Conditions: Diffuse Large B-cell Lymphoma
Keywords: Lymphoma Loncastuximab Tesirine Rituximab Non-Hodgkin's lymphoma Elderly R-mini-CHOP Geriatric Assessment FIL Tool Unfit Frail
Allocation: NON_RANDOMIZED | Intervention model: SEQUENTIAL
Enrollment: 41
Healthy volunteers: no

Brief summary:
The main objective of the trial is to assess the efficacy and tolerability of Lonca-R in unfit and frail participants with previously untreated DLBCL.

Detailed description:
The primary objectives of this trial are shown below:

Cohort A: To assess the efficacy of a response-adapted treatment of Lonca-R in unfit participants with previously untreated DLBCL, high-grade B cell lymphoma (HGBCL), or Grade 3b follicular lymphoma (FL).

Cohort B: To assess the tolerability and efficacy of a response-adapted treatment of Lonca-R in frail participants with previously untreated DLBCL, or HGBCL, or Grade 3b FL who are ineligible for standard R-mini-CHOP.

The simplified geriatric assessment (sGA) developed by the Fondazione Italiana Linfomi (FIL) identifies three distinct categories (fit, unfit, and frail) based on age, activities of daily living (ADL), instrumental activities of daily living (IADL) and the Cumulative Illness Rating Scale for Geriatrics (CIRS-G). Participants will be assigned to Cohort A (unfit) or B (frail) using the sGA.

Arms:
arm 1: Participants who are unfit (per sGA) will receive Lonca-R for 3 cycles. Participants who achieve a complete response (CR) will receive Lonca-R for 1 additional cycle. Participants who achieve a partial response (PR) will receive Lonca-R for 3 additional cycles.

Lonca-R will be administered as rituximab 375 mg/m\^2 on Day 1 of Cycle 1 and loncastuximab tesirine 150 µg/kg on Day 2 of Cycle 1. During Cycle 2, Lonca-R will be administered as rituximab\* 375 mg/m\^2 and loncastuximab tesirine 150 µg/kg on Day 1. For cycles 3 and beyond, Lonca-R will be administered as rituximab 375 mg/m\^2 and loncastuximab tesirine 75 µg/kg on Day 1.

\*subcutaneous rituximab 1400mg/dose may be used during Cycle 2 and beyond arm 2: Participants who are frail (per sGA) or participants with cardiac comorbidities will receive Lonca-R for 3 cycles. Participants who achieve a CR will receive Lonca-R for 1 additional cycle. Participants who achieve a PR will receive Lonca-R for 3 additional cycles for a total of up to 6 cycles. Only participants enrolled in Cohort B, who achieve stable disease (SD) and deriving clinical benefit per the treating physician, may also receive Lonca-R for an additional 3 cycles.

Lonca-R will be administered as rituximab 375 mg/m\^2 on Day 1 of Cycle 1 and loncastuximab tesirine 150 µg/kg on Day 2 of Cycle 1. During Cycle 2, Lonca-R will be administered as rituximab\* 375 mg/m\^2 and loncastuximab tesirine 150 µg/kg on Day 1. For cycles 3 and beyond, Lonca-R will be administered as rituximab 375 mg/m\^2 and loncastuximab tesirine 75 µg/kg on Day 1.

\*subcutaneous rituximab 1400mg/dose may be used during Cycle 2 and beyond

Interventions: intervention 1: Loncastuximab Tesirine intervention 2: Rituximab
Intervention descriptions: intervention 1: Intravenous (IV) Infusion intervention 2: Cycle 1 - Intravenous (IV) Infusion. Cycle 2+ - Intravenous (IV) Infusion or Subcutaneous (SC) Administration.

Protocol document:
Prot_000.pdf: 
Protocol Number: ADCT-402-203 
 
Official Title: A Phase 2 Open-label Study of Loncastuximab Tesirine in Combination with 
Rituximab (Lonca-R) in Previously Untreated Unfit/Frail Patients with Diffuse Large B-cell 
Lymphoma (DLBCL) (LOTIS-9) 
 
NCT Number: NCT05144009 
 
Document Date: 08 August 2022 


ADC Therapeutics 
Loncastuximab Tesirine 
ADCT-402-203 (LOTIS-9) 
Protocol Amendment 3 
Confidential 
Template version: 31 July 2020 
Page 1 of 89 
CLINICAL STUDY PROTOCOL 
IND: 126138 
EudraCT Number: 2021-005312-57 
A Phase 2 Open-label Study of Loncastuximab Tesirine in Combination 
with Rituximab (Lonca-R) in Previously Untreated Unfit/Frail Patients 
with Diffuse Large B-cell Lymphoma (DLBCL) (LOTIS-9) 
PROTOCOL ADCT-402-203 
PHASE 2 
ADC Therapeutics SA 
Route de la Corniche, 3B 
1066 Epalinges 
Switzerland 
Date of Protocol Amendment 3 
08 August 2022 
Confidentiality Statement 
The concepts and information contained in this document or generated during the study are 
confidential and proprietary information of ADC Therapeutics SA and may not be disclosed 
in whole or in part without prior written permission of ADC Therapeutics SA. 
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ADC Therapeutics 
Loncastuximab Tesirine 
ADCT-402-203 (LOTIS-9) 
Protocol Amendment 3 
Confidential 
Page 3 of 89 
Declaration of Investigator 
I have read and understood all sections of the protocol entitled: “A Phase 2 Open-label Study 
of Loncastuximab Tesirine in Combination with Rituximab (Lonca-R) in Previously 
Untreated Unfit/Frail Patients with Diffuse Large B-cell Lymphoma (DLBCL) 
(LOTIS-9)” and the accompanying Investigator’s Brochure (IB).  
I agree to supervise all aspects of the protocol and to conduct the clinical investigation in 
accordance with the Protocol Amendment 3, 08 Aug, 2022, the current version of International 
Council for Harmonisation (ICH) harmonized tripartite guideline E6: Good Clinical Practice, 
and all applicable governmental regulations. I will not make changes to the protocol before 
consulting with ADC Therapeutics or implement protocol changes without independent ethics 
committee approval except to eliminate an immediate risk to patients. I agree to administer the 
study drug only to patients under my personal supervision or the supervision of a sub-
Investigator. 
I will not supply the study drug to any person not authorized to receive it. Confidentiality will 
be protected. Patient identity will not be disclosed to third parties or appear in any study reports 
or publications. 
I will not disclose information regarding this clinical investigation or publish results of the 
investigation without authorization from ADC Therapeutics SA.  
 
 
 
 
 
 
Signature of Principal Investigator 
 
Date 
 
 
 
 
Printed Name of Principal Investigator 
 
 
 
 
Institution Name 
 
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Loncastuximab Tesirine 
ADCT-402-203 (LOTIS-9) 
Protocol Amendment 3 
Confidential 
Page 5 of 89 
List of Prior Protocol Versions  
Document 
Version Date 
Rationale for Changes  
Protocol 
Amendment 2 
07 March 2022 
The primary reason for this protocol amendment 
was to provide a clarification for the exclusion 
criterion about prior exposure to the combination 
of loncastuximab tesirine and rituximab 
Protocol 
Amendment 1 
19 January 2022 
The primary reason for this protocol amendment 
was to align the protocol with FDA comments, in 
particular removal of Part 2. 
Protocol Original 
01 November 2021 
Not applicable 
 
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Loncastuximab Tesirine 
ADCT-402-203 (LOTIS-9) 
Protocol Amendment 3 
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Table of Contents 
Protocol Approval - Sponsor Signatory .................................................................................... 2 
Declaration of Investigator ....................................................................................................... 3 
Summary of Changes ................................................................................................................ 4 
List of Prior Protocol Versions .................................................................................................. 5 
Table of Contents ...................................................................................................................... 6 
List of Tables ........................................................................................................................... 10 
List of Figures ......................................................................................................................... 10 
List of Abbreviations............................................................................................................... 11 
Protocol Synopsis.................................................................................................................... 15 
Schedule of Events .................................................................................................................. 23 
1 
Introduction and Background ......................................................................................... 28 
1.1 
Diffuse Large B-cell Lymphoma and Unfit/Frail Patients .............................................28 
1.2 
Description of the Study Drugs ......................................................................................29 
1.2.1 
Loncastuximab Tesirine ..............................................................................................29 
1.2.2 
Rituximab ...................................................................................................................30 
1.3 
Loncastuximab Tesirine - Clinical Results .....................................................................30 
1.3.1 
Phase 1 Study, ADCT-402-101 ...................................................................................30 
1.3.2 
Phase 2 Study, ADCT-402-201 ...................................................................................31 
1.4 
Benefit/Risk Assessment ................................................................................................32 
2 
Study Rationale .............................................................................................................. 33 
2.1 
Rationale for Study Design ............................................................................................33 
2.2 
Rationale for Dose Selection ..........................................................................................34 
3 
Study Objectives and Endpoints ..................................................................................... 35 
4 
Study Design .................................................................................................................. 37 
4.1 
Overview ........................................................................................................................37 
4.2 
Study Periods ..................................................................................................................38 
4.2.1 
Screening Period .........................................................................................................38 
4.2.2 
Treatment Period .........................................................................................................38 
4.2.3 
End of Treatment ........................................................................................................39 
4.2.4 
Follow-up Period ........................................................................................................39 
4.2.5 
End of Study ...............................................................................................................39 
4.3 
Steering Committee (SC) ...............................................................................................39 
5 
Patient Population ........................................................................................................... 40 
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Loncastuximab Tesirine 
ADCT-402-203 (LOTIS-9) 
Protocol Amendment 3 
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5.1 
Inclusion Criteria ............................................................................................................40 
5.2 
Exclusion Criteria ...........................................................................................................42 
5.3 
Screening Failures ..........................................................................................................43 
5.4 
Re-screening Procedures ................................................................................................43 
5.5 
Discontinuation ..............................................................................................................43 
5.5.1 
Discontinuation from Study Treatment ......................................................................43 
5.5.2 
Discontinuation from the Study ..................................................................................44 
5.5.3 
Lost to Follow-up .......................................................................................................45 
5.5.4 
Patient Replacements ..................................................................................................45 
6 
Study Treatment .............................................................................................................. 46 
6.1 
Study Drugs ....................................................................................................................46 
6.1.1 
Loncastuximab Tesirine ..............................................................................................46 
6.1.2 
Rituximab ...................................................................................................................46 
6.2 
Management of Clinical Supplies ..................................................................................46 
6.2.1 
Packaging and Storage ................................................................................................46 
6.2.2 
Preparation and Administration ..................................................................................47 
6.3 
Study Treatment Assignment and Dosing ......................................................................47 
6.4 
Premedication .................................................................................................................48 
6.5 
Treatment Compliance ...................................................................................................48 
6.6 
Definition and Management of Overdose ......................................................................48 
6.7 
Dose Delays and Modifications .....................................................................................49 
6.7.1 
Dose Delays and Modifications for Loncastuximab Tesirine .....................................49 
6.8 
Supportive Care ..............................................................................................................50 
6.8.1 
Management of Edema and Pleural Effusion .............................................................50 
6.8.2 
Prevention and Management of Infusion-Related Hypersensitivity Reactions ..........50 
6.8.3 
Prevention and Management of Skin Toxicity ...........................................................50 
6.8.4 
Prevention of Tumor Lysis Syndrome ........................................................................51 
6.8.5 
Prevention of Febrile Neutropenia ..............................................................................51 
6.8.6 
Prevention of Infection ...............................................................................................51 
6.8.7 
Other Supportive Care ................................................................................................51 
6.9 
Concomitant Medications and Procedures .....................................................................51 
6.9.1 
Permitted During Study ..............................................................................................51 
6.9.2 
Prohibited During Study .............................................................................................52 
7 
Study Assessments and Procedures ................................................................................ 53 
7.1 
Informed Consent ...........................................................................................................53 
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Loncastuximab Tesirine 
ADCT-402-203 (LOTIS-9) 
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7.2 
Demographics and Baseline Characteristics ..................................................................53 
7.3 
Efficacy Assessments .....................................................................................................53 
7.4 
Safety Assessments ........................................................................................................54 
7.4.1 
Physical Examination .................................................................................................54 
7.4.2 
ECOG Performance Status .........................................................................................55 
7.4.3 
Height and Weight ......................................................................................................55 
7.4.4 
Vital Signs ...................................................................................................................55 
7.4.5 
Laboratory Tests .........................................................................................................55 
7.4.6 
Pregnancy Test ............................................................................................................56 
7.4.7 
Electrocardiograms .....................................................................................................56 
7.5 
Pharmacokinetics, 
, and Immunogenicity .......................................56 
7.5.1 
Pharmacokinetic Assessment ......................................................................................56 
7.5.2 
Immunogenicity ..........................................................................................................57 
7.5.3 
 
7.5.3.1 
 
7.5.3.2 
 
7.6 
Patient Reported Outcomes ............................................................................................58 
8 
Adverse Events Reporting .............................................................................................. 59 
8.1 
Definition of Adverse Events and Serious Adverse Events ...........................................59 
8.1.1 
Adverse Events ...........................................................................................................59 
8.1.2 
Serious Adverse Events ..............................................................................................59 
8.1.3 
Clinical Laboratory Abnormalities and Other Abnormal Assessments as Adverse 
Events or Serious Adverse Events ..............................................................................60 
8.2 
Eliciting and Reporting Adverse Events/Serious Adverse Events .................................60 
8.3 
Assessment of Severity ..................................................................................................61 
8.4 
Assessment of Causality .................................................................................................61 
8.5 
Special Situations Reports ..............................................................................................62 
8.5.1 
Definitions of Special Situations ................................................................................62 
8.5.2 
Reporting Pregnancy ..................................................................................................62 
8.5.3 
Reporting Overdose ....................................................................................................63 
8.5.4 
Reporting Other Special Situations ............................................................................63 
8.6 
Data Monitoring Committee ..........................................................................................63 
9 
Statistical Considerations ............................................................................................... 64 
9.1 
Sample Size Determination ............................................................................................64 
9.2 
Analysis Populations ......................................................................................................64 
9.3 
Interim Analysis .............................................................................................................64 
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Loncastuximab Tesirine 
ADCT-402-203 (LOTIS-9) 
Protocol Amendment 3 
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9.4 
Final Analysis .................................................................................................................65 
9.5 
Demographics and Baseline Characteristics ..................................................................65 
9.6 
Exposure to Treatments ..................................................................................................65 
9.7 
Efficacy Analyses ...........................................................................................................65 
9.7.1 
Complete Response Rate ............................................................................................65 
9.7.2 
Overall Response Rate ................................................................................................65 
9.7.3 
Duration of Response .................................................................................................65 
9.7.4 
2-year Progression-free Survival ................................................................................66 
9.7.5 
3-year Overall Survival ...............................................................................................66 
9.8 
Safety Analyses ..............................................................................................................66 
9.8.1 
Adverse Events ...........................................................................................................66 
9.8.2 
Clinical Laboratory Results ........................................................................................66 
9.8.3 
Additional Safety Assessments ...................................................................................67 
9.9 
Pharmacokinetic Analysis ..............................................................................................67 
9.10 Immunogenicity Analysis ..............................................................................................67 
9.11 Subgroup Analyses .........................................................................................................68 
9.12 Patient-reported Outcomes .............................................................................................70 
9.13 
 
10 
Regulatory, Ethical, and Study Oversight/Management Considerations ....................... 71 
10.1 Regulatory and Ethical Considerations ..........................................................................71 
10.2 Financial Disclosure and Obligations ............................................................................71 
10.3 Patient Information and Consent ....................................................................................71 
10.4 Data Protection ...............................................................................................................72 
10.5 Data Quality Assurance ..................................................................................................72 
10.6 Source Documents ..........................................................................................................73 
10.7 Study and Site Closure ...................................................................................................73 
10.8 Monitoring of the Study .................................................................................................74 
10.9 Publications ....................................................................................................................74 
11 
References ...................................................................................................................... 75 
12 
Appendices ..................................................................................................................... 78 
12.1 Appendix: Eastern Cooperative Oncology Group Performance Status .........................78 
12.2 Appendix: Response Assessment of Hodgkin and NonHodgkin Lymphoma (Lugano 
Classification) .................................................................................................................79 
12.3 Appendix: FACT-Lym ....................................................................................................83 
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Loncastuximab Tesirine 
ADCT-402-203 (LOTIS-9) 
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12.4 Appendix: Katz Activities of Daily Living ....................................................................86 
12.5 Appendix: Modified Instrumental Activities of Daily Living ........................................88 
12.6 Appendix: Modified Cumulative Illness Rating Scale - Geriatric .................................89 
 
List of Tables 
Table 1 
Treatment with Lonca-R ...................................................................................... 22 
Table 2 
Schedule of Events (SoE) .................................................................................... 23 
Table 3 
Study Objectives and Endpoints .......................................................................... 35 
Table 4 
Treatment Regimens During the Course of the Study ......................................... 48 
Table 5 
Criteria for Dose Delay or Dose Modification of Loncastuximab Tesirine or 
Rituximab in Lonca-R regimen ........................................................................... 49 
Table 6 
Definition of Severity Grades for CTCAE .......................................................... 61 
Table 7 
Estimated Complete Response Rate and 95% CI for each cohort ....................... 64 
 
List of Figures 
Figure 1 
Schematic Representation and Chemical Structure of Loncastuximab Tesirine . 30 
Figure 2 
Study Design ........................................................................................................ 38 
Figure 3 
Anti-drug Antibody Tiered Immunogenicity Testing Strategy ............................ 68 
 
