Clinical trial NCT03685344
Conditions: Diffuse Large B-Cell Lymphoma Mantle Cell Lymphoma Follicular Lymphoma
Keywords: Loncastuximab Tesirine in Combination with Durvalumab
Sponsor: ADC Therapeutics S.A.
Start date: 2019-02-04; Completion date: 2020-10-27
Enrollment: 13 participants; Allocation: NA; Intervention model: SEQUENTIAL

Brief summary:
The purpose of this phase 1 study is to evaluate the safety and anti-tumor activity of Loncastuximab Tesirine (ADCT-402) and Durvalumab in participants with Advanced Diffuse Large B-Cell Lymphoma, Mantle Cell Lymphoma, or Follicular Lymphoma

Detailed description:
This is a Phase 1b, open-label, single-arm combination study with a dose escalation phase (Part 1) followed by a dose expansion phase (Part 2). The study will enroll approximately 75 participants.

A standard 3+3 dose escalation design will be used for Part 1. The DLT period will be the 21 days after the first durvalumab dose.

Part 2 will consist of up to 3 expansion cohorts, one for DLBCL, one for MCL, and one for FL. Each cohort will be approximately 20 participants treated at the dose determined in Part 1.

The study will include a Screening Period (of up to 28 days), a Treatment Period (cycles of 3, 6, and 4 weeks), and a Follow-up Period (approximately every 12 week visits for up to 2 years after treatment discontinuation).

Arms: arm 1: Dose escalation phase: Ascending doses of Loncastuximab tesirine will be administered using a traditional 3+3 design. Dose level 1: 90 µg/kg, every 3 weeks (Q3W). Dose level 2: 120 µg/kg, Q3W. Dose level 3: 150 µg/kg, Q3W. Loncastuximab tesirine will be given for 2 doses, 3 weeks apart.

Dose expansion phase: Loncastuximab tesirine will be administered at the recommended dose determined in the dose escalation phase. Durvalumab will also be administered at a dose of 1500 mg once every 4 weeks (Q4W) throughout the dose escalation phase and dose expansion phase.
Interventions: intervention 1: Loncastuximab Tesirine and Durvalumab
Intervention descriptions: intervention 1: intravenous infusion

Protocol documents:
Prot_000.pdf: 
Protocol Number:  ADCT-402-104 
 
Official Title:    A Phase 1 Open-Label Study to Evaluate the Safety and Antitumor Activity 
of Loncastuximab Tesirine and Durvalumab in Patients with Advanced 
Diffuse Large B-Cell Lymphoma, Mantle Cell Lymphoma, or Follicular 
Lymphoma 
 
NCT Number:  NCT03685344 
 
Document Date:  14-Jan-2019 


ADC Therapeutics 
Loncastuximab Tesirine in Combination with Durvalumab 
ADCT-402-104 Clinical Protocol 
Protocol Amendment 1 
Date of Protocol Amendment 1: 14-January-2019 
Page 1 
CLINICAL STUDY PROTOCOL 
IND: 126138 
EudraCT Number: 2018-002670-43 
A Phase 1 Open-Label Study to Evaluate the Safety and Antitumor Activity 
of Loncastuximab Tesirine and Durvalumab in Patients with Advanced 
Diffuse Large B-Cell Lymphoma, Mantle Cell Lymphoma, or Follicular 
Lymphoma 
PROTOCOL NO.: ADCT-402-104 
Sponsor: 
Sponsor Contact: 
Date of Original Protocol: 
Protocol Amendment 1: 
ADC Therapeutics SA 
Route de la Corniche, 3B 
1066 Epalinges 
Switzerland 
 
Head of US Oncology Clinical Development 
ADC Therapeutics America Inc. 
 
1-August-2018
14-January-2019
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 SA. 


ADC Therapeutics 
ADCT-402-104 Clinical Protocol 
Loncastuximab Tesirine in Combination with Durvalumab 
Protocol Amendment 1 
Protocol Approval - Sponsor Signatory 
Study Title: 
Protocol Number: 
Date of Original: 
Protocol Amendment 1: 
Protocol accepted and approved by: 
 
A Phase I Open-Label Study to Evaluate the Safety 
and Antitumor Activity of Loncastuximab Tesirine 
and Durvalumab in Patients with Advanced Diffuse 
Large B-Cell Lymphoma, Mantle Cell Lymphoma, or 
Follicular Lymphoma 
ADCT-402-104 
1-August-2018 
14-January-2019 
Head of US Oncology Clinical Development 
ADC Therapeutics America Inc. 
 
