Clinical trial NCT03684694
Conditions: Diffuse Large B-Cell Lymphoma Mantle Cell Lymphoma
Keywords: Loncastuximab Tesirine in Combination with Ibrutinib
Sponsor: ADC Therapeutics S.A.
Start date: 2018-12-01; Completion date: 2022-11-08
Enrollment: 136 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
The purpose of this Phase 1/2 study is to evaluate the safety and efficacy of Loncastuximab Tesirine (ADCT-402) in combination with Ibrutinib in participants with Advanced Diffuse Large B-Cell Lymphoma or Mantle Cell Lymphoma.

Detailed description:
The Phase 1 portion of the study will cover the dose escalation portion of the study. This will then be followed by the Phase 2 portion of the study, which will treat participants with the dose of loncastuximab tesirine determined in the Phase 1 portion of the study. The ibrutinib dose of 560 mg daily, will remain the same throughout both phases of the study.

A standard 3+3 dose escalation design will be used for the Phase 1 portion of the study. The dose-limiting toxicity (DLT) period will be the 21 days following the first dose of ibrutinib. The dose escalation cohort will receive loncastuximab tesirine for 2 cycles with concurrent ibrutinib (concomitant therapy) and may then continue ibrutinib therapy up to one year.

The Phase 2 portion of the study will involve 3 cohorts:

* Non-germinal center B-cell diffuse large B-cell lymphoma (Non-GCB DLBCL) cohort
* Germinal center B-cell diffuse large B-cell lymphoma (GCB DLBCL) cohort
* Mantle cell lymphoma (MCL) cohort

Each of the cohorts will be treated with the recommended dose of loncastuximab tesirine determined in the Phase 1 portion of the study.

The study will include a Screening Period (of up to 28 days), a Treatment Period (cycles of 3 to 4 weeks), and a Follow-up Period (approximately every 12 week visits for up to 2 years after treatment discontinuation).

Arms: arm 1: A standard 3+3 dose escalation design will be used. The dose-limiting toxicity (DLT) period will be the 21 days following the first dose of ibrutinib. The dose escalation cohort will receive loncastuximab tesirine for Cycle 1 and 2 (3 weeks each) with concurrent ibrutinib (concomitant therapy) daily. Participants may continue to receive ibrutinib therapy up to 1 year after Cycle 1 Day 1 (once every 4 weeks from Cycle 3 onwards). Loncastuximab tesirine will be administered intravenously (IV). arm 2: Participants with non-germinal center B-cell diffuse large B-cell lymphoma (Non-GCB DLBCL) will receive the maximum tolerated dose (MTD) or recommended Phase 2 dose (RP2D) of loncastuximab tesirine, as determined in Phase 1, once every 3 weeks for Cycle 1 and 2 and a daily dose of ibrutinib. Participants can continue treatment up to 1 year (once every 4 weeks from Cycle 3 onwards). Loncastuximab tesirine will be administered IV. arm 3: Participants with germinal center B-cell diffuse large B-cell lymphoma (GCB DLBCL) will receive the maximum tolerated dose (MTD) or recommended Phase 2 dose (RP2D) of loncastuximab tesirine, as determined in Phase 1, once every 3 weeks for Cycle 1 and 2 and a daily dose of ibrutinib. Participants can continue treatment up to 1 year (once every 4 weeks from Cycle 3 onwards). Loncastuximab tesirine will be administered IV. arm 4: Participants with mantle cell lymphoma (MCL) will receive the maximum tolerated dose (MTD) or recommended Phase 2 dose (RP2D) of loncastuximab tesirine, as determined in Phase 1, once every 3 weeks for Cycle 1 and 2 and a daily dose of ibrutinib. Participants can continue treatment up to 1 year (once every 4 weeks from Cycle 3 onwards). Loncastuximab tesirine will be administered IV.
Interventions: intervention 1: Loncastuximab Tesirine intervention 2: Ibrutinib
Intervention descriptions: intervention 1: Intravenous (IV) infusion. intervention 2: Oral capsule.

Protocol documents:
Prot_000.pdf: 
Protocol Number: ADCT-402-103 
 
Official Title: A Phase 1/2 Open-Label Study to Evaluate the Safety and Efficacy of Loncastuximab 
Tesirine and Ibrutinib in Patients with Advanced Diffuse Large B-Cell Lymphoma or Mantle Cell 
Lymphoma (LOTIS-3) 
 
NCT Number: NCT03684694 
 
Document Date: 31 August 2021 


ADC Therapeutics 
Loncastuximab Tesirine in Combination with Ibrutinib 
ADCT-402-103 (LOTIS-3) 
Final Protocol Amendment 5 
 
Confidential  
Page 1 
 
 
CLINICAL STUDY PROTOCOL 
IND: 126138 
EudraCT Number: 2018-002625-38 
 
 
 
A Phase 1/2 Open-Label Study to Evaluate the Safety and Efficacy of 
Loncastuximab Tesirine and Ibrutinib in Patients with Advanced Diffuse 
Large B-Cell Lymphoma or Mantle Cell Lymphoma (LOTIS-3) 
 
 
PROTOCOL NO.: ADCT-402-103 
 
 
Sponsor: 
ADC Therapeutics SA 
 
 
 
 
Sponsor Contact: 
 
Head of Early Clinical Development 
ADC Therapeutics America Inc. 
Phone: 
 
e-mail: 
 
Protocol Amendment 5: 
31 August 2021 
 
 
 
 
 
Confidentiality Statement 
The concepts and information contained in this document or generated during the study are 
considered proprietary and may not be disclosed in whole or in part without the express written 
consent of ADC Therapeutics 
 
 


ADC Therapeutics 
Loncastuximab Tesirine in Combination with Ibrutinib 
ADCT-402-103 (LOTIS-3) 
Final Protocol Amendment 5 
 
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PROTOCOL APPROVAL – SPONSOR SIGNATORY 
 
 
 
Study Title: 
“A Phase 1/2 Open-Label Study to Evaluate the Safety 
and Efficacy of Loncastuximab Tesirine and Ibrutinib in 
Patients with Advanced Diffuse Large B-Cell Lymphoma 
or Mantle Cell Lymphoma (LOTIS-3)” 
Protocol Number: 
ADCT-402-103 
Protocol Amendment 5: 
31 August 2021 
 
 
 
Protocol accepted and approved by: 
 
 
Head of Early Clinical Development 
ADC Therapeutics America Inc. 
Phone: 
 
e-mail: 
  
 
 
 
 
Signature 
 
Date 
 
31 August 2021


ADC Therapeutics 
Loncastuximab Tesirine in Combination with Ibrutinib 
ADCT-402-103 (LOTIS-3) 
Final Protocol Amendment 5 
 
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DECLARATION OF INVESTIGATOR 
 
I have read and understood all sections of the protocol entitled: “A Phase 1/2 Open-Label Study 
to Evaluate the Safety and Efficacy of Loncastuximab Tesirine and Ibrutinib in Patients with 
Advanced Diffuse Large B-Cell Lymphoma or Mantle Cell Lymphoma (LOTIS-3)” 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 5, dated 31 August 2021, the current version of 
International Council for Harmonisation (ICH) harmonised tripartite guideline E6: Good Clinical 
Practice, and all applicable governmental regulations. I will not make changes to the protocol 
before consulting with ADC Therapeutics SA or implement protocol changes without Independent 
Ethics Committee approval except to eliminate an immediate risk to patients. I agree to administer 
the study drugs only to patients under my personal supervision or the supervision of a 
sub-Investigator. 
I will not supply the study drugs 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 
 
 
 


ADC Therapeutics 
Loncastuximab Tesirine in Combination with Ibrutinib 
ADCT-402-103 (LOTIS-3) 
Final Protocol Amendment 5 
 
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TABLE OF CONTENTS 
 
TABLE OF CONTENTS ................................................................................................................ 4 
LIST OF TABLES .......................................................................................................................... 8 
LIST OF FIGURES ........................................................................................................................ 9 
LIST OF ABBREVIATIONS ....................................................................................................... 10 
SUMMARY OF CHANGES AND RATIONALE ...................................................................... 13 
Protocol Amendment 5 ..........................................................................................................13 
Protocol Amendment 4 ..........................................................................................................16 
Protocol Amendment 3 ..........................................................................................................18 
Protocol Amendment 2 ..........................................................................................................20 
Protocol Amendment 1 ..........................................................................................................23 
LIST OF PRIOR PROTOCOL VERSIONS................................................................................. 24 
PROTOCOL SYNOPSIS.............................................................................................................. 25 
SCHEDULE OF EVENTS ........................................................................................................... 37 
1 
INTRODUCTION AND BACKGROUND ......................................................................... 43 
1.1 
Non-Hodgkin Lymphoma and CD19 ...........................................................................43 
1.1.1 
Diffuse Large B-cell Lymphoma ....................................................................43 
1.1.2 
Mantle Cell Lymphoma ..................................................................................44 
1.2 
Loncastuximab Tesirine and Ibrutinib .........................................................................44 
1.2.1 
Loncastuximab Tesirine Description ..............................................................44 
1.2.2 
Safety and Efficacy of Loncastuximab Tesirine .............................................46 
1.2.3 
Ibrutinib Description .......................................................................................48 
1.2.4 
Safety and Efficacy of Ibrutinib .....................................................................48 
2 
STUDY RATIONALE ......................................................................................................... 50 
2.1 
Rationale for Study Design ..........................................................................................50 
2.2 
Rationale for Dose Selection .......................................................................................51 
3 
STUDY OBJECTIVES AND ENDPOINTS ....................................................................... 53 
4 
STUDY DESIGN ................................................................................................................. 56 
4.1 
Overview ......................................................................................................................56 
4.2 
Screening Period ..........................................................................................................57 
4.3 
Treatment Period ..........................................................................................................58 


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4.4 
End of Treatment .........................................................................................................58 
4.5 
Follow-up Period .........................................................................................................58 
4.6 
End of Study ................................................................................................................59 
5 
PATIENT POPULATION ................................................................................................... 60 
5.1 
Inclusion Criteria .........................................................................................................60 
5.2 
Exclusion Criteria ........................................................................................................61 
5.3 
Screen Failures .............................................................................................................62 
6 
STUDY TREATMENT ........................................................................................................ 63 
6.1 
Study Drugs .................................................................................................................63 
6.1.1 
Loncastuximab Tesirine ..................................................................................63 
6.1.2 
Ibrutinib ..........................................................................................................63 
6.2 
Management of Clinical Supplies ................................................................................63 
6.2.1 
Packaging and Storage ....................................................................................63 
6.2.2 
Preparation and Administration ......................................................................64 
6.2.3 
Accountability .................................................................................................64 
6.3 
Dosing of Study Drugs.................................................................................................64 
6.3.1 
Loncastuximab Tesirine Dosing .....................................................................64 
6.3.2 
Ibrutinib Dosing ..............................................................................................66 
6.4 
Dose Escalation ............................................................................................................66 
6.4.1 
Dose Escalation Design ..................................................................................66 
6.4.2 
Dose-Limiting Toxicity Period .......................................................................67 
6.4.3 
Dose-Limiting Toxicity Definition .................................................................67 
6.4.4 
Dose Escalation Steering Committee .............................................................68 
6.5 
Dose Delays and Modifications ...................................................................................69 
6.5.1 
Loncastuximab Tesirine ..................................................................................69 
6.5.2 
Ibrutinib ..........................................................................................................71 
6.6 
Overdose Management ................................................................................................72 
6.7 
Premedication and Supportive Care .............................................................................72 
6.7.1 
Premedication for Loncastuximab Tesirine ....................................................72 
6.7.2 
Treatment of Edema and Pleural Effusion ......................................................72 
6.7.3 
Treatment and Prophylaxis of Infusion-Related Hypersensitivity Reactions .72 
6.7.4 
Skin Toxicity ..................................................................................................73 
6.7.5 
Other Supportive Care ....................................................................................73 
6.8 
Concomitant Medications and Procedures ...................................................................73 
6.8.1 
Permitted During Study ..................................................................................73 


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6.8.2 
Prohibited During Study .................................................................................74 
7 
DISCONTINUATION ......................................................................................................... 75 
7.1 
Discontinuation from Study Treatment .......................................................................75 
7.2 
Discontinuation from the Study ...................................................................................75 
7.3 
Loss to Follow-Up .......................................................................................................76 
8 
STUDY ASSESSMENTS AND PROCEDURES ............................................................... 77 
8.1 
Efficacy Assessments ...................................................................................................77 
8.2 
Adverse Events ............................................................................................................78 
8.2.1 
Definition of Adverse Events and Serious Adverse Events ...........................78 
8.2.2 
Eliciting and Reporting Adverse Events/Serious Adverse Events .................78 
8.2.3 
Assessment of Severity ...................................................................................80 
8.2.4 
Assessment of Causality .................................................................................80 
8.2.5 
Regulatory Reporting ......................................................................................81 
8.2.6 
Pregnancy Reporting ......................................................................................81 
8.3 
Safety Assessments ......................................................................................................81 
8.3.1 
Physical Examination .....................................................................................81 
8.3.2 
ECOG Performance Status .............................................................................81 
8.3.3 
Height and Weight ..........................................................................................82 
8.3.4 
Vital Signs ......................................................................................................82 
8.3.5 
Laboratory Tests .............................................................................................82 
8.3.6 
Pregnancy Test ................................................................................................82 
8.3.7 
ECG ................................................................................................................83 
8.4 
Pharmacokinetics, 
 and Immunogenicity .....................................85 
8.4.1 
Pharmacokinetics ............................................................................................85 
8.4.2 
Immunogenicity ..............................................................................................88 
 
 
 
 
8.5 
Patient-Reported Outcomes Questionnaires ................................................................89 
8.5.1 
European Organization for Research and Treatment of Cancer Quality of Life 
Questionnaire – EORTC QLQ-C30 ................................................................89 
8.5.2 
Lymphoma Subscale (LymS) of FACT-Lym .................................................89 
8.5.3 
EuroQol-5 Dimensions-5 Levels (EQ-5D-5L) ...............................................90 
9 
STATISTICAL CONSIDERATIONS ................................................................................. 91 
9.1 
Sample Size ..................................................................................................................91 


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ADCT-402-103 (LOTIS-3) 
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9.1.1 
Phase 2 Sample Size Calculation for non-GCB DLBCL Cohort Where 
Loncastuximab Tesirine is Given Intermittently in Combination with 
Ibrutinib ..........................................................................................................91 
9.1.2 
Phase 2 Sample Size Calculation for the Cohort Where Loncastuximab 
Tesirine is Given at Every Cycle in Combination with Ibrutinib ...................91 
9.2 
Analysis Populations ....................................................................................................92 
9.3 
Phase 2 Interim Analysis for Futility ...........................................................................92 
9.3.1 
Non-GCB Cohort Where Loncastuximab Tesirine is Given Intermittently in 
Combination with Ibrutinib ............................................................................92 
9.3.2 
Cohort Where Loncastuximab Tesirine is Given at Every Cycle in 
Combination with Ibrutinib ............................................................................92 
9.4 
Final Analysis ..............................................................................................................93 
9.5 
Demographics and Baseline Characteristics ................................................................93 
9.6 
Exposure to Treatments ...............................................................................................93 
9.7 
Efficacy Analyses ........................................................................................................93 
9.7.1 
Complete Response Rate ................................................................................93 
9.7.2 
Overall Response Rate ....................................................................................94 
9.7.3 
Duration of Response .....................................................................................94 
9.7.4 
Relapse-free Survival ......................................................................................94 
9.7.5 
Progression-free Survival ...............................................................................94 
9.7.6 
Overall Survival ..............................................................................................94 
9.8 
Safety and Subgroup Analyses ....................................................................................95 
9.8.1 
Adverse Events ...............................................................................................95 
9.8.2 
Clinical Laboratory Results ............................................................................95 
9.8.3 
Additional Safety Assessments .......................................................................95 
9.9 
Pharmacokinetic Analyses ...........................................................................................96 
9.10 Immunogenicity Analyses ...........................................................................................96 
 
10 
DATA MANAGEMENT AND QUALITY ASSURANCE ................................................ 98 
11 
ETHICAL, REGULATORY, AND STUDY MANAGEMENT CONSIDERATIONS ..... 99 
11.1 Regulatory and Ethical Conduct of the Study..............................................................99 
11.2 Independent Ethics Committee or Institutional Review Board ...................................99 
11.3 Patient Information and Consent .................................................................................99 
11.4 Confidentiality ...........................................................................................................100 
11.5 Financial Disclosure and Obligations ........................................................................100 
11.6 Serious Adverse Events Report Requirements ..........................................................100 


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ADCT-402-103 (LOTIS-3) 
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11.7 Study Conduct ............................................................................................................100 
11.8 Protocol Amendments ................................................................................................100 
11.9 Monitoring of the Study .............................................................................................101 
11.10 Records Retention ......................................................................................................101 
11.11 Publications ................................................................................................................101 
12 
REFERENCE LIST ............................................................................................................ 102 
 
 
LIST OF TABLES 
 
Table 1 
Schedule of Events: Phase 1 ...................................................................................... 37 
Table 2 
Schedule of Events: Phase 2 ...................................................................................... 40 
Table 3 
Study Objectives and Endpoints ................................................................................ 53 
Table 4 
Phase 1: Concomitant Treatment with Loncastuximab Tesirine and Ibrutinib ......... 65 
Table 5 
Phase 2: Concomitant Treatment with Loncastuximab Tesirine and Ibrutinib ......... 66 
Table 6 
Loncastuximab Tesirine Guidelines for Dose Modifications .................................... 69 
Table 7 
Definition of Severity Grades for CTCAE ................................................................ 80 
Table 8 
Schedule for Triplicate ECG Collection: Phase 1 ..................................................... 83 
Table 9 
Schedule for Triplicate ECG Collection: Phase 2 for Cohort Where Loncastuximab 
Tesirine Is Given Intermittently in Combination with Ibrutinib ............................... 84 
Table 10 
Schedule for Triplicate ECG Collection: Phase 2 for Cohort Where Loncastuximab 
Tesirine Is Given at Every Cycle in Combination with Ibrutinib .............................. 84 
Table 11 
Sampling Schedule for PK and ADA: Phase 1 .......................................................... 86 
Table 12 
Sampling Schedule for PK and ADA: Phase 2 .......................................................... 87 


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LIST OF FIGURES 
 
Figure 1 
Schematic Representation and Chemical Structure of Loncastuximab Tesirine ....... 45 
Figure 2 
Anti-drug Antibody Tiered Immunogenicity Testing Strategy ................................. 97 
 
 


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LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
ABW 
adjusted body weight 
ADA 
anti-drug antibody 
ADC 
antibody drug conjugate 
ADR 
adverse drug reaction 
AE 
adverse event 
AESI 
adverse event of special interest 
AI 
accumulation index 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
AlloSCT 
allogeneic stem cell transplant 
ANC 
absolute neutrophil count 
AST 
aspartate aminotransferase 
AUCinf 
area under the concentration-time curve from time zero to infinity 
AUClast 
area under the concentration-time curve from time zero to the last 
quantifiable concentration 
AUCtau 
area under the concentration-time curve from time zero to the end of the 
dosing interval 
BID 
BMI 
twice a day 
body mass index 
B-NHL 
B-cell NHL 
BOR 
best overall response 
BP 
blood pressure 
BTK 
Bruton’s tyrosine kinase 
C  
cycle 
C1D1 
Cycle 1 Day 1 
CAR-T 
chimeric antigen receptor T-cell 
CD19 
cluster of differentiation 
CFR 
cfDNA 
Code of Federal Regulations 
circulating free DNA 
CI 
confidence interval 
CL 
apparent systemic clearance 
Cmax 
maximum concentration 
CNS 
central nervous system 
CR 
complete response 
CRO 
Contract Research Organization 
CRR 
complete response rate 
CSR 
clinical study report 
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
D 
day 
DESC 
Dose Escalation Steering Committee 
DLBCL 
diffuse large B-cell lymphoma 
DLT 
dose-limiting toxicity 


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ADCT-402-103 (LOTIS-3) 
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Abbreviation 
Definition 
DNA 
deoxyribonucleic acid 
DOR 
duration of response 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 
EDC 
electronic data capture 
EOI 
end of infusion 
EORTC 
The European Organization for Research and Treatment of Cancer 
EOT 
EQ-5D-5L 
FACT-Lym 
end of treatment 
EuroQoL-5 Dimensions-5 Levels 
Functional Assessment of Cancer Therapy-Lymphoma 
FDA 
Food and Drug Administration 
FFPE 
formalin-fixed paraffin-embedded 
GCB 
germinal center B-cell 
GCP 
gDNA 
Good Clinical Practice 
genomic DNA 
GGT 
gamma glutamyl transferase 
HBV 
hepatitis B virus 
β-HCG 
beta-human chorionic gonadotropin 
HCV 
hepatitis C virus 
HD-ASCT 
high-dose chemotherapy and autologous stem cell transplant 
HIV 
human immunodeficiency virus 
HRQoL 
Health-related quality of life 
IB 
Investigator’s Brochure 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
IHC 
IEC 
Immunohistochemistry 
Independent Ethics Committee 
INR 
international normalized ratio 
IRB 
IRC 
Institutional Review Board 
Independent Review Committee 
IV 
LymS 
intravenous(ly) 
lymphoma subscale 
MedDRA 
Medical Dictionary for Regulatory Activities 
MCL 
mantle cell lymphoma 
mmHg 
millimeters of mercury 
MRI 
magnetic resonance imaging 
MSD-ECL 
Meso-Scale Discovery Electrochemiluminescence 
MTD 
maximum tolerated dose 
NHL 
non-Hodgkin lymphoma 
ORR 
overall response rate 
OS 
overall survival 
PBD 
pyrrolobenzodiazepine 
PD 
progressive disease 
PET 
positron emission tomography 


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Abbreviation 
Definition 
PFS 
progression-free survival  
P-gp 
P-glycoprotein 
PK 
pharmacokinetic(s) 
po 
orally/per os 
PR 
PRO 
partial response 
patient-reported outcome 
PTT 
partial thromboplastin time 
QLQ 
quality of life questionnaire 
QoL 
quality of life  
QT 
measure between Q wave and T wave in the electrocardiogram 
QTcF 
Fredericia correction of the QT measure 
Q3W 
every 3 weeks 
RBC 
red blood cell 
RFS 
relapse-free survival 
RP2D 
Recommended Phase 2 Dose 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SD 
stable disease 
SOC 
standard of care 
SoE 
Schedule of Events 
SUSAR 
Suspected Unexpected Serious Adverse Reactions 
TEAE 
treatment-emergent adverse event 
Thalf 
apparent terminal half-life 
TLS 
tumor lysis syndrome 
Tmax 
time to maximum concentration 
µL 
microliter 
ULN 
upper limit of normal 
US 
United States 
Val 
valine 
Vss 
apparent volume of distribution 
WBC 
white blood cell 
WHO 
World Health Organization 
WOCBP 
women of childbearing potential 
 


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SUMMARY OF CHANGES AND RATIONALE  
Protocol Amendment 5 
The primary reason for this global Protocol Amendment 5 was to amend the study design for the 
Phase 2 by enrolling approximately 100 patients with relapsed or refractory Diffuse Large B-Cell 
Lymphoma (DLBCL) to a new treatment cohort in which loncastuximab tesirine will be given 
every cycle (rather than intermittently) in combination with ibrutinib. This is to explore if the 
intensified regimen improves treatment response and durability in patients with advanced 
DLBCL. The RP2D for loncastuximab tesirine which has been determined as 60 µg/kg will be 
re-determined after the testing of 75 µg/kg dose has been completed in the Phase 1 portion of the 
study. In this new treatment cohort loncastuximab tesirine will be given at re-determined RP2D. 
Ibrutinib will be given orally at 560 mg daily on Cycle 1 (C1) and C2, and subsequent doses of 
ibrutinib will be given at 420 mg daily to mitigate potential additive adverse events.  
The summary of changes and the rationale in Protocol Amendment 5 is as follows: 
• Section 3 Study Objectives and Endpoints:  
o The primary objective for Phase 2 study was modified to evaluate the efficacy of 
loncastuximab tesirine given at every cycle in combination with ibrutinib in patients with 
relapsed or refractory DLBCL. 
o The primary endpoint for Phase 2 study was changed to Complete Response Rate (CRR) 
according to the 2014 Lugano classification as determined by independent review 
committee (IRC) in all DLBCL patients given loncastuximab tesirine at every cycle in 
combination with ibrutinib, instead of the non-GCB DLBCL cohort only receiving 
intermittent dosing of loncastuximab tesirine. The latter has been moved to a secondary 
endpoint. 
 
 
  
 
• Section 4.1 Study Design Overview:  
o Updated the study design by introducing a new treatment cohort for DLBCL patients in 
which loncastuximab tesirine is given at every cycle in combination with ibrutinib to 
potentially improve response rate and durability in Phase 2 once a re-determined 
MTD/PR2D has been defined. Ibrutinib will be given at 560 mg po daily for first 
2 cycles, then 420 mg po daily for subsequent cycles starting at C3 for this new 
treatment. The dose selection rationale for this new DLBCL treatment cohort was added 
in Section 2.2. Also, a two-stage design with futility monitoring was added for the new 
treatment cohort. The new treatment cohort was added in Section 4.3 Treatment Period 
and Section 6.3 Dosing of Study Drug. A table of two treatment cohorts for Phase 2 was 
generated for easy reference in Section 6.3.  


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o Closed the patient enrollment to non-GCB DLBCL cohort where loncastuximab tesirine 
is given intermittently in combination with ibrutinib in Phase 2.  
o Updated the study sample size from 161 to 243 taking into account 100 DLBCL patients 
in the new treatment cohort and the early enrollment closure of the non-GCB DLBCL 
cohort where loncastuximab tesirine is given intermittently in combination with ibrutinib 
in Phase 2. Section 9.1 Sample Size was amended for the same reasons.  
 
• Section 5.1 Inclusion Criteria: 
o Clarified criterion 3 to allow patients not considered by the investigator to be a candidate 
for stem cell transplantation to participate in the study.  
o For inclusion criterion 11 added a barrier method to hormonal contraceptives (oral, 
injectable, patch, intrauterine devices) as one of highly effective forms of birth control 
to follow contraception recommendation for ibrutinib. 
 
• Section 6.5.2 Dose Delays and Modifications_Ibrutinib:  
o Updated the dose modification of ibrutinib in case of toxicity when given at a dose of 
420 mg daily. 
o Updated the ibrutinib dose modification recommendations during coadministration of a 
strong or moderate CYP3A inhibitor in reference to ibrutinib Investigator Brochure (IB). 
Section 6.8.2 was updated as well. 
o Updated to allow ibrutinib dose re-escalation during the study treatment. 
 
