Conditions: Non Hodgkin Lymphoma Follicular Lymphoma Relapsed Follicular Lymphoma
Keywords: Radioimmunotherapy Lu-177 Betalutin Phase 1b Combination Rituximab
Allocation: NON_RANDOMIZED | Intervention model: SEQUENTIAL
Enrollment: 7
Healthy volunteers: no

Brief summary:
This study is a Phase 1b, open-label, single arm dose escalation study of Betalutin followed by rituximab in patients with previously treated follicular lymphoma. The purpose of this study is to characterise the safety, tolerability, pharmacokinetics, pharmacodynamics and preliminary anti-tumour activity of Betalutin in combination with rituximab.

Detailed description:

Arms:
arm 1: 10 MBq/kg Betalutin administered with lilotomab pre-dose on day 0; rituximab administered weekly x 4 doses from day 7, then every 3 months for 2 years arm 2: 15 MBq/kg Betalutin administered with lilotomab pre-dose on day 0; rituximab administered weekly x 4 doses from day 7, then every 3 months for 2 years

Interventions: intervention 1: 10 MBq/kg Betalutin intervention 2: 15 MBq/kg Betalutin
Intervention descriptions: intervention 1: 10 MBq/kg Betalutin, lilotomab 40mg, rituximab 375 mg/m2 intervention 2: 15 MBq/kg Betalutin, lilotomab 40mg, rituximab 375 mg/m2

Protocol document:
Prot_SAP_000.pdf: 
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CLINICAL STUDY PROTOCOL 
Protocol Title: A phase 1b open-label study of Betalutin in combination with rituximab 
in patients with relapsed/refractory follicular lymphoma (Archer-1) 
 
Protocol Number: 4.0_ 04 Oct 2021 
Amendment Number: 3 
Study Number: LYMRIT-37-07 
Short Title: Study of safety and efficacy of Betalutin and rituximab in patients with FL 
 
Sponsor Name and Legal Registered Address:  
Nordic Nanovector ASA 
Kjelsåsveien 168B 
N-0884 Oslo 
Norway  
 
 
EudraCT Number: 2017-004506-18 
 
 
 
Statement about Proper Study Conduct 
This study will be conducted in compliance with Good Clinical Practices, according to ICH 
Harmonized Tripartite Guideline. 
 
Confidentiality Statement 
The information in this document is provided to you as an Investigator, potential Investigator, 
consultant, or contractor, for review by you, your staff, and the appropriate Institutional 
Review Board or Ethics Committee. By accepting this document, you agree that the 
information contained herein will not be disclosed to others without written authorization 
from the study centre/Sponsor, except to the extent necessary to initiate the study or conduct 
study-related activities. 


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SPONSOR SIGNATURE PAGE 
 
 
Study Number: 
LYMRIT-37-07 
 
 
Study Title: 
A phase 1b open-label study of Betalutin in combination with rituximab 
in patients with relapsed/refractory follicular lymphoma (Archer-1) 
 
Authorised Representative on behalf of 
Nordic Nanovector ASA: 
 
Christine Wilkinson Blanc MD 
Chief Medical Officer 
Nordic Nanovector ASA 
Kjelsåsveien 168B 
N-0884 Oslo, Norway 
 
 
Signature: 
 
 
______________________________ 
Christine Wilkinson Blanc, MD  
 
 
Date:  
 
 
______________________________ 
 
 
Albert Chau 
Biostatistician 
Datacision Limited 
55 Station Road 
Beaconsfield, Buckinghamshire 
HP9 1QL, United Kingdom 
Signature: 
 
 
______________________________ 
Albert Chau, CStat, CSci 
Date:  
 
 
______________________________ 
 
 
Contact details for all the study personnel are provided in the study procedures manual. 
 
 
04-Oct-2021
04-Oct-2021


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CO-ORDINATING INVESTIGATOR SIGNATURE PAGE 
 
 
Study Number: 
LYMRIT-37-07 
 
 
Study Title: 
A phase 1b open-label study of Betalutin in combination with rituximab 
in patients with relapsed/refractory follicular lymphoma (Archer-1) 
 
 
Study Centre: 
Department of Oncology, Oslo University Hospital, Radiumhospitalet, 
Norway 
 
 
 
 
By my signature, I agree to personally supervise the conduct of this study and to ensure its 
conduct in compliance with the protocol, including any study protocol amendments, informed 
consent, Ethics Committee procedures, the Declaration of Helsinki, International Council for 
Harmonisation (ICH) Good Clinical Practice (GCP) guidelines and the local regulations 
governing the conduct of clinical studies. 
 
 
 
 
 
Signature: ……………………………….  Date: ................................................. 
 
Printed name: Alexander FOSSÅ 
Title: 
Chief Physician, MD 
 
 
 
 
Address: 
Oslo University Hospital 
 
Radiumhospitalet 
 
Montebello, N-0310 Oslo 
 
Norway 
 
 
 
 
04-Oct-2021


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Reasons for this Amendment  
The primary reasons for this amendment are: 
1. 
To update the design and size of the study to remove the study expansion phase, due to 
difficulties in recruitment in the study. 
2. 
To restrict individual patient’s follow-up to a maximum of 25 months (including 
clarification of reasons for earlier withdrawal), which is the follow-up required for the 
study primary endpoint. A longer follow up was envisaged for efficacy assessment but 
has a limited value considering the reduced sample size.  
3. 
To update the study objectives to formally list the biodistribution of Betalutin in 
combination with rituximab (RTX) and to establish a recommended dose of Betalutin in 
combination with RTX for phase 2 studies as objectives and to describe the endpoints for 
pharmacokinetics, pharmacodynamics and biodistribution studies. This is to rectify an 
oversight in the initial protocol. 
Other reasons for the amendment are: 
4. 
Details of study personal have been updated where appropriate 
5. 
Correction of typographical errors have been made, where relevant. Section headings and 
formatting were updated, where applicable.  
6. 
A clarification was added that tumour scans must be kept at the study site for potential 
review by the Sponsor but it is not mandatory to send them for storage. 
Changes made to the body text have been reflected in the synopsis.  
Protocol Amendment Summary of Changes Table 
DOCUMENT HISTORY 
Document 
Date 
Version 1.0 
6th February 2018 
Version 2.0 
16th October 2018 
Version 3.0 
19th December 2018  
Version 4.0 
04 October 2021 (this document) 
 
The changes are individually listed in Appendix 6. 
 
 


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Contents
REASONS FOR THIS AMENDMENT .............................................................................................................4
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE..............................................................4
CONTENTS..........................................................................................................................................................5
LIST OF TABLES................................................................................................................................................8
LIST OF FIGURES..............................................................................................................................................9
1.
PROTOCOL SUMMARY........................................................................................................................10
1.1.
SYNOPSIS..............................................................................................................................................10
1.2.
SCHEDULE OF ACTIVITIES (SOA): ........................................................................................................16
2.
INTRODUCTION.....................................................................................................................................22
2.1.
STUDY RATIONALE...............................................................................................................................22
2.2.
BACKGROUND ......................................................................................................................................24
Disease background ....................................................................................................................24
2.2.1.1.
Non-clinical pharmacodynamics ...........................................................................................25
2.2.1.2.
Non-clinical pharmacokinetics and biodistribution...............................................................25
2.2.1.3.
Toxicology.............................................................................................................................26
Clinical experience with Betalutin ..............................................................................................26
2.2.2.1.
Phase 1/2 single, ascending dose study in patients with relapsed indolent NHL 
(LYMRIT-37-01)...................................................................................................................26
2.3.
OVERVIEW OF COMBINATION TREATMENT WITH BETALUTIN PLUS RITUXIMAB....................................28
Non-clinical experience...............................................................................................................28
Clinical experience......................................................................................................................29
Potential for overlapping toxicities between Betalutin and rituximab........................................29
2.4.
BENEFIT/RISK ASSESSMENT.................................................................................................................30
3.
OBJECTIVES AND ENDPOINTS..........................................................................................................31
4.
STUDY DESIGN.......................................................................................................................................33
4.1.
OVERALL DESIGN.................................................................................................................................33
4.2.
RATIONALE FOR STUDY DESIGN...........................................................................................................35
4.3.
RATIONALE FOR DOSE..........................................................................................................................35
4.4.
PATIENT AND STUDY COMPLETION ......................................................................................................36
4.5.
END OF STUDY DEFINITION..................................................................................................................36
5.
POPULATION..........................................................................................................................................37
5.1.
INCLUSION CRITERIA............................................................................................................................37
5.2.
EXCLUSION CRITERIA...........................................................................................................................38
6.
STUDY TREATMENT ............................................................................................................................40
6.1.
DOSING REGIMEN .................................................................................................................................40
6.2.
TREATMENTS ADMINISTERED ..............................................................................................................42
6.3.
PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY ......................................................................43
Preparation and administration of Betalutin ..............................................................................43
Patient protection........................................................................................................................44


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Administration of Rituximab .......................................................................................................44
Administration of Lilotomab .......................................................................................................44
Drug Accountability ....................................................................................................................45
6.4.
TREATMENT COMPLIANCE ...................................................................................................................45
6.5.
SUPPORTIVE CARE GUIDELINES ...........................................................................................................45
6.6.
PRIOR AND CONCOMITANT THERAPY...................................................................................................46
7.
DISCONTINUATION OF STUDY TREATMENT AND PATIENT WITHDRAWAL / 
DISCONTINUATION........................................................................................................................................47
7.1.
DISCONTINUATION OF STUDY TREATMENT..........................................................................................47
7.2.
PATIENT WITHDRAWAL/DISCONTINUATION FROM THE STUDY ............................................................47
7.3.
REPLACEMENT POLICY .........................................................................................................................48
7.4.
LOST TO FOLLOW-UP ...........................................................................................................................48
8.
STUDY PROCEDURES...........................................................................................................................49
8.1.
SCREENING PERIOD ..............................................................................................................................49
8.2.
TREATMENT PERIOD.............................................................................................................................51
Visit 2 (Day -14) – Hospital Visit................................................................................................51
Visit 3 (Day 0) – Hospital Visit ...................................................................................................51
Visit 4 (Day 7) – Hospital Visit ...................................................................................................53
Visit 5 (Day 14) – Hospital Visit .................................................................................................54
Visit 6 (Day 21) – Hospital Visit .................................................................................................54
Visit 7 (Day 28) – Hospital Visit .................................................................................................54
Visit 8, 9 and 10 (Week 5, 6 and 7) – Lab Visit...........................................................................55
Visit 11 (Month 2/Week 8) – Hospital Visit.................................................................................56
Visits 12, 13 and 14 (Weeks 9, 10 and 11) – Lab Visit................................................................56
Visit 15 (Month 3/Week 12) – Hospital Visit...............................................................................56
Visits 16 (Month 3/Week 14) – Hospital Visit .............................................................................57
Visits 17 (Month 6/Week 26) – Hospital Visit .............................................................................58
Visits 18 (Month 9/Week 39) – Hospital Visit .............................................................................58
Visit 19 (Month 12/Week 52) – Hospital Visit.............................................................................59
Visit 20 (Month 15/Week 65) – Hospital Visit.............................................................................60
Visit 21 (Month 18/Week 78) – Hospital Visit.............................................................................60
Visit 22 (Month 21/Week 91) – Hospital Visit.............................................................................61
Visit 23 (Month 24/Week 104) – Hospital Visit...........................................................................61
End of study visit – Hospital Visit ...............................................................................................62
8.3.
ADDITIONAL OPTIONAL PROCEDURES..................................................................................................62
9.
STUDY ASSESSMENTS..........................................................................................................................64
9.1.
EFFICACY ASSESSMENTS......................................................................................................................64
Contrast enhanced CT examination or MRI................................................................................64
PET/CT and CT/MRI examination..............................................................................................64
PET/CT score..............................................................................................................................65
Definitions of Tumour Response Criteria....................................................................................66
9.2.
SAFETY ASSESSMENTS .........................................................................................................................68
Definition.....................................................................................................................................68
9.2.1.1.
Definition of adverse event....................................................................................................68
9.2.1.2.
Definition of adverse drug reaction .......................................................................................68
9.2.1.3.
Definition of serious adverse event .......................................................................................69


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9.2.1.4.
Definition of unexpected adverse drug reaction ....................................................................69
9.2.1.5.
Suspected unexpected serious adverse reaction (SUSAR) ....................................................69
9.2.1.6.
Definition of treatment-emergent adverse event....................................................................69
9.2.1.7.
Definition of adverse events of special interest (AESI).........................................................70
Safety review ...............................................................................................................................70
Assessments of adverse events; seriousness, causality, severity and expectedness.....................70
Reporting of adverse events ........................................................................................................72
Reporting of serious adverse events............................................................................................73
9.2.5.1.
Investigator’s Responsibilities...............................................................................................73
9.2.5.2.
Sponsor’s Responsibilities.....................................................................................................74
Other Safety Parameters .............................................................................................................74
9.2.6.1.
Physical examination.............................................................................................................74
9.2.6.2.
Vital signs..............................................................................................................................75
9.2.6.3.
12-lead electrocardiogram .....................................................................................................75
9.2.6.4.
Clinical laboratory parameters...............................................................................................76
9.2.6.5.
Immunogenicity assessment ..................................................................................................77
9.2.6.5.1.
Assessments....................................................................................................................77
9.2.6.5.2.
Human biosamples collection schedule..........................................................................77
9.2.6.5.3.
Human biosamples handling ..........................................................................................77
Volume of blood to be drawn from each patient .........................................................................78
Pregnancy ...................................................................................................................................80
9.3.
PHARMACOKINETICS ............................................................................................................................80
Assessments.................................................................................................................................80
Human biosamples collection schedule.......................................................................................80
Human biosamples handling.......................................................................................................81
9.3.3.1.
Total radioactivity in blood ...................................................................................................81
9.3.3.2.
Monitoring of RTX concentration in serum ..........................................................................81
9.4.
BIODISTRIBUTION AND DOSIMETRY......................................................................................................81
9.5.
BIOMARKERS........................................................................................................................................82
9.6.
BIOBANKING ........................................................................................................................................82
10.
STATISTICAL CONSIDERATIONS.....................................................................................................85
10.1.
STATISTICAL ANALYSES.......................................................................................................................85
Populations for analysis..............................................................................................................85
Other Analyses ............................................................................................................................85
11.
REFERENCES..........................................................................................................................................86
12.
APPENDICES...........................................................................................................................................90
APPENDIX 1: ABBREVIATIONS ..........................................................................................................................91
APPENDIX 2: STUDY GOVERNANCE CONSIDERATIONS .....................................................................................94
Regulatory and Ethical Considerations ....................................................................................................94
Financial Disclosure.................................................................................................................................94
Informed Consent Process.........................................................................................................................94
Data Protection.........................................................................................................................................95
Dissemination of Clinical Study Data .......................................................................................................95
Source Documents.....................................................................................................................................96
Study and Site Closure ..............................................................................................................................96
APPENDIX 3: CONTRACEPTIVE GUIDANCE AND COLLECTION OF PREGNANCY INFORMATION..........................97


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Definitions ................................................................................................................................................. 97 
Woman of Childbearing Potential (WOCBP) ........................................................................................ 97 
Women in the following categories are not considered WOCBP .......................................................... 97 
Contraception Guidance ........................................................................................................................... 97 
Male patients .......................................................................................................................................... 97 
Collection of Pregnancy Information ........................................................................................................ 99 
Male patients with partners who become pregnant ................................................................................ 99 
Female Patients who become pregnant .................................................................................................. 99 
APPENDIX 4: GENETICS .................................................................................................................................. 100 
APPENDIX 5: BIODISTRIBUTION AND DOSIMETRY ASSESSMENTS .................................................................... 101 
APPENDIX 6: LIST OF CHANGES SINCE VERSION 3.0 ....................................................................................... 103 
 
List of Tables 
Table 1-1  
Treatment, safety and efficacy (Screening to Month 3/Week 12) .................................................. 16 
Table 1-2  
Treatment, safety and efficacy (Month 3/Week 14 to Month 25/Week 108 - EOS) ...................... 18 
Table 1-3  
Pharmacokinetics and biodistribution ............................................................................................ 21 
Table 3-1  
Study objectives and endpoints ...................................................................................................... 31 
Table 8-1  
Procedure and assessments at Screening Visit (Visit 1) ................................................................. 49 
Table 8-2  
Procedures and assessments for rituximab administration at Visit 2 (Day -14) [±2 days] ............. 51 
Table 8-3  
Procedures and assessments before lilotomab administration at Visit 3 (Day 0) ........................... 52 
Table 8-4  
Procedures and assessments for lilotomab administration at Visit 3 (Day 0) ................................ 52 
Table 8-5  
Procedures and assessments for Betalutin administration at Visit 3 (Day 0) ................................. 53 
Table 8-6  
Procedures and assessments for rituximab administration at Visit 4 (Day 7 [±2 days]) ................ 53 
Table 8-7  
Procedures and assessments for rituximab administration at Visit 5 (Day 14 [±2 days]) .............. 54 
Table 8-8  
Procedures and assessments for rituximab administration at Visit 6 (Day 21 [±2 days]) .............. 54 
Table 8-9  
Procedures and assessments for rituximab administration at Visit 7 (Day 28 [±2 days]) .............. 55 
Table 8-10  
Procedures and assessments at Visit 8, 9 and 10 (Week 5, 6 and 7 [±2 days]) .............................. 55 
Table 8-11  
Procedures and assessments at Visit 11 (Week 8 [±2 days]) ......................................................... 56 
Table 8-12  
Procedures and assessments at Visits 12, 13 and 14 (Weeks 9, 10 and 11 [±2 days]) ................... 56 
Table 8-13  
Procedures and assessments at Visit 15 (Week 12 [±7 days]) ....................................................... 56 
Table 8-14  
Procedures and assessments at Visit 16 (Week 14 [±7 days]) ....................................................... 57 
Table 8-15  
Procedures and assessments at Visit 17 (Month 6/Week 26 [±7 days]) ......................................... 58 
Table 8-16  
Procedures and assessments at Visit 18 (Month 9/Week 39 [±7 days]) ......................................... 58 
Table 8-17  
Procedures and assessments at Visit 19 (Month 12/Week 52 [±7 days]) ....................................... 59 
Table 8-18  
Procedures and assessments at Visit 20 (Month 15/Week 65 [±7 days]) ....................................... 60 
Table 8-19  
Procedures and assessments at Visit 21 (Month 18/Week 78 [±7 days]) ....................................... 60 
Table 8-20  
Procedures and assessments at Visit 22 (Month 21/Week 91 [±7 days]) ....................................... 61 


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Table 8-21  
Procedures and assessments at Visit 23 (Month 24/Week 104 [±7 days]) ..................................... 61 
Table 8-22  
Procedures and assessments at end of study visit  .......................................................................... 62 
Table 8-23  
Optional Procedures and assessments following relapse or disease progression ........................... 62 
Table 9-1  
Criteria for tumour response evaluation ......................................................................................... 66 
Table 9-2  
Definition of ECOG performance status ........................................................................................ 75 
Table 9-3  
Clinical laboratory parameters ....................................................................................................... 76 
Table 9-4  
Volume of blood to be drawn from each patient during the screening and treatment period 
(Screening to End of study visit) .................................................................................................... 79 
Table 9-5  
Biomarker assessments .................................................................................................................. 83 
Table 12-1  
Highly Effective Contraceptive Methods ....................................................................................... 98 
 
List of Figures 
Figure 2-1 
The effect of combining Betalutin plus RTX on tumour volume and survival in a preclinical NHL 
model.............................................................................................................................................. 28 
Figure 4-1  
Study dosing and imaging plan ...................................................................................................... 34 
 
 


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1. 
Protocol Summary 
1.1. 
Synopsis 
Investigational drug 
Betalutin® (lutetium [177Lu] lilotomab satetraxetan) 
Lilotomab   
Rituximab   
Protocol number 
Version 4.0_04 Oct 2021 
Sponsor  
Nordic Nanovector ASA, Oslo, Norway 
Study phase 
Phase 1b 
Study title 
A phase 1b open-label study of Betalutin in combination with rituximab in patients with 
relapsed/refractory follicular lymphoma (Archer-1) 
Short title 
Study of safety and efficacy of Betalutin and rituximab in patients with FL 
Background/ 
Rationale 
Indolent Non-Hodgkin lymphoma (iNHL) remains largely incurable, despite good response 
rates to first line therapy, and nearly all patients eventually relapse. As patients relapse, they 
become resistant or refractory to commonly used therapies, including rituximab (RTX) and 
alkylating agents, and their prognosis worsens, especially for those who are no longer able 
to tolerate chemotherapy. New therapies with different mechanisms of action are thus 
needed to improve outcomes in patients who have recurrent NHL following RTX or other 
anti-CD20-based therapy.  
CD37 is highly expressed in B-cell NHL and is an attractive target for treatment. Betalutin 
is a novel CD37-directed antibody radionuclide conjugate (ARC) that has demonstrated 
clinical activity and is well-tolerated in patients with relapsed iNHL. Preliminary data from 
a phase 1/2 clinical study (LYMRIT 37-01) show that Betalutin is active as a single agent, 
and has a favourable toxicity profile, with reversible neutropenia and thrombocytopenia 
being the main toxicities reported [Kolstad, 2017]. 
RTX-based combination regimens are a mainstay of NHL treatment. Recently, preclinical 
data were reported demonstrating that sequential therapy with Betalutin followed by RTX 
significantly reduced tumour growth and improved overall survival in a murine model of 
NHL, suggesting synergism between the 2 agents [Repetto-Llamazares, 2016]. One 
mechanism may be via increased surface CD20 expression following Betalutin exposure 
[Repetto-Llamazares, 2015]. These data suggest a potential immunomodulatory role of 
Betalutin in modulating CD20 expression on NHL cells, which may potentially enhance the 
efficacy of RTX, and support evaluating the combination of Betalutin followed by RTX in 
patients with recurrent NHL.  
This phase 1b study will investigate the dosing of Betalutin in combination with RTX, 
whereby RTX is given shortly following Betalutin to capitalise on potential enhanced CD20 
expression after Betalutin administration. One phase 2 study evaluating short course 
cyclophosphamide, hydroxydaunorubicin, oncovin and prednisone (CHOP)-RTX 
chemotherapy followed by 90Y-ibritumomab tiuxetan (Zevalin®) in treatment-naïve 


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follicular lymphoma (FL) patients has been reported [Jacobs, 2008]. Fifty-five patients 
received 3 courses of CHOP-RTX followed by Zevalin® once haematologic recovery was 
attained. One week following Zevalin administration, four additional weekly doses of RTX 
were given. The incidences of grade 3/4 neutropenia and thrombocytopenia were 51% and 
44% respectively, consistent with previously reported data (prescribing information for 
RTX), and all patients had full haematologic count recovery by 12 weeks post-Zevalin. The 
use of RTX six months following Zevalin® administration in previously untreated high 
tumour burden FL patients was reported to convert all partial responses (PRs) to complete 
responses (CRs) in one study [Rajguru, 2014], but the optimal duration of rituximab therapy 
is unknown. Combining Betalutin with RTX may be attractive to patients due to a favourable 
dosing schedule, and potential for maintaining a good quality of life. We hypothesise that 
combining Betalutin with RTX could enhance both the response rates and the durability of 
responses in patients with recurrent FL.  
This protocol describes a Phase 1b, open-label, single-arm, dose escalation study of 
Betalutin followed by RTX in patients with previously treated FL. The purpose of this study 
is to characterise the safety, tolerability, pharmacokinetics, pharmacodynamics and anti-
tumour activity of Betalutin in combination with RTX. 
Objectives (key 
primary and 
secondary) 
Primary 
• 
To evaluate the safety and tolerability of Betalutin in combination with RTX 
Secondary 
• 
To establish a recommended dose of Betalutin in combination with RTX for phase 2 
studies in NHL patients 
• 
To evaluate the preliminary anti-tumour activity of combination treatment based on 
Investigator assessment of tumour response rates 
• 
To evaluate the duration of tumour control in patients receiving Betalutin in 
combination with RTX 
• 
To investigate the immunogenicity of Betalutin in combination with RTX 
Endpoints (key 
primary and 
secondary) 
Primary 
• 
Frequency and severity of adverse events (AEs), serious adverse events (SAEs) and 
changes in laboratory values graded according to Common Terminology Criteria for 
Adverse Events (CTCAE) version 4.03 
Secondary 
• 
Responses (overall response rate [ORR], CR, PR, stable disease [SD], progressive 
disease [PD]) as per Cheson 2014 
• 
Duration of response (DoR) 
• 
Progression free survival (PFS) 
• 
Time to progression (TTP) 
• 
Overall survival (OS) 
• 
Monitoring of the anti-drug antibody (ADA) response towards lilotomab, Betalutin 
and/or RTX 
Study design 
This protocol describes a Phase 1b open-label, single-arm dose escalation study to 
investigate the activity and safety and preliminary efficacy of Betalutin combined with 
RTX in patients with FL who have received one or more prior therapies. 


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All patients will receive a single intravenous (i.v.) dose of RTX (375 mg/m2) on Day -14, 
and then sequential iv administration of lilotomab (40 mg) followed by Betalutin (10 or 
15 MBq/kg) within 4 hours on Day 0. Patients will then be administered RTX (375 mg/m2) 
i.v. on Days 7, 14, 21 and 28. 
Two cohorts of 3-6 patients will be evaluated for dose limiting toxicity, in a 3+3 escalation 
pattern, to determine the Betalutin dose for future phase 2 studies in NHL. 
Patients will undergo clinical and laboratory assessments during screening/baseline and 
periodically during treatment. PET/CT and CT (or MRI) imaging will be performed at 
baseline and then at 3 and 6 months. CT with contrast (or MRI) will be performed at 12, 18, 
24 months or until disease progression or withdrawal from the study for any other reason 
(whichever comes first) . 
Patients who achieve SD, CR or PR on their Month 3 imaging scan will be administered 
maintenance RTX 375 mg/m2 i.v. or 1400 mg s.c. every 3 months for up to 2 years 
(8 infusions in total), or until disease progression or withdrawal from the study for any other 
reason (whichever comes first). 
Population  
FL patients who have received one or more prior therapies  
Inclusion/ exclusion 
criteria 
Inclusion: 
Patients are eligible to be included in the study only if all of the following criteria apply: 
1) 
3DWLHQWPXVWEH\HDUVDWWKHWLPHRIsigning the informed consent 
2) 
A pre-study Eastern Cooperative Oncology Group (ECOG) performance status  
of 0-2 
3) 
Histologically confirmed diagnosis (by 2008 World Health Organisation [WHO] 
classification) of iNHL FL (grade 1, 2 or 3a)  
4) 
At least one (but not more than 3) prior regimens with an anti-CD20 antibody (alone 
or in combination with chemotherapy), with documented relapsed, refractory disease 
(must not be anti-CD20 antibody-refractory) or PD 
5) 
Presence of at least one bi-dimensionally measurable lesion by CT or MRI: longest 
diameter (LDi) >1.5 cm for a nodal lesion; LDi >1.0 cm for an extranodal lesion 
within 28 days prior to start of treatment  
6) 
Normal organ and bone marrow function defined as: 
a) 
$EVROXWHQHXWURSKLOFRXQW[9/L; 
b) 
3ODWHOHWFRXQW[9/L;  
c) 
+DHPRJORELQJG/ 
d) 
Total bilirubin 1.5 x upper limit of normal (ULN) (except patients with 
documented Gilbert’s syndrome [<3.0 mg/dL]); 
e) 
Liver enzymes: Aspartate transaminase (AST); Alanine transaminase (ALT) 
or Alkaline phosphatase (ALP) [8/1RU[8/1LIOLYHU
involvement by primary disease); 
f) 
Adequate renal function as demonstrated by a serum creatinine within the 
upper limit of normal range 
7) 
Bone marrow involvement by lymphoma <25% 
8) 
Life expectancy >3 months 
9) 
Negative hepatitis B, hepatitis C and human immunodeficiency virus (HIV) 
screening tests 
10) Undetectable human anti-murine antibodies (HAMA) at screening  


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11) Women of childbearing potential must: 
a. 
have a negative serum pregnancy test at screening  
b. 
understand that the study medication is expected to have teratogenic risk 
c. 
agree to use, and be able to comply with, highly effective method of birth 
control with a Pearl-Index  
Contraception is required without interruption, from 4 weeks before starting study 
drug, throughout study drug therapy and for 12 months after end of study drug 
therapy, even if she has amenorrhea 
12) Male patients must agree to use condoms during intercourse throughout study drug  
therapy and for 12 months after end of study drug therapy 
13) The patient is willing and able to comply with the protocol, and agrees to return to 
the hospital for follow-up visits and examination 
14) Capable of giving signed informed consent which includes compliance with the 
requirements and restrictions listed in the informed consent form (ICF) and in this 
protocol 
Exclusion: 
Patients are excluded from the study if any of the following criteria apply: 
1. 
Previous haematopoietic stem cell transplantation (autologous and allogenic) 
2. 
Evidence of histological transformation from FL to diffuse large B-cell lymphoma  
          (DLBCL) at time of screening 
3. 
Previous total body irradiation 
4. 
Chemotherapy, immunotherapy, or investigational therapy within 28 days before the 
start of study drug administration FRUWLFRVWHURLGWUHDWPHQWDWGRVHVRIPJGD\
topical or inhaled corticosteroids, granulocyte colony-stimulating factor [G-CSF] or 
granulocyte-macrophage colony-stimulating factor [GM-CSF] are permitted up to 
2 weeks prior to start of study treatment) or failure to recover from AEs associated 
with prior treatment 
5. 
Previous treatment with radioimmunotherapy 
6. 
Patients who are receiving any other investigational medicinal products 
7. 
Known or suspected central nervous system (CNS) involvement of lymphoma 
8. 
History of a previous treated cancer except for the following:  
a. 
adequately treated local basal cell or squamous cell carcinoma of the skin 
b. 
cervical carcinoma in situ 
c. 
superficial bladder cancer 
d. 
localised prostate cancer undergoing surveillance or surgery 
e. 
localised breast cancer treated with surgery and radiotherapy but not 
including systemic chemotherapy 
f. 
other adequately treated Stage 1 or 2 cancer currently in CR 
9. 
Pregnant or lactating women 
10. Exposure to another CD37 targeting drug 
11. A known hypersensitivity to RTX, lilotomab, Betalutin or murine proteins or any 
excipient used in rituximab, lilotomab or Betalutin  
12. Receipt of live, attenuated vaccine within 30 days prior to enrolment 
13. Evidence of severe or uncontrolled systemic diseases: 
a. 
Uncontrolled infection including evidence of ongoing systemic bacterial, 
fungal, or viral infection (excluding viral upper respiratory tract infections) at 
the time of initiation of study treatment 
b. 
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c. 
Hepatic, renal, neurological, or metabolic conditions - which in the opinion of 
the Investigator would compromise the protocol objectives 
d. 
Psychiatric conditions e.g. patients unlikely to comply with the protocol, e.g. 
mental condition rendering the patient unable to understand the nature, scope, 
and possible consequences of participating in the study 
e. 
History of erythema multiforme, toxic epidermal necrolysis or 
Stevens-Johnson syndrome 
f. 
Cardiac conditions, including: 
i. 
history of acute coronary syndromes (including unstable angina) 
ii. 
class II, III or IV heart failure as defined by the New York Heart 
Association (NYHA) functional classification system 
iii. 
known uncontrolled arrhythmias (except sinus arrhythmia) in the past 
24 weeks 
Sample size 
6 to 12 patients will be enrolled 
Treatment groups, 
dose, route of 
administration, 
treatment regimen 
Single arm study with patients to be treated with the following study drugs: 
Rituximab - 375 mg/m2 to be administered by i.v. infusion through dedicated line at 
Days -14, 7, 14, 21 and 28.  Patients who achieve SD, CR or PR on their Month 3 imaging 
scan will be administered maintenance RTX 375 mg/m2 i.v. or 1400 mg s.c. every 3 
months for up to 2 years (8 infusions in total), or until disease progression or withdrawal 
from the study for any other reason (whichever comes first). 
Lilotomab – 40 mg to be administered by i.v. infusion at Day 0 
Betalutin – 10 or 15 MBq/kg to be administered by slow bolus i.v. injection within 
4 hours following lilotomab on Day 0  
Efficacy assessment(s) 
PET/CT and CT (or MRI) imaging will be performed at baseline and then at 3 and 6 months. 
CT with contrast (or MRI) will be performed at 12, 18, 24 months or until disease 
progression or withdrawal from the study for any other reason (whichever comes first)  
Tumour response will be determined locally according to Recommendations for Initial 
Evaluation, Staging and Response Assessment of Hodgkin and non-Hodgkin Lymphoma 
[Cheson, 2014] 
Safety assessment(s) 
In the treatment phase vital signs, electrocardiogram (ECG), physical examination, 
haematology, serum biochemistry and all AEs are collected at specified time points.  
Two cohorts of 3-6 patients will be initially evaluated for dose limiting toxicity before 
determining the subsequent Betalutin dose for the remainder of the study. Dose-escalation 
decisions will be made by the Investigator(s) and Sponsor following review of the safety 
data once haematologic recovery has occurred. 
After the last dose of rituximab, vital signs, ECG (final visit only), physical examination, 
haematology, serum biochemistry, Adverse Drug Reaction (ADR) and Adverse Events of 
Special Interest (AESI) will be collected at an end of study visit that will occur at least 28 
days post last administration of study treatment. Patients in survival follow-up at time of 
Protocol v4.0 approval can have the EOS visit at their next scheduled visit or an earlier 
convenient time point. 
Pharmacokinetics and 
biodistribution 
Total radioactivity measurements in blood will be performed at certain intervals until Day 
28. Mandatory at Radium Hospital (Oslo, Norway) only, otherwise optional. Patients will 
undergo SPECT imaging at certain time points in order to measure distribution of 


