions, the 
terms suspected transmission and transmission are considered synonymous. Confirmation of 
contamination (including inadequate inactivation/attenuation of infectious agents as active 
substances) of the concerned medicinal product increases the evidence for transmission of an 
infectious agent. 
 
 
 

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- 
Tumour-lysis syndrome (TLS)  
Tumor lysis syndrome (TLS) is a well-known constellation of metabolic abnormalities 
resulting from spontaneous or treatment-related tumor necrosis or fulminant apoptosis. The 
metabolic abnormalities include: hyperkalemia, hyperuricemia and hyperphosphatemia with 
secondary hypocalcaemia with risk of renal failure. TLS has been reported in patients receiving 
anti-CD20 antibody therapy plus chemotherapy.  
The presence of known risk factors such as bulky disease, preexisting (moderate) renal 
insufficiency, high ALC and high uric acid levels (> 8 mg/dL) prior to therapy are known to 
increase the likelihood of TLS. Early identification of patients at risk and the prevention of 
TLS development with the initiation of preventive measures, as well as the careful monitoring 
for early signs of laboratory TLS and the prompt initiation of supportive care are critical to 
prevent potentially life-threatening metabolic derangements [64]. 
 
All AESIs will be entered into the pharmacovigilance database. However, if none of the ‘seriousness’ 
criteria applies, the AESIs are not to be handled as serious adverse events. Hence, even if they are 
‘unexpected’ and potentially related to the IMP, they will not undergo expedited reporting.    
 
10.1.7 Grading of AEs 
 
The grading of AEs in this trial will be carried out on the basis of the 5-grade scale defined in the 
CTCAE v4.03: 
 
Grade 1: 
Mild 
Grade 2: 
Moderate 
Grade 3:  
Severe 
Grade 4: 
Life threatening or causing disablement 
Grade 5: 
Death 
 
The grading of all AEs listed in the CTCAE v4.03 will be based on the information contained therein. 
The grading of all other AEs, i.e., those, which are not listed in the CTCAE v4.03 will be performed 
by a responsible investigator, based on definitions given above. 
Clarification of the difference in meaning between "serious" and "severe": 
The terms “serious” and “severe” are not synonymous. The term ‘severe’ should be used to describe 
the intensity (severity) of a specific event; the event itself, however, may be of relatively minor 
significance (such as severe headache). This is not the same as “serious”, which is based on the 
existence of one of the above mentioned seriousness criteria. 
If the intensity of AEs worsened or if there are different CTC-grades during the course of trial, the 
highest intensity should be documented generally. If applicable, dependent on the AE, one AE for each 
intensity level should be recorded. 
In case of lab parameters of CTC-grade 4 but without any clinical symptoms, it should be reconsidered 
whether the event is classified as serious. If so, the SAE reporting to the KKS Heidelberg is 
additionally necessary (see section 9.3). Anyway, if one of the seriousness criteria, e.g. hospitalisation 
required or life-threatening condition, applies, the SAE reporting is essential. 

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10.1.8 Relationship and outcome of AEs 
The investigator and second assessor will evaluate each AE that occurred after administration of 
Gazyvaro regarding the relationship with the administration of Gazyvaro and in this clinical trial also 
to the radiation therapy: 
 
Definitely related: 
There is a reasonable possibility that the event may have been caused by 
the IMP/radiation therapy. A certain event has a strong temporal 
relationship and an alternative cause is unlikely. 
Probable: 
An AE that has a reasonable possibility that the event is likely to have been 
caused by the IMP/radiation therapy. The AE has a timely relationship 
and follows a known pattern of response, but a potential alternative cause 
may be present. 
Possible: 
An AE that has a reasonable possibility that the event may have been 
caused by the IMP/radiation therapy. The AE has a timely relationship to 
the IMP; however, the pattern of response is untypical, and an 
alternative cause seems more likely, or there is significant uncertainty 
about the cause of the event. 
Unlikely: 
Only a remote connection exists between the IMP/radiation therapy and the 
reported adverse event. Other conditions including concurrent illness, 
progression or expression of the disease state or reaction of the 
concomitant medication appear to explain the reported adverse event. 
Not related: 
An AE that does not follow a reasonable temporal sequence related to the 
IMP/radiation therapy and is likely to have been produced by the subject’s 
clinical state, other modes of therapy or other known aetiology. 
Not assessable: 
There is insufficient or incomplete evidence to make a clinical  
judgement of the causal relationship. 
 