 
Date of Protocol Amendment I : I 4-January-20 I 9 
Page 2 


ADC Therapeutics 
Loncastuximab Tesirine in Combination with Durvalumab 
ADCT-402-104 Clinical Protocol 
Protocol Amendment 1 
 
Date of Protocol Amendment 1: 14-January-2019 
 
Page 3 
Declaration of Investigator 
 
I have read and understood all sections of the protocol entitled: “A Phase 1 Open-Label Study 
to Evaluate the Safety and Antitumor Activity of Loncastuximab Tesirine and Durvalumab in 
Patients with Advanced Diffuse Large B-Cell Lymphoma, Mantle Cell Lymphoma, or 
Follicular Lymphoma” and the accompanying Investigator’s Brochures (IB).  
I agree to supervise all aspects of the protocol and to conduct the clinical investigation in 
accordance with the protocol amendment 1, dated 14-January-2019, 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 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 Durvalumab 
ADCT-402-104 Clinical Protocol 
Protocol Amendment 1 
 
Date of Protocol Amendment 1: 14-January-2019 
 
Page 4 
Table of Contents 
 
TABLE OF CONTENTS .......................................................................................................... 4 
LIST OF TABLES .................................................................................................................... 7 
LIST OF FIGURES .................................................................................................................. 7 
LIST OF ABBREVIATIONS ................................................................................................... 8 
OVERALL SUMMARY AND RATIONALE FOR CHANGES .......................................... 11 
PROTOCOL SYNOPSIS........................................................................................................ 12 
SCHEDULE OF EVENTS ..................................................................................................... 20 
1 
INTRODUCTION AND BACKGROUND ................................................................... 23 
1.1 
Non-Hodgkin Lymphoma and CD-19 ........................................................................ 23 
1.1.1 Diffuse Large B-cell Lymphoma ............................................................................ 23 
1.1.2 Mantle Cell Lymphoma .......................................................................................... 24 
1.1.3 Follicular Lymphoma ............................................................................................. 24 
1.2 
Loncastuximab Tesirine and Durvalumab .................................................................. 25 
1.2.1 Loncastuximab Tesirine Description ...................................................................... 25 
1.2.2 Safety and Efficacy of Loncastuximab Tesirine ..................................................... 26 
1.2.3 Durvalumab Description ......................................................................................... 27 
1.2.4 Safety and Efficacy of Durvalumab ........................................................................ 27 
2 
STUDY RATIONALE ................................................................................................... 29 
2.1 
Rationale for Study Design ......................................................................................... 29 
2.2 
Rationale for Dose Selection ...................................................................................... 29 
3 
STUDY OBJECTIVES AND ENDPOINTS .................................................................. 30 
4 
STUDY DESIGN ............................................................................................................ 31 
4.1 
Overview ..................................................................................................................... 31 
4.2 
Screening Period ......................................................................................................... 31 
4.3 
Treatment Period ......................................................................................................... 31 
4.4 
End of Treatment ........................................................................................................ 32 
4.5 
Follow-up Period ........................................................................................................ 32 
4.6 
End of Study ............................................................................................................... 32 
5 
PATIENT POPULATION .............................................................................................. 33 
5.1 
Inclusion Criteria ........................................................................................................ 33 
5.2 
Exclusion Criteria ....................................................................................................... 34 
5.3 
Screen Failures ............................................................................................................ 36 
6 
STUDY TREATMENT .................................................................................................. 37 
6.1 
Study Drugs ................................................................................................................ 37 
6.1.1 Loncastuximab Tesirine .......................................................................................... 37 
6.1.2 Durvalumab ............................................................................................................ 37 
6.2 
Management of Clinical Supplies ............................................................................... 37 
6.2.1 Packaging and Storage ............................................................................................ 37 
6.2.2 Preparation and Administration .............................................................................. 38 
6.2.3 Accountability ......................................................................................................... 38 
6.3 
Dosing of Study Drugs................................................................................................ 38 
6.3.1 Loncastuximab Tesirine Dosing ............................................................................. 38 
6.3.2 Durvalumab Dosing ................................................................................................ 39 
6.4 
Dose Escalation ........................................................................................................... 39 


ADC Therapeutics 
Loncastuximab Tesirine in Combination with Durvalumab 
ADCT-402-104 Clinical Protocol 
Protocol Amendment 1 
 