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Betalutin in the body and calculate absorbed radiation dose to target organs/tissues and 
tumours.  
Biomarker 
assessments 
Biomarkers assessments including CD20 and CD37 expression in tumour tissue biopsy 
and immunophenotyping of circulating lymphocyte subsets (absolute cell counts), will be 
performed at various time points throughout the study 
Other biomarker 
studies on additional 
samples 
Biomarkers including but not exclusive to MRD (blood) and gene expression changes 
related to disease treatment in tumour tissue (archival or newly collected biopsy at 
screening, relapse or disease progression), will be assessed at various time points 
throughout the study. Patient’s major histocompatibility complex (MHC) class I/II 
haplotype will be defined using peripheral blood (DNA) or saliva (DNA). Anti-tumour T-
cell responses will be explored by flow cytometry after co-culture of peripheral 
mononuclear cells (blood) and autologous lymphoma cells (biopsy and/or needle aspirate), 
and other biomarkers at selected time points throughout the study at Radium Hospital 
(Oslo, Norway) only. 
Statistical methods 
and data analysis 
The safety analysis population will include all patients who received at least one dose of 
any study drug.  
The intent-to-treat (ITT) population will consist of all patients who were enrolled and 
treated with lilotomab/Betalutin, regardless if RTX therapy was initiated. The number and 
percentage of patients with each response and overall (complete + partial responders) will 
be presented for each time point for the ITT population.  
Pharmacokinetic, biodistribution and biomarker exploratory analyses will be described in 
the statistical analysis plan finalised before database lock. 
Key dates 
The start date of the study (first patient included) was in October 2018. 
The expected accrual time is 18 months.  
Patients will be followed up for up to 25 months (End of study visit) after Betalutin 
administration. 
Patients in survival follow at time of Protocol version 4.0 approval can have the EOS visit 
at their next scheduled visit or an earlier convenient time point 
                                                                                                                                                                               


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1.2. 
Schedule of Activities (SoA):  
Table 1-1  
Treatment, safety and efficacy (Screening to Month 3/Week 12) 


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Screening
Pre-study
  D-14
D0
D+7
D+14
D+21
D+28
Week5+
Month 2
Month 2+
Month 3
Protocol
Section
(Up to 4 
weeks before 
1st rituximab 
dose)
Dosing Day
Dosing Day
Week 1 
Dosing Day
Week 2 
Dosing Day
Week 3 
Dosing Day
Week 4 
Dosing Day
Weeks 5, 6 
and 7
Week 8
Weeks 9, 10 
and  1117
Week 12
(±2 days)
(±2 days)
(±2 days)
(±2 days)
(±2 days)
(±2 days)
(±2 days)
(±7 days)
Hospital visit
X
X
X
X
X
X
X
X
X
Obtain informed consent
Appendix 2
X
Demographics
Section 8.1
X
Inclusion/exclusion criteria
Section 5
X
Medical history (includes substance useage)
Section 8.1
X
Urinalaysis
Section 8.1
X
Concomitant medication/therapy
Section 6.6
X
X
X12
X
X
X
X
X
X
Antineoplastic therapy since discontinuation
Section 8.3
Physical examination
Section 9.2.6.1
X
X
X
X
X
Height
Section 8.1 / 8.2
X
Weight
Section 8.1 / 8.2
X
X
X
X
Vital signs
Section 9.2.6.2
X
X
X13,14
X
X
X
X
X
X
12-lead ECG (also to be performed at any other stage if clinically indicated)
Section 9.2.6.3
X
X13
X
X
X
ECOG Performance Status
Section 9.2.6.1
X
X
X
X
X
X
Haematology 
Section 9.2.6.4
X
X
X
X
X
X
X
X
X
X
X
Serum biochemistry
Section 9.2.6.4
X
X
X
X
X
X
X
X
X
X
X
Immunophenotyping1
Section 9.2.6.4
X
X13
X
X
Coagulation
Section 9.2.6.4
X
X
HIV test
Section 9.2.6.4
X
Hepatitis B and C test
Section 9.2.6.4
X
Pregnancy test (WOCBP only)
Section 8.1
X
X13
X
Immunoglobulin levels
Section 9.2.6.4
X
X
X
HAMA at screening2
Section 9.2.6.4
X
Immunogenicity3
Section 9.2.6.5
X
X
X
Immunohistochemistry4
Section 9.4
X
Gene expression analysis in tumour (optional)5
Section 9.5
X
HLA haplotyping (blood or saliva)6
Section 9.4
X
Minimal Residual Disease
Section 9.4
X10
X18
Bone marrow biopsy
Sections 8.1 / 8.2 / 8.3
X
X19
Radiology assessments
Section 9.1
X11
X11
Anti-tumour T cell response (Optional, Radium Hospital only)
New tumour tissue biopsy (surgical)7
X
New tumour tissue biopsy (Fine needle aspiration)8
X13, 15
X
Additional blood collection9
X
X
Study drug administration
          Rituximab administration
Section 6.3.3
X
X
X
X
X
          Lilotomab administration
Section 6.3.4
X16
          Betalutin administration
Section 6.3.1
X
Adverse events
Section 9.2
AESI monitoring
Sections 9.2.1.4 / 9.2.1.7
Survival status
Section 7.2
Procedure
Continuous
Treatment Period
Section 9.4


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Table 1-2  
Treatment, safety and efficacy (Month 3/Week 14 to Month 25/Week 108 - EOS) 


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Table 1-3  
Pharmacokinetics and biodistribution 
 
 
1) Lilotomab infusion within 2-4 hours prior to Betalutin injection. 
2) One baseline blood sample before lilotomab and Betalutin dose. 
3) To be performed at Radium Hospital (Oslo, Norway) only; otherwise optional. 
4) Before RTX dosing. 


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2. 
Introduction 
Betalutin® (177Lu-lilotomab satetraxetan) is a beta-emitting antibody radionuclide conjugate 
(ARC) composed of a murine anti-CD37 immunoglobulin G1 (IgG1) antibody (lilotomab) 
conjugated via lysine groups to a p-SCN-benzyl-DOTA chelator (satetraxetan). Betalutin is 
specifically designed to treat non-Hodgkin lymphoma (NHL). The chelator complexes the 
radionuclide,177Lu, to form the ARC. The CD37 antigen is highly expressed (>90%) on B-cells 
and on the surface of tumours of B-cell origin, including NHL and chronic lymphocytic 
leukaemia [1-3]. Betalutin is administered systemically. Lutetium-177 emits beta-radiation, 
resulting in DNA damage and tumour cell death. ARCs may be a beneficial approach for 
treating NHL, because this disease is radiosensitive.  
Betalutin has been in clinical development for almost 5 years and approximately 65 patients 
(the majority with indolent NHL [iNHL]) have been dosed. It is currently being investigated 
as a single agent in clinical studies in iNHL and relapsed/refractory diffuse large B-cell 
lymphoma (DLBCL). Betalutin is injected after pre-treatment with the anti-CD20 antibody 
rituximab (RTX) to deplete B-cells (given 2 weeks prior to Betalutin), within 4 hours following 
pre-dosing with the cold antibody lilotomab. The clinical development is currently most 
advanced in patients with relapsed iNHL/follicular lymphoma (FL). 
2.1. 
Study Rationale 
Indolent NHL remains largely incurable, despite good response rates to first line therapy, and 
nearly all patients eventually relapse. As patients relapse, they become resistant or refractory 
to commonly used therapies, including RTX and alkylating agents, and their prognosis worsens, 
especially for those who are no longer able to tolerate chemotherapy. New therapies with 
different mechanisms of action are thus needed to improve outcomes in patients who have 
recurrent NHL following RTX or other anti-CD20-based therapy.  
CD37 is highly expressed in B-cell NHL and is an attractive target for treatment. Betalutin is 
a novel CD37-directed ARC that has demonstrated preliminary efficacy and safety in patients 
with relapsed iNHL. Preliminary data from a phase 1/2 clinical study (LYMRIT 37-01) show 
that Betalutin is active as a single agent, and has a favourable toxicity profile, with reversible 
neutropenia and thrombocytopenia being the main toxicities reported [4]. 
RTX-based combination regimens are a mainstay of NHL treatment. To be effective, RTX 
depends on selective expression of sufficient numbers of CD20 antigens per cell. Treatment 
with RTX alone or in combination with chemotherapy can, however, result in RTX resistance 
through downregulation or disappearance of CD20 expression [5-8] which can result in 
significantly reduced clinical effect of subsequent CD20 targeted treatments [5, 9, 10].  
Recently, preclinical data were reported demonstrating that sequential therapy with Betalutin 
followed by RTX significantly reduced tumour growth and improved overall survival in a 
murine model of NHL, suggesting synergism between the 2 agents [11]. One mechanism may 
be via increased surface CD20 expression following Betalutin exposure [12]. These data 
suggest a potential role of Betalutin in modulating CD20 expression on NHL cells, which may 
potentially enhance the efficacy of RTX, and support evaluating the combination of Betalutin 
followed by RTX in patients with recurrent FL. Increased in vivo anti-tumour activity of the 
combination of a 177Lu-labelled anti-CD22 antibody followed by RTX has also been reported 
[13]. Another mechanism of action for the synergism between 177Lu-ARC therapy and RTX 
might be the immunomodulatory effect of low dose-rate radiation. Regulatory T-cells (Tregs) 


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produce anti-inflammatory cytokines and create an immunosuppressive environment [14] so 
that the immune cells that are necessary for RTX anti-tumour action are not recruited to the 
tumour site. The Tregs are very radiosensitive and 177Lu-ARC therapy targeted to the tumour 
site will inactivate them and potentially increase the effect of subsequent RTX therapy [15]. 
Combination regimens using biologics and immunomodulatory agents are becoming more 
popular due to both reduced toxicity compared to chemotherapy and the potential for better 
efficacy due to alternative mechanisms of action. Patients may benefit from higher response 
rates, a longer duration of response and delayed time to progression.  
The combination of lenalidomide/RTX is efficacious in patients with relapsed, non-rituximab-
refractory NHL, however prolonged daily administration of lenalidomide is required, and there 
are associated toxicities of cytopenias, rash and fatigue, some leading to treatment 
discontinuation, and a risk of thrombosis [16].  
This phase 1b study will investigate the dosing of Betalutin in combination with RTX, whereby 
RTX is given shortly following Betalutin to capitalise on potential enhanced CD20 expression 
after Betalutin administration. One phase 2 study evaluating short course cyclophosphamide, 
hydroxydaunorubicin, oncovin and prednisone (CHOP)-rituximab chemotherapy followed by 
90Y-ibritumomab tiuxetan (Zevalin®) in treatment-naïve FL patients has been reported [17]. 
Fifty-five patients received 3 courses of CHOP-RTX followed by Zevalin® once haematologic 
recovery was attained. One week following Zevalin administration, four additional weekly 
doses of RTX were given. The incidences of grade 3/4 neutropenia and thrombocytopenia were 
51% and 44% respectively, consistent with previously reported data (prescribing information 
for MabThera), and all patients had full haematologic count recovery by 12 weeks post-Zevalin. 
The use of RTX 6 months following Zevalin® administration in previously untreated high 
tumour burden FL patients was reported to convert all partial responses (PRs) to complete 
responses (CRs) in one study [18], but the optimal duration of RTX therapy is unknown. 
Combining Betalutin with RTX may be attractive to patients due to a favourable dosing 
schedule, and potential for maintaining a good quality of life. We hypothesise that combining 
Betalutin with RTX could enhance both the response rates and the durability of responses in 
patients with recurrent FL.  
This protocol describes a Phase 1b, open-label, single-arm, dose escalation study of Betalutin 
followed by RTX in patients with previously treated FL. The purpose of this study is to 
characterise the safety, tolerability, pharmacokinetics (PK), pharmacodynamics and 
anti-tumour activity of Betalutin in combination with RTX. 
 
 


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2.2.
Background
Disease background
NHLs are a heterogeneous group of lymphoproliferative malignancies primarily of B-cell 
origin that account for approximately 5% of all new cases of cancer in the US per year. The 
World Health Organization (WHO) classification of lymphoma recognises a variety of NHL 
subtypes that can be categorised as indolent in nature [19]. The most common of these is FL, 
which represents approximately 25% of all newly diagnosed cases of NHL and 70% of indolent 
lymphomas. The incidence of NHL is strongly related to age; approximately 50% of cases are 
diagnosed in patients age 65 and above, with the peak incidence being between the ages of 75
and 85 [www.seer.gov], thus many patients have co-morbidities, which can complicate or 
render them ineligible for current treatment options.
An estimated 72,240 new cases of NHL (approximately 15,000 new FL cases) are expected in 
the US in 2017 (4.3% of all new cancer cases), and an estimated 20,140 people will die of this 
disease [www.seer.gov]. Patients with recurrent FL who develop resistance to RTX and 
alkylating agents, particularly the elderly, and those who experience disease progression within 
2 years of first-line therapy have the greatest need for new treatment approaches in FL. The 
5-year overall survival rates for RTX-refractory FL patients and those with early disease 
progression are 58% and 50% compared to approximately 90% for all FL patients [19, 20]
[www.seer.gov].
The diagnosis and staging of FL are made on the basis of lymph node and bone marrow biopsies, 
and PET/CT scans. The hallmark t(14;18) translocation is found in 85% of FL, and induces 
lymphomagenesis. The current grading system evaluates the histological proportion of 
centrocytes to centroblasts: grade 1-)/LVGHILQHGDVFHQWUREOasts per high-powered field, 
and grade 3 FL has >15 centroblasts per high-powered field. Grade 3 FL is further 
subcategorised as 3A or 3B; 3B is a distinct biologic entity characterised by an absence of 
centrocytes and has a clinical course more similar to DLBCL.
Indolent B-cell NHLs and FL are usually diagnosed in the advanced stage and require systemic 
therapy. The standard of care for patients with advanced-stage, symptomatic or high tumour-
burden grade 1, 2 and 3A FL is immuno-chemotherapy with cyclophosphamide, vincristine 
and prednisolone (CVP), CHOP or bendamustine in combination with an anti-CD20 
monoclonal antibody (mAb) [21-23]. The addition of RTX to chemotherapy has improved 
response rates, duration of response and overall survival; median survival is now estimated to 
be greater than 12-15 years [24, 25] Use of maintenance RTX has improved progression free 
survival (PFS) compared to observation, with no impact on overall survival (OS) as of yet [24].
While immuno-chemotherapy regimens are initially effective in inducing responses in most, 
the majority of patients inevitably relapse, and the same therapies show decreasing efficacy 
with repeated administration. Many patients become resistant to RTX or RTX-containing 
regimens. Treatment options for patients who have failed first-line therapy depend upon factors 
such as prior treatment used, patient age and co-morbidities, and duration of prior response. 
Bendamustine or CHOP is commonly given with RTX. For patients who relapsed after, or are 
refractory to RTX, the combination of bendamustine-obinutuzumab followed by obinutuzumab 
monotherapy was recently shown to be superior to bendamustine alone for PFS in the phase 3 
“GADOLIN” study. This resulted in a full approval by the European Medicines 
Agency (EMA) and the US Food and Drug Administration (FDA) in 2016 for the treatment of 
patients with FL who relapsed after, or are refractory to, a RTX-containing regimen. 


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Fludarabine-based regimens are another option [22] but caution is warranted for use in elderly 
or heavily pre-treated patients due to toxicity. Radioimmunotherapy targeting CD20 (Yttrium-
90 [90Y]-ibritumomab tiuxetan; Zevalin) is approved for patients with relapsed or refractory, 
low-grade or follicular B-cell NHL, but is underused [26].  
Thus, there remains a significant unmet medical need for therapies for patients with recurrent 
FL, especially for elderly patients who are at risk for developing long-term toxicities such as 
cumulative myelosuppression, cardiac toxicity and immunosuppression. 
2.2.1.1. 
Non-clinical pharmacodynamics 
Betalutin targets and binds the human CD37 antigen, which is abundant on the cell surface of 
tumours of human B-cell origin, including FL. 
Lilotomab does not bind to FcJRIIIA and does not induce antibody dependent cellular 
cytotoxicity (ADCC). It does not bind to the neonatal Fc receptor either. This is a desirable 
property as it limits the half-life of lilotomab in the blood and reduces the time for Betalutin to 
irradiate normal organs which are rich in blood. In addition, lilotomab binds to human C1q at 
concentrations above 2 Pg/mL but does not induce complement dependent in vitro cytotoxicity. 
In vitro, Betalutin is highly cytotoxic in multiple lymphoma cell lines with high expression of 
CD37, appearing to be superior in reduction of cell growth when compared with 177Lu-RTX. 
Betalutin is internalised, which may result in a higher absorbed radiation dose to cells treated 
with Betalutin than with cells treated with non-internalizing Radioimmunoconjugates (RICs), 
such as 177Lu-RTX. The effect of the unlabelled lilotomab antibody on the growth of lymphoma 
cells in vitro and in vivo has been tested in Daudi and Ramos Burkitt’s lymphoma models. No 
growth inhibition of Daudi cells in vitro treated with 100 Pg/mL lilotomab for 2 hours or 
18 hours was observed.  
In vivo, Betalutin was highly active, increasing survival compared with controls in 
immune-compromised mice (SCID) mice after intravenous (i.v.) injection of CD37-positive 
Daudi cells, and inhibiting tumour growth and increasing survival in Nude mice with Ramos 
lymphoma xenografts in vivo [27, 28]. The main toxicities were haematological in nature. In 
an i.v. model of mantle cell lymphoma (Rec-1 cells), Betalutin alone and in combination with 
RTX resulted in significantly improved survival as compared with no treatment [12]. In a 
subcutaneous (s.c.) model of Burkitt’s lymphoma (Daudi cells), Betalutin showed a strong 
synergistic effect with RTX [11].  There was no effect on survival of SCID mice i.v. injected 
Daudi cells treated with a single injection of 50 Pg lilotomab or on Ramos s.c. xenografts 
treated with a single injection with 15 mg/kg lilotomab compared with control.  
The cross reactivity of the lilotomab antibody to different human tissues and to other animal 
species has been evaluated by immunohistochemistry and flow cytometry. Antigen specific 
binding to B-cells (and not to T-cells or natural killer [NK] cells) was observed and no cross-
reactivity was found to any of the other species investigated (rhesus and cynomolgus monkeys, 
marmoset, rabbit, rat, mouse, dog, mini-pig and guinea-pig).   
2.2.1.2. 
Non-clinical pharmacokinetics and biodistribution 
Biodistribution studies with Betalutin in mouse models have been performed to investigate the 
uptake in tumour and normal tissues, and to compare the biodistribution of Betalutin to that of 
anti-CD20 antibody RTX (177Lu-RTX). 


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Betalutin was stable when injected into mice, with no dissociation of the radionuclide detected, 
and was targeted to tumour xenografts in mice, where it accumulated up to 4 days. Betalutin 
distribution was similar for mice with Daudi and Ramos tumour xenografts, with the exception 
of an observation of higher uptake in lymph nodes with Ramos xenografts, and pre-treatment 
with either rituximab or lilotomab had no significant effect on biodistribution of Betalutin. 
Biodistribution of Betalutin and 177Lu-RTX was similar in normal organs and Daudi tumour 
xenografts in nude mice. 
2.2.1.3.
Toxicology
As no relevant animal model with cross-reactivity to the lilotomab antibody could be identified, 
the most relevant studies identified for safety evaluation to determine tolerability and target 
organ toxicity were combined toxicity and therapy studies in immune-compromised SCID and 
nude mice). The maximum tolerated dose (MTD) of Betalutin in SCID mice with bone marrow 
lymphoma involvement was between 50 and 100 MBq/kg, and 530 MBq/kg in nude mice. The 
most common toxicities were reversible leukopenia and thrombocytopenia, occurring 3 weeks 
after Betalutin administration, and recovering after 7 weeks.
A detailed description of the chemistry, pharmacology, efficacy and safety of Betalutin is 
provided in the Investigator’s Brochure.
Clinical experience with Betalutin
2.2.2.1.
Phase 1/2 single, ascending dose study in patients with relapsed indolent 
NHL (LYMRIT-37-01)
This first-in-human study was performed to evaluate the safety, preliminary efficacy, PK and 
biodistribution of Betalutin in patients with relapsed iNHL (subtypes mantle cell, follicular 
grade I-IIIa, marginal zone, small lymphocytic, lymphoplasmacytic lymphoma). Patients were 
enrolled into 4 dose escalation arms of 3 patients each to receive a single i.v. dose of Betalutin 
(10, 15, 20 MBq/kg) following pre-treatment with RTX (1 or 2 doses at least 2 weeks prior), 
and immediate pre-dosing with lilotomab 40 mg (Arm 1) or 100 mg/m2 (Arm 4), RTX (Arm 
3) or no pre-dose (Arm 2) to define the MTD of Betalutin, and to collect additional PK data 
(n=3; Arm 5).  The Phase 1 part of the study utilises a 3+3 dose-escalation study design with 
the primary objective of defining the MTD of Betalutin. Secondary objectives are to identify a 
recommended dose of Betalutin for the Phase II part of the study, and investigate the safety, 
biodistribution, PK and efficacy of Betalutin. 
As of 03 July 2017, 62 patients have been enrolled in the study. NHL subtypes were FL (n=47 
76%), mantle cell lymphoma (MCL) (n=7; 11%), and marginal zone lymphoma (MZL) (n=8; 
13%). The median age of the patients was 69; 46 patients (74ZHUH\HDUVROG7KH
median number of prior therapies was 3 (range 1-8); 42 patients (68 UHFHLYHG  SULRU
therapies, and 34 patients (55UHFHLYHGSULRURTX courses. 
Three patients were enrolled in Arm 2; the dose-limiting toxicity (DLT) rate exceeded 20% 
with a Betalutin dose of 15 MBq/kg, and this arm was closed. Three patients were enrolled in 
Arm 3 and received 15 MBq/kg Betalutin; one developed a DLT. Arm 3 was closed following 
a review of the first 3 patients as RTX pre-dosing on Day 0 was observed to have a lesser 
protective effect on neutropenia/thrombocytopenia development than either 40 mg or 
100mg/m2 of lilotomab.


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With a lilotomab pre-dose of 40 mg (Arm 1), the recommended dose of Betalutin for phase 2 
expansion was 15 MBq/kg. In total, 36 patients have received this regimen (25 with FL); the 
overall response rate (ORR) is 64% (CR 25%), and 72% (CR 24%) for the FL subset, and the 
toxicity profile is favourable. The incidence of grade 3/4 neutropenia and thrombocytopenia 
was 20/36 (56%) for both. Grade 4 neutropenia and thrombocytopenia were reported in 
7 patients (19%) and 6 patients (17%) respectively. Of these, there were 2 patients with grade 
4 neutropenia lasting >7 days, and 2 with grade 4 thrombocytopenia >7 days. 
In Arm 4 (lilotomab pre-dose of 100 mg/m2), the recommended Betalutin dose for phase 2 
expansion was 20 MBq/kg. Eight patients have been enrolled; the ORR is 50%. Two FL 
patients have had a CR. The incidences of grade 3/4 neutropenia and thrombocytopenia were 
3/8 (38%) and 4/8 (50%) respectively (there was one grade 4 thrombocytopenia reported). One 
patient had a DLT of haematuria with thrombocytopenia (platelet count of 40 x 109/L) and 
received a platelet transfusion. A phase 2 expansion cohort is currently enrolling up to 
15 patients.    
Overall, Betalutin treatment was well-tolerated, with the most common adverse events (AEs) 
reported being neutropenia and thrombocytopenia which were transient and generally required 
no intervention. Bruising/bleeding episodes were reported in 3 and 4 patients respectively; only 
2 patients required platelet transfusions for bleeding events in association with 
thrombocytopenia (one with epistaxis and one with haematuria). Overall, 23 patients (39%) 
developed infections, with urinary and respiratory tract infections (including nasopharyngitis) 
being most commonly reported (19 patients [32%]). The majority of infections were low grade 
in nature. The dosing regimen was generally well tolerated, with only 2 infusion reactions 
reported; both were related to RTX. 
Serious adverse events (SAEs) were reported in 14 patients (23%). Treatment-emergent SAEs 
occurring in 2 or more patients were thrombocytopenia (n=2), atrial fibrillation (n=2), sepsis 
(n=2) and lymphoma progression (n=2). Both atrial fibrillation episodes were grade 2 in nature 
and resolved within 24 hours with oral therapy. One episode was reported 9 months after 
Betalutin administration. Two patients were reported with sepsis; both episodes occurred in 
association with neutropenia around Day 40, and both fully resolved within 7-10 days with 
antibiotic therapy. One patient had an antecedent urinary tract infection. An SAE of 
myelodysplastic syndrome (MDS)/ Acute myeloid leukaemia (AML) was reported in one 
patient 24 months after Betalutin administration. This patient had a history of prior alkylating 
exposure and went on to receive 6 courses of bendamustine/RTX following Betalutin 
administration. MDS/AML was reported 18 months later; the outcome was fatal, and the SAE 
was judged to be possibly related to Betalutin and/or prior therapy by the Investigator. There 
was one on-study death (i.e. within 12 weeks of Betalutin administration) due to disease 
progression that was not considered related to Betalutin.  
The PK profile of Betalutin as assessed by measuring the total radioactivity in blood shows an 
impact of pre-dosing with lilotomab (40 mg and 100 mg/m2), with lilotomab increasing the 
activity-adjusted area under the curve (AUC), and reducing the volume of distribution and rate 
of clearance of Betalutin, while having little effect on activity-adjusted maximum plasma drug 
concentration (Cmax) compared to no lilotomab pre-dosing. These observations could be 
consistent with blocking of the CD37 antigen sink in the bone marrow by lilotomab and 
consequently a reduced absorbed radiation dose compared to Arm 2. Preliminary 
biodistribution data (dosimetry) also indicate that both the 40 mg and the 100 mg/m2 lilotomab 
pre-dosing regimens of Arms 1 and 4 protect the bone marrow as compared with no pre-dosing 
in Arm 2, since the absorbed radiation doses to red marrow are lower for Arm 1 and 4 than for 


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Arm 2. The maximum absorbed radiation dose to the red marrow for all patients in Arms 1 and 
4 is below the previously published radiological tolerance limit (3 Gy).
For more details, please refer to the Investigator’s Brochure.
2.3.
Overview of combination treatment with Betalutin plus rituximab
Non-clinical experience
In vitro models of Burkitt’s (Ramos cells) and mantle cell lymphoma (Rec-1 cells)
demonstrated increased surface CD20 expression following 177Lu-HH1 (Betalutin) treatment 
compared with cells treated with unlabelled HH1 (lilotomab) [12].  Treatment of nude mice 
with Ramos xenografts with Betalutin resulted in a 3-fold higher uptake of radiolabelled RTX
in tumour xenografts 5 days after start of treatment than in mice treated with unlabelled HH1
(p <0.05). In SCID mice with i.v. injected Rec-1 cells, the combination of Betalutin and RTX 
resulted in significantly improved survival as compared with saline (NaCl) or RTX alone [12].
The therapeutic effect of the combination of Betalutin and rituximab was also studied in nude 
mice with s.c. Burkitt's lymphoma (Daudi) xenografts [11]. Sequential therapy with Betalutin 
followed by RTX substantially reduced tumour growth and improved overall survival
compared to either agent alone, suggesting synergism between the 2 agents (Figure 2-1).
Figure 2-1
The effect of combining Betalutin plus RTX on tumour volume and survival 
in a preclinical NHL model


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Clinical experience
There are no clinical data or ongoing studies combining Betalutin with RTX. One phase 2 study 
has been reported combining Zevalin with RTX in FL patients (summarised in Section 2.3.3).
Potential for overlapping toxicities between Betalutin and rituximab
Although there have been no prior combination studies with Betalutin and RTX, there is one 
report of a phase 2 study in treatment-naïve FL patients exploring short course CHOP-RTX 
followed at haematologic count recovery by 90Y-ibritumomab tiuxetan (Zevalin) and 4-weekly 
RTX doses (375 mg/m2), starting within 1-2 weeks of receiving radioimmunotherapy (RIT)
[17]. For the 55 (out of 60) patients who completed all 3 therapies per protocol, the most 
frequent toxicities reported following RIT/RTX were grade 3/4 neutropenia and 
thrombocytopenia in 51% and 44% (grade 4 for both in 20%) of patients respectively, one 
prolonged episode of grade 3 serum sickness-like toxicity, and one episode of febrile 
neutropenia. All patients had normal white blood cell and platelet counts by Week 12 post-RIT.
The main toxicities of RTX reported in NHL patients are infusion reactions, fever, 
lymphopenia, chills, infection and asthenia (MabThera-prescribing information). In patients
with NHL receiving RTX monotherapy, grade 3 and 4 cytopenias were reported in 48% of 
patients. These included lymphopenia (40%), neutropenia (6%), leukopenia (4%), anaemia
(3%) and thrombocytopenia (2%). Grade 3/4 lymphopenia has been reported in approximately 
30% of patients receiving Betalutin. Therefore, while combining RTX with Betalutin is not 
expected to contribute significantly to the development of neutropenia, thrombocytopenia or 
anaemia, prolonged lymphopenia may increase the incidence of infection. Patients will be 
monitored frequently by clinical and laboratory assessments for sequelae of myelosuppression 
(infections, bruising and bleeding, febrile neutropenia).