• Section 6.7.3 Treatment and Prophylaxis of Infusion-Related Hypersensitivity Reactions: 
Removed the protocol specified guidance for prophylaxis of infusion-related 
hypersensitivity reaction as ranitidine is not available in some countries, and institutional 
standard of care is a good alternative.  
• Section 7.1 Discontinuation from Study Treatment: Added transplant therapy as one of 
reasons for end of study treatment to document the events.  
• Section 8.3.7 ECG: Table 10 of ECG collection schedule for Phase 2 patients in 
loncastuximab tesirine given at every cycle in combination with ibrutinib was added to 
clearly indicate the monitoring of cardiac safety for patients in newly added cohort.  
• Section 8.4.2 Immunogenicity: Updated Table 12: For Phase 2 study removed ADA 
collections at C6 and C10 for all patients and added ADA collection to C13 for patients 
receiving loncastuximab tesirine given at every cycle in combination with ibrutinib to 
monitor ADA titer. A footnote was added to clarify the applicable protocol version for the 
removal of C6 and C10 collection.  


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• Section 9.3.2 Cohort Given Loncastuximab Tesirine at Every Cycle in Combination with 
Ibrutinib: This new subsection was added under Section 9.3 Phase 2 Interim Analysis for 
Futility per new study design. The interim analysis for futility when Lonca was given 
intermittently is now located in section 9.3.1. 
• Section 9.4 Final Analysis: Deleted the exact binomial test for final analysis of Phase 2 
primary endpoint as it does not apply in the new study design.  
In addition, non-substantial clarifications/corrections for inconsistencies, as well as 
administrative and editorial changes were included; revisions to the protocol text have also been 
applied to the synopsis section and Schedule of Events (SoE), Table 2 for Phase 2 study. 


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Protocol Amendment 4 
The primary reasons for Protocol Amendment 4 were to extend the contraception duration for 
applicable subjects to align with the current regulatory guidance; to update guidance to 
investigators regarding loncastuximab tesirine dose delays and modifications as well as 
prohibited medication for concurrent use with loncastuximab tesirine; and to remove the 
loncastuximab tesirine dose adjustment for patients with a body mass index (BMI) ≥35kg/m2. 
This amendment also provided two clarifications: one regarding patient reported outcome (PRO) 
collection time points during the study follow-up and the other notifying that mantle cell 
lymphoma (MCL) patients enrolled into the Phase 2 part of the study will have central reviews of 
their scans. Lastly, this amendment incorporated all country specific amendments from the 
country specific protocols to this global protocol to eliminate country specific protocols going 
forward. 
The summary of changes and the rationale in Protocol Amendment 4 is as follows: 
• To align with the current regulatory guidance (United States [US] Federal Drug 
Administration, “Oncology Pharmaceuticals: Reproductive Toxicity Testing and 
Labeling Recommendations”, May 2019 and Clinical Trials Facilitation and Coordination 
Group, “Recommendations related to contraception and pregnancy testing in clinical 
trials”, 21 Sep 2020), the contraception duration required for women of childbearing 
potential (WOCBP) and for men with female partners of childbearing potential were 
extended to the time from signing informed consent form to at least 9 months and 
6 months post last loncastuximab tesirine treatment, respectively, when applicable. The 
sections below in the protocol were revised to comply with the change. 
o Section 5.1 Inclusion Criteria: Revised Inclusion Criterion #11 to: Women of 
childbearing potential must agree to use a highly effective method of contraception 
from the time of giving informed consent until at least 9 months after the last dose 
of loncastuximab tesirine or 1 month after last dose of ibrutinib, whichever comes 
last. Men with female partners who are of childbearing potential must agree that 
they will use a highly effective method of contraception from the time of giving 
informed consent until at least 6 months after the patient receives his last dose of 
loncastuximab tesirine or 3 months after last dose of ibrutinib, whichever comes 
last.  
o Section 8.2.6 Pregnancy Reporting: Updated the duration of reporting pregnancy 
to align with the contraception duration. 
o Section 8.3.6 Pregnancy Test: Added a final pregnancy test for female patients at 
≥9 months post last dose of loncastuximab tesirine during the study follow-up, if 
applicable. Specified to allow a remote pregnancy test during follow-up. Clarified 
that additional tests may be obtained, if needed. The Schedule of Events (SoE) 
Tables (Table 1 and Table 2) were updated accordingly. 


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• Schedule of Events Table 2 for Phase 2 Study:  
o Updated PRO collection time point, footnote 13 (and delete footnote 14) to read: 
“Collect EQ-5D-5L only, via phone or at the study site every 12 weeks after the 
end of treatment for 1 year.” This was to ensure that PRO is collected uniformly for 
all patients and to minimize protocol deviations that can occur when trying to 
collect data from patients who progress after discontinuing study treatment.  
o Updated pregnancy test and provided specifications in the footnote 14.  
• Section 5.1 Inclusion Criteria: Added a note to Inclusion Criteria #2 & #4 to exclude MCL 
patients in Italy to incorporate the country specific requirement. 
• Section 6.2.2 Study Treatment Preparation and Administration: A clarification was made 
for the loncastuximab tesirine dose adjustment when subject weight change is 10% or more 
at subsequent dosing from the baseline to align with the instructions from the pharmacy 
manual.  
• 
Section 6.3.1 Loncastuximab Tesirine Dosing: Removed dosing adjustment for patients 
with a BMI ≥35kg/m2 as recent population pharmacokinetics analysis revealed the dose 
adjustment is not needed. 
• Section 6.5.1 Dose Delays and Modifications/Loncastuximab Tesirine:  
o Modified dose holding for liver function test abnormalities to ≥Grade 3 only, based 
on the updated safety profile.  
o Added dose discontinuation criteria: Grade 4 infusion related reactions and Hy’s 
law liver injury to provide the standard criteria across the study for study drug 
discontinuation due to severity of both events and to align with other 
Loncastuximab Tesirine studies.  
• Section 6.8.2 Prohibited During Study:  
o Made a correction for inconsistency on strong CYP3A inducers. 
o Removed P-glycoprotein (P-gp) inhibitors as prohibited medications for concurrent 
use with loncastuximab tesirine as the IC50 values for the inhibition are 
considerably in excess of the likely clinical exposure to SG3199, and deleted 
Appendix 4. 
• Section 8.1 Efficacy Assessments: Modified to include images from MCL patients treated 
in the Phase 2 study to be submitted for central review to ensure that all patients enrolled 
in the Phase 2 study undergo central review of their radiographic scans.  
• Section 9.10 Immunogenicity Analyses: Updated to follow FDA Immunogenicity Testing 
Guidance 2019.  
• Section 11.1 Regulatory and Ethical Conduct of the Study: Added a note to exclude the 
patient’s legally authorized representative/legal guardian in France to incorporate a country 
specific requirement.  
In addition, non-substantial clarifications/corrections for inconsistencies, as well as 
administrative and editorial changes were included; revisions to the protocol text have also been 
applied to the synopsis section.  


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Protocol Amendment 3 
In order to potentially increase the duration of response in patients enrolled and treated with 
loncastuximab tesirine and ibrutinib, this study has been amended to allow for additional doses 
of loncastuximab tesirine to be administered on Day 1 of Cycles 5, 6, 9 and 10 in the Phase 2 
portion of the study.  
In addition, the Sponsor on a case-by-case review will allow patients benefitting clinically at 
1 year to receive additional doses of study drug(s).  
The following changes have occurred:  
• 
Study Title was updated with program number – LOTIS-3 
• Table 1, Schedule of Events was modified to remove coagulation and urinalysis collection 
during the study and to include assessments only relevant to the Phase 1 portion of the 
study.  
• Table 2, Schedule of Events: a new table was added for Phase 2 only and includes 
additional doses of loncastuximab tesirine administration and updates to the collection 
times for coagulation and urinalysis, electrocardiogram (ECG), pharmacokinetics (PK), 
anti-drug antibody (ADA), and patient-reported outcomes (PROs).  
• Section 1.2.1, Loncastuximab Tesirine Description shows an updated loncastuximab 
tesirine compound figure (Figure 1). 
• Section 2.2, Rationale for Dose Selection was modified to include additional doses of 
loncastuximab tesirine in Phase 2.  
• Section 4.3, Treatment Period was updated to include additional doses of loncastuximab 
tesirine in Phase 2 and to allow for additional dosing of study drugs for patients benefitting 
clinically at 1 year. 
• Section 6.1.1, Loncastuximab Tesirine was modified to include frozen liquid formulation 
of loncastuximab tesirine in Phase 2. 
• Section 6.3.1, Loncastuximab Tesirine Dosing was updated to include administration of 
loncastuximab tesirine for patients with complete response (CR), partial response (PR) and 
stable disease (SD) on Day 1 of Cycles 5, 6, 9, and 10 in Phase 2 of the study.  
• Section 6.3.2, Ibrutinib Dosing was updated to specify that ibrutinib dosing will begin 
simultaneously with loncastuximab tesirine dosing (concomitant treatment). 
• Section 6.5.1, Loncastuximab Tesirine was updated to allow continued dosing with 
ibrutinib if loncastuximab tesirine is delayed or discontinued due to related toxicity.  
• Section 6.5.2, Ibrutinib was updated to include guidance for Grade 2 adverse events (AEs). 
Additional update to allow continued dosing with loncastuximab tesirine if ibrutinib is 
delayed or discontinued due to related toxicity was provided.  
• 
Section 8.1, Efficacy Assessment was updated to include that Week 14 imaging should be 
performed prior to C5D1 
• Section 8.3.7, ECG: a new table (Table 8) was added for triplicate ECG collection in 
Phase 2.  


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• Section 8.4.1, Pharmacokinetics: Table 9 (formerly Table 7) was modified to remove 
ADA collection in C5 and subsequent odd cycles in Phase 1.  
• Section 8.4.1, Pharmacokinetics: a new table (Table 10) for PK and ADA collection was 
added for Phase 2. 
• Section 8.5, Patient-Reported Outcomes Questionnaires was updated with a summary 
statement and PRO collection guidance.  
• Sections 13.5, 13.6, and 13.7, sample PRO questionnaires, EORTC QLQ-C30 
(Appendix 5), LymS of FACT-Lym (Appendix 6) and EQ-5D-5L (Appendix 7) were 
added.  
• Protocol synopsis was revised to align with the changes in the protocol. 
• 
Editorial corrections and clarifications were applied throughout.  


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Protocol Amendment 2 
Based on the observed complete response (CR) rate in patients who were enrolled and treated 
with loncastuximab tesirine and ibrutinib in part 1, this trial has been amended to a Phase 1/2 
protocol. There were two dose-limiting toxicities (DLTs) during the DLT period at 90 µg/kg of 
loncastuximab tesirine in a concomitant therapy with ibrutinib. Since the two DLTs would 
require the maximum tolerated dose (MTD) to be at a lower than anticipated dose of 
loncastuximab tesirine, the Sponsor may consider exploring and evaluating a new dose level of 
75 µg/kg loncastuximab tesirine in concomitant therapy with ibrutinib in the dose escalation of 
Phase 1.  
Patients with the germinal center B-cell-like (GCB) subtype of diffuse large B-cell lymphoma 
(DLBCL) account for a significant portion of patients with DLBCL. Considering that the 
Sponsor has seen encouraging results in the current non-GCB DLBCL patient subgroup, this trial 
will expand enrollment to allow GCB DLBCL patients on study treatment. 
The trial sample size has been increased to approximately 161 patients, and its Phase 2 will 
evaluate efficacy in non-GCB DLBCL patients as its primary endpoint. 
Supplementary secondary endpoints are added in Section 3.  
The following changes have occurred: 
• Table 1, Schedule of Events was modified to add genomic deoxyribonucleic acid (gDNA), 
circulating free DNA (cfDNA) samples, and patient-reported outcomes (PROs) 
questionnaire collection for Phase 2. 
• Section 1.2.1, Loncastuximab Tesirine Description section shows an updated 
loncastuximab tesirine compound figure. 
• Section 1.2.2, Safety and Efficacy of Loncastuximab Tesirine was updated to show new 
data from ADCT-402-101 study. 
• Section 2, Study Rationale was updated to support the changed study design. 
• Section 2.1, Rationale for Study Design was modified to include potential expansion in 
Phase 2. 
• Section 2.2, Rationale for Dose Selection was modified to include language on Phase 2 and 
the verbiage of sequential therapy was removed. 
• Patients tolerated concomitant therapy of loncastuximab tesirine with ibrutinib very well 
during Part 1; therefore, sequential dosing was no longer needed.  
• Table 3, Study Objectives and Endpoints was revised to show updated objectives and 
endpoints for both phases.  
• Section 4.1, Overview was modified to remove sequential therapy language and to allow 
GCB DLBCL patients on trial. 
• Section 5.1, Inclusion Criteria: To further evaluate efficacy and safety in the 
DLBCL treatment group, Inclusion Criterion #2 was modified to allow all patients with 
pathologic diagnosis of DLBCL on trial. 


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• Section 5.1, Inclusion Criteria: To adhere to Clinical Trial Facilitation Group guidance, 
Inclusion Criterion #11 was modified to show that men with female partners of 
childbearing potential must agree to use highly effective contraception from the time of 
consent until 20 weeks after last treatment. 
• Section 6.1.1, Loncastuximab Tesirine was updated to show loncastuximab tesirine’s new 
drug formulation that will be used on trial for both phases. 
• Section 6.2.1, Packaging and Storage was updated to match packaging and storage 
instructions for the loncastuximab tesirine’s new formulation.  
• Section 6.3.1, Loncastuximab Tesirine Dosing shows the addition of a third dose level for 
the escalation portion of Phase 1 and the removal of sequential therapy, as sequential 
dosing will no longer need to be conducted. 
• Table 4, Concomitant Treatment with Loncastuximab Tesirine and ibrutinib was updated 
to remove the two loncastuximab tesirine doses of 120 µg/kg and 150 µg/kg as a 
concomitant therapy. 
• Section 6.5.1, Loncastuximab Tesirine: dose modification guidelines are now shown in a 
tabular format and specific skin toxicity dose modification guidelines have been added to 
help investigators manage skin related incidences for patients during study treatment. 
• Section 6.7.4, Skin Toxicity was modified to include recommendation on the avoidance of 
sun exposure and treatment measures.  
• Section 6.8.2, Prohibited During Study shows an addition of P-glycoprotein (P-gp) 
inhibitors that should be avoided in concomitant use with loncastuximab tesirine.  
• Section 8.1, Efficacy Assessments were modified to include central imaging reviews. 
Additionally, to better understand concomitant therapy response, this trial will collect 
response data during Follow up Period for patients who receive chimeric antigen receptor 
T-cell (CAR-T) therapy after treatment with the combination of loncastuximab tesirine and 
ibrutinib.  
• Section 8.2.2, Eliciting and Reporting Adverse Events/Serious Adverse Events was 
modified to add adverse event (AE)/serious adverse event (SAE) reporting requirements 
for patients who receive CAR-T therapy after study drug discontinuation. 
 
 
 
• Section 8.5, Patient-Reported Outcomes Questionnaires were added.  
• Section 9.1, Sample Size was changed to approximately 161 patients. 
• Section 9.1.1, Phase 2 Sample Size Calculation for non-GCB DLBCL Cohort was added. 
• Section 9.3, Phase 2 Interim Analysis for Futility has been revised to show that this trial 
will have a single interim analysis using Simon’s 2 stage design in the non-GCB DLBCL 
cohort.  
• Section 9.4, Final Analysis was changed to add language on the analysis needed for the 
Phase 2 portion of this trial. 
• Section 9.8, Safety and Subgrouping Analyses was changed to add language in regards to 
Phase 2 analyses. 


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• Section 9.9, Pharmacokinetic Analyses was updated to enrich the pharmacokinetic (PK) 
profile by adding apparent systemic clearance (CL), apparent volume of distribution, and 
apparent terminal half-life to its determination. 
• Section 13.4, Appendix 4: P-gp Inhibitors was added to the study protocol.  
• Protocol Synopsis was revised to align with the changes in the protocol. 
• Editorial corrections and clarifications were applied throughout. 


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Protocol Amendment 1 
• Table 1, Schedule of Events was revised to include HBV, HCV, and HIV tests at screening 
for patients who have unknown status to allow for data to be available for all patients to 
determine whether they meet Exclusion Criterion 10. 
• Section 5.2, Exclusion Criteria was modified to remove the notation from 
Exclusion Criterion 10 that testing for HIV, HBV, and HCV is not mandatory to allow for 
data to be available for all patients to determine whether they meet this exclusion criterion.  
• Section 5.2, Exclusion Criteria, Criterion 15 was modified to add the exclusion of patients 
with tuberculosis infection. 
• Section 6.2.1, Packaging and Storage was updated to match the ibrutinib Investigator’s 
Brochure (IB). 
• Section 6.2.2, Preparation and Administration was updated to include precautions 
concerning extravasation of loncastuximab tesirine based on updated safety information. 
• Section 6.3.1, Loncastuximab Tesirine Dosing was revised to clarify the criteria for using 
sequential dosing. 
• Section 6.4.1, Dose Escalation Design was revised to specify a minimum of 5 days between 
dosing the first and second patient at each dose level during dose escalation (Part 1) to align 
with the dose escalation procedure being used, and was also revised to allow enrollment of 
additional patients during the dose escalation phase at the discretion of the Dose Escalation 
Steering Committee (DESC) to accommodate the potential need for additional safety 
information. 
• Section 6.4.3, Dose-Limiting Toxicity Definition was modified to clarify the 
non-hematologic DLT definition. 
• Section 6.5.1, Loncastuximab Tesirine was revised to clarify criteria for dose hold and 
resumption for non-hematologic and hematologic toxicity.  
• Section 6.7.1, Premedication for Loncastuximab Tesirine and Section 6.7.3, Treatment and 
Prophylaxis of Infusion-Related to Hypersensitivity Reactions were modified to allow the 
use of intravenous (IV) dexamethasone. 
• Section 8.2.2.1, Adverse Events of Special Interest (AESIs) was added to provide 
information regarding reporting the AESI of major hemorrhage. 
• Section 8.3.5, Laboratory Tests added HBV, HCV, and HIV testing. 
• Table 9 was revised to show updated PK time points for C5 and C6; this change has also 
been reflected in the Schedule of Events (Table 1). 
• Section 9.8.1, Adverse Events was revised to clarify which treatment-emergent adverse 
events (TEAEs) will be included in the statistical analysis. 
• Protocol Synopsis was revised to align with the changes in the protocol. 
• 
Editorial corrections and clarifications were applied throughout. 


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LIST OF PRIOR PROTOCOL VERSIONS  
Document 
Version Date 
Protocol Amendment 4.0 
26 March 2021 
Protocol Amendment 3.0 
14 May 2020 
Protocol Amendment 2.0 
9 January 2020 
Protocol Amendment 1.0  
8 July 2019 
Protocol Original 
21 June 2018 


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PROTOCOL SYNOPSIS 
 
Protocol Number: 
ADCT-402-103 
Title: 
A Phase 1/2 Open-Label Study to Evaluate the Safety and Efficacy of 
Loncastuximab Tesirine and Ibrutinib in Patients with Advanced Diffuse 
Large B-Cell Lymphoma or Mantle Cell Lymphoma 
Sponsor: 
ADC Therapeutics SA 
Study Phase: 
Phase 1/2 
Indication: 
Diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL) 
Rationale: 
Non-Hodgkin Lymphoma (NHL) is the 7th most common type of cancer 
in the United States (US) and accounted for an estimated 4.3% of new 
cancer cases in 2017. It is most commonly a disease of older individuals 
with approximately 75% of new cases diagnosed in individuals 55 years 
of age or older (median age at diagnosis= 66 years). Response to initial 
treatment generally exceeds 50% and the overall 5-year survival rate in 
the US is 70%. However, a significant proportion of patients will relapse. 
The poor prognosis for relapsed patients, especially those with 
chemotherapy-refractory disease with a short interval between remission 
and relapse, or those who relapse after high-dose therapy and autologous 
stem cell transplant (HD-ASCT), highlights the need for new forms of 
treatment for NHL. 
Loncastuximab tesirine (ADCT-402) is an antibody drug conjugate 
(ADC) that has been designed to target and kill cluster of differentiation 
19 (CD19)-expressing malignant B-cells. Loncastuximab tesirine (is 
approved in the United States for the treatment of adults with relapsed or 
refractory (R/R) large B-cell lymphoma after two or more lines of 
systemic therapy. Preliminary data from a Phase 1 study also showed 
activity of loncastuximab tesirine in patients with R/R MCL.  
Ibrutinib is a small-molecule inhibitor of Bruton’s tyrosine kinase (BTK), 
a mediator of the B-cell-receptor signaling pathway implicated in the 
pathogenesis of B-cell cancers. Ibrutinib is approved for use in patients 
with R/R MCL. It has also shown some activity in R/R DLBCL. 
While both compounds have shown activity as a single agent, a 
substantial proportion of patients will not have a complete response (CR) 
to either agent, and most patients will progress at some point. 
Combining two agents with different mechanisms of action has the 
potential to have increased activity compared to either agent alone. Thus, 
combining an ADC such as loncastuximab tesirine with a BTK inhibitor 
such as ibrutinib represents a rational approach for study in the clinic. 
The primary purpose of this study is to explore whether loncastuximab 
tesirine and ibrutinib can be safely combined, and if so, identify the 
dose(s) and regimens appropriate for further study. In addition, the study 


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can generate preliminary evidence as to whether loncastuximab tesirine 
and ibrutinib may increase the response rate and durability of response 
compared to previous results with either compound as a single agent. 
Due to preliminary antitumor activity in Phase 1/2, the study will be 
expanded into a new treatment cohort in Phase 2 in order to explore and 
confirm the safety and efficacy of the combination. 
Objectives: 
Primary Objective 
Phase 1: 
• To characterize the safety and tolerability of loncastuximab tesirine 
in combination with ibrutinib, and to identify the 
MTD/recommended dose and schedule for future studies 
Phase 2:  
To evaluate the efficacy of loncastuximab tesirine given at every cycle in 
combination with ibrutinib in patients with relapsed or refractory DLBCL 
Secondary Objectives 
Phase 1: 
• To evaluate the antitumor effect of the combination of 
loncastuximab tesirine with ibrutinib 
• To characterize the pharmacokinetic (PK) profile of loncastuximab 
tesirine when given in combination with ibrutinib 
• To evaluate the immunogenicity of loncastuximab tesirine when 
given in combination with ibrutinib 
Phase 2: 
• To further evaluate the safety and efficacy of loncastuximab tesirine 
in combination with ibrutinib in non-GCB DLBCL, GCB DLBCL, 
all DLBCL, and MCL patients 
• To further evaluate the PK profile and immunogenicity of 
loncastuximab tesirine when given in combination with ibrutinib 
• To evaluate the impact of the combination on patient-reported 
outcomes (PROs) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Endpoints: 
Primary Endpoints 
Phase 1: 
• 
Frequency and severity of adverse events (AEs) and serious adverse 
events (SAEs) 
• 
Incidence of dose-limiting toxicities (DLTs) (dose escalation only) 
• 
Frequency of dose interruptions and dose reductions 
• 
Changes from baseline of safety laboratory values, vital signs, Eastern 
Cooperative Oncology Group (ECOG) performance status, and 12-lead 
electrocardiograms (ECGs) 
Phase 2: 
• 
Complete response rate (CRR) according to the 2014 Lugano 
classification (Cheson et al., 2014) as determined by Independent 
Review Committee (IRC) in all DLBCL patients given loncastuximab 
tesirine at every cycle in combination with ibrutinib; CRR defined as 
the proportion of patients with a best overall response (BOR) of CR. 
 
Secondary Endpoints 
Phase 1: 
• 
Overall response rate (ORR) according to the 2014 Lugano 
classification as determined by Investigator. ORR defined as the 
proportion of patients with a BOR of CR or partial response (PR)  
Phase 1 and Phase 2: 
• 
Duration of response (DOR) defined as the time from the 
documentation of first tumor response to disease progression or death, 
in the non-GCB DLBCL, GCB DLBCL, all DLBCL and MCL patients  
• Relapse-free survival (RFS) defined as the time from the 
documentation of CR to disease progression or death in the non-GCB 
DLBCL, GCB DLBCL, all DLBCL, and MCL patients 
• Progression-free survival (PFS) defined as the time between start of 
treatment and the first documentation of progression, or death in the 
non-GCB DLBCL, GCB DLBCL, all DLBCL and MCL patients  
• Overall survival (OS) defined as the time between the start of treatment 
and death from any cause, in the non-GCB DLBCL, GCB DLBCL, all 
DLBCL and MCL patients  
• 
Concentrations and PK parameters of loncastuximab tesirine 
(total antibody, pyrrolobenzodiazepine (PBD)-conjugated antibody, 
and unconjugated cytotoxin SG3199) in the non-GCB DLBCL, GCB 
DLBCL, all DLBCL, and MCL patients 
• 
Anti-drug antibody (ADA) titers and, if applicable, neutralizing activity 
to loncastuximab tesirine, in the non-GCB DLBCL, GCB DLBCL, all 
DLBCL and MCL patients 


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Phase 2: 
• 
ORR according to the 2014 Lugano classification in the non-GCB 
DLBCL, GCB DLBCL, all DLBCL, and MCL patients. ORR as 
determined by Investigator and/or IRC.  
• 
CRR according to the 2014 Lugano classification (Cheson et al., 2014) 
as determined by Investigator and/or IRC in non-GCB DLBCL, 
GCB DLBCL, and MCL patients  
• 
CRR according to the 2014 Lugano classification (Cheson et al., 2014) 
as determined by Investigator and/or IRC in all DLBCL patients in the 
cohort where loncastuximab tesirine is given intermittently in 
combination with ibrutinib. 
• 
CRR according to the 2014 Lugano classification (Cheson et al., 2014) 
as determined by Investigator in all DLBCL patients in the cohort 
where loncastuximab tesirine is given at every cycle in combination 
with ibrutinib. 
• 
Frequency and severity of AEs and SAEs, in the non-GCB DLBCL, 
GCB DLBCL, all DLBCL, and MCL patients 
• 
Changes from baseline of safety laboratory values, vital signs, ECOG 
performance status, and 12-lead ECGs in the non-GCB DLBCL, GCB 
DLBCL, all DLBCL and MCL patients 
• 
Change from baseline in symptoms, functions and overall health status 
as measured by The European Organization for Research and 
Treatment of Cancer (EORTC) quality of life questionnaire 
(QLQ)-C30, LymS of FACT-Lym, and EQ-5D-5L in the non-GCB 
DLBCL, GCB DLBCL, all DLBCL and MCL patients 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study Design: 
This is a Phase 1/2 open-label single-arm combination study, with a dose 
escalation Phase 1 followed by Phase 2. The study will enroll 
approximately 243 patients. 
Phase 1: 
A standard 3+3 dose escalation design will be used. The DLT Period will 
be the 21 days following the first dose of ibrutinib. The dose escalation 
cohort will receive loncastuximab tesirine for 2 cycles with concurrent 
ibrutinib (concomitant therapy) and may then continue ibrutinib therapy 


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up to 1 year. An additional dose level of 75 µg/kg loncastuximab tesirine 
may be explored and evaluated during this phase of the study.  
A DESC composed of study investigators and ADC Therapeutics 
personnel will be responsible for decisions concerning dose escalation. 
When the maximum tolerated dose (MTD) or Recommended Phase 2 
Dose (RP2D) is defined there will be an efficacy and safety evaluation 
made by the Sponsor in consultation with investigators to determine 
benefit risk of the combination therapy.  
Once MTD or RP2D is determined and if there is a ≥10% improvement 
observed in CRR or ORR in any of the treatment cohorts in all DLBCL, 
non-GCB, GCB, or MCL when compared to the loncastuximab tesirine 
monotherapy, along with an acceptable safety profile, then Phase 2 of the 
study will commence. 
Phase 2: 
Once the dose level of loncastuximab tesirine has been defined, the Phase 
2 portion of the study planned to enroll in 3 separate cohorts: non-GCB 
DLBCL, GCB DLBCL, and MCL. 
 