All subjects who have reportable AEs, whether considered associated with the use of the trial 
medication or not, must be monitored to determine the outcome. The clinical course of the AE will be 
followed up until resolution or normalisation of changed laboratory parameters or until it has changed 
to a stable condition. This also holds for on-going AEs/SAEs of withdrawn subjects. 
The outcome of an AE at the time of the last observation will be classified as: 
Recovered / resolved: 
All signs and symptoms of an AE disappeared without any 
sequels at the time of the last interrogation. 
Recovering / resolving: 
The intensity of signs and symptoms has been diminishing and / 
or their clinical pattern has been changing up to the time of the 
last interrogation in a way typical for its resolution. 
Not recovered/not resolved: 
Signs and symptoms of an AE are mostly unchanged or worsened 
at the time of the last interrogation. 
Recovered / resolved with 
sequel: 
Actual signs and symptoms of an AE disappeared but there are 
sequels related to the AE. 
Fatal: 
Resulting in death. If there is more than one adverse event only 
the adverse event leading to death (possibly related) will be 
characterised as ‘fatal‘. 

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Unknown 
The outcome is unknown or implausible and the information 
cannot be supplemented or verified. 
 
The action taken with the IMP/radiation therapy will be assigned to one of the following categories: 
Dose not changed: 
No change in the dose of the IMP/radiation therapy. 
Dose reduced: 
Reduction in the dose of the IMP/radiation therapy. 
Dose increased:  
Increase in the dose of the IMP/radiation therapy. 
Drug withdrawn: 
Discontinuation of the IMP/radiation therapy. 
Unknown: 
The information is unknown or implausible and it cannot be supplemented 
or verified 
Not applicable: 
The question is implausible (e.g. the subject is dead). 
 
The term “countermeasures” refers to the specific actions taken to treat or alleviate adverse events or 
to avoid their sequels. Following categories will be used to categorise the countermeasures to adverse 
events: 
None: 
No action taken. 
Drug treatment: 
Newly prescribed medication or change in dose of a medication. 
Others: 
Other countermeasures, e.g. an operative procedure. 
 
10.2 Period of Observation and Documentation 
Adverse events (AEs) will be ascertained by the investigators using non-leading questions, noted as 
spontaneously reported by the patients to the medical staff or observed during any measurements on all 
study days. The observation period begins with the first administration of the Gazyvaro (before the 
first administration of the Gazyvaro: medical history) and ends with the last study visit, i.e. 30 month 
after the last take of study medication. AEs will be documented in the patient file and in the CRF. All 
subjects who present AEs, whether considered associated with the use of the trial medication/radiation 
therapy or not, will be monitored by the responsible investigator to determine their outcome; this 
applies to withdrawals too. 
The end date of the SAE is defined typically the same as for AEs. The end date of the SAE must not be 
later than the end date of the corresponding AE. 
AEs and SAEs that are on-going at the time of death are considered not resolved or resolving. 
All SAEs and their relevance for the benefit/risk assessment of the study will be evaluated 
continuously during the study and for the final report. All SAEs will be documented in the "Serious 
Adverse Event" form.  
 
10.3 Reporting of Serious Adverse Events by Investigator 
All SAEs must be reported by the investigator to the responsible Safety Officer at the KKS Heidelberg 
within 24 hours after the SAE becomes known using the "Serious Adverse Event" form. The initial 
report must be as complete as possible including details of the current illness and (serious) adverse 
event and an assessment of the causal relationship between the event and the trial medication/radiation 
therapy.  
The reporting will be performed by faxing a completed ‘SAE Form’ to the KKS Heidelberg, fax 
number: 06221-56-33725 
The investigator must also inform the site monitor in all cases. 

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10.4 Expedited Reporting 
SUSARs are to be reported to the responsible ethics committee, the competent authority (PEI) and to 
all participating investigators within defined timelines, i.e. they are subject to an expedited reporting.  
 
All SAEs will be subject to a second assessment by a designated person, who will be independent from 
the reporting investigator. The designated person for the present trial, referred to as the second assessor 
is the LKP:  
Prof. Dr. K. Herfarth, Radiation Oncology, University Hospital Heidelberg, INF 400, 69120 
Heidelberg 
 
Dr. J. Schmier, Internal Medicine V, University Hospital Heidelberg, INF 410, 69120 Heidelberg 
 
The second assessor will fill out a ‘Second Assessment Form’ for each SAE and send it back per fax to 
the responsible person at the KKS Heidelberg within 48 hours, fax-number:  
06221 – 56 – 33725 
 
The ‘Second Assessment Form’ will contain the following information:  
I) 
Assessment of relationship between SAE and IMP/radiation therapy (causality) 
II) Assessment of expectedness of SAE (derived from IB)  
III) Statement if the benefit/ risk assessment for the trial did change as a result of SAE.  
The expedited reporting (to competent authority, responsible ethics committee and investigators) will 
be carried out by a responsible Safety Officer at KKS Heidelberg. Only SUSARs occurring after 
administration of Gazyvaro will undergo expedited reporting.  
Details concerning the reporting of SUSARs will be described in a separate document “Safety 
Manual”. 
 