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2.4. 
Benefit/Risk Assessment 
Patients to be included in this study are adults with relapsed, refractory (not anti-CD20 antibody 
refractory) FL. The patient will have received and be considered to have experienced treatment 
failures from prior treatment regimens, including chemotherapy and immunotherapy treatment 
regimens. Treatment options for patients with relapsed/refractory FL are dependent upon the 
prior regimens that the patient received, and whether the patient is elderly or able to tolerate 
chemotherapy (due to presence of comorbidities). Generally, chemoimmunotherapy + 
rituximab maintenance therapy is recommended per ESMO Clinical Practice Guidelines for 
relapsed FL [29] For example, if a patient received prior chemoimmunotherapy with CHOP-
rituximab (CHOP-R) previously, then bendamustine-rituximab (BR) may be tried, or vice 
versa. Another option, particularly for elderly patients with comorbidities prohibiting 
chemotherapy, is rituximab monotherapy, however this is associated with an ORR of 
approximately 50% and a median time to progression of around 7-10 months [30, 31]. 
Radioimmunotherapy is another option but is underused. The safety profile of Betalutin is 
well-characterised. The most common grade 3/4 toxicities for Betalutin are thrombocytopenia 
and neutropenia which resolve by 3 months for the majority of patients. The incidence of 
bruising/bleeding episodes (7 patients), which were mostly mild in nature, and grade 3/4 
infections (5 patients) was low. Infections occurred in association with neutropenia. Lilotomab 
pre-dosing was shown to mitigate the severity of cytopenia; evaluation of efficacy with a higher 
lilotomab pre-dose is on-going.  
Betalutin has demonstrated clinical activity as a single agent and preliminary evidence of 
durable responses and is well-tolerated in patients with relapsed/refractory iNHL and FL. 
Preliminary efficacy data show an ORR of at least 70% for FL patients pre-treated with 40 mg 
lilotomab followed by 15 MBq/kg of Betalutin (Arm 1), which is the dosing regimen to be used 
in this study. Eighty-four per cent of patients in the LYMRIT 37-01 study have experienced 
some degree of decrease in tumour size [4]. Early duration of response data from Arm 1 (n=28) 
also suggests clinical benefit with a median duration of response of over 12 months. These are 
promising results in a population of primarily older, heavily pre-treated relapsed iNHL patients 
with advanced-stage disease. 
Patients will be closely monitored for evidence of any overlapping toxicities due to combining 
Betalutin with RTX, such as infections, febrile neutropenia, bruising or bleeding episodes. 
Taken together, the data provided demonstrate a positive benefit:risk balance for Betalutin for 
the treatment of patients with recurrent FL, a primarily elderly population with a high unmet 
medical need.  
 


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3. 
Objectives and Endpoints 
Objectives and related endpoints are described in Table 3-1 below. 
Table 3-1  
Study objectives and endpoints 
Objectives 
Endpoints 
Primary 
 
x 
To evaluate the safety and tolerability of 
Betalutin in combination with RTX  
x 
Frequency and severity of adverse events (AEs), 
serious adverse events (SAEs) and changes in 
laboratory values graded according to CTCAE 
version 4.03 
Secondary 
 
x 
To establish a recommended dose of Betalutin 
in combination with RTX for phase 2 studies 
in NHL patients 
x 
Frequency and severity of AEs, SAEs and changes 
in laboratory values graded according to CTCAE 
version 4.03 
x 
To evaluate the preliminary anti-tumour 
activity of combination treatment based on 
Investigator assessment of tumour response 
rates 
x 
Responses (overall response rate [ORR], complete 
response [CR], partial response [PR], stable disease 
[SD], progressive disease [PD]) per Cheson 2014 
[30] 
x 
To evaluate the duration of tumour control in 
patients receiving Betalutin in combination 
with RTX 
x 
Duration of response (DoR) 
x 
Progression free survival (PFS) 
x 
Time to progression (TTP) 
x 
Overall survival (OS) 
x 
To investigate the immunogenicity of 
Betalutin in combination with RTX 
x 
Monitoring of the anti-drug antibodies (ADA) 
response towards lilotomab, Betalutin and/or RTX 
Exploratory 
 
x 
To characterise the pharmacokinetics (PK) of 
Betalutin in combination with RTX 
x 
Estimation of the levels of remnant administered 
radioactivity in blood over time (Betalutin PK) 
x 
To assess the pharmacodynamic effects of 
Betalutin in combination with RTX 
x 
Change from baseline in peripheral blood B-cell, T-
cell and NK cell counts, tumour CD20 and CD37 
expression  
x 
Biomarker assessments 
x 
To investigate the biodistribution of 
Betalutin in combination with RTX 
x 
Estimation of whole-body retention of radioactivity 
at each imaging time post-injection.  
x 
Estimation of the individual organ uptake/retention 
of radioactivity at each imaging time-point after 
injection.  
x 
Calculation of estimated absorbed radiation dose to 
target organ. 
x 
To evaluate minimal residual disease in 
patients with a CR 
x 
Monitoring of detectable disease to assess early 
treatment response and detect relapse using next 
generation sequencing (NGS) (molecular Minimal 
Residual Disease (MRD)) 


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x 
To evaluate the relationship between anti-
tumour activity and NHL-related genes in 
tumour samples 
x 
Gene expression analysis using a panel of cancer-
related genes 
 
x 
To assess anti-tumour T-cell responses  
x 
Anti-tumour response measured by flow cytometry 
after co-culture of peripheral mononuclear cells and 
autologous lymphoma cells and other biomarkers 


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4. 
Study Design 
4.1. 
Overall Design 
This protocol describes a Phase 1b open-label, single-arm, dose escalation study to investigate 
the activity and safety and preliminary efficacy of Betalutin combined with RTX in patients 
with FL who have received one or more prior therapies. It is planned that 6-12 evaluable 
patients will be enrolled in the study. 
All patients will receive a single i.v. dose of RTX (375 mg/m2) on Day -14, and then sequential 
i.v. administrations of lilotomab (40 mg) followed by Betalutin (10 or 15 MBq/kg) within 
4 hours on Day 0. Patients will then be administered RTX (375 mg/m2) i.v. on Days 7, 14, 21 
and 28. 
Patients will undergo clinical and laboratory assessments during screening/baseline and 
periodically during treatment as outlined in the Schedule of activities (Section 1.2). Two 
cohorts of 3-6 patients will be initially evaluated for DLT, in a 3+3 escalation pattern, before 
determining the subsequent Betalutin dose for the remainder of the study (Section 6.1). 
Tumour-tissue biopsies and blood samples will be collected to study the mechanisms of tumour 
response to therapy as described in the biomarkers section (Section 9.4). The collection of these 
samples is optional and, at Radium Hospital (Oslo, Norway) only. 
PET/CT and CT imaging (or MRI) will be performed at baseline and then at 3 and 6 months. 
CT with contrast (or MRI) will be performed at 12, 18, 24 months or until disease progression 
or withdrawal from the study for any other reason (whichever comes first). 
Patients who achieve SD, CR or PR on their Month 3 imaging scan will be administered 
maintenance RTX 375 mg/m2 i.v. or 1400 mg s.c. every 3 months for up to 2 years (8 infusions 
in total), or until disease progression or withdrawal from the study for any other reason 
(whichever comes first). 
The schedule plan for dosing and imaging is illustrated in Figure 4-1. 
 


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Figure 4-1  
Study dosing and imaging plan 
 
 


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4.2. 
Rationale for Study Design 
This phase 1b exploratory study will investigate the dosing of Betalutin in combination with 
RTX, whereby RTX is given 7 days following Betalutin to capitalise on potential enhanced 
CD20 expression following Betalutin administration. Repeat RTX doses (4-weekly, i.v.) have 
been safely administered to 55 treatment-naïve FL patients 1-2 weeks after 3 courses of 
CHOP-RTX followed by Zevalin once hematologic recovery was attained in a phase 2 study. 
[17]. All patients had full hematologic count recovery by 12 weeks post-RIT.  
As summarised in Section 2.1, both Betalutin and RTX deplete B-lymphocytes and B-cell NHL 
cells. Grade 3 or higher myelosuppression (anaemia, neutropenia and thrombocytopenia) has 
been reported in 6% of NHL patients receiving RTX (MabThera prescribing information). 
Thus, it is anticipated that dosing RTX one week following Betalutin will not impact the 
development of myelosuppression acutely, although there is potential for prolonged 
B-lymphocyte depletion. Therefore, all patients will be closely followed clinically and with 
laboratory tests to monitor for infection. We hypothesise that combining Betalutin with RTX 
could enhance both the response rates and the durability of responses in patients with recurrent 
FL, providing an alternative to a chemotherapy-containing regimen for patients.  
Patients with relapsed/refractory FL are reported to benefit from rituximab maintenance 
therapy, with improved overall survival [31]. Therefore, responding patients (i.e. those having 
a CR, PR or SD response following Betalutin and the 4-weekly doses of i.v. RTX) will receive 
maintenance RTX every 3 months for up to 2 years (a total of 8 doses), or until disease 
progression, commencing at Week 14. This may be administered by either i.v. (375 mg/m2) or 
s.c. (fixed dose of 1400 mg) routes.  
The safety of patients in this study will be monitored as described in Section 9.2 (Safety 
Assessments). Two cohorts of 3-6 patients will be initially evaluated for DLT before 
determining the subsequent Betalutin dose for the remainder of the study (see Section 6.1). 
4.3. 
Rationale for Dose 
This is the first study evaluating the combination of Betalutin and RTX. The starting dose of 
Betalutin (10 MBq/kg) following a lilotomab pre-dose of 40 mg is one dose level lower than 
the recommended phase 2 dose for expansion (15 MBq/kg) in the LYMRIT 37-01 study and 
has been safely administered to 3 NHL patients. This starting dose for Betalutin is chosen to 
reduce the risk for overlapping toxicities, and for subsequent patients, the Betalutin dosing 
regimen chosen (40 mg lilotomab pre-dose and 15 MBq/kg Betalutin) has been administered 
to 36 patients in the LYMRIT 37-01 study, and has been well-tolerated (see Section 2.2.2.1). 
As of the writing of this protocol, 11 patients (evaluable for safety) have received a lilotomab 
pre-dose of 100 mg/m2 followed by 20 MBq/kg Betalutin, therefore the clinical profile of the 
former regimen is better characterised.  
Regarding immunogenicity, the presence of anti-drug antibodies (ADA) was reported for 7 out 
of 62 patients enrolled. The observed ADA response was transitory, detected after 7 days (n=1) 
or 1 month (n=6). For one of the two patients with 12-months post-treatment results available, 
a new onset of ADA was observed. Two patients who were treated with a lilotomab pre-dose 
of 100 mg/m2 developed ADAs at 1 month that disappeared by 3 months. None of the patients 
treated with 40 mg lilotomab and 15 MBq/kg Betalutin developed ADAs. 


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The dose regimen of RTX chosen is that which had been approved for use in relapsed/refractory 
FL patients. RTX has single agent activity in relapsed FL and has been safely combined using 
both single and multiple doses with a number of myelosuppressive chemotherapeutic agents 
and regimens including bendamustine, CHOP (cyclophosphamide, doxorubicin, vincristine, 
prednisone) and CVP (cyclophosphamide, vincristine, prednisone) as standard therapy for 
NHL patients. In contrast to standard chemotherapy, side effects of RTX are modest (mostly 
chills, fevers, headache and infusion reactions) and mainly confined to the first infusion of 
rituximab. In combination with CHOP and CVP, the incidence of grade 3 or 4 neutropenia is 
approximately 10% higher than with CVP or CHOP alone, without a difference in overall 
infection rate or sepsis [24, 33]. 
As discussed in the previous section, as patients with relapsed/refractory FL are reported to 
benefit from rituximab maintenance therapy [31], responding patients (i.e. those having a CR, 
PR or SD response following Betalutin and the 4-weekly doses of i.v. RTX) will receive 
maintenance RTX every 3 months for up to 2 years (a total of 8 doses), or until disease 
progression or withdrawal from the study for any other reason (whichever comes first), 
commencing at Week 14.   
4.4. 
Patient and Study Completion 
Approximately 10-15 patients will be screened to achieve 6-12 patients assigned to study 
treatment and evaluable.  
4.5. 
End of Study Definition 
The end of study for all patients will be the date of the last patient last visit upon completion 
of their end of study visit(25 months after receiving their Betalutin treatment if ending study 
treatment per protocol, or after disease progression or withdrawal from the study for any other 
reason, (whichever comes first) or if the study is terminated early.  
 


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5. 
Population 
This study will be conducted in adult patients with relapsed FL or who are refractory (not 
anti-CD20 antibody refractory) and have received one or more prior therapies, including 
anti-CD20 therapy. 
5.1. 
Inclusion Criteria 
Patients are eligible to be included in the study only if all of the following criteria apply: 
1) 
3DWLHQWPXVWEH\HDUVDWWKHWLPHRIVLJQLQJWKHLQIRUPHGFRQVHQW 
2)  
A pre-study Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 
3) 
Histologically confirmed diagnosis (by 2008 World Health Organization [WHO] 
classification) of indolent non-Hodgkin B-cell FL (grade 1, 2 or 3a)  
4)  
At least one (but not more than 3) prior regimens with an anti-CD20 antibody (alone or 
in combination with chemotherapy), with documented relapsed, refractory disease (must 
not be anti-CD20 antibody-refractory) or PD 
5)  
Presence of at least one bi-dimensionally measurable lesion by CT or MRI: longest 
diameter (LDi) >1.5 cm for a nodal lesion; LDi >1.0 cm for an extranodal lesion within 
28 days prior to start of treatment  
6)  
Normal organ and bone marrow function defined as: 
a. 
$EVROXWHQHXWURSKLOFRXQW[9/L; 
b. 3ODWHOHWFRXQW[9/L;  
c. 
+DHPRJORELQJG/ 
d. Total bilirubin 1.5 x upper limit of normal (ULN) (except patients with documented 
Gilbert’s syndrome [<3.0 mg/dL]); 
e. 
Liver enzymes: Aspartate transaminase (AST); Alanine transaminase (ALT) or 
Alkaline phosphatase (ALP) [8/1RU[8/1LIOLYHULQYROYHPHQWE\
primary disease); 
f. 
Adequate renal function as demonstrated by a serum creatinine within the upper limit 
of normal range 
7)  
Bone marrow involvement by lymphoma <25% 
8)  
Life expectancy >3 months 
9)  
Negative hepatitis B, hepatitis C and human immunodeficiency virus (HIV) screening 
tests 
10) Undetectable human anti-murine antibody (HAMA) at screening  
11)  Women of childbearing potential (see Appendix 3) must: 
a.  have a negative serum pregnancy test at screening  
b.  understand that the study medication is expected to have teratogenic risk 
c.  agree to use, and be able to comply with, highly effective method of birth control 
with a Pearl-,QGH[ 
Contraception is required without interruption, from 4 weeks before starting study drug, 
throughout study drug therapy and for 12 months after end of study drug therapy, even 
if she has amenorrhea 


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12)  Male patients must agree to use condoms (See Appendix 3) during intercourse throughout 
study drug therapy and for 12 months after end of study drug therapy 
13)  The patient is willing and able to comply with the protocol, and agrees to return to the 
hospital for follow-up visits and examination 
14) Capable of giving signed informed consent which includes compliance with the 
requirements and restrictions listed in the informed consent form (ICF) and in this 
protocol 
5.2. 
Exclusion Criteria  
Patients are excluded from the study if any of the following criteria apply: 
1) 
Previous haematopoietic stem cell transplantation (autologous and allogenic) 
2) 
Evidence of histological transformation from FL to DLBCL at time of screening.  
3) 
Previous total body irradiation 
4) 
Chemotherapy, immunotherapy or investigational therapy within 28 days before the start 
of study drug administration FRUWLFRVWHURLGWUHDWPHQWDWGRVHVRIPJGD\WRSLFDORU
inhaled corticosteroids, granulocyte colony-stimulating factor [G-CSF] or granulocyte-
macrophage colony-stimulating factor [GM-CSF] are permitted up to 2 weeks prior to 
start of study treatment) or failure to recover from AEs associated with prior treatment 
5) 
Previous treatment with radioimmunotherapy 
6) 
Patients who are receiving any other investigational medicinal products 
7) 
Known or suspected central nervous system (CNS) involvement of lymphoma 
8) 
History of a previous treated cancer except for the following:  
a) adequately treated local basal cell or squamous cell carcinoma of the skin 
b) cervical carcinoma in situ 
c) superficial bladder cancer or localised prostate cancer undergoing surveillance or 
surgery 
d) localised breast cancer treated with surgery and radiotherapy but not including 
systemic chemotherapy 
e) other adequately treated Stage 1 or 2 cancer currently in CR 
9)  
Pregnant or lactating women (See Appendix 3) 
10)  Exposure to another CD37 targeting drug 
11)  A known hypersensitivity to RTX, lilotomab, Betalutin or murine proteins or any 
excipient used in RTX, lilotomab or Betalutin  
12)  Receipt of live, attenuated vaccine within 30 days prior to enrolment 
13) Evidence of severe or uncontrolled systemic diseases: 
a. 
Uncontrolled infection including evidence of ongoing systemic bacterial, fungal, 
or viral infection (excluding viral upper respiratory tract infections) at the time of 
initiation of study treatment 
b. 
Pulmonary conditions e.g. unstable or uncompensated respiratory disease 
c. 
Hepatic, renal, neurological, or metabolic conditions - which in the opinion of the 
Investigator would compromise the protocol objectives 


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d. 
Psychiatric conditions e.g. patients unlikely to comply with the protocol, e.g. 
mental condition rendering the patient unable to understand the nature, scope, and 
possible consequences of participating in the study 
e. 
History of erythema multiforme, toxic epidermal necrolysis or Stevens-Johnson 
syndrome 
f. 
Cardiac conditions, including: 
i. history of acute coronary syndromes (including unstable angina) 
ii. class II, III or IV heart failure as defined by the New York Heart Association 
(NYHA) functional classification system 
iii. known uncontrolled arrhythmias (except sinus arrhythmia) in the past 
24 weeks 


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6. 
Study Treatment  
For this study, the term “study drug(s)” refer to RTX, lilotomab or Betalutin.  
RTX, lilotomab and Betalutin can all be administered on an outpatient basis, dependent on 
local regulations. The patient should be under surveillance at the clinic/hospital for at least 
2 hours after administration (unless local regulations require a longer surveillance period). 
Detailed written instructions on labelling and preparation will be given to the study site prior 
to patient inclusion. See also Investigator’s Brochure and RTX prescribing information. 
6.1. 
Dosing regimen 
Two cohorts of 3-6 patients will initially be evaluated. The first cohort of 3 patients will be 
treated with a single i.v. dose of RTX (375 mg/m2) on Day -14, and then on Day 0, sequential 
i.v. administration of lilotomab (40 mg) followed by Betalutin (10 MBq/kg) within 4 hours on 
Day 0. The patients will then be administered RTX (375 mg/m2) i.v. on Days 7, 14, 21 and 28.  
Patients must have received all doses of study drug and have had an adequate period of follow-
up (i.e. having achieved haematological recovery to  grade 2) to be considered evaluable for 
a dose escalation decision or to determine the dose for further Phase 2 studies following 
enrolment of the second cohort of 3-6 patients. The dose for the next cohort of 3 patients will 
be determined by the Investigator(s) and Nordic Nanovector study personnel via 
teleconference. Decisions will be based on a review of all safety data (clinical and laboratory) 
and are outlined as follows: 
1. 
If 0/3 patients experience a DLT (defined below), the next cohort of 3 patients will 
receive lilotomab 40 mg plus Betalutin 15 MBq/kg prior to RTX on Day 0. 
2. 
If 1/3 patients experience a DLT, then 3 more patients will be enrolled in the current 
cohort at this dose level (Betalutin 10 MBq/kg). 
3. 
If 2/3 patients experience a DLT, then subsequent Betalutin/lilotomab and/or RTX 
dosing will be determined by the Investigator(s) and Sponsor after a review of the safety 
data. 
4. 
If 1/6 patients experience a DLT, the next cohort of 3 patients will be treated with 
Betalutin 15 MBq/kg. 
5. 
If 0/3 patients receiving Betalutin 15 MBq/kg experience a DLT, the remainder of the 
patients in the study will continue to be treated with Betalutin 15 MBq/kg. 
6. 
If 1/3 patients experience a DLT, then 3 more patients will be enrolled at this dose level 
(Betalutin 15 MBq/kg).  
7. 
If 1/6 patients receiving Betalutin 15 MBq/kg experience a DLT, the dose for further 
Phase 2 studies will be Betalutin 15 MBq/kg. 
8. 
If 2/6 patients experience a DLT, then 3 more patients will be treated at the lower 
Betalutin dose (10 MBq/kg).  
9. 
The final recommendation for Betalutin/lilotomab dosing for further Phase 2 studies will 
be determined by the Investigator(s) and Sponsor after a review of the available safety 
data.  
 


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DLT is defined as:  
Haematological: Anemia, neutropenia or thrombocytopenia CTCAE (v4.03) grade 4 lasting 
>7 days, or grade 3 thrombocytopenia with clinically significant bleeding, or febrile 
neutropenia (ANC <1000/mm3 ZLWKDWHPSHUDWXUH!Û& 
Non-haematological: An AE of CTCAE (v4.03) grade 3 or higher where the relationship to 
study treatment cannot be ruled out, and is not primarily related to disease, disease progression, 
intercurrent illness or concomitant medications that occurs within the first 12 weeks of 
treatment. Other clinically significant toxicities may also be considered to be DLTs by the 
Investigators and Sponsors, even if not CTCAE grade 3 or higher. 
Responding patients (i.e. those having a CR, PR or SD response following Betalutin and the 
4-weekly doses of i.v. RTX) will receive maintenance RTX every 3 months for up to 2 years 
(a total of 8 doses), or until disease progression, commencing at Week 14. This may be 
administered by either i.v. (375 mg/m2) or s.c. (fixed dose of 1400 mg) routes.  
 
 
 


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6.2. 
Treatments Administered 
Study Treatment Name: 
Rituximab 
Lilotomab 
Betalutin 
Dosage formulation: 
 
As per approved product 
information 
Single use vial containing 
10 mL of lilotomab at a 
concentration of 5 mg/mL 
formulated in 40 mM 
phosphate buffer (35.5 mM 
disodium hydrogen 
phosphate dodecahydrate and 
4.5 mM sodium dihydrogen 
phosphate dihydrate), pH 7.6, 
8.7 mM NaCl, 5% sucrose 
and 0.02% polysorbate-20 
 
 
Single use vial containing 
8-10 mL of Lutetium (177Lu) 
lilotomab satetraxetan at a 
concentration of 0.78 mg/mL 
formulated in: 6.2 mM 
(0.48 mg/mL) Ammonium 
acetate, 161.5 mM (32 
mg/mL) of sodium ascorbate, 
0.81 mM (0.32 mg/mL) of 
diethylenetriamine pentaacetic 
acid (DTPA), 19.3 mM 
(0.77 mg/mL) of NaOH, 
64 mg/mL of recombinant 
Albumin, 25.4  mM (3.5 
mg/mL) of Sodium 
dihydrogen phosphate 
monohydrate and 77 mM 
(4.5 mg/mL) of NaCl.  
HCl is added in trace amounts 
to reach a pH in the Betalutin 
drug product of 6.9 ±0.5. 
Recombinant albumin 
constitutes for about 60% of 
the dry weight of the Betalutin 
drug product.  
The total radioactivity in the 
vial is in the range from 
3222-3938 MBq. 
Unit dose 
strength(s)/Dosage 
level(s): 
375 mg/m2 
40 mg 
10 or 15 MBq/kg 
Route of Administration  
i.v. infusion through dedicated 
line or s.c. injection (as per site 
practice). s.c. injection 
(different dose) may only be 
used for the maintenance RTX 
dosing commencing at Week 
14. 
i.v. infusion through 
dedicated line     
Slow bolus i.v. injection  
Dosing instructions: 
 
As per approved product 
information 
Provided in drug specific 
Handling Plan 
Provided in drug specific 
Handling Plan 
Packaging and Labeling 
 
As per approved product 
information 
Treatment will be provided 
in a glass vial. Each vial will 
be labeled as required per 
country requirement.  
Treatment will be provided in 
a glass vial. Each vial will be 
labeled as required per country 
requirement.  
 
 


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6.3. 
Preparation/Handling/Storage/Accountability 
1. 
The Investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study drug received and any discrepancies are reported 
and resolved before use of the study drug. 
2. 
Only patients enrolled in the study may receive study drug and only authorised site staff 
may supply or administer study drug. All study drugs must be stored in a secure, 
environmentally controlled, and monitored (manual or automated) area in accordance 
with the labeled storage conditions with access limited to the Investigator and authorised 
site staff. 
3. 
The Investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study drug accountability, reconciliation, and record maintenance 
(i.e., receipt, reconciliation, and final disposition records). 
4. 
Detailed handling and preparation for the study drugs can be found in the appropriate 
Drug Handling Plans. 
5. 
Further guidance and information for the final disposition of unused study drug are 
provided in in the appropriate Drug Handling Plans. 
 
Preparation and administration of Betalutin 
The total activity to be injected will be calculated volumetrically using the patient’s body 
weight (kg) on the day of injection, the dose level, and decay correction factor (DC) to correct 
for physical decay of 177Lu. A table with correction factors is provided in the Drug Handling 
Plan. The dose will be capped for patients who weigh more than 130 kg (patients heavier than 
130 kg will receive the dose for a 130-kg patient). Patients will receive Betalutin under 
supervision of a nuclear medicine specialist and the total radioactivity injected, the activity 
dose and the volume injected will also be recorded as above. The measured dose of Betalutin 
must be within ±10% of the intended prescribed dose. 
The total amount (volume to be drawn into the syringe) to be administered to a patient should 
be calculated as follows:  
 Volume (ml)  =   dose 10 or 15 MBq/kg x body weight (up to a max of 130 kg) 
 
 
Decay corr factor x radioactivity conc. (MBq/ml) 
 
Filling of the syringe should take place at a dedicated area for working with radioactive 
solutions. Site staff should wear medical gloves and eye protection during syringe filling to 
prevent contamination of the radioactive solution of skin and eyes. The individual responsible 
for Betalutin preparation will draw the correct volume of the study drug into a syringe, and 
control the correct activity for administration in a dose calibrator. Data regarding activity and 
volume to be injected for the various patients should be recorded on the study drug 
administration electronic case report form (eCRF) page. 
The syringe should be shielded from radiation during preparation and administration of the 
patient doses. Aseptic technique should be used in the administration of Betalutin. Each patient 
will receive one dose in accordance with the treatment schedule. Betalutin will be given as a 
slow bolus i.v. injection using a shielded syringe driver. After administration, the syringe and 


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line must be flushed with a minimum of 10 mL of sterile normal saline (0.9% NaCl), as detailed 
in the Drug Handling Plan. The equipment used in connection with the preparation and 
administration of the study drug, are to be treated as radioactive waste and should be disposed 
in accordance with hospital procedure for handling of radioactive material. 
 
Patient protection 
The patient will receive verbal and written instructions in accordance with the hospital radiation 
safety policies and procedures regarding precautions, as necessary, after receiving the 
radioactive drug.  Betalutin can be administered on an outpatient basis, dependent on local 
regulations. 
 
Administration of Rituximab 
RTX will be ordered through the standard procedure at the study site. The study drug should 
be administered according to the approved product information (prescribing information) for 
RTX. Pre-medication consisting of an antipyretic and an antihistamine, e.g. paracetamol 
and dexchlorpheniramine or cetirizine, should always be administered before each 
infusion of RTX. The types of pre-medication used prior to RTX infusion will follow each 
study site routine, including any use of corticosteroids. The prepared RTX solution should 
be administered as an i.v. infusion through a dedicated line or s.c. injection (as per study site 
practice). Subcutaneous RTX may be used for the maintenance dosing only. RTX should not 
be administered as an i.v. push or bolus. The standard hospital procedure for infusion of RTX 
will be followed. If an AE occurs, the infusion will be stopped. When the symptoms have 
disappeared, the infusion will be re-started with 50% decreased infusion rate. Any AEs and 
information about pre-medication will be recorded in the eCRF. Other information such as drug 
accountability will be detailed in the RTX Drug Handling Plan. 
 
Administration of Lilotomab  
Lilotomab will be delivered in vials of approximately 5 mg/mL lilotomab. Lilotomab for 
infusion will be prepared aseptically at the hospital and made ready for infusion as detailed in 
the Lilotomab Drug Handling Plan. Pre-medication consisting of an antipyretic and 
antihistamine medication should be administered before infusion of lilotomab. 
The patient must be observed closely during the infusion and in the first hour after the infusion. 
Blood pressure and heart rate are measured before infusion and subsequently every 15 minutes 
until the patient seems clinically stable. The blood pressure and heart rate must be measured at 
30 minutes and at 1 hour after the infusion has ended.  
Temperature is measured before, and 1 hour after, the lilotomab infusion.  
If the patient experiences any reactions, vital signs must be recorded frequently until the patient 
is stable. If any AEs occur, such as a drop in blood pressure, chills, fever and/or dyspnea, the 
infusion should be stopped. When the symptoms disappear, the infusion should be started again 
at 50% reduced infusion rate. The infusion rate of lilotomab may be adjusted depending on 
how well lilotomab is tolerated. Medication and supportive care measures should always be 
available during an infusion and information about pre-medication be recorded in the eCRF.  
 


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Drug Accountability
The study drugs, i.e. RTX, Betalutin and lilotomab, should be kept in a secure place and must 
be administered only to patients in the study. For all three study drugs, an appointed individual 
is responsible for maintaining accurate records of the study drug. A list of study drug (received, 
administered to patients, destroyed) must be prepared and signed by the dedicated person 
responsible for drug handling.
When the drug accountability has been monitored by the Sponsor representative, the vials can 
be destroyed in accordance with hospital procedure. Betalutin should be stored for a minimum 
of 3 months (>10 half-lives) before disposal.
See the Drug Handling Plans for further details.
6.4.
Treatment Compliance
Site staff will check the administration volume for all RTX, lilotomab and Betalutin doses and 
record these in the patient’s source documents and eCRF. Patients will receive Betalutin under 
supervision of a nuclear medicine specialist and the total radioactivity injected, the activity 
dose and the volume injected will also be recorded as described in Section 6.3.
6.5.
Supportive Care Guidelines
Persistent neutropenia (neutrophils/granulocytes <0.5 x 109/L) without fever
Patients with persistent neutropenia may be started on G-CSF 5 μg/kg/daily given s.c. until the 
neutrophil count has reached the local hospital’s reference range.
Neutropenia with fever (neutrophils/granulocytes <1 x 109/L; fever >38qC)
Blood cultures will be obtained from the patient. The patient should start on empiric antibiotics 
as long as clinically indicated. Provision of G-CSF to such patients is highly recommended.
Severe thrombocytopenia (platelets <20 x 109/L) or bleeding with platelets <50 x 109/L 
Patients will be transfused with platelets to maintain a platelet count >20 x 109/L or higher if 
clinically indicated to control bleeding. Epsilon aminocaproic acid may be given to patients
with mucosal bleeding and platelet count <50 x 109/L.
Severe anaemia (Haemoglobin <8.0 g/dL)
Patients will be transfused with packed red blood cells to maintain haemoglobin level 
>8.0 g/dL.
Hypersensitivity
In case of hypersensitivity reactions, study drug administration must be stopped immediately. 
Medicinal products for the treatment of hypersensitivity reactions, e.g. adrenaline, 
antihistamines and corticosteroids, must be available for immediate use in the event of an 
allergic reaction during administration of RTX, lilotomab or Betalutin. 
Extravascular administration 
If extravascular administration of Betalutin or lilotomab, i.e. leakage of the injection to the 
surrounding tissue is suspected, the administration must be terminated immediately. Rinse with 
isotonic saline, elevate the arm and gently massage the arm to facilitate lymphatic drainage.


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6.6. 
Prior and Concomitant Therapy 
Any medication or vaccine (including over-the-counter or prescription medicines, vitamins 
and/or herbal supplements) that the patient is receiving at the time of enrolment or receives 
during the study until 4 weeks following final RTX administration must be recorded in the 
eCRF along with: 
x 
Reason for use 
x 
The generic or trade name 
x 
Start and end dates of administration 
x 
Dosage information including dose and frequency 
The Medical Monitor should be contacted if there are any questions regarding concomitant or 
prior therapy. 
Haematology parameters should be carefully checked prior to administration of any other 
myelosuppressive therapy.  
Warfarin should be changed to low-molecular heparin. The dose of low-molecular heparin 
should be temporarily reduced if platelets are <50 x 109/L, and be temporarily stopped if 
platelets are <25 x 109/L. 
Prophylaxis with allopurinol for tumour lysis will be permitted at the discretion of the 
Investigator. 
Use of live or attenuated vaccines is prohibited throughout the course of the study. 
 