Date of Protocol Amendment 1: 14-January-2019 
 
Page 5 
6.4.1 Dose Escalation Design .......................................................................................... 39 
6.4.2 Dose Limiting Toxicity Period ............................................................................... 39 
6.4.3 Dose Limiting Toxicity Definition ......................................................................... 40 
6.4.4 Dose Escalation Steering Committee ..................................................................... 41 
6.5 
Dose Delays and Modifications .................................................................................. 42 
6.5.1 Loncastuximab Tesirine .......................................................................................... 42 
6.5.2 Durvalumab ............................................................................................................ 42 
6.6 
Overdose Management ............................................................................................... 43 
6.7 
Premedication and Supportive Care ............................................................................ 43 
6.7.1 Premedication ......................................................................................................... 43 
6.7.2 Treatment of Edema and Pleural Effusion .............................................................. 43 
6.7.3 Treatment and Prophylaxis of Infusion-related Hypersensitivity Reactions .......... 44 
6.7.4 Skin Rash ................................................................................................................ 44 
6.7.5 Other Supportive Care ............................................................................................ 44 
6.7.6 Concomitant Medications and Procedures ............................................................. 45 
6.7.7 Permitted During Study .......................................................................................... 45 
6.7.8 Prohibited During Study ......................................................................................... 45 
7 
DISCONTINUATION .................................................................................................... 46 
7.1 
Discontinuation from Study Treatment ...................................................................... 46 
7.2 
Discontinuation from the Study .................................................................................. 46 
7.3 
Loss to Follow-up ....................................................................................................... 47 
8 
STUDY ASSESSMENTS AND PROCEDURES .......................................................... 48 
8.1 
Efficacy Assessments .................................................................................................. 48 
8.2 
Adverse Events ........................................................................................................... 49 
8.2.1 Definition of Adverse Events and Serious Adverse Events ................................... 49 
8.2.2 Eliciting and Reporting Adverse Events/Serious Adverse Events ......................... 49 
8.2.3 Assessment of Severity ........................................................................................... 50 
8.2.4 Assessment of Causality ......................................................................................... 50 
8.2.5 Regulatory Reporting .............................................................................................. 51 
8.2.6 Pregnancy ................................................................................................................ 51 
8.3 
Safety Assessments ..................................................................................................... 51 
8.3.1 Physical Examination ............................................................................................. 51 
8.3.2 ECOG Performance Status ..................................................................................... 51 
8.3.3 Height and Weight .................................................................................................. 52 
8.3.4 Vital Signs ............................................................................................................... 52 
8.3.5 Laboratory Tests ..................................................................................................... 52 
8.3.6 Pregnancy Test ........................................................................................................ 53 
8.3.7 ECG ........................................................................................................................ 53 
8.4 
Pharmacokinetics, Pharmacodynamics, and Immunogenicity .................................... 54 
8.4.1 Pharmacokinetics .................................................................................................... 54 
8.4.2 Immunogenicity ...................................................................................................... 56 
 
 
 
9 
STATISTICAL CONSIDERATIONS ............................................................................ 57 
9.1 
Sample Size ................................................................................................................. 57 
9.2 
Analysis Populations ................................................................................................... 57 


ADC Therapeutics 
Loncastuximab Tesirine in Combination with Durvalumab 
ADCT-402-104 Clinical Protocol 
Protocol Amendment 1 
 
Date of Protocol Amendment 1: 14-January-2019 
 
Page 6 
9.3 
Interim Analysis for Futility ....................................................................................... 57 
9.4 
Final Analysis ............................................................................................................. 57 
9.5 
Demographics and Baseline Characteristics ............................................................... 57 
9.6 
Exposure to Treatments .............................................................................................. 58 
9.7 
Efficacy Analyses ....................................................................................................... 58 
9.7.1 Overall Response Rate ............................................................................................ 58 
9.7.2 Duration of Response .............................................................................................. 58 
9.7.3 Complete Response Rate ........................................................................................ 58 
9.7.4 Relapse-free Survival .............................................................................................. 58 
9.7.5 Progression-free Survival ....................................................................................... 59 
9.7.6 Overall Survival ...................................................................................................... 59 
9.8 
Safety Analyses ........................................................................................................... 59 
9.8.1 Adverse Events ....................................................................................................... 59 
9.8.2 Clinical Laboratory Results .................................................................................... 59 
9.8.3 Additional Safety Assessments ............................................................................... 60 
9.9 
Pharmacokinetic Analyses .......................................................................................... 60 
9.10 
Immunogenicity Analyses .......................................................................................... 60 
 
 
10 DATA MANAGEMENT AND QUALITY ASSURANCE .......................................... 62 
11 ETHICAL, REGULATORY, AND STUDY MANAGEMENT CONSIDERATIONS 63 
11.1 
Regulatory and Ethical Conduct of the Study............................................................. 63 
11.2 
Independent Ethics Committee or Institutional Review Board .................................. 63 
11.3 
Patient Information and Consent ................................................................................ 63 
11.4 
Confidentiality ............................................................................................................ 64 
11.5 
Financial Disclosure and Obligations ......................................................................... 64 
11.6 
Serious Adverse Events Report Requirements ........................................................... 64 
11.7 
Study Conduct ............................................................................................................. 64 
11.8 
Protocol Amendments ................................................................................................. 64 
11.9 
Monitoring of the Study .............................................................................................. 65 
11.10 
Records Retention ................................................................................................... 65 
11.11 
Publications ............................................................................................................. 65 
12 REFERENCE LIST ........................................................................................................ 66 
13 APPENDICES ................................................................................................................ 68 
13.1 
Appendix 1 Eastern Cooperative Oncology Group Performance Status .................... 68 
13.2 
Appendix 2 Response Assessment of Hodgkin and Non-Hodgkin Lymphoma 
(Lugano Classification) ........................................................................................................... 69 
13.3 
Appendix 3 Guidelines for Durvalumab Dose Modification for Specific Immune-
mediated Reactions ................................................................................................................. 74 
 