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Loncastuximab Tesirine 
ADCT-402-203 (LOTIS-9) 
Protocol Amendment 3 
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List of Abbreviations  
Abbreviation 
Definition 
β-HCG 
human chorionic gonadotropin 
Ab 
antibodies 
ADA 
anti-drug antibody 
ADC 
antibody-drug conjugate 
ADL 
activities of daily living 
AE 
adverse event 
AIDS 
acquired immunodeficiency syndrome 
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count 
ASCO 
American Society of Clinical Oncology 
AST 
aspartate aminotransferase 
BID 
twice daily 
BOR 
best overall response 
C1D1 
Cycle 1, Day 1 
CD19 
cluster of differentiation 19 
CI 
confidence interval 
CIRS-G 
Cumulative Illness Rating Scale for Geriatrics 
CR 
complete response 
CRF 
case report form 
CRO 
contract research organization 
CRR 
complete response rate 
CSR 
clinical study report 
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
DLBCL 
diffuse large B-cell lymphoma 
DLT 
dose limiting toxicities 
DMC 
Data Monitoring Committee 
DNA 
deoxyribonucleic acid 
DoR 
duration of response 
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Loncastuximab Tesirine 
ADCT-402-203 (LOTIS-9) 
Protocol Amendment 3 
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Abbreviation 
Definition 
ECG 
electrocardiogram(s) 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 
EDC 
electronic data capture 
EoS 
end of study 
EoT 
end of treatment 
EoT CR 
end of treatment complete response 
EPI 
elderly prognostic index 
FACT-Lym 
Functional Assessment of Cancer Therapy-Lymphoma 
FDA 
Food and Drug Administration 
FDG 
fluorodeoxyglucose 
FIL 
Fondazione Italiana Linfomi 
FL 
follicular lymphoma 
FSH 
follicle stimulating hormone 
GCB 
germinal center B-cell 
GCP 
Good Clinical Practice 
G-CSF 
granulocyte colony-stimulating factor 
GGT 
gamma glutamyl transferase 
HBsAg 
hepatitis B surface antigen 
HBV 
hepatitis B virus 
HCV 
hepatitis C virus 
HGBCL 
high-grade B cell lymphoma 
HIV 
human immunodeficiency virus 
HR 
hazard ratio 
HRQoL 
health-related quality of life 
IADL 
instrumental activities of daily living 
IB 
Investigator’s Brochure 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
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Loncastuximab Tesirine 
ADCT-402-203 (LOTIS-9) 
Protocol Amendment 3 
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Abbreviation 
Definition 
IEC 
independent ethics committee 
IPI 
International Prognostic Index 
IRB 
institutional review board 
IV 
intravenous 
LAR 
legally authorized representative 
Lonca 
loncastuximab tesirine 
Lonca-R 
loncastuximab tesirine and rituximab 
LVEF 
left ventricular ejection fraction 
MCL 
mantle cell lymphoma 
MRI 
magnetic resonance imaging 
NHL 
non-Hodgkin’s lymphoma 
ORR 
overall response rate 
OS 
overall survival 
PBD 
pyrrolobenzodiazepine 
PD 
progressive disease 
PET-CT 
positron emission tomography-computed tomography 
PFS 
progression-free survival 
PK 
pharmacokinetic(s) 
PO 
per os (by mouth) 
PR 
partial response 
PRO 
patient reported outcome 
PS 
performance status 
Q3W 
every 3 weeks 
QT 
measure between Q wave and T wave in the electrocardiogram 
QTcB 
Bazett correction of the QT measure 
QTcF 
Fridericia correction of the QT measure 
R 
Rituximab 
RBC 
red blood cell 
R/R 
relapsed/refractory 
R-CHOP 
combination of rituximab, cyclophosphamide, doxorubicin, vincristine, 
and prednisone  
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Loncastuximab Tesirine 
ADCT-402-203 (LOTIS-9) 
Protocol Amendment 3 
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Abbreviation 
Definition 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
s.c. 
subcutaneous 
SC  
Steering Committee 
SCP 
screening cut-point 
SD 
stable disease 
sGA 
simplified geriatric assessment 
SoC 
standard of care 
SoE 
schedule of events 
TEAE 
treatment-emergent adverse event 
ULN 
upper limit of normal 
USPI 
United States Package Insert 
WBC 
white blood cell 
WHO 
World Health Organization 
 
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Loncastuximab Tesirine 
ADCT-402-203 (LOTIS-9) 
Protocol Amendment 3 
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Protocol Synopsis 
Protocol Number: 
ADCT-402-203 
Title: 
A Phase 2 Open-label Study of Loncastuximab Tesirine in Combination 
with Rituximab (Lonca-R) in Previously Untreated Unfit/Frail Patients 
with Diffuse Large B-cell Lymphoma (DLBCL) (LOTIS-9) 
Sponsor: 
ADC Therapeutics SA 
Study Phase: 
Phase 2 
Rationale: 
Diffuse large B-cell lymphoma (DLBCL) is the most frequently diagnosed 
non-Hodgkin’s lymphoma (NHL) with more than one-third of patients 
75 years or older at diagnosis. In general, patients who are ≥75 years face 
unique treatment challenges and experience poor outcomes due to multiple 
factors, including unfavorable disease biology, comorbidities, and an 
inability to tolerate standard first-line therapy. Additionally, up to 25% of 
older adults with DLBCL do not receive any first-line therapy and this 
number is even higher in patients ≥ 75 years of age or in patients with poor 
performance status. There is also a significant heterogeneity in how older 
patients are evaluated for fitness and ability to tolerate therapy. American 
Society of Clinical Oncology (ASCO) guidelines currently recommend a 
comprehensive geriatric assessment for all older patients > 65 years of age, 
however, very few studies in patients with DLBCL required a geriatric 
assessment tool for inclusion or to inform treatment choice. The simplified 
geriatric assessment (sGA) developed by the Fondazione Italiana Linfomi 
(FIL) identifies three distinct categories (fit, unfit, and frail) based on age, 
activities of daily living (ADL), instrumental activities of daily living 
(IADL) and the Cumulative Illness Rating Scale for Geriatrics (CIRS-G). 
In all age groups, including patients ≥ 75 years who are fit, standard 
first-line therapy consists of immuno-chemotherapy, such as R-CHOP 
(rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone). 
Unfit patients, defined (per sGA) as ≥ 80 years of age with co-existing 
medical conditions are often unable to tolerate full-dose R-CHOP. The 
current recommendation in this patient population favors the use of 
R-mini-CHOP (50% of R-CHOP dose) as a compromise between efficacy 
and safety. In the SENIOR study, the overall response rate (ORR) was 73% 
and the complete response (CR) rate was 53% with a 2-year progression 
free survival (PFS) of 56% in patients who received R-mini-CHOP. An 
ORR of 61.5% and CR rate of 43.5% with single-agent mosunetuzumab, a 
CD20 × CD3 T-cell engaging bispecific, was reported in a similar patient 
population. Frail patients, defined (per sGA) as ≥ 80 years of age with more 
significant co-existing medical conditions are often unable to tolerate 
R-mini-CHOP and have no definitive standard of care (SoC). There is an 
additional population of patients who are > 65 years of age with cardiac 
comorbidities that preclude the use of an anthracycline-containing regimen 
and for which there is no SoC. Recent studies in patients who are unable to 
tolerate anthracycline-containing regimens demonstrate an ORR of 
approximately 61% and a CR rate of 29.5% to 53% with a 2-year PFS 
between 38% to 49.8% There remains an unmet need to improve outcomes 
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ADCT-402-203 (LOTIS-9) 
Protocol Amendment 3 
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for these patients by incorporating novel agents into effective regimens 
with improved safety and tolerability when compared to existing SoC. 
Loncastuximab tesirine (ADCT-402) is an antibody-drug conjugate (ADC) 
directed against human cluster of differentiation 19 (CD19) that is well 
tolerated and has been shown to have antitumor activity in patients with 
relapsed/refractory (R/R) DLBCL, with ~48% of adult patients having a 
response. In LOTIS-1, a Phase 1 dose finding and expansion study in R/R 
NHL, there were 27 patients with R/R DLBCL who were ≥ 75 years of age 
with an ORR of 55.6% across all dose levels. In LOTIS-2, a pivotal Phase 
2 single-arm study in patients with R/R DLBCL, there were 21 patients 
who were ≥ 75 years of age with an ORR of 52.4% and a CR rate of 38.1%. 
The combination of loncastuximab tesirine and rituximab (Lonca-R) is 
based on preclinical evidence that the addition of rituximab to anti-CD19 
ADC therapy may result in prolonged tumor control. Other clinical studies 
show that the addition of rituximab to standard chemotherapy regimens 
(e.g., CHOP, GemOx [gemcitabine and oxaliplatin]) improves efficacy.  
Lonca-R is also being explored in a Phase 3 randomized study in patients 
with R/R DLBCL (LOTIS-5; NCT04384484).  
Objectives: 
Primary Objectives 
Cohort A 
• 
To assess the efficacy of a response-adapted treatment of Lonca-R 
in unfit patients with previously untreated DLBCL, or HGBCL, or 
Grade 3b FL 
Cohort B 
• 
To assess the tolerability and efficacy of a response-adapted 
treatment of Lonca-R in frail patients or patients with cardiac 
comorbidities with previously untreated DLBCL, or HGBCL, or 
Grade 3b FL, who are ineligible for standard R-mini-CHOP 
Secondary Objectives 
Cohort A and Cohort B  
• 
Further evaluate the efficacy of Lonca-R  
• 
To characterize the safety profile of Lonca-R 
• 
To characterize the PK profile of Lonca when given in combination 
with rituximab  
• 
To evaluate the immunogenicity of Lonca when given in 
combination with rituximab  
• 
To evaluate the impact of Lonca-R treatment on treatment-related 
and disease-related symptoms, patient-reported functions, and 
overall health status 
Exploratory Objectives 
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Loncastuximab Tesirine 
ADCT-402-203 (LOTIS-9) 
Protocol Amendment 3 
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Endpoints: 
(Co-)Primary Endpoints 
Cohort A  
• 
CR rate according to the 2014 Lugano Classification criteria  
Cohort B 
• 
CR rate according to the 2014 Lugano Classification criteria 
• 
Tolerability: Percentage of patients completing a total of 4 cycles of 
therapy divided by the total number of patients. 
Secondary Endpoints 
Cohort A and B 
• 
ORR according to the 2014 Lugano Classification 
• 
2-yr PFS  
• 
3-yr overall survival (3-yr OS) 
• 
Duration of response (DoR)  
• 
Frequency and severity of adverse events (AEs) and serious adverse 
events (SAEs) 
• 
Changes from baseline in safety laboratory variables, vital signs, 
physical examinations, Eastern Cooperative Oncology Group scale 
of performance status (ECOG PS) 
• 
Concentrations and PK parameters of loncastuximab tesirine 
pyrrolobenzodiazepine (PBD)-conjugated antibody, total antibody, 
and SG3199 unconjugated warhead 
• 
Frequency of confirmed positive anti-drug antibody (ADA) 
responses, their associated titers and, if applicable, neutralizing 
activity to loncastuximab tesirine after treatment with loncastuximab 
tesirine when given in combination with rituximab  
• 
Changes in patient-reported outcomes (e.g., symptoms, functions, 
and overall health status) from baseline as evaluated by Functional 
Assessment of Cancer Therapy - Lymphoma (FACT-Lym)  
Exploratory Endpoints 
 
Study Design: 
This is a Phase 2, multicenter, multi-cohort, open-label study of Lonca-R 
in unfit/frail patients with previously untreated DLBCL. Fitness and frailty 
of the patients will be assessed using the sGA tool developed by the FIL. 
A response-adapted approach will be used in this study. Two parallel 
cohorts will enroll patients; Cohort A will enroll unfit patients and 
Cohort B will enroll frail patients or patients with cardiac comorbidities.  
A treatment cycle in the study is defined as 3 weeks (i.e., 21 days). 
Cohort A will assess efficacy and Cohort B will assess the efficacy and 
tolerability of Lonca-R. 
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After completion of 3 cycles of Lonca-R treatment, patients who achieve 
CR or PR will continue to receive 1 additional cycle or 3 cycles of Lonca-R, 
respectively. Patients in Cohort A who do not achieve a CR or PR will 
discontinue study treatment. For Cohort B only, patients who achieve stable 
disease (SD) and derive clinical benefit per the treating physician may 
continue to receive additional 3 cycles of Lonca-R. 
Based on the results from Cohort A and/or B, a protocol amendment will 
be considered to further evaluate the Lonca-R combination in these patient 
populations. 
Patient Selection:  
Inclusion Criteria: 
Inclusion Criteria for both cohorts: 
1. Male or female  
2. Pathologic diagnosis of DLBCL, as defined by the 2016 
World Health Organization (WHO) classification (including patients 
with DLBCL transformed from indolent lymphoma), or high-grade 
B cell lymphoma (HGBCL), or Grade 3b follicular lymphoma (FL). 
3. Measurable disease as defined by the 2014 Lugano Classification  
4. Stages I-IV  
5. ECOG PS 0-2; ECOG PS 3 allowed if decline in status is deemed 
related to lymphoma & felt to be potentially reversible by the treating 
physician  
6. Adequate organ function as defined by screening laboratory values 
within the following parameters: 
a. Absolute neutrophil count (ANC) ≥ 1.0 × 103/µL (off growth 
factors at least 72 hours) 
b. Platelet count ≥ 75 × 103/µL without transfusion in the past 
7 days 
c. Alanine aminotransferase (ALT), aspartate aminotransferase 
(AST), and gamma glutamyl transferase (GGT) ≤ 2.5 × the 
upper limit of normal (ULN)  
d. Total bilirubin ≤ 1.5 × ULN (patients with known Gilbert’s 
syndrome may have a total bilirubin up to ≤ 3 × ULN)  
e. Calculated creatinine clearance > 30 mL/min by the Cockcroft 
and Gault equation 
Note: A laboratory assessment may be repeated a maximum of two times 
during the screening period to confirm eligibility.  
7. Women of childbearing potential (WOCBP) must agree to use a 
highly effective method of contraception from the time of giving 
informed consent until at least 12 months after the last dose of study 
treatment. Men with female partners who are of childbearing 
potential must agree to use a condom when sexually active or practice 
total abstinence from the time of the first dose until at least 7 months 
after the patient receives her/his last dose of study treatment 
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Inclusion Criteria specific for Cohort A: 
8. Unfit as defined by the sGA (includes all of the following):  
a. Aged ≥ 80 years  
b. ADL score of 6 
c. IADL score of 8 
d. CIRS-G: no score of 3-4 and < 5 scores of 2 
Inclusion Criteria specific for Cohort B: 
9. Frail as defined by the sGA: 
a. Aged ≥ 80 years  
b. ADL score of < 6 and/or 
c. IADL score of < 8 and/or 
d. CIRS-G ≥ 1 score of 3-4 and/or ≥ 5 scores of 2  
OR 
10. Aged ≥ 65 - <80 with at least one of the following cardiac 
comorbidities 
that 
make 
anthracycline-containing 
regimens 
inadvisable as determined by the investigator. 
a. Left ventricular ejection fraction (LVEF) ≥ 30 to < 50% 
b. History of myocardial infarction within 6 months prior to 
screening 
c. Ischemic heart disease 
d. History of stroke within 12 months prior to screening 
Exclusion Criteria: 
1. Known history of hypersensitivity to or positive serum human 
anti-drug antibody to a CD19 antibody 
2. Previous therapy for DLBCL, HGBCL, Grade 3b FL (with exception 
of corticosteroid course for symptom management of less than 
14 days) 
3. Previous therapy with loncastuximab tesirine and rituximab for any 
indication 
4. Known history of hypersensitivity to any component of study 
treatment (loncastuximab tesirine and rituximab) 
5. Human immunodeficiency virus (HIV) seropositive with any of the 
following: 
a. CD4+ T-cell (CD4+) counts < 350 cells/µL 
b. Acquired immunodeficiency syndrome (AIDS) - defining 
opportunistic infection within 12 months prior to screening 
c. Not on anti-retroviral therapy, or on anti-retroviral therapy for 
< 4 weeks at the time of screening 
d. HIV viral load ≥ 400 copies/mL 
6. Serologic evidence of chronic hepatitis B virus (HBV) infection and 
unable or unwilling to receive standard prophylactic antiviral 
therapy or with detectable HBV viral load 
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7. Serologic evidence of hepatitis C virus (HCV) infection without 
completion of curative treatment or with detectable HCV viral load 
8. History of Stevens-Johnson syndrome or toxic epidermal necrolysis 
9. Lymphoma with active central nervous system involvement at the 
time of screening, including leptomeningeal disease 
10. Clinically significant third space fluid accumulation (i.e., ascites 
requiring drainage or pleural effusion that is either requiring 
drainage or associated with shortness of breath) 
11. Major surgery, radiotherapy, chemotherapy, or other anti-neoplastic 
therapy within 14 days prior to start of study drug (Cycle 1 Day 1 
[C1D1]), except shorter if approved by the Sponsor 
12. Use of any other experimental medication within 14 days prior to 
start of study drug (C1D1) 
13. Received live vaccine within 4 weeks of C1D1 
14. Congenital long QT syndrome or a corrected QTcF interval of 
> 480 ms at screening (unless secondary to pacemaker or bundle 
branch block)  
15. Active second primary malignancy other than non-melanoma skin 
cancers, non-metastatic prostate cancer, in situ cervical cancer, 
ductal or lobular carcinoma in situ of the breast, or other malignancy 
that the Sponsor’s Medical monitor and Investigator agree, and 
document should not be exclusionary 
16. Any other significant medical illness, abnormality, or condition that 
would, in the Investigator’s judgment, make the patient 
inappropriate for study participation or put the patient at risk 
Estimated Duration 
of Patient 
Participation and 
Study Duration: 
The duration of the study participation for each patient is defined as the 
time from the date of signed written informed consent to the completion of 
the follow-up period, withdrawal of consent, loss to follow-up, or death, 
whichever occurs first. 
The study will include a Screening Period (up to 28 days), a Treatment 
Period (4-6 cycles [each of 3 weeks]), and a Follow-up Period (up to 
5 years after treatment discontinuation). 
After the last dose of Lonca-R, all patients will be followed every 12 weeks 
for 1 year, then every 24 weeks for up to 3 years, then annually up to 
5 years. 
The visits will be generally completed at the clinic. However, when disease 
assessments are not planned for a follow-up visit, the visit can be done by 
phone. 
Patients who have progressed will be followed for survival for up to 5 years 
after the last dose of study drug. 
The end of study occurs at the last scheduled visit/procedure for the last 
patient, unless the study is terminated earlier by the Sponsor. 
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Efficacy 
Assessments: 
Disease 
assessments: 
positron 
emission 
tomography-computed 
tomography (PET-CT) Note: If the disease is not fluorodeoxyglucose 
(FDG)- avid at baseline, CT or magnetic resonance imaging (MRI) may be 
used. The assessment method determined to identify sites of disease at 
baseline should be used for all subsequent assessments. 
Safety Assessments: 
• 
Physical examination 
• 
ECOG PS 
• 
Height and weight 
• 
Vital signs 
• 
Pregnancy test, if applicable 
• 
Safety laboratories (hematology, chemistry, urinalysis)  
• 
AEs/SAEs, grading per Common Terminology Criteria for Adverse 
Events (CTCAE), version 5.0 
Other Assessments: 
• 
Patient-reported outcomes (PROs) 
• 
Blood sampling for PK, ADA
  
• 
 
Study Drug, Dosage, 
and Mode of 
Administration: 
A treatment cycle is defined as every 3 weeks (Q3W) 
• 
Lonca-R 
o Loncastuximab tesirine is administered in a 30-minute 
intravenous (IV) infusion (see Table 1 for administration 
schedule) 
o Rituximab is administered in an IV infusion on day 1 of each 
cycle. Use of the subcutaneous (s.c.) formulation (Cycle 2 and 
beyond) or biosimilars is allowed. 
During the Screening Period, patients may receive pre-phase therapy with 
prednisone 40 mg/m2 for up to 14 days per the treating investigator’s 
discretion.  
Details of dose and administration scheme of the study are described in 
Table 1. 
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Table 1 
Treatment with Lonca-R  
Cohort 
Treatment Regimen 
(1 cycle = 3 weeks [21 days]) 
Cohort A and 
Cohort B 
Lonca-R 
Cycle 1: 
Day 1: Rituximab IV 375 mg/m2 
Day 2: Loncastuximab tesirine 150 µg/kg IV  
Cycle 2: 
Day 1:Rituximab IV* 375 mg/m2 and loncastuximab 
tesirine 150 µg/kg IV 
Cycles 3-4:† 
Day 1: Rituximab IV* 375 mg/m2 and 
loncastuximab tesirine 75 µg/kg IV 
*If subcutaneous rituximab is used, the dose is 1400 mg, flat dose 
†Up to 6 total cycles of Lonca-R may be administered per protocol 
 
Granulocyte colony-stimulating factor (G-CSF) may be administered as 
primary prophylaxis starting with Cycle 1 of therapy and continue through 
each cycle of therapy for patients per the treating investigator’s discretion 
and institution guidelines (optional). 
Cycle 2 and beyond when loncastuximab tesirine and rituximab are given 
concomitantly, loncastuximab tesirine will be administered prior to 
rituximab at a dose as specified in Table 1. 
Sample Size: 
Approximately 40 patients in Cohort A and approximately 40 patients in 
Cohort B  
Statistical 
Considerations: 
A sample size of 40 patients for each cohort is considered adequate to 
assess safety and efficacy in the corresponding study population. 
The percentage of ORR and CR rate with its 95% CI will be presented 
descriptively.  
Safety analyses will be presented descriptively. 
 