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7. 
Discontinuation of Study Treatment and Patient Withdrawal / 
Discontinuation 
7.1. 
Discontinuation of Study Treatment 
The study may be discontinued at the discretion of the investigator or Sponsor in the event of 
the following:  
x 
Occurrence of serious adverse reactions, including abnormalities in laboratory analysis 
and vital signs which by virtue of their nature, severity and duration are considered 
evidence that the safety of the study patients is no longer assured  
x 
Medical or ethical reasons affecting the continued performance of the study 
x 
Difficulties in the recruitment of patients 
x 
Cancellation of drug development 
7.2. 
Patient Withdrawal/Discontinuation from the Study 
In accordance with the Declaration of Helsinki, each patient is free to withdraw from the study 
at any time. Investigator(s) also have the right to withdraw patients from the study in the event 
of illness, AEs, or other reasons concerning the health or well-being of the patient, or in the 
case of lack of cooperation. 
Should a patient decide to withdraw after administration of the study drug(s) or should the 
Investigator(s) decide to withdraw the patient, all efforts will be made to complete and report 
the observations up to the time of withdrawal as thoroughly as possible. A complete final 
evaluation at the time of the patient’s withdrawal (end of study visit) should be made within 
28 days (± 3 days) of receiving the last study treatment administration if ending treatment per 
protocol, or within 7 days of taking the decision to withdraw if it occurs > 28 days after the last 
study treatment administration and an explanation given of why the patient is withdrawing or 
being withdrawn from the study. The reason and date for withdrawal must be noted in the 
eCRF. If the reason for withdrawal is a clinical AE or an abnormal laboratory test result, 
monitoring will continue until the outcome is evident. The specific event or test result(s) must 
be recorded in the eCRF. If the reason for withdrawal is due to disease progression, the study 
site should make all effort to continue with the safety monitoring.  
Haematological toxicity was observed in the phase 1/2 LYMRIT-37-01 study, with nadir 
values 5 to 7 weeks after injection of Betalutin. It is advisable to monitor the haematology 
parameters of the withdrawn patients between 6 and 9 weeks after the last RTX administration 
or until recovery to CTCAE grade 1 or less. 
Single patient study discontinuation is per definition, when the patient: 
x 
has completed Month 24 administration of rituximab, per protocol or 
x 
experiences one of the following situations before per protocol end of study: 
- 
withdraws consent to participate in the study 
- 
has died 
- 
is lost to follow up 
- 
has disease progression  
- 
starts further anticancer therapy or 
x 
when the patient is withdrawn for a reason other than described above 


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If the reason for withdrawal is death, the immediate cause of death should be noted, in addition 
to death caused by underlying disease, the investigator’s judgement on possible relationship to 
study drug should be recorded in the eCRF.  
Furthermore: 
x 
Survival information, Adverse Drug Reaction (ADR) and Adverse Events of Special 
Interest (AESI) will continue to be collected for any single patient until end of study 
visit, consent withdrawal, lost to follow up or death  
x 
If the patient withdraws consent for disclosure of future information, the Sponsor may 
retain and continue to use any data collected before such a withdrawal of consent 
x 
If a patient withdraws from the study, he/she may request destruction of any samples 
taken and not tested, and the Investigator must document this in the study site records 
x 
The Investigator and Sponsor may continue to use publicly available information to 
establish the survival status of patients who have withdrawn consent 
See Schedule of activities (Section 1.2) for data to be collected at the time of treatment 
discontinuation and follow-up and for any further evaluations that need to be completed. 
7.3. 
Replacement policy 
Patients will not be replaced in the study. However, if a patient is considered to be 
non-evaluable for dose evaluation, enrolment of a new patient to the current cohort will be 
considered if there is less than the required number of evaluable patients.  
7.4. 
Lost to Follow-Up 
A patient will be considered lost to follow-up if he/she repeatedly fails to return for scheduled 
visits and is unable to be contacted by the study site.  
The following actions must be taken if a patient fails to return to the clinic for a required study 
visit: 
x 
The site must attempt to contact the patient and reschedule the missed visit as soon as 
possible and counsel the patient on the importance of maintaining the assigned visit 
schedule and ascertain whether or not the patient wishes to and/or should continue in 
the study. 
x 
Before a patient is deemed lost to follow-up, the Investigator or designee must make 
every effort to regain contact with the patient (where possible, 3 telephone calls and, if 
necessary, a certified letter to the patient’s last known mailing address or local 
equivalent methods). These contact attempts should be documented in the patient’s 
medical record. 
x 
Should the patient continue to be unreachable, he/she will be considered to have 
withdrawn from the study with a primary reason of lost to follow-up.  
Discontinuation of specific sites or termination of the study as a whole is discussed in Study 
Governance Considerations (Appendix 2). 


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8. 
Study Procedures 
Safety and efficacy measurements obtained during the course of the study are summarised in 
the Schedule of activities (Section 1.2) and Section 4. 
As highlighted in Section 8.2.2, safety assessments are to be performed before lilotomab 
infusion during Visit 3. Betalutin to be administered within 4 hours of lilotomab infusion.  
Unless specified, blood samples at each visit to be taken before study drug administration. The 
urine pregnancy test at day 0 to be taken and negative results confirmed before lilotomab or 
Betalutin adminisitered.  
12-lead ECG to be performed during visits described below and also at any other stage during 
the study if clinically indicated. 
8.1. 
Screening Period 
During the initial screening visit at the study site, the Investigator must inform each prospective 
study patient of the nature of the study, explain the potential risks, and obtain written informed 
consent from the patient prior to performing any study-related screening procedures. Once the 
informed consent document has been signed, the patient may undergo the screening 
procedures. 
Pre-treatment period is defined from start of screening to the administration of the first RTX 
dose.  
The tests and assessments outlined in Table 8-1 will be performed within 4 weeks prior to RTX 
infusion (pre-treatment period). 
Table 8-1  
Procedure and assessments at Screening Visit (Visit 1) 
 
Assessment or Procedure 
Explanation 
Obtain Informed Consent 
The patient must be fully informed about the study and 
sign the Informed consent form (ICF). The ICF needs to 
be signed before any treatment or study-related 
procedures are initiated. 
Demographics 
Date of birth, sex, ethnic origin, race should be recorded 
Inclusion/exclusion criteria 
See Section 5 
Medical History 
Record details of all previous or concomitant conditions 
or surgical procedures 
Urinalysis 
To check for urinary infection 
Concomitant medication/therapy 
If the patient is receiving any medication for conditions 
mentioned on the Medical History page, details need to be 
recorded on the Concomitant therapies record 
Physical examination 
Check and describe any significant abnormal physical 
examinations findings (heart, lung, abdomen, general, 
skin, oral cavity, chest and lymph nodes). Any 
abnormalities will be recorded on Medical History record 
Height and weight 
Record height and weight details 
Vital signs 
Systolic/diastolic blood pressure, heart rate, and body 
temperature 


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12-lead ECG 
A copy of the medically reviewed ECG page will be 
signed, dated and interpreted before storing in the patient 
file 
ECOG 
ECOG performance status for study inclusion 
Haematology 
Including haemoglobin, platelet count, white blood cell 
count and differential (absolute count of neutrophils, 
lymphocytes, monocytes, eosinophils and basophils) 
Serum biochemistry 
Including sodium, potassium, calcium, magnesium, 
creatinine, urea, uric acid, alkaline phosphatase (ALP), 
aspartate transaminase (ASAT), alanine transaminase 
(ALAT), lactate dehydrogenase (LDH), gamma-
glutamyltransferase (GGT), glucose, total bilirubin and 
albumin 
Immunophenotyping 
Define absolute cell counts for circulating T-cells, CD4 T-
cells, CD8 T-cells, B-cells and NK cells, respectively 
defined as CD3+, CD3+CD4+, CD3+CD8+, CD19+ and 
CD3- CD16+ CD56+ lymphocytes by flow cytometry 
Coagulation 
International normalised ratio (INR), partial 
thromboplastin time (PTT) 
Serum virology 
HIV test, Hepatitis B test (HBsAg and anti-HBc), 
Hepatitis C 
Pregnancy test 
For women of childbearing potential: serum beta human-
chorionic gonadotropin (ß-HCG) pregnancy test 
Immunoglobulin levels 
Quantitative serum immunoglobulins (IgG, IgA and IgM) 
HAMA screening  
To screen for pre-existing human anti-mouse antibodies. 
A serum sample will be sent to a central laboratory 
(mandatory). Eligibility can be assessed using a local test 
such as the Milenia Quickline® HAMA test (optional) 
Immunogenicity 
Monitoring ADA response (RTX, lilotomab and Betalutin 
baseline) 
Tumour tissue biopsy (if no available 
archived FFPE block, a new surgical 
tumour tissue biopsy will be 
performed) 
Assessments to be performed: 
x 
Mandatory: CD20 and CD37 expression in 
tumour by immunohistochemistry 
x 
Mandatory: Calibration of the blood MRD test 
x 
Optional: Gene expression analysis in tumour 
(DNA, RNA, proteins) to evaluate the 
relationship between anti-tumour activity and 
NHL-related genes.  
Note: If FFPE block not biobanked at Covance Central 
Laboratories (CCLS), preparation of the 5μM FFPE slides 
for the respective analyses only after Sponsor request 
Optional: HLA haplotyping – (saliva 
sample direct or mouth swab, only if 
not possible to collect blood sample) 
Human Major Histocompatibility Complex (MHC) class 
I/II haplotyping  
Minimal Residual Disease 
(biopsy1 and peripheral blood sample) 
MRD monitoring to assess early treatment response and 
detect relapse (baseline)  
Bone marrow, biopsy 
To verify <25% tumour cells in bone marrow, biopsy 
taken from a site not previously irradiated.  
Radiology - FDG PET/CT 
Using standard institutional guidelines. Patient needs to be 
fasting 6 hours prior to PET/CT examination.  Information 
about FDG administration and standardised uptake value 
(SUVmax) will be recorded. The same camera should 
preferably be used throughout the study. 


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Radiology - CT scans with contrast or 
MRI
CT/MRI of neck, thorax, abdomen and pelvis. 
Information about contrast medium, target lesion location 
and measurements and non-measurable lesions will be 
recorded. The same camera should preferably be used 
throughout the study.
Optional, only at Radium Hospital, 
(Oslo, Norway): Exploration of the 
anti-tumour T cell responses
The following human biosamples will be collected:
x
New tumour tissue biopsy (surgical)
x
Additional peripheral blood samples
Adverse events
Any AEs occurring after informed consent has been 
signed should be recorded
1A sample of an archived tumour biopsy collected before treatment or a new tumour tissue biopsy collected at screening will 
be used to calibrate the blood MRD test (see tumour tissue biopsy).
8.2.
Treatment Period
Patients will undergo the following visits during the treatment period.
Visit 2 (Day -14) – Hospital Visit
Procedures outlined in Table 8-2 will be performed at Visit 2 (Day -14). This will be 2 weeks 
before Betalutin administration.
Table 8-2
Procedures and assessments for rituximab administration at Visit 2 
(Day -14) [±2 days]
Assessment or Procedure
Explanation
Concomitant 
medication/therapy
Recording of concomitant medication used since the screening 
visit
Physical examination
Any abnormal findings should be recorded in the AE record.
Weight
Record weight details
Vital signs
Systolic/diastolic blood pressure, heart rate, and body temperature
ECOG
ECOG performance status
Haematology
Including haemoglobin, platelet count, white blood cell count and 
differential (absolute count of neutrophils, lymphocytes, 
monocytes, eosinophils and basophils)
Serum biochemistry
Including sodium, potassium, calcium, magnesium, creatinine, 
urea, uric acid, ALP, ASAT, ALAT, LDH, GGT, glucose, total 
bilirubin and albumin
Rituximab administration
(375 mg/m2) i.v.
Weight, body surface area, dose administered, start and end time 
of administration and pre-medication will be recorded 
Adverse events
Any AEs occurring after Visit 1 should be recorded
Visit 3 (Day 0) – Hospital Visit
The procedures outlined in this section are for procedures and assessments during Visit 3:
a)
before lilotomab administration (Table 8-3)
b)
lilotomab administration (Table 8-4)
c)
Betalutin administration (Table 8-5)


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The procedures outlined in Table 8-3 will be performed at Visit 3 before lilotomab 
administration. This can be one day before (Day-1) or on the same day (Day 0) as lilotomab 
administration. 
Table 8-3 Procedures and assessments before lilotomab administration at Visit 3 (Day 0)  
Assessment or Procedure 
Explanation 
Concomitant 
medication/therapy 
Concomitant medication used since prior visit will be recorded 
Weight 
Record weight details 
Vital signs 
Systolic/diastolic blood pressure, heart rate and body temperature 
12-lead ECG 
A copy of the medically reviewed ECG page will be signed, dated 
and interpreted before storing in the patient file 
ECOG 
ECOG performance status 
Haematology 
Including haemoglobin, platelet count, white blood cell count and 
differential (absolute count of neutrophils, lymphocytes, 
monocytes, eosinophils and basophils) 
Serum biochemistry 
Including sodium, potassium, calcium, magnesium, creatinine, 
urea, uric acid, ALP, ASAT, ALAT, LDH, GGT, glucose, total 
bilirubin and albumin 
Immunophenotyping 
Define absolute cell counts for circulating T-cells, CD4 T-cells, 
CD8 T-cells, B-cells and NK cells, respectively defined as CD3+, 
CD3+CD4+, CD3+CD8+, CD19+ and CD3- CD16+ CD56+ 
lymphocytes by flow cytometry 
Pregnancy test 
For women of childbearing potential: urine  pregnancy test. Result 
to be confirmed as negative prior to lilotomab administration.  
Optional, only at Radium 
Hospital (Oslo, Norway): 
Exploration of the anti-tumour 
T cell responses 
New tumour tissue biopsy (fine needle aspirate) will be collected. 
This sample may be collected on DAY-1 or DAY0 (before 
lilotomab dosing) 
PK sampling (Radium 
Hospital, Oslo, Norway) only. 
otherwise optional 
PK sample before lilotomab infusion will be taken for total 
radioactivity in blood assessment 
Adverse events 
Any AEs occurring since prior visit will be recorded 
 
Following the above procedures, lilotomab will be administered as outlined in Table 8-4. 
Table 8-4 Procedures and assessments for lilotomab administration at Visit 3 (Day 0) 
Assessment or Procedure 
Explanation 
Lilotomab infusion (40 mg) 
within 4 hours before Betalutin 
administration 
Dose (assigned and actual), start and end time of infusion, batch 
number and pre-medication needs to be recorded. Record pulse 
rate, blood pressure and body temperature pre-infusion, 
15 minutes, 30 minutes, 45 minutes, 1 hour after infusion start and 
30 minutes and 1hour post-infusion 
Adverse events 
Any AEs occurring after lilotomab infusion will be recorded 
 
Following the above procedures, Betalutin will be administered as outlined in Table 8-5. 


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Table 8-5 Procedures and assessments for Betalutin administration at Visit 3 (Day 0)
Assessment or Procedure
Explanation
Betalutin injection (10 or 
15 MBq/kg) – see Section 6.1
Betalutin administered within 
4 hours of lilotomab infusion
Patient weight, assigned dose level, volume injected, batch number, 
time of injection and radioactivity in syringe prior and after injection 
need to be recorded
PK sampling - Radium 
Hospital, (Oslo, Norway) only.
otherwise optional
PK samples will be taken for total radioactivity in blood assessment.
Approximate time points: 5 minutes, 60 minutes, 2 hours, 24 hours and 
Day 4 after Betalutin administration. The exact clock time that samples 
are taken need to be recorded in eCRF.
Physical examination
2 hours post-dose: Describe any significant findings
Vital signs
Will be taken 2-4 hours post-Betalutin dose: systolic/diastolic blood 
pressure, heart rate and body temperature
SPECT/CT - Radium Hospital, 
(Oslo, Norway) only. 
Otherwise optional
At 2 hours after dosing, at 24 hours and at Day 4 for biodistribution 
evaluation
Concomitant 
medication/therapy
Concomitant medication received since receiving lilotomab should be 
recorded
Adverse events
Any AEs occurring after Betalutin administration should be recorded
Visit 4 (Day 7) – Hospital Visit
Procedures outlined in Table 8-6 will be performed at Visit 4 (Day 7), when a further dose 
RTX will be administered. This will be 1 week after Betalutin administration.
Table 8-6
Procedures and assessments for rituximab administration at Visit 4 (Day 7 
[±2 days])
Assessment or Procedure
Explanation
Concomitant 
medication/therapy
Concomitant medication used since prior visit will be recorded
Vital signs
Systolic/diastolic blood pressure, heart rate and body temperature
12-lead ECG
A copy of the medically reviewed ECG page will be signed, dated 
and interpreted before storing in the patient file
Haematology
Including haemoglobin, platelet count, white blood cell count and 
differential (absolute count of neutrophils, lymphocytes, 
monocytes, eosinophils and basophils)
Serum biochemistry
Including sodium, potassium, calcium, magnesium, creatinine, 
urea, uric acid, ALP, ASAT, ALAT, LDH, GGT, glucose, total 
bilirubin and albumin
SPECT/CT - Radium Hospital, 
(Oslo, Norway) only. 
Otherwise optional
For biodistribution evaluation
PK sampling - Radium 
Hospital (Oslo, Norway) only.
otherwise optional 1
PK sample will be taken for total radioactivity in blood 
assessment.
Rituximab administration
(375 mg/m2) i.v.
Weight, body surface area, dose administered, start and end time 
of administration and pre-medication will be recorded 
Adverse events
Any AEs occurring since prior visit will be recorded
1Before RTX dosing


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Visit 5 (Day 14) – Hospital Visit
Procedures outlined in Table 8-7 will be performed at Visit 5 (Day 14), when a further dose of 
RTX will be administered. This will be 2 weeks after Betalutin administration.
Table 8-7 Procedures and assessments for rituximab administration at Visit 5 (Day 14 
[±2 days])
Assessment or Procedure
Explanation
Concomitant medication/therapy
Concomitant medication used since prior visit will be recorded
Vital signs
Systolic/diastolic blood pressure, heart rate and body temperature
Haematology
Including haemoglobin, platelet count, white blood cell count and 
differential (absolute count of neutrophils, lymphocytes, 
monocytes, eosinophils and basophils)
Serum biochemistry
Including sodium, potassium, calcium, magnesium, creatinine, 
urea, uric acid, ALP, ASAT, ALAT, LDH, GGT, glucose, total 
bilirubin and albumin
Rituximab administration
(375 mg/m2) i.v.
Weight, body surface area, dose administered, start and end time 
of administration and pre-medication will be recorded 
Adverse events
Any AEs occurring since prior visit will be recorded
Visit 6 (Day 21) – Hospital Visit
Procedures outlined in Table 8-8 will be performed at Visit 6 (Day 21), when a further dose 
RTX will be administered. This will be 3 weeks after Betalutin administration.
Table 8-8 Procedures and assessments for rituximab administration at Visit 6 (Day 21 
[±2 days])
Assessment or Procedure
Explanation
Concomitant 
medication/therapy
Concomitant medication used since prior visit will be recorded
Vital signs
Systolic/diastolic blood pressure, heart rate and body temperature
Haematology
Including haemoglobin, platelet count, white blood cell count and 
differential (absolute count of neutrophils, lymphocytes, monocytes, 
eosinophils and basophils)
Serum biochemistry
Including sodium, potassium, calcium, magnesium, creatinine, urea, 
uric acid, ALP, ASAT, ALAT, LDH, GGT, glucose, total bilirubin and 
albumin
Rituximab administration
(375 mg/m2) i.v.
Weight, body surface area, dose administered, start and end time of 
administration and pre-medication will be recorded 
Adverse events
Any AEs occurring since prior visit will be recorded
Visit 7 (Day 28) – Hospital Visit
Procedures outlined in Table 8-9 will be performed at Visit 7 (Day 28), when a further dose 
RTX will be administered. This will be 4 weeks after Betalutin administration.


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Table 8-9
Procedures and assessments for rituximab administration at Visit 7 
(Day 28 [±2 days])
Assessment or Procedure
Explanation
Concomitant 
medication/therapy
Concomitant medication used since prior visit will be recorded
Physical examination
Any abnormal findings should be recorded in the AE record.
Vital signs
Systolic/diastolic blood pressure, heart rate and body temperature
12-lead ECG
A copy of the medically reviewed ECG page will be signed, dated 
and interpreted before storing in the patient file
ECOG
ECOG performance status
Haematology
Including haemoglobin, platelet count, white blood cell count and 
differential (absolute count of neutrophils, lymphocytes, 
monocytes, eosinophils and basophils)
Serum biochemistry
Including sodium, potassium, calcium, magnesium, creatinine, 
urea, uric acid, ALP, ASAT, ALAT, LDH, GGT, glucose, total 
bilirubin and albumin
Immunophenotyping
Define absolute cell counts for circulating T-cells, CD4 T-cells, 
CD8 T-cells, B-cells and NK cells, respectively defined as CD3+, 
CD3+CD4+, CD3+CD8+, CD19+ and CD3- CD16+ CD56+
lymphocytes by flow cytometry
Pregnancy test
For women of childbearing potential: serum beta human-chorionic 
gonadotropin (ß-HCG) pregnancy test
Immunoglobulin levels
Quantitative serum immunoglobulins (IgG, IgA and IgM)
Immunogenicity
Monitoring ADA response (lilotomab, Betalutin, RTX)
PK sampling - Radium 
Hospital (Oslo, Norway) only.
otherwise optional 1
PK sample will be taken for total radioactivity in blood 
assessment
Rituximab administration
(375 mg/m2) i.v.
Weight, body surface area, dose administered, start and end time 
of infusion and pre-medication will be recorded 
Adverse events
Any AEs occurring since prior visit will be recorded
1Before RTX dosing
Visit 8, 9 and 10 (Week 5, 6 and 7) – Lab Visit
Procedures outlined in Table 8-10 will be performed at Visits 8, 9 and 10 (Weeks 5, 6 and 7). 
Table 8-10
Procedures and assessments at Visit 8, 9 and 10 (Week 5, 6 and 7 [±2 days])
Assessment or Procedure
Explanation
Haematology
Including haemoglobin, platelet count, white blood cell count and 
differential (absolute count of neutrophils, lymphocytes, 
monocytes, eosinophils and basophils)
Serum biochemistry
Including sodium, potassium, calcium, magnesium, creatinine, 
urea, uric acid, ALP, ASAT, ALAT, LDH, GGT, glucose, total 
bilirubin and albumin


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Visit 11 (Month 2/Week 8) – Hospital Visit
Procedures outlined in Table 8-11 will be performed at Visit 11 (Week 8). This will be 4 weeks
after the last RTX administration.
Table 8-11 Procedures and assessments at Visit 11 (Week 8 [±2 days])
Assessment or Procedure
Explanation
Concomitant 
medication/therapy
Concomitant medication used since prior visit will be recorded
Physical examination
Any abnormal findings will be recorded in the AE record
Vital signs
Systolic/diastolic blood pressure, heart rate and body temperature
ECOG
ECOG performance status
Haematology
Including haemoglobin, platelet count, white blood cell count and 
differential (absolute count of neutrophils, lymphocytes, 
monocytes, eosinophils and basophils)
Serum biochemistry
Including sodium, potassium, calcium, magnesium, creatinine, 
urea, uric acid, ALP, ASAT, ALAT, LDH, GGT, glucose, total 
bilirubin and albumin
Adverse events
Any AEs occurring since prior visit will be recorded
Visits 12, 13 and 14 (Weeks 9, 10 and 11) – Lab Visit
Procedures outlined in Table 8-12 will be performed at Visits 12, 13 and 14 (Weeks 9, 10 
and 11). 
Table 8-12
Procedures and assessments at Visits 12, 13 and 14 (Weeks 9, 10 and 11 
[±2 days])
Assessment or Procedure
Explanation
Haematology
Including haemoglobin, platelet count, white blood cell count and 
differential (absolute count of neutrophils, lymphocytes, 
monocytes, eosinophils and basophils)
Serum biochemistry
Including sodium, potassium, calcium, magnesium, creatinine, 
urea, uric acid, ALP, ASAT, ALAT, LDH, GGT, glucose, total 
bilirubin and albumin
Visit 15 (Month 3/Week 12) – Hospital Visit
Safety follow-up and imaging procedures outlined in Table 8-13 will be performed at Visit 15 
(Week 12). 
Table 8-13 Procedures and assessments at Visit 15 (Week 12 [±7 days])
Assessment or Procedure
Explanation
Concomitant 
medication/therapy
Concomitant medication used since prior visit will be recorded
Weight
Record weight details
Vital signs
Systolic/diastolic blood pressure, heart rate and body temperature
12-lead ECG
A copy of the medically reviewed ECG page will be signed, dated 
and interpreted before storing in the patient file
ECOG
ECOG performance status


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Assessment or Procedure
Explanation
Haematology
Including haemoglobin, platelet count, white blood cell count and 
differential (absolute count of neutrophils, lymphocytes, 
monocytes, eosinophils and basophils)
Serum biochemistry
Including sodium, potassium, calcium, magnesium, creatinine,
urea, uric acid, ALP, ASAT, ALAT, LDH, GGT, glucose, total 
bilirubin and albumin
Immunophenotyping
Define absolute cell counts for circulating T-cells, CD4 T-cells, 
CD8 T-cells, B-cells and NK cells, respectively defined as CD3+, 
CD3+CD4+, CD3+CD8+, CD19+ and CD3- CD16+ CD56+
lymphocytes by flow cytometry
Coagulation
INR, PTT
Immunoglobulin levels
Quantitative serum immunoglobulins (IgG, IgA and IgM)
Immunogenicity
Monitoring ADA response (lilotomab, Betalutin, RTX)
Minimal Residual Disease1
(peripheral blood sample)
MRD monitoring to assess early treatment response and detect 
relapse
Bone marrow biopsy
BM biopsy required for initial confirmation of CR if patient had 
BM infiltration at baseline
Radiology - FDG PET/CT
Using standard institutional guidelines. Patient needs to be fasting 
for 6 hours prior to PET/CT examination. Information about 
FDG administration and uptake (SUVmax) will be recorded. The 
same camera should preferably be used throughout the study
Radiology - CT scans with 
contrast or MRI
CT or MRI of neck, thorax, abdomen and pelvis. Information 
about contrast medium, target lesion location and measurements 
and non-measurable lesions will be recorded. The same camera 
should preferably be used throughout the study
Optional, only at Radium 
Hospital (Oslo, Norway): 
Exploration of the anti-tumour 
T cell responses
The following human biosamples will be collected:
x
New tumour tissue biopsy (fine needle aspiration)
x
Additional peripheral blood samples
Adverse events
Any AEs occurring since prior visit will be recorded
1 Mandatory, unless relapse or disease progression has been clinically observed since the previous blood sampling
Visits 16 (Month 3/Week 14) – Hospital Visit
Providing patient is deemed not to have PD following the Week 12 imaging scan (above), 
Rituximab maintenance dosing will commence, as outlined in Table 8-14.
Table 8-14 Procedures and assessments at Visit 16 (Week 14 [±7 days])
Assessment or Procedure
Explanation
Concomitant 
medication/therapy
Concomitant medication used since prior visit will be recorded
Physical examination
Any abnormal findings will be recorded in the AE record
Vital signs
Systolic/diastolic blood pressure, heart rate and body temperature
Rituximab administration
375 mg/m2 iv or 1400 mg s.c.
Weight, body surface area, dose administered, start and end time 
of administration and pre-medication will be recorded 
Adverse events
Any AEs occurring since prior visit will be recorded


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Visits 17 (Month 6/Week 26) – Hospital Visit
Rituximab maintenance dosing and imaging, as outlined in Table 8-15.
Table 8-15 Procedures and assessments at Visit 17 (Month 6/Week 26 [±7 days])
Assessment or Procedure
Explanation
Concomitant medication 
Concomitant medication used since prior visit will be recorded
Vital signs
Systolic/diastolic blood pressure, heart rate and body temperature
ECOG
ECOG performance status
Haematology
Including haemoglobin, platelet count, white blood cell count and 
differential (absolute count of neutrophils, lymphocytes, 
monocytes, eosinophils and basophils)
Serum biochemistry
Including sodium, potassium, calcium, magnesium, creatinine, 
urea, uric acid, ALP, ASAT, ALAT, LDH, GGT, glucose, total 
bilirubin and albumin
Immunophenotyping
Define absolute cell counts for circulating T-cells, CD4 T-cells, 
CD8 T-cells, B-cells and NK cells, respectively defined as CD3+, 
CD3+CD4+, CD3+CD8+, CD19+ and CD3- CD16+ CD56+
lymphocytes by flow cytometry
Immunoglobulin levels
Quantitative serum immunoglobulins (IgG, IgA and IgM)
Immunogenicity
Monitoring ADA response (lilotomab, Betalutin, RTX)
Minimal Residual Disease1
(peripheral blood sample)
MRD monitoring to assess early treatment response and detect 
relapse
Bone marrow biopsy
BM biopsy required for initial confirmation of CR if patient had 
BM infiltration at baseline
Radiology - FDG PET/CT
Using standard institutional guidelines. Patient needs to be fasting
for 6 hours prior to PET/CT examination. Information about FDG 
administration and uptake (SUVmax) will be recorded. The same 
camera should preferably be used throughout the study
Radiology - CT scans with 
contrast or MRI
CT or MRI of neck, thorax, abdomen and pelvis. Information 
about contrast medium, target lesion location and measurements 
and non-measurable lesions will be recorded. The same camera 
should preferably be used throughout the study
Optional, only at Radium 
Hospital: Exploration of the 
anti-tumour T cell responses
New tumour tissue biopsy (fine needle aspiration)2
Rituximab administration
375 mg/m2 i.v. or 1400 mg s.c.
Weight, body surface area, dose administered, start and end time 
of administration and pre-medication will be recorded 
Adverse events
Any AEs occurring since prior visit will be recorded
1 Mandatory, unless relapse or disease progression has been clinically observed since the previous blood sampling
2 Optional biopsy, to be taken before RTX dosing and only if there is sufficient tumour remaining at this timepoint
Visits 18 (Month 9/Week 39) – Hospital Visit
Rituximab maintenance dosing, as outlined in Table 8-16.
Table 8-16
Procedures and assessments at Visit 18 (Month 9/Week 39 [±7 days])
Assessment or Procedure
Explanation
Concomitant 
medication/therapy
Recording of concomitant medication used since the previous visit
Physical examination
Any abnormal findings will be recorded in the AE record