 
 


ADC Therapeutics 
Loncastuximab Tesirine in Combination with Durvalumab 
ADCT-402-104 Clinical Protocol 
Protocol Amendment 1 
 
Date of Protocol Amendment 1: 14-January-2019 
 
Page 7 
List of Tables 
 
Table 1 
Schedule of Events .............................................................................................. 20 
Table 2 
Study Objectives and Endpoints .......................................................................... 30 
Table 3 
Definition of Severity Grades for CTCAE .......................................................... 50 
Table 4 
Schedule for Triplicate ECG Collection .............................................................. 53 
Table 5 
Sampling Schedule for Loncastuximab Tesirine PK and ADA .......................... 55 
 
 
List of Figures 
 
Figure 1 
Schematic Representation and Chemical Structure of Loncastuximab Tesirine . 25 
Figure 2 
Anti-drug Antibody Tiered Immunogenicity Testing Strategy ........................... 61 
 
 
 
 
 


ADC Therapeutics 
Loncastuximab Tesirine in Combination with Durvalumab 
ADCT-402-104 Clinical Protocol 
Protocol Amendment 1 
 
Date of Protocol Amendment 1: 14-January-2019 
 
Page 8 
List of Abbreviations 
Abbreviation 
Definition 
ABW 
adjusted body weight 
ADA 
anti-drug antibody 
ADC 
antibody-drug conjugate 
ADR 
adverse drug reaction 
AE 
adverse event 
AI 
accumulation index 
Ala 
alanine 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
AlloSCT 
allogeneic stem cell transplant 
ANC 
absolute neutrophil count 
ASCT 
autologous stem cell transplant 
AST 
aspartate aminotransferase 
AUC0-∞ 
area under the concentration-time curve from time zero to infinity 
AUC0-last 
area under the concentration-time curve from time zero to the last 
quantifiable concentration 
AUC0-τ 
area under the concentration-time curve from time zero to the end of 
the dosing interval 
β-HCG 
beta-human chorionic gonadotropin 
BMI 
body mass index 
BOR 
best overall response 
C 
cycle  
CAR 
chimeric antigen receptor 
CD 
cluster of differentiation 
C1D1 
Cycle 1 Day 1 
CFR 
Code of Federal Regulations 
CI 
confidence interval 
CL 
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 
DNA 
deoxyribonucleic acid 
DOR 
duration of response 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 


ADC Therapeutics 
Loncastuximab Tesirine in Combination with Durvalumab 
ADCT-402-104 Clinical Protocol 
Protocol Amendment 1 
 
Date of Protocol Amendment 1: 14-January-2019 
 
Page 9 
Abbreviation 
Definition 
eCRF 
electronic case report form 
EDC 
electronic data capture 
EOT 
end of treatment 
EU 
European Union 
FDA 
Food and Drug Administration 
FFPE 
formalin-fixed paraffin-embedded 
FL 
follicular lymphoma 
GCP 
Good Clinical Practice 
GGT 
gamma-glutamyltransferase 
HBV 
hepatitis B virus 
HCV 
hepatitis C virus 
HD-ASCT 
high-dose chemotherapy and autologous stem cell transplant 
HIV 
human immunodeficiency virus 
hr 
hour 
IB 
Investigator’s Brochure 
IC 
immune cells 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committee 
IgG 
immunoglobulin G 
ILD 
interstitial lung disease 
INR 
international normalized ratio 
IRB 
Institutional Review Board 
IV 
intravenous 
LFT 
liver function test 
mAb 
monoclonal antibody 
MedDRA 
Medical Dictionary for Regulatory Activities 
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 
PET-CT 
positron emission tomography - computed tomography 
PFS 
progression-free survival 
PK 
pharmacokinetic(s) 
PO 
per os 
pp 
predicted probability 
PR 
partial response 
PTT 
partial thromboplastin time 
QT 
measure between Q wave and T wave in the electrocardiogram 


ADC Therapeutics 
Loncastuximab Tesirine in Combination with Durvalumab 
ADCT-402-104 Clinical Protocol 
Protocol Amendment 1 
 
Date of Protocol Amendment 1: 14-January-2019 
 
Page 10 
Abbreviation 
Definition 
QTcF 
Fridericia correction of the QT measure 
Q3W 
every 3 weeks 
Q4W 
every 4 weeks 
RBC 
red blood cell 
RFS 
relapse-free survival 
RR 
respiratory rate 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SCT 
stem cell transplant 
SD 
stable disease 
SOC 
system organ class 
SoE 
Schedule of Events 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TEAE 
treatment-emergent adverse event 
TLS 
tumor lysis syndrome 
Tmax 
time to maximum concentration 
µL 
microliter 
ULN 
upper limit of normal 
US 
United States 
Val 
valine 
WBC 
white blood cell 
WHO 
World Health Organization 
wk 
week 
WOCBP 
women of childbearing potential 
 
 
 


