Clinical trial NCT02658968
Conditions: Relapsed, Diffuse Large B-cell Lymphoma Refractory Diffuse Large B-Cell Lymphoma
Keywords: Radioimmunotherapy Lu-177 Phase I study Betalutin ARC Antibody Radionuclide Conjugate HH1 Rituximab 177Lu-DOTA-HH1 Lilotomab Lutetium (177Lu)-lilotomab satetraxetan Additional relevant MeSH terms: Lymphoma Lymphoma, Non-Hodgkin Immune System Diseases Immunoproliferative Disorders Diffuse Large B-Cell Lymphoma Lymphatic Diseases Lymphoproliferative Disorders Neoplasms Neoplasms by Histologic Type DLBCL Refractory DLBCL Relapsed DLBCL
Sponsor: Nordic Nanovector
Start date: 2017-03-02; Completion date: 2021-07-10
Enrollment: 18 participants; Allocation: NA; Intervention model: SEQUENTIAL

Brief summary:
This study is a phase 1, dose finding, open-label study in patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL). This is a dose escalating study to define the maximum tolerated dose (MTD) of lutetium (177Lu)-lilotomab satetraxetan (Betalutin®) in DLBCL patients who are not eligible for autologous stem cell transplant. The study will also assess safety and tolerability, pharmacokinetics, biodistribution and efficacy.

Detailed description:

Arms: arm 1: 10 MBq/kg b.w., in escalated doses with lilotomab pre-dosing
Interventions: intervention 1: Betalutin
Intervention descriptions: intervention 1: Dose finding study, starting on 10 MBq/kg b.w. Betalutin® (lutetium (177Lu)-lilotomab satetraxetan), single injection with lilotomab pre-dosing.

Protocol documents:
Prot_SAP_000.pdf: 
Investigational Product:
Lutetium (177Lu)-lilotomab satetraxetan (Betalutin)
Confidential
Study Number: LYMRIT-37-05
26 April 2019
Page 1 of 99
LYMRIT-37-05
EudraCT number: 2015-001933-26
CLINICAL STUDY PROTOCOL
A Phase 1 Dose finding study of lutetium (177Lu)-lilotomab satetraxetan (Betalutin®) in
patients with relapsed/refractory, diffuse large B-cell lymphoma, not eligible for
autologous stem cell transplant
Protocol:
26th April 2019
Study Principal Investigator:
Tim Illidge BSc PhD MB BS DRCOG MRCP FRCR FRCPath
Professor of Targeted Therapy and Oncology
University of Manchester
Manchester Cancer Research Centre
Christie NHS Foundation Trust,
Wilmslow Road,
Withington,
M20 4BX
UK
Sponsor:
Nordic Nanovector ASA
Lisa Rojkjaer, MD
Kjelsåsveien 168B
N-0884 Oslo
Norway
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 lead site/sponsor, except to the extent necessary to initiate the study or conduct
study-related activities.


Investigational Product:
Lutetium (177Lu)-lilotomab satetraxetan (Betalutin)
Confidential
Study Number: LYMRIT-37-05
26 April 2019
Page 2 of 99
LIST OF CHANGES IN THIS AMENDMENT
Section number
Section title
Description of change(s)
List of Abbreviations
Updated
1
Protocol Synopsis
Relevant sections updated to reflect changes
made in this amendment (below)
2.3
Rituximab
MabThera and Rituxan removed to allow for
the use of biosimilars
2.5.4; 2.5.5;
2.6.1; 2.6.2.1;
2.6.3; 2.6.4
Potential Benefits and
Risks; Rationale and
Dose Selection
Inclusion of more recent data; aligned with IB
vsn 11; removal of superseded data
3.1, 3.2 and 3.3
Study objectives
Minor administrative changes and inclusion of
additional safety endpoint for monitoring of
ADA response; clarification of the PK
endpoints; separated out exploratory endpoints
4.1
Overview of study
design
Expansion of MTD dose in 20 patients (10
relapsed, non-refractory and 10 refractory) to
allow for further evaluation of safety, PK and
preliminary efficacy.
4.5
Pharmacokinetics,
biodistribution and
dosimetry
Removal of superseded calculation method
Table 4
Schedule of Study
Assessments
Updated HAMA to immunogenicity
Table 5
Schedule of study
assessments for the
pharmacokinetics,
biodistribution and
dosimetry sub-study
Removal of footnote
4.7
Study procedures by
visit
Updated section numbering; changed references
from HAMA to immunogenicity; a number of
minor clarifications


Investigational Product:
Lutetium (177Lu)-lilotomab satetraxetan (Betalutin)
Confidential
Study Number: LYMRIT-37-05
26 April 2019
Page 3 of 99
5.1
Inclusion criteria
Minor administrative changes; clarification of
refractory; updated criteria for high dose
chemotherapy and autologous stem cell
transplantation; updated murine to mouse in the
HAMA description; changed bilirubin limits to
align with other liver function criteria; updated
contraception from acceptable to effective to
align with IB vsn 11
5.2
Exclusion criteria
Removed corticosteroid restrictions as per SRC
recommendation
6.1.1.3
Preparation and
administration
Inclusion of limits for the intended prescribed
dose
6.2
Treatment Allocation
Clarification of patient inclusion process
6.5; 7.1
Supportive Care
Guidelines; Adverse
Events
Updated section numbering to allow for easier
navigation of the document
7.1.1.6
Definition of Adverse
Events of Special
Interest (AESI)
Inclusion of new section describing AESI
7.8
Immunogenicity
Assessments
Updated HAMA references to immunogenicity
(and throughout protocol); inclusion of
additional information regarding the use of the
immunogenicity biobanked samples; inclusion
of HAMA results for patients treated in the
study in cohorts 1-3
8.1.3
Overall Tumour
Response Evaluation
Corrections made to align with Cheson 2014
9.1
Pharmacokinetics
Clarification of the pharmacokinetic tests that
will be performed
11.1
Sample Size
Updated to include patients in the expansion
phase
11.2
Analysis population
Clarification of planned populations analyses


Investigational Product:
Lutetium (177Lu)-lilotomab satetraxetan (Betalutin)
Confidential
Study Number: LYMRIT-37-05
26 April 2019
Page 4 of 99
11.5
Statistical
Considerations
Minor administrative changes and
clarifications; clarification of the parameters
which will be analysed; inclusion of how the
relapsed and refractory patient’s data will be
analysed
12.1
Patient Data Handling
Inclusion of GDPR text
16
References
Inclusion of a recent ASH 2018 reference






Investigational Product:
Lutetium (177Lu)-lilotomab satetraxetan (Betalutin)
Confidential
Study Number: LYMRIT-37-05
26 April 2019
Page 7 of 99
SPONSOR PERSONNEL
Zoe Mackintosh,
Clinical Study Manager
Email: zmackintosh@nordicnanovector.com
Phone: +44 7939 842586
Switchboard: +47 22183301
Telefax: +47 22580007
COLLABORATORS
Pharmacovigilance:
Covance Inc
Address
For US/Canada:
Princeton Office
1-888-724-4908 Hotline
1-888-887-8097 Safety Fax
For EU:
Maidenhead Office
+44 (0)1628 548 171 Hotline
+44 (0)1628 540 028 Safety Fax


Investigational Product:
Lutetium (177Lu)-lilotomab satetraxetan (Betalutin)
Confidential
Study Number: LYMRIT-37-05
26 April 2019
Page 8 of 99
TABLE OF CONTENTS
LIST OF TABLES..........................................................................................................................11
LIST OF FIGURES........................................................................................................................11
LIST OF ABBREVIATIONS.........................................................................................................12
1
PROTOCOL SYNOPSIS........................................................................................................15
2
INTRODUCTION...................................................................................................................22
2.1
Background ........................................................................................................................22
2.2
Lutetium (177Lu)-lilotomab satetraxetan (Betalutin®)...........................................................24
2.3
Rituximab...........................................................................................................................25
2.4
Lilotomab antibody.............................................................................................................26
2.5
Potential Benefits and Risks................................................................................................27
2.5.1
Disease and Patient Population and Alternative Treatments to Betalutin ..............27
2.5.2
Non-clinical Risk Assessment of Betalutin ..........................................................27
2.5.3
Risk with Rituximab Pre-treatment......................................................................29
2.5.4
Risk with Lilotomab Pre-dosing ..........................................................................29
2.5.5
Potential Risk Factors and Proposed Risk Minimization Activities ......................30
2.6
Rationale and Dose Selection..............................................................................................32
2.6.1
Selection of Dose of Betalutin.............................................................................32
2.6.2
Justification of Pre-treatment with Rituximab and Selection of Dose ...................33
2.6.3
Justification of Pre-dosing with lilotomab and Selection of Dose .........................34
2.6.4
Clinical experience with Betalutin.......................................................................36
3
STUDY OBJECTIVES ...........................................................................................................38
3.1
Primary objectives: .............................................................................................................38
3.2
Secondary objectives: .........................................................................................................38
3.3
Study endpoints ..................................................................................................................38
3.3.1
Safety Endpoints:................................................................................................38
3.3.2
Biodistribution, and Pharmacokinetics endpoints:................................................38
3.3.3
Efficacy endpoints...............................................................................................39
3.3.4
Exploratory endpoint:..........................................................................................39
4
STUDY DESIGN.....................................................................................................................39
4.1
Overview of Study Design..................................................................................................39
4.2
Dose Limiting Toxicity Definition and Dose Escalation......................................................41
4.2.1
Dose Limiting Toxicity .......................................................................................41
4.2.2
Dose-escalation:..................................................................................................41
4.3
Schedule of Assessments ....................................................................................................43
4.4
Safety .................................................................................................................................44
4.5
Pharmacokinetics, biodistribution and dosimetry.................................................................44
4.6
Efficacy..............................................................................................................................44
4.7
Study Procedures by Visit...................................................................................................48
4.7.1
Pre-screening/screening (–42 to -14 days) ...........................................................48
4.7.2
Rituximab Administration (-14 days +/- 2 days) ..................................................49


Investigational Product:
Lutetium (177Lu)-lilotomab satetraxetan (Betalutin)
Confidential
Study Number: LYMRIT-37-05
26 April 2019
Page 9 of 99
4.7.3
Pre-Betalutin assessments, lilotomab infusion and Betalutin administration (Day -1 or
0) ...................................................................................................................49
4.7.4
Post-Betalutin Assessments.................................................................................50
4.7.5
Withdrawal .........................................................................................................52
4.7.6
Relapse ...............................................................................................................53
4.7.7
After Withdrawal ................................................................................................53
5
STUDY POPULATION..........................................................................................................53
5.1
Inclusion Criteria................................................................................................................53
5.2
Exclusion Criteria...............................................................................................................55
5.3
Withdrawal and Termination Criteria..................................................................................57
5.3.1
Patient Withdrawal..............................................................................................57
5.3.2
Procedures for Discontinuation............................................................................58
5.3.3
Study Treatment Discontinuation ........................................................................58
5.3.4
Study or Site Termination....................................................................................58
6
TREATMENT PLAN .............................................................................................................59
6.1
Investigational Medicinal Products .....................................................................................59
6.1.1
Betalutin .............................................................................................................59
6.1.2
Rituximab ...........................................................................................................61
6.1.3
Lilotomab ...........................................................................................................61
6.1.4
Investigational Product Complaints .....................................................................61
6.2
Treatment Allocation ..........................................................................................................61
6.3
Permitted and Restricted Concomitant Medications/Treatments ..........................................62
6.4
Pre-Medication Guidelines..................................................................................................62
6.5
Supportive Care Guidelines.................................................................................................62
6.5.1
Severe thrombocytopenia (platelets <20x109/L)...................................................62
6.5.2
Injection site irritation .........................................................................................62
6.5.3
Persistent neutropenia (neutrophils/granulocytes <0.5x109/L) without fever.........63
6.5.4
Neutropenia with fever (neutrophils/granulocytes <1x109/L; fever >38°C) ..........63
6.5.5
Severe anaemia (haemoglobin <8.0 g/dL)............................................................63
6.5.6
Hypersensitivity..................................................................................................63
6.5.7
Extravascular administration ...............................................................................63
6.5.8
Precautions during administration of lilotomab:...................................................63
6.6
Treatment Compliance........................................................................................................64
7
SAFETY ASSESSMENTS......................................................................................................64
7.1
Adverse Events...................................................................................................................64
7.1.1
Definitions ..........................................................................................................64
7.1.2
Responsibility .....................................................................................................66
7.1.3
Assessments of Adverse Events: Seriousness, Causality, Severity and Expectedness67
7.1.4
Reporting of Adverse Events Regardless of Causality..........................................69
7.1.5
Reporting of Serious Adverse Events ..................................................................70
7.2
Physical Examination..........................................................................................................71
7.3
Bone Marrow Biopsy..........................................................................................................71
7.4
ECOG Performance Status..................................................................................................71
7.5
Vital Signs..........................................................................................................................72


Investigational Product:
Lutetium (177Lu)-lilotomab satetraxetan (Betalutin)
Confidential
Study Number: LYMRIT-37-05
26 April 2019
Page 10 of 99
7.6
12-lead ECG.......................................................................................................................72
7.7
Clinical Laboratory Parameters...........................................................................................72
7.8
Immunogenicity Assessment (HAMA)................................................................................74
7.9
Potential Long Term Toxicity .............................................................................................75
7.10
Pregnancy...........................................................................................................................75
7.11
Misuse and overdose...........................................................................................................76
8
EFFICACY ASSESSMENTS .................................................................................................76
8.1
Tumour Response...............................................................................................................76
8.1.1
Contrast Enhanced CT Examination....................................................................76
8.1.2
PET/CT Examination ..........................................................................................77
8.1.3
Overall Tumour Response Evaluation..................................................................78
8.2
Clinical Benefit...................................................................................................................82
8.3
Quality of Life....................................................................................................................82
9
PHARMACOKINETICS, BIODISTRIBUTION AND DOSIMETRY.................................82
9.1
Pharmacokinetics................................................................................................................82
9.1.1
Blood clearance...................................................................................................83
9.1.2
Urine clearance ...................................................................................................83
9.2
Biodistribution and Dosimetry ............................................................................................83
10
BIOMARKER AND PHARMACODYNAMIC ASSESSMENTS.........................................84
10.1
Archived Biopsy.................................................................................................................84
10.2
Fresh Biopsy.......................................................................................................................84
11
STATISTICAL METHODS AND PLANNED ANALYSES.................................................84
11.1
Sample Size........................................................................................................................84
11.2
Analysis Populations...........................................................................................................85
11.3
End of Study and Study Completion ...................................................................................85
11.4
Database lock .....................................................................................................................85
11.5
Statistical Considerations....................................................................................................85
11.5.1
Analysis of Demographic and Pre-treatment Characteristics ................................85
11.5.2
Analysis of Safety Data.......................................................................................86
11.5.3
Analysis of Tumour Response.............................................................................86
11.5.4
Pharmacokinetic, Biodistribution and Dosimetry Analysis...................................86
11.5.5
Handling of Drop-outs and/or Missing Data ........................................................87
11.5.6
Sub-group Analysis.............................................................................................87
12
DATA HANDLING ................................................................................................................87
12.1
Patient Data Protection........................................................................................................87
12.2
Electronic Case Report Forms (eCRFs)...............................................................................88
12.3
Data Management...............................................................................................................88
12.4
Retention of Documents......................................................................................................89
13
SPECIAL REQUIREMENTS AND PROCEDURES............................................................90
13.1
Independent Ethics Committee/Institutional Review Board .................................................90
13.2
Protocol Amendments and Discontinuation.........................................................................90
13.3
Investigator’s Overall Responsibility...................................................................................91


Investigational Product:
Lutetium (177Lu)-lilotomab satetraxetan (Betalutin)
Confidential
Study Number: LYMRIT-37-05
26 April 2019
Page 11 of 99
13.4
Patient Informed Consent....................................................................................................91
13.5
Direct Access to Source Data/Documents............................................................................92
13.6
Confidentiality Regarding Study Patients............................................................................92
13.7
Study Monitoring................................................................................................................92
13.8
Audit and Inspection...........................................................................................................93
13.9
Laboratory Accreditation ....................................................................................................93
13.10 Patient Insurance and Indemnity .........................................................................................93
14
INVESTIGATOR AGREEMENT..........................................................................................93
14.1
Financial Disclosure ...........................................................................................................93
14.2
Study Agreement and Payment of Grant..............................................................................94
15
CONFIDENTIALITY AND REPORTING AND PUBLICATION OF RESULTS..............94
15.1
Statistical and Clinical Reports ...........................................................................................94
15.2
Regulatory Use of Data.......................................................................................................94
15.3
Publication of Results .........................................................................................................94
16
REFERENCES........................................................................................................................96
LIST OF TABLES
Table 1
Potential risk factors of Betalutin treatment and proposed risk minimization activities....... 30
Table 2
Betalutin Dose Escalation Schedule................................................................................... 40
Table 3
Dose Escalation Rules....................................................................................................... 42
Table 4
Schedule of Study Assessments – see Section 4.7– Study Procedures by Visit................... 45
Table 5
Schedule of study assessments for the pharmacokinetic, biodistribution and dosimetry sub-study
......................................................................................................................................... 47
Table 6
Classification of ECOG performance status....................................................................... 71
Table 7
Laboratory parameters ...................................................................................................... 73
Table 8 Approximate volume of blood to be drawn from each patient during the initial assessment period
to Week 12........................................................................................................................ 74
Table 9 Monitoring of the HAMA response in LYMRIT 37-05......................................................... 75
Table 10 Uptake score with the use of Deauville criteria ................................................................... 78
Table 11 Overall tumour response evaluation.................................................................................... 79
LIST OF FIGURES
Figure 1 Study flow chart................................................................................................................ 43


Investigational Product:
Lutetium (177Lu)-lilotomab satetraxetan (Betalutin)
Confidential
Study Number: LYMRIT-37-05
26 April 2019
Page 12 of 99
LIST OF ABBREVIATIONS
177Lu
β-particle–emitting radionuclide lutetium-177
ADA
Anti-drug antibody
ADL
Activity of Daily Living
AR
Adverse reaction
AE
Adverse event
AESI
Adverse event of special interest
ALP
Alkaline phosphatase
ALT or ALAT
Alanine transaminase
AML
Acute myeloid leukemia
APTT
Activated partial thromboplastin time
ARC
Antibody-radionuclide-conjugate
ASAT
Aspartate transaminase
AST
Aspartate transaminase
Betalutin
177Lu-lilotomab satetraxetan
BUN
Blood urea nitrogen
b.w.
Body weight
CA
Competent authority
CHMP
Committee for Medicinal Products for Human Use
CHOP
Cyclophosphamide, hydroxydaunorubicin, oncovin and prednisone
CI
Confidence interval
CIOMS
Council for International Organisations of Medical Sciences
CLL
Chronic lymphocytic leukaemia
CR
Complete response
CRF
Case report form
CRO
Contract research organization
CT
Computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
DC
Decay correction factor
DLBCL
Diffuse large b-cell lymphoma
DLBCL-NOS
Diffuse large b-cell lymphoma, not otherwise specified
DLT
Dose-limiting toxicity
DNA
Deoxyribonucleic acid
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]
EC
Ethic Committee
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
Electronic case report form
Emax
Maximal effect at high drug concentration
EU
European Union