 
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Schedule of Events 
Table 2 
Schedule of Events (SoE) 
 
Protocol 
Section 
Screening 
Treatment Period 
 
 
Follow-up 
Period (up to 
5 years from 
EoT) 
1 cycle = 21 days 
 
 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 
4-6 
EoT2 
 
 
 
 
Day - 28 to 
Day -1 
Day 1 
Day 2 
(+2 days) 
Day 9 
(±2 days) 
Day 1 
(±2 days) 
Day 1 
(±2 days) 
Day 15 
(±2 days) 
Day 1 
(±2 days) 
 
 
Informed consent 
7.1 
X 
 
 
 
 
 
 
 
 
 
Eligibility criteria 
5.1, 
5.2 
X 
 
 
 
 
 
 
 
 
 
Geriatric Assessment 
(sGA)  
5.1, 
7.2 
X1 
 
 
 
 
 
 
 
 
 
Demography 
7.2, 
9.5 
X 
 
 
 
 
 
 
 
 
 
Medical/Cancer history3 
5.1, 
9.5 
X 
 
 
 
 
 
 
 
 
 
Physical examination 
7.4.1 
X 
X 
 
X 
X 
X 
 
X 
X 
 
Vital signs4 
7.4.4 
X 
X 
X 
X 
X 
X 
 
X 
X 
 
12-lead ECG 
7.4.7 
X 
 
 
 
 
 
 
 
 
 
Height 
7.4.3 
X 
 
 
 
 
 
 
 
 
 
Weight 
7.4.3 
X 
X 
 
X 
X 
X 
 
X 
X 
 
ECOG PS 
7.4.2 
X 
X 
 
 
X 
X 
 
 
X 
 
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Protocol 
Section 
Screening 
Treatment Period 
 
 
Follow-up 
Period (up to 
5 years from 
EoT) 
1 cycle = 21 days 
 
 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 
4-6 
EoT2 
 
 
 
 
Day - 28 to 
Day -1 
Day 1 
Day 2 
(+2 days) 
Day 9 
(±2 days) 
Day 1 
(±2 days) 
Day 1 
(±2 days) 
Day 15 
(±2 days) 
Day 1 
(±2 days) 
 
 
Disease assessment 
7.3 
X6 
 
 
 
 
 
X6 
X 
(end of C6 
only) 
X6  
 
X 
Every 12 weeks 
until 1 year, 
then every 
24 weeks for 
2 years then 
annually 
Hematology and 
Chemistry7 
7.4.5 
X 
XF 
X 
X 
X 
X 
 
X 
X 
 
HIV, HBV, HCV status 
7.4.5 
X 
 
 
 
 
 
 
 
 
 
UrinalysisF 
7.4.5 
X 
X 
 
 
 
 
 
 
X 
 
Pregnancy test8 
7.4.6 
X 
X 
 
 
 
X 
 
 
X 
X 
LVEF (Echo/MUGA) 
5.1 
X 
 
 
 
 
 
 
 
X 
 
PK sample9 
7.5.1 
 
 
X 
(pre-dose, 
Lonca EOI) 
 
X (pre-
dose, 
Lonca 
EOI) 
X 
(pre-dose, 
Lonca 
EOI) 
 
X 
(pre-dose, 
Lonca 
EOI) 
X 
 
ADA sample10 
7.5.2 
 
 
X 
(pre-dose) 
 
X 
(pre-dose) 
 
 
X 
(C4 and 
C6 only; 
pre-dose) 
X 
 
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Protocol 
Section 
Screening 
Treatment Period 
 
 
Follow-up 
Period (up to 
5 years from 
EoT) 
1 cycle = 21 days 
 
 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 
4-6 
EoT2 
 
 
 
 
Day - 28 to 
Day -1 
Day 1 
Day 2 
(+2 days) 
Day 9 
(±2 days) 
Day 1 
(±2 days) 
Day 1 
(±2 days) 
Day 15 
(±2 days) 
Day 1 
(±2 days) 
 
 
Patient Reported 
Outcomes Assessment12 
7.6 
 
X12 
 
 
X12 
X12 
 
X12 
X12 
 
Optional Pre-Phase 
Therapy 
4.2.1 
X 
 
 
 
 
 
 
 
 
 
Lonca-R13 
 
Premedication14 
6.4 
 
X 
 
 
X 
X14 
 
X14 
 
 
Rituximab 
administration 
6.3 
 
X 
 
 
X 
X13 
 
X13 
 
 
Loncastuximab tesirine 
administration 
6.3 
 
 
X 
 
X 
X13 
 
X13 
 
 
Concomitant 
medications 
6.9 
From ICF signature date or D-14, whichever is earlier, until 30 days after last dose of study treatment and as indicated 
for AE/SAEs thereafter. 
AEs 
8 
All AE/SAEs, regardless of the relationship to study treatment, will be reported from ICF signature date until 15 weeks 
after last dose of study treatment or the start of new anti-cancer therapy, whichever is earlier; thereafter, only related 
SAEs will be reported. 
Survival information 
 
 
 
 
 
 
 
 
 
 
X 
X 
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Protocol 
Section 
Screening 
Treatment Period 
 
 
Follow-up 
Period (up to 
5 years from 
EoT) 
1 cycle = 21 days 
 
 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 
4-6 
EoT2 
 
 
 
 
Day - 28 to 
Day -1 
Day 1 
Day 2 
(+2 days) 
Day 9 
(±2 days) 
Day 1 
(±2 days) 
Day 1 
(±2 days) 
Day 15 
(±2 days) 
Day 1 
(±2 days) 
 
 
First new anticancer 
treatment information 
 
 
 
 
 
 
 
 
 
 
X 
X 
Note: Same SoE will be followed for all the enrolled patients irrespective of cohort of the study.  
Abbreviations: AE, adverse event; 
; ECG, electrocardiogram; ECOG PS, Eastern Cooperative Oncology Group scale of 
performance status; EoT, end of treatment;
 
 HBV, hepatitis B virus; HCV, hepatitis C virus; HIV, 
human immunodeficiency syndrome; ICF, informed consent form; LVEF, left ventricular ejection fraction; MUGA, multiple-gated acquisition; PET-CT, Positron 
emission tomography - computed tomography; SAE, serious adverse event; sGA, simplified geriatric assessment; SoE, schedule of event. 
1. 
sGA is based on the scores of 3 surveys: ADL (Appendix 12.4), IADL (Appendix 12.5) and CIRS-G (Appendix 12.6). sGA should be done at the end of the 
screening period once all other eligibility criteria have been met.  
2. 
End of Treatment visit (EoT) should occur 28 (±7) days from the last dose of study treatment, and in any case prior to the initiation of new anticancer 
treatment. When EoT visit coincides with a scheduled visit, the scheduled visit will become EoT visit. 
3. 
Cancer history to include but not limited to histologic subtype, cell of origin, international prognostic index (IPI), Ann Arbor stage, extranodal involvement, 
bulky disease (≥ 10 cm). 
4. 
Vital signs should include arterial blood pressure, heart rate, respiratory rate, and body temperature. 
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6. 
Screening imaging (PET-CT) must be performed within 4 weeks prior to C1D1 and the same assessment method must be used throughout the study. Imaging 
should be performed at the indicated time points even if drug dosing is delayed. Imaging prior to Cycle 4 and at end of Cycle 6 should be performed within 
±1 weeks of the scheduled time point; all other imaging will be performed within ±2 weeks of the scheduled time point. If a scan was performed within 6 
weeks of EoT, it does not need to be repeated at the EoT visit.  
7. 
For assessment of intermediate or high risk tumor lysis syndrome (TLS), related laboratory tests including complete blood count with white blood cells 
(WBC) differential, and blood chemistry (potassium, uric acid, phosphorus, calcium, lactate dehydrogenase [LDH] and creatinine) will be checked daily 
during first 24-72 hours after C1D1 or according to institutional routine. 
8. 
Pregnancy test will be limited to females of childbearing potential; a final pregnancy test should be performed ≥ 12 months after the last dose of study drug 
has been administered (remote testing may be performed).  
9. 
For days of loncastuximab tesirine infusion, PK will be collected predose (preferably within 2 h prior to start of infusion), and at the end (within -5 to 
+10 min) of Lonca infusion. 
10. ADA samples will be collected predose (preferably within 2 h prior to start of infusion) on C1D2, C2D1 and then every other cycle beginning with C4. 
Patients who test positive for ADAs may be requested to supply additional ADA samples. 
12. PRO instrument should be completed prior to clinical assessment. 
13. Patients in both cohorts will receive 1 additional cycle of assigned therapy (Cycle 4) if in CR and 3 additional cycles if PR (Cycles 4-6) based on PET-CT 
after Cycle 3. Patients in cohort B who achieve stable disease and are receiving clinical benefit may receive 3 additional cycles (Cycles 4-6). 
14. Premedication for the Lonca-R regimen consists of dexamethasone 4 mg PO/IV BID × 3 days beginning the day prior to loncastuximab tesirine; 
premedication(s) for rituximab will be given according to institution standard. 
 
Visit Scheduling Windows:  
• 
Treatment Period: C1D1 is the reference day, otherwise visit day ± 2 days, except of visit day 2 where the time window is +2 days.  
• 
EoT: Patients who complete all assigned treatment cycles of treatment should have their EoT visit performed 28 (±7) days from the last dose of study 
treatment, and in any case prior to the initiation of new anticancer treatment.  
• 
Follow-up Period: visit day ± 14 days. 
 
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1 Introduction and Background 
1.1 
Diffuse Large B-cell Lymphoma and Unfit/Frail Patients 
Diffuse large B-cell lymphoma (DLBCL) is the most frequently diagnosed non-Hodgkin’s 
lymphoma (NHL) with more than one-third of patients 75 years or older at diagnosis. 
In general, patients who are ≥75 years face unique treatment challenges and experience poor 
outcomes due to a number of factors including unfavorable disease biology, comorbidities, and 
an inability to tolerate standard first-line therapy. Additionally, up to 25% of older adults with 
DLBCL do not receive any first-line therapy and this number is even higher in patients 
≥75 years of age or in patients with poor performance status (Di, 2021). There is also a 
significant heterogeneity in how older patients are evaluated for fitness and ability to tolerate 
therapy. The current American Society of Clinical Oncology (ASCO) guidelines recommend 
a comprehensive geriatric assessment for all older patients > 65 years of age, however, very 
few studies in patients with DLBCL required a geriatric assessment tool for inclusion or to 
inform treatment choice (Tavares & Moreira, 2021). The simplified geriatric assessment (sGA) 
developed by the Fondazione Italiana Linfomi (FIL) identifies three distinct categories (fit, 
unfit, and frail) based on age, activities of daily living (ADL), instrumental activities of daily 
living (IADL) and the Cumulative Illness Rating Scale for Geriatrics (CIRS-G) (Merli, 2021; 
Katz, 1963; Parmelee, 1995; Lawton, 1969)  
In all age groups, including patients ≥75 years who are fit, standard first-line therapy consists 
of immuno-chemotherapy, such as R-CHOP (rituximab, cyclophosphamide, doxorubicin, 
vincristine, and prednisone) (NCCN Guidelines, 2021). Unfit patients, defined (per sGA) as 
≥80 years of age with co-existing medical conditions are often unable to tolerate full-dose 
R-CHOP. The current recommendation in this patient population favors the use of 
R-mini-CHOP (50% of R-CHOP dose) as a compromise between efficacy and safety 
(Peyrade, 2011). In the SENIOR study by Oberic (2021), the overall response rate (ORR) was 
73% and the complete response (CR) rate was 53% with a 2-year progression-free survival 
(PFS) of 56% in patients who received R-mini-CHOP. Olszewski (2021) reported an ORR of 
61.5% and CR rate of 43.5% with single-agent mosunetuzumab, a CD20 × CD3 T-cell 
engaging bispecific, was reported in a similar patient population. Frail patients, defined per 
sGA, who are ≥ 80 years of age with more significant co-existing medical conditions are often 
unable to tolerate R-mini-CHOP and have no definitive standard of care (SoC) 
(Morrison, 2020). There is an additional population of patients who are > 65 years of age with 
cardiac comorbidities that preclude the use of an anthracycline-containing regimen and for 
which there is no SoC (Hitz, 2016; Moccia, 2021). Recent studies in patients who are unable 
to tolerate anthracycline-containing regimens demonstrate an ORR of approximately 61% and 
a CR rate of 29.5% to 53% with a 2-year PFS between 38% to 49.8% (Fields, 2014; 
Storti, 2018). There remains an unmet need to improve outcomes for these patients by 
incorporating novel agents into effective regimens with improved safety when compared to 
existing SoC.  
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Loncastuximab tesirine (ADCT-402) is an antibody-drug conjugate (ADC) directed against 
human cluster of differentiation 19 (CD19) that is well tolerated and has been shown to have 
antitumor activity in patients with relapsed or refractory (R/R) DLBCL, with ~48% of adult 
patients having a response.  
In LOTIS-1, a Phase 1 dose-finding and expansion study in R/R NHL, there were 27 patients 
with R/R DLBCL who were ≥ 75 years of age with an ORR of 55.6% across all dose levels.  
In LOTIS-2, a pivotal Phase 2 single-arm study in patients with R/R DLBCL, there were 
21 patients who were ≥ 75 year of age with an ORR of 52.4% and a CR of 38.1%. 
The addition of rituximab is based on preclinical evidence that the addition of rituximab to anti 
CD19 ADC therapy may result in prolonged tumor control (Ryan, 2017) and on clinical studies 
showing that the addition of rituximab to standard chemotherapy regimens (e.g., CHOP, 
GemOx 
[gemcitabine 
and 
oxaliplatin]) 
improves 
efficacy 
(Corazzelli, 2009; 
Habermann, 2006). As the pyrrolobenzodiazepine (PBD) component of loncastuximab tesirine 
produces cell death via deoxyribonucleic acid (DNA) damage in a fashion similar to many 
cytotoxic chemotherapy agents, the addition of rituximab is expected to produce a similar 
improvement in outcome and potentially result in prolonged tumor control. Rituximab will be 
given at the standard dose every 3 weeks (Q3W) to coincide with the administration schedule 
for loncastuximab tesirine to minimize the burden of therapy. This combination is also being 
explored in a Phase 3 randomized study in patients with R/R DLBCL (LOTIS-5; 
NCT04384484). 
1.2 
Description of the Study Drugs 
1.2.1 Loncastuximab Tesirine 
Loncastuximab tesirine (ADCT-402) is an ADC, composed of a humanized monoclonal 
antibody (RB4v1.2) directed against human CD19 conjugated through a cathepsin-cleavable 
linker to SG3199, a PBD dimer cytotoxin. The toxin SG3199 attached to the linker is 
designated as SG3249.  
Pyrrolobenzodiazepines are a class of naturally occurring antitumor antibiotics found in 
Streptomyces. Pyrrolobenzodiazepine monomers bind in the DNA minor groove and form a 
single covalent aminal linkage to the exocyclic N2-amino group of guanine within 
purineguanine-purine sequences. Pyrrolobenzodiazepine dimers, obtained by joining two PBD 
monomers together via an appropriate polymethylene tether, have the ability to produce 
two covalent bonds forming highly cytotoxic DNA interstrand crosslinks (Hartley, 2011).  
The schematic representation of loncastuximab tesirine is presented in Figure 1.  
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ADCT-402-203 (LOTIS-9) 
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Figure 1 
Schematic Representation and Chemical Structure of Loncastuximab 
Tesirine  
Abbreviations: Ala, alanine; mAb, human monoclonal antibody being studied (RB4v1.2); PABC, 
para-aminobenzyl carbamate; PEG, polyethylene glycol; Val, valine. 
 