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Assessment or Procedure
Explanation
Vital signs
Systolic/diastolic blood pressure, heart rate and body temperature
ECOG
ECOG performance status
Haematology
Including haemoglobin, platelet count, white blood cell count and 
differential (absolute count of neutrophils, lymphocytes, 
monocytes, eosinophils and basophils)
Serum biochemistry
Including sodium, potassium, calcium, magnesium, creatinine, 
urea, uric acid, ALP, ASAT, ALAT, LDH, GGT, glucose, total 
bilirubin and albumin
Immunophenotyping
Define absolute cell counts for circulating T-cells, CD4 T-cells, 
CD8 T-cells, B-cells and NK cells, respectively defined as CD3+, 
CD3+CD4+, CD3+CD8+, CD19+ and CD3- CD16+ CD56+
lymphocytes by flow cytometry.
Optional, only at Radium 
Hospital: Exploration of the 
anti-tumour T cell responses
Additional peripheral blood samples1
Rituximab administration
375 mg/m2 i.v. or 1400 mg s.c.
Weight, body surface area, dose administered, start and end time 
of administration and pre-medication will be recorded 
Adverse events
Any AEs occurring since prior visit will be recorded
1 To be taken before RTX dosing
Visit 19 (Month 12/Week 52) – Hospital Visit
Rituximab maintenance dosing and imaging, as outlined in Table 8-17.
Table 8-17
Procedures and assessments at Visit 19 (Month 12/Week 52 [±7 days])
Assessment or Procedure
Explanation
Concomitant medication 
Recording of concomitant medication used since the previous visit
Vital signs
Systolic/diastolic blood pressure, heart rate and body temperature
ECOG
ECOG performance status
Haematology
Including haemoglobin, platelet count, white blood cell count and 
differential (absolute count of neutrophils, lymphocytes, 
monocytes, eosinophils and basophils)
Serum biochemistry
Including sodium, potassium, calcium, magnesium, creatinine, 
urea, uric acid, ALP, ASAT, ALAT, LDH, GGT, glucose, total 
bilirubin and albumin
Immunophenotyping
Define absolute cell counts for circulating T-cells, CD4 T-cells, 
CD8 T-cells, B-cells and NK cells, respectively defined as CD3+, 
CD3+CD4+, CD3+CD8+, CD19+ and CD3- CD16+ CD56+
lymphocytes by flow cytometry
Immunoglobulin levels
Quantitative serum immunoglobulins (IgG, IgA and IgM)
Immunogenicity
Monitoring ADA response (lilotomab, Betalutin, RTX)
Minimal Residual Disease1
(peripheral blood sample)
MRD monitoring to assess early treatment response and detect 
relapse
Bone marrow biopsy
BM biopsy required for initial confirmation of CR if patient had 
BM infiltration at baseline
Radiology - CT scans with 
contrast or MRI
CT or MRI of neck, thorax, abdomen and pelvis. Information 
about contrast medium, target lesion location and measurements 
and non-measurable lesions will be recorded. The same camera 
should preferably be used throughout the study


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Assessment or Procedure
Explanation
Rituximab administration
375 mg/m2 i.v. or 1400 mg s.c.
Weight, body surface area, dose administered, start and end time 
of administration and pre-medication will be recorded 
Adverse events
Any AEs occurring since prior visit will be recorded
1 Mandatory, unless relapse or disease progression has been clinically observed
Visit 20 (Month 15/Week 65) – Hospital Visit
Rituximab maintenance dosing, as outlined in Table 8-18.
Table 8-18
Procedures and assessments at Visit 20 (Month 15/Week 65 [±7 days])
Assessment or Procedure
Explanation
Concomitant medication
Recording of concomitant medication used since the previous visit
Physical examination
Any abnormal findings will be recorded in the AE record
Vital signs
Systolic/diastolic blood pressure, heart rate and body temperature
ECOG
ECOG performance status
Haematology
Including haemoglobin, platelet count, white blood cell count and 
differential (absolute count of neutrophils, lymphocytes, 
monocytes, eosinophils and basophils)
Serum biochemistry
Including sodium, potassium, calcium, magnesium, creatinine, 
urea, uric acid, ALP, ASAT, ALAT, LDH, GGT, glucose, total 
bilirubin and albumin
Rituximab administration
375 mg/m2 i.v. or 1400 mg s.c.
Weight, body surface area, dose administered, start and end time 
of administration and pre-medication will be recorded 
Adverse events
Any AEs occurring since prior visit will be recorded
Visit 21 (Month 18/Week 78) – Hospital Visit
Rituximab maintenance dosing and imaging, as outlined in Table 8-19.
Table 8-19
Procedures and assessments at Visit 21 (Month 18/Week 78 [±7 days])
Assessment or Procedure
Explanation
Concomitant medication 
Recording of concomitant medication used since the previous visit
Physical examination
Any abnormal findings will be recorded in the AE record
Vital signs
Systolic/diastolic blood pressure, heart rate and body temperature
ECOG
ECOG performance status
Haematology
Including haemoglobin, platelet count, white blood cell count and 
differential (absolute count of neutrophils, lymphocytes, 
monocytes, eosinophils and basophils)
Serum biochemistry
Including sodium, potassium, calcium, magnesium, creatinine, 
urea, uric acid, ALP, ASAT, ALAT, LDH, GGT, glucose, total 
bilirubin and albumin
Immunogenicity
Monitoring ADA response (lilotomab, Betalutin, RTX)
Bone marrow biopsy
BM biopsy required for initial confirmation of CR if patient had 
BM infiltration at baseline
Radiology - CT scans with 
contrast or MRI
CT or MRI of neck, thorax, abdomen and pelvis. Information 
about contrast medium, target lesion location and measurements 
and non-measurable lesions will be recorded. The same camera 
should preferably be used throughout the study
Rituximab administration
375 mg/m2 i.v. or 1400 mg s.c.
Weight, body surface area, dose administered, start and end time 
of administration and pre-medication will be recorded 


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Assessment or Procedure
Explanation
Adverse events
Any AEs occurring since prior visit will be recorded
Visit 22 (Month 21/Week 91) – Hospital Visit
Rituximab maintenance dosing, as outlined in Table 8-20.
Table 8-20
Procedures and assessments at Visit 22 (Month 21/Week 91 [±7 days])
Assessment or Procedure
Explanation
Concomitant 
medication/therapy
Recording of concomitant medication used since the previous visit
Physical examination
Any abnormal findings will be recorded in the AE record
Vital signs
Systolic/diastolic blood pressure, heart rate and body temperature
ECOG
ECOG performance status
Haematology
Including haemoglobin, platelet count, white blood cell count and 
differential (absolute count of neutrophils, lymphocytes, 
monocytes, eosinophils and basophils)
Serum biochemistry
Including sodium, potassium, calcium, magnesium, creatinine, 
urea, uric acid, ALP, ASAT, ALAT, LDH, GGT, glucose, total 
bilirubin and albumin
Rituximab administration
375 mg/m2 i.v. or 1400 mg s.c.
Weight, body surface area, dose administered, start and end time 
of administration and pre-medication will be recorded 
Adverse events
Any AEs occurring since prior visit will be recorded
Visit 23 (Month 24/Week 104) – Hospital Visit
Rituximab maintenance dosing and imaging, as outlined in Table 8-21.
Table 8-21
Procedures and assessments at Visit 23 (Month 24/Week 104 [±7 days])
Assessment or Procedure
Explanation
Concomitant medication 
Recording of concomitant medication used since the previous visit
Physical examination
Any abnormal findings will be recorded in the AE record
Vital signs
Systolic/diastolic blood pressure, heart rate and body temperature
ECOG
ECOG performance status
Haematology
Including haemoglobin, platelet count, white blood cell count and 
differential (absolute count of neutrophils, lymphocytes, 
monocytes, eosinophils and basophils)
Serum biochemistry
Including sodium, potassium, calcium, magnesium, creatinine, 
urea, uric acid, ALP, ASAT, ALAT, LDH, GGT, glucose, total 
bilirubin and albumin
Immunogenicity
Monitoring ADA response (lilotomab, Betalutin, RTX)
Minimal Residual Disease1
(peripheral blood sample)
MRD monitoring to assess early treatment response and detect 
relapse
Bone marrow biopsy
BM biopsy required for initial confirmation of CR if patient had 
BM infiltration at baseline
Radiology - CT scans with 
contrast or MRI
CT or MRI of neck, thorax, abdomen and pelvis. Information 
about contrast medium, target lesion location and measurements 
and non-measurable lesions will be recorded. The same camera 
should preferably be used throughout the study
Rituximab administration
375 mg/m2 i.v. or 1400 mg s.c.
Weight, body surface area, dose administered, start and end time 
of administration and pre-medication will be recorded 


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Assessment or Procedure
Explanation
Adverse events
Any AEs occurring since prior visit will be recorded
1
Mandatory, unless relapse or disease progression has been clinically observed
End of study visit – Hospital Visit
The end of study visit should occur:
x
28 days (± 3 days) post last rituximab administration for patients, who complete the 
study per protocol (Month 25/Week 108)
x
Within 7 days of decision of withdrawing from the study is made if the decision occurs 
> 28 days post last administration of study treatment for patients who discontinue from 
the study before Month 24 (e.g. disease progression, start of new anti-cancer therapy, 
other reason) An end of study visit is not expected for patients, who discontinue due to 
death, lost to follow up or withdrawal of consent.
Safety follow-up procedures 4 weeks after administration of the final RTX study dose are 
outlined in Table 8-22.
Patients in survival follow-up at the time of Protocol v4.0 approval can have the EOS visit at 
their next scheduled visit or an earlier convenient time point
Table 8-22
Procedures and assessments at end of study visit 
Assessment or Procedure
Explanation
Concomitant medication
Recording of concomitant medication used since the previous visit
Physical examination
Any abnormal findings will be recorded in the AE record
Vital signs
Systolic/diastolic blood pressure, heart rate and body temperature
ECOG
ECOG performance status
Haematology
Including haemoglobin, platelet count, white blood cell count and 
differential (absolute count of neutrophils, lymphocytes, 
monocytes, eosinophils and basophils)
Serum biochemistry
Including sodium, potassium, calcium, magnesium, creatinine, 
urea, uric acid, ALP, ASAT, ALAT, LDH, GGT, glucose, total 
bilirubin and albumin
Adverse events
Any AEs / AESIs occurring since prior visit will be recorded
8.3.
Additional Optional Procedures
During the treatment period optional procedures may be performed at visits following relapse 
or disease progression. Table 8-23 outlines these procedures.
Table 8-23
Optional Procedures and assessments following relapse or disease 
progression
Assessment or Procedure
Explanation
Tumour tissue biopsy (new 
tumour tissue biopsy will be 
performed surgically)
Assessments to be performed:
x
Optional: CD20 and CD37 expression in tumour by 
immunohistochemistry


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Assessment or Procedure 
Explanation 
x 
Optional: Gene expression analysis in tumour (DNA, 
RNA, proteins) to evaluate the relationship between anti-
tumour activity and NHL-related genes. 
  
Note: If FFPE block not biobanked at CCLS, preparation 
of the 5μM FFPE slides for the respective analyses only 
after Sponsor request 
 
 


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9.
Study Assessments
9.1.
Efficacy Assessments
Tumour response will be determined locally according to Recommendations for Initial 
Evaluation, Staging and Response Assessment of Hodgkin and non-Hodgkin Lymphoma [36].
Investigator assessment will be applied as a measure for assessment of tumour response and as 
a basis for all protocol guidelines for management of the patient related to disease status. CT 
or MRI scans are the required methods for tumour assessments. The same method of 
assessment and the same technique should be used to characterize each lesion at baseline and 
during follow-up.
All scans and other data supporting efficacy measurements will be stored at the study site and 
available for subsequent collection, if necessary, for review by the Sponsor and/or independent 
external reviewer(s).
Contrast enhanced CT examination or MRI
A baseline contrast-enhanced CT scan or MRI must be performed within 4 weeks prior to the 
first RTX infusion. Table 1-1 and Table 1-2 show the frequency of subsequent contrast 
enhanced CT scans/MRI per patient for follow-up.
A CT volume scan re-constructed in 3 mm slides with use of i.v.-injected contrast agent will 
be performed per examination. The target lesions will be selected and measured at baseline and 
followed at each efficacy assessment. The longest perpendicular diameters (major and minor 
axis) will be recorded in the eCRF.
PET/CT and CT/MRI examination
PET/CT and CT or MRI imaging will be done at baseline and then at 3 and 6 months. CT with 
contrast or MRI will be performed at 12, 18, 24 months or until disease progression or other 
withdrawal for any other reason (whichever comes first). Baseline imaging must be performed 
within 4 weeks prior to administration of the first RTX infusion.
Standard institutional guidelines will be followed. The patient needs to be fasting during 
6 hours prior to PET/CT imaging, water is allowed. The blood glucose level must be 
<11 mmol/L before injection of 18Fluor doxy glucose (FDG). Anti-diabetic drugs cannot be 
taken on the day of PET/CT examination. 
PET/CT examination will be performed by a commercial combined PET/CT scanner. All scans 
should be performed on the same camera. PET/CT imaging will be performed about 60 to 
70 minutes after i.v. administration of 5 to 10 mCi (185 to 370 MBq) of FDG. Same activity 
±20% and time window must be used in the subsequent PET scans. 
PET/CT scans will be done before contrast enhanced CT or MRI when both modalities are to 
be done on the same day.
All measurements of uptake will be based on standardised uptake values (SUV). Lesions 
<15 mm in short axis with abnormal activity: focal, above the surrounding background, above 
average liver SUV. 


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Guidelines for baseline CT/MRI examination:
1)
Target lesions on the CT/MRI scans do not need to match those evaluated on the PET 
scan.
2)
Target nodes should be chosen according to Cheson criteria, version 2014 [35]
3)
Up to 6 target nodes should be selected; there must be at least one target node
4)
The largest target nodes should be selected
5)
Nodes should be from different body regions if possible
6)
Mediastinal and retroperitoneal nodes should be included as target nodes if involved
7)
A measurable node must have a LDi greater than 1.5 cm
8)
A measurable extranodal lesion should have an LDi greater than 1.0 cm 
Guidelines for baseline PET examination:
1)
Target lesions on the CT/MRI scans do not need to match those evaluated on the PET 
scan
2)
The lesions with the highest activity level should be chosen for the PET scan
PET/CT score
PET is scored on a 5-point scale (5PS), and follow-up will be assessed as described below. In 
addition, SUVmax will be recorded, and lean body mass (SULmax) is optional. In case of 
discrepancy between the criteria below and SUVmax/SULmax the Investigators will be involved 
in decision-making.
Images will be evaluated and scored according to the 5PS. The PET/CT scans will be scored 
with reference to sites of presumed lymphomatous involvement on the PET/CT staging scan 
(Deauville criteria).
5-point scale (5PS)
Negative 
1 
no uptake 
2 
XSWDNHPHGLDVWLQXP
3 
XSWDNH!PHGLDVWLQXPEXWOLYHU
NOTE if mediastinal blood pool activity is equal or greater than liver then the uptake within 
the lesion should be compared with liver (lesion uptake less than liver=score 2; lesion uptake 
equal to liver = score 3) 
Positive 
4 
moderately increased uptake compared to liver at any site 
5 
markedly increased uptake compared to liver at any site 
X 
new areas of uptake unlikely to be related to lymphoma 
Mediastinal and liver uptake is defined as SUVmax ±10%
Consider binary response scale for lung, bone/bone marrow, liver and spleen involvement.


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Definitions of Tumour Response Criteria
Investigator assessment will be applied as a measure for assessment of tumour response and as 
a basis for all protocol guidelines for management of the patient related to disease status using 
Cheson criteria version 2014 [35] (see Table 9-1).
Table 9-1
Criteria for tumour response evaluation
Response and Site
PET/CT-Based Response
CT/MRI-Based Response
Complete
Complete metabolic response
Complete radiologic response 
(all of the following)
Lymph nodes and 
extralymphatic sites
Score 1, 2 or 3 with or without a residual mass 
on 5PS (Sec 9.1.3).
It is recognised that in Waldeyer’s ring or 
extranodal sites with high physiologic uptake or 
with activation within spleen or marrow (e.g.
with chemotherapy or myeloid colony-
stimulating factors), uptake may be greater than 
normal mediastinum and/or liver. In this 
circumstance, complete metabolic response may 
be inferred if uptake at sites of initial 
involvement is no greater than surrounding 
normal tissue even if the tissue has high 
physiologic uptake.
-
Target nodes/nodal 
masses must regress to 
FPLQ/'L
-
No extralymphatic sites 
of disease
Non-measured lesion
Not applicable
Absent
Organ enlargement
Not applicable
Regress to normal
New lesions
None
None
Bone marrow
No evidence of FDG-avid disease in marrow
Normal by morphology; if 
indeterminate, IHC negative
Partial
Partial metabolic response
Partial remission (all of the 
following)
Lymph nodes and 
extralymphatic sites
Score 4 or 5 on 5PS (Sec 9.1.3) with reduced 
uptake compared with baseline and residual 
mass(es) of any size.
At interim, these findings suggest responding 
disease
At end-of-treatment, these findings indicate 
residual disease
-
GHFUHDVHLQ63'RI
up to 6 measurable nodes 
target and extranodal 
sites
-
When a lesion is too 
small to measure on CT, 
assign 5 x 5 mm as the 
default value
-
When no longer visible, 
0 x 0 mm
-
For a node >5 x 5 mm, 
but smaller than normal, 
use actual measurement 
for calculation
Non-measured lesion
Not applicable
Absent/normal, regressed, but 
no increase
Organ enlargement
Not applicable
Spleen must have regressed by 
>50% in length beyond normal
New lesions
None
None


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Response and Site 
PET/CT-Based Response 
CT/MRI-Based Response 
Bone marrow 
Residual uptake higher than uptake in normal 
marrow but reduced compared with baseline 
(diffuse uptake compatible with reactive 
changes from chemotherapy allowed). If there 
are persistent focal changes in the marrow in the 
context of a nodal response, consideration 
should be given to further evaluation with 
magnetic resonance imaging (MRI) or biopsy or 
an interval scan. 
Not applicable 
No response or stable 
disease 
No metabolic response 
Stable disease 
Target nodes/nodal 
masses, extranodal 
lesions 
Score 4 or 5 on 5PS (Sec 9.1.3) with no 
significant change in FDG uptake from baseline 
at interim or end-of-treatment 
<50% decrease from baseline 
in SPD of up to 6 dominant, 
measurable nodes and 
extranodal sites; no criteria for 
progressive disease are met 
Non-measured lesions 
Not applicable 
No increase consistent with 
progression 
Organ enlargement 
Not applicable 
No increase consistent with 
progression 
New lesions 
None 
None 
Bone marrow 
No change from baseline 
Not applicable 
Progressive disease 
Progressive metabolic disease 
Progressive disease requires at 
least 1 of the following 
individual product of the 
perpendicular diameters (PPD) 
progression: 
Individual target 
nodes/nodal masses 
Score 4 or 5 on 5PS (Sec 9.1.3) with an increase 
in intensity of uptake from baseline and/or 
 
Extranodal lesions 
New FDG-avid foci consistent with lymphoma 
at interim or end-of-treatment assessment 
An individual node/lesion 
must be abnormal with: 
- 
 LDi >1.5 cm and  
- 
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PPD nadir and  
- 
An increase in LDi or SDi 
from nadir  
- 
FPIRUOHVLRQVFP 
- 
1.0 cm for lesions >2 cm  
In the setting of splenomegaly, 
the splenic length must 
increase by >50% of the extent 
of its prior increase beyond 
baseline (e.g. a 15-cm spleen, 
must increase to >16 cm). If 
no prior splenomegaly, must 
increase by at least 2 cm from 
baseline. 
New or recurrent 
splenomegaly 
Non-measured lesions 
None 
New or clear progression of 
pre-existing non-measured 
lesions 


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Response and Site
PET/CT-Based Response
CT/MRI-Based Response
New lesions
New FDG-avid foci consistent with lymphoma 
rather than another aetiology (e.g. infection, 
inflammation). If uncertain regarding aetiology 
of new lesions, biopsy or interval scan may be 
considered
Regrowth of previously 
resolved lesions
A new node >1.5 cm in any 
axis
A new extranodal site >1.0 cm 
in any axis, if <1.0 cm in any 
axis, its presence must be 
unequivocal and must be 
attributable to lymphoma.
Assessable disease of any size 
unequivocally attributable to 
lymphoma
Bone marrow
New or recurrent FDG-avid foci
New or recurrent involvement
9.2.
Safety Assessments
Safety assessments will consist of monitoring and recording of AEs, including SAEs, the 
monitoring of haematology, blood chemistry, immunogenicity, vital signs, ECGs, physical 
condition and body weight as detailed in Section 1.2.
Definition
9.2.1.1.
Definition of adverse event
An AE is defined as the appearance of (or worsening of any pre-existing) undesirable sign(s), 
symptom(s) or medical condition(s) that occur after the patient signed ICF has been obtained.
An AE can be any unfavourable and unintended sign (including an abnormal laboratory 
finding), symptom, or disease temporally associated with the use of a study drug, whether or 
not considered related to the study drug. 
Abnormal laboratory values or test results occurring after informed consent constitute AEs only 
if they induce clinical signs or symptoms, are considered clinically significant, require therapy 
(e.g. blood or platelet transfusion) or require changes in medications. Laboratory abnormalities 
that meet the criteria for AE should be followed until they have returned to normal. Laboratory 
abnormalities not requiring clinical intervention or further investigation will be captured as part 
of overall laboratory monitoring and should not be reported as AEs.
AEs that begin or worsen after informed consent should be recorded in the eCRF. Conditions 
that were already present at the time of informed consent should be recorded in the patient’s
Medical History CRF page. All AEs should be reported until 4 weeks following their last RTX
maintenance dose or 12 weeks after Betalutin administration for patients who do not qualify 
for RTX maintenance therapy (see Section 4.1). Only ADR (see Section 9.2.1.2) and AESI (see 
Section 9.2.1.7) will be reported during follow-up. 
Please see Section 9.2.4 for guidance on AE reporting.
9.2.1.2.
Definition of adverse drug reaction
An ADR is all untoward and unintended responses to study drug related to any dose 
administered.


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All AEs judged by either the reporting Investigator or the Sponsor as having a reasonable causal 
relationship to a study drug qualify as ADRs.  The expression ‘reasonable causal relationship’ 
means to convey in general that there is evidence or argument to suggest a causal relationship. 
9.2.1.3. 
Definition of serious adverse event 
An SAE is defined as one of the following: 
x 
Results in death (i.e. all deaths within 12 weeks of study drug administration excluding 
deaths due to disease progression). Deaths occurring later than 12 weeks following 
study drug administration do not need to be reported as SAEs unless they result from 
an event that started within 12 weeks following study drug administration. The reported 
AE should be the AE that caused the death. Any AE resulting in death that occurs 
outside the AE reporting period that the Investigator assesses as possibly/probably 
related to the study drug should also be reported as serious. 
x 
Is life-threatening. 
x 
Requires inpatient hospitalisation or prolongation of existing inpatient hospitalisation. 
x 
Results in persistent or significant disability or incapacity. 
x 
Is medically important, i.e. defined as an event that jeopardises the patient or may 
require medical or surgical intervention to prevent one of the outcomes listed above. 
x 
Constitutes a congenital anomaly/birth defect. 
Life-threatening in the definition of a SAE refers to an event in which the patient was at risk 
of death at the time of event; it does not refer to an event which hypothetically might have 
caused death if it were more severe. Medical judgment should be exercised in deciding whether 
an AE/ADR is serious in other situations.   
Hospitalisation for elective surgery or surgery which takes place during the reporting period 
but was planned prior to enrolment is not to be reported as an SAE (unless the reason for 
surgery or any complications during or after surgery fulfil any other of the seriousness criteria). 
9.2.1.4. 
Definition of unexpected adverse drug reaction 
An unexpected ADR is an ADR of which the nature or severity is not consistent with the 
applicable product information (e.g., Investigator’s Brochure for an unapproved investigational 
product or summary of product characteristics for an authorised product). When the outcome 
of the ADR is not consistent with the applicable product information this ADR should be 
considered as unexpected. 
9.2.1.5. 
Suspected unexpected serious adverse reaction (SUSAR) 
All suspected ADRs that are considered related to any of the study medication and are both 
unexpected and serious (SUSARs) are subject to expedited reporting. It is the Sponsor who 
reports the SUSARs, based on information from the Investigator, see Section 9.2.5.1. 
9.2.1.6. 
Definition of treatment-emergent adverse event 
Treatment-emergent AEs (TEAEs) are defined as events which occur following the first 
injection of study drug, or that started prior to the first injection and worsened during treatment. 


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9.2.1.7.
Definition of adverse events of special interest (AESI)
AESIs are defined as events (serious or non-serious) which are of medical concern specific to 
Betalutin, for which ongoing monitoring and rapid communication by the Investigator to the 
Sponsor may be appropriate. Such events may require further investigation in order to
characterise them. One potential risk for Betalutin is that as an antibody-radionuclide-
conjugate, it may over long-term induce secondary malignancies, including myelodysplastic 
syndrome (MDS), acute leukaemia and others. During the protocol-mandated follow-up visits,
the Investigator will observe for indications of potential late-toxicity, such as the development 
of secondary malignancies, MDS, acute leukaemia or aplastic anaemia. These events will be 
recorded as SAEs. In addition, physical examination will be performed and blood samples for 
haematology and serum biochemistry taken.
AESIs are defined on the basis of an ongoing review of the safety data, and are reflected in the 
Investigators Brochure.
Safety review
A safety monitoring board will not be used for this study. Instead, Nordic Nanovector will have 
frequent access to the safety and other clinical data and will host Investigator teleconferences 
on a regular basis during the study to review the ongoing safety of the patients.
After the first 3 patients are enrolled, and once haematological recovery has occurred, Nordic 
Nanovector will convene a teleconference with the Investigators to discuss and evaluate all of 
the safety data before dosing additional patients.
The following safety data will be collected and evaluated (see Section 9.2.6):
x
AEs
x
Laboratory variables: haematology, serum biochemistry and immunoglobulin levels 
data
x
Immunogenicity
x
Vital signs 
x
12-lead ECGs
x
Physical examination
x
Long-term toxicity
The time points for all assessments are shown in the Schedule of activities (Section 1.2) AEs 
will be graded and recorded throughout the study according to NCI CTCAE version 4.03.
Assessments of adverse events; seriousness, causality, severity and 
expectedness
Each individual AE should be evaluated by the Investigator with regard to date of onset, its 
seriousness, severity, duration, causal relationship to the study drug and/or concomitant therapy 
and outcome.
Seriousness will be determined according to the definition, see Section 9.2.1.3.
Causality will be determined based on the definition in Section 9.2.1.2. All AEs judged by the 
Investigator or the Sponsor as having a reasonable suspected causal relationship to a study drug 
qualify as ADRs. The Sponsor will not overrule the causality assessment given by the 


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Investigator. If the Sponsor disagrees with the Investigator’s causality assessment, both the 
opinion of the Investigator and of the Sponsor will be provided with the report. 
All toxicities/AEs will be graded according to NCI CTCAE version 4.03. In the eCRF the 
Investigator’s opinion of the relationship of the AEs to the study drug, will be categorised as 
unrelated, possibly or probably related, as defined below. 
Unrelated: An AE, which after careful examination at the time of evaluation, is judged to be 
clearly and incontrovertibly due to extraneous causes (disease, environment, etc.) 
and do not meet the criteria for drug relationship listed under possible or probable. 
Possible: 
An AE, which after careful examination at the time of evaluation, the connection 
with the study drug administration cannot be ruled out. 
Probable: 
An AE, which after careful examination at the time of evaluation, the connection 
to the study drug administration appears, with a high degree of certainty, to be 
related to the study drug  
In addition to the Investigator’s own description of the AE, each AE will be encoded by 
Sponsor’s representative, according to the Medical Dictionary for Regulatory Activities 
(MedDRA). 
Severity: The term “severe” is used to describe the intensity (severity) of a specific event.  Note 
that it is not the same as “serious”, which is based on patient/event outcome or action criteria. 
The severity of all events will be graded according to the NCI CTCAE version 4.03 by the 
Investigator. NCI CTCAE grade 5 (death) will not be used in this study; rather information 
about deaths will be collected through a death form. For events not listed in the toxicity table, 
severity should be recorded as: 
Grade 1:  
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated.   
Grade 2:  
Moderate; minimal, local or non-invasive intervention indicated; limiting 
age-appropriate instrumental activities of daily living (ADL 
Grade 3:  
Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting 
self-care ADL 
Grade 4:  
Life-threatening consequences; urgent intervention indicated. 
,QVWUXPHQWDO $'/ UHIHU WR SUHSDULQJ PHDOV VKRSSLQJ IRU JURFHULHV RU FORWKHV XVLQJ WKH
telephone, managing money, etc. 
6HOI-care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking 
medications and not bedridden. 
Expectedness Reports have to be considered as unexpected if they add significant information 
on the specificity or severity of an expected ADR. The expectedness of an AE/ADR will be 
determined by the Sponsor. The event is unexpected if it is not consistent with the applicable 
product information, i.e. the Investigator’s Brochure for Betalutin and lilotomab or the 
approved product information (prescribing information) for RTX.  


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Reporting of adverse events
Any AEs that occur after a patient has signed the ICF and up to 12 weeks after their Betalutin 
or 4 weeks following their last maintenance RTX drug administration, must be reported, 
whether or not it is considered related to any of the study drugs. All AEs will be reported in the 
patient eCRFs. If more than one AE occurs, each event should be recorded separately. AEs 
and/or laboratory abnormalities shall be reported to the Sponsor according to the reporting 
requirements and within the time periods specified in the protocol. All AEs will be followed 
up until resolved or as clinically required.  AEs that occur from 12 weeks after their Betalutin 
administration or 4 weeks after their last maintenance RTX drug administration, that are judged 
to be related to any of the study drugs will be reported when they come to the Investigator’s 
attention.
Specific information about secondary malignancies such as leukaemia, MDS and aplastic 
anaemia or any other malignancy, will be collected up to 2 years after Betalutin administration 
or relapse of disease, including information about treatment given to the patient due to NHL
(See Section 9.2.1.7).
Death is not defined as an AE but as an outcome of an AE. It is important that the event leading 
to the death be reported. It will be reported as an AE up to 12 weeks after their last study drug
administration. Thereafter, death it will be collected in the eCRFs as survival information. It 
will be reported as the outcome of an ADR when it is judged as related to study drug.
Progression of disease: 
Disease progression is not reported as an AE if it is clearly consistent with the suspected 
progression as determined by the protocol. Hospitalization due solely to disease progression 
should NOT be reported as an SAE. Any associated symptoms may be reported as AEs if there 
is any uncertainty about the symptom being exclusively due to disease progression, or if it does 
not fit the expected pattern of progression of the disease.
AEs due to RTX injection: The expected AEs with RTX are described in the package insert for 
RTX. This should be taken into consideration when reporting an AE. 
AEs may be reported spontaneously by the patient or elicited through open (non-leading) 
questioning during each visit to the study site and at the end of the AEs follow-up. As far as 
possible all AEs must be described by their duration (start and stop date), severity (graded 
according to NCI CTCAE version 4.03), relationship to treatment (unrelated, possible, 
probable), according to the need of other specific therapy and outcome. 
The following information should be recorded in the AE eCRF page:
x
Whether the event is serious or non-serious
x
Relationship to study drug
x
Severity of the event (CTC grade)
x
Onset date and time
x
Resolution date and time, or date and time of death
x
Action taken
x
Outcome of the event


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Reporting of serious adverse events
9.2.5.1.
Investigator’s Responsibilities
The Investigator shall report all SAEs, regardless of suspected causality, occurring after the 
patient has provided informed consent up to 12 weeks after their Betalutin or 4 weeks following 
their last maintenance RTX drug administration, immediately (within 24 hours of the 
Investigator becoming aware of the event) to the Sponsor’s representative. The immediate 
report shall be followed by detailed written report(s). SAEs will be reported in the following 
time periods:
x
SAEs will be collected from signing informed consent to ensure that any protocol-
related SAEs are collected
x
Up to 12 weeks after their Betalutin or 4 weeks following their last maintenance RTX 
drug administration, whether or not considered related to study drug
x
At any time beyond 12 weeks after their Betalutin or 4 weeks following their last 
maintenance RTX drug administration, when it comes to the Investigator’s attention 
and is judged to be related to the patient’s participation in the study or related to the 
study drug. If such event is observed post end of study visit, it should be notified to the 
Sponsor using the following email address: SAE@nordicnanovector.com
Any SAEs experienced beyond 12 weeks after their Betalutin or 4 weeks following their last 
maintenance RTX drug administration should only be reported to Nordic Nanovector if the 
Investigator suspects a causal relationship to the study treatment, or if it is an AESI. Recurrent 
episodes, complications or progression of the initial SAE must be reported as follow-up to the 
original episode within 24 hours of the Investigator receiving the follow-up information. An 
SAE occurring at a different time interval or otherwise considered completely unrelated to a 
previously reported one should be reported separately as a new event. All SAEs must be 
reported to Sponsor’s representative as follows:
1.
Immediately (within 24 hours of discovery of the event) report the event to 
representative preferably by using the SAE module within the eCRF or by email, 
telephone or fax.
2.
Complete the SAE report form within the eCRF or by using the paper form (only if the 
eCRF is not available) and send it to representative within 3 working days of the 
discovery of the event.
3.
Follow-up the SAE until resolved or as clinically required, all follow-up evaluations 
must be reported to representative.
4.
Document the SAE in the hospital records.
It is important to send “as complete as possible” a report within the timelines. Incomplete 
information must NOT delay reporting of SAEs. Additional information must be reported once 
it is available; in follow-up reports using the same SAE forms but marked as a follow-up report. 
The Sponsor or assigned designee is responsible for reporting all the relevant safety 
information to the Independent Ethics Committees (IECs)/Institutional Review Boards (IRBs) 
and Competent Authorities concerned. Where applicable as per local requirements, the 
Investigator will inform the EC/IRB and/or the Competent Authority of the SAE. For reporting 
death of a patient, the Investigator shall supply the Sponsor and the IEC/IRB with any 
additional information requested.