Investigational Product:
Lutetium (177Lu)-lilotomab satetraxetan (Betalutin)
Confidential
Study Number: LYMRIT-37-05
26 April 2019
Page 13 of 99
eV
Electronvolt
FACT-Lym
Functional Assessment of Cancer Therapy–Lymphoma
FDA
Food and Drug Administration
FDG
18Fluorodeoxy glucose
5PS
5-point scale
GCP
Good Clinical Practice
G-CSF
Granulocyte-colony stimulating factor
GGT
Gamma-glutamyl transferase
GI
Gastrointestinal
GM-CSF
Granulocyte-macrophage colony-stimulating factor
GMP
Good Manufacturing Practice
HAMA
Human anti-mouse antibody
HD-ASCT
High-dose chemotherapy with autologous stem cell transplantation
HH1
Lilotomab
HIV
HRU
Human immunodeficiency virus
Healthcare Resource Utilisation
IB
Investigator Brochure
ICH
International Conference on Harmonisation
IEC
Independent Ethics Committee
IgG
Immunoglobulin G
IHC
Immunohistochemistry
IMP
Investigational medicinal product
INR
International normalized ratio
IRB
Institutional Review Board
LDH
Lactate dehydrogenase
LDi
Longest transverse diameter of a lesion
Lu
Lutetium
MBq
Mega Becquerel
MDS
Myelodysplastic syndrome
MedDRA
Medical Dictionary for Regulatory Activities
meV
Megaelectronvolt
MRI
Magnetic resonance imaging;
MTD
Maximum tolerated dose
NCI
National Cancer Institute
NHL
Non-Hodgkin lymphoma
NYHA
New York Heart Association
ORR
Overall response rate
OS
Overall survival
PD
Pharmacodynamic
PD
Progressive disease
PET
Positron-emission tomography
PFS
Progression free survival
PK
Pharmacokinetic


Investigational Product:
Lutetium (177Lu)-lilotomab satetraxetan (Betalutin)
Confidential
Study Number: LYMRIT-37-05
26 April 2019
Page 14 of 99
PPD
Cross product of the LDi and perpendicular diameter
PR
Partial response
QoL
Quality of life
R-CHOP
Rituximab and the chemotherapy combination of cyclophosphamide,
hydroxydaunorubicin, oncovin and prednisone
RBC
Red blood cell
RIT
Radioimmunotherapy
SAE
Serious adverse event
SAP
Statistical Analysis Plan
SCID
Severe combined immune deficient
SD
Stable disease
SDi
Shortest axis perpendicular to the LDi
SPD
Sum of the product of the perpendicular diameters for multiple lesions
SPECT
Single-photon emission computerized tomography
SUV
Standardized uptake value
SUSAR
Suspected unexpected serious adverse reaction
TMF
Trial Master File
T½
Half-life
ULN
Upper limit of normal
US
United States
WB
Whole body
WHO
World Health Organization


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I n vesti g ati o n al Pr o d uct:
L uteti u m ( 1 7 7L u) -lil ot o m a b s atetr a xet a n ( Bet al uti n)
C o nfi de nti al
St u d y N u m ber: L Y M RI T -3 7 -0 5
2 6 A pril 2 0 1 9
P a ge 1 8 of 9 9
O nce t he M T D is i de ntifi e d, t he M T D d os e l e vel will be f urt her e x pa n de d b y a p pr o xi mat el y 1 0 a d diti o nal pati e nts w h o
rel a ps e d ≥6 m o nt hs aft er l ast t hera p y aft er ha vi n g ac hi e ve d a C R/ P R, a n d a p pr o xi mat el y 1 0 pati e nts w h o were refract or y
t o t heir l ast li ne of t hera p y (P D, S D or C R/ P R l asti n g < 6 m o nt hs) t o f urt her ass ess s afet y, a nti -t u m o ur acti vit y a n d P K.
A d diti o nal pati e nts ma y be e nr oll e d t o all o w f or n o n -e val ua bl e pati e nts t o be re pl ace d (e. g. pati e nts w h o are e nr oll e d b ut
are wit h dra w n pri or t o st u d y dr u g or Bet al uti n a d mi nistrati o n).
Tr e at me nt Sc he d ul e a n d St u d y Ass ess me nts:
I n di vi d u al ti m e s c he d ul e f or all p ati e nts
N ote t h at patie nts i n cl u d e d i n t h e p h ar mac o ki n etics, bi o distri b uti o n a n d d osi metr y s u b -st u d y will ha ve a d diti o nal visits d uri n g t he first 3 wee ks after
Betal uti n a d mi nistr ati o n .
A visit wi n d o w of ± 2 d a ys is per mitte d f or Da y 0 a n d Da y -1 4 . T he d ose of r a di oacti vit y will be base d o n t he patie nt wei g ht o n t he act ual
a d mi nistr ati o n d ate.
P ati e nts c o nsi dere d s uit a bl e t o be s cree ne d f or t he st u d y w ill u n der g o a s cree ni n g ass ess me nt. P ati e nts will att e n d t he
cli ni c o n da y -1 4 , Da y 0 (t he d osi n g da y) a n d e ver y wee k u p t o 1 2 wee ks aft er Bet al uti n i njecti o n. T he pati e nts will t he n
be e val uat e d i n t he cli ni c m o nt hl y u ntil M o nt h 6 (i.e. 6 m o nt hs fr o m Da y 0 [d a y of Bet al uti n i nj ecti o n ]). O n c o m pl eti o n
of t he 6 m o nt h f oll o w -u p visit, pati e nts will be f oll o we d wit h cli ni c visits e ver y 3 m o nt hs u p t o 2 4 m o nt hs p ost -
treat me nt, t o ass ess dis eas e pr o gressi o n a n d s ur vi val. T he pati e nt will be wit h dra w n fr o m f oll o w-u p if f urt her a nti ca ncer
t hera p y is st art e d.
S af et y:
I n t he treat me nt peri o d (fr o m t he ti me of t he first rit u xi ma b i nf usi o n t hr o u g h Da y 0 Bet al uti n a d mi nistrati o n) a n d t he
s h ort t er m f oll o w-u p peri o d (u p t o 1 2 wee ks aft er Bet al uti n a d mi nistrati o n) vi t al si g ns, p h ysi cal e xa mi nati o n,
hae mat ol o g y a n d s er u m bi oc he mistr y, all A Es a n d c o nc o mita nt me di cati o ns will be c oll ecte d at s pecifi e d ti me p oi nts or
m ore fre q ue ntl y per dis creti o n of t he treati n g p h ysi ci a n . D uri n g t he l o n g t er m f oll o w-u p peri o d (fr o m 1 2 wee ks u ntil
2 years), S A Es a n d A Es rel at e d t o st u d y dr u g, hae mat ol o g y, s er u m bi oc he mistr y, as well as a n y l at e t o xi cit y s uc h as
s ec o n d pri mar y mali g na nci es will be rec or de d e ver y m o nt h d uri n g t he first 6 m o nt hs f oll o wi n g st u d y treat me nt a n d
e ver y 3 m o nt hs t hereaft er, u ntil t he pati e nt has bee n t hr o u g h his/ her 2-year visit or u ntil i niti ati o n of ot her ca ncer rel at e d
treat me nt, w hi c he ver occ urs first.
P h ar m ac o ki neti cs, bi o distri b uti o n a n d d osi metr y :
P ati e nts w h o parti ci pat e i n a bi o distri b uti o n s u b -st u d y will ha ve bl o o d s a m pl es c oll ect e d f or ra di oacti vit y a n d a nti b o d y
meas ure me nts at t he f oll o wi n g ti me p oi nts wit h refere nce t o t he lil ot o ma b a d mi nistrati o n o n Da y 0: 0 ( pre-d os e), 5, 3 0,
6 0 a n d 1 2 0 mi n ut es, a n d t he n at t hes e ti me p oi nts f oll o wi n g Bet al uti n a d mi nistrati o n: 0 (pre -d os e ), 1 5 mi n ut es , 1, 2, 4
a n d 2 4 h o urs p ost -d os e, pl us Da ys 2 , 3 , 4 , 7 ( ± 1), 1 4 ( ± 2) a n d 2 1 ( ± 2)..
T he d osi metr y a n d bi o distri b uti o n s u b -st u d y will als o i ncl u de w h ole b o d y ga m ma s ca ns a n d si n gl e -p h ot o n e missi o n
c o m p ut eri ze d t o m o gra p h y ( S P E C T)/ c o m p ut e d t o m o gra p h y ( C T) s ca ns at 2 -4 a n d 2 4 h o urs, Da y 4 a n d 7 aft er Bet al uti n
S cr e e ni n g
D a y -4 2 t o
D a y -1 4
Tr e at m e nt
D a y -1 4 t o
D a y 0
F oll o w -u p
M o nt h 3 t o 6
L o n g -t er m f oll o w-u p
M o nt h s 6 t o 2 4
P o st -tr e at m e nt
D a y 0 t o
W e e k 1 2 ( M o nt h 3)
Rit u x i m a b
( D a y -1 4)
B et al uti n
( D a y 0)
Vi sit e v er y w e e k
Vi sit e v er y
m o nt h
Vi sit e v er y 3
m o nt h s
Lil ot o m a b
( D a y 0: wit hi n 4 h
pri or t o B et al uti n)


Investigational Product:
Lutetium (177Lu)-lilotomab satetraxetan (Betalutin)
Confidential
Study Number: LYMRIT-37-05
26 April 2019
Page 19 of 99
treatment. Note that samples times may vary based on on-going analysis but will not exceed this maximum number of
assessments. A Day 4 SPECT/CT scan is optional for patients not participating in the biodistribution sub-study. A
window of ±1 day is permitted for the Day 4 SPECT/CT scan.
Efficacy:
Positron-emission tomography (PET)/CT and contrast enhanced CT images will be performed at baseline, and at 3 and 6
months after Betalutin administration. Thereafter, contrast enhanced CT scan will be done every 6 months up to Month
24. Survival data will be recorded for all patients until the last patient has been through the 2-year follow-up period.
Patient Selection:
Inclusion Criteria
Eligible patients must meet the following criteria at the time of enrolment:
1.
Male or female aged ≥18 years.
2.
Histologically confirmed DLBCL (WHO classification).
3.
Received at least one prior line of therapy including immuno-chemotherapy.
4.
In first or subsequent relapse, or refractory to the last treatment (defined as less than a complete metabolic response
to the last treatment, or disease progression within 6 months from the last treatment)
5.
Not suitable for or declined/unwilling to undergo intensive therapy, including high dose chemotherapy and
autologous stem cell transplantation (ASCT). The decision of whether a patient is unsuitable or not for ASCT
should be made by the investigator following a thorough review of the patient. For guidance possible reasons
patients may be unsuitable for ASCT may include but are not limited to; excessively elderly or frail patients, those
with an increased bilirubin or creatinine level (to be eligible for this study patients must still meet inclusion criteria
11), low cardiac ejection fraction, forced expiratory volume in 1 second and/or lower than predicted carbon
monoxide diffusion test.
6.
Presence of radiographically measurable lymphadenopathy or extranodal lymphoid malignancy (at least one
objectively bi-dimensionally measurable (nodal) lesion (>1.5 cm in its largest dimension by CT scan).
7.
Negative human anti-mouse antibody (HAMA) test.
8.
Life expectancy of at least 3 months.
9.
Bone marrow tumour infiltration <25% tumour cells (in biopsy taken from a site not previously irradiated).
10. Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2
11. Normal organ and bone marrow (normocellular) function defined as:
a.
Absolute neutrophil count ≥1.5 x 109/L;
b.
Platelet count ≥150 x 109/L;
c.
Haemoglobin ≥9 g/dL;
d.
Total bilirubin ≤2.5 x upper limit of normal (ULN) (except patients with documented Gilbert’s syndrome);
e.
Liver enzymes: Aspartate transaminase (AST); Alanine transaminase (ALT) or Alkaline phosphatase
(ALP) ≤2.5 x ULN (or ≤5.0 x ULN if liver involvement by primary disease);
f.
Adequate renal function as demonstrated by a serum creatinine ≤1.5 mg/dL or a creatinine clearance
>60 mL/min;
g.
Normal coagulation parameters (elevated international normalized ratio (INR), prothrombin time or
activated partial thromboplastin time (APTT) ≤1.3 ULN range acceptable).
12. Women of childbearing potential, defined as neither post-menopausal nor permanently sterile must agree to the
contraceptive requirements below. Permanent sterilisation methods may include hysterectomy, bilateral
salpingectomy and bilateral oophorectomy and postmenopausal is defined as no menses for 12 months without an
alternative medical cause.
Women of childbearing potential must


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Investigational Product:
Lutetium (177Lu)-lilotomab satetraxetan (Betalutin)
Confidential
Study Number: LYMRIT-37-05
26 April 2019
Page 21 of 99
10. Allergy to X ray contrast agents.
11. A known hypersensitivity to rituximab, lilotomab, Betalutin or murine proteins or any excipient used in rituximab,
lilotomab or Betalutin.
12. Has received a live attenuated vaccine within 30 days prior to enrolling in the study.
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.
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.
Concomitant Medication:
Warfarin should be changed to low-molecular heparin. The dose of low-molecular heparin should be temporarily
reduced if platelets are below 50 x 109/L, and be temporarily stopped if platelets are below 25 x 109/L.
Prophylaxis with allopurinol for tumour lysis will be permitted at the discretion of the investigator.
Safety Review Committee:
The recommendation of whether to enrol patients in the next cohort with an increased dose, and the decision on the
MTD for the expansion phase will be made by the Safety Review Committee based on the safety data in the database at
the time the last patient in the current cohort has peripheral blood count recovery or until 8 weeks after the Betalutin
dose (the follow-up may get extended up to 12 weeks if a patient’s platelets or neutrophils do not recover to grade 1 by 8
weeks). The Safety Review Committee consists of at least three experts including the co-ordinating and principal
investigators from ongoing Betalutin studies.
Statistical Methods and Sample Size:
The total number of patients enrolled into the study will depend on the number of dose levels explored and the toxicity
observed. Up to approximately 24 patients may be enrolled into the dose escalation portion of the study and
approximately an additional 20 patients for expansion of the MTD. The results from this study will be presented using
descriptive statistical methods.


Investigational Product:
Lutetium (177Lu)-lilotomab satetraxetan (Betalutin)
Confidential
Study Number: LYMRIT-37-05
26 April 2019
Page 22 of 99
2
INTRODUCTION
2.1
Background
Non-Hodgkin lymphomas (NHL) as a group is the most common malignant haematological
disease. NHLs are a diverse group of blood cancers that include any kind of lymphoma except
Hodgkin lymphoma. NHLs vary in their clinical behaviour, morphologic appearance,
immunologic and molecular phenotype (2). The various types represent neoplastic lymphoid
cells arrested at different stages of differentiation. Based on their natural history, NHLs can be
clinically classified as indolent, aggressive, and highly aggressive. Diffuse large B-cell
lymphoma (DLBCL) and follicular lymphoma are the most common subtypes.
NHL (all subtypes combined) is the tenth most common cancer worldwide, with nearly 386,000
new cases diagnosed in 2012 (3% of the total). NHL incidence rates are highest in Northern
America and lowest in South Central Asia, but this partly reflects varying data quality
worldwide (3). In the USA, NHL is the fifth most common cause of cancer, with an estimated
71,850 new cases expected in 2015 (4). In developed countries, NHL registrations have
increased approximately three-fold since the mid-1970s, with much of the rise occurring before
the mid-1990s (5-8). The disease is uniformly fatal without treatment, but the majority of
patients are effectively treated with current chemo-immunotherapy strategies. Patients with
diffuse large B-cell lymphoma (DLBCL) tend to be older than those with other types of NHL;
the peak incidence for DLBCL occurs in the seventh decade of life. [Savage KJ, Gregory SA.
Lymphomas. In: Gregory SA, McCrae KR, eds. ash®-sap. ASH Self-Assessment Program. 4th
ed. 2010:511–554.]
The initial management of DLBCL is centred around chemotherapy regimens, with various
permutations of the anti-CD20 antibody rituximab and the chemotherapy combination of
cyclophosphamide, hydroxydaunorubicin, vincristine (“Oncovin”) and prednisone (CHOP).
Using CHOP with rituximab (R-CHOP), approximately 70% of patients with DLBCL will be
disease-free at five years (9,10). Conversely, the remaining one-third of patients will have
relapsed or have refractory disease. This represents a group with poor prognosis and an
untreated overall survival of only about six months. They are, therefore, a patient population
significantly devoid of effective therapeutic options (11). The most meaningful treatment
approach for patients with relapsed or refractory disease is high-dose chemotherapy combined
with autologous stem cell transplantation (HD-ASCT) (12). However, approximately half of
patients with relapsed/refractory disease are ineligible for HD-ASCT, due to co-morbidities or
a failure to demonstrate chemo-responsiveness to salvage therapy given prior to transplant (13).
Of the remaining patients who can undergo HD-ASCT, only about 20% achieve a lasting
response (13).
In recent years a novel way of treating NHL with radiation has emerged; radioimmunotherapy
(RIT), which refers to using a radiolabelled monoclonal antibody to specifically target an