 
 
 
 
 
 
 
 
1.2.2 Rituximab 
For rituximab or rituximab biosimilar or subcutaneous (s.c.) rituximab formulation, refer 
respectively to each United States Package Insert (USPI) for detailed information including 
safety and efficacy. 
1.3 
Loncastuximab Tesirine - Clinical Results 
1.3.1 Phase 1 Study, ADCT-402-101 
ADCT-402-101 (NCT02669017) is a first-in-human Phase 1 dose-escalation study of 
loncastuximab tesirine in R/R B-NHL patients, who have failed or are intolerant to established 
therapies, or have no other treatment options available. The study was completed with 
183 patients enrolled. 
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Toxicity was manageable. The most common (observed in at least 5% of patients) Grade ≥ 3 
treatment-emergent adverse events (TEAEs) were gamma glutamyl transferase (GGT) 
increased (21.3%); neutropenia (16.9%); anemia (15.3%); neutrophil count decreased (14.8%); 
thrombocytopenia (12.0%); platelet count decreased (10.4%). The TEAEs in 35 (19.1%) 
patients led to treatment discontinuation. Dose-limiting toxicities (DLT) were reported in 
4 patients (3 thrombocytopenia and 1 febrile neutropenia). 
Out of 180 evaluable patients with B-NHL, 48 (26.7%) achieved CR and 34 (18.9%) achieved 
partial response (PR), for an ORR of 82/180 (45.6%). Out of 137 evaluable patients with 
DLBCL, 32 (23.4%) achieved CR and 26 (19.0%) achieved PR, for an ORR of 58/137 (42.3%). 
Out of 14 evaluable patients with FL, 9 (64.3%) achieved CR and 2 (14.3%) achieved PR, for 
an ORR of 11/14 (78.6%). Out of 15 evaluable patients with mantle cell lymphoma (MCL), 
5 (33.3%) achieved CR and 2 (13.3%) achieved PR, for an ORR of 7/15 (46.7%). 
1.3.2 Phase 2 Study, ADCT-402-201 
Study ADCT-402-201 is a Phase 2 study to evaluate the efficacy of loncastuximab tesirine 
used as monotherapy in patients with R/R DLBCL. The study determines the ORR according 
to the 2014 Lugano Classification, as well as evaluate the duration of response (DoR), CR, 
survival, safety, pharmacokinetics (PK), and health-related quality of life (HRQoL). 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Additional details may be found in the current loncastuximab tesirine investigator’s brochure 
(IB). 
1.4 
Benefit/Risk Assessment 
Although R-mini-CHOP has anticancer activity in patients with untreated DLBCL who are 
unfit for full-dose R-CHOP, there is a need for regimens with an improved safety profile and 
better CR and PFS. In addition, there is no current SoC for patients who are frail and/or 
ineligible for anthracycline-based therapy. The combination of loncastuximab tesirine and 
rituximab is expected to provide an increased anti-tumor response however, the efficacy and 
safety of this combination in untreated unfit/frail patients has not been established.  
More detailed information about the known and expected benefits and risks and reasonably 
expected adverse events (AEs) of loncastuximab tesirine may be found in the current IB. 
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2 Study Rationale 
Loncastuximab tesirine is an ADC that has been designed to target and kill CD19-expressing 
malignant B-cells. The Phase 1 study of loncastuximab tesirine in R/R B-cell NHL shows 
significant activity of loncastuximab tesirine with an acceptable safety profile in patients with 
R/R DLBCL, FL, and MCL (Section 1.3.1). The Phase 2 study results verified the efficacy and 
durability of response in heavily pretreated patients with DLBCL and was well-tolerated when 
administered in repeated 3-week cycles at 150 µg/kg for the first two cycles and 75 µg/kg for 
the 
subsequent 
cycles 
(Section 1.3.2). 
A 
Biologics 
License 
Application 
of 
loncastuximab tesirine for R/R DLBCL was approved by the Food and Drug Administration 
(FDA) on 23 April 2021.  
As illustrated above, loncastuximab tesirine has single agent activity against B–NHL subtypes, 
including transformed lymphoma, with significant proportion of disease response in DLBCL, 
including complete remission. The disease course of Grade 3b FL resembles that of DLBCL 
and should be treated accordingly (Salaverria & Siebert, 2011). Patients with Grade 3b FL with 
a significant diffuse component have inferior survival outcomes similar to that of DLBCL 
(Hans, 2003). These patients are often excluded from clinical trials and most treatment 
recommendations are based on retrospective data and small case studies; the curative potential 
of combination chemoimmunotherapy in Grade 3b FL remains unclear (Barraclough, 2021). 
Including this subset of patients is consistent with current international clinical practice 
guidelines that identify Grade 3b FL as an aggressive lymphoma and recommend immediate 
treatment similar to that of DLBCL (Barraclough, 2021; Dreyling,   2020; 
NCCN Guidelines, 2021). The hypothesis is that loncastuximab tesirine in combination with 
rituximab may potentially have improved efficacy & safety for 1st line treatment in unfit/frail 
patients with DLBCL.  
2.1 
Rationale for Study Design 
This is a Phase 2, multi-center adaptive design study with two parallel cohorts which will enroll 
in total approximately 80 unfit or frail patients with previously untreated DLBCL (respectively 
Cohort A and Cohort B, n = 40 patients each). The primary objective will be to determine the 
safety and efficacy of loncastuximab tesirine in combination with rituximab (Lonca-R) in this 
patient population. 
An analysis for efficacy and safety in Cohorts A and B (n = 40 each) as assigned by sGA 
(Merli, 2021) will be conducted. The sGA is a validated objective tool to assess fitness status 
to predict overall survival in older patients with DLBCL.  
A response-adapted approach for both cohorts will be utilized where patients in the unfit & 
frail cohorts who achieve a CR after 3 cycles of therapy will receive one additional cycle of 
therapy (4 cycles total). Patients in the unfit cohort (Cohort A) who achieve a PR after 3 cycles 
of therapy will receive 3 additional cycles of therapy (6 cycles total). Patients in the frail cohort 
(Cohort B) who achieve a PR/stable disease (SD) will receive 3 additional cycles of therapy 
(6 cycles total). In the patient population being evaluated, de-escalating therapy to a total of 
4 cycles in patients who achieve a CR may minimize toxicity while preserving efficacy. End of 
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treatment CR was recently found to be highly predictive for PFS and OS in DLBCL after 
first-line immunochemotherapy (Kostakoglu, 2021). 
2.2 
Rationale for Dose Selection 
In the pivotal monotherapy Phase 2 study for R/R DLBCL, ADCT-402-201, 
loncastuximab tesirine was dosed every 3 weeks, with 150 μg/kg for first two cycles and 
75 μg/kg for the subsequent cycles, which resulted in a high level of efficacy and was well 
tolerated. In addition, PK analyses show that this dosing regimen resulted in comparable 
exposure between Cycle 1 and subsequent cycles and that this dosing regimen resulted in 
consistent drug exposure across cycles. The dosing regimen chosen for this study is based on 
the regimen of loncastuximab tesirine used in the Phase 2 study. This study will utilize the 
same dosing regimen for Lonca-R as the ongoing Phase 3 clinical trial LOTIS-5 comparing 
the Lonca-R regimen (after a safety run-in) to R-GemOx in 2L transplant-ineligible patients 
with DLBCL. Treatment-naïve patients will present with levels of lymphocytes (within normal 
limits) which are believed to function as an antigen sink to loncastuximab tesirine. 
Administration of rituximab is known to reduce lymphocytes levels within a day 
(Blasco, 2009). Therefore, loncastuximab administration in Cycle 1 is given 1 day (+2 days) 
after rituximab administration. 
 
 
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3 Study Objectives and Endpoints 
Table 3 
Study Objectives and Endpoints 
Objectives 
Endpoints 
Primary 
 
Cohort A 
To assess the efficacy of a response-adapted treatment of 
Lonca-R in unfit patients with previously untreated DLBCL 
or HGBCL or Grade 3b FL. 
 
Cohort B 
• 
To assess the tolerability and efficacy of a response-
adapted treatment of Lonca-R in frail patients or patients 
with cardiac comorbidities with previously untreated 
DLBCL or HGBCL or Grade 3b FL who are ineligible 
for standard R-mini-CHOP. 
(Co-)Primary Endpoints: 
Cohort A 
CR rate, defined as proportion of patients with a BOR of CR according to the 
2014 Lugano Classification criteria (Appendix 12.2). 
 
Cohort B 
• 
CR rate, defined as proportion of patients with a BOR of CR according to 
the 2014 Lugano Classification criteria. 
• 
Tolerability as defined by the percentage of patients completing a total of 
4 cycles of therapy divided by the total number of patients. 
Secondary 
Cohort A and Cohort B: 
• 
Further evaluate the efficacy of Lonca-R  
• 
To characterize the safety profile of Lonca-R 
• 
To characterize the PK profile of Lonca when given in 
combination with rituximab  
• 
To evaluate the immunogenicity of Lonca when given in 
combination with rituximab 
• 
To evaluate the impact of Lonca-R treatment on 
treatment-related and disease-related symptoms, patient-
reported functions, and overall health status 
Cohort A and Cohort B: 
• 
ORR according to the 2014 Lugano Classification, defined as the 
proportion of patients with a BOR of CR or PR. 
• 
2-year PFS, defined as the proportion of patients that are PFS event-free at 
2 years. 
• 
3-yr OS, defined as the proportion of patients that are OS event-free at 
3 years. 
• 
DoR defined as the time from the first documentation of tumor response 
(CR or PR) to disease progression or death 
• 
Frequency and severity of AEs and SAEs. 
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Objectives 
Endpoints 
• 
Changes from baseline in safety laboratory variables, vital signs, physical 
examinations, ECOG PS 
• 
Concentrations 
and 
PK 
parameters 
of 
loncastuximab tesirine 
PBD-conjugated antibody, total antibody, and SG3199 unconjugated 
warhead 
• 
Frequency of confirmed positive ADA responses, their associated titers 
and, if applicable, neutralizing activity to loncastuximab tesirine after 
treatment with loncastuximab tesirine when given in combination with 
rituximab  
• 
Changes in patient-reported outcomes (e.g., symptoms, functions, and 
overall health status) from baseline as evaluated by FACT-Lym 
Exploratory 
Abbreviations: ADA, anti-drug antibody; AE, adverse event; BOR, best overall response; CR, complete response; DLBCL, diffuse large B-cell lymphoma; DoR, 
duration of response; EoT, end of treatment; ECOG PS, Eastern Cooperative Oncology Group scale of performance status; FACT-Lym, Functional Assessment of 
Cancer Therapy-Lymphoma; Lonca-R, loncastuximab tesirine and rituximab; ORR, overall response rate; OS, overall survival; PBD, pyrrolobenzodiazepine; PFS, 
progression free survival; PK, pharmacokinetic; PR, partial response; PS, performance status; R-CHOP, combination of rituximab, cyclophosphamide, doxorubicin, 
vincristine, and prednisone, SAE, serious adverse event. 
 
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4 Study Design 
4.1 
Overview 
This is a Phase 2 open-label, study of Lonca-R in previously untreated unfit/frail patients with 
DLBCL. The study will include a Screening Period (up to 28 days), a Treatment Period 
(4-6 cycles [each of 3 weeks]), and a Follow-up Period (for up to 5 years after treatment 
discontinuation) (Section 4.2).  
A response-adapted approach will be used in this study. Two parallel cohorts will enroll 
patients in the study. Cohort A will enroll unfit patients and Cohort B will enroll frail patients 
or patients with cardiac comorbidities. Cohort A will assess efficacy and Cohort B will assess 
the efficacy and tolerability of Lonca-R. Fitness and frailty of the patients will be assessed 
based on the sGA tool developed by the FIL (Merli, 2021). See Section 7.2 for details about 
sGA.  
The study will enroll approximately 80 patients (approximately 40 patients in each cohort).  
Based on the results from Cohort A and/ or B a protocol amendment will be considered to 
further evaluate the Lonca-R combination in these patient populations. 
Enrolled patients in both cohorts will receive Lonca-R for 3 cycles. Patients who achieve CR 
after 3 cycles of Lonca-R treatment will continue to receive one additional cycle of Lonca-R. 
Patients who achieve PR after 3 cycles of Lonca-R will continue to receive additional 3 cycles 
of Lonca-R. Additionally, for Cohort B only, patients who achieve SD and derive clinical 
benefit per the treating physician may also continue to receive additional 3 cycles of Lonca-R. 
Details of dosing regimen are described in Section 6.3 (Table 4), (see Figure 2). 
The duration of the study participation for each patient is defined as the time from the date of 
signed written informed consent to the completion of the follow-up period, withdrawal of 
consent, loss to follow-up, or death, whichever occurs first. Each patient enrolled in both 
cohorts will have the same duration of study participation.  
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18 weeks) or unacceptable toxicity, or other discontinuation criteria (see Section 5.5), 
whichever occurs first. Details of the treatment regimen are described in Table 4.  
4.2.3 End of Treatment 
An EoT visit should occur 28 (±7) days from the last dose of the study treatment, and in any 
case prior to the initiation of new anticancer treatment.  
When EoT visit coincides with a scheduled visit, the scheduled visit will become EoT visit. 
4.2.4 Follow-up Period 
All patients, regardless of disease status, will be followed for up to 5 years from EoT, or until 
withdrawal of consent, loss to follow-up, or death, whichever occurs first. All patients will be 
followed every 12 weeks for 1 year, then every 24 weeks for up to 3 years then annually for up to 
5 years from EoT. 
When disease assessments are not planned for a follow-up visit, respective visit can be done 
by phone. 
4.2.5 End of Study 
The end of study (EoS) occurs at the last scheduled visit/procedure for the last patient, unless 
the study is terminated earlier by Sponsor. The date of death of individual patient is considered 
as EoS whose survival status was informed at any later contact date. 
4.3 
Steering Committee (SC) 
A Steering Committee (SC) has been established for the study. It is composed of global DLBCL 
experts, who may participate in the study, and the Sponsor’s representatives. The SC will 
collaborate with the Sponsor throughout the conduct of the trial by providing insights and 
recommendations towards successful study execution, assist with data interpretation, and 
advise if changes to the trial are warranted. More details can be found in the 
Steering Committee charter. 
 
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5 Patient Population 
Patients must meet all inclusion criteria and none of the exclusion criteria to be eligible for the 
study. All criteria have to be assessed during screening, unless otherwise specified. 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known 
as protocol waivers or exemptions, is not permitted. 
5.1 
Inclusion Criteria 
Inclusion Criteria for both cohorts: 
1. Male or female  
2. Pathologic diagnosis of DLBCL, as defined by the 2016 World Health Organization 
(WHO) classification (including patients with DLBCL transformed from indolent 
lymphoma), or high-grade B cell lymphoma (HGBCL), or Grade 3b 
follicular lymphoma (FL). 
3. Measurable disease as defined by the 2014 Lugano Classification (Appendix 12.2). 
4. Stages I-IV  
5. Eastern Cooperative Oncology Group scale of performance status (ECOG PS) 0-2; 
ECOG PS 3 allowed if decline in status is deemed related to lymphoma & felt to be 
potentially reversible by the treating physician  
6. Adequate organ function as defined by screening laboratory values within the 
following parameters: 
a. Absolute neutrophil count (ANC) ≥ 1.0 × 103/µL (off growth factors at least 
72 hours) 
b. Platelet count ≥ 75 × 103/µL without transfusion in the past 7 days 
c. Alanine aminotransferase (ALT), AST, and GGT ≤ 2.5 × the upper limit of normal 
(ULN)  
d. Total bilirubin ≤ 1.5 × ULN (patients with known Gilbert’s syndrome may have a 
total bilirubin up to ≤ 3 × ULN)  
e. Calculated creatinine clearance > 30 mL/min by the Cockcroft and Gault equation 
Note: A laboratory assessment may be repeated a maximum of two times during the 
screening period to confirm eligibility.  
7. Women of childbearing potential (WOCBP)* must agree to use a highly effective** 
method of contraception from the time of giving informed consent until at least 
12 months after the last dose of study treatment. Men with female partners who are of 
childbearing potential must agree to use a condom when sexually active or practice 
total abstinence from the time of the first dose until at least 7 months after the patient 
receives her/his last dose of study treatment 
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* WOCBP are defined as sexually mature women who have not undergone bilateral 
tubal ligation, bilateral oophorectomy, or hysterectomy; or who have not been 
postmenopausal (i.e., who have not menstruated at all) for at least one year. 
A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. A high follicle stimulating hormone (FSH) level in the postmenopausal 
range may be used to confirm a postmenopausal state in women not using hormonal 
contraception or hormonal replacement therapy. However, in the absence of 
12 months of amenorrhea, a single FSH measurement is insufficient. 
** Highly effective forms of birth control are methods that achieve a failure rate of less 
than 1% per year when used consistently and correctly. Highly effective forms of birth 
control include: hormonal contraceptives associated with inhibition of ovulation (oral, 
injectable, patch, and intrauterine devices), male partner sterilization, or total 
abstinence from heterosexual intercourse, when this is the preferred and usual lifestyle 
of the patient. 
Note: The double-barrier method (e.g., synthetic condoms, diaphragm, or cervical cap 
with spermicidal foam, cream, or gel), periodic abstinence (such as calendar, 
symptothermal, post ovulation), withdrawal (coitus interruptus), lactational 
amenorrhea method, and spermicide-only are not acceptable as highly effective 
methods of contraception. 
Inclusion Criteria specific for Cohort A: 
8. Unfit as defined by the sGA (includes all of the following): 
a. Aged ≥ 80 years  
b. ADL score of 6 
c. IADL score of 8 
d. CIRS-G: no score of 3-4 and < 5 scores of 2 
Inclusion Criteria specific for Cohort B: 
9. Frail as defined by the sGA: 
a. Aged ≥ 80 years  
b. ADL score of < 6 and/or 
c. IADL score of < 8 and/or 
d. CIRS-G: ≥ 1 score of 3-4 and/or ≥ 5 scores of 2 
OR 
10. Aged ≥ 65 - < 80  with at least one of the following cardiac comorbidities that make 
anthracycline-containing regimens inadvisable as determined by the investigator 
a. Left ventricular ejection fraction (LVEF) ≥ 30 to < 50% 
b. History of myocardial infarction within 6 months prior to screening 
c. Ischemic heart disease 
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d. History of stroke within 12 months prior to screening 
5.2 
Exclusion Criteria 
1. Known history of hypersensitivity to or positive serum human anti-drug antibody to a 
CD19 antibody 
2. Previous therapy for DLBCL, HGBCL, or Grade 3b FL (with exception of 
corticosteroid course for symptom management of less than 14 days) 
3. Previous therapy with loncastuximab tesirine and rituximab for any indication 
4. Known history of hypersensitivity to any component of study treatment 
(loncastuximab tesirine and rituximab) 
5. Human immunodeficiency virus (HIV) seropositive with any of the following: 
a. CD4+ T-cell (CD4+) counts < 350 cells/µL 
b. Acquired immunodeficiency syndrome (AIDS) – defining opportunistic 
infection within 12 months prior to screening 
c. Not on anti-retroviral therapy, or on anti-retroviral therapy for < 4 weeks at the 
time of screening 
d. HIV viral load ≥ 400 copies/mL 
6. Serologic evidence of chronic hepatitis B virus (HBV) infection and unable or 
unwilling to receive standard prophylactic antiviral therapy or with detectable HBV 
viral load 
7. Serologic evidence of hepatitis C virus (HCV) infection without completion of 
curative treatment or with detectable HCV viral load 
8. History of Stevens-Johnson syndrome or toxic epidermal necrolysis 
9. Lymphoma with active central nervous system involvement at the time of screening, 
including leptomeningeal disease 
10. Clinically significant third space fluid accumulation (i.e., ascites requiring drainage or 
pleural effusion that is either requiring drainage or associated with shortness of breath) 
11. Major surgery, radiotherapy, chemotherapy, or other anti-neoplastic therapy within 
14 days prior to start of study drug (Cycle 1 Day 1 [C1D1]), except shorter if approved 
by the Sponsor 
12. Use of any other experimental medication within 14 days prior to start of study drug 
(C1D1) 
13. Received live vaccine within 4 weeks of C1D1 
14. Congenital long QT syndrome or a corrected QTcF interval of > 480 ms at screening 
(unless secondary to pacemaker or bundle branch block)  
15. Active second primary malignancy other than non-melanoma skin cancers, 
non-metastatic prostate cancer, in situ cervical cancer, ductal or lobular carcinoma in 
situ of the breast, or other malignancy that the Sponsor’s Medical monitor and 
Investigator agree, and document should not be exclusionary  
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16. Any other significant medical illness, abnormality, or condition that would, in the 
Investigator’s judgment, make the patient inappropriate for study participation or put 
the patient at risk 
 