In the non-GCB DLBCL cohort, a Simon's 2-stage design will be used 
with an interim analysis for futility on the first 22 patients. If ≥6 patients 
achieve CR, this cohort will proceed to complete full enrollment. 
Enrollment will continue during the interim analysis; however, further 
enrollment in this cohort will be halted if futility is confirmed. 
As of the data cutoff April 21, 2021, the interim analysis for Non-GCB 
and GCB DLBCL cohorts was performed and the futility on non-GCB 
DLBCL was not met.  
Subsequent to the interim analysis showing the potential of every cycle 
dosing of loncastuximab tesirine (see Section 2.2), the following will be 
performed:  
• RP2D will be re-determined by DESC 
• Enrollment of the non-GCB DLBCL cohort treated with the 
combination of loncastuximab tesirine administered at an 
intermittent dose schedule and daily ibrutinib will be closed. GCB 
and MCL will complete the enrollment target set forth in the 
initial phase 2 design and remain under the initial treatment 
schedule. 
• 
A new Phase 2 cohort of approximately 100 R/R DLBCL patients 
(with at least 40 patients each of GCB and non-GCB) will be 
introduced at the re-determined RP2D of loncastuximab tesirine 
administered in every cycle in combination with ibrutinib po daily 
given. 


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A two-stage design with futility monitoring will be used for this new 
Phase 2 cohort. In the first stage, 60 patients will be accrued. If there are 
20 or fewer CRs in these 60 patients, this cohort will be stopped. 
Otherwise, 40 additional patients will be accrued for a total of 100.  
Patient Selection:  
Inclusion Criteria: 
1. Male or female patient aged 18 years or older 
2. Pathologic diagnosis of DLBCL; or MCL (For Italy Sites Only: 
MCL patients are excluded.) 
3. Patients with DLBCL must have relapsed or refractory disease and 
have failed or been intolerant to available standard therapy 
(including stem cell transplant if patient was eligible) 
4. Patients with MCL must have relapsed or refractory disease and 
have received at least one prior line of therapy (For Italy Sites 
Only: This exclusion criterion is not applicable)  
5. Patients who have received previous CD19-directed therapy must 
have a biopsy which shows CD19 expression after completion of the 
CD19-directed therapy 
6. Measurable disease as defined by the 2014 Lugano Classification  
7. Availability of formalin-fixed paraffin-embedded (FFPE) tumor 
tissue block (or minimum 10 freshly cut unstained slides if block is 
not available) 
Note: Any biopsy since initial diagnosis is acceptable, but if several 
samples are available, the most recent sample is preferred. 
8. ECOG performance status 0 to 2 
9. Screening laboratory values within the following parameters: 
a) Absolute neutrophil count (ANC) ≥1.0 × 103/ microliter (µL) (off 
growth factors at least 72 hours) 
b) Platelet count ≥75 × 103/µL without transfusion in the past 7 days 
c) Hemoglobin ≥8 g/dL (4.96 mmol/L), transfusion allowed 
d) Alanine aminotransferase (ALT), aspartate aminotransferase 
(AST), and gamma glutamyl transferase (GGT) ≤2.5 × the upper 
limit of normal (ULN)  
e) Total 
bilirubin 
≤1.5 
× 
ULN 
(patients 
with 
known 
Gilbert’s syndrome may have a total bilirubin up to ≤3 × ULN)  
f) Blood creatinine ≤1.5 × ULN or calculated creatinine clearance 
≥60 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.  
10. Negative beta-human chorionic gonadotropin (β-HCG) pregnancy 
test within 7 days prior to start of study drugs on C1D1 (cycle 1 
day 1) for women of childbearing potential 


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11. Women of childbearing potential must agree to use a highly 
effective method of contraception from the time of giving informed 
consent until at least 9 months after the last dose of loncastuximab 
tesirine or 1 month after last dose of ibrutinib, whichever comes last. 
Men with female partners who are of childbearing potential must 
agree that they will use a highly effective method of contraception 
from the time of giving informed consent until at least 6 months after 
the patient receives his last dose of loncastuximab tesirine or 
3 months after last dose of ibrutinib, whichever comes last  
* Women of childbearing potential 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 1 
year. 
** 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 (oral, injectable, patch, intrauterine devices), male 
partner sterilization, or total abstinence from heterosexual 
intercourse, when this is the preferred and usual lifestyle of the 
patient. In addition, a barrier method along with hormonal 
contraceptive is required as per manufacturer's recommendation for 
ibrutinib use. 
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 
Exclusion Criteria: 
1. Known history of hypersensitivity to or positive serum human ADA 
to a CD19 antibody 
2. Known history of hypersensitivity to ibrutinib 
3. Previous therapy with ibrutinib or other BTK inhibitors 
4. Previous therapy with loncastuximab tesirine 
5. Requires treatment or prophylaxis with a moderate or strong 
cytochrome P450 (CYP) 3A inhibitor 
6. Allogenic or autologous transplant within 60 days prior to start of 
study drugs (C1D1) 
7. Active graft-versus-host disease 
8. Post-transplantation lymphoproliferative disorder 


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9. Active autoimmune disease, including motor neuropathy considered 
of autoimmune origin and other central nervous system (CNS) 
autoimmune disease 
10. Known seropositive and requiring anti-viral therapy for human 
immunodeficiency (HIV) virus, hepatitis B virus (HBV), or hepatitis 
C virus (HCV).  
11. History of Stevens-Johnson syndrome or toxic epidermal necrolysis 
12. Lymphoma with active CNS involvement at the time of screening, 
including leptomeningeal disease 
13. 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) 
14. Breastfeeding or pregnant 
15. Significant medical comorbidities, including but not limited to, 
uncontrolled 
hypertension 
(blood 
pressure 
[BP] 
≥160/100 
millimeters of mercury (mmHg) repeatedly), unstable angina, 
congestive heart failure (greater than New York Heart Association 
class II), electrocardiographic evidence of acute ischemia, coronary 
angioplasty or myocardial infarction within 6 months prior to 
screening, uncontrolled atrial or ventricular cardiac arrhythmia, 
poorly controlled diabetes mellitus, severe chronic pulmonary 
disease, or tuberculosis infection (tuberculosis screening based on 
local standards) 
16. Major surgery, radiotherapy, chemotherapy, or other anti-neoplastic 
therapy within 14 days prior to start of study drugs (C1D1), except 
shorter if approved by the Sponsor 
17. Use of any other experimental medication within 14 days prior to 
start of study drugs (C1D1) 
18. Planned live vaccine administration after starting study drugs 
(C1D1)  
19. Any condition that could interfere with the absorption or metabolism 
of ibrutinib including malabsorption syndrome, disease significantly 
affecting gastrointestinal function, or resection of the stomach or 
small bowel 
20. Inherited or acquired bleeding disorders 
21. Ongoing 
anticoagulation 
treatment, 
except 
for 
low-dose 
heparinisation or equivalent 
22. Failure to recover to Grade ≤1 (Common Terminology Criteria for 
Adverse Events [CTCAE] version 4.0) from acute non-hematologic 
toxicity (Grade ≤2 neuropathy or alopecia) due to previous therapy 
prior to screening 


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23. Congenital long QT syndrome or a corrected QTcF interval of >480 
ms at screening (unless secondary to pacemaker or bundle branch 
block) 
24. 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 
25. 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 (of up to 28 days), a Treatment 
Period (cycles of 3 to 4 weeks), and a Follow-up Period (approximately 
every 12 weeks for up to 2 years after treatment discontinuation).  
Patients may continue treatment for up to 1 year or until disease 
progression, unacceptable toxicity, or other discontinuation criteria. 
The end of study will occur at the last visit or last scheduled procedure 
for the last patient, unless the study is terminated earlier by Sponsor.  
Efficacy 
Assessments: 
• Disease assessments: Positron emission tomography-computed 
tomography (PET-CT) 
Note: If tumor is not PET-avid at baseline, CT with contrast or magnetic 
resonance imaging (MRI) must be used for follow-up disease 
assessments. 
The assessment method determined to identify sites of disease at baseline 
should be used for all subsequent assessments. 
Safety 
Assessments: 
• Physical examinations 
• ECOG Performance status 
• Height and weight 
• Vital signs 
• Safety laboratories (hematology, chemistry, coagulation, urinalysis) 
• Pregnancy test, if applicable 
• 12-lead ECGs (triplicate) 
• AEs/SAEs, graded according to CTCAE version 4.0. 
Other 
Assessments: 
• Blood sampling for PK, ADA
 
 
 
• PROs: EORTC QLC-C30, LymS of FACT-Lym and EQ-5D-5L 


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Study Drugs, 
Dosage, and Mode 
of Administration: 
Phase 1: 
All dose levels will have ibrutinib dosing beginning simultaneously with 
loncastuximab tesirine dosing (concomitant treatment). During this 
phase, the study may explore and evaluate a new dose level of 75 µg/kg 
loncastuximab tesirine in combination with ibrutinib as a concomitant 
therapy after the first interim data analysis in Phase 2. 
 
Concomitant Treatment with Loncastuximab Tesirine and Ibrutinib 
Dose 
Level 
Loncastuximab Tesirine 
Ibrutinib 
1 
60 µg/kg IV Q3W × 2 
560 mg/day po continuous beginning C1D1 
2 
90 µg/kg IV Q3W × 2 
560 mg/day po continuous beginning C1D1 
3 
75 µg/kg IV Q3W × 2 
560 mg/day po continuous beginning C1D1 
Note: Dose Levels 1 and 2 have completed enrollment, the subsequent Dose Level 3 has 
been added to further explore the combination. 
The DLT Period will be the first 21 days of ibrutinib treatment for all 
patients in Phase 1 dose escalation.  
At the discretion of the DESC, enrollment may be expanded to further 
evaluate safety and efficacy at any dose level that has completed the 3+3 
dose escalation cohort with no more than 1 DLT in 6 patients. Additional 
patients may be added only if there is at least 1 patient with documented 
PR or CR. 
No more than 10 patients each in the 2 treatment cohorts (GCB DLBCL 
and MCL) can be treated at the expanded enrollment portion of Phase 1, 
and up to 20 patients may be treated at the non-GCB DLBCL cohort. 
This will allow the trial to enroll up to 40 patients among the 3 cohorts, 
in the expansion portion of Phase 1. 
Patients who have a response of PR or stable disease (SD) at the 14-week 
disease assessment may receive 2 additional doses of loncastuximab 
tesirine given 4 weeks apart at C5 and C6. 
Phase 2: 
Two treatment cohorts will be tested: 
• Patients assigned to a cohort where loncastuximab tesirine is given 
intermittently in combination with ibrutinib will receive 
loncastuximab tesirine at the initial recommended dose (60 µg/kg) 
determined in the Phase 1 portion of the study. Loncastuximab 
tesirine will be administered to the patients Q3W for 2 cycles (C1D1 
and C2D1). Patients who have a response of CR, PR, and SD at later 
disease assessments (Week 14 and Week 30) will receive additional 
doses of loncastuximab tesirine on C5D1, C6D1, C9D1, and C10D1. 
Ibrutinib dosing at 560 mg/day po daily will begin simultaneously 
with loncastuximab tesirine dosing and continue throughout the 
treatment. 


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• Patients assigned to a cohort where loncastuximab tesirine is given at 
every cycle in combination with ibrutinib will receive loncastuximab 
tesirine at re-determined RP2D at every treatment cycles. 
Loncastuximab tesirine will be infused through IV Q3W for first 2 
cycles and followed by Q4W for all subsequent treatment cycles. 
Ibrutinib dosing will begin simultaneously with loncastuximab 
tesirine dosing. Ibrutinib 560 mg/day po daily will be taken in C1 and 
C2 only. Ibrutinib dose will be reduced to 420 mg/day po daily at C3 
and for all subsequent treatment cycles. 
Concomitant Treatment with Loncastuximab Tesirine and Ibrutinib  
Treatment 
Cohort 
Loncastuximab 
Tesirine 
Ibrutinib 
Targeted 
Enrollment 
Loncastuximab 
Tesirine Given 
Intermittently in 
Combination with 
Ibrutinib  
Initial RP2D 
(60 µg/kg) IV Q3W 
for C1 and C2, then 
Q4W at C5, C6 and 
C9, C10 when a 
response of CR, PR or 
SD is observed. 
560 mg/day po daily 
beginning C1D1 
Non-GCB 
DLBCL (n=66. 
Enrollment will be 
closed at n=48) 
GCB DLBCL 
(n=30) 
MCL (n=10) 
Loncastuximab 
Tesirine Given at 
Every Cycle in 
Combination with 
Ibrutinib 
Re-determined RP2D 
IV Q3W for C1 and 
C2, followed by Q4W 
at all subsequent 
cycles.  
560 mg/day po daily 
beginning C1D1 for 
C1 and C2, then 
reduced to 420 mg/day 
daily for all 
subsequent cycles.  
All DLBCL 
(n=100 with ≥40 
patients each 
from GCB and 
Non-GCB) 
 
Sample Size: 
Approximately 243 patients for the entire study. 
Phase 1: 
Up to 55 patients will be treated with the combination of loncastuximab 
tesirine and ibrutinib. 
Phase 2: 
Approximately 188 patients will be enrolled to Phase 2 study.  
Approximately 88 patients will be treated with the combination of 
loncastuximab tesirine given intermittently with ibrutinib daily in three 
different disease cohorts:  
• Non-GCB DLBCL cohort was to enroll approximately 
66 patients. Enrollment was paused in this cohort after interim 
data analysis for futility. The study will close with approximately 
48 patients.  
• GCB DLBCL cohort will enroll approximately 30 patients, and  
• MCL cohort will enroll approximately 10 patients. 
 
Approximately 100 R/R DLBCL patients with at least 40 patients each 
for GCB and non-GCB will be accrued to the new treatment cohort where 
loncastuximab tesirine is given at every cycle with ibrutinib po daily. 


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Statistical 
Considerations: 
Statistical Analysis: 
ORR, CR rate with 95% confidence interval (CI) will be presented. DOR, 
PFS, RFS, and OS will be analyzed using the Kaplan-Meier approach.  
Safety analyses will be presented descriptively. 
Phase 2 Sample Size Justification for the non-GCB DLBCL Cohort 
Where Loncastuximab Tesirine is Given Intermittently in 
Combination with Ibrutinib  
Simon's 2-stage design (Simon, 1989) will be used. The null hypothesis 
that the true CRR is 0.2 will be tested against a one-sided alternative. In 
the first stage, 22 patients will be accrued. If there are 5 or fewer CRs in 
these 22 patients, this cohort will be stopped. Otherwise, 44 additional 
patients will be accrued for a total of 66. The null hypothesis will be 
rejected if 20 or more CRs are observed in 66 patients. This design yields 
a type I error rate of 0.05 and power of 90% when the true CRR is 0.4. 
Phase 2 Sample Size Justification for the Cohort Where 
Loncastuximab Tesirine is Given at Every Cycle in Combination 
with Ibrutinib 
Two-stage design with futility monitoring (Zeng et al., 2015) will be 
used. The null hypothesis that the true CRR is 0.3 will be tested against 
a one-sided alternative. In the first stage, 60 patients will be accrued. If 
there are 20 or fewer CRs in these 60 patients, this cohort will be stopped. 
Otherwise, 40 additional patients will be accrued for a total of 100. 
The null hypothesis will be rejected if 40 or more CRs are observed in 
100 patients. This design yields a type I error rate of 0.05 and power of 
85% when the true CRR is 0.45. Enrollment will continue during the 
interim analysis. 
 


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SCHEDULE OF EVENTS 
Table 1 
Schedule of Events: Phase 1 
 
Protocol 
Section 
Screening 
Treatment Period 
Follow-up Period 
(up to 2 years from EOT) 
 
 
 
Cycle 1 and Cycle 2 (C1 and 
C2) 
(3-week cycles) 
C3 and beyond  
(up to 1 year after C1D1) 
(4-week cycles) 
EOT 
Every 12 weeks 
Day (D) 
 
-28 to –1 
1 
8 
15 
1 
 
 
Informed consent 
11.3 
X 
 
 
 
 
 
 
Eligibility criteria 
5 
X 
 
 
 
 
 
 
Demography 
9.5 
X 
 
 
 
 
 
 
Medical/cancer history 
9.5 
X 
 
 
 
 
 
 
Physical examination 
8.3.1 
X 
X 
X 
X 
X 
X 
 
ECOG performance status 
8.3.2 
X 
X 
 
 
X 
X 
 
Height 
8.3.3 
X 
 
 
 
 
 
 
Weight 
8.3.3 
X 
X 
X 
X 
X 
X 
 
Vital signs (BP, HR, RR, Temp) 
8.3.4 
X 
X 
X 
X 
X 
X 
 
Disease assessment2 
8.1 
X 
6 weeks and 14 weeks after C1D1, then every 8 weeks 
X3 
Every 12 weeks until 1 year 
from EOT, then every 
6 months until disease 
progression3 
Hematology and chemistry 
8.3.5 
X 
X4 
X 
X 
X 
X 
 
Coagulation and urinalysis 
8.3.5 
X 
 
 
 
 
 
 
HIV, HCV, HBV5 
8.3.5 
X 
 
 
 
 
 
 
Pregnancy test, if applicable 
8.3.6 
X 
X4 
 
 
X 
X 
X6  
12-lead ECG7 
8.3.7 
Table 8 
X 
X 
(pre-dose, 
EOI-, and 
4 h 
post-dose) 
X 
X 
X8 
X 
 
Table continued on next page. 


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Protocol 
Section 
Screening 
Treatment Period 
Follow-up Period 
(up to 2 years from EOT) 
 
 
 
Cycle 1 and Cycle 2 (C1 and 
C2) 
(3-week cycles) 
C3 and beyond  
(up to 1 year after C1D1) 
(4-week cycles) 
EOT 
Every 12 weeks 
Day (D) 
 
-28 to –1 
1 
8 
15 
1 
 
 
Premedication  
6.7 
 
D-1 to D2 
 
 
X9 
 
 
Loncastuximab tesirine 
administration7 
6.3.1 
 
X 
 
 
X 
(C5 and C6 for patients 
who are SD or PR at 
Week 14 evaluation) 
 
 
Ibrutinib administration 
6.3.2 
 
Daily × 21 days 
(concomitant administration 
only) 
Daily × 28 days10 
 
 
Loncastuximab tesirine 
PK sample 
8.4.1 
Table 11 
 
X7 
(pre-dose, 
EOI, and 
4 h 
post-dose) 
X 
X 
X 
(C3 for all patients; 
C5 and C6 pre-dose for 
patients receiving 
loncastuximab tesirine, 
C7 for patients receiving 
loncastuximab tesirine 
during C5 and C6) 
X 
 
Loncastuximab tesirine 
ADA sample7 
8.4.2 
Table 11 
 
X7 
(pre-dose) 
 
X 
(C1 only) 
X11 
X12 
 
Concomitant medications 
6.8 
From ICF signature date or D -14, whichever is earlier, until 30 days after last dose of study drug(s) 
Adverse events 
8.2 
AE/SAEs from ICF signature date until 30 days after last dose of study drug(s); thereafter, related SAEs only 
1st new anticancer treatment 
4.4 
 
 
 
 
 
X 
X 
Survival 
7.1 
 
 
 
 
 
X 
X 
Abbreviations: ADA: anti-drug antibody; AE: adverse event; BP: blood pressure; C: Cycle; 
; ECG: electrocardiogram; ECOG: Eastern Cooperative 
Oncology Group; EOI: end of infusion; EOT: end of treatment; 
; h: hour; HBV: hepatitis B virus; HCV: hepatitis C virus; HIV: human immunodeficiency 
virus; HR: heart rate; ICF: informed consent form; PK: pharmacokinetics; PR: partial response; RR: respiratory rate; SAE: serious AE; SD: stable disease; Temp: temperature 
 
Visit Scheduling Windows:  
 Treatment Period: Visit Day ± 2 days (excluding C1D1, which is the reference day). 
 EOT: As soon as possible after decision to discontinue the study drug(s) but preferably within 30 days after last dose of study drug(s) unless a new anticancer 
treatment is planned to be administered before the 30 days, in which case EOT should be conducted before initiation of the new anticancer treatment.  
 Follow-up Period: Visit Day ± 14 days.  
 Physical examination, ECOG, hematology, and chemistry can be performed within 24 hours prior to administration of study drug(s). 


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Final Protocol Amendment 5 
 
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2  
Screening imaging (PET-CT, positron emission tomography) must be performed within 4 weeks prior to C1D1 and the same assessment method should be 
used throughout the study. Week 6 imaging should be performed prior to C3D1 and Week 14 imaging should be performed prior to C5D1. All other imaging 
for disease assessment for patients on study drug(s) should be performed within ± 2 weeks of the scheduled time point. Disease assessments should be 
performed at the time points specified even if study drug dosing is delayed. If a scan has been performed within 8 weeks of EOT, it does not need to be 
repeated at EOT.  
3  
Disease assessments to be performed in patients having discontinued study drug(s) for reasons other than disease progression. 
4  
Not needed if screening assessment was performed within 3 days prior to C1D1. 
5  
Only for patients whose status is unknown. 
6  
A final pregnancy test is to be performed at ≥9 months post last loncastuximab tesirine dose if applicable. A remote pregnancy test is acceptable during study 
follow-up. The pregnancy test can be performed if clinical indicated during the study. 
7  
On days when loncastuximab tesirine is administered, ECG, PK, and ADA time points are in relation to start of loncastuximab tesirine infusion. 
8  
Cycle 3 only. 
9  
For patients dosed with loncastuximab tesirine on C5 and C6 only. 
10  
Ibrutinib will be dosed at 560 mg po daily in all cycles for all patients.  
11  
C3 for all patients; C5 and C6 pre-dose for patients receiving loncastuximab tesirine, C7 for patients receiving loncastuximab tesirine during C5 and C6, see 
Table 11. 
12  
Patients who test positive for ADAs will be requested to supply additional ADA samples as specified in the protocol, Section 8.4.2. 
 
 
 


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Table 2 
Schedule of Events: Phase 2 
 
Protocol 
Section 
Screening
Treatment Period 
Follow-up 
Period 
(up to 2 years 
from EOT) 
 
 
 
Cycle 1 and Cycle 2 (C1 and C2) 
(3-week cycles) 
C3 and beyond  
(up to 1 year after C1D1) 
(4-week cycles) 
EOT 
Every 12 weeks 
Day (D) 
 
-28 to –1 
1 
8 
15 
1 
 
 
Informed consent 
11.3 
X 
 
 
 
 
 
 
Eligibility criteria 
5 
X 
 
 
 
 
 
 
Demography 
9.5 
X 
 
 
 
 
 
 
Medical/cancer history 
9.5 
X 
 
 
 
 
 
 
Physical examination 
8.3.1 
X 
X 
X 
X 
X 
X 
 
ECOG performance status 
8.3.2 
X 
X 
 
 
X 
X 
 
Height 
8.3.3 
X 
 
 
 
 
 
 
Weight 
8.3.3 
X 
X 
X 
X 
X 
X 
 
Vital signs (BP, HR, RR, Temp) 
8.3.4 
X 
X 
X 
X 
X 
X 
 
Disease assessment2 
8.1 
X 
6 weeks and 14 weeks after C1D1, then every 8 weeks 
X3 
Every 12 weeks 
until 1 year from
EOT, then every
6 months until 
disease 
progression3 
Hematology and chemistry 
8.3.5 
X 
X4 
X 
X 
X 
X 
 
Coagulation and urinalysis 
8.3.5 
X 
 
 
 
 
 
 
HIV, HCV, HBV5 
8.3.5 
X 
 
 
 
 
 
 
Pregnancy test, if applicable 
8.3.6 
X 
X4 
 
 
X 
X 
X6 
12-lead ECG 
8.3.7 
Table 9& 
Table 10 
X 
X 
(pre-dose, EOI-, 
and 4 h 
post-dose) 
X 
X 
X8 
X 
 
Table continued on next page. 


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Protocol 
Section 
Screening
Treatment Period 
Follow-up 
Period 
(up to 2 years 
from EOT) 
 
 
 
Cycle 1 and Cycle 2 (C1 and C2) 
(3-week cycles) 
C3 and beyond  
(up to 1 year after C1D1) 
(4-week cycles) 
EOT 
Every 12 weeks 
Premedication  
6.7 
 
D-1 to D2 
 
 
X9 
 
 
Loncastuximab tesirine 
administration10 
6.3.1 
 
X 
 
 
X11 
 
 
Ibrutinib administration 
6.3.2 
 
Daily × 21 days 
(concomitant administration only) 
Daily × 28 days12 
 
 
Loncastuximab tesirine PK sample 
8.4.1 
Table 12 
 
X10 
(pre-dose, EOI, 
and 
4 h 
post-dose) 
X 
X 
X 
(C3, C5, C6, C7, C9, C10, 
and C11 pre-dose) 
X 
 
Loncastuximab tesirine ADA sample7 
8.4.2 
Table 12 
 
X10 
(pre-dose) 
 
X 
(C1 Only) 
X13 
X14 
 
PROs15 
8.5 
 
X 
(pre-dose) 
 
 
X 
(pre-dose) 
X 
X16 
Concomitant medications 
6.8 
From ICF signature date or D -14, whichever is earlier, until 30 days after last dose of study drug(s) 
Adverse events 
8.2 
AE/SAEs from ICF signature date until 30 days after last dose of study drug(s); thereafter, related SAEs 
only 
1st new anticancer treatment 
4.4 
 
 
 
 
 
X 
X 
Survival 
7.1 
 
 
 
 
 
X 
X 
Abbreviations: ADA: anti-drug antibody; AE: adverse event; BP: blood pressure; C: Cycle; 
; ECG: electrocardiogram; 
ECOG: Eastern Cooperative Oncology Group; EOI: end of infusion; EOT: end of treatment; 
; h: hour; HBV: hepatitis B virus; HCV: hepatitis C virus; HIV: 
human immunodeficiency virus; HR: heart rate; ICF: informed consent form; PK: pharmacokinetics; PR: partial response; PRO: patient-reported outcome; RR: respiratory rate; 
SAE: serious AE; SD: stable disease; Temp: temperature 
Visit Scheduling Windows:  
• Treatment Period: Visit Day ± 2 days (excluding C1D1, which is the reference day). 
• EOT: As soon as possible after decision to discontinue the study drug(s) but preferably within 30 days after last dose of study drug(s) unless a new anticancer 
treatment is planned to be administered before the 30 days, in which case EOT should be conducted before initiation of the new anticancer treatment.  