Investigational Product:
Lutetium (177Lu)-lilotomab satetraxetan (Betalutin)
Confidential
Study Number: LYMRIT-37-05
26 April 2019
Page 23 of 99
antigen expressed on tumour cells or within tumour tissue. Thus, the toxicity to normal cells
without the antigen will be limited. Several studies have shown that beta-emitting
radioimmunoconjugates possess high levels of antitumour activity in patients with relapsed or
refractory B-cell lymphomas (14-17), including those refractory to rituximab (18,19) and
chemotherapy (20). However, so far, no RIT has been approved for the treatment of DLBCL,
as all the approved products are approved for follicular lymphoma, mantle cell lymphoma and
chronic lymphocytic leukaemia.
Clinical data have indicated that RIT may be more cost effective and more efficacious than
nonradioactive immunotherapy (21,22). More recently, single-arm studies with upfront RIT
administered either alone or with chemotherapy to previously untreated indolent NHL patients
have reported overall response rates of 90-100 %, complete response rates of 60-95 % and
durable remissions (23-26).
A phase 3 study of RIT as part of frontline therapy for indolent NHL reported that consolidation
therapy with 90Y-ibritumomab tiuxetan (Zevalin®) after induction chemotherapy markedly
prolonged progression free survival in patients with previously untreated stage II or IV follicular
lymphoma (27). In another study, patients with indolent and aggressive NHLs received four
cycles of chemotherapy followed by high myeloablative dose of 90Y-ibritumomab tiuxetan
followed by autologous stem cell support (28). After a follow-up time of 30 months the overall
survival rate was 87% and the event free survival was 69%. Although myeloablative doses of
90Y-ibritumomab tiuxetan were given, the RIT was well tolerated. The low dose-rate permits
RIT to be effective for hematologic malignancies while causing minimal non-haematological
toxicity.
When anti-CD20 RIT is given to patients, the RIT is administered with large quantities of
unlabelled cold anti-CD20 antibody immediately before radiolabelled anti-CD20 antibodies.
Such a priming dose is necessary to optimize radiolabelled antibody concentrations in tumour
(16,29), presumably by partially saturating easily accessible B-cells in the blood and the spleen
and permitting sufficient radiolabelled antibody to bypass these sites and penetrate less
accessible compartments, such as lymph nodes and large tumour masses. However, too much
cold anti-CD20 antibody over a long time can result in blocking of the CD20 antigen on tumour
cells and thus reduce the effect of anti-CD20 RIT. Both clinical and non-clinical studies have
shown that in some circumstances quite low rituximab concentrations in the blood can reduce
tumour cell targeting and thus impair the clinical efficacy of CD20-directed RIT (30). A solution
to this problem might be to omit cold rituximab from the last cycles of therapy before RIT.
Alternatively, one could choose to target another B-cell surface antigen such as CD37.
The chloramine T method of 131I-labeling was used in the early studies of CD37 RIT (31). 131I
labelled to antibodies with the iodogen or the chloramine T method are not retained in the cells
if the antigen-antibody complex is internalized (32,33). Inside the cells the nuclide is removed
from the antibody by intracellular enzymes and diffuses out and away from the tumour cells


Investigational Product:
Lutetium (177Lu)-lilotomab satetraxetan (Betalutin)
Confidential
Study Number: LYMRIT-37-05
26 April 2019
Page 24 of 99
(34). The same so-called dehalogenation has been shown with CD22 antibodies, which are also
internalized (35). Metallic radionuclides labelled to antibodies with so-called chelators are,
however, more stable and remain contained inside the tumour cells to a much higher degree
(36). Use of metallic radionuclides facilitates therapeutic applications targeting internalizing
antigens, and tumour uptake may also be higher than for non-internalizing antibodies.
2.2
Lutetium (177Lu)-lilotomab satetraxetan (Betalutin®)
Betalutin (lilotomab labelled with lutetium-177 via the chelator p-SCN-benzyl-DOTA) has
been developed by Nordic Nanovector in collaboration with the Norwegian Radium Hospital
(Oslo, Norway) for the treatment of relapsed NHL patients.
Betalutin (lutetium (177Lu)-lilotomab satetraxetan) targets the CD37 antigen, which is abundant
on the cell surface of tumours of B-cell origin, including NHL and chronic lymphocytic
leukaemia (CLL) (37-39). CD37 antigen is a promising target, which at present is not addressed
by any approved treatment.
The most common radiopharmaceuticals used in therapy today utilize substances that
disintegrate resulting in the emission of a beta particle. Beta particles are electrons emitted from
the nucleus of an atom. Beta emitters currently approved for therapy include iodine-131 (half-
life [T½] = 8 days), yttrium-90 (T½ = 2.7 days) and lutetium-177 (T½ = 6.7 days). Lutetium-177
has been selected for use in Betalutin since it has proven to be suitable for labelling of the
lilotomab anti-CD37 antibody and has an energy of the emitted β-particle that is suitable for
treatment of lymphoma (Emax = 0.497 MeV, T½= 6.7 days). Furthermore, it has a low abundance
of photons with almost ideal energy for imaging (E = 113 keV, abundance = 6.5%; E = 208
keV, abundance = 11%).
Therapy with an antibody-radionuclide-conjugate (ARC) such as Betalutin, which incorporates
the beta-emitter lutetium-177, permits delivery of a therapeutic (lethal) dose of radiation directly
to the DNA of tumour cells. The radiation emitted from the radiolabelled antibody affects not
only the antibody-binding cell but also neighbouring cells up to an average of 0.23 mm from
the radionuclide, via the “cross-fire” effect.
Betalutin has been tested for targeting, therapeutic and toxic effects in cells, in mice, and in
humans. The murine monoclonal antibody against CD37, lilotomab, has similar or better
binding properties to CD37 than rituximab has to CD20. Therapy against single cells showed a
significantly better effect of Betalutin than of 177Lu-rituximab. The maximum tolerated dose
(MTD) of Betalutin in severe combined immune deficient (SCID) mice with tumour cells in the
bone marrow was between 50 and 100 MBq/kg (150-300 MBq/m2). Extrapolation to human
dose by allometric equivalence based on body surface area, however, shows that 550 MBq/kg
in mice (20 g body weight and surface area of 0.0066 m2) is equivalent to 43 MBq/kg in humans
(70 kg, 1,8 m2 body surface area). The MTD in mice can be increased by giving it as multiple


Investigational Product:
Lutetium (177Lu)-lilotomab satetraxetan (Betalutin)
Confidential
Study Number: LYMRIT-37-05
26 April 2019
Page 25 of 99
injections. Biodistribution studies with Betalutin have shown high uptake in tumour and uptake
in normal organs similar to the uptake of 177Lu-rituximab. The preclinical data to date indicates
that Betalutin has a suitable biodistribution profile with high uptake in tumour cells, and that
the efficacy results in the mouse models show promise of potentially interesting clinical results.
Relevant animal species that share a cross-reactive or identical target antigen as humans have
not been found. The antibody lilotomab did not elicit a response by human immune effectors in
vitro. No significant antibody-dependent effect of lilotomab was observed by complement
activation or immune cell cytotoxicity. Human tissues cross-reactivity studies showed that the
morphology and distribution of cells stained with lilotomab were consistent with that of B-cells.
Betalutin is prepared as a solution for intravenous administration. 1 mg/mL lilotomab antibody
will be used, between 8 to 10 mg lilotomab antibody per patient. The amount of lutetium (177Lu)-
lilotomab satetraxetan injected per patient will depend on the dose level and the patient’s
weight.
The first clinical trial of Betalutin in patients with recurrent indolent NHL was initiated in
December 2012. See Section Error! Reference source not found. for a summary of clinical
data.
Please see the IB for further information about Betalutin.
2.3
Rituximab
In this study, rituximab, a chimeric anti-CD20 antibody will be used as pre-treatment to clear
the circulating normal peripheral B-lymphocytes in the blood and in the spleen before
administration of Betalutin. This pre-treatment is commonly used in RIT regimens in lymphoma
and should ensure greater penetration of Betalutin to less accessible compartments such as
lymph nodes and larger tumour masses. Rituximab targets CD20 and will not block the binding
sites of Betalutin CD37 on the B-lymphocytes or tumour cells.
One intravenous infusion of 375 mg/m2 rituximab as pre-treatment will be given to all patients
on Day -14 (+/- 2 days) prior to administration of Betalutin. Pre-medication consisting of an
antipyretic and antihistamine medication should be administered before each infusion of
rituximab, according to the institutional guideline. For detailed guidance on use of rituximab
and possible side effects see the summary of product characteristics.
Rituximab is used as a standard treatment for patients with B-cell NHL either as monotherapy
or in combination with chemotherapy. The description of rituximab in this section is taken from
its prescribing information and package insert.


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Investigational Product:
Lutetium (177Lu)-lilotomab satetraxetan (Betalutin)
Confidential
Study Number: LYMRIT-37-05
26 April 2019
Page 27 of 99
The CD37 antigen positive cells in the spleen, bone marrow and liver that are left after the
rituximab pre-treatment can be blocked by pre-dosing with lilotomab before Betalutin. It is
assumed that lilotomab will bind to the most easily accessible CD37 positive cells in the
lymphoid organs and therefore prevent binding of Betalutin to the spleen and bone marrow,
increasing its circulating half-life and therefore increasing the exposure to the tumour.
RIT with CD37 as target has been explored previously using a 131I-labeled murine monoclonal
antibody (MB-1) against CD37 both in a mouse model and in the clinic.
Clinical data from the Norwegian Radium Hospital has shown that 99.5% (216 of 217) of human
lymphoma biopsies express CD37, confirming CD37 as a suitable target for lymphoma RIT
(45).
Please see the IB for further information about lilotomab.
For a description of the scientific rationale for the use of lilotomab see section 2.6.3.
2.5
Potential Benefits and Risks
Intravenous administration of Betalutin is an experimental treatment for patients with
relapsed/refractory DLBCL. No clinical studies have yet been completed. Limited clinical data
are available. The following benefit–risk discussion is based on anticipated effects.
2.5.1
Disease and Patient Population and Alternative Treatments to Betalutin
The outcome of patients with relapsed/refractory DLBCL not eligible for autologous stem cell
transplantation is very poor, with essentially no chance at prolonged control of disease (40).
Attempts at conventional salvage regimens in this population of generally older patients do not
result in disease control and have substantial morbidity. Therefore, goals of therapy in this
setting are purely palliative, and toxicities of treatment need to be considered given their limited
benefit. For this reason, in this population of patients, single-agent therapies, often in
combination with rituximab, are recommended. Given these limited options, this group of
patients should be referred for clinical trials. The only way to definitively improve outcome and
change the natural history for this large majority of patients with relapsed/refractory DLBCL is
with the incorporation of novel agents and approaches. This patient population is in need of new
treatment options.
Patients to be included in this study are adults, presenting with relapsed/refractory DLBCL who
have received at least 1 prior line of therapy and who are not eligible for, unwilling or declined
autologous stem cell transplantation.


Investigational Product:
Lutetium (177Lu)-lilotomab satetraxetan (Betalutin)
Confidential
Study Number: LYMRIT-37-05
26 April 2019
Page 28 of 99
2.5.2
Non-clinical Risk Assessment of Betalutin
There are no directly relevant animal models available to evaluate fully the non-clinical safety
of Betalutin, as there are no animals with cross-reactivity to the lilotomab antibody. Safety has
been evaluated by use of the most relevant studies to determine tolerability and target organ
toxicity namely, combined toxicity and therapy studies in immune-compromised mice. There
are no therapies in current use which target the lilotomab antibody so there are no additional
data from which potential risks may be identified.
Betalutin is a beta-emitting ARC designed specifically for the treatment of NHL (including
DLBCL). The radionuclide lutetium-177 was chosen since it allows effective irradiation of
single cells as well as micro-metastases and larger tumours. The murine antibody lilotomab was
chosen for its excellent properties in binding to the CD37 antigen. The radionuclide, antibody
and chelator used for radiolabelling are prepared in compliance with Good Manufacturing
Practice (GMP) regulations.
From cell cytotoxicity assays in vitro and antitumour studies in vivo, effective antitumour
activity of Betalutin has been demonstrated at dose levels that were well tolerated in the
sensitive SCID mouse model.
The pharmacological rationale of lutetium (177Lu)-lilotomab satetraxetan is considered
sufficiently evaluated to provide evidence to support a favourable risk: benefit assessment for
Betalutin. The expression of CD37 in human NHL has been demonstrated, thereby identifying
this receptor as a target for treatment of NHL. The binding properties of lilotomab to lymphoma
cells in vitro and in vivo have been evaluated and the cytotoxic activity of the investigational
medicinal product (IMP) has been evaluated in animal models of NHL. The selection of the
lutetium-177 metallic radionuclide is considered optimal, as the half-life of the isotope is 6.7
days, consistent with the rate of localisation of Betalutin to the CD37 antigen. After binding of
Betalutin to the CD37-antigen, the antibody-antigen complex may be internalised. The antibody
lilotomab has not been shown to elicit a response by human immune effectors in vitro and no
antibody-dependent effect of lilotomab has been observed by complement activation or immune
cell cytotoxicity, indicating that the mechanism of cytotoxicity of the IMP Betalutin is due to
the radiation effect mediated by delivery of lutetium-177 to the site of action.
Even though there is a lack of pharmacologically relevant animal models for the evaluation of
Betalutin mechanism of action or safety studies, there is a considerable clinical experience with
anti-CD37 targeted antibodies, lutetium-177 radiolabelled agents and the DOTA chelator.
Human experience is considered more relevant to the development of Betalutin and can provide
significant insight into the anticipated clinical response. Lutetium-177-labelled rituximab,
prepared using the same DOTA chelator as for Betalutin, has recently been administered
clinically (41,42). The maximum tolerated dose was 50 mCi/m2 (approximately 48 MBq/kg
b.w.) and efficacy results in NHL patients were promising. This report confirms that the


Investigational Product:
Lutetium (177Lu)-lilotomab satetraxetan (Betalutin)
Confidential
Study Number: LYMRIT-37-05
26 April 2019
Page 29 of 99
radiolabelling procedure for Betalutin is compatible with human administration and provides
supportive evidence of the safety of both DOTA and lutetium-177.
It is anticipated that benefits of administration of Betalutin will include a targeted antitumour
response, evidenced by improvements in progression-free survival and overall survival.
Furthermore, the targeted binding of lilotomab to CD37 expressed on lymphoma cells is
anticipated to increase delivery of lutetium-177 to the desired site of action, thus minimising
general systemic toxicity typically associated with external radiation therapy.
2.5.3
Risk with Rituximab Pre-treatment
The treatment regimen in this study begins on Day -14 (+/- 2 days) with the intravenous
administration of the antibody rituximab.
It is likely that the majority of patients enrolled in the study will have received rituximab
treatment before
enrolment. Frequently experienced
AEs associated with rituximab
administration include fever, chills, nausea, abdominal pain, dyspnoea, dizziness, erythema and
rash. Infusion related symptoms are often reported in association with the initial administration
of the treatment, but the incidence decreases substantially with subsequent infusions. Additional
information regarding reported AEs associated with rituximab administration is provided in the
prescribing information for this drug. All patients enrolled in the study will receive pre-
treatment with antihistaminic agents and anti-pyretics per standard of care for antibody
infusions at the study centres.
2.5.4
Risk with Lilotomab Pre-dosing
All patients will be administered a single infusion of 60 mg/m2 of lilotomab in cohort 1 and 100
mg/m2 in cohort 2 on Day 0, within 4 hours before administration of Betalutin. The dose of
lilotomab used in subsequent cohorts will be determined following a review of the reported
DLTs in cohort 1 and 2 and will be 100 mg/m2 unless this dose is considered by the safety
review committee to be unsafe. The administration of lilotomab is designed to improve the
biodistribution of Betalutin.
The same procedure used for the rituximab infusion will be used for lilotomab. If the patient
experiences AEs including drop in blood pressure, chills, fever or dyspnoea the infusion will be
stopped. When the symptoms disappear, the infusion will start again with 50% reduced infusion
rate.
Since lilotomab is a fully murine antibody, a risk of developing an immune response is
anticipated. Therefore, all patients will be screened for anti-mouse antibodies (HAMA), and
monitored for the development of an immune response after injection of lilotomab and
Betalutin.


Investigational Product:
Lutetium (177Lu)-lilotomab satetraxetan (Betalutin)
Confidential
Study Number: LYMRIT-37-05
26 April 2019
Page 30 of 99
The pre-treatment with “cold” lilotomab antibody should improve the biodistribution of
Betalutin to the desired tumour sites, since CD37 binding sites in the spleen and bone marrow
will be occupied by lilotomab. This could lead to improved circulation half-life of Betalutin,
which could facilitate better tumour uptake of the radioimmunoconjugate, as suggested from
development studies with CD37 targeting with 131I-MB-1 (21).
2.5.5
Potential Risk Factors and Proposed Risk Minimization Activities
Haematological toxicity has been observed in the phase 1/2 LYMRIT-37-01 study, with nadir
values 5 to 7 weeks after injection of Betalutin. It is also advisable to monitor haematology
parameters for withdrawn patients at least through 6 and 9 weeks after Betalutin administration.
Potential risk factors of Betalutin treatment regimen and proposed risk minimization activities
are presented in Table 1.
The efficacy and safety of Betalutin for patients with DLBCL has not been clinically tested. In
the LYMRIT-37-01 study patients with relapsed indolent NHL, the majority with follicular
lymphoma, have been exposed to doses up to 20 MBq/kg. For a summary of the safety profile
reported during the LYMRIT-37-01 study please refer to the IB.
As seen in the LYMRIT-37-01 study, the ionizing radiation from Betalutin is expected to have
a selective effect on the tumour cells.