10.5 Emergency Treatment 
During and following a subject’s participation in the trial, the investigator should ensure that adequate 
medical care is provided to a subject for any AE including clinically significant laboratory values. The 
investigator should inform a subject when medical care is needed for intercurrent illness(es) of which 
the investigator becomes aware. 
 
 
11. STATISTICAL PROCEDURES 
 
11.1 Number of Patients 
Due to the descriptive character of the trial, no assessment of any formal statistical hypotheses is 
performed. The calculation of the number of patients is primarily based on the aspects of practicability 
and precision of the results. The following calculations are based on the intention-to-treat (ITT) 
population. Since the strength of the results for the primary endpoint may be weakened due to early 
drop-outs (as described later), the number of patients needed should be high enough to compensate for 
potential drop-outs. Primary endpoint is the rate of metabolic CR in week 18 in patients with initially 
remaining lymphoma judged by FDG-PET/CT. Based on the morphologic CR rate of 37-84% after 2 x 
2 Gy in the literature (see Table 2) and in face of a lack of data for metabolic CR after 2x2 Gy, a CR 
rate of 60% (about the median of CR in Table 2 and approximately the CR rate in week 18 in the MIR 

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trial (62%)) is assumed. If fifty patients enter the FDG-PET/CT and the observed metabolic CR rate 
amounts to 60%, the half width of the asymptotic two-sided 95% confidence interval amounts to about 
± 13.5%.  
Based on the experience of the MIR trial, a general drop-out rate of 10% is assumed, and about 30% of 
the included patients are expected to have no remaining lymphoma after initial surgery to prove the 
histology. In addition, we expect an additional drop-out rate of about 15% after the initial FDG-PET 
due to stage-shifting in a stage III disease based on the Barrington paper about PET staging [45]. 
These considerations lead to the following calculation: 
If 93 patients are being recruited, about 15% will drop out due to a stage-shift to higher stages after 
FDG-PET (79 patients remaining). Of these 79 patients, about 30% will have no remaining PET-
positive lymphoma after initial surgery (according to the experiences in the MIR trial). Therefore, 55 
patients would start therapy with the goal of reaching the primary endpoint assessment. Assuming a 
drop-out rate of 10%, 50 patients will be available for final assessment of the primary endpoint. 
The number of n=93 is at the upper limit of the patients to be included. This number of definitively 
included patients might drop during the trial (e.g. if less patients show a stage-shift or more patients 
show remaining lymphoma). 
 
11.2 Variables of analysis  
Primary endpoint is the metabolic complete response (CR) in week 18 in patients with initially 
remaining lymphoma judged by FDG-PET/CT. 
 
Secondary endpoints are: 
 
 Morphologic CR, PR, SD, PD in week 7, week 18 and month 6 in patients with initially 
remaining lymphoma judged by CT/MRI  
 Historical comparison of the morphologic response with MIR data (using MabThera); the 
comparison of the CR rate in week 7 would be a comparison of the two different CD20 
antibodies. Based on the patient numbers no matched pair analysis will be possible 
 Progression-free survival (PFS) of all treated patients (2 years after individual treatment start) 
 Toxicity (NCI-CTC criteria, version 4.03) of all patients 
 Relapse rate and pattern of recurrence of all treated patients at all follow-up visits. 
 Overall survival (OS) of all treated patients (2 years) 
 Quality of life according EORTC QLQ C30 and FACT-Lym questionnaires at inclusion and in 
week 18, month 12, 24 and 30 (all treated patients) 
 MRD response: initially, week 18, months 12 and month 24 (all treated patients). MRD is 
evaluated by the laboratory of C. Pott (Kiel) using at least the markers: t(14:18) PCR for MBR, 
3’mbr, 5’mcr and MCR; clonal IGH rearrangements (FR1-3); clonal IGL rearrangements (IGK 
and Kappa-KDE) 
 
11.3 Definition of the Trial Populations  
All patients, who received at least parts of the treatment defined in this protocol, will be analyzed in 
the intention-to-treat (ITT) population as well as in the safety population. All patients, who deviated 
less than 20% from the protocol-defined dose and fulfill all inclusion and exclusion criteria, will be 
analyzed in the per-protocol (PP) population. Efficacy will be evaluated in the ITT- as well as in the 
PP population. Toxicity data will be analyzed in safety population. 
 