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• Follow-up Period: Visit Day ± 14 days. 
• Physical examination, ECOG, hematology, and chemistry can be performed within 24 hours prior to administration of study drug(s).  
 
  
 
 
2. 
Screening imaging (PET-CT, positron emission tomography) must be performed within 4 weeks prior to C1D1 and the same assessment method should be 
used throughout the study. Week 6 imaging should be performed prior to C3D1 and Week 14 imaging should be performed prior to C5D1. All other imaging 
for disease assessment for patients on study drug(s) should be performed within ± 2 weeks of the scheduled time point. Disease assessments should be 
performed at the time points specified even if study drug dosing is delayed. If a scan has been performed within 8 weeks of EOT, it does not need to be 
repeated at EOT.  
3  
Disease assessments to be performed in patients having discontinued study drug(s) for reasons other than disease progression. 
4  
Not needed if screening assessment was performed within 3 days prior to C1D1. 
5  
Only for patients whose status is unknown. 
6  
A final pregnancy test is to be performed at ≥9 months post last dose of loncastuximab tesirine, if applicable. A remote pregnancy test is acceptable during 
study follow-up. The pregnancy test can be performed if clinical indicated during the study. 
  
 
8  
C 3 (pre-dose), C5 (pre-dose), C6 (pre-dose and EOI), C9 (pre-dose), and C10 (pre-dose and EOI) for patients with loncastuximab tesirine given 
intermittently in combination with ibrutinib; and C3 and beyond pre-dose only for patients with loncastuximab tesirine given at every cycle in combination 
with ibrutinib; see Table 9 and Table 10. 
9  
For all patients when dosed with loncastuximab tesirine. 
10  
Loncastuximab tesirine is dosed at 60 µg/kg for patients with loncastuximab tesirine given intermittently in combination with ibrutinib; Loncastuximab 
tesirine is dosed at re-determined RP2D for patients with loncastuximab tesirine given at every cycle in combination with ibrutinib. On days when 
loncastuximab tesirine is administered, ECG, PK, and ADA time points are in relation to loncastuximab tesirine infusion.  
11  
Loncastuximab tesirine will be administered at C5, C6, C9, and C10 for patients assigned to loncastuximab tesirine given intermittently in combination with 
ibrutinib who have a response of CR, PR, and SD at later disease assessments. Loncastuximab tesirine will be administered at every cycle for patients 
assigned to loncastuximab tesirine given at every cycle in combination with ibrutinib. 
12  
For patients in the cohort given loncastuximab tesirine intermittently in combination with ibrutinib, ibrutinib will be taken at 560 mg po daily in all cycles.  
 
For patients in the cohort given loncastuximab tesirine at every cycle in combination with ibrutinib, ibrutinib will be taken at 560 mg po daily in C1 & C2 
only, then a dose reduction to 420 mg daily po at C3 and all subsequent cycles  
13  
For treatment cohort where loncastuximab tesirine is given intermittently in combination with ibrutinib ADA sample will be collected pre-dose on C3 C5, 
C7, C9, C11. 
For Treatment cohort where loncastuximab tesirine is given at every cycle in combination with ibrutinib ADA sample will be collected pre-dose on C3 C5, 
C7, C9, C11, C13. Please refer to Table 12 for further details.  
14  Patients who test positive for ADAs will be requested to supply additional ADA samples as specified in the protocol, Section 8.4.2.  
15  Should be collected prior to clinical assessments and treatment. 
16  
Collect EQ-5D-5L only, via phone or at the study site every 12 weeks after the end of treatment for 1 year. 
 


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1 INTRODUCTION AND BACKGROUND 
1.1 Non-Hodgkin Lymphoma and CD19 
Non-Hodgkin lymphoma (NHL) represents a biologically and clinically diverse group of 
hematologic malignancies arising from precursor and mature B, T, and natural killer cells. 
It is the 7th most common type of cancer in the United States (US) and will account for an estimated 
4.3% (n=72,240) of new cancer cases in 2017 (Siegel et al., 2017). In the US, tumors of B-cell 
origin make up 85% to 90% of NHL. 
Human CD19 antigen is a 95 kd transmembrane glycoprotein belonging to the immunoglobulin 
superfamily. In normal human tissue, expression of CD19 continues through pre-B and mature 
B-cell differentiation until it is finally down regulated during terminal differentiation into plasma 
cells (Scheuermann, 1995); however, expression of CD19 is maintained in hematologic B-cell 
malignancies, including diffuse large B-cell lymphoma (DLBCL). 
1.1.1 Diffuse Large B-cell Lymphoma 
Diffuse 
large 
B-cell 
lymphoma 
accounts 
for 
an 
estimated 
32.5% 
of NHL 
(Al-Hamadani et al., 2015). Standard first-line therapy uses immuno-chemotherapy such as 
R-CHOP. The response rate to front-line R-CHOP is >80% but approximately 30% to 50% of 
patients with DLBCL are not cured, and most patients who fail a rituximab-containing 
chemotherapy regimen (e.g., R-CHOP) will die from their disease. Salvage therapy, including 
high-dose chemotherapy and autologous stem cell transplant (HD-ASCT), can be effective 
treatment for DLBCL patients with chemotherapy-sensitive relapse. However, over half of the 
patients treated in this fashion will not have long-term disease control (Gisselbrecht et al., 2010). 
The prognosis of patients whose disease is refractory to initial chemotherapy and are therefore not 
eligible for HD-ASCT, or who relapse early after HD-ASCT, is extremely poor. These patients 
have a poor response to salvage therapy, with an overall response rate (ORR) of 26% 
(complete response [CR] rate 7%) and a median survival of approximately 6 months 
(Crump et al., 2017). The management of patients with DLBCL who are ineligible for HD-ASCT 
or who relapse after HD-ASCT is difficult. Additional immuno-chemotherapy following a second 
HD-ASCT or allogeneic stem cell transplant (AlloSCT) produces responses in only a small 
proportion of patients with substantial toxicity. 
Recently, 
autologous 
anti-CD19 
chimeric 
antigen 
receptor 
(CAR) 
T-cell 
therapy 
(axicabtagene ciloleucel [Yescarta®] and tisagenlecleucel [Kymriah®]) has been shown to produce 
responses in ~50% to 70% of patients with relapsed or refractory (R\R) DLBCL, 
with ~30% to 50% achieving CR. Durable responses have been achieved in patients who achieve 
a CR, but the duration of response (DOR) in patients with a partial response (PR) is short 
(2.1 months for axicabtagene ciloleucel). Moreover, there is significant toxicity, particularly 
cytokine 
release 
syndrome 
and 
neurologic 
events, 
including 
encephalopathy. 
It is only available at specialized centers and requires substantial lead-time for preparation, with 
approximately 10% of patients being unable to receive the planned therapy. 


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The poor prognosis for relapsed patients, especially those with chemotherapy-refractory disease 
with a short interval between remission and relapse or those who relapse after high-dose therapy 
and stem cell transplant (SCT), highlights the unmet medical need for more effective salvage 
treatments for patients with R/R DLBCL (Coiffier et al., 2016; Epperla et al., 2017) 
1.1.2 Mantle Cell Lymphoma 
Mantle cell lymphoma (MCL) is a rare and aggressive form of NHL that predominantly affects 
older individuals. Standard first-line therapy uses immuno-chemotherapy. Patients who are 
eligible for consolidation with HD-ASCT are typically treated with cytarabine-based regimens. 
Patients who are not eligible for treatment with HD-ASCT receive regimens such as R-CHOP or 
R-bendamustine. Most patients (80% to 90%) respond to front-line therapy, but many will relapse. 
There are a number of agents available for second-line therapy, including bortezomib, 
lenalidomide, and ibrutinib. However, the response rates are low for bortezomib and lenalidomide, 
at 33% and 28% respectively. The response to ibrutinib is higher at 65%, but only 17% of these 
are CR. Thus, there remains unmet medical need for additional salvage treatments for patients with 
R/R MCL (Campo et al., 2015). 
1.2 Loncastuximab Tesirine and Ibrutinib 
1.2.1 Loncastuximab Tesirine Description 
Loncastuximab tesirine (ADCT-402) is an antibody drug conjugate (ADC), composed of a 
humanized monoclonal antibody (RB4v1.2) directed against human cluster of differentiation 19 
(CD19) conjugated through a cathepsin-cleavable linker to SG3199, a pyrrolobenzodiazepine 
(PBD) dimer cytotoxin. The toxin SG3199 attached to the linker is designated as SG3249.  
The schematic representation of loncastuximab tesirine is presented in Figure 1. 


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Figure 1 
Schematic Representation and Chemical Structure of Loncastuximab 
Tesirine  
 
Abbreviations: Ala, alanine; PABA, para-aminobenzoic acid; PBD, pyrrolobenzodiazepine; PEG, polyethylene 
glycol; RB4v1.2, humanized monoclonal antibody directed against CD19 antigen; Val, valine.  
 
Loncastuximab tesirine binds with picomolar affinity to human CD19. After binding and 
internalization, loncastuximab tesirine trafficks to the lysosomes, where the protease-sensitive 
linker is cleaved and unconjugated PBD dimers (SG3199) are released inside the target cell. 
The released PBD dimers bind in the minor groove of deoxyribonucleic acid (DNA) and form 
potent cytotoxic DNA interstrand cross-links. The cross-links result in a stalled DNA replication 
fork, blocking cell division and causing cell death (Hartley, 2011). The cross-links formed by 
PBD dimers are relatively non-distorting to the DNA structure, making them hidden to repair 
mechanisms (Adair et al., 2012; Beck et al., 2017).  
Loncastuximab tesirine (Zynlonta™) was approved in the United States in April 2021 for the 
treatment of adults with R/R large B-cell lymphoma, including diffuse large B-cell lymphoma 
(DLBCL) not otherwise specified, DLBCL arising from low-grade lymphoma, and high-grade 
B-cell lymphoma, after two or more lines of systemic therapy. (Zynlonta FDA-US PI) 
 
CH2
CH3
CH2
CH3
CL
VL
CH1
VH
LC
HC
VH
CH1
VL
CL
HC
LC
SG3199 PBD dimer
Conjugation Sites
Interchain Disulfide
SG3249 PBD drug linker
RB4v1.2 monoclonal antibody
Maleimide
PEG8
Val-Ala
dipeptide
PABA
LC C211-HC C223
HC C229-HC C229
HC C232-HC C232
Conjugation Sites
Interchain Disulfide


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1.2.2 Safety and Efficacy of Loncastuximab Tesirine 
 Phase 1 Study, ADCT-402-101 
ADCT-402-101 (NCT02669017) is a first-in-human Phase 1 study of loncastuximab tesirine in 
patients with R/R B-cell lineage NHL (B-NHL). Eligible patients are ≥18 years of age and have 
failed or are intolerant to established therapies or have no other treatment options available. The 
study design involves a dose escalation phase (Part 1) followed by a dose expansion phase (Part 2). 
The primary objectives for Part 1 are to evaluate the safety and tolerability of loncastuximab 
tesirine, and to determine the maximum tolerated dose (MTD) and/or the recommended dose(s) to 
use in Part 2. The primary objective for Part 2 is to evaluate the safety and tolerability of the dose(s) 
determined in Part 1. Efficacy (ORR, DOR, progression-free survival [PFS], and overall survival 
[OS]), pharmacokinetics (PK), 
 and immunogenicity are also being assessed 
in both parts of the study. 
A total of 183 patients with R/R B-NHL received at least 1 infusion of loncastuximab tesirine, at 
dose levels from 15 to 200 µg/kg. The protocol defined MTD was not reached in Part 1 of the 
study. Doses of 120 and 150 µg/kg every 3 weeks (Q3W) were chosen to be further evaluated in 
Part 2 of the study based on antitumor activity and tolerability seen during the dose escalation part. 
The study was completed on 24-Jun-2019. 
The median age was 63 years (range: 20 to 87). The median number of previous chemotherapy 
regimens was 3 (range: 1 to 13) with 23% of patients having prior stem cell transplant. 
The most common non-hematologic TEAEs (observed in at least 15% of patients), regardless of 
relationship to study treatment, were fatigue (42.6%); nausea (32.2%); edema peripheral (31.7%); 
GGT increased (31.1%); rash (24.6%); dyspnea (22.4%); constipation (21.9%); pleural effusion 
(21.3%); blood alkaline phosphatase increased (20.2%); cough, decreased appetite, and 
AST increased (18.6%, each); pyrexia (18.0%); vomiting (17.5%); ALT increased (17.5%); 
abdominal pain (15.8%); and diarrhea (15.3%). 
The most common non-hematologic Grade ≥3 TEAEs (observed in at least 5% of patients) were 
GGT increased (21.3%), blood alkaline phosphatase increased (6.6%), febrile neutropenia (5.5%), 
and hypokalemia (5.5%). TEAEs in 16 (11.1%) patients led to treatment discontinuation. 
TEAEs in 35 (19.1%) patients led to treatment discontinuation. Dose-limiting toxicity (DLT) was 
reported in 4 patients (3 thrombocytopenia and 1 febrile neutropenia). 
There were 152 serious adverse event (SAE) reports (197 events) from 96 (52.5%) patients. 
Of these, 47 reports in 34 patients were considered at least possibly related to study drug. Of these 
47 SAE reports (60 events), only 10 events were seen in multiple patients: pleural effusion (8), 
febrile neutropenia (7), lung infection (3), pericardial effusion (3), sepsis (3), dyspnea (2), 
fluid overload (2), generalized edema (2), injection site extravasation (2), and pyrexia (2). 
Based on the Phase 1 experience, edema and effusion related reactions, abnormal liver function 
tests (particularly GGT), and skin-related toxicities are considered important potential risks for 
loncastuximab tesirine. These events have also been observed with other compounds containing 


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the same warhead. The events of febrile neutropenia and pleural effusion are likely related to 
loncastuximab tesirine and are, therefore, considered adverse drug reactions (ADRs). 
Out of 180 evaluable patients with B-NHL, 48 (26.7%) achieved CR and 34 (18.9%) achieved PR, 
for an ORR of 82/180 (45.6%). Median PFS was 3.09 months and median DOR was 5.36 months.  
Out of 137 evaluable patients with DLBCL, 32 (23.4%) achieved CR and 26 (19%) achieved PR, 
for ORR of 58/137 (42.3%). Median PFS was 2.83 months and median DOR was 4.47 months.  
Out of 15 evaluable patients with MCL, 5 (33.3%) achieved CR and 2 (13.3%) achieved PR, 
for ORR of 7/15 (46.7%). Median DOR was not reached, and median PFS was 4.8 months.  
Out of 14 evaluable patients with follicular lymphoma, 9 (64.3%) achieved CR and 2 (14.3%) 
achieved PR, for ORR of 11/14 (78.6%). Median DOR and median PFS were not reached. 
 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. 
As of the data cut-off date on 06 April 2020, the enrollment was completed and a total of 
145 patients with R/R DLBCL received at least one dose of loncastuximab tesirine. The median 
age was 66.0 years (range: 23-94). The median number of previous chemotherapy regimens was 
3 (range: 2-7) with 16.6% of patients having prior stem cell transplantation.  
Loncastuximab tesirine was effective, producing durable responses in heavily pretreated patients 
with DLBCL. The ORR was 48.3% by independent central review, with a complete response rate 
(CRR) of 24.1%, and responses were rapid with median time to first response of 41.0 days. 
Responses were durable, with a median DOR of 10.25 months. The probability to maintain a 
response for at least nine months was 63.8%. The median PFS was 4.93 months, and the median 
OS was 9.92 months. 
In addition, Loncastuximab tesirine was effective in patients with high-risk disease, producing 
durable responses in patients with double hit/triple hit disease, advanced stage disease 
(Stage III/IV), transformed disease, primary refractory disease, and disease which was refractory 
to all prior systemic therapies; and was also effective in elderly patients and in patients who had 
failed previous aggressive salvage therapy, including CD19-directed CAR-T therapy. 
Loncastuximab tesirine was well-tolerated when administered in repeated 3-week cycles at 
150 µg/kg for two cycles and 75 µg/kg for subsequent cycles. Toxicities were generally reversible 
and manageable in most patients with dose delays/reductions and standard supportive care. 
Overall, 105 (72.4%) patients had grade ≥3 TEAEs. The most common (≥10%) grade ≥3 TEAEs 
were neutropenia (25.5%), thrombocytopenia (17.9%), GGT increased (16.6%), and anemia 
(10.3%). Treatment-related TEAEs leading to treatment discontinuation occurred in 24 patients 
(16.6%), most commonly GGT increased (14 patients; 9.7%). No increase in toxicity was seen in 
patients aged ≥65 years compared with younger patients. 


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Additional details may be found in the current loncastuximab tesirine Investigator’s Brochure (IB). 
1.2.3 Ibrutinib Description 
Ibrutinib is a small-molecule inhibitor of Bruton’s tyrosine kinase (BTK), a mediator of the 
B-cell-receptor signaling pathway implicated in the pathogenesis of B-cell cancers. BTK’s role in 
signaling results in activation of pathways necessary for B-cell trafficking, chemotaxis, and 
adhesion. Ibrutinib forms a covalent bond with a cysteine residue in the BTK active site, leading 
to inhibition of BTK enzymatic activity. Nonclinical studies show that ibrutinib inhibits malignant 
B-cell proliferation and survival in vivo as well as cell migration and substrate adhesion in vitro. 
Ibrutinib is indicated for the treatment of a variety of B-cell malignancies, including MCL, chronic 
lymphocytic leukemia/small lymphocytic leukemia, Waldenström’s macroglobulinemia, and 
marginal zone lymphoma. Specifically, it is indicated for the treatment of patients with MCL who 
have received at least one prior line of therapy.  
1.2.4 Safety and Efficacy of Ibrutinib 
The safety and efficacy of ibrutinib in patients with MCL who have received at least one prior 
therapy were evaluated in an open-label, multi-center, single-arm trial of 111 previously treated 
patients (Imbruvica® PI). The median age was 68 years (range, 40 to 84 years), 77% were male, 
and 92% were Caucasian. At baseline, 89% of patients had a baseline Eastern Cooperative 
Oncology Group (ECOG) performance status of 0 or 1. The median time since diagnosis was 
42 months, and median number of prior treatments was 3 (range, 1 to 5 treatments), including 11% 
with prior stem cell transplant. At baseline, 39% of subjects had at least one tumor ≥ 5 cm, 49% had 
bone marrow involvement, and 54% had extranodal involvement at screening. 
Ibrutinib was administered orally at 560 mg once daily until disease progression or unacceptable 
toxicity. Tumor response was assessed according to the revised International Working Group for 
NHL criteria. The primary endpoint in this study was investigator-assessed ORR.  
The most commonly occurring adverse reactions (≥ 20%) were thrombocytopenia, diarrhea, 
neutropenia, anemia, fatigue, musculoskeletal pain, peripheral edema, upper respiratory tract 
infection, nausea, bruising, dyspnea, constipation, rash, abdominal pain, vomiting and decreased 
appetite. The most common Grade 3 or 4 non-hematological adverse reactions (≥ 5%) were 
pneumonia, abdominal pain, atrial fibrillation, diarrhea, fatigue, and skin infections. Fatal and 
serious cases of renal failure have occurred with ibrutinib therapy. Increases in creatinine 1.5 
to 3 times the upper limit of normal (ULN) occurred in 9% of patients. Ten patients (9%) 
discontinued treatment due to adverse reactions in the trial (N=111). The most frequent adverse 
reaction leading to treatment discontinuation was subdural hematoma (1.8%). Adverse reactions 
leading to dose reduction occurred in 14% of patients.  
Out of 111 evaluable patients with MCL, 17.1% achieved a CR and 48.6% achieved a PR, for an 
ORR of 65.8%. The median DOR was 17.5 months. 
Ibrutinib has also shown activity in DLBCL at the dose planned for this study, although this 
appears to be limited to the activated B-cell (ABC) subtype. A Phase 1/2 clinical trial involving 


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80 subjects showed an ORR of 37% (14/38) for patients with the ABC subtype, but only 5% (1/20) 
for patients with the germinal center B-cell (GCB) subtype (Wilson et al., 2015). 
Additional details may be found in the current ibrutinib IB. 
 


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2 STUDY RATIONALE 
While both loncastuximab tesirine and ibrutinib have shown activity as single agents, a substantial 
proportion of patients will not have a CR to either agent, and most patients will progress at some 
point. 
Combining two agents with different mechanisms of action has the potential to increase activity 
compared to either agent alone. Thus, combining an ADC such as loncastuximab tesirine with a 
BTK inhibitor such as ibrutinib represents a rational approach for study in the clinic. 
The activity of combining loncastuximab tesirine with ibrutinib has been observed, and further 
exploration is needed to establish efficacy and safety of the combination therapy taken in a 
concomitant regimen. 
2.1 Rationale for Study Design 
This is a Phase 1/2, multi-center study to assess the safety and efficacy of loncastuximab tesirine 
in combination with ibrutinib for patients with R/R DLBCL and MCL.  
Phase 1: 
As this is the first study combining the two agents, a standard 3+3 dose escalation design will be 
used. At the discretion of the DESC, enrollment may be expanded to further evaluate safety and 
efficacy at any dose level that has completed the 3+3 dose escalation cohort with no more than 
1 DLT of 6 patients. Additional patients may be added only if there is at least 1 patient with 
documented PR or CR. No more than 10 patients in each of the two treatment cohorts (GCB 
DLBCL and MCL) can be treated at the expanded enrollment portion of Phase 1, and up to 
20 patients may be treated in the non-GCB DLBCL cohort. This expansion will allow the trial to 
enroll approximately 40 patients among the 3 cohorts. 
Phase 2: 
A Dose Escalation Steering Committee (DESC) composed of study investigators and 
ADC Therapeutics personnel will be responsible for decisions concerning dose escalation. 
When the MTD or Recommended Phase 2 Dose (RP2D) is defined, there will be an efficacy and 
safety evaluation made by the Sponsor in consultation with investigators to determine benefit risk 
of the combination therapy.  
Once MTD or RP2D is determined and if there is a ≥10% improvement observed in complete 
response rate (CRR) or ORR in any of the treatment cohorts in all DLBCL, non-GCB, GCB, or 
MCL when compared to the loncastuximab tesirine monotherapy, along with an acceptable safety 
profile, then Phase 2 will commence. 
MCL patients must have had at least one prior therapy, in line with the approved indication for 
ibrutinib. DLBCL patients will be required to have failed or been intolerant to available standard 
therapies. 


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2.2 Rationale for Dose Selection 
Ibrutinib will be given at the approved dose of 560 mg po (per os) daily. As this is a novel 
combination, loncastuximab tesirine administration will start at 60 µg/kg intravenously (IV) Q3W, 
which is 40% of the RP2D of 150 µg/kg. An additional dose level of 75 µg/kg has been added and 
may be explored and evaluated during dose escalation portion of Phase 1. Because of the potential 
for extended toxicity with prolonged administration, loncastuximab tesirine will be limited to 
2 doses initially. 
Phase 2 will use the RP2D decided by the DESC or the MTD of loncastuximab tesirine explored 
and evaluated in Phase 1. Loncastuximab tesirine will be administered on C1D1 and C2D1. 
Patients who have a response of CR, PR, or SD at later disease assessments (Week 14 and Week 
30) will receive additional doses of loncastuximab tesirine on C5D1, C6D1, C9D1, and C10D1. 
The additional doses of loncastuximab tesirine are anticipated to further increase the duration of 
response while maintaining an acceptable toxicity profile as observed in the Phase 1 portion of the 
study. The ibrutinib dose will be at 560 mg po daily for this combination.  
Two treatment cohorts (60 µg/kg or 90 µg/kg of loncastuximab tesirine Q3W x 2 in combination 
with ibrutinib at 560 mg PO daily) were initially tested in Phase 1 dose escalation portion, the 
RP2D was determined to be 60 µg/kg loncastuximab tesirine plus ibrutinib by DESC.  
As of the data cutoff April 21, 2021, the interim data analysis of Phase 2 non-GCB and GCB 
DLBCL cohorts with intermittent doses of 60 µg/kg loncastuximab tesirine at Q3W at C1, C2, and 
Q4W at C5, C6, C9, and C10 in combination with ibrutinib was completed, and the futility on 
non-GCB DLBCL was not met. Six out of 22 non-GCB DLBCL patients achieved complete 
response. CRR for non-GCB DLBCL, GCB DLCBL and all DLBCL were 27.3%, 46.2% and 
34.2% respectively. ORR for non-GCB DLBCL, GCB DLCBL and all DLBCL were 45.5%, 
76.9% and 57.1% respectively. Based on the interim data analysis, the RP2D is being 
re-determined by testing loncastuximab tesirine dose at 75 µg/kg in combination with ibrutinib in 
Phase 1dose escalation to maximize ORR and DOR. Meanwhile the enrollment to non-GCB 
DLBCL cohort with the combination regimen of intermittent dosing of loncastuximab tesirine at 
60 µg/kg and daily ibrutinib was paused (N=approximately 48 of a planned 66 patients). GCB and 
MCL will complete the enrollment target set forth in the initial phase 2 design. All patients treated 
with loncastuximab tesirine intermittently in combination with ibrutinib will remain in the same 
dose and schedule until the end of treatment.  
Rationale for exploring the 75 µg/kg dose level in Phase 1 is based on using PK/Exposure-response 
modeling of loncastuximab tesirine as a monotherapy. Predictions of average PBD-conjugated 
antibody concentration (Cavg) were shown to increase substantially from 0.271 µg/kg anticipated 
with the current intermittent cycle regimen (60 µg/kg Q3W in Cycles 1 and 2, then Q4W during 
Cycles 5 and 6) to values of 0.658 µg/mL and 0.526 µg/mL for the 75 µg/kg and 60 µg/kg doses, 
respectively, for the every cycle treatment regimens (Appendix 7). Probabilities of ORR 
anticipated with the every cycle treatment regimens are predicted to increase commensurately with 
values of 0.727 (75 µg/kg) and 0.677 (60 µg/kg), relative to a reference response rate of 0.57 for 
the intermittent cycle regimen. At the discretion of the DESC, loncastuximab tesirine will be 
administered at every cycle in combination with ibrutinib in Phase 2. 