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Investigational Product:
Lutetium (177Lu)-lilotomab satetraxetan (Betalutin)
Confidential
Study Number: LYMRIT-37-05
26 April 2019
Page 34 of 99
(8-10 mg/patient) with the antibody dose levels used for both Zevalin (3.2 mg/patient) and
Bexxar (35 mg/patient) treatment.
2.6.2
Justification of Pre-treatment with Rituximab and Selection of Dose
2.6.2.1
Pre-treatment
The intention of the pre-treatment with rituximab is to clear circulating normal peripheral B
lymphocytes in the blood and spleen in order to optimize the biodistribution of Betalutin. It is
envisaged that, as a consequence of peripheral B lymphocyte clearance, increased levels of
radiolabelled antibodies will be available and thereby penetrate less accessible yet
therapeutically relevant compartments, such as lymph nodes and larger tumour masses, while
potentially sparing bone marrow. Importantly, as rituximab targets CD20, this treatment is not
considered likely to block the binding of Betalutin CD37 to either B lymphocytes or tumour
cells.
The dose to be used is the same as for rituximab monotherapy, 375 mg/m2. All patients will
receive one infusion of rituximab at Day -14 (+/- 2 days) prior to administration of Betalutin.
The administration of rituximab has been shown to rapidly and specifically deplete B-cells from
the peripheral blood of lymphoma patients within 24 to 72 hours and this reduction continues
for at least 2 to 3 months following administration (46). Therefore, a single administration of
rituximab should be sufficient to reduce the circulating lymphocytes of patients without
delaying the start of their treatment. A single dose of pre-treatment with rituximab is also similar
to the pre-treatment schedule used for the treatment of lymphoma with ibritumomab.
Rituximab is used as a standard treatment for patients with B-cell NHL either as monotherapy
or in combination with chemotherapy. The description of rituximab is to be found in the
prescribing information and package insert for the product. However, due to the fact that these
patients will already have relapsed/refractory disease after at least one treatment and that
therapeutic treatment regimens with rituximab contain multiple administrations (4-8) no
therapeutic effect can be expected from this pre-treatment with one infusion of rituximab.
2.6.3
Justification of Pre-dosing with lilotomab and Selection of Dose
A pre-dose of 60 mg/m2 of lilotomab (up to a maximum of 2.7m2) prior to Betalutin was selected
for Cohorts 1 and 2 as an intermediate between the 40 mg pre-dose used in the LYMRIT-37-01
study and 100 mg/m2, since preliminary data from the LYMRIT-37-01 study showed a
reduction in the incidence of grade 4 cytopenias with lilotomab pre-dosing compared to no pre-
dosing. It was also considered that increasing the dose of lilotomab above 40 mg may further
improve the AE profile of Betalutin allowing for a higher MTD and improved efficacy.
Following a safety review by the SRC, a pre-dose of 100 mg/m2 of lilotomab was administered
in Cohort 3 and is also planned for Cohort 4. Pre-dosing with lilotomab reduces the non-tumour


Investigational Product:
Lutetium (177Lu)-lilotomab satetraxetan (Betalutin)
Confidential
Study Number: LYMRIT-37-05
26 April 2019
Page 35 of 99
specific binding of Betalutin by blocking CD37-positive B cells which are predominantly
located in the spleen, bone marrow and liver, thereby reducing the severity of myelosuppression.
Based on the available pre-clinical and in vitro data of lilotomab, it was not previously
considered that a higher dose of lilotomab would pose a risk to patient safety. This has now
been confirmed in the LYMRIT-37-01 study. No relevant animal species have been identified
that share a cross-reactive target antigen for lilotomab in immunohistology studies of lymphoma
tissues and blood cells from different animals (mouse, rat, guinea pig, rabbit, minipig, dog,
cynomolgus monkey, rhesus monkey and marmoset). Lilotomab does not elicit a response by
human immune effectors in vitro. No significant antibody-dependent effect of lilotomab was
observed by complement activation or immune cell cytotoxicity. The human tissue cross-
reactivity studies showed that the morphology and distribution of cells stained with lilotomab
were consistent with that of B-cells.
Lilotomab pre-doses of 40 mg, 60 mg/m2 and 100 mg/m2 have now been administered to 42, 3
and 22 patients respectively in the LYMRIT-37-01 study. A summary of the preliminary results
from the first part of the study, including the DLTs observed is described in Section 2.6.4.
Using the same radioisotope as Betalutin, Forrer et al 2010 conducted a phase 1/2 dose
escalation trial of 177-Lutetium labelled rituximab in follicular and mantle cell lymphoma
patients (40). Using a Day 0 pre-dosing of unlabeled rituximab of 250 mg/m2 (~475 mg total
dose) patients were able to receive up to 1850 MBq/m2 of radioactive isotope equivalent to
approximately 45 MBq/kg.
Given the same isotope and patient populations are used in the two studies, the dose of 15
MBq/kg of Betalutin (with 40 mg lilotomab) selected for the phase 2 stage of the LYMRIT-37-
01 study may be compared to the MTD of 45 MBq/kg with a pre-dose of ~475 mg rituximab.
A linear extrapolation in a plot of MTD versus the size of the pre-dose in milligrams using both
177Lu-rituximab and Betalutin indicates that increasing the dose of unlabeled antibody to
100 mg/m2 may allow an MTD of approximately 25 MBq/kg of Betalutin. This extrapolation is
complicated by the different antibodies and different targets used in the two studies. However,
CD20 and CD37 are expressed on the same cell types in both the tumour tissue and normal
tissue and the apparent expression level of the two targets appears to be similar. In addition, the
toxicity defining the MTD for both 177Lu-rituximab and 177Lu-lilotomab is likely to be defined
by the radioisotope (which is the same in both studies). With a minimal contribution to the
toxicity profile defining the MTD in either study originating from the activity of the monoclonal
antibody used (compared to the isotope). This extrapolation was considered to be a reasonable
assumption in the absence of further clinical data at the time.
Two radio-labelled antibodies approved for the treatment of recurrent NHL (ibritumomab and
tositumomab) used pre-dosing with unlabeled antibody on the day of administration to improve


Investigational Product:
Lutetium (177Lu)-lilotomab satetraxetan (Betalutin)
Confidential
Study Number: LYMRIT-37-05
26 April 2019
Page 36 of 99
the biodistribution. The dose of 100 mg/m2 of unlabeled antibody is significantly below that
used by either ibritumomab (250mg/m2) or tositumomab (450mg).
Recently published dosimetry data for some of the phase 1 LYMRIT-37-01 patients from each
arm of the study demonstrate that bone marrow absorption of Betalutin was highest in Arm 2,
where no lilotomab pre-dose was given compared to Arms 1 and 4 (40 mg and 100 mg/m2
lilotomab pre-dose respectively) (Stokke C et al, 2018). In addition, the tumour absorption of
Betalutin appeared to be highest in Arm 4. Radiation dosimetry thus confirms the hypothesis
that pre-dosing with lilotomab protects the bone marrow without decreasing the effect on the
tumour cells. 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).
In summary, there is an improved side-effect profile of Betalutin with pre-dosing with 40 mg
lilotomab, an altered PK characteristics and dosimetry that suggests that it is beneficial with
predosing. Therefore, an increase in lilotomab dose is justified to examine whether this would
further improve the side effect profile and tumour response. The dose of 100 mg/m2 has been
chosen after careful consideration of the antibody concentration used with similar products and
the clinical, PK and dosimetric data from Betalutin.
2.6.4 Clinical experience with Betalutin
2.6.4.1
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. 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/recommended dose for phase 2 expansion (RDE) of Betalutin, and to
collect additional PK data with a lilotomab pre-dose of 60 mg/m2 (n=3; Arm 5). The Phase 1
part of the study utilised a 3+3 dose-escalation study design with the primary objective of
defining the MTD of Betalutin. Secondary objectives were to identify a recommended dose of
Betalutin for the Phase II part of the study (RDE), and investigate the safety, biodistribution,
PK and efficacy of Betalutin.
A total of 74 patients were enrolled in the first part of the study (46). NHL subtypes were FL
(n=57), mantle cell lymphoma (MCL) (n=7), marginal zone lymphoma (MZL) (n=9) and small
lymphocytic lymphoma (n=1). The median age of the patients was 69; the median number of
prior therapies was 3 (range 1-8); 48 patients (65%) received ≥2 prior therapies.
Three patients were enrolled in Arm 2 (no lilotomab pre-dosing); the dose-limiting toxicity
(DLT) rate exceeded 20% with a Betalutin dose of 15 MBq/kg, and this arm was closed. Three


Investigational Product:
Lutetium (177Lu)-lilotomab satetraxetan (Betalutin)
Confidential
Study Number: LYMRIT-37-05
26 April 2019
Page 37 of 99
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 100 mg/m2 of lilotomab.
The ORR for all patients enrolled was 61% (CR 28%), and 65% (CR 28%) for the FL subset.
The overall incidence of grade 3/4 neutropenia and thrombocytopenia was 54% and 45%
respectively (grade 4 neutropenia and thrombocytopenia were reported in 14 patients (19%) and
15 patients (20%) respectively). Of these, there were 5 patients with grade 4 neutropenia lasting
>7 days (1 from the Arm 1 RDE cohort, see below), and 4 with grade 4 thrombocytopenia >7
days, none at either RDE.
For Arm 1 (lilotomab pre-dose of 40 mg), the RDE of Betalutin was 15 MBq/kg. One patient
developed grade 4 neutropenia and thrombocytopenia for 9 and 12 days respectively. Thirty
additional patients were enrolled in a phase 2 expansion cohort (total: 36 patients at RDE). The
ORR for 25 FL patients at the RDE was 64% (CR 32%).
For Arm 4 (lilotomab pre-dose of 100 mg/m2), the RDE of Betalutin was 20 MBq/kg. One
patient had a DLT of haematuria associated with a platelet count of 40 x 109/L and received a
platelet transfusion. Twelve additional patients were enrolled in a phase 2 expansion cohort
(total: 19 patients at RDE). The ORR for 16 FL patients at the RDE was 69% (CR 25%).
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; 7% were grade 3/4. The dosing regimen was generally well tolerated, with 2 infusion
reactions reported that were both 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.


Investigational Product:
Lutetium (177Lu)-lilotomab satetraxetan (Betalutin)
Confidential
Study Number: LYMRIT-37-05
26 April 2019
Page 38 of 99
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 2 RDE’s from Arms 1 and 4 (lilotomab 40 mg + Betalutin 15 MBq/kg; lilotomab 100 mg/m2
+ Betalutin 20 MBq/kg) are now being compared in a randomized phase 2b arm of LYMRIT-
37-01 in a population of relapsed, anti-CD20 refractory FL patients who have received ≥2 prior
therapies.
In the phase I part of Study LYMRIT 37-01, the development of an immune response after
treatment was monitored using either a commercial HAMA test or an immune-fluorometric
bridging assay detecting the full spectrum of the potential ADA response towards lilotomab
and Betalutin. The presence of ADA was reported for 5 out 62 patients enrolled. The observed
ADA response was transitory, with an onset detected 1 month after treatment. Available data
show that the ADA response onset was resolve at the 3 months (n=3) or 6 months (n=1) visit,
with anew ADA onset observed for one patient. There were no reports of development of a
HAMA response in Phase 1. Onset of HAMA was reported at the 12 months follow up visit
for 2 patients enrolled in the Phase 2a of the study.
The preliminary 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.
For more details, please refer to the Investigator’s Brochure.


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Investigational Product:
Lutetium (177Lu)-lilotomab satetraxetan (Betalutin)
Confidential
Study Number: LYMRIT-37-05
26 April 2019
Page 40 of 99
3.3.3
Efficacy endpoints
Overall response rate (CR + PR), Tumour response duration. Progression-free survival and
Overall survival
3.3.4
Exploratory endpoint:
Quality of life (QoL) assessed using Functional Assessment of Cancer Therapy–Lymphoma
(FACT-Lym) questionnaire.
4
STUDY DESIGN
4.1
Overview of Study Design
This is a Phase 1, single arm, multi-centre, dose escalation, study to determine the maximum
tolerated dose of Betalutin in patients with relapsed/refractory DLBCL who have received at
least one prior line of therapy including immune-chemotherapy and who are not eligible for,
unwilling or declined autologous stem cell transplantation.
All patients will receive pre-treatment with rituximab 375 mg/m2 14 days (+/- 2 days) before
Betalutin injection. Patients in cohort 1 will receive 60 mg/m2 of lilotomab within 4 hours of
Betalutin, patients in cohort 2 will receive 100 mg/m2 of lilotomab within 4 hours of Betalutin.
A dose of 100 mg/m2 will be used in subsequent cohorts with escalating doses of Betalutin
unless following a review of the reported DLTs in cohorts 1 and 2 the dose of 100 mg/m2 is
considered unsafe by the safety review committee.
All patients will receive a single dose of Betalutin. The planned Betalutin starting dose and
planned dose escalation are shown in Table 2.


Investigational Product:
Lutetium (177Lu)-lilotomab satetraxetan (Betalutin)
Confidential
Study Number: LYMRIT-37-05
26 April 2019
Page 41 of 99
Table 2
Betalutin Dose Escalation Schedule
Cohort
Treatment
Rituximab Day -14 (+/- 2 days)
Lilotomab Day 0
Betalutin Day 0
Number of patients
Cohort 1
10 MBq/kg Betalutin
+ 60 mg/m2 lilotomab
3 patients with no DLT or expand to 6 patients
if 1 DLT reported.
Cohort 2
10 MBq/kg +
100 mg/m2 lilotomab
3 patients with no DLT or expand to 6 patients
if 1 DLT reported.
Cohort 3
15 MBq/kg +
100 or 60 mg/m2 lilotomab
3 patients with no DLT or expand to 6 patients
if 1 DLT reported.
Cohort 4
20 MBq/kg +
100 or 60 mg/m2 lilotomab
3 patients with no DLT or expand to 6 patients
if 1 DLT reported.
The starting dose has been selected based on safety and tolerability data from a Phase 1, dose
escalation study of Betalutin in patients with NHL, which has predominantly enrolled patients
with follicular indolent lymphoma (Protocol LYMRIT-37-01).
Patients will be treated sequentially and no more than 1 patient will be dosed at the same time.
The patients will attend study centre visits during the screening, treatment and follow-up
period. The treatment period is defined from start of rituximab infusion on Day -14 (+/- 2
days) through administration of Betalutin dosage on Day 0. The 12-week short term follow-up
period is defined from completion of Betalutin injection on Day 0 to 12 weeks after Betalutin
dosing. Patients will be followed in a subsequent long term follow-up period for resolution of
any ongoing study drug toxicity for up to 2 years after administration of Betalutin, or until
disease progression with institution of subsequent anticancer therapy, whichever occurs first.
Once the MTD is identified, the MTD dose level will be further expanded by approximately
10 additional patients who relapsed ≥6 months after last therapy after having achieved a
CR/PR, and approximately 10 patients who were refractory to their last line of therapy (PD,
SD or CR/PR lasting <6 months) to further assess safety, anti-tumour activity and PK.
Additional patients may be enrolled to allow for non-evaluable patients to be replaced (e.g.
patients who are enrolled but are withdrawn prior to study drug or Betalutin administration).


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Page 42 of 99
4.2
Dose Limiting Toxicity Definition and Dose Escalation
4.2.1
Dose Limiting Toxicity
DLT is defined as:
a. Hematologic toxicity
i.
Grade 4 neutropenia observed for greater than 7 days duration
ii.
Grade 4 thrombocytopenia observed for greater than 7 days duration
iii.
Grade 3-4 neutropenia associated with fever (≥ 38.5 °C) of any duration
iv.
Grade 3-4 thrombocytopenia with bleeding
v.
Thrombocytopenia with any requirement for more than one platelet transfusion
before recovering to grade 1 of less
vi.
Grade 4 anemia, unexplained by underlying disease
b. Non-Hematologic toxicity
i.
Grade 3 nausea/vomiting/diarrhea lasting longer than 72 hours despite maximal
care or grade 4
ii.
Any other grade 3 or 4 non-hematologic toxicities
iii.
Any grade 3 or 4 electrolyte abnormalities that do not resolve to grade 1
or baseline within 24 hours
4.2.2
Dose-escalation:
The dose escalation rules are shown in Table 3.


Investigational Product:
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Study Number: LYMRIT-37-05
26 April 2019
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Table 3
Dose Escalation Rules
Dose
level
Betalutin and
Lilotomab Dose
(administered activity)
Pre-set dose escalation rules
1
10 MBq/kg + 60 mg/m2
of lilotomab
Escalate dose when the third subject (or sixth subject
in the case of 1 DLT) completes 8 weeks of follow-up
after treatment, or when blood counts have recovered
with ANC ≥ 1.5 x 109/L and platelets ≥ 100 x 109/L
and no DLT occurred. The follow-up may get
extended up to 12 weeks if a patient’s platelets or
neutrophils do not recover to grade 1 by 8 weeks.
2
10 MBq/kg +
100 mg/m2 of lilotomab
Escalate dose when the third subject (or sixth subject
in the case of 1 DLT) completes 8 weeks of follow-up
after treatment, or when blood counts have recovered
with ANC ≥ 1.5 x 109/L and platelets ≥ 100 x 109/L
and no DLT occurred. The follow-up may get
extended up to 12 weeks if a patient’s platelets or
neutrophils do not recover to grade 1 by 8 weeks. If
more than 2 DLTs occur a dose reduction to
7.5MBq/kg will be considered only if the risk-benefit
profile is considered likely to be favourable to the
patients and if the safety review committee agree.
3
15 MBq/kg +
100 or 60 mg/m2 of
lilotomab
Escalate dose when the third subject (or sixth subject
in the case of 1 DLT) completes 8 weeks of follow-up
after treatment, or when blood counts have recovered
with ANC ≥ 1.5 x 109/L and platelets ≥ 100 x 109/L
and no DLT occurred. The follow-up may get
extended up to 12 weeks if a patient’s platelets or
neutrophils do not recover to grade 1 by 8 weeks.
4
20 MBq/kg +
100 or 60 mg/m2 of
lilotomab
Maximum pre-determined dose to be tested.


I n vesti g ati o n al Pr o d uct:
L uteti u m ( 1 7 7L u) -lil ot o m a b s atetr a xet a n ( Bet al uti n)
C o nfi de nti al
St u d y N u m ber: L Y M RI T -3 7 -0 5
2 6 A pril 2 0 1 9
P a ge 4 4 of 9 9
A n assess me nt of all a vaila ble safet y data at t he ti me will be d o n e pri or t o all o wi n g t he st u d y t o
pr ocee d t o t he ne xt d ose le vel. A re p ort i ncl u di n g a n o verall rec o m me n dati o n o n t he ne xt ste p
will be pre pare d. T h e fi nal rec o m me n dati o n t o m o v e t o t h e n e xt
d ose le vel , as well as
i de ntificati o n of t he M T D f or e x pa nsi o n will be d o ne b y t he S afet y R e vie w C o m mittee i n t he
st u d y.
If a d diti o nal ra diati o n d oses need t o be e x pl ore d, t he Safet y Re vie w C o m mittee will a d vise o n
t he re q uire me nt f or de -escalati o n or escalati o n of d ose i n s maller ste ps base d o n t h or o u g h
e val uati o n of t he a v aila bl e safet y d ata.
T he Safet y R e vie w C o m mittee c o nsist s of at l east t h ree e x perts i ncl u di n g t h e c o-or di nati n g a n d
pri nci pal i n vesti gat ors fr o m o n g oi n g Betal uti n st u dies.
4. 3
Sc he d ule of Assess me nts
T he st u d y fl o w c hart is s h o w n i n Fi g ure 1 a n d t he sc he d ule of s t u d y ass ess me nts are s h o w n i n
Ta ble 4 a n d T a ble 5 .
Fi g ure 1
St u d y fl o w c h art
N ote t h at patie nts i n cl u d e d i n t h e p h ar mac o ki n etic s, bi o distri b uti o n a n d d osi metr y s u b -st u d y will ha ve a d diti o nal visits d uri n g t he first
3 wee ks after Betal uti n a d mi nistr ati o n.
A visit wi n d o w of ± 2 d a ys is per mitte d f or Da y 0 a n d Da y -1 4 . T he b o ne marr o w bi o ps y ma y ha ve bee n ta ke n u p t o 8 wee ks pri or t o
rit u xi ma b a d mi nistr ati o n. T h e d ose of r a di oacti vit y will be base d o n t he act ual a d mi nistr ati o n date.
Patie nts c o nsi dere d s uita ble t o be scree ne d f or t he st u d y will u n der g o scree ni n g assess me nts.
Patie nts will atte n d t he cli nic o n t he d osi n g da y a n d e ver y w ee k u p t o 1 2 w ee ks aft er Betal uti n
i njecti o n, h o we ver p atie nts partici pati n g i n t he bi o distri b uti o n a n d d osi metr y s u b st u d y will be
re q uire d t o visit t he h os pital o n da ys 1 t o 4 as well. T he patie nts will be f oll o we d u p m o nt hl y
u ntil m o nt h 6 i.e. 6 m o nt hs fr o m Da y 0 (d a y of Betal uti n i nje cti o n). O n c o m pleti o n of t he 6
S cr e e ni n g
D a y -4 2 t o
D a y -1 4
Tr e at m e nt
D a y -1 4 t o
D a y 0
F oll o w -u p
M o nt h 3 t o 6
L o n g -t er m f oll o w-u p
M o nt h s 6 t o 2 4
P o st -tr e at m e nt
D a y 0 t o
W e e k 1 2 ( M o nt h 3)
Rit u xi m a b
( D a y -1 4)
B et al uti n
( D a y 0)
Vi sit e v er y w e e k
Vi sit e v er y
m o nt h
Vi sit e v er y 3
m o nt h s
Lil ot o m a b
( D a y 0: wit hi n 4 h
pri or t o B et al uti n)