ADC Therapeutics 
Loncastuximab Tesirine in Combination with Durvalumab 
ADCT-402-104 Clinical Protocol 
Protocol Amendment 1 
Date of Protocol Amendment 1: 14-January-2019 
Page 11 
Overall Summary and Rationale for Changes 
Protocol Amendment 1  
•
Section 3
 
•
Section 5.1 Inclusion criterion 8d was modified to remove exception to ALT, AST, 
and GGT criteria in patients with liver involvement to align with requirement to hold 
study drug for Grade ≥2 LFT increases
•
Section 5.2 Exclusion criterion 18 was modified to remove the exception regarding 
patients with prior anti-PD-1, anti-PD-L1, or anti-CTLA-4 therapy as patients who 
have received these therapies are excluded in exclusion criterion 2
•
Section 6.4.3 Dose Limiting Toxicity Definition was modified to clarify the 
non-hematologic DLT definition
•
Section 6.7.1 Premedication and Section 6.7.3 Treatment and Prophylaxis of 
Infusion-related Hypersensitivity Reactions were modified to allow the use of IV 
dexamethasone
•
Section 9.8.1 Adverse Events was modified to align with the reporting period specified 
in in Section 8.2.2 Eliciting and Reporting Adverse Events/Serious Adverse Events
•
Section 13.3 (Appendix 3) was modified to remove information related to management 
of toxicities in patients with hepatocellular carcinoma as no patients with hepatocellular 
carcinoma will be enrolled in the study
•
Protocol synopsis was revised to align with the changes in the protocol
•
Editorial corrections and clarifications were applied throughout 


ADC Therapeutics 
Loncastuximab Tesirine in Combination with Durvalumab 
ADCT-402-104 Clinical Protocol 
Protocol Amendment 1 
 
Date of Protocol Amendment 1: 14-January-2019 
 
Page 12 
Protocol Synopsis 
 
Protocol Number: 
ADCT-402-104 
Title: 
A Phase 1 Open-Label Study to Evaluate the Safety and Antitumor 
Activity of Loncastuximab Tesirine and Durvalumab in Patients with 
Advanced Diffuse Large B-Cell Lymphoma, Mantle Cell Lymphoma, 
or Follicular Lymphoma 
Sponsor: 
ADC Therapeutics SA 
Study Phase: 
Phase 1b 
Indication: 
Diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma 
(MCL), follicular lymphoma (FL) 
Rationale: 
Non-Hodgkin lymphoma (NHL) is the 7th most common type of cancer 
in the U.S. 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 U.S. 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 (ASCT), highlights the need for new 
forms of treatment for NHL. 
Loncastuximab tesirine (ADCT-402) is an antibody-drug conjugate 
(ADC) directed against human cluster of differentiation 19 (CD19) that 
is well tolerated and has shown activity in patients with relapsed or 
refractory B-cell NHL in a Phase 1 study. It is anticipated to become a 
component of combination therapies that increase the response rate and 
durability of treatment.  
Checkpoint activation is an immune-evasion strategy that is operative 
in various tumors, both solid and hematological. There is pre-clinical 
evidence suggesting that the combination of an antibody-drug 
conjugate (ADC) and a checkpoint inhibitor (such as a PD-L1 blocker) 
may be more potent than either of the respective monotherapies 
(Müller et al., 2015). Early results from clinical trials combining ADCs 
and checkpoint inhibitors show potential increased effectiveness of the 
combination (Diefenbach et al., 2015; Diefenbach et al., 2016). 


ADC Therapeutics 
Loncastuximab Tesirine in Combination with Durvalumab 
ADCT-402-104 Clinical Protocol 
Protocol Amendment 1 
 
Date of Protocol Amendment 1: 14-January-2019 
 
Page 13 
The primary purpose of this study is to explore whether loncastuximab 
tesirine and durvalumab can be safely combined, and if so, identify the 
dose(s) and regimens appropriate for further study. In addition, the 
study will potentially generate preliminary evidence as to whether 
loncastuximab tesirine combined with durvalumab may increase the 
response rate and durability of response compared to previous results 
with either compound as a single agent. 
Objectives: 
Primary Objective 
• To characterize the safety and tolerability of loncastuximab 
tesirine in combination with durvalumab, and to identify the 
recommended dose and schedule for future studies  
Secondary Objectives 
• To evaluate the antitumor effect of the combination of 
loncastuximab tesirine with durvalumab 
• To 
characterize 
the 
pharmacokinetic 
(PK) 
profile 
of 
loncastuximab tesirine when given in combination with 
durvalumab 
• To evaluate the immunogenicity of loncastuximab tesirine when 
given in combination with durvalumab 
 
 
 
 
 
 
 
 
 
Endpoints: 
Primary Endpoints 
• Frequency and severity of adverse events (AEs) and serious 
adverse events (SAEs) 
• Incidence of dose limiting toxicities (DLTs) during the 21 days 
after the first durvalumab dose (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) 