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Once the re-determined RP2D will be defined, the new Phase 2 cohort will commence: 
loncastuximab tesirine will be infused at re-determined RP2D on Day 1 of every treatment cycle; 
and ibrutinib dose at 560 mg po daily will be given only at Cycles 1 and 2, followed by a dose 
reduction to 420 mg daily at Cycle 3 and for subsequent cycles. This dose regimen employing 
loncastuximab tesirine in every treatment cycle is designed to expose the tumor with the maximum 
antitumor activity in a tolerable dose combination at the first two cycles to maximize dose intensity 
and is anticipated to further improve the tumor response and/or extend the duration of response by 
giving loncastuximab tesirine infusion on Day 1 of every treatment cycle as compared to the 
intermittent loncastuximab tesirine dosing regimen. To reduce potential additive adverse events 
such as bone marrow suppression from the combination regimen, ibrutinib dose will be reduced to 
420 mg daily from Cycle 3 and beyond. This is supported by the observation from the data 
collected in this trial: as of the data cutoff on April 21, 2021, 6 of 8 AEs leading to ibrutinib dose 
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3 STUDY OBJECTIVES AND ENDPOINTS 
Table 3 
Study Objectives and Endpoints 
Primary 
 
Objectives 
Endpoints 
Phase 1: 
• To characterize the safety 
and tolerability of 
loncastuximab tesirine in 
combination with ibrutinib, 
and to identify the 
MTD/recommended dose 
and schedule for future 
studies 
 
Phase 2: 
• To evaluate the efficacy of 
loncastuximab tesirine given 
at every cycle in 
combination with ibrutinib 
in patients with relapsed or 
refractory DLBCL  
Phase 1: 
• Frequency and severity of adverse events (AEs) and serious adverse 
events (SAEs) 
• Incidence of dose-limiting toxicities (DLTs) (dose escalation only) 
• Frequency of dose interruptions and dose reductions 
• Changes from baseline of safety laboratory values, vital signs, 
Eastern Cooperative Oncology Group (ECOG) performance status, and 
12-lead electrocardiograms (ECGs) 
 
 
Phase 2: 
• CRR according to the 2014 Lugano classification (Cheson et al., 2014) as 
determined by independent review committee (IRC) in all DLBCL 
patients given loncastuximab tesirine at every cycle in combination with 
ibrutinib; CRR defined as the proportion of patients with a best overall 
response (BOR) of complete response (CR)  
Table continued on next page. 


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Secondary 
 
Objectives 
Endpoints 
Phase 1: 
• To evaluate the antitumor 
effect of the combination of 
loncastuximab tesirine with 
ibrutinib 
• To characterize the PK 
profile of loncastuximab 
tesirine when given in 
combination with ibrutinib 
• To evaluate the 
immunogenicity of 
loncastuximab tesirine when 
given in combination with 
ibrutinib 
 
 
 
 
 
 
 
 
 
 
 
 
Phase 2: 
• To further evaluate the safety 
and efficacy of 
loncastuximab tesirine in 
combination with ibrutinib in 
non-GCB DLBCL, GCB 
DLBCL, all DLBCL, and 
MCL patients 
• To further evaluate the PK 
profile and immunogenicity 
of loncastuximab tesirine 
when given in combination 
with ibrutinib 
• To evaluate the impact of the 
combination on patient-
reported outcomes (PROs) 
 
Phase 1: 
• Overall response rate (ORR) according to the 2014 Lugano classification 
as determined by Investigator. ORR defined as the proportion of patients 
with a BOR of CR or partial response (PR)  
 
Phase 1 and Phase 2: 
• Duration of response (DOR) defined as the time from the documentation 
of first tumor response to disease progression or death, in the non-GCB 
DLBCL, GCB DLBCL, all DLBCL, and MCL patients  
• Relapse-free survival (RFS) defined as the time from the documentation of 
CR to disease progression or death in the non-GCB DLBCL, GCB 
DLBCL, all DLBCL, and MCL patients  
• Progression-free survival (PFS) defined as the time between start of 
treatment and the first documentation of progression, or death in the 
non-GCB DLBCL, GCB DLBCL, all DLBCL and MCL patients  
• Overall survival (OS) defined as the time between the start of treatment 
and death from any cause in the non-GCB DLBCL, GCB DLBCL, all 
DLBCL and MCL patients  
• Concentrations 
and 
PK 
parameters 
of 
loncastuximab 
tesirine 
(total antibody, pyrrolobenzodiazepine (PBD)-conjugated antibody, and 
unconjugated cytotoxin SG3199) in the non-GCB DLBCL, GCB DLBCL, 
all DLBCL and MCL patients  
Anti-drug antibody (ADA) titers and, if applicable, neutralizing activity to 
loncastuximab tesirine in the non-GCB DLBCL, GCB DLBCL, all 
DLBCL and MCL patients  
 
Phase 2: 
• ORR according to the 2014 Lugano classification in the non-GCB DLBCL, 
GCB DLBCL, all DLBCL, and MCL patients. ORR defined as the 
proportion of patients with a BOR of CR or PR for all treated patients. ORR 
as determined by IRC and/or Investigator.  
• CRR according to the 2014 Lugano classification (Cheson et al., 2014) as 
determined by Investigator and/or IRC in Non-GCB DLBCL, GCB 
DLBCL, and MCL patients  
• CRR according to the 2014 Lugano classification (Cheson et al., 2014) as 
determined by Investigator and/or IRC in all DLBCL patients in the cohort 
where loncastuximab tesirine is given intermittently in combination with 
ibrutinib 
• CRR according to the 2014 Lugano classification (Cheson et al., 2014) as 
determined by Investigator in all DLBCL patients in the cohort where 
loncastuximab tesirine is given at every cycle in combination with 
ibrutinib.  
• Frequency and severity of AEs and SAEs in the non-GCB DLBCL, 
GCB DLBCL, all DLBCL and MCL patients 
• Changes from baseline of safety laboratory values, vital signs, 
ECOG performance status, and 12-lead ECGs in the non-GCB DLBCL, 
GCB DLBCL, all DLBCL and MCL patients 
• Change from baseline in PROs as measured by The European Organization 
for Research and Treatment of Cancer (EORTC) QLQ-C30, LymS of 
FACT-Lym, and EQ-5D-5L in the non-GCB DLBCL, GCB DLBCL, all 
DLBCL and MCL patients 
Table continued on next page. 


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4 STUDY DESIGN 
4.1 Overview 
This is a Phase 1/2, open-label, single-arm combination study to assess the safety and efficacy of 
loncastuximab tesirine in combination with ibrutinib in patients with R/R DLBCL (non-GCB, 
GCB) and MCL. Phase 1 will cover the dose escalation portion of the study, which will then be 
followed by Phase 2. 
The study will enroll approximately 243 patients.  
Phase 1 will enroll up to 55 patients who will be treated with the combination of loncastuximab 
tesirine and ibrutinib. 
A standard 3+3 dose escalation design will be used in Phase 1. The DLT Period will be the first 
21 days of ibrutinib treatment. The dose escalation cohort will receive loncastuximab tesirine for 
2 cycles with concurrent ibrutinib (concomitant therapy) and may then continue ibrutinib therapy 
up to 1 year. An additional dose level of 75 µg/kg has been added and may be explored and 
evaluated. 
At the discretion of the DESC, enrollment may be expanded to further evaluate safety and efficacy 
at any dose level that has completed the 3+3 dose escalation cohort with no more than 1 DLT in 
6 patients. Additional patients may be added only if there is at least 1 patient with documented 
PR or CR.  
No more than 10 patients in each of the 2 treatment cohorts (GCB DLBCL and MCL) can be 
treated at the expanded enrollment portion of Phase 1, and up to 20 patients will be treated in the 
non-GCB DLBCL cohort. This will allow the trial to enroll up to 40 patients among the 3 expanded 
cohorts. 
When the MTD or RP2D is defined, there will be an efficacy and safety evaluation made by the 
Sponsor in consultation with investigators to determine benefit risk of the combination therapy.  
Once MTD or RP2D is determined and if there is a ≥10% improvement observed in CRR or ORR 
in any of the treatment cohorts in all DLBCL, non-GCB DLBCL, GCB DLBCL, or MCL when 
compared to the loncastuximab tesirine monotherapy, along with an acceptable safety profile, then 
the Phase 2 portion of the study will commence. 
Patients who have a response of PR or SD at the 14-week assessment may receive two additional 
doses of loncastuximab tesirine given 4 weeks apart. 
Each of the cohorts will be treated at the RP2D dose of loncastuximab tesirine determined in 
Phase 1 and ibrutinib. An IRC will be used in all cohorts to evaluate the response to the 
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Phase 2 planned to enroll approximately 106 patients who were to be treated with the 
combination of loncastuximab tesirine administered at an intermittent dose schedule and daily 
ibrutinib in three different disease cohorts:  
• Non-GCB DLBCL cohort was to enroll approximately 66 patients. .  
• GCB DLBCL cohort will enroll approximately 30 patients, and  
• MCL cohort will enroll approximately 10 patients. 
In the non-GCB DLBCL cohort, a Simon's 2-stage design (Simon, 1989) will be used with an 
interim analysis for futility on the first 22 patients (see Section 9.3). If ≥6 patients achieve CR 
assessed by an IRC, this cohort will proceed to complete full enrollment. Enrollment will continue 
during the interim analysis. However, further enrollment in this cohort will be halted if futility is 
confirmed. 
Subsequent to the interim analysis with the data cutoff April 21, 2021 showing the potential of 
every cycle dosing of loncastuximab tesirine (see Section 2.2), the following will be performed:  
• RP2D will be re-determined by DESC 
• Enrollment of the non-GCB DLBCL cohort treated with the combination of loncastuximab 
tesirine administered at an intermittent dose schedule and daily ibrutinib will be closed. 
Approximately 48 patients with non-GCB DLBCL are enrolled to this cohort. 
• 
A new Phase 2 cohort of 100 R/R DLBCL patients (with at least 40 patients each of GCB 
and non-GCB) will be introduced at the re-determined RP2D of loncastuximab tesirine 
administered in every cycle in combination with ibrutinib po daily given. 
A two-stage design with futility monitoring (Zeng et al., 2015) will be used for this new cohort. In 
the first stage, 60 patients will be accrued. If there are 20 or fewer CRs in these 60 patients, this 
cohort will be stopped. Otherwise, 40 additional patients will be accrued for a total of 100. 
Enrollment will continue during the interim analysis.  
Taken together, the Phase 2 will enroll approximately 188 patients. 
The study will include a Screening Period (of up to 28 days), a Treatment Period (cycles of 3 to 
4 weeks), and a Follow-up Period (approximately every 12-week visits for up to 2 years after 
treatment discontinuation).  
4.2 Screening Period 
Informed consent must be obtained for each patient and documented with a signed informed 
consent form (ICF) prior to any study procedures. Procedures that are performed as part of standard 
of care (SOC) may be used to satisfy screening requirements if they are performed in the 
appropriate window. 
The Screening Period is from 28 days to 1 day prior to the start of the study drug(s). The screening 
assessments must be performed within this period in order to assess the eligibility of the patient 
against the inclusion and exclusion criteria (Sections 5.1 and 5.2, respectively). 
See Section 5.3 for the information to be collected on screening failures. 


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4.3 Treatment Period 
The Treatment Period will start on the date when a patient receives the first dose of study drug(s) 
and continues until the End of Treatment (EOT) visit.  
A treatment cycle is defined as 3 weeks (i.e., 21 days) for Cycles 1 and 2 and 4 weeks 
(i.e., 28 days) for subsequent cycles. Loncastuximab tesirine will be administered as an IV infusion 
over 30 minutes on Day 1 of each cycle containing loncastuximab tesirine.  
During Phase 1, patients will receive loncastuximab tesirine Q3W for 2 cycles (C1D1 and C2D1). 
Patients who have a response of PR or SD at the 14-week disease assessment may receive two 
additional doses of loncastuximab tesirine given 4 weeks apart (C5D1 and C6D1). Ibrutinib will 
be administered orally once daily continuously during all cycles containing ibrutinib.  
During Phase 2, patients on the cohort where loncastuximab tesirine is given intermittently in 
combination with ibrutinib will receive loncastuximab tesirine Q3W for 2 cycles (C1D1 and 
C2D1). Patients who have a response of CR, PR, or SD at later disease assessments (Week 14 and 
Week 30) will receive additional doses of loncastuximab tesirine at C5D1, C6D1, C9D1, and 
C10D1. Ibrutinib will be administered orally at 560 mg once daily continuously during all cycles. 
Patients on the cohort where loncastuximab tesirine is given at every cycle in combination with 
ibrutinib will receive loncastuximab tesirine Q3W on Day 1 of first 2 cycles, followed by Q4W on 
Day 1 of every subsequent cycles. Ibrutinib will be administered at 560 mg po daily for first two 
cycles, then a dose reduction to 420 mg po daily for subsequent cycles.  
Patients may continue treatment for up to 1 year or until disease progression, unacceptable toxicity, 
or other discontinuation criteria (Section 7), whichever occurs first.  
Additionally, patients benefitting clinically at 1 year may continue treatment on a case-by-case 
basis after review and approval by the Sponsor. 
4.4 End of Treatment 
The EOT visit should be performed as soon as possible after the decision to discontinue the study 
drug, preferably within 30 days after last dose of study drug and before initiation of any new 
anticancer treatment. 
When EOT coincides with a scheduled visit, the scheduled visit will become EOT. 
4.5 Follow-up Period 
All patients, regardless of disease status, will be followed every 12 weeks for up to 2 years from 
EOT, or until withdrawal of consent, loss to follow-up, or death, whichever occurs first. 
When disease assessments are not planned for a follow-up visit, the visit can be done by phone. 


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4.6 End of Study 
The end of study for each patient will be the date of last visit/contact or date of death, whichever 
occurs last, and the end of study for the study as a whole will be the last visit or last scheduled 
procedure for the last patient, unless the study is terminated earlier by the Sponsor. 
 


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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 at screening, unless otherwise specified (e.g., criterion to be 
confirmed within 28 days to 1 day prior to the start of study drug on Cycle 1 Day 1 [C1D1]). 
5.1 Inclusion Criteria 
1. 
Male or female patient aged 18 years or older 
2. 
Pathologic diagnosis of DLBCL or MCL (For Italy Sites Only: MCL patients are 
excluded) 
3. 
Patients with DLBCL must have relapsed or refractory disease and have failed or been 
intolerant to available standard therapy (including stem cell transplant if patient was 
eligible) 
4. 
Patients with MCL must have relapsed or refractory disease and have received at least one 
prior line of therapy (For Italy Sites Only: This exclusion criterion is not applicable)  
5. 
Patients who have received previous CD19-directed therapy must have a biopsy which 
shows CD19 expression after completion of the CD19-directed therapy 
6. 
Measurable disease as defined by the 2014 Lugano Classification  
7. 
Availability of formalin-fixed paraffin-embedded (FFPE) tumor tissue block (or minimum 
10 freshly cut unstained slides if block is not available) 
Note: Any biopsy since initial diagnosis is acceptable, but if several samples are available, 
the most recent sample is preferred. 
8. 
ECOG performance status 0 to 2 
9. 
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. Hemoglobin ≥8 g/dL (4.96 mmol/L), transfusion allowed 
d. Alanine aminotransferase (ALT), aspartate aminotransferase (AST), and gamma 
glutamyl transferase (GGT) ≤2.5 × the ULN 
e. Total bilirubin ≤1.5 × ULN (patients with known Gilbert’s syndrome may have a total 
bilirubin up to ≤3 × ULN)  
f. Blood creatinine ≤1.5 × ULN or calculated creatinine clearance ≥60 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.  
10. Negative beta-human chorionic gonadotropin (β-HCG) pregnancy test within 7 days prior 
to start of study drugs on C1D1 for women of childbearing potential (WOCBP) 


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11. Women of childbearing potential* must agree to use a highly effective** method of 
contraception from the time of giving informed consent until at least 9 months after the 
last dose of loncastuximab Tesirine or 1 month after last dose of ibrutinib, whichever 
comes last. Men with female partners who are of childbearing potential must agree that 
they will use a highly effective method of contraception from the time of giving informed 
consent until at least 6 months after the patient receives his last dose of or 3 months after 
last dose of ibrutinib, whichever comes last. 
* Women of childbearing potential 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 1 year. 
** 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 (oral, injectable, patch, intrauterine devices), 
male partner sterilization, or total abstinence from heterosexual intercourse, when this 
is the preferred and usual lifestyle of the patient. In addition, a barrier method along with 
hormonal contraceptive is required as per manufacturer's recommendation for ibrutinib 
use. 
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. 
 
5.2 Exclusion Criteria 
1. 
Known history of hypersensitivity to or positive serum human anti-drug antibody (ADA) 
to a CD19 antibody 
2. 
Known history of hypersensitivity to ibrutinib 
3. 
Previous therapy with ibrutinib or other BTK inhibitors 
4. 
Previous therapy with loncastuximab tesirine 
5. 
Requires treatment or prophylaxis with a moderate or strong cytochrome P450 (CYP) 3A 
inhibitor 
6. 
Allogenic or autologous transplant within 60 days prior to start of study drugs (C1D1) 
7. 
Active graft-versus-host disease 
8. 
Post-transplantation lymphoproliferative disorder 
9. 
Active autoimmune disease, including motor neuropathy considered of autoimmune origin 
and other central nervous system (CNS) autoimmune disease 
10. Known seropositive and requiring anti-viral therapy for human immunodeficiency (HIV) 
virus, hepatitis B virus (HBV), or hepatitis C virus (HCV)  
11. History of Stevens-Johnson syndrome or toxic epidermal necrolysis 
12. Lymphoma with active CNS involvement at the time of screening, including 
leptomeningeal disease 


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13. 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) 
14. Breastfeeding or pregnant 
15. Significant medical comorbidities, including but not limited to, uncontrolled hypertension 
(blood pressure [BP] ≥160/100 millimeters of mercury (mmHg) repeatedly), 
unstable angina, congestive heart failure (greater than New York Heart Association class 
II), electrocardiographic evidence of acute ischemia, coronary angioplasty or myocardial 
infarction within 6 months prior to screening, uncontrolled atrial or ventricular cardiac 
arrhythmia, poorly controlled diabetes mellitus, severe chronic pulmonary disease, or 
tuberculosis infection (tuberculosis screening based on local standards) 
16. Major surgery, radiotherapy, chemotherapy, or other anti-neoplastic therapy within 
14 days prior to start of study drugs (C1D1), except shorter if approved by the Sponsor 
17. Use of any other experimental medication within 14 days prior to start of study drugs 
(C1D1) 
18. Planned live vaccine administration after starting study drugs (C1D1)  
19. Any condition that could interfere with the absorption or metabolism of ibrutinib including 
malabsorption syndrome, disease significantly affecting gastrointestinal function, or 
resection of the stomach or small bowel 
20. Inherited or acquired bleeding disorders 
21. Ongoing anticoagulation treatment, except for low-dose heparinisation or equivalent 
22. Failure to recover to Grade ≤1 (Common Terminology Criteria for Adverse Events 
[CTCAE] version 4.0) from acute non-hematologic toxicity (Grade ≤2 neuropathy or 
alopecia) due to previous therapy prior to screening 
23. Congenital long QT syndrome or a corrected QTcF interval of >480 ms at screening 
(unless secondary to pacemaker or bundle branch block) 
24. 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 
25. 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 Screen Failures 
Patients who signed the ICF but were found not eligible for the study prior to receiving study 
drugs, 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 
• SAEs and/or death occurring during the Screening Period 


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6 STUDY TREATMENT 
6.1 Study Drugs 
6.1.1 Loncastuximab Tesirine 
• Loncastuximab tesirine will be provided as a frozen liquid or lyophilized formulation in Phase 
1. For Phase 2, frozen liquid or a refrigerated lyophilized formulation of loncastuximab 
tesirine will be provided. The liquid formulation will be provided in 10 mL glass vials 
designed to deliver 3.2 mL of loncastuximab tesirine at a concentration of 5 mg/mL (16 mg 
loncastuximab tesirine per vial) and stored at -65°C or below. It is a sterile, frozen liquid 
formulated in 30 mM histidine, 200 mM sorbitol, and 0.02% polysorbate 20, at pH 6.0. Prior 
to use, the frozen formulation is thawed at ambient temperature, gently swirled to ensure 
homogeneity, and visually inspected. 
• The lyophilized formulation will be provided as a lyophilized white to off-white powder in 
8 mL glass vials (10 mg loncastuximab tesirine per vial) and stored at 2-8°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 is reconstituted with 2.2 mL of 
Sterile Water for Injection to deliver 2.0 mL at a concentration of 5 mg/mL, gently swirled to 
ensure complete dissolution and homogeneity, and visually inspected. Sterile water for 
injection is to be provided by study sites. 
Patients will receive the same formulation for their entire treatment. 
6.1.2 Ibrutinib 
Ibrutinib will be provided as 140 mg capsules. Each capsule contains ibrutinib (active ingredient) 
and the following inactive ingredients: croscarmellose sodium, magnesium stearate, 
microcrystalline cellulose, sodium lauryl sulfate. The capsule shell contains gelatin, titanium 
dioxide, and black ink. 
6.2 Management of Clinical Supplies 
Detailed instructions regarding shipment of study drugs, handling, storage, and preparation are 
included in the pharmacy manual. 
6.2.1 Packaging and Storage 
The study drugs will be supplied by the Sponsor through the designated distribution center.  
Once the package arrives at the study site, the receiving site pharmacy will complete the procedures 
listed in the pharmacy manual to acknowledge receipt. 
All study drugs must be stored according to the pharmacy manual, in a secure area. 
• Loncastuximab tesirine liquid formulation: loncastuximab tesirine must be protected from 
light and stored at -65°C or below. Loncastuximab tesirine must be thawed under ambient 
conditions. 


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• Loncastuximab tesirine lyophilized formulation: must be protected from light and stored at 
2-8°C. 
• Ibrutinib: Packaging and storage information is provided in the ibrutinib IB.  
 
6.2.2 Preparation and Administration  
Loncastuximab tesirine solution at the concentration of 5 mg/mL will be the basis for the 
preparation of the infusion solution. The amount of the product to be prepared will depend on the 
dose level and the weight of the patient. The weight of the patient at Cycle 1 Day 1 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 the weight used to calculate the previous dose, then the dose should 
be recalculated based on the new weight. Additional details are included in the pharmacy manual. 
Loncastuximab tesirine will be administered as a 30-minute IV infusion. 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 deviations.  
Extravasation of loncastuximab tesirine may be associated with local irritation, swelling, pain, or 
tissue damage. The IV infusion site should be monitored for signs of IV infiltration or drug 
extravasation, and patients should be instructed to report immediately any signs of IV infiltration 
or drug extravasation during or after the infusion. Suspected extravasation of loncastuximab 
tesirine should be managed according to institutional protocol for management of extravasation of 
cytotoxic chemotherapy. For patients who have a central line, administration of loncastuximab 
tesirine via this central line should be considered. 
Sufficient ibrutinib will be dispensed so each patient can take 560 mg or 420 mg orally once daily 
until the next visit. 
6.2.3 Accountability 
The Investigator must maintain accurate records of receipt of all study drugs, including dates of 
receipt. In addition, accurate records must be kept regarding when and how much study drug is 
dispensed and used by each patient in the study. Reasons for departure from the expected 
dispensing regimen must also be recorded. All study drugs must be reconciled and retained or 
destroyed according to applicable regulations. 
6.3 Dosing of Study Drugs 
6.3.1 Loncastuximab Tesirine Dosing 
Administration of loncastuximab tesirine will be performed by the Investigator or a qualified 
designee.  
During Phase 1, loncastuximab tesirine will be administered on Day 1 of Cycle 1 and Cycle 2 per 
the dose escalation plan below. 


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The Sponsor in consultation with the DESC will explore and evaluate a new dose level of 75 µg/kg 
loncastuximab tesirine in combination with ibrutinib as a concomitant therapy. 
Table 4 
Phase 1: Concomitant Treatment with Loncastuximab Tesirine and 
Ibrutinib  
Dose Level 
Loncastuximab Tesirine 
Ibrutinib 
1 
60 µg/kg IV Q3W × 2 
560 mg/day po continuous beginning C1D1 
2 
90 µg/kg IV Q3W × 2 
560 mg/day po continuous beginning C1D1 
3 
75 µg/kg IV Q3W × 2 
560 mg/day po continuous beginning C1D1 
Abbreviations: Q3W, every 3 weeks; po, orally; C1D1, Cycle 1 Day 1 
Note: Dose Levels 1 and 2 have completed enrollment, the subsequent Dose Level 3 has been added to further explore the 
combination.  
 
Patients who have a response of PR or SD at the 14-week disease assessment may receive 
2 additional doses of loncastuximab tesirine given 4 weeks apart (C5D1 and C6D1). 
During Phase 2, two treatment cohorts (Table 5) will be tested:  
• Patients assigned to a cohort where loncastuximab tesirine is given intermittently in 
combination with ibrutinib will receive loncastuximab tesirine at the initial recommended 
dose (60 µg/kg) determined in the Phase 1 portion of the study. Loncastuximab tesirine will 
be administered to the patients Q3W for 2 cycles (C1D1 and C2D1). Patients who have a 
response of CR, PR, and SD at later disease assessments (Week 14 and Week 30) will receive 
additional doses of loncastuximab tesirine on C5D1, C6D1, C9D1, and C10D1.  
• Patients assigned to a cohort where loncastuximab tesirine is given at every cycle in 
combination with ibrutinib will receive loncastuximab tesirine at re-determined RP2D at 
every treatment cycles. Loncastuximab tesirine will be infused through IV Q3W for first 
2 cycles and followed by Q4W for all subsequent treatment cycles.  


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Table 5 
Phase 2: Concomitant Treatment with Loncastuximab Tesirine and 
Ibrutinib  
Treatment Cohort 
Loncastuximab Tesirine 
Ibrutinib 
Targeted 
Enrollment 
Loncastuximab 
Tesirine Given 
Intermittently in 
Combination with 
Ibrutinib  
Initial RP2D (60 µg/kg) IV 
Q3W for C1 and C2, then 
Q4W at C5, C6 and C9, C10 
when a response of CR, PR 
or SD is observed. 
560 mg/day po daily 
beginning C1D1 
Non-GCB DLBCL 
(n=66. Enrollment 
will be closed at 
N=48) 
GCB DLBCL 
(n=30) 
MCL (n=10) 
Loncastuximab 
Tesirine Given at 
Every Cycle in 
Combination with 
Ibrutinib 
Re-determined RP2D IV 
Q3W for C1 and C2, 
followed by Q4W at all 
subsequent cycles.  
560 mg/day po daily 
beginning C1D1 for C1 
and C2, then reduced 
to 420 mg/day daily at 
C3D1and for all 
subsequent cycles.  
All DLBCL (n=100 
with ≥40 patients 
each from GCB and 
Non-GCB) 
 
Refer to Section 6.7 for premedication and supportive care. 
 