Investigational Product:
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Confidential
Study Number: LYMRIT-37-05
26 April 2019
Page 45 of 99
months follow-up visit, patients will be followed up every 3 months to assess disease
progression, survival, details of next treatment for DLBCL (where applicable), up to 24
months from Day 0. The patient will be withdrawn if further anticancer therapy is started.
4.4
Safety
In the treatment period (from the time of the first rituximab infusion up to Betalutin
administration) and (the short term follow-up period up to 12 weeks after Betalutin
administration) vital signs, physical examination, haematology and serum biochemistry, all
AEs and concomitant medications will be collected at specified time points. During the long
term follow-up period (from 12 weeks until 2 years), SAEs and AEs related to study drug,
haematology, serum biochemistry, as well as any late toxicity such as second primary
malignancies will be recorded every month during the first 6 months following study
treatment and every 3 months thereafter, until the patient has been through his/her 2-year visit
or until initiation of other cancer related treatment whichever occurs first.
4.5
Pharmacokinetics, biodistribution and dosimetry
Patients who participate in the PK, biodistribution and dosimetry sub study will have blood
samples collected for radioactivity and antibody measurements at the following time points
with reference to the lilotomab administration on Day 0: 0 (pre-dose), 5, 30, 60 and 120
minutes, and then at these time points following Betalutin administration: 0 (pre-dose), 15
minutes, 1, 2, 4 and 24 hours post-dose, plus Days 2, 3, 4, 7 (±1), 14 (±2) and 21 (±2).
These PK assessments are optional and performed at selected sites only.
The dosimetry and biodistribution sub-study will also include whole body gamma scans and
single-photon emission computerized tomography (SPECT)/computed tomography (CT) scans
at 2-4 and 24 hours, Day 4 and 7 after Betalutin treatment. Note that samples times may vary
based on on-going analysis but will not exceed this maximum number of assessments. A Day
4 SPECT/CT scan is optional for patients not participating in the biodistribution sub-study. A
window of ±1 day is permitted for the Day 4 SPECT/CT scan.
4.6
Efficacy
Positron-emission tomography (PET)/CT and contrast enhanced CT images will be performed
at baseline, and at 3 and 6 months after Betalutin administration. Thereafter, contrast
enhanced CT scan will be done every 6 months up to Month 24. Survival data will be
recorded for all patients until the last patient has been through the 2-year follow-up period.


I n vesti g ati o n al Pr o d uct:
L uteti u m ( 1 7 7L u )-lil ot o m a b s atetr a xet a n ( Bet al uti n)
C o nfi de nti al
St u d y N u m ber: L Y M RI T -3 7 -0 5
2 6 A pril 2 0 1 9
P a ge 4 6 of 9 9
T a ble 4
Sc he d ule of S tu d y A ssess me nts – s ee Secti o n 4. 7 – St u d y P r oce d ures b y Visit
S cr ee ni n g
Tr eat me nt Peri o d
S h ort t er m f oll o w -u p
L o n g -ter m
f oll o w-u p
Rel a ps e
Wit h -
dra wal
Da y ( D), We e k ( W) or
M o nt h ( M)
D -4 2 t o
D -1 4
D -1 4
Ba s eli n e
D -1 or D0 1 1
D o si n g da y
D 0 1 1
D4
D 7
( W1)
D 1 4
( W2)
D2 1
( W3)
D2 8
( W4)
W5, 6, 7
W8
W9,
1 0,1 1
W1 2
( M3)
M4, 5, 6
M 9, 1 2
M1 5,
1 8,2 1,2 4
T ests in ad diti on t o
st an dard t ests perf or me d at
visit wh en t he rel aps e or
wit h dra wal occurs
Vi sit wi n d o w
± 2 d
Pr e -
Bet al uti n
d os e
P ost -
Bet al uti n
d os e
± 1 d
± 1 d
± 2 d
± 3 d
± 3 d
± 3 d
± 3 d
± 3 d
± 2 w
± 2 w
± 2 w
± 3 w
Hos pital visit
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Rit uxi ma b ad mi nistrati o n
X
Lil ot o mab ad mi nistrati o n
X 1
B etal uti n a d mi nistr ati on
X
I nf or me d c ons ent
X
De mo gr ap hics
X
Wei g ht
X
X
Dis e as e st agi ng, pri or
N HL tr e at me nts &
me dical hist ory
X
Co nco mit a nt medicati o n/
pr oc ed ures
X
X
X
X
X
X
X
X
X
X
X
X
X 9
X 9
X 9
P hysical exa mi nati o n
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Ly mph no de
exa mi n atio n
X
X
X
X
X
X
X
Vit al sig ns i ncl udi ng
t e mp er atur e
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
1 2 -l ead E C G
X
X
X
X
E C O G P erf or ma nc e
St at us
X
X
X
X
X
X
X
X
X
Ha e mat olo gy 2
X
X
X
X
X
X
X
X
X
X
X
X
X
X
S eru m bi oche mistry 2
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Uri n alysis
X
X
X
X
X
X
X
X
X
X
X
X
S eru m pr e gna ncy test
X
X
HI V t est
X
He p atit is B t est
X
Ly mph ocyt e s ubset
X
X
X
X
I m mu n o glo buli n l evels
X
X
X
X
I m mu n o ge nicity
X 3
C D3 7 expr essi on
X
X 1 3
B on e marr o w bio psy 1 2
X
C T sca n wit h contr ast
X
X 5
X 5
X 5
X 5
X
F D G/ P E T C T i ma ges
X
X
X 7
S P E C T/ C T sc an 1 0
X
A Es (fr o m st art of first
rit uxi ma b i nfusion)
X
X
X
X
X
X
X
X
X
X
X
X
A dv ers e re acti on only
X
X
X
S A Es
X
X
X
X
X
X
X
X
X
X
X
X
X


I n vesti g ati o n al Pr o d uct:
L uteti u m ( 1 7 7L u )-lil ot o m a b s atetr a xet a n ( Bet al uti n)
C o nfi de nti al
St u d y N u m ber: L Y M RI T -3 7 -0 5
2 6 A pril 2 0 1 9
P a ge 4 7 of 9 9
S cr ee ni n g
Tr eat me nt Peri o d
S h ort t er m f oll o w -u p
L o n g -ter m
f oll o w-u p
Rel a ps e
Wit h -
dra wal
Da y ( D), We e k ( W) or
M o nt h ( M)
D -4 2 t o
D -1 4
D -1 4
Ba s eli n e
D -1 or D0 1 1
D o si n g da y
D 0 1 1
D4
D 7
( W1)
D 1 4
( W2)
D2 1
( W3)
D2 8
( W4)
W5, 6, 7
W8
W9,
1 0,1 1
W1 2
( M3)
M4, 5, 6
M 9, 1 2
M1 5,
1 8,2 1,2 4
T ests in ad diti on t o
st an dard t ests perf or me d at
visit wh en t he rel aps e or
wit h dra wal occurs
Vi sit wi n d o w
± 2 d
Pr e -
Bet al uti n
d os e
P ost -
Bet al uti n
d os e
± 1 d
± 1 d
± 2 d
± 3 d
± 3 d
± 3 d
± 3 d
± 3 d
± 2 w
± 2 w
± 2 w
± 3 w
F A C T -L Y M, Qo L
ass ess me nt
X
X
X 8
S urvival st atus/disease
pr ogr essio n/c anc er -
r el at ed me dic atio n a nd
pr oc ed ures
X
X
X
L on g -ter m t oxicity
X
X
X
(1 ) O n Da y 0, lil ot o ma b is t o be a d mi nister e d wit hi n 4 h o urs pri or t o Betal uti n a d mi nistr ati o n.
(2 ) At u nsc h e d ule d visits, la b or at or y test r es ults will be r ec or de d i n t he e C R F.
(3 ) H A M A teste d l ocall y d uri n g scr ee ni n g w h er e p ossi ble. Bl o o d sa m ples s hi p pe d t o ce ntral la b or at or y f or i m m u n o ge nicit y testi n g a n d bi o ba n ki n g.  Perf or me d at M o nt h 3, 6
a n d 1 2
(4 ) T u m o ur tiss u e sa m ple s hi p pe d t o ce ntral la b or at or y, t he test r es ult is n ot r e q uir e d pri or t o e nr olme nt .
(5 ) O ne C T sca n at 3, 6, 1 2, 1 8 a n d 2 4 m o nt hs.
(6 ) M o nt h 1 2 o nl y
or i f t h e patie nt wit h dra ws pri or t o M o nt h 1 2 .
( 7) F D G/ P E T m o nt h 6 .
( 8) M o nt h 1 2 o nl y.
( 9) T o be c ollecte d if A d verse r eacti o n r e p orte d .
( 1 0) O pti o n al f or t h ose sites partici pati n g i n t h e q ualitati ve assess me nts .
( 1 1) A visit wi n d o w of ± 2 d a ys is per mit te d f or Da y 0 visit. T he d ose of r a di oacti vit y will be base d o n t he act ual a d mi nistr ati o n date.
( 1 2) A b o n e marr o w bi o ps y ta ke n u p t o 8 wee ks pri or t o t he a d mi nistr ati o n of rit u xi ma b is per mitte d.
( 1 3) O pti o n al


I n vesti g ati o n al Pr o d uct:
L uteti u m ( 1 7 7L u )-lil ot o m a b s atetr a xet a n ( Bet al uti n)
C o nfi de nti al
St u d y N u m ber: L Y M RI T -3 7 -0 5
2 6 A pril 2 0 1 9
P a ge 4 8 of 9 9
T a ble 5
S c he d ule o f st u d y assess me nts f or t he ph ar m a c o ki netic, b i o distri b uti o n a n d dosi met r y s u b-st u d y
Da y
Da y -14
Da y 0 4 (r el ativ e t o lil ot o ma b d osi n g)
Da y 0 4 (rel ativ e t o Betal uti n d osi n g)
Da y 1
Da y 2
Da y 3
Da y 4
Da y 7
Da y 14
Da y 21
2 we ek s
pri or t o
d osi n g
0 mi n
( pre -
d os e)
5 mi n
3 0
mi n
1 h o ur
2 h o urs
0 mi n
( pre-
d os e)
1 5
mi n
1 h o ur
2 h o urs
2 -4
h o ur s
2 4
h o ur s
4 8
h o ur s
7 2
h o ur s
9 6
h o ur s
1 68
h o ur s
We e k 2
We e k
3
Vi sit wi n d o w
± 2 d
± 1 d
± 2 d
± 2 d
Lil ot o mab P K an alysis i n
bl oo d 6
X
X
X
X
X
X 1
X
X
X
X 3
X
X
X
X
X
X
X
T otal Ra di oactivity in bl ood 6
X 1
X
X
X
X 3
X
X
X
X
X
X
Uri n e c ollectio n 2
Fro m 0 t o 2 -4 hrs W B sc an; fro m 2 -4 hrs W B sca n t o 2 4 h ours
W B sca n. First voi d coll ect ed sep arat ely.
S eri al whol e b ody ( W B) an d
S P E C T/ C T sc an
X
X
X 5
X
I n ge n er al, uri n e, bl o o d sa m ples a n d i ma gi n g f or p har mac o ki netic a n d bi o distri b uti o n will be d o ne u ntil c o u nts ar e n o l o n ger si g nifica nt fr o m bac k gr o u n d c o u nts, a n d as l o n g as t he i ma ges are
mea ni n gf ul. T h e ti me p oi nts ma y be a dj uste d after e x perie nce fr o m t he first patie nts.
( 1) O ne baseli n e bl o o d sa m ple bef or e Betal uti n i njecti o n.
(2 ) Uri ne c ollecti o n w h e n feasi ble
(3 ) Sa m ple t o be ta ke n at 4 h o urs after Betal uti n d osi n g.
(4 ) A visit wi n d o w of ± 2 d a ys is per mitte d f or Da y 0. T he d ose of r a di oacti vit y will be base d o n t he act ual a d mi nistr ati o n date.
(5 ) A wi n d o w of ± 1 d a y is per mitte d f or t h e Da y 4 w h ole b o d y ( W B) a n d S P E C T/ C T sca n.
(6 ) lil ot o ma b P K sa m ples s h o ul d be ta ke n acc or di n g t o ta ble a b o ve u p t o t he ti me of Betal uti n a d mi nistr ati o n, at w hic h p oi nt t he sa m pli n g c a n be perf or me d c o nc urr e ntl y f or b ot h lil ot o ma b P K a n d
r a di oacti vit y i n bl o o d).


I n vesti g ati o n al Pr o d uct:
L uteti u m ( 1 7 7L u) -lil ot o m a b s atetr a xet a n ( Bet al uti n)
C o nfi de nti al
St u d y N u m ber: L Y M RI T -3 7 -0 5
2 6 A p ril 2 0 1 9
P a ge 4 9 of 9 9
4. 7
St u d y Pr oce d ures b y Visit
St u d y ass ess me nts b y visit are descri be d bel o w. Please als o refer t o t he Sc he d ul e of St u d y
Assess me nts i n T a ble 4 . T he p har mac o ki netics s u b -st u d y is des cri be d i n Secti o n 9. 1 a n d t h e
bi o distri b uti o n s u b -st u d y is descri be d i n S ecti o n 9. 2 .
4. 7. 1
Pre -scree ni n g/scree ni n g (– 4 2 t o -1 4 d a ys)
I nf or me d c o ns e nt i ncl u di n g o pti o nal c o nse nt f or fres h bi o ps y sa m ples f or bi o mar ker a n d
p har mac o d y n a mi c (P D ) assess me nts.
Scree ni n g e val uati o ns will be perf or me d acc or di n g t o t he eli gi bilit y criteri a. I nf or mati o n will
be c ollect e d re gar di n g t h e n u m b er of patie nts w h o e ntere d t he scree ni n g p h ase b ut di d n ot f ulfil
t he i ncl usi o n a n d e x cl usi o n criteria t o get her wit h t he reas o ns f or n o n-f ulfil me nt.
T he scree ni n g peri o d is u p t o 2 8 da ys, defi n e d fr o m t he start of scree ni n g t o a d mi nistrati o n of
rit u xi ma b. If scree ni n g assess me nts ha ve bee n c o m plete d i n less t ha n 2 8 da ys treat me nt wit h
rit u xi ma b ca n be gi n wit h o ut dela y.
If all scree ni n g pr oce d ures are n ot c o n d u cte d a n d eli gi bilit y is n ot c o nfir me d wit hi n 2 8 da ys
pri or t o first d ose of rit u xi ma b, t he me dical m o nit or s h o ul d be c o ntacte d t o deter mi ne if t h e
scree ni n g pr o ce d ures s h o ul d be re peate d pri or t o d osi n g.

I nf or me d c o ns ent .

De m o gra p hic i nf or mati o n.

C o nc o mita nt me dicati o n s a n d pr oce d ure s.

Pre vi o us treat me nts of N H Ls .

Me dical hist or y (t o i ncl u de D L B C L hist or y) .

C D 3 7 e x pressi o n (t he res ult of t he assa y is n ot re q uire d f or e nr ol me nt i nt o t he st u d y)

I n cl usi o n/e x cl usi o n c hec ks.

C li nical assess me nts i ncl u di n g:
o
F ull p h ysical e x a mi nati o n i ncl u di n g l y m p h n o d e e x a mi nati o n.
o
Wei g ht .
o
Vital si g ns .
o
Te m p erat ure .
o
1 2 -lea d electr ocar di o gra p h y (E C G ).
o
Easter n C o o perati ve O nc ol o g y Gr o u p ( E C O G) p erf or ma nce stat us.