ADC Therapeutics 
Loncastuximab Tesirine in Combination with Durvalumab 
ADCT-402-104 Clinical Protocol 
Protocol Amendment 1 
 
Date of Protocol Amendment 1: 14-January-2019 
 
Page 14 
Secondary Endpoints 
• Overall response rate (ORR) according to the 2014 Lugano 
classification as determined by the Investigator. ORR is the 
proportion of patients with a best overall response (BOR) of 
complete response (CR) or partial response (PR) 
• Duration of response (DOR) defined as the time from the 
documentation of first tumor response to disease progression or 
death  
• CR rate defined as the percentage of patients with a BOR of CR 
• Relapse-free survival (RFS) defined as the time from the 
documentation of CR to disease progression or death 
• Progression-free survival (PFS) defined as the time between start 
of treatment and the first documentation of recurrence, 
progression, or death  
• Overall survival (OS) defined as the time between the start of 
treatment and death from any cause 
• Concentrations and PK parameters of loncastuximab tesirine 
(total antibody, PBD-conjugated antibody, and unconjugated 
cytotoxin SG3199) 
• Anti-drug antibody (ADA) titers and, if applicable, neutralizing 
activity to loncastuximab tesirine 
 
 
 
 
 
 
 
 
 
 
 
Study Design: 
This is a Phase 1b, open-label, single-arm combination study with a 
dose escalation phase (Part 1) followed by a dose expansion phase 
(Part 2). The study will enroll approximately 75 patients. 
A standard 3+3 dose escalation design will be used. The DLT period 
will be the 21 days after the first durvalumab dose. 
The dose expansion phase (Part 2) will consist of 3 cohorts of 
approximately 20 patients each, one for DLBCL, one for MCL, and one 
for FL, to obtain additional safety and preliminary antitumor activity 
information at the maximum tolerated dose (MTD)/RDE. 
A Dose Escalation Steering Committee (DESC), composed of study 
investigators and ADC Therapeutics personnel, will be responsible for 
decisions concerning dose escalation. 


ADC Therapeutics 
Loncastuximab Tesirine in Combination with Durvalumab 
ADCT-402-104 Clinical Protocol 
Protocol Amendment 1 
 
Date of Protocol Amendment 1: 14-January-2019 
 
Page 15 
Patient Selection:  
Inclusion criteria: 
1. Male or female patient aged 18 years or older 
2. Pathologic diagnosis of DLBCL, MCL, or FL 
3. Patients must have relapsed or refractory disease and have failed 
or been intolerant to standard therapy 
4. Patients who have received previous CD19-directed therapy 
must have a biopsy that shows CD19 expression after 
completion of the CD19-directed therapy 
5. Measurable disease as defined by the 2014 Lugano 
Classification  
6. Patients must be willing to undergo tumor biopsy 
7. ECOG performance status 0-1 
8. 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 ≥9.0 g/dL (5.59 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 - Gault equation 
Note: A laboratory assessment may be repeated a maximum of two 
times during the Screening period to confirm eligibility.  
9. Negative beta-human chorionic gonadotropin (β-HCG) 
pregnancy test within 3 days prior to start of study drug on 
C1D1 for women of childbearing potential 
10. Women of childbearing potential must agree to use a highly 
effective method of contraception from the time of giving 
informed consent until at least 16 weeks after the last dose of 
study therapy. 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 16 weeks after the patient 
receives his last dose of study therapy. 


ADC Therapeutics 
Loncastuximab Tesirine in Combination with Durvalumab 
ADCT-402-104 Clinical Protocol 
Protocol Amendment 1 
 
Date of Protocol Amendment 1: 14-January-2019 
 
Page 16 
Exclusion criteria: 
1. Known history of hypersensitivity to or positive serum human 
ADA to a CD19 antibody. 
2. Previous therapy with any checkpoint inhibitor 
3. Autologous stem cell transplant within 100 days prior to start of 
study drug (C1D1) 
4. History of allogenic stem cell transplant 
5. History of solid organ transplant 
6. Active or prior documented autoimmune or inflammatory 
disorders (including inflammatory bowel disease [e.g., colitis or 
Crohn’s disease], diverticulitis [with the exception of 
diverticulosis], 
systemic 
lupus 
erythematosus, 
Sarcoidosis syndrome, or Wegener syndrome [granulomatosis 
with polyangiitis, Graves’ disease, rheumatoid arthritis, 
hypophysitis, uveitis, etc.]). The following are exceptions to this 
criterion: 
a. Patients with vitiligo or alopecia 
b. Patients with hypothyroidism (e.g., following Hashimoto 
syndrome) stable on hormone replacement  
c. Any chronic skin condition that does not require systemic 
therapy 
d. Patients without active disease in the last 5 years may be 
included 
but 
only 
after 
consultation 
with 
the 
Study Physician 
e. Patients with celiac disease controlled by diet alone 
7. Active infection including tuberculosis (clinical evaluation that 
includes clinical history, physical examination and radiographic 
findings, and tuberculosis testing in line with local practice) 
8. Known seropositive and requiring anti-viral therapy for human 
immunodeficiency (HIV) virus, hepatitis B virus (HBV), or 
hepatitis C virus (HCV)  
9. History of Stevens-Johnson syndrome or toxic epidermal 
necrolysis 
10. Lymphoma with active central nervous system (CNS) 
involvement at the time of screening, including leptomeningeal 
disease 
11. 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) 
12. Breastfeeding or pregnant 
13. Significant medical comorbidities, including but not limited to, 
uncontrolled hypertension (blood pressure [BP] ≥160/100 
mmHg repeatedly), unstable angina, congestive heart failure 