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Sponsor will inform all Investigators concerned of relevant information about SUSARs.
Contact address for reporting SAEs:
PharmaLex Norway AS
Karoline Kristiansens vei 1, 0661 Oslo, Norway
Phone: 
+47 22 23 88 80
Fax: 
+47 21 01 80 19
Email:
PV-nordic@pharmalex.com
9.2.5.2.
Sponsor’s Responsibilities
The Sponsor is responsible for the ongoing safety evaluation of the study drug.
The Sponsor is responsible for the prompt notification to all concerned Investigators, the 
IECs/IRBs and Competent Authorities where Betalutin studies are ongoing, of findings that 
affect the health of the patients, impact on the conduct of the study or alter the Competent 
Authority’s authorization to continue the study in accordance with Directive 2001/20/EC.
The Sponsor has to keep detailed records of all AEs reported to him by the Investigators and 
to perform an evaluation with respect to seriousness, causality and expectedness. These records 
shall be submitted to the Competent Authorities in the countries where the clinical study is 
being conducted, if they so request.
Each individual AE should be evaluated by the Sponsor, with regard to its seriousness and 
causal relationship to the study drug and/or concomitant therapy. The Sponsor will assess 
whether or not the AE is unexpected.
Other Safety Parameters 
9.2.6.1.
Physical examination
A physical examination will be performed at each hospital visit by the physician. 
Any physical examination finding that is classified by the Investigator as a clinically significant 
change (worsening compared to previous examination) will be considered as an AE/SAE, 
documented on the patient’s eCRF, and followed until the outcome is known. 
The Investigator will also assess the ECOG performance status at time points given in Schedule 
of activities (Section 1.2).


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Table 9-2  
Definition of ECOG performance status 
Grade ECOG* 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of a light 
or sedentary nature, e.g., light house work, office work 
2 
Ambulatory and capable of all self-care but unable to carry out any work activities. Up and 
about more than 50% of waking hours 
3 
Capable of only limited self-care, confined to bed or chair more than 50% of waking hours 
4 
Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair 
5 
Dead 
* As published in Am. J. Clin. Oncol.: Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E., 
McFadden, E.T., Carbone, P.P.: Toxicity And Response Criteria Of The Eastern Cooperative Oncology Group. 
Am J Clin Oncol 5:649-655, 1982 
 
Performance status response and progression will be evaluated as: 
x 
Improvement or worsening by 1-point or more on the ECOG scale from the baseline 
value. 
9.2.6.2. 
Vital signs 
Vital signs (systolic/diastolic blood pressure, heart rate and body temperature) will be measured 
as described in the Schedule of activities (Section 1.2). Additional vital signs assessments will 
be done under the Investigator’s judgment.  
Blood pressure will be measured on the arm contralateral to the site of study drug 
administration. 
Both “new” and “worsening” vital sign abnormalities are anticipated in patients over the course 
of a clinical study. A “new” abnormality is defined as one that occurs when a patient’s normal 
baseline vital signs develop clinically significant values (“notable”) post-baseline. A 
“worsening” abnormality is defined as one that occurs when a patient’s “notable” baseline vital 
signs become worse post-baseline by 25%. 
Notable vital signs results should be interpreted in conjunction with the clinical situation of the 
patient. Once AE/SAE notification is decided upon, the Investigator is required to follow the 
procedure described for AE notification and document the clinically notable abnormality on 
the AE eCRF page. Any notable abnormal vital signs finding or related AE must be followed 
until outcome is known.  
9.2.6.3. 
12-lead electrocardiogram 
A standard 12-lead ECG will be performed as per the Schedule of activities (Section 1.2). 
Results will be recorded as normal or abnormal; abnormal findings will be described in the 
eCRF. The ECG will be evaluated by the Investigator. Additional vital signs assessments will 
be done under the Investigator’s judgment. 
A copy of the ECG page, signed, dated and interpreted should be stored in the patient file. 


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9.2.6.4. 
Clinical laboratory parameters 
Blood samples for the determination of haematology and serum biochemistry parameters will 
be drawn at pre-specified time points, as per the Schedule of activities (Section 1.2).  
The following laboratory tests will be performed: 
Table 9-3  
Clinical laboratory parameters 
Serum Biochemistry 
Haematology 
Urine 
Sodium 
Haemoglobin 
Urine pregnancy test at day 0 
Potassium 
Platelets 
Calcium 
White blood cell count 
Creatinine 
Differential 
Uric acid 
Neutrophils 
Alkaline Phosphatase (total ALP) 
Lymphocytes 
Aspartate aminotransferase (ASAT) 
Monocytes 
Alanine aminotransferase (ALAT) 
Eosinophils 
Lactate Dehydrogenase (LDH) 
Basophils 
Glucose 
,PPXQRSKHQRW\SLQJ 
Bilirubin, total 
Coagulation: 
International normalised ratio 
(INR), prothrombin time (PTT) 
Gamma-glutamyl transferase (GGT) 
Magnesium 
Albumin 
+,9WHVW 
Hepatitis B test (HBsAg and anti-
+%F 
+HSDWLWLV& 
b-K&*SUHJQDQF\WHVW 
Quantitative serum 
immunoglobulins (IgG, IgA and 
IgM) 
+$0$DWVFUHHQLQJ 
 
 A serum sample will be sent for HAMA screening to a central laboratory (mandatory). Eligibility can be assessed 
using a local test such as the Milenia Quickline® HAMA test (optional). If the Milenia Quickline® HAMA test 
is positive, eligibility can only be assessed using the results from the central laboratory. 
Absolute cell counts for circulating T-cells, CD4 T-cells, CD8 T-cells, B-cells and NK cells, respectively 
defined as CD3+, CD3+CD4+, CD3+CD8+, CD19+ and CD3- CD16+ CD56+ lymphocytes by flow cytometry. At 
certain time points specified in Schedule of activities (Section 1.2).  
Reference ranges from the laboratory will be provided to the Sponsor. If during the study, 
ranges should be changed, the Investigator is requested to provide updated laboratory normal 
values. 
The Investigator will interpret all clinical laboratory test results outside the reference range, 
using the following criteria: 
1 = Value out of reference range, but not a clinically significant worsening from previous 
examination. 
2 = Value out of reference range, and a clinically significant worsening from previous 
examination. 


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Laboratory values outside reference range recorded in the CTCAE, will be graded 1 to 4 
according to NCI CTCAE version 4.03. The laboratory values might be an SAE if meeting any 
of the seriousness criteria defined in Section 9.2.1.3. During the follow-up period only changes 
in laboratory values judged to be related to study drug will be reported as AEs. 
Once AE notification is decided upon, Investigators are required to follow the procedure 
described for AE notification and document the notable laboratory results on the AE eCRF 
page. Any notable laboratory abnormality or related AE must be followed until the outcome is 
known.  
The signed and interpreted laboratory results will be kept together with the patient’s eCRF as 
supplemental pages at the study site. 
9.2.6.5. 
Immunogenicity assessment 
9.2.6.5.1. Assessments 
Immunogenicity i.e. development of ADAs is of concern as ADA can reduce the efficacy of 
the therapeutic protein but also, in some specific cases, impact on patient safety [36-38]. 
In this study, the immunogenicity risk for the patient is related to the immunogenicity potential 
of (1) lilotomab, (2) the chemical linker p-SCN-Bn-DOTA (satetraxetan), and (3) RTX. The 
immunogenicity potential of ARC using satetraxetan is suggested to be dependent of the carrier 
molecule rather than DOTA itself [39]. RTX immunogenicity has been reported but without a 
demonstrated clinical relevance [40-42]. Therefore, immunogenicity assessments for ADA 
monitoring will be focused on lilotomab and RTX as follow: 
x 
Monitoring of the ADA response after injection of lilotomab/Betalutin according to a 
tiered approach (https://www.fda.gov/downloads/Drugs/Guidances/UCM192750.pdf), 
using a bridging assay format 
x 
Monitoring of the ADA response after RTX dosing, before – during – and after 
combination with Betalutin. A commercial kit will be used for this assessment.  
x 
HLA class II haplotype of the patients [43] (see section 9.4). 
9.2.6.5.2. Human biosamples collection schedule 
Sampling of peripheral blood for ADA monitoring will be performed at the following 
approximate time points: 
x 
Screening (Baseline for lilotomab, Betalutin and RTX ADA monitoring) 
x 
After Betalutin administration, at Day 28 and 3, 6, 12, 18 and 24 months. It has to be 
noted that at Day 28, peripheral blood sampling should be done before RTX dosing. 
The time points mentioned are approximate time points. The exact time point when the sample 
is taken needs to be recorded in the eCRF.  
9.2.6.5.3. Human biosamples handling 
A volume of approximately 6 mL of peripheral blood will be collected by venipuncture at each 
time point (see above and Section 1-2) to monitor the development of an ADA response post 
lilotomab/Betalutin treatment. Serum samples will be isolated, aliquoted and frozen on site at 
 -20°C the day of collection. All the aliquots of serum will be shipped on dry ice to Covance 
Central Laboratories (Geneva, Switzerland), where they will be biobanked for future use.  


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An additional volume of approximately 4 mL of peripheral blood will be collected in a similar 
fashion at each time point (see above and Section 1-2) for RTX immunogenicity assessment
and monitoring of RTX concentration in serum (see Section 9.3). Serum samples will be 
isolated, aliquoted and frozen on site at -20°C the day of collection. All serum aliquots will 
be shipped on dry ice to Covance Central Laboratories (Geneva, Switzerland), where they will 
be biobanked for future use.
Instructions for handling procedures, preparation, storage and shipping of the serum samples 
will be provided in the study laboratory manual.
Volume of blood to be drawn from each patient
The total volume of blood that will be drawn from each patient in this study will vary depending 
on how long the patient remains on study. Table 9-4 indicates the range for patients during the 
treatment period (28 months).


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Table 9-4 Volume of blood to be drawn from each patient during the screening and treatment period (Screening to End of study visit) 
Assessment 
Max volume 
(1 draw) 
No. of samples 
(30 days) 
Max volume 
(30 days) 
No. of samples 
(Total) 
Max volume 
(Total) 
On site laboratory analyses 
 
 
 
 
 
x 
Biochemistry 
4 mL 
Max 7 
28 ml 
Max 23 
92 mL 
x 
Haematology 
4 mL 
Max 7 
28 mL 
Max 23 
92 mL 
x 
Serum virology & pregnancy test (screening) 
4.5 mL 
Max 1 
4.5 mL 
Max 1 
4.5 mL 
x 
Immunoglobulin levels 
5 mL 
Max 2 
10 mL 
Max 5 
25 mL 
x 
Coagulation 
4 mL 
Max 1 
4 mL 
Max 2 
8 mL 
HAMA at screening 
4 mL 
Max 1 
4 mL 
Max 1 
4 mL 
Immunogenicity assessment1 (lilotomab, Betalutin ADA) 
6 mL 
Max 2 
12 mL 
Max 7 
42 mL 
RTX immunogenicity (ADA)/PK2 
4 mL 
Max 2 
8 mL 
Max 7 
28 mL 
Minimal Residual Disease 
8 mL 
Max 1 
8 mL 
Max 5 
40 mL 
Pharmacokinetic – Total radioactivity3 
2 mL 
Max 8 
16 mL 
Max 8 
16 mL 
HLA haplotyping (optional) 
2 mL 
Max 1 
2 mL 
Max 1 
2 mL 
In vitro T-cell responses4 (optional) 
100 mL 
Max 1 
100 mL 
Max 3 
300 mL 
TOTAL - maximum volume to be drawn for patients not 
participating in the PK3 and in vitro T-cell assessments 
45.5 mL 
- 
108.5 mL 
- 
337.5 mL 
TOTAL - maximum volume for a few patients (<10) participating 
in the PK3 but not in vitro T-cell assessments 
47.5 mL  
- 
124.5 mL 
- 
353.5 mL 
TOTAL - maximum volume to be drawn for patients participating 
in the in vitro T-cell but not PK3 assessments 
145.5 mL 
- 
208.5 mL 
- 
637.5 mL 
TOTAL - maximum volume to be drawn for patients participating 
in both the PK3 and in vitro T-cell assessments 
147.5 mL 
- 
224.5 mL 
- 
653.5 mL 
Max = maximum number of samples to be taken from screening to End of  Study 
2 Monitoring of rituximab concentration in serum and the ADA response towards rituximab.  
3 To be performed at Radium Hospital (Oslo, Norway) only; otherwise optional 
4At Radium Hospital (Oslo, Norway) only. Optional, additional blood volumes collected to explore the anti-tumour T cell responses 


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Pregnancy
x
Details of all pregnancies in female patients and female partners of male patients will 
be collected after the start of study treatment. The pregnant patient or the patient’s 
partner should be followed-up during the entire course of the pregnancy up to 6-8 weeks 
beyond the estimated delivery date.
x
If a pregnancy is reported, the Investigator should inform the Sponsor within 24 hours 
of learning of the pregnancy and should follow the procedures outlined in Appendix 3.
x
Abnormal pregnancy outcomes (e.g. spontaneous abortion, foetal death, stillbirth, 
congenital anomalies or ectopic pregnancy) are considered SAEs.
9.3.
Pharmacokinetics
Assessments
Betalutin PK samples will be collected from patients to evaluate whether the combination with 
RTX impact the total radioactivity in blood profile observed in the LYMRIT 37-01 study. In 
vitro measurements will be performed by measuring the total radioactivity (Betalutin, 
177Lu-satetraxetan chelate, 177Lu-DTPA chelate, and 177Lu) per mL of blood using a gamma 
counter. This assessment will be mandatory at Radium Hospital (Oslo, Norway), otherwise 
optional.
It has to be noted that it is not expected to detect 177Lu in blood due to its high binding affinity 
to satetraxetan and DTPA. DTPA chelates the 177Lu not radiolabelled to satetraxetan in 
Betalutin formulation, with 177Lu-DTPA chelate expected to have a fast-renal clearance 
[44-46].
RTX is widely used in onco-haematology at a dose of 375 mg/m2, as neither dose-response 
relationship nor DLT were identified. As PK studies have demonstrated large inter-individual 
variability of rituximab exposure [47, 48], monitoring of RTX serum concentration will be 
performed to support the assessment of any potential interference of RTX in immunogenicity 
assessments (see Section 9.2.6.5). 
Human biosamples collection schedule
Sampling of peripheral blood for Betalutin PK will be performed at the following 
approximate time points:
x
Before lilotomab administration (baseline)
x
After Betalutin administration: 
x
5 (±2), and 60 (±10) minutes
x
2 hours (±15 minutes), 24 (±4) hours, and 96 (±24) hours
x
7 (±2) days and 28 (±2) days
It has to be noted that on Days 7 and 28, PK sampling should be done before RTX dosing. The 
time points mentioned are approximate time points. The exact time point when the sample is 
taken needs to be recorded in the eCRF. Each patient group will be monitored continuously,
and adaptation of the sampling times may become necessary depending on the results. 
Sampling of peripheral blood for RTX concentration in serum will be performed at the time 
points agreed for the immunogenicity assessments (See Section 9.2.6.5.2.).


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Human biosamples handling
9.3.3.1.
Total radioactivity in blood
A volume of approximately 2 mL of peripheral blood will be collected on EDTA at each time 
point (see above and Section 1-2).  An exact volume of 1 mL of peripheral blood will be 
transferred on-site into a 5 mL transfer tube. Radioactivity measurement will be performed 
on-site at Nordic Nanovector ASA (Oslo, Norway) or selected sites that are experienced and 
equipped to perform these assessments. The total radioactivity per mL of blood will be 
determined from each sample. 
Instructions for handling procedures, preparation, storage and shipping of the serum samples 
will be provided in the laboratory manual for this study.
9.3.3.2.
Monitoring of RTX concentration in serum
A volume of approximately 4 mL of peripheral blood will be collected and handled as described 
in Section 9.2.6.5. and Section 1-2.
Serum samples will be shipped to Covance Central Laboratories (Geneva, Switzerland), where 
they will be biobanked for future use. 
Instructions for handling procedures, preparation, storage and shipping of the serum samples 
will be provided in the laboratory manual for this study.
9.4.
Biodistribution and dosimetry
The biodistribution and dosimetry study will provide estimates for the absorbed radiation dose 
to normal body structures as well as to tumours that can be identified in the images. The 
radioactivity in the actual organs will be measured in absolute terms, at different times after 
injection. The time series will allow to estimate the cumulative activity in each organ and by 
measurements/estimates of organ weight the absorbed dose.
Measurements will be performed as described in Appendix 5. 
The measurements will be performed on a SPECT/CT scanner containing 2 gamma camera 
heads (Siemens SYMBIA –T16) equipped with medium energy collimators, which. will be 
used for CT, SPECT, and whole-body scanning. Quantification will be carried out by use of 
the software of the vendor and using computer programs (IDL, ITT visual solutions) Full 
details of the scans required for biodistribution and dosimetry and of acquisition specifications 
are provided in a dedicated dosimetry protocol.
The images obtained will enable the characterisation of the biodynamics and the calculation of 
the cumulative activity in each organ, with dose estimates obtained using the OLINDA 
program.
The conjugated whole-body studies and the quantification in regions drawn around each organ 
together with assay of activity in blood will allow for:
x
Estimation of whole-body retention of radioactivity at set imaging times post-injection.
x
Estimation of the individual organ uptake/retention of radioactivity at set points after 
injection.
x
Estimate retention of administered radioactivity in blood.
x
Calculation of estimated absorbed radiation dose to target organs and to tumours.


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9.5. 
Biomarkers 
Biomarker research is part of this study. Following informed consent from the patients, human 
biosamples, including but not exclusive to tumour tissue biopsy, needle aspirate and peripheral 
blood samples, will be collected to evaluate pharmacodynamics [49, 50] and gene expression 
changes related to disease treatment and/or relapse/disease progression in tumour [51-56]. 
HLA class I and II haplotype of the patients will be addressed using DNA extracted from either 
peripheral blood leucocytes or saliva [43, 57]. Anti-tumour T-cell responses will be measured 
by flow cytometry after co-culture of peripheral blood mononuclear cells and autologous 
lymphoma cells [58] and other relevant in vitro biomarker analyses. 
Details regarding the assessments, technologies in scope and biobanking are reported in 
Table 9-5. Except for CD37/CD20 expression in tumour prior to treatment and monitoring of 
the MRD, these assessments are optional, and some will be performed at selected sites only 
(e.g. anti-tumour T-cell responses). The results of these analyses are not required for enrolment 
into the study and may not be reported to the clinical study database, nor have impact on patient 
management but could be published in scientific journals. 
Instructions for handling procedures, preparation, storage and shipping of the biological 
material will be provided in the laboratory manual for this study. Analyses performed to 
explore the anti-tumour T-cell responses will be mainly performed at Radium Hospital (Oslo, 
Norway) but some analyses may require having an aliquot of this biological material (collected 
and biobanked at Radium Hospital (Oslo, Norway) to be sent to contract research organisations 
located outside of Norway. 
9.6. 
Biobanking 
The patient may be asked if he/she is willing to have part of the available tumour biopsy 
samples (archived or newly obtained at screening visit, disease progression and/or relapse) to 
be biobanked at Covance Central Laboratories (Geneva, Switzerland) for future analysis of the 
tumour tissue samples or its derivatives (DNA, RNA, proteins). If a tumour block is provided, 
it will be returned to the hospital upon request.  
Additional biological material collected for research studies focusing the anti-tumour T-cell 
responses (e.g. tumour biopsy and peripheral blood samples and derivatives such as cells, 
plasma, DNA, RNA) collected at Radium Hospital (Oslo, Norway) only, will be processed and 
biobanked on-site for future use. 


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Table 9-5 Biomarker assessments 
Assessment 
Human biosamples 
collected 
Human biosamples 
or derivatives used 
in assay 
Method 
Schedule of assessments 
Biobanking 
Purpose 
CD37 & 
CD20 
expression in 
tumour tissue 
Tumour tissue biopsy 
(surgical) 
FFPE 5 µM slides 
Immunohistochemistry, 
whole slide digital 
image quantitative 
analysis 
Mandatory prior to 
treatment (archived or 
newly collected at 
screening) 
Optional at relapse or 
disease progression (newly 
collected biopsy) 
FFPE block on-site or CCLS 
5µM FFE slides to be prepared 
only upon sponsor request to 
ensure integrity of the 
biomaterial and quality of the 
analysis 
To characterize PD and 
identify potential predictors of 
efficacy 
Gene 
expression 
profiling in 
tumour 
Tumour tissue biopsy 
(surgical)1 
FFPE 5 µM slides 
and derivatives such 
as DNA, RNA and 
proteins 
Gene expression arrays 
(RNA) 
RNA sequencing 
(RNA) 
DNA sequencing(DNA) 
Other relevant methods 
Optional 
Archived tumour tissue 
biopsies or newly collected at 
screening, relapse and/or 
disease progression 
 
 
5µM FFE slides to be prepared 
only upon sponsor request to 
ensure integrity of the 
biomaterial and quality of the 
analysis 
To identify prognostic and/or 
treatment-related predictive 
biomarkers 
Minimal 
Residual 
Disease 
Tumour tissue biopsy 
(surgical)1 
Peripheral blood 
 
FFPE 5 µM slides 
 
Cell and cell-free 
(in plasma) tumour 
DNA 
Next generation 
sequencing (DNA) 
Biopsy: Mandatory, archived 
tumour tissue biopsy or newly 
collected at screening1 
Blood: Mandatory, at prior to 
treatment, Week 12, Week 26, 
Week 52 and at EOS  , unless 
relapse or disease progression 
has been clinically observed 
since the previous blood 
sample 
 
5µM FFE slides to be prepared 
only upon sponsor request to 
ensure integrity of the 
biomaterial and quality of the 
analysis 5µM FFE slides to be 
prepared only upon sponsor 
request to ensure integrity of the 
biomaterial and quality of the 
analysis 
Bulk material (whole blood 
without plasma) and plasma, at 
CCLS 
To calibrate the blood MRD 
test 
 
To assess early treatment 
response and detect relapse 


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Assessment 
Human biosamples 
collected 
Human biosamples 
or derivatives used 
in assay 
Method 
Schedule of assessments 
Biobanking 
Purpose 
In vitro anti-
tumour T-cell 
response 
Peripheral blood and 
tumour tissue biopsy 
(surgical or needle 
aspirate – See Tables 
1-1 and 1-2) 
Peripheral blood 
leucocytes, tumour 
cells, plasma, and 
derivatives such as 
DNA, RNA and 
proteins 
In vitro cell based assay 
using flow cytometry as 
readout and other 
biomarker analyses 
(DNA, RNA, proteins) 
Optional 
Peripheral blood: Prior to 
treatment, Week 12 and Week 
39 
Tumour biopsy: Prior to 
treatment, Day -1 or Day 0, 
Week 12 and Week 25 
Peripheral blood leucocytes, 
tumour cells, plasma and 
derivatives such as DNA, RNA, 
proteins, at Radium Hospital 
(Oslo, Norway) 
To explore further the anti-
tumour T-cell responses driven 
by the combination of 
lilotomab, Betalutin and RTX 
HLA class I II 
haplotype 
Peripheral blood 
Saliva sample or 
mouth swab is 
acceptable if blood 
collection not possible 
DNA 
Gene array (DNA) 
Optional 
Prior to treatment 
Peripheral blood, saliva, mouth 
swab and at CCLS 
To (i) investigate the 
mechanism underlying a 
potential ADA response and 
(ii) characterize the anti-
tumour T-cell response  
1 NOTE: No additional tumour tissue biopsy will be collected (sample may be taken from an archived and/or newly collected biopsy at screening, relapse and/or disease progression for CD20 & 
CD37 expression in tumour) 
 


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10. 
Statistical Considerations  
10.1. 
Statistical Analyses 
The study is a single-arm, open-label study to further assess the risk/benefit of a pre-dose of 
lilotomab and Betalutin to enhance tumour response to RTX therapy. Six to 12 patients is a 
reasonable sample size to evaluate any potential safety/tolerability signals and for obtaining 
preliminary estimates of the response rates and variability of the response rates. 
The primary endpoint is the frequency and type of AEs. Study data will be summarised with 
respect to demographic and baseline characteristics, safety observations and measurements, 
efficacy observations and measurements (response rates, duration of response, PFS, TTP, OS), 
and PK measurements. Categorical data will be presented in tables; descriptive statistics will be 
used to summarise response rates, etc. Patients who have withdrawn from the study, including 
those who have died, will be counted as having PD for all visits after the time of withdrawal. 
The number and percentage of patients with each response, and overall (CR + PR) will be 
presented for each time point for the ITT population. All data obtained after treatment with 
lilotomab/Betalutin will be summarized by the dose of Betalutin received and overall doses. 
 
Populations for analysis 
Intent-to-treat (ITT) population: The ITT population will consist of all patients who were 
enrolled and treated with lilotomab/Betalutin, regardless if RTX therapy was initiated. 
Safety Population: The safety analysis population will include all patients who received at least 
one dose of any study drug.   
PK population: The PK population consists of all patients who have a PK assessment with a 
sufficient number of evaluable blood samples. 
 
Other Analyses  
PK, and biomarker exploratory analyses will be described in the statistical analysis plan (SAP), 
which will be finalised before database lock. Analyses will be presented separately from the 
main clinical study report (CSR).  


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Herold M, Dölken G, Fiedler F, et al. Randomized phase III study for the treatment of advanced 
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chemotherapy plus rituximab. Ann Hematol 2003; 82(2): 77-9. 
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Schaefer NG, Huang P, Buchanan JW, et al. Radioimmunotherapy in non-Hodgkin lymphoma: 
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Dahle J, Repetto-Llamazares AH, Mollatt CS, et al. Evaluating antigen targeting and anti-tumor 
activity of a new anti-CD37 radioimmunoconjugate against non-Hodgkin's lymphoma. 
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Repetto-Llamazares AH, Larsen RH, Patzke S, et al. Targeted Cancer Therapy with a Novel 
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Lymphoma. PLoS One 2015; 10(6): e0128816. 
29.  
Dreyling M, Ghielmini M, Rule S, et al. Newly diagnosed and relapsed follicular lymphoma: 
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Maloney DG, Grillo-Lopez AJ, White CA, et al. IDEC-C2B8 (Rituximab) anti-CD20 
monoclonal antibody therapy in patients with relapsed low-grade non-Hodgkin's lymphoma. 
Blood 1997; 90(6): 2188-95. 
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treatment in relapsed advanced-stage follicular lymphomas: results of a phase-II study of the 
German Low-Grade Lymphoma Study Group. Ann Hematol 2000; 79(9): 493-500. 
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Vidal L, Gafter-Gvili A, Salles G, et al. Rituximab maintenance for the treatment of patients 
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Marcus R, Imrie K, Belch A, et al. CVP chemotherapy plus rituximab compared with CVP as 
first-line treatment for advanced follicular lymphoma. Blood 2005; 105(4): 1417-23. 
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Shankar G, Arkin S, Cocea L, et al. Assessment and reporting of the clinical immunogenicity of 
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Rosenberg AS. Immunogenicity of biological therapeutics: a hierarchy of concerns. Dev Biol 
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Perico ME, Chinol M, Nacca A, et al. The humoral immune response to macrocyclic chelating 
agent DOTA depends on the carrier molecule. J Nucl Med 2001; 42(11): 1697-703. 
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Van Walle I, Gansemans Y, Parren PW, et al. Immunogenicity screening in protein drug 
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Keating GM. Rituximab: a review of its use in chronic lymphocytic leukaemia, low-grade or 
follicular lymphoma and diffuse large B-cell lymphoma. Drugs 2010; 70(11): 1445-76. 
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Dunn N, Juto A, Ryner M, et al. Rituximab in multiple sclerosis: Frequency and clinical 
relevance of anti-drug antibodies. Mult Scler 2018; 24(9): 1224-33. 
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Barbosa MD, Vielmetter J, Chu S, et al. Clinical link between MHC class II haplotype and 
interferon-beta (IFN-beta) immunogenicity. Clin Immunol 2006; 118(1): 42-50. 
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Li WP, Ma DS, Higginbotham C, et al. Development of an in vitro model for assessing the in 
vivo stability of lanthanide chelates. Nucl Med Biol 2001; 28(2): 145-54. 
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Breeman WA, van der Wansem K, Bernard BF, et al. The addition of DTPA to [177Lu-
DOTA0,Tyr3]octreotate prior to administration reduces rat skeleton uptake of radioactivity. Eur 
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46. 
Forrer F, Chen J, Fani M, et al. In vitro characterization of (177)Lu-radiolabelled chimeric anti-
CD20 monoclonal antibody and a preliminary dosimetry study. Eur J Nucl Med Mol Imaging 
2009; 36(9): 1443-52. 
47. 
Cartron G, Blasco H, Paintaud G, et al. Pharmacokinetics of rituximab and its clinical use: 
thought for the best use? Crit Rev Oncol Hematol 2007; 62(1): 43-52. 
48. 
Tout M, Casasnovas O, Meignan M, et al. Rituximab exposure is influenced by baseline 
metabolic tumor volume and predicts outcome of DLBCL patients: a Lymphoma Study 
Association report. Blood 2017; 129(19): 2616-23. 
49. 
Schaue D, Kachikwu EL, McBride WH. Cytokines in radiobiological responses: a review. 
Radiat Res 2012; 178(6): 505-23. 
50. 
Werner E, Wang H, Doetsch PW. Role of Pro-inflammatory Cytokines in Radiation-Induced 
Genomic Instability in Human Bronchial Epithelial Cells. Radiat Res 2015; 184(6): 621-9. 
51. 
Pastore A, Jurinovic V, Kridel R, et al. Integration of gene mutations in risk prognostication for 
patients receiving first-line immunochemotherapy for follicular lymphoma: a retrospective 
analysis of a prospective clinical trial and validation in a population-based registry. Lancet 
Oncol 2015; 16(9): 1111-22. 
52. 
Roschewski M, Staudt LM, Wilson WH. Dynamic monitoring of circulating tumor DNA in non-
Hodgkin lymphoma. Blood 2016; 127(25): 3127-32. 
53. 
He J, Abdel-Wahab O, Nahas MK, et al. Integrated genomic DNA/RNA profiling of 
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54. 
Weigert O, Weinstock DM. The promises and challenges of using gene mutations for patient 
stratification in follicular lymphoma. Blood 2017; 130(13): 1491-8. 
55. 
Pott C, Belada D, Danesi N, et al. Analysis of Minimal Residual Disease in Follicular 
Lymphoma Patients in Gadolin, a Phase III Study of Obinutuzumab Plus Bendamustine Versus 
Bendamustine in Relapsed/Refractory Indolent Non-Hodgkin Lymphoma. Blood 2015; 126(23): 
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Herrera AF, Kim HT, Kong KA, et al. Next-generation sequencing-based detection of 
circulating tumour DNA After allogeneic stem cell transplantation for lymphoma. Br J 
Haematol 2016; 175(5): 841-50. 
57. 
Rosenberg AS, Sauna ZE. Immunogenicity assessment during the development of protein 
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Kolstad A, Kumari S, Walczak M, et al. Sequential intranodal immunotherapy induces antitumor 
immunity and correlated regression of disseminated follicular lymphoma. Blood 2015; 125(1): 
82-9. 