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Investigational Product:
Lutetium (177Lu)-lilotomab satetraxetan (Betalutin)
Confidential
Study Number: LYMRIT-37-05
26 April 2019
Page 55 of 99
5. Not suitable for, or declined/unwilling to undergo intensive therapy, including high dose
chemotherapy and autologous stem cell transplantation (ASCT). The decision of whether a
patient is unsuitable or not for ASCT should be made by the investigator following a
thorough review of the patient. For guidance, possible reasons patients may be unsuitable
for ASCT may include but are not limited to; excessively elderly or frail patients, those
with an increased bilirubin or creatinine level (to be eligible for this study patients must
still meet inclusion criteria 11), low cardiac ejection fraction, forced expiratory volume in
1 second and/or lower than predicted carbon monoxide diffusion test.
6. Presence of radiographically measurable lymphadenopathy or extranodal lymphoid
malignancy (at least one objectively bi-dimensionally measurable (nodal) lesion (>1.5 cm
in its largest dimension by CT scan).
7. Negative human anti-mouse antibody (HAMA) test.
8. Life expectancy of at least 3 months.
9. Bone marrow tumour infiltration <25% tumour cells (in biopsy taken from a site not
previously irradiated).
10. Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2.
11. Normal organ and marrow (normocellular) function defined as:
a. Absolute neutrophil count ≥1.5 x 109/L;
b. Platelet count ≥150 x 109/L;
c. Haemoglobin ≥9 g/dL;
d. Total bilirubin ≤2.5 x upper limit of normal (ULN) (except patients with
documented Gilbert’s syndrome);
e. Liver enzymes: Aspartate transaminase (AST); Alanine transaminase (ALT) or
Alkaline phosphatase (ALP) ≤2.5 x ULN (or ≤5.0 x ULN if liver involvement by
primary disease);
f.
Adequate renal function as demonstrated by a serum creatinine ≤1.5 mg/dL or a
creatinine clearance >60 mL/min;
g. Normal coagulation parameters (elevated international normalized ratio (INR),
prothrombin time or activated partial thromboplastin time (APTT) ≤1.3 ULN range
acceptable).
12. Women of childbearing potential, defined as neither post-menopausal nor permanently
sterile must agree to the contraceptive requirements below. Permanent sterilisation
methods may include hysterectomy, bilateral salpingectomy and bilateral oophorectomy
and postmenopausal is defined as no menses for 12 months without an alternative medical
cause.
Women of childbearing potential must:
a.
understand that the study medication may have a teratogenic risk


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Investigational Product:
Lutetium (177Lu)-lilotomab satetraxetan (Betalutin)
Confidential
Study Number: LYMRIT-37-05
26 April 2019
Page 57 of 99
4. Prior anti-lymphoma therapy (chemotherapy, immunotherapy or other investigational
agent), excluding corticosteroids within 4 weeks prior to start of study treatment (i.e.
rituximab) (G-CSF or GM-CSF are permitted up to 2 weeks prior to start of study
treatment.).
5. Patients who are receiving any other investigational agents.
6. Patients with known or suspected central nervous system involvement of lymphoma.
7. 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. localized 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 complete remission;
8. Pregnant or breastfeeding women.
9. Exposure to another CD37 targeting drug.
10. Allergy to X ray contrast agents
11. A known hypersensitivity to rituximab, lilotomab, Betalutin or murine proteins or any
excipient used in rituximab, lilotomab or Betalutin.
12. Has received a live attenuated vaccine within 30 days prior to enrolling in the study.
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.
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)


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Investigational Product:
Lutetium (177Lu)-lilotomab satetraxetan (Betalutin)
Confidential
Study Number: LYMRIT-37-05
26 April 2019
Page 60 of 99
6
TREATMENT PLAN
6.1
Investigational Medicinal Products
The IMPs, rituximab, lilotomab and Betalutin, can be administered on an outpatient basis. The
patient should be under surveillance at the hospital for at least 2 hours after administration
(unless local regulations require a longer surveillance period). Adequate resuscitation
equipment needs to be available for patients in the event of an emergency.
A drug handling plan including supply, packaging, handling, storage, accountability, labelling,
preparation and administration, will be given to the personnel prior to patient inclusion. See also
Investigator’s Brochure.
6.1.1
Betalutin
The generic name for Betalutin drug product is lutetium (177Lu)-lilotomab satetraxetan. The
antibody lilotomab is labelled with lutetium-177 via the chelator p-SCN-benzyl-DOTA.
Lutetium-177 is a beta particle emitter with a physical half-life of 6.7 days. The ARC Betalutin
is a ready-to-use, sterile, non-pyrogenic, clear and pale yellow solution of lutetium (177Lu)-
lilotomab satetraxetan for intravenous administration.
The total radioactivity of the Betalutin vial at the reference date will depend on the patient body
weight. When administered on a day other than the reference day, the volume should be
corrected according to the physical decay table included in the IMP manual.
6.1.1.1
Supply and packaging
Betalutin is shipped as a Type A radioactive package according to international transportation
guidelines for radioactive materials.
Each vial will be labelled with a unique vial number, identifying the specific vial as well as the
batch number. The content of the labels will be according to national requirements.
Each vial should be used for one patient only.
6.1.1.2
Handling and storage
A dedicated person, with the responsibility delegated from the Principal Investigator, will be
responsible for handling and storage of the study drug; i.e. that the vials containing the study
drug is correctly received and recorded, handled and stored safely and properly, and used in
accordance with this protocol. The study drug is a radiopharmaceutical and should be handled
by individuals who are qualified by training and have experience in the safe handling of
radionuclides. A deputy person should also be nominated.


Investigational Product:
Lutetium (177Lu)-lilotomab satetraxetan (Betalutin)
Confidential
Study Number: LYMRIT-37-05
26 April 2019
Page 61 of 99
6.1.1.3
Preparation and administration
The total activity to be injected will be calculated volumetrically using the patient’s body weight
(kg) on the day of injection, the dose, and decay correction factor (DC) to correct for physical
decay of lutetium-177. A table with correction factors is provided in the drug handling plan.
The measured dose of Betalutin should be within +/- 10% of the intended prescribed dose. 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).
Filling of the syringe should take place at a dedicated area for working with radioactive solutions
under aseptic conditions. Personnel 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 study drug 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 eCRF page.
The syringe should be shielded to protect the operator from exposure to radiation during
preparation and administration of the patient doses. Each patient will receive one dose in
accordance with the treatment schedule. Betalutin will be given as a slow bolus injection. After
administration, the equipment used in connection with the preparation and administration of
drug, is to be treated as radioactive waste and should be disposed in accordance with hospital
procedure for handling of radioactive material.
6.1.1.4
Drug accountability
The nuclear medicine specialist at the centre is responsible for drug accountability. The study
drug should be kept in a secure place and must be administered only to patients in the study. An
appointed individual is responsible for maintaining accurate records of the study drug. A list of
study drug 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 for the handling of radioactive material,
provided they have been stored for a minimum of 3 months (>10 half-lives for lutetium-177)
before disposal.
6.1.1.5
Patient protection
The patient will receive verbal and written instructions in accordance with the institutional
radiation safety policies and procedures regarding precautions, as necessary, after receiving the
radioactive drug. The study drug can be administered on an outpatient basis


Investigational Product:
Lutetium (177Lu)-lilotomab satetraxetan (Betalutin)
Confidential
Study Number: LYMRIT-37-05
26 April 2019
Page 62 of 99
6.1.2
Rituximab
Rituximab will be ordered through the standard procedure at the study centre. Patients will be
pre-treated with rituximab delivered by infusion at a dose of 375 mg/m2 14 days before Betalutin
administration (Day -14 +/- 2 days).
The product should be administered according to the approved product information (prescribing
information) for rituximab. Premedication consisting of an anti-pyretic and an antihistamine,
e.g. paracetamol and dexchlorpheniramine or cetrizine, should always be administered before
rituximab infusion. The types of pre-medication used prior to rituximab infusion will follow
institutional guidelines, including any use of corticosteroids. The prepared rituximab solution
should be administered as an intravenous infusion through a dedicated line. It should not be
administered as an intravenous push or bolus. The institutional guideline for infusion of
rituximab 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.
6.1.3
Lilotomab
Lilotomab will be supplied in vials containing lilotomab 5 mg/ml concentrate for solution for
infusion and will be prepared aseptically at the institution and made ready for infusion using the
same procedure as for rituximab. Pre-medication consisting of an antipyretic and antihistamine
medication should be administered before infusion of lilotomab.
Lilotomab will be infused within 4 hours of the Betalutin administration. Lilotomab at a dose
of 60 mg/m2 or 100 mg/m2 (up to a maximum of 2.7m2) will be infused over 60 minutes. Body
surface area should be calculated using the duBois calculation. The infusion rate may be
adjusted depending on how well it is tolerated. If the patient experiences AEs as drop in blood
pressure, chills, fever and dyspnoea the infusion will be stopped. When the symptoms disappear,
the infusion will start again with 50% reduced infusion rate.
The patient will be under surveillance during infusion. Blood pressure and pulse rate are
measured before infusion, each 15 minutes during infusion and about 1 hour after the end of
infusion. Any AEs will be recorded in the eCRFs.
6.1.4
Investigational Product Complaints
Pharmaceutical technical complaints associated with the investigational product must be
reported to the sponsor immediately. The same reporting timelines as for SAEs apply.
6.2
Treatment Allocation
A patient number will be assigned when a patient signs the informed consent form and is
evaluated for inclusion into the study.


Investigational Product:
Lutetium (177Lu)-lilotomab satetraxetan (Betalutin)
Confidential
Study Number: LYMRIT-37-05
26 April 2019
Page 63 of 99
The Investigator will contact the CRA. after the completion of all the screening evaluations to
confirm the patient eligibility
6.3
Permitted and Restricted Concomitant Medications/Treatments
All prescription, non-prescription, or over-the-counter medications including herbal remedies,
dietary and nutritional supplements and complementary and alternative therapies given to or
taken by the patient at study entry (including Screening) and during the study must be clearly
documented on the eCRF.
Any medication considered necessary for the patient’s safety and well-being may be given at
the discretion of the Investigator(s).
For treatment of DLT or any other clinically significant events, any available standard therapy
may be used as required. In the case of anaemia, transfusions with packed red blood cells
(pRBC) can be administered. See Section 6.5 (Supportive Care Guidelines) for further details.
Start of possible new cancer treatment after Betalutin administration will be recorded in the
eCRF.
Warfarin should be changed to low-molecular heparin. The dose of low-molecular heparin
should be temporarily reduced if platelets are below 50 x 109/L, and be temporarily stopped if
platelets are below 25 x 109/L.
Prophylaxis with allopurinol for tumour lysis will be permitted at the discretion of the
investigator.
6.4
Pre-Medication Guidelines
Pre-medication guidelines may be introduced or recommended where clinically significant
injection site reactions or other study-related events e.g. histamine release, are seen on study.
These guidelines will be reviewed by the Safety Review Committee.
6.5
Supportive Care Guidelines
6.5.1
Severe thrombocytopenia (platelets <20x109/L)
Patients will be transfused with platelets to maintain a platelet count >20x109/L or higher if
clinically indicated to control bleeding.
6.5.2
Injection site irritation
Local irritation at the injection site may be treated according to local treatment guidelines.


Investigational Product:
Lutetium (177Lu)-lilotomab satetraxetan (Betalutin)
Confidential
Study Number: LYMRIT-37-05
26 April 2019
Page 64 of 99
6.5.3
Persistent neutropenia (neutrophils/granulocytes <0.5x109/L) without fever
Patients with persistent neutropenia will be started on granulocyte-colony stimulating factor
(G-CSF) 5 µg/kg/daily given subcutaneously until the neutrophil count has reached the local
hospital’s reference range.
6.5.4
Neutropenia with fever (neutrophils/granulocytes <1x109/L; fever >38°C)
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.
6.5.5
Severe anaemia (haemoglobin <8.0 g/dL)
Patients will be transfused with packed red cells to maintain haemoglobin level >8.0g/dL, at the
discretion of the investigator.
6.5.6
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 rituximab, lilotomab or Betalutin.
6.5.7
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.
6.5.8
Precautions during administration of lilotomab:
Premedication should be given. The premedication should be the same as standard site specific
premedication for rituximab administration.
If an adverse event occurs, such as drop in blood pressure, chills, fever and/or dyspnoea, 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.
The patient will be under surveillance during infusion. Blood pressure and pulse rate are
measured before infusion, each 15 minutes during infusion and about 1 hour after the end of
infusion. Temperature of the patient will be measured before and after infusion.
Medication and supportive care measures should always be available during an infusion.


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I n vesti g ati o n al Pr o d uct:
L uteti u m ( 1 7 7L u) -lil ot o m a b s atetr a xet a n ( Bet al uti n)
C o nfi de nti al
St u d y N u m ber: L Y M RI T -3 7 -0 5
2 6 A p ril 2 0 1 9
P a ge 6 7 of 9 9
7. 1. 1. 4
Defi niti o n of U ne x pecte d A d v ers e Re a cti o n
A n u ne x pecte d A R is a n A R of w hic h t he nat ure or se verit y is n ot c o nsiste nt wit h t he a p plica ble
pr o d uct i nf or mati o n (e. g., I B f or a n u na p pr o v e d i n vesti gati o nal pr o d u ct or s u m mar y of pr o d u ct
c haracteristics f or a n a ut h orize d pr o d uct). W h e n t he o utc o me of t he A R is n ot c o nsiste n t wit h
t he a p plica ble pr o d u ct i nf or mati o n t his A R s h o ul d be c o nsi dere d as u ne x pecte d.
7. 1. 1. 5
S us pecte d U ne x pecte d Seri o us A d vers e Re a cti o n ( S U S A R)
All s us pecte d A Rs t hat are c o nsi dere d relat e d t o st u d y dr u g a n d are b ot h u ne x pecte d a n d seri o us
( S U S A Rs) are s u bject t o e x pe dite d re p orti n g. It is t he S p o ns or w h o re p orts t he S U S A Rs, base d
o n i nf or mati o n fr o m t he I n vesti gat or, s ee Secti o n 7. 1. 5 .
7. 1. 1. 6
Defi niti o n of A d verse E ve nts of S peci al I nterest ( A E SI)
A d verse e ve nts of s peci al i nterest ( A E SI) are defi ne d as e ve nts (seri o us or n o n-seri o us) w hi c h
are of 
me dical c o ncer n s pecific t o Betal uti n, f or w hic h o n g oi n g m o nit ori n g a n d ra pi d
c o m m u nicati o n b y t h e in vesti gat or t o t he S p o ns or ma y b e a p pr o priate. S u c h e ve nts ma y re q uire
f urt her i n vesti gati o n i n or der t o c h aracterise t he m. O ne p ote ntial ris k f or B etal uti n is t hat as a n
a nti b o d y-ra di o n ucli de-c o nj u gate, it 
ma y o v er l o n g-ter m i n d uce sec o n dar y 
mali g na n cies,
i ncl u di n g m yel o d ys plastic s y n dr o me ( M D S), ac ut e le u kae mia a n d ot hers.
D uri n g t he pr ot oc ol-ma n date d f oll o w -u p visits, t he de vel o p me nt of sec o n dar y mali g na n cies,
m yel o d ys plastic s y n dr o me, ac ute
le u kae mia or a plastic a nae mia will be assesse d b y t he
in vesti gat or. T h ese e v e nts will be rec or d e d as S A Es .
A E SIs are defi n e d o n t he b asis of a n o n g oi n g re vi e w of t he safet y data a n d are reflecte d i n t he
I n v esti gat ors Br oc h ure.
7. 1. 2
Res p o nsi bilit y
7. 1. 2. 1
I n vesti g at o r’s Res p o nsi bilities
T he I n vesti gat or s hall re p ort all S A Es i n de pe n de nt i m me diatel y ( wit hi n 2 4 h o urs of t he
I n v esti gat or bec o mi n g a ware of t he e v e nt) t o t he S p o ns or’s re prese ntati ve e x ce pt f or t h ose t hat
t he pr ot oc ol or I B i de ntifies as n ot re q uiri n g i m me diate re p orti n g. T he i m me diat e re p ort s hall
be f oll o we d b y detaile d writte n re p ort(s).
A Es a n d/ or la b orat or y a b n or malities i de ntifie d i n t he pr o t oc ol as critical t o safet y e val u ati o ns
s hall be re p orte d t o t he S p o ns or acc or di n g t o t h e re p orti n g re q uire me nts a n d wit hi n t he ti me
peri o ds s pecifie d i n t he pr ot oc ol.
F or re p orti n g deat h of a patie nt, t he I n vesti gat or s hall s u p pl y t h e S p o ns or a n d t he Et hi c
c o m mittee wit h a n y a d diti o nal i nf or mati o n re q uest e d.


I n vesti g ati o n al Pr o d uct:
L uteti u m ( 1 7 7L u) -lil ot o m a b s atetr a xet a n ( Bet al uti n)
C o nfi de nti al
St u d y N u m ber: L Y M RI T -3 7 -0 5
2 6 A p ril 2 0 1 9
P a ge 6 8 of 9 9
Eac h i n di vi d ual A E s h o ul d be e val uate d b y t he I n v esti gat or wit h re gar d t o date of o nset, its
seri o us ness, se verit y, a n d d urati o n, ca usal relati o ns hi p t o t he i n vesti gati o nal me dici nal pr o d uct
a n d/ or c o n c o mita nt t hera p y a n d o ut c o me.
7. 1. 2. 2
S p o ns or’s R es p o nsi bilities
T he S p o ns or is res p o nsi ble f or t h e o n g oi n g safet y e val uati o n of t he i n vesti gati o nal me dici n al
pr o d uct.
T he S p o ns or is res p o nsi ble f or t he pr o m pt n otificati o n t o all c o ncer ne d I n v esti gat ors, t he et hics
c o m mittees ( E Cs )/ I nstit uti o nal Re vie w B oar d (I R Bs) a n d R e g ulat or y
A ut h orities w here
Betal uti n st u dies are o n g oi n g, of fi n di n gs t hat affect t he healt h of t he pati e nts, i m pact o n t he
c o n d uct of t he st u d y or alter t he c o m pete nt a ut h orit y’s a ut h orizati o n t o c o nti n ue t he st u d y i n
acc or d a nce wit h Directi ve 2 0 0 1/ 2 0/ E C a n d t he C o de of Fe deral Re g ulati o ns Title 2 1 .
T he S p o ns or has t o kee p detaile d rec or ds of all A Es re p ort e d t o hi m b y t h e I n vesti gat ors a n d t o
perf or m a n e v al uati o n wit h res pect t o seri o us ness, ca u salit y a n d e x pecte d ness. T hese rec or ds
s hall be s u b mitte d t o t he Re g ulat or y i n t he c o u ntri es w here t he cli nical st u d y is bei n g c o n d u cte d,
if t he y s o re q uest.
Eac h i n di vi d ual A E s h o ul d be e val uate d b y t he S p o ns or, wit h re gar d t o its seri o us ness a n d
ca usal r elati o ns hi p t o t he i n vesti gati o nal me dici nal pr o d uct a n d/ or c o nc o mita nt t hera p y. T he
S p o ns or will assess w h et her or n ot t he A E is u ne x pecte d.
7. 1. 3
Assess me nts of A d verse E ve nts : Seri o us ness, C a us alit y, Se v erit y a n d
E x pecte d ness
7. 1. 3. 1
Seri o us ness
Seri o us ness will be d eter mi ne d acc or di n g t o t he d efi niti o n, see Secti o n 7. 1. 1 3 .
7. 1. 3. 2
C a us alit y
Ca usalit y will be deter mi ne d base d o n t he defi niti o n i n Secti o n
7. 1. 2 All A Es j u d ge d b y t he
I n v esti gat or or t he S p o ns or as ha vi n g a reas o na ble s us pecte d ca usal relati o ns hi p t o a n
i n vesti gati o nal me dici nal pr o d uct q ualif y as A Rs. T he S p o ns or will n ot o verr ule t he ca us alit y
assess me nt gi ve n b y t he I n v esti gat or. If t he S p o ns or disa grees wit h t he I n v esti gat or’s ca usalit y
assess m e nt, b ot h t he o pi ni o n of t he I n vesti gat or a n d t he S p o ns or will be pr o vi de d wit h t he
re p ort.
All t o xicities/ A Es will be gra de d acc or di n g t o C T C A E versi o n 4 . I n t he eC R F t h e I n v esti gat or’s
o pi ni o n of t he relati o ns hi p of t he A E(s) t o t he i n vesti gati o nal dr u g, will be cate g orize d as
u nrelate d, p ossi bl y or pr o ba bl y relate d, as defi ne d bel o w.