11.4 Statistical Methods  
There will be a descriptive analysis of the data. The rate of metabolic CR in week 18 will be calculated 
as relative frequency. The related 95% confidence interval will be calculated using the “score method” 
by Wilson [65]. This method showed excellent performance characteristics as compared to alternative 

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approaches of constructing confidence intervals for rates [64]. In addition, the rate of metabolic CR 
will be estimated using the Kaplan-Meier method and the 95% Greenwood confidence interval to take 
into account a potential influence of censored values. (ITT and PP population) 
PFS and OS at 2 years after initiation of the therapy of each patient will be analyzed using the Kaplan-
Meier method and the two-sided 95% confidence intervals according to Greenwood. (ITT and PP 
population). 
Remission- and recurrence rates will be calculated as relative frequencies and reported together with 
the 95% confidence intervals according to Wilson. (ITT and PP population) 
Quality of life will be evaluated according to the evaluation guide of the two questionnaires. (ITT and 
PP population) 
Toxicity will be evaluated for frequency and intensity (safety population). Adverse events will be 
coded by MedDRA (actual version at the time of data base lock). The counts of the events and the 
counts of patients will be listed in a table. All patients under observation will be taken into account for 
the calculations of the frequency of recurrences at the respective time. 
All statistical procedures will be defined in a statistical analysis plan (SAP), which will be finalized 
before data base lock. The responsible statistician and the LKP will authorize the SAP. 
 
11.5 Interim Analysis 
No interim analysis is planned. 
 
11.6 Definition of Target Variables  
Progression-free survival:  
a) Calculated from start of therapy up to the time of progression (morphologic or metabolic) or death  
b) Calculated from start of therapy up to the time of progression (morphologic or metabolic) or death 
in patients with initially remaining lymphoma (morphologic or metabolic)  
 
Overall survival:  
Calculated from start of therapy up to the time of death 
 
12. DATA MANAGEMENT 
  
12.1 Data Collection  
All entries in the CRF must be verifiable by source documents. In advance, exceptions to this rule can 
be defined by the sponsor. A detailed list will be provided in the Investigator Site File. Regardless, 
there must be a minimum documentation, which provides information on study participation and 
includes all medical information necessary for appropriate medical care outside of the clinical trial in 
the patient record. 
In addition, source documents must mention that the patient has been included in an investigational 
study. Finally, there must be no data that are inconsistent between CRF and source documents. 
The investigator is responsible for ensuring that all sections of the CRF are completed correctly and 
that entries can be verified against source data. Any errors should have a single line drawn through 
them so that the original entry remains legible and the correct data should be entered at the side with 
the investigator's signature, date and reason for change. Self-explanatory corrections need not to be 
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The correctness of entries in CRF will be confirmed by dated signature of the responsible investigator. 
The original CRF will be transferred to the data management in the Institute of Medical Biometry and 
Informatics (IMBI) Heidelberg; one copy will be remained by the investigator. 
 
12.2 Data Handling  
All data will be entered in a database as recorded in the CRF by trained staff of the IMBI. To ensure 
data quality, a double data entry will be done. The data management will check completeness, validity, 
and plausibility of data by validation programs, which will generate queries.  
All missing data or inconsistencies will be reported back to the centre(s) and have to be clarified by the 
responsible investigator prior to database lock. If no further corrections are to be made in the database 
it will be declared locked and used for statistical analysis. 
All data management activities will be done according to the current SOPs of the IMBI. 
Original files of the CRF will be transferred to the LKP after analysis and completion of the trial 
report. 
 
12.3 Archiving of Essential Documents  
The investigator(s) will archive all trial data (source data and Investigator Site File (ISF) including 
subject identification list and relevant correspondence) according to the section 4.9 of the ICH 
Consolidated Guideline on GCP (E6) and to local law or regulations. 
The sponsor or other owner like investigators of the data shall retain all other documentation 
pertaining to the trial for at least 10 years according to the §13 of the German GCP-Ordinance. These 
procedures shall include: 
 The protocol including the rationale, objectives and statistical design and methodology of the 
trial, with conditions under which it is performed and managed, and details of the 
investigational product used. 
 Standard operating procedures 
 All written opinions on the protocol and procedures, 
 Final report, 
 Case report forms (not RDE), 
 Audit certificate(s), if available. 
 All other relevant documents of the trial master file, according to the ICH-GCP guideline 
Any change of data ownership shall be documented. All data shall be made available if requested by 
relevant authorities.  
According to the §28c of the German X-Ray Directive and to the §87 of the German Radiation 
Protection Directive the informed consent forms including subjects’ consent for trial participation, 
application of x-rays, application of radioactive materials or irradiation and data transmission to the 
competent authority will be archived for at least 30 years after the trial termination. 
The LKP is responsible for archiving of the trial master file (TMF). It will be archived according the 
SOP for archiving of the University Hospital of Heidelberg. 
The investigator will archive all study documents including patient identification list and relevant 
correspondence in the Investigator Site File (ISF). The ISF, all source documents as well as all other in 
section 8 of the ‚ICH Consolidated Guideline on GCP’ listed documents are to be stored and archived 
after the regular or early ending of the trial according to the legal regulations. 
 