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12. 
Appendices 


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Appendix 1: Abbreviations 
AE 
AESI 
Adverse events 
Adverse events of Special Interest 
ADA 
Anti-drug antibody 
ADL 
Activities of daily living 
ADR 
Adverse drug reaction 
ALP 
Alkaline phosphatase 
ALAT 
Alanine transaminase 
AML 
Acute myeloid leukaemia 
ANC 
Absolute neutrophil count 
ARC 
Antibody-radionuclide-conjugate 
ASAT 
Aspartate transaminase 
AUC 
ȕ-HCG 
Area under plasma drug concentration-time curve  
beta human-chorionic gonadotropin 
CCLS 
Covance Central Laboratories 
CHOP 
Cyclophosphamide, hydroxydaunorubicin, oncovin and prednisone 
Cmax 
Maximum plasma drug concentration;  
CNS 
Central nervous system  
CR 
Complete response 
CSR 
Clinical study report 
CT 
Computed tomography 
CTCAE 
CVP 
Common Terminology Criteria for Adverse Events 
Cyclophosphamide, vincristine and prednisolone 
DC 
Decay correction factor 
DLBCL 
Diffuse Large B-Cell Lymphoma 
DLT 
Dose limiting toxicity 
DoR 
Duration of response 
DOTA 
Abbreviation/company code for the chelator p-SCN-benzyl-DOTA 
IUPAC name: 1,4,7,10-Tetraazacyclododecane-1,4,7,10-tetraacetic 
acid, 2-[(4-isothiocyanatophenyl)methyl] 
DTPA 
Diethylenetriaminepentaacetic acid 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic Case Report Form 
EDTA 
Ethylenediaminetetraacetic acid 
Emax 
Maximum energy 
FACT-Lym 
Functional Assessment of Cancer Therapy–Lymphoma 
FDA 
FFPE 
FDG 
Food and Drug Administration 
Formalin fixed paraffin embedded 
(18F) Fluor deoxy glucose 
FL 
FSH 
GCP 
Follicular lymphoma 
Follicle stimulating hormone 
Good clinical Practice 
G-CSF 
GGT 
Granulocyte colony-stimulating factor 
Gamma-glutamyl transferase 
GM-CSF 
Granulocyte-macrophage colony-stimulating factor 
HAMA 
Human anti-murine antibody 


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HBsAg 
HRT 
Anti-HBc 
Hepatitis B surface antigen 
Hormonal replacement therapy 
Antibody to hepatitis B core antigen 
HIV 
Human immunodeficiency virus  
HLA 
Human leucocyte antigen 
I 
Iodine 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committee 
IgG 
Immunoglobulin G 
In 
INR 
Indium 
International Normalized Ratio 
iNHL 
Indolent non-Hodgkin B-cell lymphoma 
IRB 
Institutional Review Board 
ITT 
Intent to Treat 
IUD 
Intrauterine device 
IUS 
Intrauterine hormone-releasing system 
i.v. 
Intravenous 
LDi 
Longest diameter 
Lu 
Lutetium 
Max 
Maximum 
MBq 
Mega becquerel 
MedDRA 
Medical Dictionary for Regulatory Activities 
MHC 
Major Histocompatibility Complex 
MAB 
MRD 
MRI 
Monoclonal antibody 
Minimal residual disease 
Magnetic resonance imaging 
MS 
Mass spectrometry 
MTD 
Maximum tolerated dose 
MDS 
NCI 
Myelodysplastic syndrome 
National Cancer Institute 
NHL 
Non-Hodgkin Lymphomas 
NYHA 
New York Heart Association 
ORR 
Overall response rate 
OS 
Overall survival 
PD 
Progressive disease 
PET 
Positron-emission tomography 
PFS 
Progression-free survival 
PK 
Pharmacokinetic 
PPD 
Individual product of the perpendicular diameters 
PR 
PTT 
Partial response 
Partial Thromboplastin Time 
QoL 
Quality of Life 
RIT 
Radioimmunotherapy 
RTX 
Rituximab 
SAE 
SAP 
s.c. 
Serious adverse event 
Statistical analysis plan 
Subcutaneous 


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SCID 
Severe combined immune deficient 
SD 
Stable disease 
SPD 
Sum of products of the 2 target tumour diameters 
SPECT 
Single Photon Emission Computed Tomography 
SUV 
Standardized uptake value 
SUSAR 
Suspected unexpected serious adverse reaction 
TEAE 
Treatment emergent adverse event 
TMF 
Trial Master File 
ULN 
Upper limit of normal 
Y 
Yttrium 
WHO 
World Health Organization 
WHO PS 
WHO Performance Status 
WOCBP 
Woman of Child Bearing Potential 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Appendix 2: Study Governance Considerations 
 
Regulatory and Ethical Considerations 
x This study will be conducted in accordance with the protocol and with the following: 
x Consensus ethical principles derived from international guidelines such as the Declaration 
of Helsinki.  
x Applicable ICH Good Clinical Practice (GCP) Guidelines 
x Applicable laws and regulations 
x The protocol, protocol amendments, ICF, Investigator Brochure, and other relevant 
documents (e.g., advertisements) must be submitted to an IEC/IRB by the Investigator and 
reviewed and approved by the IEC/IRB before the study is initiated.  
x Any amendments to the protocol will require IEC/IRB approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an immediate 
hazard to study patients.  
x The Investigator will be responsible for the following: 
x Providing written summaries of the status of the study to the IEC/IRB annually or more 
frequently in accordance with the requirements, policies, and procedures established by the 
IEC/IRB  
x Notifying the IEC/IRB of SAEs or other significant safety findings as required by IEC/IRB 
procedures 
x Providing oversight of the conduct of the study at the study site and adherence to 
requirements of 21 CFR, ICH guidelines, the IEC/IRB, European regulation 536/2014 for 
clinical studies (if applicable), and all other applicable local regulations 
 
Financial Disclosure 
Investigators and sub-Investigators will provide the Sponsor with sufficient, accurate financial 
information as requested to allow the Sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators are 
responsible for providing information on financial interests during the course of the study and 
for 1 year after completion of the study. 
 
Informed Consent Process 
x The Investigator or his/her representative will explain the nature of the study to the patient 
or his/her legally authorised representative and answer all questions regarding the study.  
x Patients must be informed that their participation is voluntary. Patients or their legally 
authorised representative will be required to sign a statement of informed consent that meets 
the requirements of 21 CFR Part 50, local regulations, ICH guidelines, Health Insurance 
Portability and Accountability Act (HIPAA) requirements, where applicable, and the 
IEC/IRB or study site.  


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x The medical record must include a statement that written informed consent was obtained 
before the patient was enrolled in the study and the date the written consent was obtained. 
The authorised person obtaining the informed consent must also sign the ICF. 
x Patients must be re-consented to the most current version of the ICF(s) during their 
participation in the study.  
x A copy of the signed ICF(s) must be provided to the patient or the patient’s legally 
authorised representative.  
Patients who are rescreened are required to sign a new ICF.  
The ICF will contain a separate section that addresses the use of remaining mandatory samples 
for optional exploratory research. The Investigator or authorised designee will explain to each 
patient the objectives of the exploratory research. Patients will be told that they are free to refuse 
to participate and may withdraw their consent at any time and for any reason during the storage 
period. A separate signature will be required to document a patient's agreement to allow any 
remaining specimens to be used for exploratory research. Patients who decline to participate in 
this 
optional 
research 
will 
not 
provide 
this 
separate 
signature. 
 
Data Protection 
x 
Patients will be assigned a unique number. Any patient records or datasets that are 
transferred to the Sponsor will contain the identifier only; patient names or any information 
which would make the patient identifiable will not be transferred.  
x 
The patient must be informed that his/her personal study-related data will be used by the 
Sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the patient.  
x 
The patient must be informed and consent that his/her medical records may be examined 
by Clinical Quality Assurance auditors or other authorised personnel appointed by the 
Sponsor, by appropriate IEC/IRB members, and by inspectors from regulatory authorities. 
 
Dissemination of Clinical Study Data 
Data Quality Assurance 
x 
All patient data relating to the study will be recorded on printed or eCRF unless 
transmitted to the Sponsor or designee electronically (e.g., laboratory data). The 
Investigator is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the CRF.  
x 
The Investigator must maintain accurate documentation (source data) that supports the 
data entered in the CRF.  
x 
The investigator must permit study-related monitoring, audits, IEC/IRB review, and 
regulatory agency inspections and provide direct access to source data documents.  
x 
The Sponsor or designee is responsible for the data management of this study including 
quality checking of the data.  
x 
Study monitors will perform ongoing source data verification to confirm that data entered 
into the CRF by authorised site staff are accurate, complete, and verifiable from source 
documents; that the safety and rights of patients are being protected; and that the study is 


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being conducted in accordance with the currently approved protocol and any other study 
agreements, ICH GCP, and all applicable regulatory requirements.  
x 
Records and documents, including signed ICFs, pertaining to the conduct of this study 
must be retained by the Investigator for 15 years after study completion unless local 
regulations or institutional policies require a longer retention period. No records may be 
destroyed during the retention period without the written approval of the Sponsor. No 
records may be transferred to another location or party without written notification to the 
Sponsor.  
 
Source Documents 
x Source documents provide evidence for the existence of the patient and substantiate the 
integrity of the data collected. Source documents are filed at the Investigator’s site. Source 
documents required will be defined in the monitoring plan. 
x Data reported on the CRF or entered in the eCRF that are transcribed from source documents 
must be consistent with the source documents or the discrepancies must be explained. The 
Investigator may need to request previous medical records or transfer records, depending on 
the study. In addition, current medical records must be available. 
 
Study and Site Closure 
The Sponsor designee reserves the right to close the study site or terminate the study at any time 
for any reason at the sole discretion of the Sponsor. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study supplies 
have been collected and a study-site closure visit has been performed. 
The Investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by the Sponsor or Investigator may include but are 
not limited to: 
x Failure of the Investigator to comply with the protocol, the requirements of the IEC/IRB or 
local health authorities, the Sponsor's procedures or GCP guidelines 
x Inadequate recruitment of patients by the Investigator 
x Discontinuation of further study treatment development 
 
 


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Appendix 3: Contraceptive Guidance and Collection of Pregnancy 
Information 
 
Definitions 
Woman of Childbearing Potential (WOCBP) 
A woman is considered fertile following menarche and until becoming post-menopausal unless 
permanently sterile (see below). 
 
Women in the following categories are not considered WOCBP 
1. 
Premenarchal 
2. 
Premenopausal female with one of the following: 
x 
Documented hysterectomy 
x 
Documented bilateral salpingectomy 
x 
Documented bilateral oophorectomy 
Note:  Documentation can come from the site staff review of the patient’s medical records, 
medical examination, or medical history interview. 
 
3. 
Postmenopausal female 
x 
A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. A high follicle stimulating hormone (FSH) level in the 
postmenopausal range may be used to confirm a postmenopausal state in women 
not using hormonal contraception or hormonal replacement therapy (HRT). 
However, in the absence of 12 months of amenorrhea, a single FSH measurement is 
insufficient.  
x 
Females on HRT and those whose menopausal status is in doubt will be required to 
use one of the non-hormonal highly effective contraception methods if they wish to 
continue their HRT during the study. Otherwise, they must discontinue HRT to 
allow confirmation of postmenopausal status before study enrolment. 
 
Contraception Guidance 
Male patients 
Male patients with female partners of childbearing potential are eligible to participate if they 
agree to ONE of the following throughout study drug therapy and the following 12 months: 
x 
Are abstinent from penile-vaginal intercourse as their usual and preferred lifestyle 
(abstinent on a long term and persistent basis) and agree to remain abstinent 
x 
Agree to use a male condom when having penile-vaginal intercourse with a WOCBP 
who is not currently pregnant 
 


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Men with a pregnant or breastfeeding partner must agree to remain abstinent from penile-vaginal 
intercourse or use a male condom during each episode of penile penetration [during the protocol-
defined time frame]. 
Refrain from donating sperm for the duration of the study and for 12 months after the last dose 
of study drug. 
 
Female patients 
Female patients of childbearing potential are eligible to participate if they agree to use a highly 
effective method of contraception consistently and correctly as described in Table 12-1. 
Table 12-1  
Highly Effective Contraceptive Methods 
Highly Effective Contraceptive Methods That Are User Dependent a  
Failure rate of <1% per year when used consistently and correctly.  
x 
Combined (oestrogen and progestogen containing) hormonal contraception associated 
with inhibition of ovulationb  
x 
Oral  
x 
Intravaginal  
x 
Transdermal  
x 
Progestogen only hormonal contraception associated with inhibition of ovulation 
x 
Oral  
x 
Injectable  
Highly Effective Methods That Are User Independent a  
Implantable progestogen only hormonal contraception associated with inhibition of ovulationb 
x 
Intrauterine device (IUD) 
x 
Intrauterine hormone-releasing system (IUS) 
x 
Bilateral tubal occlusion 
x 
Vasectomised partner  
A vasectomised partner is a highly effective contraception method provided the partner is the 
sole male sexual partner of the WOCBP and the absence of sperm has been confirmed. If not, 
an additional highly effective method of contraception should be used.  
x 
Sexual abstinence  
Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study treatment. 
The reliability of sexual abstinence needs to be evaluated in relation to the duration of the 
study and the preferred and usual lifestyle of the patient.  
NOTES:  
a) Typical use failure rates may differ from those when used consistently and correctly. Use 
should be consistent with local regulations regarding the use of contraceptive methods for 
patients participating in clinical studies.  
b) Hormonal contraception may be susceptible to interaction with the study treatment, which 
may reduce the efficacy of the contraceptive method. In this case, two highly effective 
methods of contraception should be utilised during the treatment period and for at least 
12 months after the last dose of study treatment  


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Pregnancy Testing 
Additional pregnancy testing should be performed 28 days after Betalutin treatment. Pregnancy 
testing will be performed whenever a menstrual cycle is missed or when pregnancy is otherwise 
suspected. 
Collection of Pregnancy Information  
Male patients with partners who become pregnant  
x The Investigator will attempt to collect pregnancy information on any male patient’s female 
partner who becomes pregnant while the male patient is in this study. This applies only to 
male patients who receive study treatment. 
x After obtaining the necessary signed informed consent from the pregnant female partner 
directly, the Investigator will record pregnancy information on the appropriate form and 
submit it to the Sponsor within 24 hours of learning of the partner’s pregnancy. The female 
partner will also be followed to determine the outcome of the pregnancy. Information on the 
status of the mother and child will be forwarded to the Sponsor.  
Female Patients who become pregnant  
x 
Should be immediately withdrawn from study. 
x 
The Investigator will collect pregnancy information on any female patient who becomes 
pregnant while participating in this study. Information will be recorded on the appropriate 
form and submitted to the Sponsor within 24 hours of learning of a patient's pregnancy. The 
patient will be followed to determine the outcome of the pregnancy. The Investigator will 
collect follow-up information on the patient and the neonate and the information will be 
forwarded to the Sponsor. Generally, follow-up will not be required for longer than 
6-8 weeks beyond the estimated delivery date. Any termination of pregnancy will be 
reported, regardless of foetal status (presence or absence of anomalies) or indication for the 
procedure. 
x 
While pregnancy itself is not considered an AE or SAE, any pregnancy complication or 
elective termination of a pregnancy will be reported as an AE or SAE. A spontaneous 
abortion is always considered an SAE and will be reported as such. Any post-study 
pregnancy related SAE considered reasonably related to the study treatment by the 
Investigator will be reported to the Sponsor as described in Section 9.2.5. While the 
Investigator is not obligated to actively seek this information in former study patients, 
he/she may learn of an SAE through spontaneous reporting.  
 
 
 
 


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Appendix 4: Genetics 
Use/Analysis of DNA/RNA 
x Gene expression variation may influence a patient’s response to therapy, susceptibility to, 
and severity and progression of disease. Variable response to therapy may be due to the 
expression of genetic determinants at the DNA or RNA level that influence drug absorption, 
distribution, metabolism, and excretion; mechanism of action of the drug; disease etiology; 
and/or molecular subtype of the disease being treated. Therefore, where local regulations 
and IEC/IRB allow, a blood, saliva and/or tissue biopsy sample will be collected for DNA 
analysis from consenting patients. 
x DNA/RNA samples will be used for research related to study drug or indication and related 
diseases. They may also be used to develop tests/assays including diagnostic tests related to 
study drug and/or treatments of this drug class and indication. Genetic research may consist 
of the analysis of one or more candidate genes or the analysis of genetic markers throughout 
the genome or analysis of the entire genome (as appropriate). 
x DNA/RNA samples will be analysed for described planned analyses. Additional analyses 
may be conducted if it is hypothesised that this may help further understand the clinical data. 
x DNA/RNA samples will be analysed (See Section 9.4 for details). Additional analyses may 
be conducted if it is hypothesised that this may help resolve issues with the clinical data.  
x The samples may be analysed as part of a multi-study assessment of genetic factors involved 
in the response to study treatment or study treatments of this class to understand study 
disease or related conditions. 
x The results of genetic analyses may be reported in the CSR or in a separate study summary. 
x The Sponsor will store the DNA/RNA samples in a secure storage space with adequate 
measures to protect confidentiality. 
x The samples will be retained while research on study treatment or study treatments of this 
class or indication continues but no longer than 15 years or other period as per local 
requirements. 
 
 
 
 


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Appendix 5: Biodistribution and dosimetry assessments 
The measurements will be performed on a SPECT/CT scanner containing 2 gamma camera 
heads (Siemens SYMBIA –T16) equipped with medium energy collimators.  
This equipment will be used for CT, SPECT, and wholebody scanning. Two (2) separate energy 
windows positioned over the photon energy peaks at 113 keV and 208 keV with 15% window 
widths will be used. Since the upper (photon energy) peak is the most intense (11% of 
disintegrations) one may end up with using only one energy window at 208 keV. This will 
enable simultaneous acquisition in 2 energy windows, one above and one below the highest 
photon energy peak. The corresponding images will then be used to estimate and correct for the 
influence of scattered radiation. These settings will be used both for wholebody scans and for 
SPECT. Quantification will be carried out partially by use of the software of the vendor and 
partially by the use of computer programs (IDL, ITT visual solutions) that are available in the 
hospital. A small plastic flask containing <70 MBq of 177Lu will be used as radioactivity 
standard in the biodistribution study.  
The sensitivity (counts/MBq min) obtained with the planned whole-body scanning speed and 
with the actual collimator, energy window etc., will be established by the use of a source of 
known activity (177Lu) in a petri-dish.   
In order to cover the entire length of the patient, wholebody scan is the only feasible way. An 
anterior and a posterior camera will acquire images simultaneously, and the attenuation 
corrected conjugated view technique reported earlier will be applied (34). 
There are 2 sources for acquiring attenuation data for wholebody scans: scanning with a 99mTc 
line source before administration of activity to the patient or by calculating the necessary 
attenuation from CT images (34). In the present series of measurements both of these methods 
will supplement each other – using CT data were available in the main trunk. The collimated 
line source is positioned on the posterior gamma camera head and moves together with the 
scanning camera head.  
Patient fixation is important, and a thin vacuum mattress will be used to ensure reproducible 
patient pose on the examination table. Nevertheless, based on earlier experience, the computer 
program (in-house development, IDL, ITT visual solutions) performs an image correlation to 
determine any shift and correct the images accordingly. The computer program performs the 
conjugated view calculation and attenuation correction and is designed such that regions may 
be drawn into a (conjugated view) whole-body image and be automatically reproduced in all the 
other conjugated view whole-body images.  
In designing the quantification scheme, it is assumed that a whole-body scan has the advantages 
of producing a good overview of the activity distribution with less noise than is associated with 
a SPECT study. A SPECT study that should always be performed together with a CT to allow 
for attenuation correction will lead to increased patient radiation dose. It is therefore the 
intention in this study to use wholebody scans as the basis means for following the activity as a 
function of time for selected organs and if possible for tumours, and SPECT studies where a 3D 
delineation of an organ or a tumour is needed  
SPECT/CT examination of the (thorax or abdominal) region will be performed to obtain 
the cross-sectional data needed to estimate organ volumes. The CT part will also be used to 
correct for photon attenuation (refer to paragraph on attenuation correction above). Especially 
the SPECT examination may be influenced by photons scattered to different energies and 


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directions inside the patient. A triple energy window technique (if feasible) will be used to 
reduce the influences on quantification.  
Full details of the scans required are provided in the dosimetry protocol.  
 
 


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Appendix 6: List of Changes since Version 3.0 
Changes to each section are identified; deleted text present in Version 3.0 is shown in 
strikethrough and new text introduced into Version 4.0 in bold font.  


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Initial Wording 
Modified or Additional Wording 
Justification  
Sponsor Signature Page 
Authorised Representative on behalf of Nordic Nanovector ASA: 
Lisa Rojkjaer MD 
Chief Medical Officer 
Nordic Nanovector ASA 
Kjelsåsveien 168B 
N-0884 Oslo, Norway 
Susan Spruill, MS, PStat® 
Biostatistician 
Applied Statistics and Consulting 
1205 Chestnut Mountain Road 
Spruce Pine 
North Carolina 28777, United States 
Sponsor Signature Page 
Authorised Representative on behalf of Nordic Nanovector ASA: 
Lisa Rojkjaer Christine Wilkinson Blanc MD 
Chief Medical Officer 
Nordic Nanovector ASA 
Kjelsåsveien 168B 
N-0884 Oslo, Norway 
Susan Spruill, MS, PStat® 
Biostatistician 
Applied Statistics and Consulting 
1205 Chestnut Mountain Road 
Spruce Pine 
North Carolina 28777, United States 
Albert Chau 
Biostatistician 
Datacision Limited 
55 Station Road 
Beaconsfield, Buckinghamshire 
HP9 1QL, United Kingdom 
4 
Coordinating Investigator Signature Page 
Printed name: 
ARNE KOLSTAD 
Email: 
ARNEK@ous-hf.no 
Coordinating Investigator Signature Page 
Printed name: 
ARNE KOLSTAD Alexander FOSSÅ 
Email: 
ARNEK@ous-hf.no 
4 
Synopsis, Objectives 
Secondary 
• 
To evaluate the preliminary anti-tumour activity of combination 
treatment based on Investigator assessment of tumour response rates 
• 
To evaluate the duration of tumour control in patients receiving Betalutin 
in combination with RTX 
Synopsis, Objectives 
Secondary 
• 
To establish a recommended dose of Betalutin in combination with 
RTX for phase 2 studies in NHL patients 
• 
To evaluate the preliminary anti-tumour activity of combination 
treatment based on Investigator assessment of tumour response rates 
3 


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Initial Wording 
Modified or Additional Wording 
Justification  
• 
To investigate the immunogenicity of Betalutin in combination with 
RTX 
• 
To evaluate the duration of tumour control in patients receiving 
Betalutin in combination with RTX 
• 
To investigate the immunogenicity of Betalutin in combination with 
RTX 
Synopsis, Study Design 
Two cohorts of 3-6 patients will be initially evaluated for dose limiting 
toxicity, in a 3+3 escalation pattern, before determining the subsequent 
Betalutin dose for the remainder of the study. 
Patients will undergo clinical and laboratory assessments during 
screening/baseline and periodically during treatment. PET/CT and CT (or 
MRI) imaging will be performed at baseline and then at 3 and 6 months. CT 
with contrast (or MRI) will be performed at 12, 18, 24 months and then yearly 
until disease progression or for a maximum of 5 years after Betalutin 
administration for all patients. 
Patients who achieve SD, CR or PR on their Month 3 imaging scan will be 
administered maintenance RTX 375 mg/m2 i.v. or 1400 mg s.c. every 3 
months for up to 2 years (8 infusions in total), or until disease progression. 
Synopsis, Study Design 
Two cohorts of 3-6 patients will be initially evaluated for dose limiting 
toxicity, in a 3+3 escalation pattern, beforeto determining determine the 
subsequent Betalutin dose for the remainder of the study future phase 2 
studies in NHL. 
Patients will undergo clinical and laboratory assessments during 
screening/baseline and periodically during treatment. PET/CT and CT (or 
MRI) imaging will be performed at baseline and then at 3 and 6 months. CT 
with contrast (or MRI) will be performed at 12, 18, 24 months and then yearly 
or until disease progression or withdrawal from the study for any other 
reason (whichever comes first) or for a maximum of 5 years after Betalutin 
administration for all patients. 
Patients who achieve SD, CR or PR on their Month 3 imaging scan will be 
administered maintenance RTX 375 mg/m2 i.v. or 1400 mg s.c. every 
3 months for up to 2 years (8 infusions in total), or until disease progression 
or withdrawal from the study for any other reason (whichever comes 
first). 
1, 2 
Synopsis, Sample Size 
20 to 25 patients will be enrolled 
Synopsis, Sample Size 
20 to 25 6 to 12 patients will be enrolled 
1 
Synopsis; Treatment groups, dose, route of administration, treatment regimen 
Rituximab - 375 mg/m2 to be administered by i.v. infusion through dedicated 
line at Days -14, 7, 14, 21 and 28.  Patients who achieve SD, CR or PR on 
their Month 3 imaging scan will be administered maintenance RTX 375 
mg/m2 i.v. or 1400 mg s.c. every 3 months for up to 2 years (8 infusions in 
total), or until disease progression  
Synopsis; Treatment groups, dose, route of administration, treatment regimen 
Rituximab - 375 mg/m2 to be administered by i.v. infusion through 
dedicated line at Days -14, 7, 14, 21 and 28.  Patients who achieve SD, CR 
or PR on their Month 3 imaging scan will be administered maintenance 
RTX 375 mg/m2 i.v. or 1400 mg s.c. every 3 months for up to 2 years (8 
infusions in total), or until disease progression or withdrawal from the 
study for any other reason (whichever comes first). 
2 


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Initial Wording 
Modified or Additional Wording 
Justification  
Synopsis, Efficacy assessment(s) 
PET/CT and CT (or MRI) imaging will be performed at baseline and then at 
3 and 6 months. CT with contrast (or MRI) will be performed at 12, 18, 24 
months and then yearly until disease progression or for a maximum of 5 years 
after Betalutin administration for all patients. 
 
Synopsis, Efficacy assessment(s) 
PET/CT and CT (or MRI) imaging will be performed at baseline and then at 
3 and 6 months. CT with contrast (or MRI) will be performed at 12, 18, 24 
months or until disease progression or withdrawal from the study for any 
other reason (whichever comes first) after Betalutin administration for all 
patients. 
2 
Synopsis, Safety Assessments 
During the follow-up period, vital signs, ECG (final visit only), physical 
examination, haematology, serum biochemistry, Adverse Drug Reaction 
(ADR) and Adverse Events of Special Interest (AESI) will be collected every 
6 months for 2 years after end of study treatment period. 
Synopsis, Safety Assessments 
During the follow-up periodAfter the last dose of rituximab, vital signs, 
ECG (final visit only), physical examination, haematology, serum 
biochemistry, Adverse Drug Reaction (ADR) and Adverse Events of Special 
Interest (AESI) will be collected every 6 months for 2 years after end of study 
treatment period at an end of study visit that will occur at least 28 days 
post last administration of study treatment. Patients in survival follow-
up at time of Protocol v4.0 approval can have the EOS visit at their next 
scheduled visit or an earlier convenient time point. 
2 
Synopsis, Biomarker Assessments 
Pharmacodynamics assessments including CD20 and CD37 expression in 
tumour tissue biopsy and immunophenotyping of circulating lymphocyte 
subsets (absolute cell counts), will be performed at various time points 
throughout the study 
Synopsis, Biomarker Assessments 
Pharmacodynamics Biomarkers assessments including CD20 and CD37 
expression in tumour tissue biopsy and immunophenotyping of circulating 
lymphocyte subsets (absolute cell counts), will be performed at various time 
points throughout the study 
3 
Synopsis, Statistical Methods and Data Analyses 
Pharmacokinetic, pharmacodynamic and biomarker exploratory analyses 
will be described in the statistical analysis plan finalised before database lock. 
Synopsis, Statistical Methods and Data Analyses 
Pharmacokinetic, 
pharmacodynamic 
biodistribution 
and 
biomarker 
exploratory analyses will be described in the statistical analysis plan finalised 
before database lock. 
3 
Synopsis, Key Dates 
All patients will be followed up for up to 5 years after Betalutin 
administration. 
 
Synopsis, Key Dates 
All Ppatients will be followed up for up to 5 25 years months (End of study 
visit) after Betalutin administration. 
Patients in survival follow at time of Protocol version 4.0 approval can 
have the EOS visit at their next scheduled visit or an earlier convenient 
time point 
2 


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Initial Wording 
Modified or Additional Wording 
Justification  
Section 1.2 Schedule of Activities 
Table 1-2 Treatment, safety and efficacy (Month 3/Week 14 to 
Month 60/Week 260) 
23) If the ADA test is found positive at Week 104, then a blood sample will 
be taken every year until the ADA test is found negative 
Section 1.2 Schedule of Activities 
Table 1-2 Treatment, safety and efficacy (Month 3/Week 14 to 
Month 6025/Week 260108 - EOS) 
23) If the ADA test is found positive at Week 104, then a blood sample will 
be taken every year until the ADA test is found negative 
25) Patients in survival follow-up at time of Protocol v4.0 approval can 
have the EOS visit at their next scheduled visit or an earlier convenient 
time point. Collection of concomitant medications is not mandated for 
these patients, but AESIs must be assessed 
Table updated 
2 
Section 3 Objectives and Endpoints  
Objectives 
Endpoints 
Secondary 
 
 
 
Exploratory 
 
x 
To characterise the pharmacokinetics 
(PK) of Betalutin in combination with 
RTX 
x 
PK parameters  
x 
To assess the pharmacodynamic 
effects of Betalutin in combination 
with RTX 
x 
Change from baseline in peripheral 
blood B-cell, T-cell and NK cell 
counts, tumour CD20 and CD37 
expression  
 
Section 3 Objectives and Endpoints  
Objectives 
Endpoints 
Secondary 
 
x 
To establish a recommended dose of 
Betalutin in combination with RTX 
for phase 2 studies in NHL patients 
x 
Frequency and severity of AEs, 
SAEs and changes in laboratory 
values graded according to CTCAE 
version 4.03 
Exploratory 
 
x 
To characterise the pharmacokinetics 
(PK) of Betalutin in combination with 
RTX 
x 
PK parameters Estimation of the 
levels of remnant administered 
radioactivity in blood over time 
(Betalutin PK) 
x 
To assess the pharmacodynamic 
effects of Betalutin in combination 
with RTX 
x 
Change from baseline in peripheral 
blood B-cell, T-cell and NK cell 
counts, tumour CD20 and CD37 
expression  
x 
Biomarker assessments 
x 
To investigate the biodistribution 
of Betalutin in combination with 
RTX 
 
 
x 
Estimation of whole-body retention 
of radioactivity at each imaging 
time post-injection.  
x 
Estimation of the individual organ 
uptake/retention of radioactivity at 
each imaging time-point after 
injection.  
3 


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Initial Wording 
Modified or Additional Wording 
Justification  
x 
Calculation of estimated absorbed 
radiation dose to target organ. 
 
 
 
Section 4.1 Overall Design 
It is planned that 20-25 patients will be enrolled in the study. 
PET/CT and CT imaging (or MRI) will be performed at baseline and then at 
3 and 6 months. CT with contrast (or MRI) will be performed at 12, 18, 24 
months and then yearly until disease progression or for a maximum of 5 years 
after Betalutin administration for all patients. 
Patients who achieve SD, CR or PR on their Month 3 imaging scan will be 
administered maintenance RTX 375 mg/m2 i.v. or 1400 mg s.c. every 
3 months for up to 2 years (8 infusions in total), or until disease progression. 
 