5.3 
Screening Failures 
Patients who signed the ICF but were found not eligible for the study prior to receiving study 
drug are defined as screening failures. 
For these patients, only limited information will be collected in the electronic case report form 
(eCRF): 
- 
Informed consent 
- 
Demographics 
- 
Inclusion/exclusion criteria 
- 
Serious adverse event (SAE) and/or death occurring during the Screening Period 
- 
Screen Fail (documenting primary reason for screen failure) 
 
5.4 
Re-screening Procedures 
A patient who did not meet the eligibility criteria, i.e., screening failure, may be considered for 
re-screening. Decision for re-screening must be confirmed by the Sponsor/Medical monitor. 
A re-screened patient will be assigned a new patient number. Patients who are rescreened are 
required to sign a new ICF. 
5.5 
Discontinuation 
The reason for discontinuation, whether it is from study treatment or from study, and the date 
of discontinuation will be recorded for all patients in the eCRF. 
Note: Once discontinued from the study for any reason, patients will not be permitted to be 
re-enrolled. 
5.5.1 Discontinuation from Study Treatment 
A patient may be discontinued from the study treatment for any of the following reasons: 
• Adverse event 
• Patient decision 
• Investigator decision 
• Major protocol deviation 
• Lost to follow-up  
• Disease progression (radiographic or clinical) 
• Study termination by the Sponsor 
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• For Cohort A, patients who did not achieve a CR or PR after 3 cycles 
• For Cohort B, patients who do not achieve a CR or PR or SD after 3 cycles 
• Other 
 
A patient with any of the following reasons will be immediately discontinued from study 
treatment: 
• Pregnancy 
• Death 
 
IMPORTANT: Study treatment discontinuation is not equivalent to discontinuation from the 
study. Patients discontinuing the study treatment will be asked to perform an EoT visit 
(Section 4.2.3) and continue with the Follow-up period (Section 4.2.4) as per protocol.  
The investigational site should make every effort to complete follow-up per protocol. 
If patients are unable to return to the site, patient status, including but not limited to survival 
status, may be obtained by site staff via phone, email, or mail. 
5.5.2 Discontinuation from the Study  
A patient may be discontinued from the study for any of the following reasons: 
• Study completion 
• Withdrawal of consent 
• Investigator decision 
• Lost to follow-up 
• Study termination by the Sponsor 
• Death 
• Other 
 
If a patient withdraws informed consent for study participation, no additional study data will 
be collected. 
The Sponsor may continue to use previously collected medical research data prior to the 
withdrawal consistent with the original authorization. If a patient withdraws from the study, 
he/she may request destruction of any samples taken and not tested, and the investigator must 
document this in the site study records. 
The study may be terminated at any time, for any reason, by the Sponsor. Patients still receiving 
study drug will have an EoT visit as described in Section 4.2.3 and schedule of events (SoE) 
(Table 2). 
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5.5.3 Lost to Follow-up 
Patients who fail to return for protocol follow-up are to be contacted by the investigative site. 
Following a minimum of two documented unsuccessful telephone calls, the investigative site 
will send a registered letter to the patient in a final attempt to ensure protocol compliance. 
5.5.4 Patient Replacements 
No enrolled patients will be replaced. 
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6 Study Treatment 
6.1 
Study Drugs 
Study drugs in this study will be loncastuximab tesirine and rituximab. 
6.1.1 Loncastuximab Tesirine 
Loncastuximab tesirine will be provided as a lyophilized white to off-white powder in single 
dose glass vials (10 mg loncastuximab tesirine per vial) and stored at 2°C to 8°C. 
The lyophilized loncastuximab tesirine is formulated in 20 mM histidine, 175 mM sucrose, 
and 0.02% polysorbate 20, at pH 6.0. Prior to use, the study drug will be reconstituted with 
2.2 mL of Sterile Water for Injection to deliver 2.0 mL at a concentration of 5 mg/mL, gently 
swirled (do not shake the vial) to ensure complete dissolution and homogeneity, and visually 
inspected. Sterile Water for Injection will be provided by study sites. Details of treatment 
regimen are described in Table 4.  
Additional description of loncastuximab tesirine is included in the IB and pharmacy manual. 
6.1.2 Rituximab 
Rituximab is administered in an IV infusion on day 1 of each cycle. Use of the subcutaneous 
(s.c.) formulation (Cycle 2 and beyond) or biosimilars is allowed. 
Refer to rituximab (or biosimilar) USPI for detailed information. Additional description is 
included in the pharmacy manual. 
6.2 
Management of Clinical Supplies 
The investigator or designee must confirm appropriate temperature conditions have been 
maintained for study drugs received and any discrepancies are reported as instructed in the 
pharmacy manual. 
Study drugs must be stored in a secure, monitored (manual or automated) area in accordance 
with the storage conditions specified in the pharmacy manual with access limited to authorized 
site staff. 
The investigator or designee is responsible for study drug accountability, reconciliation, and 
record maintenance (i.e., receipt, reconciliation, and final disposition records). 
Detailed instructions regarding study drug shipment, handling, storage, preparation, 
administration, and final disposition of unused study treatment are included in the pharmacy 
manual. 
6.2.1 Packaging and Storage 
The study drugs will be supplied by the Sponsor through the designated packaging, labeling, 
and distribution center.  
All study drugs must be stored according to the pharmacy manual, in a secure area. 
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The lyophilized formulation of loncastuximab tesirine must be stored refrigerated (2°C to 8°C) 
in original carton to protect from long-term exposure to light. Storage conditions of the study 
drugs will be described in pharmacy manual. 
6.2.2 Preparation and Administration 
The loncastuximab tesirine solution at the concentration of 5 mg/mL (see Section 6.1) will be 
the basis for the preparation of the infusion solution. The amount of the product to be diluted 
will depend on the dose level and the body weight of the patient. The weight of the patient at 
C1D1 can be used for calculating the dose. If the patient’s weight measured on subsequent 
dosing days has changed by 10% or more compared to C1D1, then the dose must be 
recalculated.  
Administration of loncastuximab tesirine will be performed by the Investigator or a qualified 
designee according to the pharmacy manual. Patients will receive an infusion of 
loncastuximab tesirine over 30 minutes on C1D2 and Day 1 of each following cycle. Variations 
in infusion times due to minor differences in IV bag overfill/underfill and the institution’s 
procedure for flushing chemotherapy lines will not result in protocol deviation. 
During cycles 2 and beyond, loncastuximab tesirine must be administered prior to rituximab 
and separated by 30 minutes (or more if clinically indicated; end time of loncastuximab tesirine 
administration used as reference). 
Preparation and administration of rituximab will be according to the prescribing information 
and local practice. 
Extravasation of intravenous (IV) study drugs may be associated with local irritation, swelling, 
pain, or tissue damage. The IV infusion site must be monitored for signs of IV infiltration or 
drug extravasation, and patients must be instructed to report immediately any signs of 
IV infiltration or drug extravasation during or after the infusion. Suspected extravasation of 
study drugs should be managed according to institutional protocol for management of 
extravasation of cytotoxic chemotherapy. 
For patients who have a central line, administration of IV study drugs via this central line 
should be considered. 
6.3 
Study Treatment Assignment and Dosing 
All patients enrolled will be assigned to Lonca-R. Details of the treatment given to the patients 
is described in Table 4. 
During the Screening Period, patients may receive pre-phase therapy with prednisone 
40 mg/m2 for up to 14 days per the treating investigator’s discretion.  
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Table 4 
Treatment Regimens During the Course of the Study 
Cohort 
Treatment Regimen 
(1 cycle = 3 weeks [21 days]) 
Cohort A 
and cohort B 
Lonca-R 
Cycle 1: 
Day 1: Rituximab IV 375 mg/m2 
Day 2: Loncastuximab tesirine 150 µg/kg IV  
Cycle 2: 
Day 1: Rituximab IV* 375 mg/m2 and loncastuximab tesirine 150 µg/kg IV 
Cycles 3-4:† 
Day 1: Rituximab IV* 375 mg/m2 and loncastuximab tesirine 75 µg/kg IV 
Abbreviations: G-CSF, granulocyte colony-stimulating factor; IV, intravenous; Lonca-R, loncastuximab tesirine 
and rituximab. 
*If subcutaneous rituximab is used, dose is 1400 mg flat dose 
†Up to 6 total cycles of Lonca-R may be administered per protocol 
Optional: G-CSF may be administered as primary prophylaxis starting with Cycle 1 of therapy and continue 
through each cycle of therapy for patients per the treating investigator’s discretion and institution guidelines. 
 
6.4 
Premedication 
Unless contraindicated, administer dexamethasone 4 mg orally or IV twice daily (BID) for 
3 days, beginning the day before loncastuximab tesirine administration. If dexamethasone 
administration does not begin the day before loncastuximab tesirine administration, 
dexamethasone begins at least 2 hours prior to administration of loncastuximab tesirine 
administration. 
Additional premedications may be given based on institutional practice for rituximab.  
6.5 
Treatment Compliance 
Compliance will be verified by the study drug administration information recorded in the 
electronic data capture (EDC). 
6.6 
Definition and Management of Overdose 
An overdose is any dose of study drug given to a patient that exceeds the maximum dose 
described in the protocol by 15% or more for loncastuximab tesirine. Any overdose, with or 
without associated AEs, must be promptly reported to the Sponsor (See Section 8.5.3). 
For loncastuximab tesirine, there are no data available to determine what the effects of 
overdose are and whether they can be reversed. For rituximab, the institutional guidelines are 
followed to manage overdose.  
Symptomatic treatment and standard supportive care measures for the management of any 
observed toxicity should be applied.  
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6.7 
Dose Delays and Modifications  
6.7.1 Dose Delays and Modifications for Loncastuximab Tesirine 
The criteria and guidance for dose delay and dose modifications of loncastuximab tesirine and 
rituximab in Lonca-R regimen are summarized in Table 5. 
Table 5 
Criteria for Dose Delay or Dose Modification of Loncastuximab Tesirine 
or Rituximab in Lonca-R regimen 
Toxicity 
Loncastuximab Tesirine 
Rituximab 
Grade ≥3 non-
hematologic 
adverse events  
• Withhold until the toxicity resolves to Grade ≤ 1, 
(Grade 1 or baseline for peripheral neuropathy) 
• If dosing is delayed by more than 3 weeks and 
the toxicity is considered at least possibly related 
to loncastuximab tesirine, then subsequent doses 
must be reduced by 50%. If the toxicity recurs 
following dose reduction, consider 
discontinuation 
• Note: Patients who have a toxicity meeting the 
criteria for dose reduction following Cycle 2 will 
receive the protocol-specified dose of 75 µg/kg 
for Cycle 3, i.e., they will not have an additional 
dose reduction for Cycle 3. 
• Hold until the 
toxicity resolves to 
Grade ≤ 1, (Grade 1 
or baseline for 
peripheral 
neuropathy) 
Grade ≥2 edema, 
effusion 
 
• Withhold until the toxicity resolves to Grade ≤ 1 
• If dosing is delayed by more than 3 weeks and 
the toxicity is considered at least possibly related 
to loncastuximab tesirine, then subsequent doses 
must be reduced by 50%. If the toxicity recurs 
following dose reduction, consider 
discontinuation. 
• Note: Patients who have a toxicity meeting the 
criteria for dose reduction following Cycle 2 will 
receive the protocol-specified dose of 75 µg/kg 
for Cycle 3, i.e., they will not have an additional 
dose reduction for Cycle 3. 
• Hold until the 
toxicity resolves to 
Grade ≤ 1 
Grade ≥3 
neutropenia or 
thrombocytopenia 
• Withhold until toxicity resolves to Grade ≤ 2 
• If dosing is delayed by more than 3 weeks and 
the toxicity is considered at least possibly related 
to loncastuximab tesirine, then subsequent doses 
must be reduced by 50%. If the toxicity reoccurs 
following dose reduction, consider 
discontinuation. 
• Note: Patients who have a toxicity meeting the 
criteria for dose reduction following Cycle 2 will 
receive the protocol-specified dose of 75 µg/kg 
for Cycle 3, i.e., they will not have an additional 
dose reduction for Cycle 3.  
• Hold until toxicity 
resolves to 
Grade ≤ 2 
 
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6.8 
Supportive Care 
6.8.1 Management of Edema and Pleural Effusion 
In patients treated with loncastuximab tesirine, spironolactone at standard doses should be 
administered for patients with weight gain greater than 1 kg from C1D1, new or worsening 
edema, and/or new or worsening pleural effusion. The dose of spironolactone may be titrated 
as clinically indicated. Additional diuretic support may be added if there is further increase in 
weight, edema, or pleural effusion. Additionally, patients should be advised to monitor their 
weight on a daily basis, at around the same time (preferably in the morning), and to notify the 
study site if they gain >1 kg (2.2 pounds) over baseline. 
6.8.2 Prevention and Management of Infusion-Related Hypersensitivity Reactions 
Medications for the treatment of severe hypersensitivity reactions, including anaphylaxis, must 
be available for immediate use and may be administered according to site standard treatment 
protocols. 
Any patient who experiences a Grade ≥ 2 infusion-related hypersensitivity reaction will 
receive prophylactic treatment in subsequent cycles according to institutional guidelines. 
6.8.3 Prevention and Management of Skin Toxicity 
Skin toxicity has been reported in patients receiving loncastuximab tesirine for hematologic 
malignancies. Often, the toxicities manifested as rash were reported in sun exposed areas; it is 
therefore recommended that precautions are taken to avoid exposure of skin to sunlight, even 
through glass (e.g., use of sun protective clothing and sunglasses, sunscreen with a sun 
protection factor ≥ 30 applied every 2 hours). Also, fragrance-free detergents and soaps are 
recommended. 
Treatment recommendations for skin toxicities include topical treatment to affected areas: 
• Maculopapular rash or photosensitivity rash: high potency topical steroid cream (e.g., 
clobetasol propionate 0.05%, halobetasol propionate 0.05%).  
• Pruritus: high potency topical steroid cream (e.g., clobetasol propionate 0.05%, 
halobetasol propionate 0.05%) and consider oral antipruritic.  
• Xerosis or hyperpigmentation: consider ammonium lactate 12% or urea 20% BID; and 
triamcinolone 0.1% and triamcinolone 0.1% cream BID.  
• Blistering rash: silvadene 1% cream BID and consider laboratory testing for blistering 
disorder (Varicella Zoster Virus /Herpes Simplex Virus and bacterial infection; bullous 
pemphigoid; pemphigus). 
 
Systemic corticosteroid therapy should be considered for giving to patients who develop 
clinically significant skin toxicity. Also, for Grade ≥2 skin toxicities consider a dermatology 
consult. 
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6.8.4 Prevention of Tumor Lysis Syndrome 
Patients are observed for development of tumor lysis syndrome (TLS). The risk of TLS will 
be assessed by the Investigator and prophylaxis and management undertaken per institutional 
guidelines prior to the initiation of the first study drug. TLS related laboratory tests in patients 
with intermediate or high risk, will be checked daily during first 24-72 hours after C1D1 or 
according to institutional routine (Table 2). Prophylaxis may include but not be limited to the 
following:  
• Appropriate hydration  
• Administration of an agent to reduce uric acid, if indicated  
• Hospitalization for high risk patients, if indicated 
 
6.8.5 Prevention of Febrile Neutropenia 
G-CSF may be administered as primary prophylaxis starting with Cycle 1 of therapy and 
continue through each cycle of therapy for patients per the treating investigator’s discretion 
and institutional guidelines. 
6.8.6 Prevention of Infection 
Anti-infectious prophylaxis (including opportunistic infections) can be given as per 
institutional guidelines. 
6.8.7 Other Supportive Care 
Patients who show evidence of prior hepatitis B infection (Hepatitis B surface antigen [HbsAg] 
positive [regardless of antibody status] or HbsAg negative but hepatitis B core 
antibody-positive) receive prophylactic antiviral therapy and be monitored for hepatitis B 
reactivation according to institutional guidelines.  
As testing in animals showed testicular toxicity (atrophy with reduced spermatogenesis), male 
patients are advised to consider cryopreservation of sperm prior to treatment with 
loncastuximab tesirine, where applicable. 
6.9 
Concomitant Medications and Procedures 
Medications (except for the study drug) and procedures will be recorded in the eCRF starting 
from the ICF signature date or from 14 days prior to C1D1, whichever is earlier, and continuing 
until at least 30 days after last dose of study treatment and as indicated for AE/SAEs thereafter. 
6.9.1 Permitted During Study 
Medications or procedures for the clinical care of the patient, including management of AEs, 
are permitted during the study, except for those listed in Section 6.9.2. 
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6.9.2 Prohibited During Study 
The following treatments are prohibited during study treatment but are allowed in the 
follow-up period. 
• Other anticancer therapy with the exception of hormonal therapy for maintenance 
treatment of breast and prostate cancer 
• Other investigational agents 
• Live vaccines until 3 months after last dose of study drug 
• Refer to USPI of rituximab (or biosimilar) for prohibited treatments 
 
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7 Study Assessments and Procedures 
Study assessments and procedures are to be completed as described below; however, there may 
be situations (e.g., safety issues) preventing their completion. In such case, the Investigator 
takes all actions necessary to ensure the safety and well-being of the patient and document the 
reason for not performing the assessment. 
7.1 
Informed Consent 
Informed consent, as documented by a signed and dated ICF, must be obtained prior to 
performing any study procedures. Results (e.g., from laboratory tests or radiographic 
evaluations, etc.) obtained prior to the date of informed consent but within the allowed 
timeframe may be used for determination of patient eligibility only if obtained as part of 
standard care. For additional details, please refer to Section 10.3. 
7.2 
Demographics and Baseline Characteristics 
These assessments include: 
• Demographic information such as age, gender, ethnicity, and race; to the extent allowed 
by local regulations. 
• Cancer medical history, which includes a complete history of all surgeries and significant 
diagnoses, and all cancer treatment, including surgery, radiation therapy, chemotherapy, 
etc. 
• Any other relevant medical history.  
• Collection of information on prior medications used from ICF signature date or at least 
within 14 days prior to C1D1, whichever is earlier. 
• Simplified geriatric assessment (sGA, Section 1.1): sGA is to be completed for patients 
aged ≥80 years old. It is based on the scores of 3 surveys: ADL (Appendix 12.4), IADL 
(Appendix 12.5) and CIRS-G (Appendix 12.6) and will be used for this study to 
determine whether a patient is unfit or frail according to Inclusion Criteria 8 and 9 
(Section 5.1), respectively. sGA should be performed by the Investigator (or delegate) 
and done at the end of the screening period once all other eligibility criteria have been 
met. 
 