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13. ETHICAL AND LEGAL ASPECTS 
  
13.1 Good Clinical Practice 
The procedures set out in this trial protocol, pertaining to the conduct, evaluation, and documentation 
of this trial, are designed to ensure that all persons involved in the trial abide by ICH harmonised 
tripartite guideline on Good Clinical Practice (ICH-GCP) and the ethical principles described in the 
applicable version of the Declaration of Helsinki. The trial will be carried out in keeping with local 
legal and regulatory requirements. 
The regulations of the AMG and GCP regulations as well as the Bundesdatenschutzgesetz (BDSG) 
will be respected. 
 
13.2 Legal Bases 
The study has to be conducted in compliance with the protocol, ICH-GCP and the applicable 
regulatory requirements 
 
13.2.1 Declaration of Helsinki 
The procedures set out in this trial protocol, pertaining to the conduct, evaluation, and documentation 
of this trial, are designed to ensure that all persons involved in the trial abide by ICH harmonised 
tripartite guideline on Good Clinical Practice (ICH-GCP) and the ethical principles described in the 
applicable version of the Declaration of Helsinki. The trial will be carried out in keeping with local 
legal and regulatory requirements. 
 
13.2.2 Other legal bases 
 
The other legal bases of this clinical trial are as follows: 
 ICH Topic E6, Guideline for Good Clinical Practice, including post Step 4 errata, September 1997 
 Directive 2001/20/EC (April 4, 2001) 
 Commission Directive 2005/28/EC (April 8, 2005) 
 National regulatory requirements/guidelines of the participating countries concerning Clinical 
Trials [e.g. federal drug law (AMG), GCP ordinance (GCP-Verordnung)] 
 Valid version of the Radiation Protection Ordinance / Röntgenverordnung 
 General national regulatory requirements, e.g. Bundesdatenschutzgesetz (BDSG) 
 
The Coordinating Investigator and all investigators will be given an up-to-date investigator’s brochure 
containing full details of the status of the pre-clinical and clinical knowledge of the study medication. 
As soon as new information is obtained, an updated version will be supplied or an amendment added 
to the existing investigator’s brochure. 
 
13.2.3 Approval and trial protocol amendments 
Before the start of the trial, the trial protocol, informed consent document, and any other appropriate 
documents will be submitted to the independent Ethics Committee (EC) as well as to the competent 
authority (PEI).  
A written favourable vote of the EC and an (implicit) approval by the competent authority are a 
prerequisite for initiation of this clinical trial. The statement of EC should contain the title of the trial, 
the trial code, the trial site, and a list of reviewed documents. It must mention the date on which the 

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decision was made and must be officially signed by a committee member. This documentation must 
also include a list of members of the EC present on the applicable EC meeting and a GCP compliance 
statement. 
The investigator and the KKS Heidelberg will keep a record of all communication with the EC and the 
regulatory authorities. 
Before the first subject is enrolled in the trial, all ethical and legal requirements must be met.  
All planned substantial changes (see §10, (1) of German GCP-Regulation) will be submitted to EC and 
the competent authority in writing as protocol amendments. They have to be signed by the sponsor and 
biometrician and approved by the EC and the competent authority.  
An approval by Federal Office for Radiation Protection (Bundesamt für Strahlenschutz) for the 
investigational use of FDG-PET/CT in this trial is prerequisite for the initiation of the trial. 
The use of radiation therapy in this trial has been reviewed by an radiation safety committee of experts 
of the DEGRO. The radiation treatment is considered as a treatment under the circumstances of 
“Heilkunde” and not as scientific research as defined by the German Radiation Protection Directive. 
 
13.2.4 Notification of regulatory authorities 
In addition to the approval by the competent authority, the clinical trial must also be notified to the 
competent authority before recruitment of the first patient (according to AMG §67).  
The local regulatory authorities responsible for each particular investigator will be informed before the 
beginning, during and at the end of the trial according to the applicable regulations. Each investigator 
is obliged to notify his/ her local regulatory authority whereas the notification of the competent 
authority is the responsibility of the sponsor. Both responsibilities have been delegated to the KKS.  
Substantial Amendments, interruption or premature end of the trial need to be reported, too.  
 