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(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, or severe chronic pulmonary disease 
14. Radiotherapy, chemotherapy, or other anti-neoplastic therapy 
within 14 days prior to start of study drug (C1D1), except shorter 
if approved by the Sponsor.  
15. Major surgery within 28 days prior to start of study drug (C1D1), 
except shorter if approved by the Sponsor. Note: Local surgery 
of isolated lesions for palliative intent is acceptable. 
16. Use of any other experimental medication within 14 days prior 
to start of study drug (C1D1) 
17. Planned live vaccine administration after starting study drug 
(C1D1)  
18. 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.. 
19.  Congenital long QT syndrome or a corrected QTcF interval 
of >470 ms at screening (unless secondary to pacemaker or bundle 
branch block) 
20.  History of another primary malignancy except for: 
a. Malignancy treated with curative intent and with no known 
active disease ≥5 years before the first dose of 
investigational product and of low potential risk for 
recurrence 
b. Adequately treated non-melanoma skin cancer or lentigo 
maligna without evidence of disease 
c. Adequately treated carcinoma in situ without evidence of 
disease 
21.  History of active primary immunodeficiency 
22. Any other significant medical illness, abnormality, or condition 
that would, in the Investigator’s judgement, 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, 6, and 4 weeks), and a Follow-up 
Period (approximately every 12 week visits for up to 2 years after 
treatment discontinuation).  


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Patients may continue treatment for up to 1 year or until disease 
progression, unacceptable toxicity, or other discontinuation criteria, 
whichever occurs first. 
The end of study occurs 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 disease is not PET avid at baseline, CT with contrast or 
magnetic resonance imaging (MRI) may 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 examination 
• ECOG Performance status 
• Height and weight 
• Vital signs 
• Safety 
laboratories 
(hematology, 
chemistry, 
coagulation, 
urinalysis, etc.) 
• Pregnancy test, if applicable 
• 12 Lead-ECG (triplicate) 
• AEs/SAEs, graded according to CTCAE v4.0 (or more recent) 
Other Assessments: 
• Blood sampling for PK, ADA 
 
 
Study Drugs, 
Dosage, and Mode 
of Administration: 
The dose of loncastuximab tesirine for patients treated at each dose 
level in Part 1 is shown below. Durvalumab will be administered every 
4 weeks starting 1 week after the first dose of loncastuximab tesirine. 
The DLT evaluation period will be the 21 days after the first 
durvalumab dose.  
Loncastuximab Tesirine Dose Escalation 
Dose Level 
Loncastuximab tesirine 
Durvalumab 
1 
90 µg/kg IV on Day 1 Q3W × 2 
1500 mg IV Q4W 
2 
120 µg/kg IV on Day 1 Q3W × 2 
1500 mg IV Q4W 
3 
150 µg/kg IV on Day 1 Q3W × 2 
1500 mg IV Q4W 
Patients who have a response of PR or SD at the 15 week assessment 
may receive 2 additional doses of loncastuximab tesirine given 4 weeks 
apart. 
Patients treated in Part 2 will receive study drugs at the dose and 
schedule determined in Part 1. 


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Sample Size: 
Approximately 75 patients. 
Statistical 
Considerations: 
Safety analyses will be presented descriptively. 
Primary antitumor activity analyses will be based on response as 
determined by the Investigator. ORR and CR rate with 95% CI will be 
presented. DOR, PFS, RFS, and OS will be analyzed using the 
Kaplan-Meier approach.  
 
 


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Schedule of Events 
Table 1 
Schedule of Events 
 
Protocol 
Section 
Screening 
Treatment Period 
Follow-up Period 
(up to 2 years from EOT) 
 
 
Cycle 1 
 (3 week cycle) 
Cycle 2   
(6 week cycle)9 
Cycle 3 and beyond  
(4 week cycles) 
EOT 
Every 12 weeks 
Day (D) 
 
-28 to –1 
1 
8 
15 
1 
8 
15 
1 
 
 
Informed consent 
11.3 
X 
 
 
 
 
 
 
 
 
 
Eligibility criteria 
5 
X 
 
 
 
 
 
 
 
 
 
Demography 
9.5 
X 
 
 
 
 
 
 
 
 
 
Medical/cancer history 
9.5 
X 
 
 
 
 
 
 
 
 
 