7.3 
Efficacy Assessments 
Disease assessments will occur as per SoE (Table 2) until progression.  
Imaging and clinical examination for lymphoma will be performed at all disease assessment 
time points. 
Positron emission tomography-computed tomography (PET-CT) of the neck/chest/abdomen/ 
pelvis and other areas of known disease or newly suspected disease, as well as a clinical 
examination for lymphoma, will be performed. If it is known that the tumor is 
fluorodeoxyglucose (FDG)-avid, the baseline CT as part of the PET-CT does not have to be 
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performed with contrast medium; however, if the baseline PET-CT shows that the tumor is not 
FDG-avid, diagnostic CT with IV contrast will need to be obtained as a baseline examination. 
For this reason, if it is known that the tumor is not FDG-avid on previous imaging, 
consideration should be given to obtaining a diagnostic quality CT with IV contrast as part of 
the initial PET-CT examination. Patients who have a contraindication to CT IV contrast 
medium have magnetic resonance imaging (MRI) examinations performed instead. 
The assessment method determined to identify sites of disease at Baseline (i.e., PET-CT, CT, 
MRI) is used for all subsequent assessments.  
Patients whose tumor is not FDG-avid have a bone marrow biopsy as part of their baseline 
staging and disease assessment if clinically appropriate. 
Screening (Baseline) imaging must be performed within 4 weeks prior to C1D1. 
During the treatment period, imaging will be performed prior to Cycle 4 and at the end of 
Cycle 6 (as applicable). Imaging prior to Cycle 4 and at end of Cycle 6 should be performed 
within ±1 weeks of the scheduled time point; all other imaging will be performed within 
±2 weeks of the scheduled time point.  
During the follow-up period, patients who discontinued study drug for reasons other than 
disease progression or initiation of (an)other anti-cancer therapy(ies) will have imaging 
performed every 12 (± 2) weeks until 1 year from EoT, then every 24 weeks up to 2 years, then 
annually up to 5 years from EoT.  
If imaging has been performed within 6 weeks of EoT, it does not need to be repeated at EoT 
visit. Additional disease assessments may be obtained, if clinically indicated.  
The patient’s response to treatment will be determined according to the 2014 Lugano 
Classification Criteria (Appendix 12.2) as CR, PR, SD, or progressive disease (PD). Upon 
indication of clinical progression (nonradiographic), a radiographic disease assessment to 
confirm the PD is expected, if clinically indicated, in order to ensure appropriate data collection 
toward the primary endpoint of this protocol.  
Images will be obtained according to local site imaging requirements. 
7.4 
Safety Assessments  
Safety will be assessed based on the procedures in the subsection below. AEs/SAEs collection 
and reporting is described in Section 8. 
Unless otherwise specified, all safety assessments on dosing days will be done prior to study 
drug administration. Additional safety assessments may be performed by the Investigator when 
clinically indicated.  
7.4.1 Physical Examination 
Planned time points for physical examination are provided in the SoE (Table 2). Physical 
examination will be performed according to institutional standards. 
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7.4.2 ECOG Performance Status 
ECOG PS grades are presented in Appendix 12.1 and will be captured at the planned time 
points provided in the SoE (Table 2). 
7.4.3 Height and Weight 
Planned time points for height and weight are provided in the SoE (Table 2). Additional 
measurements will be performed if clinically indicated. 
Patients are advised to monitor their weight at home to mitigate the risks for edema/effusions. 
Refer to Section 6.8 for further details. 
7.4.4 Vital Signs 
Planned time points for vital signs are provided in the SoE (Table 2). Vital signs include the 
measurements of arterial blood pressure (systolic and diastolic), heart rate, respiratory rate, and 
body temperature and will be performed according to the institutional standards. 
For Day 1 of each cycle and C1D2, vital signs are to be measured before the start of the study 
drug infusion and at the end of infusion. 
7.4.5 Laboratory Tests 
Samples will be collected at the time points specified as per SoE (Table 2).  
Additional sample(s) may be collected and analyzed if clinically indicated. The C1D1 
laboratory tests do not need to be repeated if the laboratory tests for eligibility were done within 
3 days of C1D1. 
Hematology: White blood cells (WBC) with 5-part differential (neutrophils, eosinophils, 
basophils, lymphocytes, and monocytes), platelet count, hemoglobin, and hematocrit.  
Chemistry: ALT, AST, GGT, alkaline phosphatase, amylase, lipase, total bilirubin 
(conjugated and unconjugated bilirubin only when total bilirubin is abnormal), sodium, 
potassium, chloride, phosphate, calcium, magnesium, blood urea nitrogen or urea, carbon 
dioxide/bicarbonate, creatinine, creatine phosphokinase, total protein, albumin, glucose, and 
lactate dehydrogenase.  
Urinalysis: pH, specific gravity, protein, WBC, red blood cell (RBC), ketones, glucose, and 
bilirubin.  
Urinalysis may be performed by dipstick. Abnormal findings will be followed up with a 
microscopic evaluation and/or additional assessments as clinically indicated. A microscopic 
evaluation consists at a minimum of WBC and RBC quantitation per high power field, as well 
as semi-quantitative assessment of other cells and substances, if present, such as epithelial cells, 
bacteria, and crystals (“few,” “moderate,” “many”). Other evaluations depending on 
microscopic findings may be added. 
Viral detection: HBV and/or HCV serology tests, and viral load test if clinically indicated. 
HIV serology tests, and HIV viral load and /or CD4+ T cell count if clinically indicated. 
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7.4.6 Pregnancy Test 
A highly sensitive human chorionic gonadotropin (β-HCG) test in urine or blood β-HCG test 
will be performed in females of childbearing potential for eligibility (see Section 5.1) and 
throughout the study as per SoE (Table 2).  
After starting the study, additional pregnancy testing will be performed according to the SoEs 
(Table 2) and as needed. 
Pregnancy test will not be required for females who are post-menopausal or those with prior 
hysterectomy. 
If a pregnancy test is positive, the study drug must be held pending till confirmation. 
If the pregnancy is confirmed, study treatment will be discontinued permanently for the patient. 
Refer to Section 8.5.2 for the handling of the patient and reporting the event. 
7.4.7 Electrocardiograms 
One 12-lead electrocardiogram (ECG) will be performed at screening as per SoE (Table 2). 
The ECG will be performed after the patient is resting for at least 5 minutes. Additional ECG 
assessments may be performed as clinically indicated.  
Assessments will include determination of heart rate and rhythm and the PR, QRS, QT, and 
QTcF intervals.  
7.5 
Pharmacokinetics, 
, and Immunogenicity 
Pharmacokinetic, ADA, 
 samples will be collected as per SoE (Table 2). 
Additional biological samples may be collected by the Investigator when clinically indicated 
(e.g., at the time of significant AEs that are at least possibly related to the study drug) and may 
be used for PK 
. 
When multiple samples are required at the same time point, collection of safety samples should 
be first followed by PK, then ADA, 
. 
In order to better understand the disease, metabolic disposition, and pharmacologic behavior 
of loncastuximab tesirine in humans, samples remaining after primary analyses may be utilized 
for further analyses. 
Biological samples may be retained for up to 10 years to further address scientific questions as 
new information in regards to the disease or the study drug becomes available.  
For detailed instructions related to central laboratory sample collection, labelling, processing, 
storage, or shipment, refer to the appropriate laboratory manual(s). 
7.5.1 Pharmacokinetic Assessment 
The concentration in serum of loncastuximab tesirine PBD-conjugated antibody, total antibody 
and SG3199 unconjugated warhead will be assessed by a central laboratory designated by the 
Sponsor using validated bioanalytical methods. 
Approximately 6 mL of whole blood will be collected as per SoE (Table 2). The predose 
PK samples will be collected preferably within 2 hours prior to start of infusion and at the end 
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(within -5 to +10 min) of Lonca infusion. Blood should be drawn from a vein away from the 
one used for study drug infusion. 
Pharmacokinetic samples must be stored at -70°C. Please refer to the laboratory manual for 
detailed instructions regarding specimen handling and shipment. 
7.5.2 Immunogenicity  
Detection of ADAs will be performed by using a screening assay for identification of antibody 
positive samples/patients, a confirmation assay, and titer assessment, and will be performed 
using the Meso-Scale Discovery Electrochemiluminescence platform. If an ADA is confirmed, 
as appropriate, a functional assay for the assessment of the neutralizing capacity of the ADA 
will be performed. 
Approximately 6 mL of whole blood will be collected as per SoE (Table 2). Blood should be 
drawn from a vein away from the one used for study drug infusion. 
For patients who test positive for ADAs, an additional ADA sample may be requested for 
testing every 12 weeks following the EOT visit until the ADA titer falls to a background level. 
ADA samples must be stored at -70°C. Please refer to the laboratory manual for detailed 
instructions regarding specimen handling and shipment. 
7.5.3 
 
7.5.3.1 
 
7.5.3.2 
 
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7.6 
Patient Reported Outcomes 
Patient reported outcomes will be administered as per SoE (Table 2). 
The impact of loncastuximab tesirine treatment on disease- and treatment-related symptoms, 
as well as various aspects of patient’s health-related quality of life will be assessed by the 
following instrument: 
• Functional Assessment of Cancer Therapy - Lymphoma (FACT-Lym) 
 
Responses from patients will be captured via paper questionnaires. 
All questionnaires will be completed in the respondent’s native language, at the scheduled 
study visit prior to the patient seeing the investigator for any clinical assessment or treatment. 
Patients will provide responses at the study site. The patient will be given enough instructions, 
space, time and privacy to complete the questionnaires by themselves and without any 
assistance from anyone else. The study coordinator encourages the patient to complete the 
questionnaire without any missing responses.  
While completing the questionnaire, some respondents might ask questions indicating they are 
having difficulty reading the PRO questionnaires. For example, a respondent may ask the 
meaning of specific items or response options so that he/she can better understand and respond. 
If this occurs, an interviewer may assist the respondent by re-reading the question or response 
options for him/her verbatim. If the respondent asks the interviewer to interpret the meaning 
of an item or response options, no explanation or interpretation will be offered but suggest that 
the subject use his/her own interpretation of the question and response options. Respondents 
answer the questions based on what they think the questions mean. 
If a respondent is having difficulty with the response choices (for example, he or she may say 
“I don’t know” or something different than what is stated on the questionnaire), it is important 
to direct the respondent to pick the response that best fit how he/she feels. The respondent must 
not record a response that is not one of the provided response options for each question 
(e.g., respondent does not write in his/her own response). The interviewer may re-read the 
response choices verbatim; however, do not rephrase the response choices or try to simplify 
the language. 
FACT-Lym 
FACT-Lym (see Appendix 12.3) is a lymphoma-specific subscale for the Functional 
Assessment of Cancer Therapy (FACT) questionnaire (Hlubocky et al., 2013). It consists of 
15 specific items that are used together with the core 27-item questionnaire FACT-G. The 
patient is asked to respond to each item with a score of 0–4, where 0 = not at all, 1 = a little bit, 
2 = somewhat, 3 = quite a bit, and 4 = very much. A higher score indicates a worse level of 
QoL. 
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8 Adverse Events Reporting 
Reporting 
of 
AEs 
to 
competent 
authorities 
and 
Independent 
Review 
Boards 
(IRBs)/Independent Ethics Committees (IECs) will be consistent with current laws, regulations, 
and guidelines. 
8.1 
Definition of Adverse Events and Serious Adverse Events 
8.1.1 Adverse Events 
An AE is defined as any untoward medical occurrence in a patient or clinical investigation 
subject administered a pharmaceutical product, which does not necessarily have to have a 
causal relationship with this treatment.  
An AE does not include the following: 
• Medical or surgical procedures such as surgery, endoscopy, tooth extraction, and 
transfusion. The condition that led to the procedure may be an AE and must be reported. 
• Pre-existing diseases, conditions, or laboratory abnormalities present or detected before 
the screening visit that do not worsen. 
• Situations where an untoward medical occurrence has not occurred (e.g., hospitalization 
for elective surgery, social and/or convenience admissions) 
 
Test results collected during the study (e.g., laboratory values, physical examination, ECGs, 
etc.) or identified from review of other documents may constitute AEs if deemed clinically 
significant.  
8.1.2 Serious Adverse Events 
An SAE is defined as any AE that: 
• results in death. 
• is life threatening (Note: The term “life-threatening” in the definition of “serious” refers 
to an event in which the subject was at risk of death at the time of the event; it does not 
refer to an event that hypothetically might have caused death if it were more severe.). 
• requires inpatient hospitalization or prolongation of existing hospitalization 
(hospitalization for elective procedures or for protocol compliance is not considered an 
SAE). 
• results in persistent or significant disability/incapacity. 
• is a congenital anomaly/birth defect. 
• important medical events that do not meet the preceding criteria but based on appropriate 
medical judgment may jeopardize the patient and may require medical or surgical 
intervention to prevent any of the outcomes listed above. Examples of medically 
important events include intensive treatment in an emergency room or at home for 
allergic bronchospasm; blood dyscrasias or convulsions that do not result in 
hospitalization; and development of drug dependency or drug abuse. For the avoidance 
of doubt, infections resulting from contaminated pharmaceutical product will be 
considered a medically important event and subject to expedited reporting requirements. 
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8.1.3 Clinical Laboratory Abnormalities and Other Abnormal Assessments as Adverse 
Events or Serious Adverse Events 
Laboratory abnormalities (e.g., clinical chemistry, hematology, and urinalysis) or other 
abnormal assessments (e.g., electrocardiogram, x-rays, vital signs) without clinical 
significance are not recorded as AEs or SAEs. However, laboratory abnormalities/other 
abnormal assessments that require medical or surgical intervention or lead to pharmaceutical 
product interruption, modification, or discontinuation must be recorded as an AE, as well as 
an SAE, if applicable. If the laboratory abnormality/other abnormal assessment is consistent 
with a clinical diagnosis, report the AE using the diagnosis (i.e., anemia), not the laboratory 
result (i.e., decreased hemoglobin). 
8.2 
Eliciting and Reporting Adverse Events/Serious Adverse Events 
Patients will be instructed to contact the Investigator at any time after ICF signature if any 
symptoms develop. At each study visit, patients will be asked a nonleading question to elicit 
any medically related changes in their well-being. Patients may also report AEs voluntarily 
and they will be instructed to contact the Investigator between visits if any symptoms develop 
or worsen.  
AEs will be reported starting when the patient provides written informed consent. 
Clinically significant medical conditions present at the time of ICF signature will be reported 
as medical history. Clinically significant medical conditions that start or worsen after 
ICF signature will be reported as AEs. 
All AE/SAEs regardless of relationship to study drug, will be reported from the time the patient 
signs the ICF until 15 weeks after the last dose of study drug or the start of new anti-cancer 
therapy, whichever is earlier; thereafter only related SAEs will be reported.  
Whenever possible, AEs should be reported as a diagnosis rather than individual signs and 
symptoms. If no diagnosis is available or has been identified, then the primary symptom is 
reported.  
In general, the term ‘disease progression’ should not be used for reporting an AE/SAE. 
However, AEs/SAEs that are complications of disease progression should be reported. 
All AEs reported or observed during the study will be recorded on the AE page of the 
eCRF. Information to be collected will include event term, date of onset, assessment of severity 
(Section 8.3), seriousness (Section 8.1), relationship to study drug (Section 8.4), action taken 
with study drug, date of resolution of the event or ongoing (when no resolution by the end of 
the reporting period), any required treatment or evaluations, and outcome. 
New SAEs and any recurrent episodes, progression, or complications of the original SAE must 
be reported to the drug safety department of the Sponsor or delegate (e.g., contract research 
organization [CRO]) within 24 hours after the time site personnel first learn about the event. 
Reporting will occur through the EDC system. 
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8.3 
Assessment of Severity 
The AEs will be graded according to Common Terminology Criteria for Adverse Events 
(CTCAE) v5.0. For events not included in the CTCAE criteria, the severity of the AE is graded 
on a scale of 1 to 5 as shown in Table 6.  
Table 6 
Definition of Severity Grades for CTCAE 
Grade 
Definition 
1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated. 
2 
Moderate; minimal, local or noninvasive intervention indicated; limiting age 
appropriate instrumental activities of daily living (ADL).a 
3 
Severe or medically significant but not immediately life threatening; hospitalization or 
prolongation of hospitalization indicated; disabling; limiting self-care ADL.b 
4 
Life-threatening consequences; urgent intervention indicated. 
5 
Death related to adverse event. 
a 
ADL refers to preparing meals, shopping for groceries or clothes, using the telephone, managing money, 
etc. 
b 
Self-care ADL refers to bathing, dressing and undressing, feeding self, using the toilet, taking medications, 
and not bedridden. 
 
The AEs characterized as intermittent do not require documentation of onset and duration of 
each episode. 
8.4 
Assessment of Causality 
The Investigator’s assessment of an AE’s relationship to study drug is an important part of 
safety reporting, but is not a factor in determining whether an AE is reported. An AE will be 
assessed as related to study drug if there is a reasonable possibility of causal relationship with 
the use of the study drug. For SAEs, whenever possible, the Investigator should provide a 
rationale for the causality assessment.  
The investigator or qualified subinvestigator is responsible for providing an assessment of the 
relationship to the study drug(s) using clinical judgment and the following considerations: 
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Causality 
Definition 
Not related 
An adverse event is not related to the study drug 
Unlikely related 
An adverse event where evidence exists for an alternative explanation 
other than the study drug e.g., concomitant medication(s), concomitant 
disease(s), or time to onset suggests unlikely relationship.  
Possibly related 
An adverse event that might be due to study drug. An alternative 
explanation (e.g., concomitant medication(s), concomitant disease(s), or 
time to onset) is inconclusive, where a causal relationship with study drug 
cannot be ruled out.  
Probably related 
An adverse event that might be due to study drug. An alternative 
explanation (e.g., concomitant medication(s), concomitant disease(s)) is 
less likely, and where a causal relationship with study drug is more 
suggestive (i.e., time to onset, positive dechallenge/rechallenge).  
Related 
An adverse event where an alternative explanation cannot be explained 
and, therefore, considered related to study drug.  
 