Investigational Product:
Lutetium (177Lu)-lilotomab satetraxetan (Betalutin)
Confidential
Study Number: LYMRIT-37-05
26 April 2019
Page 69 of 99
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 test drug administration cannot be ruled out.
Probable:
An AE which after careful examination at the time of evaluation, the
connection to the test drug administration appears, with a high degree of
certainty, to be related to test drug.
In addition to the Investigator’s own description of the AE, each AE will be encoded by
Sponsor’s representative, according to a dictionary of medical codes (Medical Dictionary for
Regulatory Activities [MedDRA]).
7.1.3.3
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 CTCAE by the Investigator. For events
not listed in the toxicity table, severity should be recorded as:
Grade 1:
Mild AE: the event causes discomfort without disruption of normal daily
activities.
Grade 2:
Moderate AE: the event causes discomfort that affects normal daily
activities.
Grade 3:
Severe, undesirable or disabling AE: the event makes the patient unable to
perform normal daily activities or significantly affects his/her clinical
status and/or causes a substantial disruption of a person’s ability to conduct
normal life functions
Grade 4:
Life-threatening or disabling AE: the patient was at risk of death at the time
of the event or the event caused death.
Grade 5:
Death related to AE
7.1.3.4
Expectedness
Expectedness is defined in Section 7.1.4 Reports have to be considered as unexpected if they
add significant information on the specificity or severity of an expected AR. The expectedness


Investigational Product:
Lutetium (177Lu)-lilotomab satetraxetan (Betalutin)
Confidential
Study Number: LYMRIT-37-05
26 April 2019
Page 70 of 99
of an AE/AR will be determined by the Sponsor. The event is unexpected if it is not consistent
with the applicable product information, i.e. the IB for Betalutin or the approved product
information (prescribing information) for rituximab.
7.1.4
Reporting of Adverse Events Regardless of Causality
Any AEs that occur after patient has received study drug (i.e. after rituximab infusion) and
within 12 weeks after study drug administration must be reported, whether or not considered
related to the study drug. All AEs will be reported in the patient eCRFs provided. If more than
one AE occurs, each event should be recorded separately. All AEs will be followed up until
resolved or as clinically required.
AEs that occur from 12 weeks after study drug administration that are judged to be related to
the study drug will be reported when they come to the Investigator’s attention. Specific
information about patient’s possible diseases such as leukaemia, myelodysplastic syndrome and
aplastic anaemia or any other secondary malignancy, will be collected up to 2 years after study
drug administration or until further anticancer treatment is given, including information about
treatment given to the patient due to NHL.
7.1.4.1
Death
Death is not defined as an AE but as an outcome of an AE. It is important that the event leading
to the death is reported. It will be reported as an AE up to 12 weeks after Betalutin injection.
Thereafter, death it will be collected in the eCRFs as survival information. It will be reported as
outcome of an AR when it is judged as related to study drug.
7.1.4.2
Progression of disease
Progression of disease will not be recorded as an AE but captured on the tumour assessment
form in the eCRF, unless it is clinical progressive disease then the symptom associated with
clinical progressive disease will be recorded.
7.1.4.3
Adverse events due to rituximab injection
Rituximab infusion is given once prior to Betalutin injection, and AEs due to rituximab could
happen. The expected AEs with rituximab are to be found in the package insert for rituximab.
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 centre 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
the CTCAE), relationship to treatment (unrelated, possible, probable), according to the need of
other specific therapy, and outcome. All information will be recorded in the Adverse Event
eCRF page.


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Investigational Product:
Lutetium (177Lu)-lilotomab satetraxetan (Betalutin)
Confidential
Study Number: LYMRIT-37-05
26 April 2019
Page 73 of 99
7.5
Vital Signs
Vital signs (systolic/diastolic blood pressure, heart rate, respiratory rate and body temperature)
will be measured as described in the Schedule of Study Assessments (Table 4) after the patient
has been resting supine for a minimum of 5 minutes. On the day of Betalutin administration,
vital signs will be assessed pre-dose and up to 2 hours after the Betalutin injection. Patient status
will be monitored during Betalutin administration and repeat vital signs will be taken if needed.
Measurement of blood pressure will be done on the arm contralateral to the site of
investigational product administration, and the exact blood pressure recorded e.g. it should not
be rounded to the nearest 5 mmHg.
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. Abnormalities in vital signs may be AEs/SAEs. 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 CRF page. Any notable abnormal vital
signs, finding or related AE must be followed until outcome is known.
7.6
12-lead ECG
12-lead ECG will be obtained at screening as noted in the Schedule of Assessments (Table 4)
during the study using an ECG machine that automatically calculates the heart rate and measures
PR, QRS, QT, and QTc intervals. A 12-lead ECG will be performed by qualified personnel at
the site after at least a five-minute rest with the subject in a semi-recumbent or supine position.
All efforts should be made to ensure that an identical ECG machine is used to collect traces
for individual patients. If any clinically significant findings are observed on the ECG, the
Investigator will record it as part of the medical history prior to start of dosing and as an AE
post-dose, where the finding represent a clinically significant change from baseline.
A copy of the ECG page signed, dated and diagnosed should be stored in the patient file.
7.7
Clinical Laboratory Parameters
Blood and urine samples for determination of clinical chemistry, haematology, coagulation
and urinalysis parameters will be taken at the times shown in the Schedule of Study
Assessments (Table 4) and as clinically indicated. The date and time of collection will be
recorded in the source data and on the eCRF.


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Clinical chemistry, haematology, coagulation analysis and urinalysis will be performed at
each site’s local laboratory or other local laboratories as appropriate. The approximate blood
volumes for clinical chemistry and haematology (including coagulation) testing are 3.5 mL
and 4 mL, respectively.
Copies of laboratory accreditation certificates and reference ranges will be provided prior to
the analysis of the first patient sample.
The local laboratory parameters to be measured are shown in Table 7.
Table 7
Laboratory parameters
Clinical chemistry
Haematology, including coagulation screen
Calcium
Red blood cell count
Albumin
Haemoglobin
Bilirubin, total
Haematocrit
Alanine transaminase (ALT, ALAT, SGPT)
Absolute reticulocyte count
Aspartate transaminase (AST, ASAT, SGOT)
Platelet count
Alkaline phosphatase (total ALP)
White blood cells count
Glucose (random)
Leucocyte differential count
Lactate dehydrogenase (LDH)
Neutrophils
Gamma glutamyl transferase (GGT)
Lymphocytes
Sodium
Monocytes
Potassium
Eosinophils
Magnesium
Basophils
Urea (BUN)
Activated partial thromboplastin time (APTT)*
Creatinine
International normalized ratio (INR) or prothrombin
time*
Uric acid
Lymphocyte subsets**
Pregnancy test as required
Protein electrophoresis*
Quantitative serum immunoglobulins**
Human anti-mouse antibody (HAMA)*
Hepatitis B test (HBsAg and anti-HBc)*
HIV test
Urinalysis
Glucose
Protein
Bilirubin
Ketones
Blood
pH
Specific gravity & microscopic examination when
indicated
* At screening only; ** At certain time points specified in the Schedule of Assessments (Table 4).


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Reference ranges from the site laboratory will be provided to Sponsor’s delegate. If during the
study, ranges should be changed, the Investigator is requested to provide updated laboratory
normal values.
Each parameter will be evaluated whether it is significant or not. When the CTC AE grade exists
for a parameter, the grade should be recorded in the eCRF.
Laboratory values outside reference range recorded in the CTCAE, will be graded 1 to 5
according to the CTCAE criteria Laboratory values with CTCAE grade 3 or higher have to be
reported as an AE. The laboratory values might be an SAE in accordance to the SAE definition.
During the long term follow-up period only changes in laboratory values judged to be related
to the study drug will be reported.
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.
Approximate 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 stays in the study. Table 8 indicates the range for patients during the
initial assessment period to Week 12.
Table 8 Approximate volume of blood to be drawn from each patient during the initial
assessment period to Week 12
Assessment
Sample volume
(mL)
No. of samples
Total volume
(mL)
Serum biochemistry/haematology/lymphocytes
subset
7
Max 14
98
Immunogenicity
9
4
36
Immunoglobulin levels
5
1
5
Total (maximum volume to be drawn)
139
Max = maximum number of samples to be taken.
Additional blood will be taken for the patients included in the pharmacokinetic sub-study.
7.8
Immunogenicity Assessment (HAMA)
Blood samples will be obtained at the times shown in the Schedule of Study Assessments
(Table 4) for the assessment of immunogenicity
Approximately 9 mL of blood will be collected at each time point for preparation of serum
samples. Full instructions for sample preparation, handling procedures, aliquoting of samples,
storage and shipping of these serum samples will be provided in the Laboratory Manual for this
study. At screening only, HAMA test can be obtained by local assessment for eligibility


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confirmation purposes and in parallel submitted to central laboratory per Laboratory Manual.
HAMA will be measured by ImmunSTRIP HAMA IgG, an ELISA test system for human
antibodies to mouse IgG. In addition, patient blood samples will be biobanked under appropriate
storage conditions, for further immunogenicity assessments to monitor the full spectrum of the
ADA response after dosing with lilotomab and Betalutin. These additional assessments will be
performed at a central laboratory.
There has been no report of development of a HAMA response for patients included so far in
cohorts 1-3 of this Study (See Table 9).
Table 9 Monitoring of the HAMA response in LYMRIT 37-05
Subject ID
Cohort
Lilotomab
dose
Betalutin
dose
Month 1
Month 3
Month 6
Month 12
7240081001
1
60 mg/m2
10 MBq/kg
Negative
Negative
NA
NA
8260021002
1
60 mg/m2
10 MBq/kg
Negative
NA
NA
NA
8260021003
1
60 mg/m2
10 MBq/kg
NA
NA
NA
NA
8400072006
2
100 mg/m2
10 MBq/kg
Negative
Negative
NA
NA
8260012007
2
100 mg/m2
10 MBq/kg
ND
ND
NA
NA
3800042008
2
100 mg/m2
10 MBq/kg
NA
NA
NA
NA
7240083002
3
100 mg/m2
15 MBq/kg
Negative
Negative
NA
NA
8260023003
3
100 mg/m2
15 MBq/kg
ND
NA
NA
NA
7240083006
3
100 mg/m2
15 MBq/kg
NA
NA
NA
NA
NA: Not applicable, patient withdrawn; ND: Not done; A negative result is considered in the range of 0-74 ng/ml
(all negative results reported in the table above resulted as <6 ng/ml and were therefore considered negative).
7.9
Potential Long Term Toxicity
At the follow-up visits the Investigator will follow the patients closely to examine if they
suffered from any new primary cancers and bone marrow changes (acute myelogenous
leukaemia, myelodysplastic syndrome, and aplastic anaemia). In addition, physical examination
will be performed and blood samples for haematology and biochemistry taken.
7.10 Pregnancy
In principle, pregnancy and the lactation period, are exclusion criteria for clinical studies
involving investigational drugs. In the event of a pregnancy occurring during the course of this
study, Nordic Nanovector must be notified immediately. If the pregnancy involves a patient


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enrolled to the trial, the patient should be immediately withdrawn from study. The pregnant
patient or the patient’s partner should be followed-up during the entire course of the pregnancy
and postpartum period.
Parental and neonatal outcomes must be recorded even if they are completely normal and
without AEs. Off-spring should be followed up for at least 8 weeks after delivery. Longer
observation periods may be determined by the sponsor if an adverse outcome of the pregnancy
was observed.
Pregnancies occurring during the study up to 90 days after final dose of IMP must be reported
to the sponsor’s represent within one working day of becoming aware of them using a Clinical
Trial Pregnancy Reporting Form. A pregnancy is not a SAE unless the outcome of the
pregnancy meets serious criteria as defined in Section 7.1.5. When a “pregnancy is detected
without an adverse outcome”, the Investigator should complete the Pregnancy Form and send
this to the sponsor’s safety department as per the above. It should be clearly stated that no AE
was observed. If the outcome of the pregnancy meets the criteria of a SAE (i.e. congenital
anomaly, stillbirth, neonatal death), then it should be reported as described in Section 7.1.5.
7.11 Misuse and overdose
Drug misuse and drug overdose should be reported in the same format and within the same
timelines as an SAE even if they may not result in an adverse outcome. For monitoring purposes,
any case of overdose must be reported on an overdose form. When an “overdose” of the
investigational product occurs without an AE, the Investigator should complete the Overdose
Form and send this to the sponsor’s represent. It should be clearly stated that no AE occurred.
If the pharmacy discovers that an overdose has or may have been administered they should
contact the Investigator and study coordinator.
8
EFFICACY ASSESSMENTS
8.1
Tumour Response
Contrast enhanced CT and PET/CT scans will be evaluated at the study centre(s). Tumour
response and progression will be evaluated by use of the Cheson 2014 criteria (1).
8.1.1
Contrast Enhanced CT Examination
Baseline CT image must be taken within 4 weeks prior to rituximab infusion. The schedule of
assessments (Table 4) shows the frequency of CT examinations per patient.
A CT volume scan re-constructed in 3 mm slices with use of intravenously 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.


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8.1.2
PET/CT Examination
PET should be performed along with low dose non-diagnostic CT (PET/CT) for anatomic co-
registration and attenuation correction. PET/CT scan will be done at baseline, 3 (Week 12)
and 6 months after Betalutin administration for all patients. Baseline imaging should be done
within 4 weeks prior to administration rituximab 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 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 intravenous administration of 5-10 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 when both modalities are to be done
on the same day.
All measurements of uptake will be based on standardized uptake value (SUV). Lesions
<15 mm in short axis with abnormal activity: focal, above the surrounding background, above
average liver SUV.
Guidelines for baseline CT examination:
1) Target lesions on the CT scans do not need to match those evaluated on the PET scan
2) Target lesions should be chosen according to Cheson criteria, 2014
3) Approximately 6 target lesions should be selected; there must be at least one target lesion
4) The largest target lesions should be selected
5) Lesions should be from disparate regions of the body if possible
6) Mediastinal and peritoneal lesions should be included in target lesions
7) None of the lesions should be < 10 mm
Guidelines for baseline PET examination:
1) Target lesions on the CT 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.
Deauville criteria - PET/CT scoring
PET scans are scored on a 5 point scale, and follow-up will be assessed as described beneath.
In addition, SUV max will be recorded. Further details will be described in the imaging
manual.


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Images will be evaluated and scored according to a 5-point scale (Table 10).
Table 10 Uptake score with the use of Deauville criteria
Negative
Positive
1.
no uptake
4.
moderately increased uptake compared to liver
at any site
2.
uptake ≤ mediastinum*
5.
markedly increased uptake compared to liver at
any site, new sites of involvement
3.
uptake > mediastinum but ≤ liver*
X.
new areas of uptake unlikely to be related to
lymphoma
*Mediastinal and liver uptake is defined as SUVmax +/-10%.; Binary response scale for extranodal involvement yes/no or +/-: 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).
8.1.3
Overall Tumour Response Evaluation
The Cheson criteria, 2014 (1) are a combined score taking into consideration, positive or
negative scored PET scan, the contrast enhanced CT images and bone marrow biopsies when
available (see Table 11).


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Table 11 Overall tumour response evaluation
Response and Site
PET-CT-Based Response
CT-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†.
It is recognized 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 ≤1.5 cm in
LDi.
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† 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
≥ 50% decrease in SPD of up
to 6 target measurable nodes
and extranodal sites
When a lesion is too small to
measure on CT, assign 5 mm x
5 mm as the default value
When no longer visible, 0 x 0
mm
For a node > 5 mm 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-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 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 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 target
nodes/nodal masses
Score 4 or 5 with an increase in intensity of
uptake from baseline and/or
PPD progression
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 increase by ≥ 50%
from PPD nadir and
An increase in LDi or SDi
from nadir
0.5 cm for lesions ≤ 2 cm
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
preexisting non-measured
lesions


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Investigational Product:
Lutetium (177Lu)-lilotomab satetraxetan (Betalutin)
Confidential
Study Number: LYMRIT-37-05
26 April 2019
Page 85 of 99
The intention is to use planar scans as the basic means for following the activity as a function
of time for selected organs, and SPECT studies for 3D delineations. Serial planar WB scans will
be obtained at ~2-4 hours on Day 0 and on Days 1, 4 and 7, including SPECT/CT images at
Days 0, 1, 4 and 7 if sites have the equipment and experience to perform WB scans. At sites
not participating in the biodistribution sub-study, a Day 4 SPECT/CT scan is optional. A visit
window of ±1 day is permitted for the Day 4 SPECT/CT scan.
For the full details of the dosimetry sub-study please refer to the Dosimetry protocol.
10 BIOMARKER AND PHARMACODYNAMIC ASSESSMENTS
10.1 Archived Biopsy
Patients with available archived tumour biopsy will be asked to provide consent for access to
some of this sample, alternatively a fresh sample is required for CD37 analysis. The result of
the assay is not required for enrolment into the study. A sample will be biobanked for future
analysis of DNA, RNA, protein and other biomarkers.
10.2 Fresh Biopsy
All patients will be asked to provide consent for access to archived tumour tissue where
available, and for sending samples to a centralised lab for CD37 analysis. If needed, fresh
biopsies will be taken pre-dose where informed consent has been given. A sample will be
biobanked for future analysis of DNA, RNA, protein and other biomarkers.
11 STATISTICAL METHODS AND PLANNED ANALYSES
11.1 Sample Size
The purpose of this study is to escalate dosing of lilotomab and/or Betalutin to achieve a
maximum tolerated dose for future studies in relapsed/refractory DLBCL. Using the 3+3 design,
it is possible that as many as 24 subjects will be treated and assessed during the escalation phase.
Approximately 50% of these patients are expected to have relapsed > 6 months after their last
line of therapy, and the remaining 50% are anticipated to be refractory to their last line of
therapy. Because there is some expectation that non-refractory relapsed patients may benefit
more from this treatment regimen, it is desirable to have sufficient numbers in both patient
subgroups to allow for adequate estimation of ORR.  Since the DLT is not anticipated to be
different in the subgroups, an attempt to balance will occur in the expansion phase for the
recommended dosing regimen, by enrolling 10 relapsed patients, not refractory to last treatment
and 10 patients refractory to last therapy. The final total should target approximately 40 patients
treated with approximately 20 treated from each subgroup.