6.3.2 Ibrutinib Dosing 
Ibrutinib 
dosing 
will 
begin 
simultaneously 
with 
loncastuximab 
tesirine 
dosing 
(concomitant treatment,). Patients will receive ibrutinib orally once daily according to the dose 
instructions given in the Table 4 and Table 5 at approximately the same time each day.  
In Phase 1, ibrutinib administration will begin on Cycle 1 Day 1 for patients receiving concomitant 
treatment (Table 4).  
In Phase 2, ibrutinib will be administered according to the recommended dose and schedule in 
Table 5.  
Home administration of ibrutinib will be documented in a patient diary, which will be reviewed 
by the Investigator or designee at each study visit. 
6.4 Dose Escalation 
6.4.1 
Dose Escalation Design 
The dose escalation of loncastuximab tesirine in Phase 1will follow a standard 3+3 design using 
the dose levels defined in Section 6.5. The dose one dose level below the dose at which ≥33% of 
patients experience a DLT will be considered the MTD. Cohorts of 3 patients will be treated, 
starting at the initial dose level. If 0 of 3 patients in the first cohort at any dose level experience a 
DLT, then the following cohort will be treated at the next higher dose level. If 2 of 3 patients 
experience a DLT, then the preceding dose level will be determined as the MTD. If 1 of 3 patients 
experiences a DLT, then 3 additional patients will be treated at that dose level. If 0 of the 
3 additional patients experience a DLT, then the following cohort will be treated at the next higher 


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dose level. If 1 or more of the 3 additional patients experience a DLT, then the preceding dose 
level will be determined as the MTD. 
 There will be a minimum of 5 days between dosing the first and second patient at each dose level 
during dose escalation. 
Patients who discontinue from the study prior to completion of the DLT Period without a DLT 
will be replaced. 
6.4.2 
Dose-Limiting Toxicity Period 
The first 21 days of ibrutinib administration will be considered the DLT Period for patients in 
Phase 1 dose escalation who are following the 3+3 study design. 
6.4.3 
Dose-Limiting Toxicity Definition 
A DLT is defined as any of the following events which occur during the DLT Period, except those 
that are clearly due to underlying disease or extraneous causes: 
A hematologic DLT is defined as: 
• Grade 4 anemia 
• Grade 3 anemia requiring transfusion 
• Grade 4 neutropenia lasting > 7 days 
• Febrile neutropenia 
• Grade 4 thrombocytopenia 
• Grade 3 thrombocytopenia which results in clinically significant bleeding or requires a 
transfusion 
A non-hematologic DLT is defined as: 
• Hy’s law case: AST and/or ALT > 3 × ULN and bilirubin > 2 × ULN, and without initial 
findings of cholestasis (serum alkaline phosphatase [ALP] activity < 2 × ULN) and no other 
reason that could explain the combination of increased transaminases and serum total 
bilirubin 
• Any other non-hematologic toxicities ≥ Grade 3, with the exception of the following 
conditions: 
o 
Grade 3 fatigue for ≤ 7 days. 
o 
Grade 3 nausea, vomiting, or diarrhea in the absence of premedication that responds to 
therapy and improves by at least 1 grade within 3 days or to ≤ Grade 1 within 7 days. 
o 
Grade 3 elevations of ALP and GGT elevations, unless considered clinically relevant by 
the Investigator.  
o 
Grade 3 elevation of serum lipase or serum amylase for ≤ 7 days if without clinical signs 
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o 
Grade 3 electrolyte abnormalities which normalize within 48 hours (with or without 
medical intervention) and which do not manifest themselves clinically; in such instance, 
a follow-up sample MUST be taken within 48 hours to check whether such 
normalization has occurred. 
Patients who experience a DLT that resolves or stabilizes with appropriate medical management 
may continue treatment at the discretion of the Investigator in consultation with the Sponsor.  
6.4.4 Dose Escalation Steering Committee 
A DESC will oversee dose escalation and general safety of the study. 
Membership of the DESC will include: 
• Medical and/or pharmacovigilance representative(s) from the Sponsor and/or designee 
• Investigator(s) from each participating site 
The DESC will be responsible for: 
• Determining dose levels to be administered and the MTD based on assessment of safety 
findings and DLTs. 
• Monitor the safety of the study and review its progress at monthly intervals or more 
frequently as required. 
Decisions made at DESC meetings will be documented in written minutes that will be distributed 
to DESC members. 


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6.5 Dose Delays and Modifications 
6.5.1 Loncastuximab Tesirine 
Table 6 
Loncastuximab Tesirine Guidelines for Dose Modifications 
Study Drug 
Loncastuximab Tesirine  
Grade ≥2 edema, effusion 
All other non-hematologic AEs Grade ≥3  
• Loncastuximab tesirine must be held until the toxicity 
resolves to Grade≤ 1, (Grade 1 or baseline for peripheral 
neuropathy) 
• If loncastuximab tesirine dosing is delayed by more than 
3 weeks and the toxicity is considered at least possibly related 
to loncastuximab tesirine, then subsequent doses of 
loncastuximab tesirine will be reduced by 50% 
• Investigator may reduce the dose of loncastuximab tesirine by 
50% if the toxicity is possibly related to loncastuximab 
tesirine, but does not result in dosing delay of more than 
3 weeks if they feel it is in the best interest of the patient 
Grade ≥3 neutropenia or thrombocytopenia 
• Loncastuximab tesirine must be held until toxicity resolves to 
Grade ≤2  
• If loncastuximab tesirine dosing is delayed by more than 
3 weeks and the toxicity is considered at least possibly related 
to loncastuximab tesirine, then subsequent doses of 
loncastuximab tesirine will be reduced by 50%  
• Investigator may reduce the dose of loncastuximab tesirine by 
50% if the toxicity is possibly related to loncastuximab 
tesirine, but does not result in dosing delay of more than 
3 weeks if they feel it is in the best interest of the patient 
Skin related toxicities including 
photosensitivity rash 
Grade ≤2 
No dose adjustment is required. 
Topical treatment to affected areas is indicated: 
• maculopapular rash, 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 
• blistering rash: silvadene 1% cream BID and consider 
laboratory testing for blistering disorder (VZV/HSV and 
bacterial infection; bullous pemphigoid; pemphigus). 
Periodic reassessment as indicated 
For Grade 2, the Sponsor recommends dermatological 
consultation 
Table continued on next page. 


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Study Drug 
Loncastuximab Tesirine  
Skin related toxicities including 
photosensitivity rash 
Grade≥3 
Hold loncastuximab tesirine until improvement to ≤ Grade 1 and 
consider dermatological consultation 
Topical treatment to affected areas is indicated: 
• 
maculopapular rash or photosensitivity rash: 
high potency topical steroid cream (e.g., clobetasol 
propionate 0.05%, halobetasol propionate 0.05%) and 
consider systemic prednisone 0.5 mg/kg for 10 days 
• 
pruritus: high potency topical steroid cream 
(e.g., clobetasol propionate 0.05%, halobetasol propionate 
0.05%) and consider oral antipruritic. 
• 
xerosis: consider ammonium lactate 12% or urea 20% 
BID; and triamcinolone 0.1% cream BID. 
• 
blistering rash: silvadene 1% cream BID and consider 
laboratory testing for blistering disorder (VZV/HSV and 
bacterial infection; bullous pemphigoid; pemphigus) and 
systemic prednisone 0.5 mg/kg for 10 days 
Periodic reassessment as indicated. 
If loncastuximab tesirine dosing is delayed by more than 3 weeks 
and the toxicity is considered at least possibly related to 
loncastuximab tesirine, then subsequent doses of loncastuximab 
tesirine will be reduced by 50%.  
The Investigator may also reduce the dose of loncastuximab 
tesirine by 50% for any Grade ≥3 toxicity that is possibly related 
to loncastuximab tesirine but does not result in dosing delay of 
more than 3 weeks if they feel it is in the best interest of the 
patients. 
Grade 4 infusion related reactions 
Permanently discontinue loncastuximab tesirine 
Hy’s law (AST and/or ALT > 3 × ULN and 
bilirubin > 2 × ULN) 
Permanently discontinue loncastuximab tesirine. 
Hy’s law defined as: AST and/or ALT > 3 × ULN and bilirubin 
>2 × ULN, and without initial findings of cholestasis (ALP 
activity <2 × ULN) and no other reason that could explain the 
combination of increased transaminases and serum total bilirubin, 
such as viral hepatitis A, B, or C, preexisting or acute liver 
disease, or another drug capable of causing the observed injury 
For ibrutinib dose modification guidance, please see Section 6.5.2. 
 
If loncastuximab tesirine dosing is delayed or discontinued and the toxicity is at least possibly 
related to locastuximab tesirine, ibrutinib dosing can continue at the discretion of the Investigator 
and in consultation with the Sponsor.  


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6.5.2 Ibrutinib 
For any Grade 2 AE, a dose reduction can occur at the discretion of the Investigator and in 
consultation with the Sponsor. 
If a patient experiences any Grade ≥3 toxicity, ibrutinib must be held until the toxicity resolves to 
Grade 1 or baseline. Once the symptoms of the toxicity have resolved to Grade 1 or baseline, 
ibrutinib therapy may be reinitiated at the original dose. 
If toxicity as described above recurs and is considered at least possibly related to ibrutinib, after a 
dose hold, subsequent doses of ibrutinib will be reduced by 140 mg to 420 mg daily, or to 280 mg 
daily where applicable. 
If toxicity as described above recurs at the reduced dose and is considered at least possibly related 
to ibrutinib, after a dose hold, subsequent doses of ibrutinib will be reduced by an additional 
140 mg to 280 mg daily, or to 140 mg daily where applicable. 
If toxicity as described above recurs after a second dose reduction and is considered at least 
possibly related to ibrutinib, ibrutinib must be discontinued permanently. 
For Grade 3 or 4 atrial fibrillation or persistent atrial fibrillation of any grade, consider the risks 
and benefits of ibrutinib treatment. If clinically indicated, the use of anticoagulants or antiplatelet 
agents may be considered for the thromboprophylaxis of atrial fibrillation. 
Ibrutinib is metabolized primarily by CYP3A4. Avoid concomitant use of systemic strong or 
moderate CYP3A inhibitors and consider alternative agents with less CYP3A inhibition. 
If a strong CYP3A inhibitor must be used, reduce ibrutinib dose to 140 mg or withhold treatment 
for the duration of inhibitor use. Subjects should be monitored for signs of ibrutinib toxicity. If a 
moderate CYP3A inhibitor must be used, reduce ibrutinib to 140 mg for the duration of the 
inhibitor use. Avoid grapefruit and Seville oranges during ibrutinib treatment, as these contain 
moderate inhibitors of CYP3A. No dose adjustment is required in combination with mild 
inhibitors.  
If the dose of ibrutinib is reduced as per protocol the dose of ibrutinib may be re-escalated, at the 
investigator’s discretion upon discussion with the sponsor, after at least 2 months of a dose 
reduction in the absence of a recurrence of the toxicity that led to the reduction. 
If a dose of ibrutinib is not taken at the scheduled time, it can be taken as soon as possible on the 
same day with a return to the normal schedule the following day. Extra doses of ibrutinib should 
not be taken to make up for the missed dose.  
If ibrutinib dosing is delayed or discontinued and the toxicity is at least possibly related to ibrutinib, 
loncastuximab tesirine dosing can continue at the discretion of the Investigator and in consultation 
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6.6 Overdose Management 
An overdose is any dose of study drug(s) given to a patient that exceeds by 15% of the dose 
described in the protocol. Any overdose, with or without associated AEs, must be promptly 
reported to the Sponsor. There are no data available to determine what the effects of overdose of 
loncastuximab tesirine are and whether they can be reversed. There is no specific experience in 
the management of ibrutinib overdose in patients. Symptomatic treatment and standard supportive 
care measures for the management of any observed toxicity should be applied. 
6.7 Premedication and Supportive Care 
6.7.1 Premedication for Loncastuximab Tesirine 
Unless contraindicated, administer dexamethasone 4 mg po twice daily: 
• the day before each loncastuximab tesirine administration (if possible),  
• the day of loncastuximab tesirine administration (first dose at least 2 hours prior to 
administration when not given the day before; otherwise, any time prior to administration), 
and  
• the day after loncastuximab tesirine administration. 
 
Dexamethasone may be given IV in patients unable to take po. 
Patients who experience an infusion-related hypersensitivity reaction will receive the alternative 
premedication regimen specified in Section 6.7.3. 
6.7.2 Treatment of Edema and Pleural Effusion 
Peripheral edema and serosal effusions (pleural and pericardial effusions, ascites) have been seen 
in patients receiving loncastuximab tesirine. Patients should be advised to monitor their weight on 
a daily basis (preferably each morning around the same time) and notify the study site of weight 
gain greater than 1 kg from baseline.  
Patients with weight gain greater than 1 kg from baseline, new or worsening edema, and/or new 
or worsening pleural effusion, pericardial effusion, or ascites, should be treated with 
spironolactone at standard doses. 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 effusion.  
6.7.3 Treatment and Prophylaxis of Infusion-Related Hypersensitivity 
Reactions 
The treatment of severe hypersensitivity reactions, including anaphylaxis, should be available for 
immediate use and may be administered according to institutional SOC.  
Any patient who experiences an infusion-related hypersensitivity reaction should receive 
prophylactic treatment in subsequent cycles according to institutional SOC. 


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6.7.4 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 h, avoidance of being outside with no protection between 10AM and 
2PM). Also, fragrance-free detergents and soaps are recommended.  
Consideration should be given to corticosteroid therapy in patients who develop clinically 
significant skin toxicity (see Table 6 for dose modifications and treatment recommendations for 
skin toxicities).  
6.7.5 Other Supportive Care 
• Although the study patient population has a low risk for development of tumor lysis 
syndrome (TLS) compared to patients with acute disease (Cairo et al., 2010), patients should 
be observed for development of TLS and treated according to site standard treatment 
protocols. 
• 
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. 
6.8 Concomitant Medications and Procedures 
Medications (except for the study drugs) 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 30 days after last dose of study drug. 
6.8.1 Permitted During Study 
All 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 6.8.2.  
Hematopoietic growth factors are permitted as per American Society of Clinical Oncology 
guidelines (Smith et al., 2006). Patients may not receive prophylactic hematopoietic growth factors 
during Cycle 1. 


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6.8.2 Prohibited During Study 
• Moderate or strong CYP3A inhibitors and strong CYP3A inducers should be avoided. If a 
strong CYP3A inhibitor must be used, reduce ibrutinib dose to 140 mg or withhold 
treatment for the duration of inhibitor use. If a moderate CYP3A inhibitor must be used, 
reduce ibrutinib to 140 mg for the duration of the inhibitor use. Information on CYP3A 
inhibitors and inducers may be found in Section 13.3 (Appendix 3) or at 
http://medicine.iupui.edu/clinpharm/ddis/main-table/ 
• Grapefruit and Seville oranges (these contain moderate CYP3A inhibitors) 
• Other anticancer therapy with the exception of hormonal therapy for maintenance treatment 
of breast and prostate cancer 
• Other investigational agents 
• Live vaccine 
 


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7 DISCONTINUATION 
The reason for discontinuation and the date of discontinuation will be collected for all patients. 
Note: Once discontinued from the study for any reason, patients are not permitted to be re-enrolled. 
7.1 Discontinuation from Study Treatment 
A patient may be discontinued from study treatment for any of the following reasons: 
• Disease progression 
• Unacceptable toxicity 
• Patient decision 
• Transplant therapy 
• Major protocol deviation 
• The Investigator determines that it is in the best interest of the patient to discontinue the 
patient’s participation in the study. 
• Discontinuation of the study by the Sponsor 
• Pregnancy 
• Death 
IMPORTANT: Study treatment discontinuation is not to be automatically considered as 
withdrawal from the study. Patients discontinuing study treatment will be asked to perform an 
EOT visit (Section 4.4) and continue with the Follow-up Period (Section 4.5) 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. 
7.2 Discontinuation from the Study  
A patient may be discontinued from the study for any of the following reasons: 
• Withdrawal of consent 
• Investigator/Sponsor decision 
• Death 
• Loss to follow-up 
If a patient withdraws consent, no additional data will be collected. The Sponsor may continue to 
use previously collected medical research data prior to the withdrawal consistent with the original 
authorization. 
The study may be terminated at any time, for any reason, by the Sponsor. Patients still receiving 
study drug(s) should have an EOT visit as described in Section 4.4 and Schedule of Events (SoE) 
(Table 1 and Table 2). 


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7.3 Loss 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 
should send a registered letter to the patient in a final attempt to ensure protocol compliance. 
 


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8 STUDY ASSESSMENTS AND PROCEDURES 
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 for screening may 
be used for determination of patient eligibility only if obtained as part of standard care. 
8.1 Efficacy Assessments 
Disease assessments will occur as per the SoE (Table 1 and Table 2) until progression. 
Disease assessments should take place at the time points specified even if dosing of study drug(s) 
is delayed. Additional disease assessments may be obtained, if clinically indicated.  
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, will be performed at baseline. 
Patients with PET-avid disease at baseline should have PET-CT for all subsequent disease 
assessments. If disease is not PET-avid at baseline, computed tomography (CT) with contrast or 
magnetic resonance imaging (MRI) must be used for subsequent disease assessments.  
Images for all patients treated during the Phase 2 portion of the study will be submitted for central 
review. Submission instructions for central review will be provided in a separate manual. Central 
imaging review will be performed using two blinded independent reviewers with adjudication by 
a third blinded independent reviewer in cases of discordance.  
Screening (Baseline) imaging must be performed within 4 weeks prior to C1D1. 
During the Treatment Period, imaging will be performed 6 weeks and 14 weeks after C1D1, 
then every 8 weeks until EOT. Week 6 imaging should be performed prior to C3D1 and Week 14 
imaging should be performed prior to C5D1. All other imaging should be performed 
within ± 2 weeks of the scheduled time point. Disease assessments should be performed at the time 
points specified even if study drug dosing is delayed. If a scan has been performed within 8 weeks 
of EOT, it does not need to be repeated at EOT. 
During the Follow-up Period, patients who discontinued study drug(s) for reasons other than 
disease progression or initiation of other anti-cancer therapy except stem cell transplant, will have 
imaging performed every 12 (± 2) weeks until 1 year from EOT, then every 6 months until disease 
progression, up to 2 years from EOT.  
Response data will be collected for patients who receive CAR-T therapy until 90 days after 
receiving CAR-T therapy.  
If a scan has been performed within 8 weeks of EOT, it does not need to be repeated at EOT.  
In case of dose delays, disease assessment should be maintained at the frequencies defined above.  


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The patient’s response to treatment will be determined according to the 2014 Lugano Classification 
Criteria in Section 13.2 (Appendix 2) as CR, PR, SD, or progressive disease (PD). Images will be 
obtained according to local site imaging protocols. 
8.2 Adverse Events 
8.2.1 Definition of Adverse Events and Serious 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.  
Test results collected during the study (e.g., laboratory values, physical examinations, ECGs, etc.) 
or identified from review of other documents may constitute AEs if deemed clinically significant.  
A SAE is defined as any AE that: 
• results in death. 
• is life threatening. 
• 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 judgement may jeopardize the patient or may require medical or surgical 
intervention to prevent any of the outcomes listed above. 
8.2.2 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 non-leading 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.  
Adverse events (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 30 days after the last dose of study drug or the start of a new anti-cancer therapy, 
whichever occurs earlier; thereafter, only related SAEs will be reported with two exceptions:  


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1. Patients who have responded to loncastuximab tesirine and undergo SCT (either autologous 
or allogeneic) after permanent discontinuation of loncastuximab tesirine treatment without 
any intervening anti-cancer therapy. These patients will have the following safety 
information reported until 180 days’ post-transplant regardless of relationship to 
loncastuximab tesirine: 
a. Grade ≥3 AEs suggestive of hepatic toxicity, veno-occlusive disease/sinusoidal 
obstruction syndrome, graft-versus-host disease, infectious complications, prolonged 
cytopenia(s), and pulmonary toxicity 
b. SAEs 
c. Death  
2. Patients who receive CAR-T therapy after permanent discontinuation of loncastuximab 
tesirine treatment will have the following safety information reported until 90 days after 
receiving CAR-T therapy regardless of relationship to loncastuximab tesirine: 
a. Grade ≥3 AEs of cytokine release syndrome, encephalopathy, edema or effusion, rash, 
hepatic toxicity 
b. SAEs 
c. Death 
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 8.2.3), seriousness (Section 8.2.1), relationship to study drug(s) (Section 8.2.4), 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 
pharmacovigilance 
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 electronic data capture (EDC) system. 
 Adverse Events of Special Interest 
Adverse Events of Special Interest (AESIs) are AEs of clinical importance that may require safety 
evaluation. For this study, events of major hemorrhage, as defined below, will be considered 
AESIs and must be reported to the pharmacovigilance department of the Sponsor or delegate 
(e.g., CRO) within 24 hours after site personnel first learn about the event. Reporting will occur 
through the EDC system. 


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Major Hemorrhage 
Major hemorrhage is defined as any of the following:  
• Any treatment-emergent hemorrhagic AE of Grade 3 or higher* 
• Any treatment-emergent SAE of bleeding of any grade 
• Any treatment-emergent CNS hemorrhage/hematoma of any grade 
*All hemorrhagic events requiring transfusion of red blood cells (RBC) should be reported as 
Grade 3 or higher AE per CTCAE v4.03. 
8.2.3 Assessment of Severity 
Adverse events will be graded according to CTCAE v4.0. For events not included in the CTCAE 
criteria, the severity of the AE will be graded on a scale of 1 to 5 as shown in Table 7.  
Table 7 
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.  
 
AEs characterized as intermittent do not require documentation of onset and duration of each 
episode. 
8.2.4 Assessment of Causality 
The Investigator’s assessment of an AE’s relationship to study drug(s) is an important part of safety 
reporting. However, it is not a factor in determining whether or not an AE is reported. An AE will 
be assessed as related to study drug(s) 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 
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8.2.5 Regulatory Reporting 
All SAEs considered at least possibly related to the study drug(s) will be reported as 
Suspected Unexpected Serious Adverse Reactions (SUSARs), unless they have been defined as 
expected in the Reference Safety Information section of the IB, and package insert for ibrutinib. 
SUSARs will be reported to competent authorities and Independent Ethics Committee (IEC) in 
accordance with current legislation. 
8.2.6 Pregnancy Reporting 
Any pregnancy in a patient that occurs from the time the patient signs the ICF up to 9 months after 
discontinuation of loncastuximab tesirine or up to 1 months after terminating ibrutinib treatment, 
whichever comes last, during the study must be reported using the Pregnancy Report Form. Any 
pregnancy in a partner of a male patient that occurs from signing the ICF up to 6 months post last 
loncastuximab tesirine or up to 3 months post last ibrutinib, whichever comes last, during the study 
must be reported. 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 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(s) must be promptly reported in the same manner. 
Once pregnancy is confirmed in a study patient, study drugs will be discontinued, see Section 8.3.6 
for additional information. 
8.3 
Safety Assessments  
Safety will be assessed based on the procedures in the subsection below. The AE/SAE collection 
and reporting are described in Section 8.2. 
Unless otherwise specified, all safety assessments on dosing days will be done prior to 
administration of study drug(s). 
8.3.1 Physical Examination 
Physical examinations will be performed according to institutional standards and will include a 
whole-body skin examination. 
8.3.2 ECOG Performance Status 
The ECOG performance status grades are presented in Section 13.1 (Appendix 1) and will be 
captured as per the SoE (Table 1 and Table 2).  


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8.3.3 Height and Weight 
Height and weight will be measured as per the SoE (Table 1 and Table 2). 
Additional measurements should be performed if clinically indicated. 
Patients should monitor their weight at home to mitigate the risks for edema/effusions. 
Refer to Section 6.7.2 for further details. 
8.3.4 Vital Signs 
Vital signs include the measurements of arterial BP (systolic and diastolic), heart rate, respiratory 
rate, and body temperature and should be performed according to the institutional standards. 
Vital signs should be measured before and after each loncastuximab tesirine infusion. 
8.3.5 Laboratory Tests 
Samples will be collected at the time points specified as per the SoE (Table 1 and Table 2).  
Hematology: white blood cells (WBC) with 5-part differential (neutrophils, eosinophils, 
basophils, lymphocytes, and monocytes), platelet count, hemoglobin, and hematocrit.  
Chemistry: ALT, AST, GGT, ALP, amylase, lipase, total bilirubin (conjugated and unconjugated 
bilirubin only when total is abnormal), sodium, potassium, chloride, phosphate, calcium, 
magnesium, blood urea nitrogen or urea, carbon dioxide/bicarbonate, creatinine, creatine 
phosphokinase, total protein, albumin, glucose, phosphorus, and lactate dehydrogenase.  
Coagulation: partial thromboplastin time (PTT) and International Normalized Ratio (INR). 
Urinalysis: pH, specific gravity, protein, WBC, RBC, ketones, glucose, and bilirubin. 
Urinalysis may be performed by dipstick. Abnormal findings should 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. 
Other Tests: HBV, HCV, and HIV  
8.3.6 Pregnancy Test 
A highly sensitive β-HCG test in urine or blood β-HCG test must be performed in WOCBP for 
eligibility (see Section 5.1, Inclusion Criterion 10) and throughout the study as per the SoE  
(Table 1 and Table 2) and as needed.  
The C1D1 pre-dose pregnancy test can be waived if the test for eligibility was done within 3 days 
of C1D1. After starting the study drug, all efforts should be made to keep the interval between 


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two consecutive pregnancy tests no more than 6 weeks. When possible, for WOCBP patients a 
final pregnancy test should be performed ≥9 months post last dose of loncastuximab tesirine if 
applicable, however, remote pregnancy test is acceptable. 
If a pregnancy test is positive, study drug must be held pending confirmation. If the pregnancy is 
confirmed, 
treatment 
must 
be 
discontinued 
permanently 
for 
the 
patient. 
Refer to Section 8.2.6 for the handling of the patient and reporting the event. 
8.3.7 ECG 
Three consecutive (also called triplicate) 12-lead ECGs will be performed at defined time points 
throughout the study as per the SoE (Table 1 and Table 2). Refer to Table 8, Table 9, and Table 10 
for the detailed schedule of ECGs. 
The ECGs should be performed after the patient is resting for at least 5 minutes. 
At time points coinciding with blood sample collection including PK, and ECGs should be taken 
prior to blood collection, and where applicable, before vital sign measurements (refer to Figure 2). 
If a patient experiences Torsade de Pointes, additional concomitant PK samples (i.e., unscheduled) 
should be collected. 
Table 8 
Schedule for Triplicate ECG Collection: Phase 1 
Cycle 
Day 
ECG Time point (window) 
Screening 
 
Any time within 28 days prior to C1D1 
C1 
D1 
Pre-dose (preferably within 2 h prior to start of infusion) 
EOI (within 10 min prior to EOI) 
Post-dose* 4 h (± 15 min) 
D8 
Post-dose* 168 h (± 48 h; but within 30 min prior to PK sample) 
D15 
Post-dose* 336 h (± 48 h; but within 30 min prior to PK sample) 
C2 
D1 
Pre-dose (within 30 min prior to PK sample) 
EOI (within 10 min prior to EOI) 
Post-dose* 4 h (± 15 min) 
D8 
Post-dose* 168 h (± 48 h; but within 30 min prior to PK sample) 
D15 
Post-dose* 336 h (± 48 h; but within 30 min prior to PK sample) 
C3 
D1 
Any time (but within 30 min prior to PK sample) 
EOT 
 
Any time (but within 30 min prior to PK sample) 
Unscheduled 
 
Any time 
Abbreviations: ECG, electrocardiogram; EOI, end of infusion; EOT, end of treatment; PK, pharmacokinetics. 
*Post-dose time point is counted from start of infusion.  
 