8.5 
Special Situations Reports 
8.5.1 Definitions of Special Situations 
Any special situation occurring in a participant that may require expedited reporting or safety 
review may include the following with the study drug: 
• Pregnancy reports (see Section 8.5.2) 
• Overdose reports (see Section 8.5.3) 
• Other special situations (see Section 8.5.4), such as: 
o Suspected misuse or abuse  
o Accidental exposure 
o Medication error 
o Exposure to the study drug from breast-feeding  
o Adverse events associated with product complaints 
o Suspected transmission of an infectious agent via a medicinal product, which will 
be classified as an SAE 
 
8.5.2 Reporting Pregnancy 
Any pregnancy in a patient that occurs from signing the ICF up to 12 months after last dose of 
study treatment must be reported using the Pregnancy Report Form. Any pregnancy in a partner 
of a male participant that occurs from signing the ICF up to 7 months after last dose of study 
treatment must be reported. 
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Pregnancy must be reported within 24 hours after the site personnel first learn of the pregnancy. 
The pregnancy itself is not considered an AE. However, the pregnancy must be followed to 
determine outcome (including spontaneous miscarriage, elective termination, normal birth, or 
congenital abnormality) and status of mother and child, even if the patient discontinued from 
the study. Abortions (elective or spontaneous) occurring during the pregnancy reporting period 
must be reported as an SAE. 
Any SAE occurring in association with a pregnancy that is brought to the Investigator’s 
attention after the patient has completed the study and considered by the Investigator as 
possibly related to the study drug must be promptly reported in the same manner. 
Once pregnancy is confirmed in a study participant, study drug will be discontinued, 
see Section 7.4.6 for additional information. 
8.5.3 Reporting Overdose 
An overdose of the study drug(s) is defined under Section 6.6. 
An overdose itself is not considered an AE. However, if such an overdose occurs during the 
study, with or without any signs or symptoms, it must be reported to drug safety department 
of the Sponsor or delegate (e.g., CRO) within 24 hours after the time site personnel first learn 
about the event.  
8.5.4 Reporting Other Special Situations 
All other special situation reports must be reported to drug safety department of the Sponsor 
or delegate (e.g., CRO) within 24 hours after the time site personnel first become aware of the 
situation.  
8.6 
Data Monitoring Committee 
A data monitoring committee (DMC) will primarily review the collection of AEs and other 
safety-related information on a periodic basis to ensure the safety of patients enrolled in this 
study. They will provide expertise and make recommendations, based on independent 
evaluation, on study conduct and progress, which concern the continuation, modification, or 
termination of the study. The DMC will be composed of at least one clinician with lymphoma 
expertise and a biostatistician. 
Details regarding the DMC responsibilities, authorities, and procedures will be included in a 
separate and mutually agreed DMC charter. 
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9.4 
Final Analysis 
All efficacy and safety endpoints will be analyzed and reported in the clinical study report 
(CSR).  
9.5 
Demographics and Baseline Characteristics 
Demographics and Baseline characteristics, such as cancer history and medications history, 
will be summarized for the All-treated Population (Cohort A and Cohort B). 
9.6 
Exposure to Treatments 
Exposure to study drug, prior, and concomitant medications will be summarized for the 
All-Treated Population by dose level. Dose interruptions, reductions, and relative dose 
intensity will also be summarized. 
9.7 
Efficacy Analyses 
Primary efficacy analyses will be based on response as determined by treating investigator.  
9.7.1 
Complete Response Rate 
The CR rate will be defined as the proportion of patients with a best overall response (BOR) 
of CR, based on response assessments obtained on or prior to the start of subsequent cancer 
treatment. The percentage of CR rate with its 95% CI will be presented. For the primary CR 
rate analysis, patients with missing response or not evaluable information will be counted as 
failures. Further details will be provided in the SAP.  
9.7.2 Overall Response Rate 
The ORR will be defined as the proportion of patients with a BOR of CR or PR. The overall 
response category will be derived based on response assessment performed on or before the 
start of subsequent anti-cancer therapy. For the primary ORR, patients with a CR or PR will 
be counted as successes and all other patients (including those with missing response 
information) will be counted as failures. 
The ORR with its 95% CI will be presented. In contrast to CR, PR, or PD, a BOR of SD can 
only be made after the patient is on-study for a minimum of 35 days after the first dose of study 
drug (Cohort A and Cohort B). Any tumor assessment indicating SD before this time period 
will be considered as a non-evaluable for BOR if no assessment after this time period is 
available. 
9.7.3 Duration of Response 
The DoR will be defined among responders (CR or PR) as the time from the earliest date of 
first response until the first date of either disease progression or death due to any cause. 
The date of disease progression will be defined as the earliest date of disease progression based 
on investigator assessment. For patients who have not progressed or died at the time of the 
analysis, censoring will be performed using the date of the last valid disease assessment on or 
prior to initiation of a new anticancer therapy. A sensitivity analysis of DoR is planned to be 
conducted in which the DoR for patients undergoing sacrococcygeal teratoma (SCT) is not 
censored at the last evaluable disease assessment prior to SCT. The data will be analyzed by 
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the Kaplan-Meier method. The median DoR and 95% CI will be presented. Further details will 
be provided in the SAP. 
9.7.4 2-year Progression-free Survival  
The PFS will be defined among All-treated patients as the time from first dose of study drug 
until the first date of either disease progression or death due to any cause.  
The date of disease progression will be defined as the earliest date of disease progression based 
on investigator assessment. For patients whose disease has not progressed at the time of the 
analysis, censoring will be performed using the date of the last valid disease assessment on or 
prior to initiation of a new anticancer therapy. 2-yr PFS is defined as the proportion of patients 
that are PFS event-free at 2 years per investigator assessment. 2-yr PFS along with 95% CI 
will be estimated using Kaplan-Meier method. Further details will be provided in the SAP.  
9.7.5 3-year Overall Survival 
The OS will be defined as the time from randomization date until death due to any cause. 
For patients who have not died at the time of the analysis, censoring will be performed using 
the date the patient was last known to be alive. The 3-year OS is defined as the proportion of 
patients that are OS event-free at 3 years. 3-year OS along with 95% CI will be estimated using 
Kaplan-Meier method. Further details will be provided in the SAP.  
9.8 
Safety Analyses 
Safety analyses will be presented descriptively.  
9.8.1 Adverse Events 
The focus of AE summarization will be on TEAEs. A TEAE is defined as an AE that occurs 
or worsens in the period extending from the first dose of study drug to 15 weeks after the last 
dose of study drug in this study or the start of a new anticancer therapy, whichever is earlier. 
All TEAEs will be summarized. Summary tables will be presented to show the number of 
patients reporting TEAEs by severity grade and corresponding percentages. A patient who 
reports multiple TEAEs within the same Preferred Term (or System Organ Class) is counted 
only once for that Preferred Term (or System Organ Class) using the worst severity grade.  
Separate summaries will be prepared for TEAEs classified as severe or life-threatening 
(≥ Grade 3); study drug-related AEs; AEs leading to treatment interruption, modification, or 
discontinuation; AEs of special interest; SAEs; and death. 
9.8.2 Clinical Laboratory Results 
Clinical hematology, biochemistry, and urinalysis data will be summarized at each scheduled 
assessment. Shifts for clinical laboratory results that can be graded according to CTCAE v5.0 
(or more recent) will be summarized by CTCAE grade. Shifts for other numeric laboratory 
results will be by high/normal/low flag. Shifts for all other laboratory results will be by 
normal/abnormal flag. 
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Summaries by visit will include data from scheduled assessments, and all data will be reported 
according to the nominal visit date for which it was recorded. Unscheduled data will be 
included in “worst-case post-Baseline” summaries, which will capture a worst case across all 
scheduled and unscheduled visits after the first dose of study drug. Further details will be 
provided in the SAP. 
9.8.3 Additional Safety Assessments 
The results of scheduled assessments of vital signs, physical examinations, ECOG performance 
status, and 12-lead ECGs will be summarized. All data will be reported according to the 
nominal visit date for which it was recorded (i.e., no visit windows will be applied). 
Unscheduled data will be included in “worst case” summaries, which will capture a worst case 
across all scheduled and unscheduled visits after the first dose of study drug. All data will be 
listed. Further details will be provided in the SAP. 
9.9 
Pharmacokinetic Analysis 
For the PK-evaluable patients, PK parameters will be determined for the typical patient and 
estimated for individual patients using a population PK analysis method. Analysis will consider 
model development for conjugated antibodies (Ab) and total Ab. If supported by available data, 
the model may also include characterization of SG3199 unconjugated measures. Intrinsic and 
extrinsic factors which may have influence on PK parameter variability will be tested and 
assessed for inclusion in the final model. Demographic data for the PK population will be 
summarized. Potential correlations of PK parameters to safety and efficacy endpoints, as 
appropriate, may be evaluated. Results of the population PK analysis will be reported 
separately. 
9.10 Immunogenicity Analysis 
Anti-drug antibody will be measured for Lonca-R arm during the study using screening and 
confirmatory assays with titer evaluation (Figure 3). 
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Figure 3 
Anti-drug Antibody Tiered Immunogenicity Testing Strategy  
Abbreviations: ADA, anti-drug antibody; ADCT-402, loncastuximab tesirine; BSA-SG3249, bovine serum 
albumin conjugated to SG3249; Intermediate monoclonal antibody RB4v1.2; irrelevant monoclonal antibody B12 
based ADC B12-SG3249; NF, normalization factor; PK, pharmacokinetics; SCP, screening cut-point. 
 
Results from ADA testing will include tabular summarization for number/proportion of 
patients with confirmed positive predose ADA response, confirmed number of patients with 
postdose ADA response only, confirmed number of patients with positive ADA response at 
any time, and confirmed positive ADA before and after dose. The denominator will be the total 
number of patients tested for ADAs in the study. 
9.11 Subgroup Analyses 
Subgroup analyses will be performed for ORR, DoR, CRR, 2-year PFS, and 3-year OS and 
safety endpoints using the following variables if appropriate. 
• Demographic variables:  
o age group (Cohort B only) 
 age 65-79  
 ≥80 
o gender  
o race 
o ECOG Performance Status 
 0-1 
 2-3 
o region (North America vs rest of world) 
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• Baseline disease characteristics:  
o tumor staging 
 I-II 
 III-IV 
o Cell of origin 
 Germinal center B-cell (GCB) 
 Non-GCB 
o International Prognostic Index (IPI) 
 0-2 
 3-5 
o Lactate dehydrogenase 
 Normal 
 Elevated 
o Albumin 
 ≤3.5 g/dL 
 ≥3.5 g/dL 
o Extranodal involvement 
 Yes 
 No 
o Bulky disease 
 ≥10 cm 
 <10 cm 
o Histology 
 DLBCL, NOS 
 HGBCL 
 Transformed iNHL 
 FL 3b 
• Pre-Phase Therapy 
o Yes 
o No 
• The proportion of patients achieving a CR after 3 cycles vs 6 cycles as follows: 
o Cohort A Lonca-R 
o Cohort B Lonca-R 
 
Other subgroup analysis factors may be evaluated as appropriate and the details will be 
provided in SAP. 
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9.12 
Patient-reported Outcomes 
Patient-reported outcomes will be analyzed among PRO population. Details will be provided 
in the SAP. 
9.13 
 
 
 
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10 Regulatory, Ethical, and Study Oversight/Management Considerations 
10.1 Regulatory and Ethical Considerations 
The study will be performed in accordance with the protocol and with the Consensus ethical 
principles derived from international guidelines including the Declaration of Helsinki and 
Council for International Organizations of Medical Sciences (CIOMS) International Ethical 
Guidelines, applicable International Council for Harmonisation (ICH) Good Clinical Practice 
(GCP) Guidelines, and applicable laws and regulations. 
The protocol, protocol amendments, ICF, Investigator’s Brochure, and other relevant 
documents (e.g., advertisements) must be submitted to an IRB/IEC by the investigator and 
reviewed and approved by the IRB/IEC before the study is initiated.  
Any amendments to the protocol will require IRB/IEC approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an immediate 
hazard to study participants.  
The investigator will be responsible for the following: 
• Providing written summaries of the status of the study to the IRB/IEC annually or more 
frequently in accordance with the requirements, policies, and procedures established by 
the IRB/IEC 
• Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures 
• Providing oversight of the conduct of the study at the site and adherence to applicable 
laws and regulations. 
 
Study information from this protocol will be posted on publicly available clinical study 
registries before enrollment of patients begins.  
10.2 Financial Disclosure and Obligations 
Investigators and sub-investigators will provide the sponsor with sufficient, accurate financial 
information as requested to allow the sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators are 
responsible for providing information on financial interests during the course of the study and 
for 1 year after completion of the study. 
10.3 Patient Information and Consent 
The investigator or his/her representative will explain the nature of the study to the participant 
or his/her LAR and answer all questions regarding the study.  
Participants must be informed that their participation is voluntary. Participants or their LAR 
will be required to sign a statement of informed consent that meets the requirements of any 
applicable regulations, guidelines, and the IRB/IEC or study center.  
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The medical record must include a statement that written informed consent was obtained before 
the participant was enrolled in the study and the date the written consent was obtained. 
The authorized person obtaining the informed consent must also sign the ICF. 
Participants must be re-consented to the most current version of the ICF(s) during their 
participation in the study, unless otherwise indicated by the IRB/IEC (local or global, as 
applicable). In such cases, the reason for not re-consenting the patient will be documented. 
A copy of the ICF(s) must be provided to the participant his/her LAR.  
Separate ICF(s) or a separate section in the main ICF may be added to allow the possibility to 
perform optional exploratory research, such as the use of remaining mandatory samples for 
future research. The investigator or authorized designee will explain to each participant the 
objectives of the exploratory research. Participants will be told that they are free to refuse to 
participate and may withdraw their consent at any time and for any reason. A separate signature 
will be required to document a participant's agreement to such optional research. Participants 
who decline to participate in this optional research will not provide this separate signature 
10.4 Data Protection 
Participants will be assigned a unique identifier. Any participant records or datasets that are 
transferred to the sponsor will contain the identifier only; participant names or any information 
which would make the participant identifiable will not be transferred.  
Sponsor maintains organizational and security measures (e.g., pseudonymisation, data 
protection policy, backups, network security, physical access control, monitoring network 
activity) to safeguard patient’s personal data that are transferred to Sponsor from loss, misuse, 
unauthorized access, disclosure, alteration or destruction and, when required, will cause third 
parties accessing your Personal Data to maintain the same and to assist Sponsor in complying 
with its obligations under applicable laws regarding personal data protection. 
The participant must be informed that his/her personal study-related data will be used by the 
sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the participant.  
The participant must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities. 
10.5 Data Quality Assurance 
Study personnel involved in conducting this study will be qualified by education training and 
experience to perform their respective tasks.  
All participant data relating to the study will be recorded on printed or eCRF unless transmitted 
to the sponsor or designee electronically (e.g., central laboratory data). The Investigator is 
responsible for verifying that data entries are accurate and correct by physically or 
electronically signing the eCRF.  
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The Investigator must maintain accurate documentation (source data) that supports the 
information entered in the eCRF.  
The Investigator must permit study-related monitoring, Sponsor/CRO audits, IRB/IEC review, 
and regulatory agency inspections and provide direct access to source data documents.  
The Sponsor or designee is responsible for the data management of this study including quality 
checking of the data.  
Study monitors will perform ongoing source data verification to confirm that data entered into 
the eCRF by authorized site personnel are accurate, complete, and verifiable from source 
documents; that the safety and rights of participants are being protected; and that the study is 
being conducted in accordance with the currently approved protocol and any other study 
agreements, ICH GCP, and all applicable regulatory requirements.  
Upon completion of the study, the Sponsor shall prepare a summary of the study outcome in 
accordance with the ICH E3 guidelines for submission to the appropriate regulatory 
authority(ies). 
Records and documents, including signed ICFs, pertaining to the conduct of this study must 
be retained by the investigator for 15 years after study completion unless local regulations or 
institutional policies require a longer retention period. No records may be destroyed during the 
retention period without the written approval of the sponsor. No records may be transferred to 
another location or party without written notification to the sponsor. 
10.6 Source Documents 
A Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. Source documents are filed at the investigator’s site. 
Data reported on the CRF/eCRF that are transcribed from source documents must be consistent 
with the source documents or the discrepancies must be explained. The Investigator may need 
to request previous medical records or transfer records, depending on the study. Also, current 
medical records must be available. 
Definition of what constitutes source data can be found in the Investigator Site File. 
10.7 Study and Site Closure 
The Sponsor reserves the right to close the study site or terminate the study at any time for any 
reason. Study sites will be closed upon study completion. A study site is considered closed 
when all required documents and study supplies have been collected and a study-site closure 
visit has been performed. 
The Investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by the sponsor or investigator may include but are 
not limited to: 
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• Failure of the investigator to comply with the protocol, the requirements of the IRB/IEC 
or local health authorities, the sponsor's procedures, or GCP guidelines 
• Inadequate recruitment of participants by the Investigator 
• Discontinuation of further study intervention development 
 