Investigational Product:
Lutetium (177Lu)-lilotomab satetraxetan (Betalutin)
Confidential
Study Number: LYMRIT-37-05
26 April 2019
Page 86 of 99
11.2 Analysis Populations
Two populations will be used for analysis, the safety population and the evaluable population,
as defined below:
Safety population: All patients who receive rituximab.
Evaluable population: All patients who receive Betalutin and have at least one post-baseline
assessment of disease response.
11.3 End of Study and Study Completion
“End of Study” for the purpose of locking the database and generating the main clinical study
report (CSR) will be defined as last follow-up Month 6 study assessment (with a Final Study
Visit for those patients who have withdrawn from the study prior to Month 6). “Study
Completion” will be defined as the point when all patients have had the opportunity to be
followed up for up to 2 years from Day 0. Additional data from the patient(s) continuing to be
followed up after Month 6 will be presented as an Addendum to the CSR upon reaching the
Study Completion.
11.4 Database lock
The clinical database lock will occur after all data are reconciled (i.e. “cleaned”) for all patients
who participate in the study. A single CSR will be generated for this study consisting of a report
on patient follow-up to Month 6, plus an addendum to this report to describe long-term follow-
up. The Statistical Analysis Plan (SAP) will be finalized and signed before the database lock
for the main CSR.
11.5 Statistical Considerations
Detailed statistical analysis information will be provided separately in the Statistical Analysis
Plan (SAP). The SAP will detail all data handling rules, including the management of missing
values and the handling of data for withdrawn patients. The SAP will also outline protocol
violation criteria along with any specific analysis population definitions. Any deviations to the
planned analyses specified or populations defined within the SAP will be justified in writing
and presented within the final CSR.
There will be no formal statistical analysis. Data will be summarized using descriptive statistics.
11.5.1 Analysis of Demographic and Pre-treatment Characteristics
Demographic data and other pre-treatment characteristics (including medical history, disease-
related characteristics and prior anti-cancer therapies) will be summarized using descriptive


Investigational Product:
Lutetium (177Lu)-lilotomab satetraxetan (Betalutin)
Confidential
Study Number: LYMRIT-37-05
26 April 2019
Page 87 of 99
statistics. Administration of the investigational medicinal products (Betalutin, lilotomab and
rituximab) will be listed by patient and summarized.
11.5.2 Analysis of Safety Data
All safety and tolerability assessments will be based on the safety analysis set, which is defined
as all patients who have received at least one dose of rituximab.
Safety parameters (see Section 7) will be summarized using descriptive statistics. Categorical
data will be presented as percentages and frequency tabulations. The incidence of AEs will be
tabulated and reviewed for potential significance and clinical importance. The number of
subjects reporting AEs, and the number of AEs reported will be presented. AEs will be coded
using MedDRA. The events will be tabulated by body system, preferred term, intensity, CTCAE
grading, severity and relationship to study medication. Duration of AEs will also be tabulated.
SAEs and AEs leading to withdrawal will be presented in separate tabulations.
For laboratory data, in addition to summary statistics, the number of abnormal and clinically
significant observations will be tabulated by time of measurement. The laboratory values will
also be graded according to toxicity graded as CTCAE.
Toxicity will be graded using CTCAE v4.0 and reported for all AEs.
11.5.3 Analysis of Tumour Response
Tumour assessment will follow the response criteria for malignant lymphoma according to
Cheson et al, 2014 (1).
Anti-tumour and clinical benefit variables will be summarized descriptively. Where
appropriate, variables will be presented in terms of absolute and relative change from baseline.
Categorical data will be presented as percentages and frequency tabulations. Response rates
(such as PFS and CR) will be presented as point estimates with 95% CIs. Time to event
endpoints such as PFS will be presented in Kaplan-Meier graphs along with the median time to
event with 95% CIs.
11.5.4 Pharmacokinetic, Biodistribution and Dosimetry Analysis
Data will be listed by patient, dose level and time point using descriptive statistics, as
appropriate. Individual PK data will be tabulated and PK assessments vs. time curves presented.
The following PK parameters will be determined using non-compartmental analyses: Cmax,
Tmax, area under curve (AUC), clearance, apparent volume of distribution and half-life.
Additional PK parameters may be calculated as appropriate.
A separate manual will be made available for the biodistribution and dosimetry handling and
analysis of data. A separate study report will be written for this sub-study.


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Investigational Product:
Lutetium (177Lu)-lilotomab satetraxetan (Betalutin)
Confidential
Study Number: LYMRIT-37-05
26 April 2019
Page 90 of 99
Data queries will be generated at data entry or if questions arise during the data validation or
detected during a manual review (safety data). The queries are entered into the eCRF and
resolved according to the electronic data capture manual.
AEs and SAEs will be handled in the same way as the other data reported in the eCRF. However,
in addition the SAEs will be coded and medical assessed for reporting to authorities according
to national regulatory requirements. Before the database is locked (i.e. Clean File declared),
reconciliation of the data will be performed. Coding of AEs and medical history will be
performed according to MedDRA and coding of concomitant medications will be performed
according to WHO-Drug dictionary.
A quality check of a random sample of the data will be performed to ensure that the consistency
between the database and the eCRFs are at least on the pre-defined level described in SOPs of
the sponsor’s subcontractor and in the data validation plan.
Clean File will be declared when all data has been entered, the data entry verified, the data
validated, and the database defined as clean by the Clinical Data Manager. After declaration of
Clean File, the data will be exported from the database to SAS datasets and both the database
and the SAS datasets will be locked and protected from changes. Subsequently then the
inclusion of patients into the three analysis sets will be done in such a way that it is ensured that
all rules have been applied equally on all patients. All statistical analyses will be performed on
the locked SAS-datasets.
12.4 Retention of Documents
The following information must be retained for at least 5 years after completion or
discontinuation of the study or longer if required by local regulations. If the data from this study
is used to support a marketing authorisation  the data must be retained for at least 15 years after
completion or discontinuation of the trial or for at least 2 years after the last approval of a
marketing application in an International Conference on Harmonisation (ICH) region and until
there are no pending or contemplated marketing applications in an ICH region; or at least 2
years have elapsed since the formal discontinuation of clinical development of the
investigational product: source data, source documents, eCRFs, protocol and amendments, drug
accountability forms, correspondence, subject identification list, informed consent forms, and
any other essential documents.
It is the responsibility of the Sponsor to inform the Investigator/institution as to when these
documents no longer need to be retained according to ICH guidelines [Good Clinical Practice
(GCP)]. The eCRFs will be archived by the Sponsor for the lifetime of the product. No study
document should be destroyed without prior written agreement between the Sponsor and the
Investigator. In accordance with data protection legislation, the subject identification list should
be destroyed when it is no longer needed. Should the Investigator wish to assign the study


Investigational Product:
Lutetium (177Lu)-lilotomab satetraxetan (Betalutin)
Confidential
Study Number: LYMRIT-37-05
26 April 2019
Page 91 of 99
records to another party or move them to another location, advance written notice should be
given to the Sponsor.
13 SPECIAL REQUIREMENTS AND PROCEDURES
13.1 Independent Ethics Committee/Institutional Review Board
The study protocol, including the patient information and informed consent to be used, must be
approved by the centre’s IEC, IRB and/or regional Ethics Committee (EC). A written approval
must be obtained before enrolment of any patients into the study. It is the responsibility of the
Investigator to supply the sponsor with a copy of the members of the hospital IEC, IRB or
regional EC and the Letter of Approval defining the version of each document approved.
The investigator will ensure that this study is conducted in accordance with ICH GCP, Seoul
(2008) amendment to Declaration of Helsinki 1964 (64th WMA General Assembly, Fortaleza,
Brazil, October 2013), 21 Code of Federal Regulations (CFR) Part 50, including notes of
clarification up to Tokyo (2004), the EU Clinical Trials Directive 2001/20/EC, the GCP
Directive 2005/28/EC, the requirements of local IRB/IECs, and with national laws and
regulations for clinical research.
The Investigator is responsible for informing the ethics committees and regulatory authorities
of any SAEs and/or major amendments to the protocol as per national requirements. The
Investigator should file all correspondence and a copy should be sent to Sponsor.
Either the Investigator or the Sponsor must submit progress reports to the IEC/IRB according
to local regulations and guidelines.
13.2 Protocol Amendments and Discontinuation
Any changes to the protocol or discontinuation of the study require a written protocol
amendment or statement, respectively. The Investigators, IEC/IRB in some cases and Sponsor
must approve the protocol amendment or statement. The Principal Investigator(s) and the
Sponsor’s authorised representative will sign the protocol amendment. Any significant
deviation from the protocol when no approved amendment exists will be regarded as a protocol
violation and will be addressed as such during the reporting of the study.
National authorities and hospital IEC, hospital IRB or regional EC will be notified about all
protocol amendments or discontinuation of the study. If the protocol amendment results in major
changes, affecting patients’ safety, the objective(s) or the scientific quality of the study, it must
be approved by the hospital/regional IEC/IRB of all participating centres as per local
regulations, as well as by the national regulatory authorities.


I n vesti g ati o n al Pr o d uct:
L uteti u m ( 1 7 7L u) -lil ot o m a b s atetr a xet a n ( Bet al uti n)
C o nfi de nti al
St u d y N u m ber: L Y M RI T -3 7 -0 5
2 6 A p ril 2 0 1 9
P a ge 9 2 of 9 9
T he S p o ns or will ha ve t h e ri g ht t o ter mi nate t he st u d y at a n y ti me i n case of safet y iss ue or if
s pecial circ u msta nces c o ncer ni n g t h e st u d y s u bsta nce or t he c o m pa n y itself s h o ul d occ ur,
ma ki n g f urt her patie nt treat me nt i m p ossi ble. T he s p o ns or will i n f or m t h e I n v esti gat ors a b o ut
t he reas o ns f or st u d y t er mi nati o n.
1 3. 3 I n vesti g at or’s O v er all Res p o nsi bilit y
T he i n vesti gat or will e ns ure t hat t his st u d y is c o n d ucte d i n f ull c o nf or ma n ce wit h t he latest
a me n d me nt t o t he Declarati o n of Helsi n ki 1 9 6 4 ( 6 4t h W M A Ge neral Asse m bl y, F ortaleza,
Brazil, Oct o ber 2 0 1 3), 2 1 C F R part 5 0, a n d wit h nati o nal la ws a n d re g ulati o ns f or cli nical
researc h.
T he I n vesti gat or is res p o nsi ble f or perf or mi n g t he st u d y i n acc or d a nce wit h t his pr ot oc ol, t he
I C H g ui deli nes o n GC P a n d l ocal re g ulati o ns, a n d f or c ollecti n g, rec or di n g, a n d re p orti n g t he
data acc uratel y a n d pr o p erl y. A gree me nt of t he I n v esti gat or t o c o n d uct a n d a d mi nister t his st u d y
i n acc or da n ce wit h t he pr ot oc ol will be d oc u me nte d i n se parate st u d y a gree me nts wit h t he
S p o ns or a n d ot h er f or ms as re q uire d b y nati o nal a ut h orities i n t he c o u ntr y w here t he st u d y ce ntre
is l ocate d.
T he I n vesti gat or is res p o nsi ble f or gi vi n g i nf or mati o n a n d trai ni n g a b o ut t he st u d y t o all staff
me m bers i n v ol ve d i n t he st u d y or i n a n y ele m e nt of s u bject ma na ge me nt, b ot h bef ore starti n g
t he practical p erf or ma nce of t he st u d y a n d d uri n g t he c o urse of t he st u d y (e. g., w he n ne w staff
bec o me i n v ol ve d).
T he I n vesti gat or will mai ntai n a rec or d of all i n di vi d uals i n v ol ve d i n t he st u d y ( me dical, n u rsi n g
a n d ot her staff).
T he I n vesti gat or is res p o nsi ble f or e ns uri n g t he pri vac y, healt h, a n d welfare of t he patie nts
d uri n g a n d aft er t he st u d y. T he I n vesti gat or m ust be fa miliar wit h t he bac k gr o u n d a n d
re q uire me nts of t he st u d y a n d wit h t he pr o perties of t he i n vesti gati o nal pr o d uct as descri be d i n
t he I n v esti gat or's Br oc h ure.
T he I n v esti gat or is res p o nsi ble f or d estr o yi n g t he s u bject i de ntificati o n list w he n it n o l o n ger
nee ds t o be retai ne d acc or di n g t o I C H g ui deli nes.
T he I n v esti gat or at eac h ce ntre has t he o verall res p o nsi bilit y f or t he c o n d u ct a n d a d mi nistrati o n
of t he st u d y at t hat ce ntre, a n d f or c o ntacts wit h st u d y ce ntre ma na ge me nt, t he I R B/ E C, a n d
wit h l ocal a ut h orities.
1 3. 4 P atie nt I nf or me d C o nse nt
Writte n a n d ver b al i nf or mati o n a b o ut t he st u d y i n a
la n g u a ge u n dersta n da ble b y t he patie nt will
be gi ve n t o all patie nts. Writte n i nf or me d c o nse nt will be o btai ne d fr o m eac h patie nt bef ore a n y
pr oce d ures or ass ess me nts are d o ne a n d aft er t he ai ms, met h o ds, a ntici pate d be nefits, p ote ntial


Investigational Product:
Lutetium (177Lu)-lilotomab satetraxetan (Betalutin)
Confidential
Study Number: LYMRIT-37-05
26 April 2019
Page 93 of 99
hazards, and insurance arrangements in force are explained. It will also be explained to the
patients that they are free to refuse entry into the study and free to withdraw from the study at
any time without prejudice to future treatment.
The patient’s willingness to participate in the study will be documented in writing in a consent
form, which will be signed and personally dated by the patient. The Investigator will keep the
original consent forms and copies will be given to the patients.
13.5 Direct Access to Source Data/Documents
The monitor(s), auditor(s), authorized personnel of the Sponsor, and health authority
inspector(s) or their agents will be given direct access to source data and documentation (e.g.,
medical charts/records, laboratory results, printouts, etc.) for SDV, provided that patient
confidentiality is maintained in accordance with local requirements.
13.6 Confidentiality Regarding Study Patients
The Investigator must assure that the privacy of the patients, including their personal identity
and all other personal medical information, will be maintained at all times. In the eCRF and
other documents or image material (including materials from all imaging modalities) submitted
to the Sponsor, patients will not be identified by their names, but by an identification code (e.g.,
initials and allocation number). Personal medical information may be scrutinized for the
purpose of verifying data recorded in the eCRF. This may be done by the monitor(s), properly
authorized persons on behalf of the Sponsor, the quality assurance unit, or regulatory authorities.
Personal medical information will always be treated as confidential.
13.7 Study Monitoring
Monitoring is a Sponsor’s process for tracking a clinical study to ensure its scientific integrity,
the data-quality, safety and well-being of the patients and compliance with the Declaration of
Helsinki and other regulatory and/or Sponsor regulations.
To ensure compliance with GCP, the monitor or Sponsor’s representative is responsible for
ensuring that the study is conducted according to the protocol, and other written instructions.
The monitor is the primary association between the Sponsor and the Investigator. The main
responsibilities of the monitor are to assure adherence to the protocol, accurate and complete
data recording and reporting in the eCRFs, and that informed consent is obtained and recorded
for all patients before their participation in the study.
The monitor will contact and visit the Investigator at regular intervals throughout the study. To
assure the accuracy and completeness of the data recorded in the study, the monitor will be
allowed to compare eCRFs with medical records and other relevant documentation during the


Investigational Product:
Lutetium (177Lu)-lilotomab satetraxetan (Betalutin)
Confidential
Study Number: LYMRIT-37-05
26 April 2019
Page 94 of 99
on-site monitoring visits to ensure the completeness, consistency, and accuracy of the data being
recorded.
The monitor is responsible for explaining the protocol and study related procedures to all study
staff, including the Investigator. Additional information will be made available during the study
when new staff become involved in the study and as otherwise agreed upon with either the
Investigator or the monitor.
As part of the supervision of the study progress other Sponsor personnel may, on request,
accompany the monitor on visits to the study centre. The Investigator and assisting staff must
agree to cooperate with the monitor to resolve any problems, errors, or possible
misunderstandings concerning the findings detected in the course of these monitoring visits.
13.8 Audit and Inspection
According to ICH Guidelines on GCP, the Sponsor may audit the investigational site to compare
raw data, source data, and associated records with the interim or final report of the study to
assure that data have been accurately reported. The Investigator must accept that regulatory
authorities, EC or an IRB may conduct an inspection to verify compliance of the study with
protocol, GCP, ICH guidelines and any applicable regulatory requirements. If the Investigator
is contacted with a request for an inspection, the Investigator must inform the Sponsor
immediately.
13.9 Laboratory Accreditation
Any clinical laboratory facility used for analysis of samples obtained under this protocol must
demonstrate adequate licensure and accreditation. Reference ranges of test results must be
provided to the Sponsor.
The study centre must have the appropriate license for any procedure involving the
administration of radioactive substances supplied by the Sponsor.
13.10 Patient Insurance and Indemnity
This study is covered under the sponsor’s liability insurance policy. A certificate of insurance
can be provided upon request.
14 INVESTIGATOR AGREEMENT
14.1 Financial Disclosure
According to the FDA 21 CFR, part 54, the Sponsor is required to completely and accurately
disclose or certify information to the FDA concerning the financial interests of a clinical
Investigator who is not a full-time or part-time employee. Therefore, the Investigator must


Investigational Product:
Lutetium (177Lu)-lilotomab satetraxetan (Betalutin)
Confidential
Study Number: LYMRIT-37-05
26 April 2019
Page 95 of 99
provide the Sponsor with sufficient, accurate financial certification that no financial
arrangements (further defined in 21 CFR 54.2) exist with the Sponsor, or fully disclose the
nature of the arrangement.
14.2 Study Agreement and Payment of Grant
A separate financial agreement (Clinical Study Agreement) including budget will be signed
between the Sponsor and the Investigator and/or the institution involved. The budget will be
itemised on a per patient basis and the payee name(s) and tax identification number(s).
Additionally, the Investigator should not begin the study until the Sponsor has confirmed the
agreed final budget in writing. The Investigator must comply with all the terms, conditions and
obligations of the study agreement for this study. In the event of any inconsistency between this
protocol and the study agreement, the study agreement shall prevail.
15 CONFIDENTIALITY AND REPORTING AND PUBLICATION OF
RESULTS
All information concerning Betalutin and the Sponsor’s research and product development
including patent applications and manufacturing processes not previously published are
considered confidential and shall remain the sole property of the Sponsor.
15.1 Statistical and Clinical Reports
The Sponsor is responsible for preparing a CSR, in cooperation with the principal Investigator.
The report will be added to the Sponsor’s data file and may be used for regulatory purposes
and/or in company publications.
If the study is terminated prematurely for any reason an abbreviated report will be prepared.
15.2 Regulatory Use of Data
By signing the protocol, the Investigator agrees that the results of this study may be used for
submission to national and/or international regulatory and supervising authorities. The
authorities will be informed of the Investigator’s name, address, qualifications and extent of
involvement.
15.3 Publication of Results
All publications will be prepared and published in collaboration between investigators and
Sponsor.
Manuscripts based on this protocol will follow the recommendations from the International
Committee of Medical Journal Editors (ICJME) Uniform Requirements for Manuscripts


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Investigational Product:
Lutetium (177Lu)-lilotomab satetraxetan (Betalutin)
Confidential
Study Number: LYMRIT-37-05
26 April 2019
Page 97 of 99
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Investigational Product:
Lutetium (177Lu)-lilotomab satetraxetan (Betalutin)
Confidential
Study Number: LYMRIT-37-05
26 April 2019
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Kolstad A, Madsbu  U, Beasley M,  Bayne  M, Illidge  T, O’Rourke N, Lagerlöf  I, Hájek 
R, Jurczak W, Willenbacher  E, Fagerli  UM, Obr A, Blakkisrud J, Muftuler Løndalen A ,
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Annual Meeting of the American Society of Hematology (ASH); December 1-4, 2018;
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