13.3 Subject Information and Informed Consent  
Before being admitted to the clinical trial, the patient must consent to participate after being fully 
informed by the investigator or a designated member of the investigating team about the nature, 
importance, risks and individual consequences of the clinical trial and their right, to terminate the 
participation at any time. 
The patient should also have the opportunity to consult the investigator, or a physician member of the 
investigating team about the details of the clinical trial. The informed consent to participate in the 
clinical trial may be withdrawn by the patient verbally in the presence of, or in written form directed 
to, the investigator or a physician member of the investigating team at any time during the trial. The 
patient must not entail any disadvantage therefor or be coerced or unduly influenced to continue to 
participate. Furthermore, the patient is not obligated to disclose reasons for the withdrawal of the 
consent. 
If the patient has a primary physician, the investigator should inform him or her about the patient’s 
participation in the trial, provided the patient agrees hereto. 
After reading the informed consent document, the patient must give consent in writing. The patient's 
consent must be confirmed by the personally dated signature of the patient and by the personally dated 
signature of the physician conducting the informed consent discussion. 
If the patient is unable to write, oral presentation and explanation of the content of the informed 
consent form and of the data protection information must take place in the presence of an impartial 
witness. The witness and the physician conducting the informed consent discussions must also sign 
and personally date the consent document. The witness must not be in any way dependent on the 
sponsor of the trial, the trial site or any member of the investigating team (e. g. an employee at the trial 
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A copy of the signed informed consent document must be given to the subject; the original will be 
filed by the investigator. The documents must be in a language understandable to the subject and must 
specify who informed the subject. 
The subjects will be informed as soon as possible if new information may influence his/her decision to 
participate in the trial. The communication of this information should be documented. 
The informed consent for genetic profiling and the extended follow-up according to a patient register 
will be independent of the consent of participation in the trial. 
 
Informed consent for irradiation and PET 
All patients will receive a separate information about the radiation procedure and will give their 
informed consent to irradiation. This information will specify the risks of the procedure according to 
the treatment site. The informed consent for the irradiation will be documented on the site specific 
forms and archived along with the radiation plan and radiation protocol. 
The informed consent for the FDG-PET/CT will also be on the site specific forms and should be 
archived with the patient’s documents. 
 
13.4 Data Protection  
The data obtained in the course of the trial will be treated pursuant to the Federal Data Protection Law 
(Bundesdatenschutzgesetz, BDSG). 
During the clinical trial, subjects will be identified solely by means of their individual identification 
code. Trial data stored on a computer will be stored in accordance with local data protection law and 
will be handled in strictest confidence. Distribution of these data to unauthorised persons has to be 
prevented strictly. The appropriate regulations of local data legislation will be fulfilled in its entirety. 
The subject consents in writing to release the investigator from his/her professional discretion in so far 
as to allow inspection of original data for monitoring purposes by health authorities and authorised 
persons (inspectors, clinical monitors, auditors). Authorised persons (inspectors, clinical monitors, 
auditors) may inspect the subject-related data collected during the trial ensuring the data protection 
law. 
The investigator will maintain a subject identification list (subject numbers with the corresponding 
subject names) to enable records to be identified. Subjects who did not consent to circulate their 
pseudonymised data will not be included into the trial. 
This protocol, the CRFs and other trial-related documents and material must be handled with strict 
confidentiality and not be disclosed to third parties except with the express prior consent of Sponsor. 
In particular, it must be ensured that the study medication is kept out of reach of third parties. Staffs of 
the investigators involved in this study are also bound by this agreement. 
 
13.5 Continuous Information to the Ethics Committee and the Competent Authority 
Pursuant to the German Drug Law (AMG) and the GCP Ordinance, the responsible EC, the competent 
authority and all participating investigators will be informed of all suspected unexpected serious 
adverse reactions (SUSARs) occurring during the trial. Both institutions will be informed in case the 
risk/ benefit assessment did change or any others new and significant hazards for subjects’ safety or 
welfare did occur. Furthermore, a report on the subjects safety will be submitted once a year – 
Development Safety Update Report (DSUR). 
The EC and the regulatory authorities must be informed of the end of the trial. They will be provided 
with a summary of trial results within one year after the end of clinical phase (LPO). 
 

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13.6 Insurance 
According to § 40 AMG, the sponsor has to subscribe to an insurance policy covering, in its terms and 
provisions, its legal liability for injuries caused to participating persons and arising out of this research 
performed strictly in accordance with the scientific protocol as well as with applicable law and 
professional standards. The insurance was taken out at  
HDI Global SE (insurance number: 57 010310 03018) 
Any impairment of health, which might occur in consequence of trial participation must be notified to 
the insurance company. The subject is responsible for notification. The insured person will agree with 
all appropriate measures serving for clarification of the cause and the extent of damage as well as the 
reduction of damage. 
During the conduct of the trial, the subject must not undergo other clinical treatment except for cases 
of emergency. The subject is bound to inform the investigator immediately about any adverse events 
and additionally drugs taken. The terms and conditions of the insurance should be delivered to the 
subject. 
The insurance company has to be informed about all amendments that could affect subjects’ safety. 
 