10.8 
Monitoring of the Study 
All aspects of the study will be carefully monitored by the Sponsor or designee for compliance 
with GCP and applicable government regulations. 
Monitoring details describing strategy (e.g., risk-based initiatives in operations and quality 
such as Risk Management and Mitigation Strategies and Analytical Risk-Based Monitoring), 
methods, responsibilities and requirements, including handling of noncompliance issues and 
monitoring techniques (central, remote, or on-site monitoring) are provided in the Monitoring 
Plan. 
Investigators and institutions involved in the study will permit study-related monitoring, 
Sponsor/CRO audits, IRB/IEC review, and regulatory inspections by providing direct access 
to source data and study records.  
The Investigator will promptly notify the Sponsor and the CRO of any inspections scheduled 
by any regulatory authorities and promptly forward copies of any inspection reports received 
to the Sponsor. 
10.9 Publications 
Following completion of the study, the results from the study will be publicly disclosed through 
posting the results on appropriate registries such as ww.clinicaltrials.gov and may be reported 
publicly by making any oral public presentation and/or submitting or presenting a manuscript, 
abstract, or other materials relating to the Study at scientific meetings and/or to a publisher, 
reviewer, or other outside person in scientific journals (“Publication”), provided; however, that 
Publication of the results from an individual site shall not be made before the first multi-site 
Publication by Sponsor. The Sponsor shall coordinate the drafting, editing, authorship, and 
other activities related to study Publication and shall mutually agree with the Investigator(s) 
on the number, medium, forum, and timing for Publication. The Sponsor shall solicit input 
regarding contents of the Publication from all Investigators and in consultation with all sites. 
The Sponsor acknowledges the right of the Investigator(s) to publish the results of this study 
after the entire study has completed, but also reserves the right to a window to review the 
Publication for regulatory compliance as well as for protection of its intellectual property. 
In particular, the Sponsor may request to remove the Sponsor’s confidential information and 
suspend Publication for a certain period of time to protect the Sponsor’s intellectual property 
interest, as further set forth in the Clinical Trial Agreement with the clinical study site(s) and 
Investigator(s). 
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SOHO 2021 Poster Presentation. 
Parmelee PA, Thuras PD, Katz IR, Lawton MP. Validation of the Cumulative Illness Rating 
Scale in a Geriatric Residential Population. J Am Geriatr Soc. 1995;43(2):130-137. 
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Peyrade F, Jardin F, Thieblemont C, Thyss A, Emile J, Castaigne S, et al. Attenuated 
immunochemotherapy regimen (R-miniCHOP) in elderly patients older than 80 years with 
diffuse large B-cell lymphoma: a multicentre, single-arm, phase 2 trial. Lancet Oncol. 
2011;12(5):460-468.  
Ryan MC, Palanca-Wessels MC, Schimpf B, Gordon K, Kostner H, Meyer B et al. Therapeutic 
potential of SGN-CD19B, a PBD-based anti-CD19 drug conjugate, for treatment of B-cell 
malignancies. Blood. 2017;130(18):2018–2026. 
Salaverria I & Siebert R. Follicular lymphoma grade 3b. Best Practice and Research Clinical 
Haematology. 2011;24:111-119.  
Storti S, Spina M, Pesce E, Salvi F, Merli M, Ruffini A, et al. Rituximab plus benamustine as 
front-liine treatment in frail elderly (>70 years) patients with diffuse large B-cell non-Hodgkin 
lymphoma: a phase II multicenter study of the Fondazione Italiana Linfomi. Haematologica. 
2018; 103(8):1345-1350. 
Tavares A, Moreira I. Diffuse large B-cell lymphoma in very elderly patients: Towards best 
tailored treatment - A systematic review. Crit Rev Oncol Hematol. 2021;160:103294.  
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12 Appendices 
12.1 
Appendix: Eastern Cooperative Oncology Group Performance Status 
Performance status will be assessed using the ECOG performance status grades as indicated 
below: 
Grade 
Definition 
0 
Fully active, able to carry on all predisease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of 
a light or sedentary nature, e.g., light house work, office work 
2 
Ambulatory and capable of all self-care but unable to carry out any work activities; 
up and about more than 50% of waking hours 
3 
Capable of only limited self-care; confined to bed or chair more than 50% of waking 
hours 
4 
Completely disabled; cannot carry on any self-care; totally confined to bed or chair 
5 
Dead 
 
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12.2 
Appendix: Response Assessment of Hodgkin and NonHodgkin Lymphoma 
(Lugano Classification) 
Response/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** 
Note: Uptake may be greater than 
normal mediastinum and/or liver 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). 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 
LD 
• 
No extralymphatic sites of 
disease 
Nonmeasured 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 × 5mm as the default 
value. 
• 
When no longer visible, 
0 × 0 mm 
• 
For a node 
> 5 mm × 5 mm, but 
smaller than normal, use 
actual measurement for 
calculation 
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Nonmeasured 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 
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 
Nonmeasured 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 
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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 
Nonmeasured lesions 
• 
None 
• 
New or clear progression of 
preexisting nonmeasured 
lesions 
New lesions 
• 
New FDG-avid foci consistent 
with lymphoma rather than 
another etiology (e.g., infection, 
inflammation). If uncertain 
regarding etiology of new 
lesions, biopsy or interval scan 
may be considered 
• 
Regrowth of previously 
resolved lesions 
• 
A new node > 1.5 cm in 
any axis 
• 
A new extranodal site 
> 1.0 cm in any axis; if 
< 1.0 cm in any axis, its 
presence must be 
unequivocal and must be 
attributable to lymphoma 
• 
Assessable disease of any 
size unequivocally 
attributable to lymphoma 
Bone marrow 
• 
New or recurrent FDG-avid foci 
• 
New or recurrent 
involvement 
Abbreviations: 5PS, 5-point scale; CT, computed tomography; FDG, fluorodeoxyglucose; IHC, 
immunohistochemistry; LDi, longest transverse diameter of a lesion; MRI, magnetic resonance imaging; PET, 
positron emission tomography; PPD, cross product of the LDi and perpendicular diameter; SDi, shortest axis 
perpendicular to the LDi; SPD, sum of the product of the perpendicular diameters for multiple lesions. 
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* A score of 3 in many patients indicates a good prognosis with standard treatment, especially if at the time of 
an interim scan. However, in trials involving PET where de-escalation is investigated, it may be preferable to 
consider a score of 3 as inadequate response (to avoid undertreatment). Measured dominant lesions: Up to six 
of the largest dominant nodes, nodal masses, and extranodal lesions selected to be clearly measurable in 
2 diameters. Nodes should preferably be from disparate regions of the body and should include, where 
applicable, mediastinal and retroperitoneal areas. Nonnodal lesions include those in solid organs (e.g., liver, 
spleen, kidneys, lungs), GI involvement, cutaneous lesions, or those noted on palpation. Nonmeasured lesions: 
Any disease not selected as measured, dominant disease and truly assessable disease should be considered not 
measured. These sites include any nodes, nodal masses, and extranodal sites not selected as dominant or 
measurable or that do not meet the requirements for measurability but are still considered abnormal, as well as 
truly assessable disease, which is any site of suspected disease that would be difficult to follow quantitatively 
with measurement, including pleural effusions, ascites, bone lesions, leptomeningeal disease, abdominal 
masses, and other lesions that cannot be confirmed and followed by imaging. In Waldeyer’s ring or in 
extranodal sites (e.g., GI tract, liver, bone marrow), FDG uptake may be greater than in the mediastinum with 
complete metabolic response, but should be no higher than surrounding normal physiologic uptake (e.g., with 
marrow activation as a result of chemotherapy or myeloid growth factors). 
** PET 5PS: 1, no uptake above background; 2, uptake ≤ mediastinum; 3, uptake > mediastinum but ≤ liver; 
4, uptake moderately > liver; 5, uptake markedly higher than liver and/or new lesions; X, new areas of uptake 
unlikely to be related to lymphoma. 
Reference: Cheson, 2014 
 
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12.3 Appendix: FACT-Lym 
Below is a list of statements that other people with your illness have said are important. Please 
circle or mark one number per line to indicate your response as it applies to the 
past 7 days. 
PHYSICAL WELL-BEING 
 
Not at 
all 
A little 
bit 
Some 
what 
Quite a 
bit 
Very 
much 
 
GP1 I have a lack of energy 
0 
1 
2 
3 
4 
GP2 I have nausea 
0 
1 
2 
3 
4 
GP3 Because of my physical condition, I have 
trouble meeting the needs of my family 
0 
1 
2 
3 
4 
GP4 I have pain 
0 
1 
2 
3 
4 
GP5 I am bothered by side effects of treatment 
0 
1 
2 
3 
4 
GP6 I feel ill 
0 
1 
2 
3 
4 
GP7 I am forced to spend time in bed 
0 
1 
2 
3 
4 
SOCIAL/FAMILY WELL-BEING 
 
Not at 
all 
A little 
bit 
Some 
what 
Quite a 
bit 
Very 
much 
GS1 I feel close to my friends 
0 
1 
2 
3 
4 
GS2 I get emotional support from my family 
0 
1 
2 
3 
4 
GS3 I get support from my friends 
0 
1 
2 
3 
4 
GS4 My family has accepted my illness 
0 
1 
2 
3 
4 
GS5 I am satisfied with family communication 
about my illness 
0 
1 
2 
3 
4 
GS6 I feel close to my partner (or the person 
who is my main support) 
0 
1 
2 
3 
4 
Q1 
Regardless of your current level of sexual 
activity, please answer the following 
question. If you prefer not to answer it, 
please mark this box and go to the next 
 
 
GS7 I am satisfied with my sex life 
0 
1 
2 
3 
4 
 
 
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EMOTIONAL WELL-BEING 
 
Not at 
all 
A little 
bit 
Some 
what 
Quite a 
bit 
Very 
much 
I feel sad 
0 
1 
2 
3 
4 
I am satisfied with how I am coping with my 
illness  
0 
1 
2 
3 
4 
I am losing hope in the fight against my 
illness  
0 
1 
2 
3 
4 
I feel nervous  
0 
1 
2 
3 
4 
I worry about dying  
0 
1 
2 
3 
4 
I worry that my condition will get worse  
0 
1 
2 
3 
4 
 
 
 
 
 
 
FUNCTIONAL WELL-BEING 
 
Not at 
all 
A little 
bit 
Some 
what 
Quite a 
bit 
Very 
much 
I am able to work (include work at home)   
0 
1 
2 
3 
4 
My work (include work at home) is fulfilling 
0 
1 
2 
3 
4 
I am able to enjoy life  
0 
1 
2 
3 
4 
I have accepted my illness  
0 
1 
2 
3 
4 
I am sleeping well  
0 
1 
2 
3 
4 
I am enjoying the things I usually do for fun 
0 
1 
2 
3 
4 
I am content with the quality of my life right 
now 
0 
1 
2 
3 
4 
 
 
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ADDITIONAL CONCERNS 
 
Not at 
all 
A little 
bit 
Some 
what 
Quite a 
bit 
Very 
much 
I have certain parts of my body where I 
experience pain 
0 
1 
2 
3 
4 
I am bothered by lumps or swelling in certain 
parts of my body (e.g., neck, armpits, or 
0 
1 
2 
3 
4 
I am bothered by fevers (episodes of high 
body temperature)  
0 
1 
2 
3 
4 
I have night sweats 
0 
1 
2 
3 
4 
I am bothered by itching 
0 
1 
2 
3 
4 
I have trouble sleeping at night 
0 
1 
2 
3 
4 
I get tired easily  
0 
1 
2 
3 
4 
I am losing weight 
0 
1 
2 
3 
4 
I have a loss of appetite 
0 
1 
2 
3 
4 
I have trouble concentrating 
0 
1 
2 
3 
4 
I worry about getting infections 
0 
1 
2 
3 
4 
I worry that I might get new symptoms of my 
illness 
0 
1 
2 
3 
4 
I feel isolated from others because of my 
illness or treatment 
0 
1 
2 
3 
4 
I have emotional ups and downs  
0 
1 
2 
3 
4 
Because of my illness, I have difficulty 
planning for the future  
0 
1 
2 
3 
4 
 
 
 
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12.4 Appendix: Katz Activities of Daily Living 
KATZ INDEX OF INDEPENDENCE IN ACTIVITIES OF DAILY 
LIVING (ADL) 
Activities 
Points (1 or 0) 
Only one option per row 
BATHING - either 
sponge bath, tub bath, 
or shower 
 
Points:______ 
(1 POINT) Receives 
no assistance (gets in 
and out 
of tub by self if tub is 
usual means of bathing) 
(1 POINT) Receives 
assistance in bathing 
only one 
part of the body (such as 
back or a leg) 
(0 POINTS) Receives 
assistance in bathing 
more than one part of 
the body (or not bathed) 
DRESSING - gets 
clothes from closets 
and drawers - 
including 
underclothes, outer 
garments and using 
fasteners (including 
braces if worn) 
 
Points:______ 
(1 POINT) Gets 
clothes and gets 
completely dressed 
without assistance 
 
(1 POINT) Gets clothes 
and gets dressed without 
assistance except for 
assistance in tying shoes 
 
(0 POINTS) Receives 
assistance in getting 
clothes or in getting 
dressed, or stays partly 
or completely 
undressed 
TOILETING - going 
to the "toilet room" 
for bowel and urine 
elimination; cleaning 
self after elimination, 
and arranging clothes 
 
Points:______ 
(1 POINT) Goes to 
"toilet room", cleans 
self, and arranges 
clothes without 
assistance (may use 
object for support such 
as cane, walker, or 
wheelchair and may 
manage night bedpan or 
commode, emptying 
same in morning) 
(0 POINTS) Receives 
assistance in going to 
"toilet 
room" or in cleansing 
self or in arranging 
clothes after elimination 
or in use of night bedpan 
or commode 
(0 POINTS) Doesn't go 
to room termed "toilet" 
for the elimination 
process 
TRANSFERRING 
 
Points:______ 
(1 POINT) Moves in 
and out of bed as well 
as in and 
out of chair without 
assistance (may be 
using object for support 
such as cane or walker) 
(0 POINTS) Moves in or 
out of bed or chair with 
assistance 
(0 POINTS) Doesn't 
get out of bed 
CONTINENCE 
 
Points:______ 
(1 POINT) Controls 
urination and bowel 
movement completely 
by self 
(0 POINTS) Has 
occasional “accidents" 
(0 POINTS) 
Supervision helps keep 
urine or bowel control; 
catheter is used, or is 
incontinent 
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KATZ INDEX OF INDEPENDENCE IN ACTIVITIES OF DAILY 
LIVING (ADL) 
FEEDING 
 
Points:______ 
(1 POINT) Feeds self 
without assistance 
(1 POINT) Feeds self 
except for getting 
assistance in cutting 
meat or buttering bread 
(0 POINTS) Receives 
assistance in feeding or 
is fed partly or 
completely by using 
tubes or intravenous 
fluids 
Total score: __________ SCORING: 6 = High (patient independent) 0 = Low (patient very dependent) 
Reference: Based on Katz et al, JAMA, 1963 
 
 
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12.5 Appendix: Modified Instrumental Activities of Daily Living 
MODIFIED INSTRUMENTAL ACTIVITIES OF DAILY LIVING 
Scoring: For each category, circle the item description that most closely resembles the client’s highest functional level 
(either 0 or 1). 
A. Ability to Use Telephone 
 
E. Laundry 
 
1. Operates telephone on own initiative, looks up 
1 
1. Does personal laundry completely 
1 
2. Dials a few well-known numbers 
1 
2. Launders small items-rinses socks, stockings, etc. 
1 
3. Answers telephone but does not dial 
1 
3. All laundry must be done by others 
0 
4. Does not use telephone at all 
0 
5. Not applicable 
1 
4. Not applicable  
1 
B. Shopping 
 
F. Mode of Transportation 
 
1. Takes care of all shopping needs independently 
1 
1. Travels independently on public transportation or 
drives own car 
1 
2. Shops independently for small purchases 
0 
2. Arranges own travel via taxi, but does not otherwise 
use public transportation 
1 
3. Needs to be accompanied on any shopping trip 
0 
3. Travels on public transportation when accompanied 
by another 
1 
4. Completely unable to shop 
0 
4. Travel limited to taxi or automobile with assistance 
0 
5. Does not travel at all 
0 
5. Not applicable 
1 
6. Not applicable 
1 
C. Food Preparation 
 
G. Responsibility for Own Medications 
 
1. Plans, prepares and serves adequate meals 
independently 
1 
1. Is responsible for taking medication in correct 
dosages at correct time 
1 
2. Prepares adequate meals if supplied with 
ingredients 
0 
2. Takes responsibility if medication is prepared in 
advance in separate dosage 
0 
3. Heats, serves, and prepares meals but does not 
maintain adequate diet 
0 
3. Is not capable of dispensing own medication 
0 
4. Needs to have meals prepared and served 
0 
5. Not applicable  
1 
4. Not applicable 
1 
D. Housekeeping 
 
H. Ability to Handle Finances 
 
1. Maintains house alone or with occasional 
assistance (e.g., "heavy work domestic help") 
1 
1. Manages financial matters independently (budgets, 
writes cheques, pays rent, bills, goes to bank), 
collects and keeps track of income 
1 
2. Performs light daily tasks but cannot maintain 
acceptable level of cleanliness 
1 
2. Manages day-to-day purchases, but needs help with 
banking, major purchases, etc. 
1 
3. Needs help with all home maintenance tasks 
1 
3. Incapable of handling money 
0 
4. Does not participate in any housekeeping tasks 
0 
5. Not applicable 
1 
4. Not applicable  
1 
Score
 
Score
 
Total score
 
Reference: Merli et al. J Clin Oncol. 2021 and associated webtool https://redcap.filinf.it/surveys/?s=89AFXML8AK 
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12.6 Appendix: Modified Cumulative Illness Rating Scale - Geriatric 
MODIFIED CUMULATIVE ILLNESS RATING SCALE (CIRS-G) 
Each system is rated as follows: 
 
0 = 
NONE: No impairment to that organ/system 
1 =  MILD:  Impairment does not interfere with normal activity; treatment may or may not be required; 
Prognosis is excellent. (Examples could be skin lesions, hernias, or hemorrhoids) 
2 =  MODERATE: Impairment interferes with normal activity; treatment is needed; prognosis is good. 
(Examples could be gallstones, diabetes, or fractures) 
3 = 
SEVERE: Impairment is disabling; treatment is urgently needed; prognosis is guarded. (Examples could 
be resectable carcinoma, pulmonary emphysema, or congestive heart failure) 
4 = 
 EXTREMELY SEVERE: Impairment is life threatening; treatment is urgent or of no avail; prognosis 
is grave. (Examples could be myocardial infarction, cerebrovascular accident, gastrointestinal bleeding, 
or embolus).  
 
Sr. 
No. 
System 
Rating 
(0-4) 
1.  
Cardiac (heart only) 
 
2.  
Hypertension (rating is based on severity; affected systems are rated separately) 
 
3.  
Vascular (blood, blood vessels and cells, marrow, spleen, lymphatics) 
 
4.  
Respiratory (lungs, bronchi, trachea below the larynx) 
 
5.  
EENT (eye, ear, nose, throat, larynx) 
 
6.  
Upper GI (esophagus, stomach, duodenum, biliary and pancreatic trees; do not 
include diabetes) 
 
7.  
Lower GI (intestines, hernias) 
 
8.  
Hepatic (liver only) 
 
9.  
Renal (kidneys only) 
 
10. 
Other GU (ureters, bladder, urethra, prostate, genitals) 
 
11. 
Musculo-Skeletal-Integumentary (muscles, bone, skin) 
 
12. 
Neurological (brain, spinal cord, nerves; do not include dementia) 
 
13. 
Endocrine-Metabolic (includes diabetes, diffuse infections, infections, toxicity) 
 
14. 
Psychiatric/Behavioral (includes dementia, depression, anxiety, agitation, 
psychosis) 
 
 
How many Ratings of 2 : ___________        How many Ratings of 3-4 : ___________     
Reference: Based on Parmelee et al. J Am Geriatr Soc 1995 
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SAP_001.pdf: 
Protocol Number: ADCT-402-203 
 
Official Title: A Phase 2 Open-label Study of Loncastuximab Tesirine in Combination with 
Rituximab (Lonca-R) in Previously Untreated Unfit/Frail Patients with Diffuse Large B-cell 
Lymphoma (DLBCL) (LOTIS-9) 
 
NCT Number: NCT05144009 
 
Document Date: 11 January 2024 










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