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Table 9 
Schedule for Triplicate ECG Collection: Phase 2 for Cohort Where 
Loncastuximab Tesirine Is Given Intermittently in Combination with 
Ibrutinib  
Cycle 
Day 
ECG Time point (window) 
Screening 
 
Any time within 28 days prior to C1D1 
C1 
D1 
Pre-dose (preferably within 2 h prior to start of infusion) 
EOI (within 10 min prior to EOI) 
Post-dose* 4 h (± 15 min) 
D8 
Post-dose* 168 h (± 48 h; but within 30 min prior to PK sample) 
D15 
Post-dose* 336 h (± 48 h; but within 30 min prior to PK sample) 
C2 
D1 
Pre-dose (within 30 min prior to PK sample) 
EOI (within 10 min prior to EOI) 
Post-dose* 4 h (± 15 min) 
D8 
Post-dose* 168 h (± 48 h; but within 30 min prior to PK sample) 
D15 
Post-dose* 336 h (± 48 h; but within 30 min prior to PK sample) 
C3 
D1 
Any time (but within 30 min prior to PK sample) 
C5 
D1 
Pre-dose (preferably within 2 h prior to start of infusion) 
C6 
D1 
Pre-dose (preferably within 2 h prior to start of infusion) 
EOI (within 10 min prior to EOI) 
C9 
D1 
Pre-dose (preferably within 2 h prior to start of infusion) 
C10 
D1 
Pre-dose (preferably within 2 h prior to start of infusion) 
EOI (within 10 min prior to EOI) 
EOT 
 
Any time (but within 30 min prior to PK sample) 
Unscheduled 
 
Any time 
Abbreviations: ECG, electrocardiogram; EOI, end of infusion; EOT, end of treatment; PK, pharmacokinetics. 
*Post-dose time point is counted from start of infusion.  
 
Table 10 
Schedule for Triplicate ECG Collection: Phase 2 for Cohort Where 
Loncastuximab Tesirine Is Given at Every Cycle in Combination with 
Ibrutinib  
Cycle 
Day 
ECG Time point (window) 
Screening 
 
Any time within 28 days prior to C1D1 
C1 
D1 
Pre-dose (preferably within 2 h prior to start of infusion) 
EOI (within 10 min prior to EOI) 
Post-dose* 4 h (± 15 min) 
D8 
Post-dose* 168 h (± 48 h; but within 30 min prior to PK sample) 
D15 
Post-dose* 336 h (± 48 h; but within 30 min prior to PK sample) 
C2 
D1 
Pre-dose (within 30 min prior to PK sample) 
EOI (within 10 min prior to EOI) 
Post-dose* 4 h (± 15 min) 
D8 
Post-dose* 168 h (± 48 h; but within 30 min prior to PK sample) 
D15 
Post-dose* 336 h (± 48 h; but within 30 min prior to PK sample) 
C3 and beyond 
D1 
Pre-dose (preferably within 2 h prior to start of infusion) 
EOT 
 
Any time (but within 30 min prior to PK sample) 
Unscheduled 
 
Any time 
 


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The ECGs will be submitted for a central review. Submission instructions for the central review 
will be provided in a separate manual. Assessments will include determination of heart rate and 
rhythm and the PR, QRS, QT, QTcF, and QTcB intervals. 
8.4 Pharmacokinetics, 
 and Immunogenicity 
The PK, ADA
 samples will be collected as per the SoE (Table 1 and 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
 testing. 
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 analysis. 
Biological samples may be retained for up to 10 years to further address scientific questions as 
new information in regard to the disease or the study drug becomes available. 
For detailed instructions related to central laboratory sample collection, labeling, processing, 
storage, or shipment refer to the appropriate laboratory manual(s).  
8.4.1 Pharmacokinetics 
The PK profile of loncastuximab tesirine (total antibody), PBD-conjugated antibody, and 
unconjugated warhead SG3199 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 Table 1 and Table 2 and Table 11 
and Table 12. 
Blood should be drawn from a vein away from the one used for study drug infusion. 
PK samples must be stored at ≤ -70°C. Please refer to the laboratory manual for detailed 
instructions regarding specimen handling and shipment.  
At time points coinciding with ECG collection, PK blood collection should occur immediately 
after the end of the ECG recording and, when applicable, after vital signs. If a patient experiences 
Torsade de Pointes, additional PK samples (e.g., unscheduled) should be collected.  


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Table 11 
Sampling Schedule for PK and ADA: Phase 1 
Cycle 
Day 
PK Time point (window) 
ADA Time point (window) 
C1 
D1 
Pre-dose (preferably within 2 h 
prior to start of infusion) 
EOI (-5 to +10 min) 
Post-dose* 4 h (± 10 min) 
Pre-dose 
(preferably within 2 h prior to start 
of infusion) 
D8 
Post-dose* 168 h (± 48 h)  
- 
D15 
Post-dose* 336 h (± 48 h) 
Post-dose* 336 h (± 48 h) 
C2 
D1 
Pre-dose (within 2 h prior to 
start of infusion) 
EOI (-5 to +10 min) 
Post-dose* 4 h (± 10 min) 
Pre-dose 
(within 2 h prior to start of infusion) 
D8 
Post-dose* 168 h (± 48 h) 
- 
D15 
Post-dose* 336 h (± 48 h) 
- 
C3 
D1 
Pre-dose (prior to ibrutinib 
dosing)  
Pre-dose (prior to ibrutinib dosing)  
C5 and C6 (only for 
patients receiving 
loncastuximab tesirine in 
C5 and C6) 
D1 
Pre-dose (preferably within 2 h 
prior to start of infusion) 
 
Pre-dose (preferably within 2 h prior 
to start of infusion) 
C7 
(patients receiving 
loncastuximab tesirine for 
C5 and C6) 
D1 
Pre-dose (prior to ibrutinib 
dosing) 
Pre-dose (prior to ibrutinib dosing) 
EOT 
 
At any time during visit day 
At any time during visit day 
Unscheduled 
 
Any time 
Any time 
(if applicable, close to PK sample) 
Abbreviations: ADA, anti-drug antibody; EOI, end of infusion; EOT, end of treatment; PK, pharmacokinetics. 
*Post-dose time point is counted from start of infusion.  
 


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Table 12 
Sampling Schedule for PK and ADA: Phase 2 
Cycle 
Day 
PK Time point (window) 
ADA Time point (window) 
C1 
D1 
Pre-dose (preferably within 2 h 
prior to start of infusion) 
EOI (-5 to +10 min) 
Post-dose* 4 h (± 10 min) 
Pre-dose  
(preferably within 2 h prior to start 
of infusion) 
D8 
Post-dose* 168 h (± 48 h)  
- 
D15 
Post-dose* 336 h (± 48 h) 
Post-dose* 336 h (± 48 h) 
C2 
D1 
Pre-dose (within 2 h prior to 
start of infusion) 
EOI (-5 to +10 min) 
Post-dose* 4 h (± 10 min) 
Pre-dose 
(within 2 h prior to start of infusion) 
D8 
Post-dose* 168 h (± 48 h) 
- 
D15 
Post-dose* 336 h (± 48 h) 
- 
C3 
D1 
Pre-dose if loncastuximab 
tesirine is dosed (preferably 
within 2 h prior to start of 
infusion)  
Pre-dose if loncastuximab tesirine is 
dosed (preferably within 2 h prior to 
start of infusion)  
C5 and C6  
D1 
Pre-dose (preferably within 2 h 
prior to start of infusion) 
Pre-dose (preferably within 2 h prior 
to start of infusion) C5 only** 
C7  
D1 
Pre-dose if loncastuximab 
tesirine is dosed (preferably 
within 2 h prior to start of 
infusion)  
Pre-dose if loncastuximab tesirine is 
dosed (preferably within 2 h prior to 
start of infusion)  
C9 and C10  
D1 
Pre-dose (preferably within 2 h 
prior to start of infusion) 
Pre-dose (preferably within 2 h prior 
to start of infusion) C9 only ** 
C11  
D1 
Pre-dose if loncastuximab 
tesirine is dosed (preferably 
within 2 h prior to start of 
infusion)  
Pre-dose if loncastuximab tesirine is 
dosed (preferably within 2 h prior to 
start of infusion)  
C13 
D1 
- 
Pre-dose (preferably within 2 h prior 
to start of infusion) for 
loncastuximab tesirine given at 
every cycle in combination with 
ibrutinib only 
EOT 
 
At any time during the visit day At any time during the visit day 
Unscheduled 
 
Any time 
Any time 
(if applicable, close to PK sample) 
Abbreviations: ADA, anti-drug antibody; EOI, end of infusion; EOT, end of treatment; PK, pharmacokinetics. 
*Post-dose time point is counted from start of infusion.  
**Applicable to protocol amendment version 5 and beyond.  
 
To understand the metabolic disposition of loncastuximab tesirine in humans, samples remaining 
after PK analysis is complete may be pooled among patients for potential metabolite identification. 


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8.4.2 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 (MSD-ECL). If an ADA is 
confirmed, 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 Table 1 and Table 2 and Table 11 
and Table 12. 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 will 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.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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8.5 Patient-Reported Outcomes Questionnaires 
The impact of study treatment on disease- and treatment-related symptoms, as well as various 
aspects of patient’s health-related quality of life (HRQoL), will be assessed by three 
questionnaires:  
• European Organization for Research and Treatment of Cancer (EORTC) Quality of Life 
Questionnaire (QLQ)-Core 30 (C30), Section 13.4 (Appendix 4). 
• Lymphoma subscale (LymS) of Functional Assessment of Cancer Therapy – Lymphoma 
(FACT-Lym), Section 13.5 (Appendix 5).  
• EuroQoL-5 Dimensions-5 Levels (EQ-5D-5L), Section 13.6 (Appendix 6).  
Questionnaires will be completed in the respondent’s native language, at the scheduled time points 
prior to the patient’s clinical assessment and treatment. Patients will provide responses at the study 
site or by phone (i.e., the collection of EQ-5D-5L post disease progression). The patient should be 
given instructions, space, time, and privacy to complete the questionnaires by themselves and 
without any assistance from anyone else. The study coordinator should encourage the patient to 
complete the questionnaires without any missing responses. 
8.5.1 European Organization for Research and Treatment of Cancer Quality 
of Life Questionnaire – EORTC QLQ-C30 
The European Organization for Research and Treatment of Cancer (EORTC) quality of life 
questionnaire (QLQ)-C30 is a validated and widely used questionnaire to assess quality of life of 
cancer patients. It is composed of 30 items assessing 15 domains, including five functional scales 
(physical, 
role, 
emotional, 
cognitive, 
and 
social), 
three 
multi-item 
symptoms 
(fatigue, nausea/vomiting, and pain), six single-item symptoms (dyspnea, insomnia, appetite loss, 
constipation, diarrhea, and financial difficulties), and one global health status/ quality of life (QoL) 
scale. All scales range from 0 to 100 after applying a linear transformation to raw scores. Higher 
scores in functional scales and global health status/ QoL scales indicate a better HRQoL whereas 
higher scores in symptom scales indicate more severe symptoms (Aaronson NK et al, 1993). 
Patients will complete this questionnaire as per the SoE (Table 2). 
8.5.2 Lymphoma Subscale (LymS) of FACT-Lym 
FACT-Lym is a HRQoL questionnaire validated in patients with NHL. It consists of a general 
HRQoL assessment (FACT-G) and a disease-specific subscale (LymS). FACT-G (27 items) 
measures physical well-being, social/family well-being, emotional well-being, and functional 
well-being. The LymS (15 items) addresses symptoms and functional limitations that are important 
to patients with NHL, such as lumps and swelling in certain parts of the body, fever, night sweats, 
itching, and weight loss. Patients are 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. To ease burden on 
patients, only LymS will be collected and consequently LymS summary score be reported in this 
trial. The LymS summary score ranges from 0 to 60, with higher scores indicating better HRQoL. 
(Hlubocky et al, 2013). Patients will complete this questionnaire as per the SoE (Table 2). 


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8.5.3 EuroQol-5 Dimensions-5 Levels (EQ-5D-5L) 
EQ-5D-5L is designed as an international, standardized, generic instrument for describing and 
evaluating HRQoL (Herdman et al., 2011). The EQ-5D-5L consists of 2 parts: 
a. The descriptive system comprises five dimensions with 1 question for each dimension: 
mobility, 
self-care, 
usual 
activities, 
pain/discomfort, 
and 
anxiety/depression. 
Each dimension has five levels of perceived problems: no problems, slight problems, 
moderate problems, severe problems, unable to/extreme problems. The descriptive system 
can be converted into a health utility index for economic evaluation. 
b. The visual analog scale (VAS): patients rate their current general health state on a scale 
ranging from 0 (worst health that can be imagined) to 100 (best health that can be 
imagined). 
Patients will complete this questionnaire as per the SoE (Table 2). 
 


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9 STATISTICAL CONSIDERATIONS 
Full details of the analysis plan, including a more technical and detailed elaboration of the 
statistical analyses, will be provided in the statistical analysis plan (SAP). 
 
 
9.1 Sample Size 
The study will enroll approximately 243 patients. Phase 1 will enroll up to 55 patients and Phase 2 
will enroll approximately 188 patients.  
9.1.1 Phase 2 Sample Size Calculation for non-GCB DLBCL Cohort Where 
Loncastuximab Tesirine is Given Intermittently in Combination with 
Ibrutinib  
The primary hypothesis is that the CRR based on central review for patients treated with 
loncastuximab tesirine and ibrutinib is significantly greater than 20% (i.e., H0: p ≤ 0.2 vs. Ha: 
p >0.2). This hypothesis will be tested at type I error of 0.05 (two sided). 
Simon's 2-stage design (Simon, 1989) will be used. The null hypothesis that the true CRR is 0.2 
will be tested against a one-sided alternative. In the first stage, 22 patients will be accrued. If there 
are 
5 
or 
fewer 
CRs 
in 
these 
22 
patients, 
this 
cohort 
will 
be 
stopped. 
Otherwise, 44 additional patients will be accrued for a total of 66. The null hypothesis will be 
rejected if 20 or more CRs are observed in 66 patients. This design yields a type I error rate of 0.05 
and power of 90% when the true CRR is 0.4. 
9.1.2 Phase 2 Sample Size Calculation for the Cohort Where Loncastuximab 
Tesirine is Given at Every Cycle in Combination with Ibrutinib  
The primary hypothesis is that the CRR is based on central review for patients treated with the 
re-determined RP2D of loncastuximab tesirine and ibrutinib combination is significantly greater 
than 30% (i.e., H0: p ≤ 0.3 vs. Ha: p > 0.3). This hypothesis will be tested at type I error of 0.05 
(two sided). 
A Two-stage design with futility monitoring (Zeng et al., 2015) will be used. The null hypothesis 
that the true CRR is 0.3 will be tested against a one-sided alternative. In the first stage, 60 patients 
will be accrued. If there are 20 or fewer CRs in these 60 patients, this cohort will be stopped. 
Otherwise, 40 additional patients will be accrued for a total of 100. The null hypothesis will be 
rejected if 40 or more CRs are observed in 100 patients. This design yields a type I error rate of 
0.05 and power of 85% when the true CRR is 0.45. Enrollment will continue during the interim 
analysis. 


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9.2 Analysis Populations 
• 
The Safety population will consist of all patients who receive study drug. 
• 
The DLT-evaluable population will consist of all patients in Phase 1 dose escalation, 
who receive study drugs, and will exclude patients who discontinue from the study during 
the DLT Period without experiencing a DLT. 
• 
The Efficacy population will consist of all patients who receive at least 1 dose of study 
drug, who have valid baseline disease assessment(s), and who have at least one valid 
post-baseline disease assessment. Patients who do not have a post-baseline assessment due 
to early clinical progression or death (after receiving study drug) will also be included. 
• 
The PK population will consist of all patients who have at least 1 pre-(C1D1) and 
1 post-dose valid PK assessment. 
 
 
 
• 
Per Protocol population: All patients in the Safety population without major protocol 
deviations, which will be further described in detail in the SAP. 
9.3 Phase 2 Interim Analysis for Futility 
9.3.1 Non-GCB Cohort Where Loncastuximab Tesirine is Given 
Intermittently in Combination with Ibrutinib  
A single interim analysis is planned using Simon’s 2 stage procedure (Simon, 1989) in the 
non-GCB DLBCL cohort where loncastuximab tesirine is given intermittently in combination with 
ibrutinib. The purpose of this interim analysis is solely to determine if there is a sufficient CRR 
observed early in the study to warrant continuing study enrollment to completion. The interim 
analysis constitutes a futility analysis; it will not be used to stop the trial early for positive efficacy. 
In the first stage of the study, an interim analysis will be performed at the time when the 22nd 
patient has two tumor assessments. Enrollment will continue during the interim analysis. If 
≥6 patients achieve CR, the study will proceed to the second stage. If <6 patients achieve CR, 
enrollment in this cohort will be halted. 
9.3.2 Cohort Where Loncastuximab Tesirine is Given at Every Cycle in 
Combination with Ibrutinib  
A two-stage design with futility monitoring (Zeng et al., 2015) is planned in the cohort given 
loncastuximab tesirine at every cycle in combination with ibrutinib for all DLBCL. The purpose 
of futility monitoring is solely to determine if there is a sufficient CRR observed early in the study 
to warrant continuing study enrollment to completion. Futility monitoring will not be used to stop 
the trial early for positive efficacy. In the first stage of the study, an interim analysis will be 
performed at the time when the 60th patient has two tumor assessments. Enrollment will continue 
during the interim analysis. If ≥21 patients achieve CR, the study will proceed to the second stage. 
If <21 patients achieve CR, enrollment in this cohort will be halted. 


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9.4 Final Analysis 
For primary and key secondary endpoints analyses, a database snapshot may be taken when all 
patients have a minimum of 6 months follow up after initial documented response. All efficacy, 
and safety endpoints will be analyzed and reported in the clinical study report (CSR). Results of 
the PK analysis will be reported separately in a PK report. 
Follow-up analyses may be performed when all the patients complete the study per protocol.  
9.5 Demographics and Baseline Characteristics 
Demographics and baseline characteristics, such as medical/medications history and cancer 
history, will be summarized for the Safety population.  
9.6 Exposure to Treatments 
Exposure to study drug and prior and concomitant medications will be summarized for the 
Safety population. Dose interruptions, reductions, and relative dose intensity will also be 
summarized. 
9.7 Efficacy Analyses 
In the non-GCB DLBCL cohort, the primary efficacy analyses will be based on response as 
determined by the IRC. 
Responses reported by investigators will be used for sensitivity analyses. Similarly, in other 
cohorts, responses by the IRC (if available) and by investigators will be summarized separately. 
Efficacy analysis will be summarized in the non-GCB DLBCL, GCB DLBCL, and MCL cohort 
and in the combined DLBCL group (non-GCB plus GCB). 
9.7.1 Complete Response Rate 
CRR will be defined as the proportion of patients with a best overall response (BOR) of CR, 
according to the 2014 Lugano classification (Cheson et al., 2014). The BOR will be derived based 
on response assessment performed on or before the start of subsequent anti-cancer therapy. 
The percentage of CRR with its 95% confidence interval (CI) will be presented. 


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9.7.2 Overall Response Rate 
The ORR will be defined as the proportion of patients with a BOR of CR or PR, according to the 
2014 Lugano classification. The overall response category will be derived based on response 
assessment performed on or before the start of subsequent anti-cancer therapy. 
The percentage of 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. 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 
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. 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. The data will be analyzed by the Kaplan-Meier method. 
The median DOR and 95% CI will be presented. Further details will be outlined in the SAP. 
9.7.4 Relapse-free Survival 
Relapse-free survival (RFS) will be defined among CR patients as the time from the earliest date 
of first CR until the first date of either disease progression or death due to any cause. 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. The data will be analyzed by the Kaplan-Meier method. 
The median RFS and 95% CI will be presented. Further details will be outlined in the SAP. 
9.7.5 Progression-free Survival 
PFS will be defined as the time from first dose of study drug until the first date of either disease 
progression or death due to any cause. 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. 
The data will be analyzed by the Kaplan-Meier method. The median PFS time and 95% CI will be 
presented. Further details will be outlined in the SAP. 
9.7.6 Overall Survival 
OS will be defined as the time from first dose of study drug 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 data will be analyzed by the Kaplan-Meier method. 
The median OS and 95% CI will be presented. Further details will be outlined in the SAP. 


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9.8 Safety and Subgroup Analyses 
Safety analyses will be presented descriptively  
Subgroup analyses may be performed for CRR, ORR, DOR, RFS, PFS, and OS using the following 
variables if appropriate: 
• 
Demographic variables: age group, gender, race, and country 
• 
Baseline disease characteristics: tumor staging, and subtype 
• 
Number of prior systemic therapies and response to prior systemic therapies 
Other subgroup analysis factors may be evaluated as appropriate and the details will be provided 
in the SAP. 
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 30 days after the last dose of 
study drug or initiation of new anti-cancer therapy (whichever occurs first). 
The 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 
or higher); study drug-related AEs; AEs leading to treatment interruption, modification, or 
discontinuation; SAEs; AESIs; and death.  
9.8.2 Clinical Laboratory Results 
Clinical hematology, coagulation panel, biochemistry, and urinalysis data will be summarized at 
each scheduled assessment. Shifts for clinical laboratory results that can be graded according to 
CTCAE v4.0 (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. 
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 


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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 Analyses 
The PK profile will include determination of: maximum concentration (Cmax), time to Cmax (Tmax), 
area under the concentration-time curve from time zero to the last quantifiable concentration 
(AUClast), area under the concentration-time curve from time zero to the end of the dosing interval 
(AUCtau), area under the concentration-time curve from time zero to infinity (AUCinf), apparent 
systemic clearance (CL), apparent volume of distribution (Vss), apparent terminal half-life (Thalf), 
and accumulation index (AI). 
PK parameters will be determined for all PK-evaluable patients using a non-compartmental 
method with Phoenix WinNonlin (Certara USA, Inc., Princeton, NJ, US) or other appropriate 
software. Results of the PK analysis may be reported separately.  
 
  
9.10 Immunogenicity Analyses 
A tiered immunogenicity strategy (Figure 2) will be undertaken to evaluate ADAs by screening 
and confirmatory assays with titer evaluation, followed by characterization and evaluation of 
neutralizing capacity as needed. ADA sample collection, banking, and testing in validated and to 
be validated assays will be according to the FDA Immunogenicity Testing of Therapeutic Protein 
Products —Developing and Validating Assays for Anti-Drug Antibody Detection Guidance for 
Industry (Jan 2019).  
 


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Figure 2 
Anti-drug Antibody Tiered Immunogenicity Testing Strategy 
 
 
 
Abbreviations: ADA, anti-drug antibody; ADC, antibody drug conjugate; BSA, bovine serum albumin; 
mAb, monoclonal antibody; PK, pharmacokinetics. 
 
Results from ADA testing will include tabular summarization for number/proportion of patients 
with positive pre-dose ADA response, number of patients with post-dose ADA response only, and 
number of patients with positive ADA response at any time. The denominator will be the total 
number of patients tested for ADAs in the study. 
 
 
 
  
 


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10 DATA MANAGEMENT AND QUALITY ASSURANCE 
The Investigator will maintain accurate source documentation including patient medical records, 
laboratory reports, ECG strips, and patient diaries. 
Investigative site qualified personnel will enter patient data into an EDC system. The analysis data 
sets will be a combination of these data and data from other sources. 
Clinical data management will be performed in accordance with applicable standards and data 
cleaning procedures to ensure the integrity of the data (e.g., removing errors and inconsistencies 
in the data). AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA). 
Concomitant medications will be coded using the World Health Organization (WHO) Drug 
Dictionary. 
After database lock, each study site will receive information about all of their site-specific eCRF 
data as entered into the EDC system for the study, including full discrepancy and audit history. 
Additionally, a copy of study data from all sites will be created and sent to the Sponsor for storage. 
The CRO will maintain a duplicate copy for its records. In all cases, patient initials will not be 
collected or transmitted to the Sponsor. 
For detailed instruction on data entry procedures and timelines, please refer to the eCRF 
Completion Guidelines. 
 


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11 ETHICAL, REGULATORY, AND STUDY MANAGEMENT 
CONSIDERATIONS 
11.1 Regulatory and Ethical Conduct of the Study 
The study will be performed in accordance with the ethical principles that have their origin in the 
Declaration of Helsinki, International Council for Harmonisation (ICH) Good Clinical Practice 
(GCP), and all applicable regulations. For France sites only: Any reference to the patient's legally 
authorized representative/legal guardian in Section 11 is not applicable, as per the request from the 
French Central Ethics Committee (CEC). 
11.2 Independent Ethics Committee or Institutional Review Board 
Federal regulations and ICH guidelines require that approval be obtained from an Institutional 
Review Board (IRB)/IEC before participation of human patients in research studies. Before study 
onset, the protocol, informed consent, advertisements to be used for the recruitment of study 
patients, and any other written information regarding this study intended to be provided to the 
patient or the patient’s legally authorized representative must be approved by the IRB/IEC. 
Documentation of all IRB/IEC approvals will be maintained by the site and will be available for 
review by the Sponsor or its designee. 
All IRB/IEC approvals should be signed by the IRB/IEC chairman or designee and must identify 
the IRB/IEC name and address, the clinical protocol by title or protocol number or both, and the 
date approval or a favorable opinion was granted. 
The Investigator is responsible for obtaining continued review of the clinical research as specified 
by the IRB/IEC, at intervals not exceeding 1 year. The Investigator must supply the Sponsor or its 
designee with written documentation of continued review of the clinical research. 
11.3 Patient Information and Consent 
Informed consent in compliance with IRB/IEC and local regulations shall be obtained from each 
patient or their legally authorized representative before performing any study procedures and will 
be documented with a signed IRB/IEC approved ICF. Before enrollment, each prospective patient 
or his or her legally authorized representative will be given a full explanation of the study and be 
allowed to read the approved ICF. Once the Investigator is assured that the patient/legally 
authorized representative understands the implications of participating in the study, 
the patient/legally authorized representative will be asked to give consent to participate in the study 
and sign the ICF. The process for obtaining consent has to be documented at the institution. 
If the ICF is revised during the course of the study, all patients on-study, including those in 
follow-up, must sign the revised form, unless otherwise indicated by the IRB/IEC 
(local or global, as applicable). In such cases, the reason for not re-consenting the patient should 
be documented. 