Section 4.1 Overall Design 
It is planned that 20-25 6-12 evaluable patients will be enrolled in the study. 
PET/CT and CT imaging (or MRI) will be performed at baseline and then at 
3 and 6 months. CT with contrast (or MRI) will be performed at 12, 18, 24 
months and then yearly or until disease progression or withdrawal from the 
study for any other reason for a maximum of 5 years after Betalutin 
administration for all patients (whichever comes first). 
Patients who achieve SD, CR or PR on their Month 3 imaging scan will be 
administered maintenance RTX 375 mg/m2 i.v. or 1400 mg s.c. every 3 
months for up to 2 years (8 infusions in total), or until disease progression or 
withdrawal from the study for any other reason (whichever comes first). 
1, 2 
Section 4.1 Overall Design 
Figure 4-1 
Section 4.1 Overall Design 
Figure 4-1 Updated to reflect removal of follow-up period 
2 
Section 4.3 Rationale for Dose 
As discussed in the previous section, as patients with relapsed/refractory FL 
are reported to benefit from rituximab maintenance therapy [31], responding 
patients (i.e. those having a CR, PR or SD response following Betalutin and 
the 4-weekly doses of i.v. RTX) will receive maintenance RTX every 3 
months for up to 2 years (a total of 8 doses), or until disease progression 
commencing at Week 14.   
 
Section 4.3 Rationale for Dose 
As discussed in the previous section, as patients with relapsed/refractory FL 
are reported to benefit from rituximab maintenance therapy [31], responding 
patients (i.e. those having a CR, PR or SD response following Betalutin and 
the 4-weekly doses of i.v. RTX) will receive maintenance RTX every 3 
months for up to 2 years (a total of 8 doses), or until disease progression or 
withdrawal from the study for any other reason (whichever comes first), 
commencing at Week 14.   
2 
Section 4.4 Patient and Study Completion 
Approximately 25 patients will be screened to achieve 20-25 patients 
assigned to study treatment and evaluable.  
Section 4.4 Patient and Study Completion 
Approximately 25 10-15 patients will be screened to achieve 20-
256-12 patients assigned to study treatment and evaluable.  
1 
Section 4.5 End of Study Definition 
The end of study for all patients will be the date of the last visit upon 
completion of the follow-up period (5 years after receiving their Betalutin 
Section 4.5 End of Study Definition 
The end of study for all patients will be the date of the last patient last visit 
upon completion of their end of study visit follow-up period (5 years 
25 months after receiving their Betalutin treatment if ending study 
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Initial Wording 
Modified or Additional Wording 
Justification  
treatment), or until discontinuation from the study for any other reason, or if 
the study is terminated early. 
treatment per protocol, or after disease progression or until 
discontinuation withdrawal from the study for any other reason, (whichever 
comes first) or if the study is terminated early.  
Section 6.1 Dosing Regimen 
Patients must have received all doses of study drug and have had an adequate 
period of follow-up (i.e. having achieved haematological recovery to 
 grade 2) to be considered evaluable for a dose escalation decision or to 
continue to be treated with Betalutin 15 MBq/kg following enrolment of the 
second cohort of 3-6 patients. 
Section 6.1 Dosing Regimen 
Patients must have received all doses of study drug and have had an adequate 
period of follow-up (i.e. having achieved haematological recovery to 
 grade 2) to be considered evaluable for a dose escalation decision or to 
continue to be treated with Betalutin 15 MBq/kg determine the dose for 
further Phase 2 studies following enrolment of the second cohort of 3-6 
patients. 
1 
Section 6.1 Dosing Regimen 
7. If 1/6 patients receiving Betalutin 15 MBq/kg experience a DLT, the 
remainder of the patients in the study will continue to be treated with 
Betalutin 15 MBq/kg. 
8. If 2/6 patients experience a DLT, then 3 more patients will be treated at 
the lower Betalutin dose (10 MBq/kg).  
9. Subsequent Betalutin/lilotomab dosing  will be determined by the 
Investigator(s) and Sponsor after a review of the available safety data.  
Section 6.1 Dosing Regimen 
7. 
If 1/6 patients receiving Betalutin 15 MBq/kg experience a DLT, the 
remainder of the patients in the study will continue to be treated with 
dose for further Phase 2 studies will be Betalutin 15 MBq/kg. 
8. 
If 2/6 patients experience a DLT, then 3 more patients will be treated at 
the lower Betalutin dose (10 MBq/kg).  
9. 
Subsequent The final recommendation for Betalutin/lilotomab dosing 
for further Phase 2 studies will be determined by the Investigator(s) 
and Sponsor after a review of the available safety data.  
1 
Section 7.2 Patient Withdrawal/Discontinuation from the Study 
Should a patient decide to withdraw after administration of the study drug(s) 
or should the Investigator(s) decide to withdraw the patient, all efforts will 
be made to complete and report the observations up to the time of withdrawal 
as thoroughly as possible. A complete final evaluation at the time of the 
patient’s withdrawal should be made and an explanation given of why the 
patient is withdrawing or being withdrawn from the study. The reason and 
date for withdrawal must be noted in the eCRF. If the reason for withdrawal 
is a clinical AE or an abnormal laboratory test result, monitoring will 
continue until the outcome is evident. The specific event or test result(s) must 
be recorded in the eCRF. If the reason for withdrawal is due to disease 
progression, the study site should make all effort to continue with the safety 
monitoring.  
Section 7.2 Patient Withdrawal/Discontinuation from the Study 
Should a patient decide to withdraw after administration of the study drug(s) 
or should the Investigator(s) decide to withdraw the patient, all efforts will 
be made to complete and report the observations up to the time of withdrawal 
as thoroughly as possible. A complete final evaluation at the time of the 
patient’s withdrawal (end of study visit) should be made within 28 days 
(± 3 days) of receiving the last study treatment administration if ending 
treatment per protocol, or within 7 days of taking the decision to 
withdraw if it occurs > 28 days after the last study treatment 
administration and an explanation given of why the patient is withdrawing 
or being withdrawn from the study. The reason and date for withdrawal must 
be noted in the eCRF. If the reason for withdrawal is a clinical AE or an 
abnormal laboratory test result, monitoring will continue until the outcome is 
evident. The specific event or test result(s) must be recorded in the eCRF. If 
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Initial Wording 
Modified or Additional Wording 
Justification  
Haematological toxicity was observed in the phase 1/2 LYMRIT-37-01 
study, with nadir values 5 to 7 weeks after injection of Betalutin. It is 
advisable to monitor the haematology parameters of the withdrawn patients 
between 6 and 9 weeks after the last RTX administration or until recovery to 
CTCAE grade 1 or less. 
Single patient termination is per definition: 
x 
when the patient is withdrawn 
x 
when the patient has died 
x 
start of further anticancer therapy after Betalutin injection 
x 
completed the Year 5 follow-up visit 
If the reason for withdrawal is death, the immediate cause of death should be 
noted, in addition to death caused by underlying disease, the investigator’s 
judgement on possible relationship to study drug should be recorded in the 
eCRF.  
Furthermore: 
x 
Survival information, Adverse Drug Reaction (ADR) and Adverse 
Events of Special Interest (AESI) will continue to be collected for any 
single patient terminations throughout the study, unless the patient 
specifically withdraws their consent for this to take place 
the reason for withdrawal is due to disease progression, the study site should 
make all effort to continue with the safety monitoring.  
Haematological toxicity was observed in the phase 1/2 LYMRIT-37-01 
study, with nadir values 5 to 7 weeks after injection of Betalutin. It is 
advisable to monitor the haematology parameters of the withdrawn patients 
between 6 and 9 weeks after the last RTX administration or until recovery to 
CTCAE grade 1 or less. 
Single patient termination study discontinuation is per definition, when the 
patient: 
x 
has completed Month 24 administration of rituximab, per protocol 
or 
x 
experiences one of the following situations before per protocol end 
of study: 
- when the patient is withdrawn withdraws consent to participate 
in the study 
- when the patient has died 
- is lost to follow up 
- has disease progression  
- starts of further anticancer therapy or after Betalutin injection 
completed the Year 5 follow-up visit 
x 
when the patient is withdrawn for a reason other than described 
above 
If the reason for withdrawal is death, the immediate cause of death should be 
noted, in addition to death caused by underlying disease, the investigator’s 
judgement on possible relationship to study drug should be recorded in the 
eCRF.  
Furthermore: 
x 
Survival information, Adverse Drug Reaction (ADR) and Adverse 
Events of Special Interest (AESI) will continue to be collected for any 
single patient terminations until end of study visit, consent 
withdrawal, lost to follow up or death throughout the study, unless 
the patient specifically withdraws their consent for this to take place 


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Initial Wording 
Modified or Additional Wording 
Justification  
Section 8.2.12 Visit 17 (Month 6/Week 26) – Hospital Visit 
Concomitant medication: Recording of concomitant medication used since 
the screening visit 
Section 8.2.12 Visit 17 (Month 6/Week 26) – Hospital Visit 
Concomitant medication: Recording of cConcomitant medication used since 
prior visit will be recorded the screening visit 
5 
Section 8.2.14 Visit 19 (Month 12/Week 52) – Hospital Visit 
Concomitant medication: Recording of concomitant medication used since 
the screening visit 
Section 8.2.14 Visit 19 (Month 12/Week 52) – Hospital Visit 
Concomitant medication: Recording of concomitant medication used since 
the screening previous visit 
5 
Section 8.2.14 Visit 21 (Month 18/Week 78) – Hospital Visit 
Concomitant medication: Recording of concomitant medication used since 
the screening visit 
Section 8.2.14 Visit 21 (Month 18/Week 78) – Hospital Visit 
Concomitant medication: Recording of concomitant medication used since 
the screening previous visit 
5 
Section 8.2.14 Visit 23 (Month 24/Week 104) – Hospital Visit 
Concomitant medication: Recording of concomitant medication used since 
the screening visit 
Section 8.2.14 Visit 23 (Month 24/Week 104) – Hospital Visit 
Concomitant medication: Recording of concomitant medication used since 
the screening previous visit 
5 
Section 8.2.19 Visit 24 (Month 25/Week 108) – Hospital Visit 
Safety follow-up procedures 4 weeks after administration of the final RTX 
study dose are outlined in Table 8-22.  
Table 8-22 Procedures and assessments at Visit 24 (Month 25/Week 108 
[±7 days]) 
Assessment or Procedure 
Explanation 
Concomitant medication/therapy 
Recording of concomitant medication used since the 
previous visit 
Physical examination 
Any abnormal findings will be recorded in the AE 
record 
Vital signs 
Systolic/diastolic blood pressure, heart rate and body 
temperature 
ECOG 
ECOG performance status 
Haematology 
Including haemoglobin, platelet count, white blood cell 
count and differential (absolute count of neutrophils, 
lymphocytes, monocytes, eosinophils and basophils) 
Section 8.2.19 Visit 24 (Month 25/Week 108) End of Study Visit – Hospital 
Visit 
The end of study visit should occur: 
x 
28 days (± 3 days) post last rituximab administration for patients, 
who complete the study per protocol (Month 25/Week 108) 
x 
Within 7 days of decision of withdrawing from the study is made if 
the decision occurs > 28 days post last administration of study 
treatment for patients who discontinue from the study before 
Month 24 (e.g. disease progression, start of new anti-cancer 
therapy, other reason) An end of study visit is not expected for 
patients, who discontinue due to death, lost to follow up or 
withdrawal of consent. 
Safety follow-up procedures 4 weeks after administration of the final RTX 
study dose are outlined in Table 8-22.  
Patients in survival follow-up at the time of Protocol v4.0 approval can 
have the EOS visit at their next scheduled visit or an earlier convenient 
time point 
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Initial Wording 
Modified or Additional Wording 
Justification  
Serum biochemistry 
Including sodium, potassium, calcium, magnesium, 
creatinine, urea, uric acid, ALP, ASAT, ALAT, LDH, 
GGT, glucose, total bilirubin and albumin 
Adverse events 
Any AEs occurring since prior visit will be recorded 
 
Table 8-22 Procedures and assessments at end of study visit Visit 24 (Month 
25/Week 108 [±7 days]) 
Assessment or Procedure 
Explanation 
Concomitant medication/therapy 
Recording of concomitant medication used since the 
previous visit 
Physical examination 
Any abnormal findings will be recorded in the AE 
record 
Vital signs 
Systolic/diastolic blood pressure, heart rate and body 
temperature 
ECOG 
ECOG performance status 
Haematology 
Including haemoglobin, platelet count, white blood cell 
count and differential (absolute count of neutrophils, 
lymphocytes, monocytes, eosinophils and basophils) 
Serum biochemistry 
Including sodium, potassium, calcium, magnesium, 
creatinine, urea, uric acid, ALP, ASAT, ALAT, LDH, 
GGT, glucose, total bilirubin and albumin 
Adverse events 
Any AEs / AESIs occurring since prior visit will be 
recorded 
 
 
 
Section 8.3 Follow-up Period 
The follow-up period starts from Week 109 or until relapse of disease, 
whichever occurs first, for a period of up to 5 years (Week 260) from Day 0. 
The patient will have a hospital visit at Months 36 (Week 156), 48 (Week 
208) and 60 (Week 260). Table 8-23 outlines the procedures and assessments 
during these visits. 
Table 8-23 Procedures and assessments at Visits 25, 26 and 27 (at Months 36 
(Week 156), 48 (Week 208) and 60 (Week 260) [±7 days each]) 
Assessment or Procedure 
Explanation 
Prior antineoplastic therapy 
Record if the patient has received any antineoplastic 
treatment since their previous visit 
Physical examination 
Any abnormal findings will be recorded in the AE record 
Section 8.3 Follow-up Period 
The follow-up period starts from Week 109 or until relapse of disease, 
whichever occurs first, for a period of up to 5 years (Week 260) from Day 0. 
The patient will have a hospital visit at Months 36 (Week 156), 48 (Week 
208) and 60 (Week 260). Table 8-23 outlines the procedures and assessments 
during these visits. 
Table 8-23 Procedures and assessments at Visits 25, 26 and 27 (at Months 36 
(Week 156), 48 (Week 208) and 60 (Week 260) [±7 days each]) 
Assessment or Procedure 
Explanation 
Prior antineoplastic therapy 
Record if the patient has received any antineoplastic 
treatment since their previous visit 
Physical examination 
Any abnormal findings will be recorded in the AE record 
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Initial Wording 
Modified or Additional Wording 
Justification  
Weight 
Record weight details 
Vital signs 
Systolic/diastolic blood pressure, heart rate and body 
temperature 
ECOG 
ECOG performance status 
Haematology 
Including haemoglobin, platelet count, white blood cell 
count and differential (absolute count of neutrophils, 
lymphocytes, monocytes, eosinophils and basophils) 
Serum biochemistry 
Including sodium, potassium, calcium, magnesium, 
creatinine, urea, uric acid, ALP, ASAT, ALAT, LDH, 
GGT, glucose, total bilirubin and albumin 
Immunogenicity1 
Monitoring 
ADA 
response 
(lilotomab, 
Betalutin, 
rituximab) 
Minimal Residual Disease2 
(peripheral blood sample) 
MRD monitoring to assess early treatment response and 
detect relapse 
Bone marrow biopsy 
BM biopsy required for confirmation of initial CR if 
patient had BM infiltration at baseline 
Radiology - CT scans with 
contrast or MRI 
CT or MRI of neck, thorax, abdomen and pelvis.  
Information about contrast medium, target lesion location 
and measurements and non-measurable lesions will be 
recorded. The same camera should preferably be used 
throughout the study. 
ADR & AESI monitoring 
Since previous visit 
Survival status3 
Patient status (survival), cause of death and date of death 
1 If the ADA test is found positive at Week 104, then a blood sample will be taken once a year 
until the ADA test is found negative [34] 
2 Mandatory, unless relapse or disease progression has been clinically observed 
3 To be followed up every 6 months during scheduled visit or by telephone 
 
Weight 
Record weight details 
Vital signs 
Systolic/diastolic blood pressure, heart rate and body 
temperature 
ECOG 
ECOG performance status 
Haematology 
Including haemoglobin, platelet count, white blood cell 
count and differential (absolute count of neutrophils, 
lymphocytes, monocytes, eosinophils and basophils) 
Serum biochemistry 
Including sodium, potassium, calcium, magnesium, 
creatinine, urea, uric acid, ALP, ASAT, ALAT, LDH, 
GGT, glucose, total bilirubin and albumin 
Immunogenicity1 
Monitoring 
ADA 
response 
(lilotomab, 
Betalutin, 
rituximab) 
Minimal Residual Disease2 
(peripheral blood sample) 
MRD monitoring to assess early treatment response and 
detect relapse 
Bone marrow biopsy 
BM biopsy required for confirmation of initial CR if 
patient had BM infiltration at baseline 
Radiology - CT scans with 
contrast or MRI 
CT or MRI of neck, thorax, abdomen and pelvis.  
Information about contrast medium, target lesion location 
and measurements and non-measurable lesions will be 
recorded. The same camera should preferably be used 
throughout the study. 
ADR & AESI monitoring 
Since previous visit 
Survival status3 
Patient status (survival), cause of death and date of death 
1 If the ADA test is found positive at Week 104, then a blood sample will be taken once a year 
until the ADA test is found negative [34] 
2 Mandatory, unless relapse or disease progression has been clinically observed 
3 To be followed up every 6 months during scheduled visit or by telephone 


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Justification  
Section 8.4 Additional Operational Procedures 
During the treatment and follow up periods optional procedures may be 
performed at visits following relapse or disease progression. Table 8-23 
outlines these procedures. 
Section 8.43 Additional Operational Procedures 
During the treatment and follow up periods optional procedures may be 
performed at visits following relapse or disease progression. Table 8-23 
outlines these procedures. 
2 
Section 9.1 Efficacy Assessments 
Tumour response will be determined locally according to Recommendations 
for Initial Evaluation, Staging and Response Assessment of Hodgkin and 
non-Hodgkin Lymphoma [36].  Investigator assessment will be applied as a 
measure for assessment of tumour response and as a basis for all protocol 
guidelines for management of the patient related to disease status. CT or MRI 
scans are the required methods for tumour assessments. The same method of 
assessment and the same technique should be used to characterize each lesion 
at baseline and during follow-up. 
 
Section 9.1 Efficacy Assessments 
Tumour response will be determined locally according to Recommendations 
for Initial Evaluation, Staging and Response Assessment of Hodgkin and 
non-Hodgkin Lymphoma [36].  Investigator assessment will be applied as a 
measure for assessment of tumour response and as a basis for all protocol 
guidelines for management of the patient related to disease status. CT or MRI 
scans are the required methods for tumour assessments. The same method of 
assessment and the same technique should be used to characterize each lesion 
at baseline and during follow-up. 
All scans and other data supporting efficacy measurements will be 
stored at the study site and available for subsequent collection, if 
necessary, for review by the Sponsor and/or independent external 
reviewer(s). 
6 
Section 9.1.2 PET/CT and CT/MRI examination 
PET/CT and CT or MRI imaging will be done at baseline and then at 3 and 
6 months. CT with contrast or MRI will be performed at 12, 18, 24 months 
and then yearly until disease progression or for a maximum of 5 years after 
Betalutin administration for all patients. Baseline imaging must be performed 
within 4 weeks prior to administration of the first RTX infusion. 
Section 9.1.2 PET/CT and CT/MRI examination 
PET/CT and CT or MRI imaging will be done at baseline and then at 3 and 
6 months. CT with contrast or MRI will be performed at 12, 18, 24 months 
and or until disease progression or other withdrawal for any other reason 
then yearly until disease progression or for a maximum of 5 years after 
Betalutin administration for all patients(whichever comes first). Baseline 
imaging must be performed within 4 weeks prior to administration of the first 
RTX infusion. 
2 
Section 9.2.4 Reporting of adverse events 
Specific information about secondary malignancies such as leukaemia, MDS 
and aplastic anaemia or any other malignancy, will be collected up to 5 years 
after Betalutin administration or relapse of disease, including information 
about treatment given to the patient due to NHL (See Section 9.2.1.7). 
Section 9.2.4 Reporting of adverse events 
Specific information about secondary malignancies such as leukaemia, MDS 
and aplastic anaemia or any other malignancy, will be collected up to 
25 years after Betalutin administration or relapse of disease, including 
information about treatment given to the patient due to NHL (See 
Section 9.2.1.7). 
2 


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Justification  
Section 9.2.5.1 Investigator’s Responsibilities 
SAEs will be reported in the following time periods: 
x 
SAEs will be collected from signing informed consent to ensure that any 
protocol-related SAEs are collected 
x 
Up to 12 weeks after their Betalutin or 4 weeks following their last 
maintenance RTX drug administration, whether or not considered related 
to study drug 
x 
At any time beyond 12 weeks after their Betalutin or 4 weeks following 
their last maintenance RTX drug administration, when it comes to the 
Investigator’s attention and is judged to be related to the patient’s 
participation in the study or related to the study drug  
 
Section 9.2.5.1 Investigator’s Responsibilities 
SAEs will be reported in the following time periods: 
x 
SAEs will be collected from signing informed consent to ensure that any 
protocol-related SAEs are collected 
x 
Up to 12 weeks after their Betalutin or 4 weeks following their last 
maintenance RTX drug administration, whether or not considered 
related to study drug 
x 
At any time beyond 12 weeks after their Betalutin or 4 weeks following 
their last maintenance RTX drug administration, when it comes to the 
Investigator’s attention and is judged to be related to the patient’s 
participation in the study or related to the study drug. If such event is 
observed post end of study vist, it should be notified to the Sponsor 
using the following email address: SAE@nordicnanovector.com 
4 
Section 9.2.5.1 Investigator’s Responsibilities 
Contact address for reporting SAEs: 
PharmaLex Norway AS 
Karoline Kristiansens vei 1, 0661 Oslo, Norway 
Principal contact: 
Ingvild Juul-Hansen 
Phone:  
+47 22 23 88 80 
Fax:  
+47 21 01 80 19 
Email: 
PV-nordic@pharmalex.com 
 
Section 9.2.5.1 Investigator’s Responsibilities 
Contact address for reporting SAEs: 
PharmaLex Norway AS 
Karoline Kristiansens vei 1, 0661 Oslo, Norway 
Principal contact: 
Ingvild Juul-Hansen 
Phone:  
+47 22 23 88 80 
Fax:  
+47 21 01 80 19 
Email: 
PV-nordic@pharmalex.com 
 
4 
Section 9.2.6.5.2 Human biosamples collection schedule 
Sampling of peripheral blood for ADA monitoring will be performed at the 
following approximate time points: 
x Screening (Baseline for lilotomab, Betalutin and RTX ADA monitoring) 
x After Betalutin administration, at Day 28 and 3, 6, 12, 18 and 24 months. 
It has to be noted that at Day 28, peripheral blood sampling should be 
done before RTX dosing. 
Section 9.2.6.5.2 Human biosamples collection schedule 
Sampling of peripheral blood for ADA monitoring will be performed at the 
following approximate time points: 
x Screening (Baseline for lilotomab, Betalutin and RTX ADA monitoring) 
x After Betalutin administration, at Day 28 and 3, 6, 12, 18 and 24 months. 
It has to be noted that at Day 28, peripheral blood sampling should be 
done before RTX dosing. 
2 


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x Additional sampling may become necessary if a test is found to be ADA-
positive at 24 months. Persistence of the ADA response will then be 
assessed annually, until the ADA test is negative [34]. 
x Additional sampling may become necessary if a test is found to be ADA-
positive at 24 months. Persistence of the ADA response will then be 
assessed annually, until the ADA test is negative [34]. 
Section 9.2.7 Volume of blood to be drawn from each patient 
Table 9-4 Volume of blood to be drawn from each patient during the 
screening and treatment period (Screening to Month 25) 
Max = maximum number of samples to be taken from screening to Month 25 
1 Additional sampling could be performed if ADA test positive at Week 104 
2 Monitoring of rituximab concentration in serum and the ADA response 
towards rituximab. Additional sampling could be performed if (a) the RTX 
ADA test is   found positive at Week 104 and/or RTX concentration in serum 
is detectable at week 104, and (b) a blood sample is taken to screen for ADA 
against lilotomab/Betalutin 
Section 9.2.7 Volume of blood to be drawn from each patient 
Table 9-4 Volume of blood to be drawn from each patient during the 
screening and treatment period (Screening to Month 25 End of study visit) 
Max = maximum number of samples to be taken from screening to End of  
Study Month 25 
1 Additional sampling could be performed if ADA test positive at Week 104 
2 Monitoring of rituximab concentration in serum and the ADA response 
towards rituximab. Additional sampling could be performed if (a) the RTX 
ADA test is   found positive at Week 104 and/or RTX concentration in serum 
is detectable at week 104, and (b) a blood sample is taken to screen for ADA 
against lilotomab/Betalutin 
2 
Section 9.2.8 Pregnancy 
If a pregnancy is reported, the Investigator should inform the Sponsor within 
24 hours of learning of the pregnancy and should follow the procedures 
outlined in Appendix 5. 
Section 9.2.8 Pregnancy 
If a pregnancy is reported, the Investigator should inform the Sponsor within 
24 hours of learning of the pregnancy and should follow the procedures 
outlined in Appendix 53. 
5 
Section 9.4 Biodistribution and dosimetry 
Not applicable – new section in Version 4.0 
Section 9.4 Biodistribution and dosimetry 
The biodistribution and dosimetry study will provide estimates for the 
absorbed radiation dose to normal body structures as well as 
to tumours that can be identified in the images. The radioactivity in the 
actual organs will be measured in absolute terms, at different times after 
injection. The time series will allow to estimate the cumulative activity 
in each organ and by measurements/estimates of organ weight the 
absorbed dose.  
Measurements will be performed as described in Appendix 5.  
The measurements will be performed on a SPECT/CT scanner 
containing 2 gamma camera heads (Siemens SYMBIA –T16) equipped 
with medium energy collimators, which. will be used for CT, SPECT, 
and whole-body scanning. Quantification will be carried out by use of 
the software of the vendor and using computer programs (IDL, ITT 
3 


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Justification  
visual solutions) Full details of the scans required for biodistribution and 
dosimetry and of acquisition specifications are provided in a dedicated 
dosimetry protocol. 
The images obtained will enable the characterisation of the biodynamics 
and the calculation of the cumulative activity in each organ, with dose 
estimates obtained using the OLINDA program.   
The conjugated whole-body studies and the quantification in regions 
drawn around each organ together with assay of activity in blood will 
allow for:  
x 
Estimation of whole-body retention of radioactivity at set imaging 
times post-injection.  
x 
Estimation of the individual organ uptake/retention of radioactivity 
at set points after injection.  
x 
Estimate retention of administered radioactivity in blood.  
x 
Calculation of estimated absorbed radiation dose to target organs 
and to tumours.  
Section 9.4 Biomarkers 
Section 9.45 Biomarkers 
Heading numbering updated due to addition of new Section 9.4 
3 
Section 9.5 Biobanking 
Section 9.56 Biobanking 
Heading numbering updated due to addition of new Section 9.4 
Table 9-5 updated to change peripheral blood sampling for minimal residual 
disease from “and annually thereafter ”Week 52 to “at EOS” 
3 
Section 10.1 Statistical Analysis 
The study is a single-arm, open-label study to further assess the risk/benefit 
of a pre-dose of lilotomab and Betalutin to enhance tumour response to RTX 
therapy. Twenty to 25 patients is a reasonable sample size to evaluate any 
potential safety/tolerability signals and for obtaining preliminary estimates 
of the response rates and variability of the response rates. 
Section 10.1 Statistical Analysis 
The study is a single-arm, open-label study to further assess the risk/benefit 
of a pre-dose of lilotomab and Betalutin to enhance tumour response to RTX 
therapy. Twenty to 25 patients Six to 12 patients is a reasonable sample size 
to evaluate any potential safety/tolerability signals and for obtaining 
preliminary estimates of the response rates and variability of the response 
rates. 
1 


CONFIDENTIAL 
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Version 4.0_04 Oct 2021 
 
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Initial Wording 
Modified or Additional Wording 
Justification  
Section 10.1.2 Other Analyses 
PK, pharmacodynamic and biomarker exploratory analyses will be described 
in the statistical analysis plan (SAP), which will be finalised before database 
lock. The PK population analysis and pharmacodynamic analyses will be 
presented separately from the main clinical study report (CSR).  
Section 10.1.2 Other Analyses 
PK, pharmacodynamic and biomarker exploratory analyses will be described 
in the statistical analysis plan (SAP), which will be finalised before database 
lock. The PK population analysis and the  pharmacodynamic aAnalyses will 
be presented separately from the main clinical study report (CSR).  
3 
Appendix 5: Biodistribution and dosimetry assessments 
Not applicable – new section in Version 4.0 
Appendix 5: Biodistribution and dosimetry assessments 
The measurements will be performed on a SPECT/CT scanner 
containing 2 gamma camera heads (Siemens SYMBIA –T16) equipped 
with medium energy collimators.  
This equipment will be used for CT, SPECT, and wholebody scanning. 
Two (2) separate energy windows positioned over the photon energy 
peaks at 113 keV and 208 keV with 15% window widths will be used. 
Since the upper (photon energy) peak is the most intense (11% of 
disintegrations) one may end up with using only one energy window at 
208 keV. This will enable simultaneous acquisition in 2 energy windows, 
one above and one below the highest photon energy peak. The 
corresponding images will then be used to estimate and correct for the 
influence of scattered radiation. These settings will be used both 
for wholebody scans and for SPECT. Quantification will be carried out 
partially by use of the software of the vendor and partially by the use of 
computer programs (IDL, ITT visual solutions) that are available in the 
hospital. A small plastic flask containing <70 MBq of 177Lu will be used 
as radioactivity standard in the biodistribution study.  
The sensitivity (counts/MBq min) obtained with the planned whole-
body scanning speed and with the actual collimator, energy window etc., 
will be established by the use of a source of known activity (177Lu) in a 
petri-dish.   
In order to cover the entire length of the patient, wholebody scan is the 
only feasible way. An anterior and a posterior camera will acquire 
images simultaneously, and the attenuation corrected conjugated view 
technique reported earlier will be applied (34).   
There are 2 sources for acquiring attenuation data for wholebody scans: 
scanning with a 99mTc line source before administration of activity to the 
patient or by calculating the necessary attenuation from CT 
3 


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Initial Wording 
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Justification  
images (34). In the present series of measurements both of these methods 
will supplement each other – using CT data were available in the main 
trunk. The collimated line source is positioned on the posterior gamma 
camera head and moves together with the scanning camera head.  
Patient fixation is important, and a thin vacuum mattress will be used to 
ensure reproducible patient pose on the examination table. Nevertheless, 
based on earlier experience, the computer program (in-house 
development, IDL, ITT visual solutions) performs an image correlation 
to determine any shift and correct the images accordingly. The computer 
program performs the conjugated view calculation and attenuation 
correction and is designed such that regions may be drawn into a 
(conjugated view) whole-body image and be automatically reproduced 
in all the other conjugated view whole-body images.  
In designing the quantification scheme, it is assumed that a whole-
body scan has the advantages of producing a good overview of the 
activity distribution with less noise than is associated with a SPECT 
study. A SPECT study that should always be performed together with a 
CT to allow for attenuation correction will lead to increased patient 
radiation dose. It is therefore the intention in this study to use wholebody 
scans as the basis means for following the activity as a function of time 
for selected organs and if possible for tumours, and SPECT studies 
where a 3D delineation of an organ or a tumour is needed  
SPECT/CT examination of the (thorax or abdominal) region will be 
performed to obtain the cross-sectional data needed to estimate organ 
volumes. The CT part will also be used to correct for photon attenuation 
(refer to paragraph on attenuation correction above). Especially the 
SPECT examination may be influenced by photons scattered to different 
energies and directions inside the patient. A triple energy window 
technique (if feasible) will be used to reduce the influences on 
quantification.  
Full details of the scans required are provided in the dosimetry protocol.  
 


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