Additional Insurance for irradiation and PET/CT: 
Since the radiation therapy is not considered as scientific research (see above), an additional insurance 
for the radiation is not necessary.  
According to §91 of the radiation protection legislation, an insurance for FDG-PET/CT as 
accompanying diagnostic tool is not necessary, since this is already covered by the insurance for trials 
under the law of AMG.   
 
 
14. QUALITY CONTROL AND QUALITY ASSURANCE 
 
The sponsor, the investigators, and all involved study personnel agree to conduct this clinical trial in 
accordance with the ICH Guideline for Good Clinical Practice 
 
14.1 Direct Access to Source Documents According to ICH GCP 
According to ICH-GCP the investigator(s)/institution(s) must provide direct access to source 
data/documents for trial related monitoring, audits and regulatory inspection. Each subject has 
consented - via written informed consent - to direct access to his/her original medical records for trial-
related monitoring, audit and regulatory inspection. Any data to be recorded directly on the CRFs (i.e., 
no prior written or electronic record of data), and to be considered to be source data must be clearly 
identified (see 11.1).  
In the absence of either an audit-trail or limited access for the monitor the electronic record of data 
must be printed out (certified copy). In case of changes a new print-out has to be made. 
 
14.2 Monitoring 
Monitoring will be done by on-site visits by a clinical monitor according to SOPs of the KKS. The 
monitor will review the entries into the CRFs on the basis of source documents. The investigator must 
allow the monitor to verify all essential documents and must provide support at all times to the 

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monitor. The monitor will document the visit in a report for the sponsor. The site will be provided with 
a follow-up letter of the findings and the necessary actions to be taken. 
By frequent communications (letters, telephone, fax, e-mail), the site monitor will ensure that the trial 
is conducted according to the protocol and regulatory requirements. 
Frequency and details of monitoring will be defined in the monitoring manual. 
If there are major findings during monitoring or an audit, the investigational site might be closed by 
the LKP.  
 
Central quality assurance of imaging 
The initial FDG-PET/CT will be sent together with the initial staging imaging in DICOM format 
(mandatory for PET images, optional for staging images) to the trial center in Heidelberg. Specialists 
for nuclear medicine, diagnostic and radiation oncology will review it. In patients with PET positive 
remaining lymphoma, there is a second FDG-PET/CT of the involved region planned in week 18. The 
DICOM data of this should also be sent to the trial center in Heidelberg and will be reviewed by 
specialists of nuclear medicine and radiation oncology. It is planned to establish a direct electronic 
transfer of the data. In case of the necessity of clarification of staging and/or response evaluation, the 
CT and/or MR images and radiation plans, which were recorded during the treatment phase and the 
follow-up phase, might also be sent for central review to the trial center in Heidelberg. 
 
14.3 Inspections and Audits 
Regulatory authorities and/ or auditors authorised by the sponsor may request access to all source 
documents, CRFs, and other trial documentation. The investigator who must provide support at all 
times for these activities must guarantee direct access to these documents.  
The investigator will inform the sponsor immediately about a planned inspection. 
 
14.4 Responsibilities of the Investigator 
The investigator ensures that all team members are informed adequately about the protocol, all 
amendments to the protocol, the study procedures und study specific duties and tasks. 
The investigator will maintain a list to delegate tasks to the team members. 
 
15. ADMINISTRATIVE AGREEMENTS 
 
15.1 Financing of the Trial  
The trial will be co-financed by Roche Pharma AG and the Department of Radiation Oncology of the 
University of Heidelberg. 
 
15.2 Financial Disclosure 
Before the start of the trial, the investigator will disclose any proprietary or financial interests he or she 
might hold in a funding company, in the investigational product(s) or any commercial organisation 
being involved in the clinical trial. The investigator has also to confirm that he/she has not entered into 
any financial arrangement, whereby the value of compensation paid could affect the outcome of the 
clinical trial. 
The investigator agrees to update this information in case of significant changes.  
 

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15.3 Reports 
Within one year of the completion of the trial, the competent federal authority and the ethics 
committee will be supplied with a summary of the final report on the clinical trial containing the 
principle results according to §42 AMG. 
 
15.4 Registration of the Trial 
Prior to the beginning of the clinical phase (FPI) the LKP will register the trial at 
http://www.clinicaltrials.gov. Thus the trial will be given a unique ISRCTN, which is a prerequisite for 
a publication in a peer-review paper.  
 
15.5 Publication  
All information concerning the trial is confidential before publication. The data will be published 
independent of their results. The LKP will determine the list of authors at the end of data analysis. 
Each site, which included at least 4 completely documented patients (receiving the protocol defined 
therapy) will be considered for the list of authors. The order of appearance on the list of authors 
depends on the count of included and fully documented patients. KKS and IMBI staff members who 
gave relevant scientific support to the study design, conductance and/or analysis of results will be 
included as coauthors. The LKP will be first or senior author. 
Study data published or disclosed to third parties must not contain data that allow the identification of 
a subject. 
A copy of all publications will be sent to the KKS. 
 