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11.4 Confidentiality 
All laboratory specimens, evaluation forms, reports, and other records will be identified in a 
manner designed to maintain patient confidentiality. All records will be kept in a secure storage 
area with limited access. Clinical information will not be released without the written permission 
of the patient (or the patient’s legal guardian), except as necessary for monitoring and auditing by 
the Sponsor, its designee, regulatory authorities, or the IRB/IEC. 
The Investigator and other study staff may not disclose or use for any purpose other than 
performance of the study any data, record, or other unpublished, confidential information disclosed 
to those individuals for the purpose of the study. Prior written agreement from the Sponsor or its 
designee must be obtained for the disclosure of any said confidential information to other parties. 
11.5 Financial Disclosure and Obligations 
Investigators are required to provide financial disclosure information to allow the Sponsor to 
submit the complete and accurate certification or disclosure statements as required under 21 Code 
of Federal Regulations (CFR) 54 and local regulations. In addition, the Investigator must promptly 
update this information if any relevant changes occur during the course of the investigation and 
for 1 year following the completion of the study. 
11.6 Serious Adverse Events Report Requirements 
The Sponsor will ensure that all relevant safety information (SAEs and SUSARs) is reported to 
the FDA and competent authorities of European Member States, and to the IRB/IEC, in accordance 
with current legislation. 
11.7 Study Conduct 
The Investigator will conduct all aspects of this study in accordance with the principles of the 
current version of ICH E6 as well as all national, state, and local laws and regulations. 
Study personnel involved in conducting this study will be qualified by education training and 
experience to perform their respective tasks. Study information from this protocol will be posted 
on publicly available clinical study registers before enrollment of patients begins.  
11.8 Protocol Amendments 
Any change in the study plan requires a protocol amendment. All amendments to the protocol must 
be reviewed and approved following the same process as the original protocol before the amended 
protocol can be implemented. The Investigator will inform the governing IRB/IEC of all protocol 
amendments issued by the Sponsor in accordance with established IRB/IEC procedure. 
Only protocol amendments intended to eliminate an apparent immediate hazard to patient(s) may 
be implemented immediately, i.e., without IRB/IEC approval, but the circumstances of the change 
must be documented and submitted to the IRB/IEC. 


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11.9 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. 
Investigators and institutions involved in the study will permit study-related monitoring, audits, 
IRB/IEC review, and regulatory inspections by providing direct access to all study records. In the 
event of an audit/inspection, the Investigator agrees to allow the Sponsor, representatives of the 
Sponsor, or a regulatory agency access to all study records. 
The Investigator should 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. 
11.10 Records Retention 
Essential documents should be retained for at least 15 years from the completion of the study 
(last patient last visit) or until at least 2 years after the last approval of a marketing application in 
an ICH region or until there are no pending or contemplated marketing applications in an 
ICH region or at least 2 years have elapsed since the formal discontinuation of clinical 
development of the investigational study drug. However, these documents should be retained for 
a longer period if required by the applicable regulatory requirements or by an agreement with the 
Sponsor. It is the responsibility of the Sponsor to inform the Investigator/institution as to when 
these documents no longer need to be retained. 
11.11 Publications 
Following completion of the study, the results from the study 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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12 REFERENCE LIST 
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Expert Opin Biol Ther 2012;12(9):1191-1206. 
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geodemographic patterns, and survival in the US: A longitudinal analysis of the National Cancer 
Data Base from 1998 to 2011. Am J Hematol 2015;90(9):790-795. 
Beck A, Goetsch L, Dumontet C, et al. Strategies and challenges for the next generation of 
antibody-drug conjugates. Nat Rev Drug Discov 2017;16(5):315-337. 
Cairo MS, Coiffier B, Reiter A, et al. Recommendations for the evaluation of risk and prophylaxis 
of tumour lysis syndrome (TLS) in adults and children with malignant diseases: An expert TLS 
panel consensus. Br J Haematol 2010;149(4):578-586. 
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J Clin Oncol 2014;32(27):3059-3067. 
Coiffier B, Sarkozy C. Diffuse large B-cell lymphoma: R-CHOP failure-what to do? 
Hematology Am Soc Hematol Educ Program 2016(1):366-378. 
Crump M, Neelapu SS, Farooq U, et al. Outcomes in refractory diffuse large B-cell lymphoma: 
results from the international SCHOLAR-1 study. Blood 2017;130(16):1800-1808. 
Epperla N, Hamadani M. Hematopoietic cell transplantation for diffuse large B-cell and follicular 
lymphoma: Current controversies and advances. Hematol Oncol Stem Cell Ther 2017;10(4): 
277-284. 
FDA Immunogenicity Testing of Therapeutic Protein Products —Developing and Validating 
Assays for Anti-Drug Antibody Detection Guidance for Industry (Jan 2019) 
Gisselbrecht C, Glass B, Mounier N, et al. Salvage regimens with autologous transplantation for 
relapsed large B-cell lymphoma in the rituximab era. J Clin Oncol 2010;28(27):4184-4190. 
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Herdman M, Gudex C, Lloyd A, Janssen MF, Kind P, Parin D, et al. Development and preliminary 
testing of the new five-level version of EQ-5D (EQ-5D-5L). Qual Life Res. 2011 Dec; 20(10): 
1727–1736. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3220807/ 
Hlubocky FJ, Webster K, Cashy J, et al. The development and validation of a measure of 
health-related Quality of Life for Non-Hodgkin’s Lymphoma: The Functional Assessment of 
Cancer Therapy-Lymphoma (FACT-Lym). Lymphoma 2013:1-9. 
Imbruvica® (ibrutinib) [package insert]. Pharmacyclics, Inc, Sunnyvale CA; . 
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Eastern Cooperative Oncology Group. Am J Clin Oncol 1982;5(6):649-655. 
Rudin CM, Pietanza MC, Bauer TM, et al. Rovalpituzumab tesirine, a DLL3-targeted 
antibody-drug conjugate, in recurrent small-cell lung cancer: a first-in-human, first-in-class, open-
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Scheuermann RH, Racila E. CD19 antigen in leukemia and lymphoma diagnosis and 
immunotherapy. Leuk Lymphoma 1995;18(5-6):385-397. 
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B cell lymphoma. Nature Medicine 2015;21(8): 922-926. 
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over or under enrollment, Stat Med. 2015 July 20; 34(16): 2417–2426.  
 
ZynlontaTM (loncastuximab tesirine) [package insert] FDA-US PI April 2021 
 

SAP_001.pdf: 
Protocol Number: ADCT-402-103 
 
Official Title: A Phase 1/2 Open-Label Study to Evaluate the Safety and Efficacy of Loncastuximab 
Tesirine and Ibrutinib in Patients with Advanced Diffuse Large B-Cell Lymphoma or Mantle Cell 
Lymphoma (LOTIS-3) 
 
NCT Number: NCT03684694 
 
Document Date: 28 March 2023 


 
 
 
 
 
 
 
Statistical Analysis Plan 
 
 
 
 
A Phase 1/2 Open-Label Study to Evaluate the Safety and Efficacy of 
Loncastuximab Tesirine and Ibrutinib in Patients with Advanced Diffuse 
Large B-Cell Lymphoma or Mantle Cell Lymphoma (LOTIS-3)
 
PROTOCOL NO.: ADCT-402-103 
 
 
 
SAP Version No./ Date: 1.0/ 28, Mar 2023 
 
 
Statistician: 
 
 
 
 
 
  
 
 
 
 
 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
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PT 
Preferred term 
QTc 
Corrected QT interval 
RP2D 
Recommended Phase 2 Dose 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SD 
Stable disease 
SOC 
System organ class 
SPD 
Sum of Product of the Perpendicular Diameters 
std 
Standard deviation 
TEAE 
Treatment-emergent adverse event 
TANT 
Tumor-associated non tumor 
WHODRUG DD 
World Health Organization Drug Dictionary  
 
 


 
 
1 
 
This statistical analysis plan (SAP) describes the statistical methods to be used during the 
reporting and analysis of data collected under ADC Therapeutics Protocol ADCT-402-103. 
This SAP should be read in conjunction with the study protocol and case report form (CRF). 
This version of the plan has been developed using the Protocol Amendment 5 dated 31 August
2021.  


 
 
2 
 
2.1 
 
 
 
 
 
2.2 
 
 
 
 
 
 
 
 
 


 
 
3 
 
Objectives 
Endpoints 
Primary 
 
 
 
Secondary 
 
Phase 1: 
To evaluate the antitumor effect 
of the combination of 
loncastuximab tesirine  with 
ibrutinib 
To characterize the PK profile of 
loncastuximab tesirine when 
given in combination with 
ibrutinib 
To evaluate the immunogenicity 
of loncastuximab tesirine when 
given in combination with 
ibrutinib  
 
Phase 2: 
To further evaluate the safety 
and efficacy of loncastuximab 
tesirine in combination with 
ibrutinib in the non-GCB 
DLBCL, GCB DLBCL, all 
DLBCL, and MCL patients   
To further evaluate the PK 
profile and immunogenicity of 
loncastuximab tesirine when 
given in combination with 
ibrutinib 
To evaluate the impact of the 
combination on patient-
reported outcomes (PROs)  
 
Phase 1: 
Overall response rate (ORR) according to the 2014 Lugano classification as 
determined by Investigator. ORR defined as the proportion of patients with a 
BOR of CR or partial response (PR) Phase 1 and Phase 2
 
Phase 1 and Phase 2: 
Duration of response (DOR) defined as the time from the documentation of first 
tumor response to disease progression or death, in the non-GCB DLBCL, 
GCB DLBCL, all DLBCL, and MCL patients 
Relapse-free survival (RFS) defined as the time from the documentation of CR to 
disease progression or death in in the non-GCB DLBCL, GCB DLBCL, all 
DLBCL, and MCL patients 
Progression-free survival (PFS) defined as the time between start of treatment and 
the first documentation of progression, or death in the non-GCB DLBCL, 
GCB DLBCL, all DLBCL, and MCL patients 
Overall survival (OS) defined as the time between the start of treatment and death 
from any cause in the non-GCB DLBCL, GCB DLBCL, all DLBCL, and 
MCL patients   
Concentrations and PK parameters of loncastuximab tesirine (total antibody, 
pyrrolobenzodiazepine (PBD)-conjugated antibody, and unconjugated 
cytotoxin SG3199) in the non-GCB DLBCL, GCB DLBCL, all DLBCL, and 
MCL patients   
Anti-drug antibody (ADA) titers and, if applicable, neutralizing activity to 
loncastuximab tesirine in the non-GCB DLBCL, GCB DLBCL, all DLBCL, 
and MCL patients   
 
Phase 2: 
ORR according to the 2014 Lugano classification in the non-GCB DLBCL, GCB 
DLBCL, all DLBCL, and MCL patients. ORR defined as the proportion of 
patients with a BOR of CR or PR for all treated patients.
ORR is determined by IRC and/or Investigator. 
CRR according to the 2014 Lugano classification(Cheson et al., 2014) as 
determined by IRC and/or Investigator in the non-GCB DLBCL, GCB 
DLBCL, all DLBCL, and MCL patients 
CRR according to the 2014 Lugano classification(Cheson et al., 2014) as 
determined by investigator in the non-GCB DLBCL patient 
Frequency and severity of AEs and SAEs in the non-GCB DLBCL, GCB DLBCL, 
all DLBCL, and MCL patients 
Change from baseline of safety laboratory values, vital signs, ECOG performance 
status, and 12-lead ECGs in the non-GCB DLBCL, GCB DLBCL, all 
DLBCL, and MCL patients 
Change from baseline in PROs as measured by the European Organization for 
Research and Treatment of Cancer (EORTC) QLQ-C30, LymS of FACT4-
ym, and EQ-5D-5L,  in the non-GCB DLBCL, GCB DLBCL, all DLBCL, 
and MCL patients 


 
 
4 
 
 
 
 
A Dose Escalation Steering Committee (DESC) composed of study investigators and ADC 
Therapeutics personnel will be responsible for decisions concerning dose escalation
 
 
 
 
 
 


 
 
 
 
 
 
 
 
will receive loncastuximab tesirine Q3W on Day 1 of first 2 cycles, followed by Q4W 
on Day 1 of every subsequent cycles. Ibrutinib will be administered at 560 mg po daily for first 
two cycles, then a dose reduction to 420 mg po daily for subsequent cycles.  
 
4.1 
 
 
 


 
 
 
 
 
 
 
 
 
Phase 2 Sample Size Justification for the non-GCB DLBCL Cohort Where 
Loncastuximab Tesirine is Given Intermittently in Combination with Ibrutinib
 
 
Phase 2 Sample Size Calculation for the Cohort Where Loncastuximab Tesirine is Given 
at Every Cycle in Combination with Ibrutinib 
 
 


 
 
4.2 
 
 
4.3 
 
Not applicable. 


 
 
5 
 
All analyses will use SAS® version 9.4 or higher.  
Unless otherwise stated, tables, listings, and figures will be broken down by cohort (
 Phase 1 tables by 
dose level for safety, demographic and dosing, Phase 1 tables by does level for dose escalation 
patients only, and tables of 60 
 
Categorical data will be presented using counts and percentages, with the number of patients 
in the analysis population as the denominator for percentages. Percentages will be rounded to 
1 decimal place and not be displayed for zero counts.  
Continuous data will be summarized using the number of observations (n), mean, standard 
deviation (std), median, minimum, and maximum. Minima and maxima will be rounded to the 
precision of the original value, and means, medians, and 95% confidence intervals (CIs) if 
presented will be rounded to 1 decimal place greater than the precision of the original value. 
The std will be rounded to 2 decimal places greater than the precision of the original value, up 
to a maximum of 3 decimal places.  
CI will be two-
For exact 
estimates, the CI will be calculated using the Clopper-Pearson exact method. For Kaplan-Meier 
estimates, the CI will 
-
log transformation. 
Kaplan-Meier plots will be provided along with Kaplan-Meier estimates. 
The Baseline value is defined as the last non-missing value or measurement taken prior to the 
first dose of study drug. 
5.1 
 
5.1.1 
 
All patients who receive study drugs. 
5.1.2 
 
 
5.1.3 
 
All patients who receive at least 1 dose of study drugs, have valid baseline disease 
assessment(s), and have at least one valid post-baseline disease assessment.  Patients who do 


 
 
not have a post-baseline assessment due to early clinical progression or death (after receiving 
study drugs) will also be included. 
5.1.4 
 
 
 
5.1.6 
 
All patients in the Safety Analysis Set without major protocol deviations. More details are in 
Section 4.3. 
5.2 
 
Enrolled subjects include all patients who signed informed consent forms. All subjects enrolled, 
including screen fails, will be summarized. Subjects who discontinued treatment and 
discontinued from the study will be summarized, along with the primary reasons for 
discontinuation. The disposition summary will be based on the Safety Analysis Set. 
 
5.3 
 
 
 
1. Patient entered the study even though they did not satisfy the entry criteria 
2. Patient received a prohibited concomitant treatment during the study 
3. Patient who met criteria for mandatory study drug discontinuation during the study but 
did not have study drug withdrawn 
4. Patient who received the wrong treatment or incorrect dose, including dose not 
specified in the protocol and actual dose of study drug was greater than 15% more or 
less than protocol planned dose. 


 
 
Important protocol deviations will be summarized and listed. 
5.4 
 
Demographic and baseline characteristics will be tabulated for the Safety Analysis Set.  
Demographic and baseline characteristics data will also be listed. 
5.5 
 
Cancer history, prior radiotherapy, prior cancer surgery, prior system treatments will be 
tabulated for the Safety Analysis Set.  
Cancer history, medical history, prior radiotherapy, prior cancer surgery, and prior system 
treatments will be listed. 
5.6 
 
Stem cell transplant, including prior to study and on study, will be tabulated for the Safety 
Analysis Set.  
Stem cell transplant will be listed. 
5.7 
All medications will be recorded in the CRF starting from the ICF signature date or from 14 
days prior to C1D1, whichever is earlier, and continuing until 30 days after last dose of study 
drug. 
All medications will be coded using the World Health Organization-Drug Dictionary (WHO-
DD) version 2019 March 01. 
 
5.8 
 
5.8.1 
 
Study drug exposures will be based on the Safety Analysis Set.  
A treatment cycle is defined as 3 weeks (i.e., 21 days) for Cycle 1 and Cycle 2, and then 4 
weeks (i.e., 28 days) for subsequent cycles.  
oncastuximab tesirine, 
 






 
 
Primary efficacy analyses will be based on CRR according to the 2014 Lugano classification 
(Cheson et al., 2014) as determined by independent review committee (IRC) in all DLBCL 
patients given loncastuximab tesirine at every cycle in combination with ibrutinib. 
 
5.9.1 
 
The CRR and its 95% two-sided exact CIs will be presented by the IRC and the investigator, 
respectively. 
5.9.2 
 
Overall response rate (ORR) is defined as the proportion of patients with a BOR of CR or 
partial response (PR).
 
For the analysis of ORR, 
The category of BOR includes complete response (CR), partial response (PR), stable 
disease (SD), progressive disease (PD), and inevaluable (NE). 
Overall responses derived for BOR must be assessed on or before the start of 
subsequent anti-cancer therapy or procedure. 
A BOR of SD requires the patient on-study for a minimum of 35 days after the first 
dose of study drug. A patient with SD only before this time will be considered as NE. 
For patients who do not have post-baseline assessment due to early clinical progression 
or death (after receiving study drug), they will be categorized separately from patients 
with assessments. 
Disease control rate (DCR) is defined as the proportion of patients with a BOR of CR, PR, or
SD. 
The ORR and DCR and their 95% two-sided exact CIs will be presented by the IRC and the 
investigator, respectively. 
Percent change from baseline in the sum of product of the perpendicular diameters (SPD) for 
target lesions will be presented and also displayed as a waterfall plot, with vertical bars 
representing the sorted values of best percent reduction for each patient.  
5.9.3 
 
Duration of response (DoR) is defined among patients with a BOR of CR or PR as the time 
from the documentation of first tumor response to either disease progression (based on 


 
 
radiographic or clinical progression at end of treatment [EOT]/end of study [EOS]) or death
.  
The censoring rules for DoR are as follow: 
For patients who are still alive at the time of analysis and without objective evidence 
of progression, patients will be censored at the last tumor assessment. 
For patients who receive subsequent anti-cancer therapy or procedure prior to disease 
progression or death, patients will be censored at the last tumor assessment prior to 
subsequent therapy or procedure. 
A sensitivity analysis might be considered: if a clinical progression or toxicity is 
observed without radiologic progression assessment confirmed, then the patient will be 
censored at the last tumor assessment.  
The DoR will be estimated by Kaplan-Meier method. The median DoR and its 95% 
CI will be presented 
. 
5.9.4 
 
Relapse-Free Survival (RFS) is defined as the time from the documentation of CR to either 
disease progression (based on radiographic or clinical progression at EOT/EOS) or death due 
to any cause, whichever occurs first.  
The censoring rules for DoR apply to RFS. 
The RFS will be estimated by Kaplan-Meier method. The median RFS and its 95% 
CI will be presented 
. 
5.9.5 
 
Progression-Free Survival (PFS) is defined as the time from first dose of study drug until either 
disease progression (based on radiographic or clinical progression at EOT/EOS) or death due 
to any cause, whichever occurs first. 
The censoring rules for PFS are as follow: 
For patients who are still alive at the time of analysis and without objective evidence 
of progression, patients will be censored at the last tumor assessment. 
For patients who receive subsequent anti-cancer therapy or procedure prior to disease 
progression or death, patients will be censored at the last tumor assessment on or prior 
to subsequent therapy or procedure. 
For patients have no post baseline tumor assessment, and have no disease progression 
or death, or receive subsequent anti-cancer therapy or procedure, patients will be 
censored at the first dose date of study drug. 


 
 
A sensitivity analysis might be considered: if a clinical progression or toxicity is 
observed without radiologic progression assessment confirmed, then the patient will be 
censored at the last tumor assessment.  
The PFS will be estimated by Kaplan-Meier method. The median PFS and its 95% 
CI will be presented 
. 
A swimmer plot will be displayed, including the points at which the criteria for response and 
progression by a specicific manifiestation were met (such as CR, PR, SD, PD, death, and stem 
cell transplant etc.). 
5.9.6 
 
Overall survival (OS) is defined as the time from first dose of study drug to the date of death 
from any cause.  
 
The OS will be estimated by Kaplan-Meier method. The median OS and its 95% 
 CI 
will be presented. 
5.9.7 
 
Subgroup analyses may be performed for CRR, ORR, DoR, RFS, PFS, and OS using the 
following variables if appropriate: 
Demographic variables: age group, gender, race, and country 
Baseline disease characteristics: tumor staging and subtype 
Number of prior systemic therapies and response to prior systemic therapies 
Other subgroup analysis factors may be evaluated as appropriate. 
5.10 
 
All safety analyses will be based on the Safety Analysis Set.  
5.10.1 
 
5.10.1.1 
 
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.  
The definition of SAEs is referred to the Protocol section 8.2.1.  


 
 
A treatment-emergent AE (TEAE) is defined as an AE that occurs or worsens in the period 
extending from the first dose of study drug to 30 days after the last dose of study drug in this 
study or start of a new anticancer therapy, whichever is earlier.  
AEs will be coded according to MedDRA Version 22.0, and the severity of the toxicities will 
be graded according to the National Cancer Institute (NCI) Common Terminology Criteria for 
Adverse Events (CTCAE) Version 4.0, where applicable. 
The summary of overall TEAEs includes: 
TEAEs 
Drug-related TEAEs (loncastuximab tesirine or ibrutinib) 
 
Drug-related 
TEAEs (loncastuximab tesirine or ibrutinib) 
Serious Adverse Events (SAEs) 
Drug-related SAEs (loncastuximab tesirine or ibrutinib) 
TEAEs leading to dose delayed, reduced or interrupted (loncastuximab tesirine or 
ibrutinib) 
TEAEs leading to discontinuation of loncastuximab tesirine or ibrutinib 
TEAEs leading to death 
Infusion related reactions 
The incidence of TEAEs will be summarized by system organ class (SOC) and preferred term 
(PT). A patient will be counted only once within a SOC and PT, even if the patient experienced 
more than one AE within a specific SOC and PT. Below TEAEs will be summarized in the 
same fashion: 
Drug-related TEAEs by SOC and PT 
TEAEs by SOC and PT 
Drug-related 
TEAEs by SOC and PT 
The most common TE
 
TEAEs by SOC, PT and maximum CTCAE grade 
TEAEs by relationship to loncastuximab tesirine or ibrutinib, maximum CTCAE grade, 
SOC and PT 
Listings of all AEs, including non-TEAEs, will be provided. Besides, TEAEs leading to dose 
discontinuation of 
, and TEAEs leading to death will also 
be provided. 


 
 
5.10.1.2 
 
Definition of DLT is referred to the Protocol section 6.4.3.  
DLTs will be summarized in each dose level in the dose-escalation part for the DLT-evaluable 
Analysis Set.  
Listings of DLTs will be provided. 
5.10.1.3 
 
A post-dose AE is defined as an AE during treatment that occurs or worsens from the first dose 
of study drug.  
 
SAEs by PT 
SAEs by SOC and PT 
SAEs by SOC, PT and maximum CTCAE grade 
Listings of SAEs will be provided. 
5.10.1.4 
 
 
5.10.1.5 
 
Definition of 
 (AESI) is referred to the Protocol section 8.2.2.1.  
 
AESIs by PT 
AESIs by SOC and PT 
AESIs by SOC, PT and maximum CTCAE grade 
Listings of AESIs will be provided. 
5.10.2 
 
Laboratory data of hematology, chemistry, and coagulation will be summarized for the actual 
value and the change from baseline value at each scheduled assessment. Besides, all data will 
be graded according to the NCI CTCAE Version 4.0, and summarized by baseline and 
maximum post-baseline CTCAE grade, including unscheduled visits. Shift tables will
summarize the shift from baseline grade to maximum post-baseline CTCAE grade. 


 
 
Listings of 
 
5.10.3 
 
 
QTcF interval > 450 ms 
QTcF interval > 480 ms 
QTcF interval > 500 ms 
QTcF interval increases from baseline > 30 ms 
QTcF interval increases from baseline > 60 ms 
Listings of ECG data will be provided. 
5.10.4 
 
 
Listings of vital sign data, including height and weight, will be provided. 
5.10.5 
 
 
Listing of ECOG performance status will be provided. 
5.10.6 
 
Listings of physical examinations will be provided. 
5.10.7 
 
Listings of pregnancy test, if applicalble, will be provided. 
5.11 
 
 


 
 
European Organization for Research and Treatment of Cancer (EORTC) Quality of Life 
Questionnaire (QLQ)-Core 30 (C30), 
Lymphoma subscale (LymS) of Functional Assessment of Cancer Therapy  Lymphoma 
(FACT-Lym),  
EuroQoL-5 Dimensions-5 Levels (EQ-5D-5L). 
Details are referred to the Protocol section 8.5.  
 
 
Summary analyses will include data up to the start of subsequent anticancer therapy/procedure.
 
5.11.1 
 
 
 
 
Have at least half of the items from the scale been answered? 
If Yes, use all the items that were completed, and apply the standard equations given on 
the previous pages for calculating the scale scores; ignore any items with missing values 
when making the calculations. 


 
 
If No, set scale score to missing. 
For single-item measures, set score to missing. 
 
5.11.2 
 
 
 
5.11.3 
 
Consisting of 15 items, LymS is a subscale of FACT-Lym questionnaire that addresses 
symptoms and functional limitations that are important to patients with non-Hodgkin 
lymphoma.  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. 
 
 
 
 
 
 


 
 
 
 
 


 
 
6 
 
 
Further details are described in a separate document, Details of Futility Analysis, dated on 14 May, 2021.
 
 
 
 


 
 
7 
 
For primary and key secondary endpoints analyses, a database snapshot may be taken when 66 
non-GCB DLBCL patients in Phase 2 have a minimum of 6 months follow up after initial 
documented response. All efficacy, safety, and PK endpoints will be analyzed and reported in 
the clinical study report (CSR). Results of the population PK analysis may be reported 
separately in a PK report. 
 
  
Follow-up analyses may be performed when all the patients complete the study per protocol. 


 
 
8 
 
8.1 
 
8.1.1 
 
In general, missing data including dates will be treated as missing and no data imputation will 
be applied, unless otherwise specified. Data that are potentially spurious or erroneous will be 
queried and examined during the review of the study data. 
 
 
8.1.2 
 
 
8.1.3 
 
 
If more than 1 assessment occurs during the same nominal visit, select the record 
closest to the nominal day for that visit. 
If there are 2 assessments that are equidistant from the nominal day, the data of the 
assessment after the scheduled study day will be used. 
The last measurement will be used if multiple measurements are taken on the same day.


 
 
9 
 
Simon R. Optimal two-stage designs for phase II clinical trials. Controlled Clinical Trials 
1989;10(1):1-10. 
Zeng D., Gao F., Hu K., Jia C., and Ibrahim JG, Hypothesis testing for two-stage designs with 
over or under enrollment, Stat Med. 2015 July 20; 34(16): 2417 2426. 
ADCT-402-103 Details of Futility Analysis, 14 May 2021