 

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16 SIGNATURES  
 
The present trial protocol was subject to critical review and has been approved in the present version 
by the persons undersigned. The information contained is consistent with: 
- 
the current risk-benefit assessment of the investigational medicinal product, 
- 
the moral, ethical, and scientific principles governing clinical research as set out in 
the latest relevant version of Declaration of Helsinki, the principles of the guidelines 
of ICH Good Clinical Practices and the applicable legal and regulatory 
requirements. 
The investigator will be supplied with details of any significant or new finding including AEs relating 
to treatment with the investigational medicinal product. 
It will be ensured that the first subject is enrolled only after all ethical and regulatory requirements are 
fulfilled. Written consent from all subjects is received after detailed oral and written information and 
according to the requirements of local law (AMG). According to GCP-V §7, Section 2 No 15, it will 
be confirmed that all study participants will be informed on the type of encoding their personal data 
(pseudo-anonymisation) and who receives or has access to such data. Subjects who do not agree to this 
data encoding and transfer will not be enrolled into the trial. In this context it will be assured 
(according to GCP-V §7, Section 3 No 15) that all investigational sites comply with the local 
regulatory requirements for data protection. 
According to GCP-V §7, Section 3 No 4 the Sponsor/ Sponsor representative states that it is not 
planned to include subjects in a relationship of any dependence to the investigator or sponsor. 
Via current versions of the clinical trial protocol and the investigator’s brochure (IB), it will be ensured 
that all principal investigators are informed about the pharmacological-toxicologial assessments and 
results regarding the benefits and risks of the clinical trial. 
 
Date: 
 
Signature: 
 
 
 
 
Prof. Klaus Herfarth 
 
 
Function: 
LKP according §40 AMG 
 
 
 
 
and authorized representative of the 
Sponsors 
 
Date: 
 
Signature: 
 
 
 
 
Prof. Meinhard Kieser 
 
 
Function: 
Statistician 
 
 
 
 
 
Datum: 
 
Unterschrift: 
 
 
 
 
Dr. Sabine Gack 
 
 
Function: 
Project manager 
 
 
 

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17. DECLARATION OF INVESTIGATOR  
 
I have read the above trial protocol and confirm that it contains all information to conduct the clinical 
trial. I pledge to conduct the clinical trial according to the protocol. 
I will enrol the first subject only after all ethical and regulatory requirements are fulfilled. I will obtain 
written consent for trial participation from all subjects after detailed oral and written information and 
according to the requirements of local law (AMG). According to GCP-V §7, Section 2 No 15 I declare 
that all study participants will be informed on the type of encoding their personal data (pseudo-
anonymisation) and who receives or has access to such data. Subjects who do not agree to this data 
encoding and transfer will not be enrolled into the trial. In this context I confirm (according to GCP-V 
§7, Section 3 No 15) that my investigational site complies with all local regulatory requirements for 
data protection. 
Furthermore I declare (according to GCP-V §7, Section 3 No 4 that to the best of my knowledge no 
subjects in a relationship of any dependence to the investigator or sponsor will be included. 
I know the requirements for accurate notification of serious adverse events and I pledge to document 
and notify such events as described in the protocol. 
I declare that I am informed about the pharmacological-toxicological assessments and results 
regarding the benefits and risks of the clinical trial by reading the description in the clinical trial 
protocol and in the current version of the investigator’s brochure (IB). I ensure that all investigators/ 
relevant staff at my site will be informed of this results and possibly new risks that are forwarded by 
the sponsor later on (e.g. via new version of the investigator’s brochure).  
I confirm that every staff will be adequately trained to guaranty compliance to the trial protocol incl. 
subsequent amendments.  
I will retain all trial-related documents and source data as described. I will provide a Curriculum Vitae 
(CV) before trial start. I agree that the CV and Financial Disclosure (FD) may be submitted to the 
responsible EC. 
As the clinical trial and the results have to be published in a clinical trial register and forwarded to the 
EC and competent authorities I agree that my name and clinic address will be part of this final trial 
(summary) report/ public register and are disclosed pursuant to §42b AMG. 
Date: 
 
 
 
 
Signature: 
 
 
 
 
 
 
 
Name (block letters): 
 
 
 
 
 
 
 
Function: 
Investigator 
 
 
Investigational Site 
(address): 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Date: 
 
 
 
 
Signature: 
 
 
 
 
 
 
 
Name (block letters): 
 
 
 
 
 
 
 
Function: 
Deputy of the Investigator 
 
 

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