Tumor biopsy 
8.5.1 
X1 
 
 
 
 
Physical examination 
8.3.1 
X 
X 
 
 
X 
 
 
X 
X 
 
ECOG performance status 
8.3.2 
X 
X 
 
 
X 
 
 
X 
X 
 
Height 
8.3.3 
X 
 
 
 
 
 
 
 
 
 
Weight 
8.3.3 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Vital signs 
(BP, HR, RR, Temp) 
8.3.4 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Disease assessment2 
8.1 
X 
6 weeks and 15 weeks after C1D1, then every 8 weeks 
X3 
Every 12 weeks until 
1 year from EOT, then 
every 6 months until 
disease progression up to 
2 years from EOT 
Hematology and 
Chemistry 
8.3.5 
X 
X4 
X 
 
X4 
X 
 
X 
X 
 
Coagulation and Urinalysis 
8.3.5 
X 
 
 
 
 
 
 
 
 
 
TSH 
(reflex free T3 or free T4) 
8.3.5 
X 
X 
 
 
X 
 
 
X 
X 
 
Hepatitis B, C, and HIV 
tests 
8.3.5 
X 
 


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Protocol 
Section 
Screening 
Treatment Period 
Follow-up Period 
(up to 2 years from EOT) 
 
 
Cycle 1 
 (3 week cycle) 
Cycle 2   
(6 week cycle)9 
Cycle 3 and beyond  
(4 week cycles) 
EOT 
Every 12 weeks 
Day (D) 
 
-28 to –1 
1 
8 
15 
1 
8 
15 
1 
 
 
Pregnancy test, 
if applicable 
8.3.6 
X 
 X4 
 
 
X 
 
 
X 
X 
 
12-lead ECG5 
8.3.7 
Table 4 
X 
X 
(pre-dose, 
EOI, and 
4 hr post-
dose) 
X 
(post-
dose) 
X 
X 
(pre-dose, 
EOI, and 
4 hr post-
dose) 
X 
X 
(post- 
dose) 
X11 
X 
 
Premedication  
6.7.1 
 
D-1 to D2 
 
 
D-1 to D2 
 
 
D-1 to D2 for cycles 
containing 
loncastuximab tesirine 
 
 
Loncastuximab tesirine 
administration 
6.3.1 
 
X 
 
 
X 
 
 
D8 of Cycles 5 and 6 
for patients who are 
PR or SD at Week 15 
evaluation 
 
 
Durvalumab 
administration 
6.3.2 
 
 
X 
 
 
 
X 
X8 
 
 
Loncastuximab tesirine 
PK5 sample 
8.4.1 
Table 5 
 
X5 
(pre-dose, 
EOI, and 
4 hr post-
dose) 
X 
X 
X 
(pre-dose, 
EOI, and 
4 hr post-
dose) 
X 
X 
 
X6 
(pre-dose) 
X 
 
Loncastuximab tesirine 
ADA5 sample 
8.4.1 
Table 5 
 
X5 
(pre-dose) 
 
X 
X 
(pre-dose) 
 
 
X6 
(pre-dose) 
X7 
 


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Protocol 
Section 
Screening 
Treatment Period 
Follow-up Period 
(up to 2 years from EOT) 
 
 
Cycle 1 
 (3 week cycle) 
Cycle 2   
(6 week cycle)9 
Cycle 3 and beyond  
(4 week cycles) 
EOT 
Every 12 weeks 
Day (D) 
 
-28 to –1 
1 
8 
15 
1 
8 
15 
1 
 
 
Durvalumab PK sample 
8.4.1 
 
 
 
 
 
 
X10 
 
 
 
Concomitant medications 
6.7.6 
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 within 30 days after last dose of study drug(s); thereafter, related SAEs only 
1st New anti-cancer 
treatment 
 
 
 
 
 
 
 
 
 
X 
X 
Survival 
 
 
 
 
 
 
 
 
 
X 
X 
Abbreviations: ADA: anti-drug antibody; AE: adverse events; BP: blood pressure; ECG: electrocardiogram; ECOG: Eastern Cooperative Oncology Group; EOI: end of infusion; 
EOT: end of treatment; HR: heart rate; ICF: informed consent form; PK: pharmacokinetics; RR: respiratory rate; SAE: serious AE; Temp: temperature; wks: weeks 
 
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. 
1 Tumor biopsy should be obtained prior to study drug administration.  
2 Screening imaging (PET-CT) 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 15 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 timepoint. Disease assessments should be performed at the timepoints 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 On days when loncastuximab tesirine is administered, ECG, PK, and ADA timepoints are in relation to loncastuximab tesirine dose. 
6 Cycle 3, C5, C6, C7; see Table 5. 
7 Patients who test positive for loncastuximab tesirine ADAs may be requested to supply additional ADA samples as specified in the protocol, Section 8.4.2. 
8 Administration of durvalumab, C3D1 will be 4 weeks after C2D15. 
9 Cycle 2 will be 6 weeks long because durvalumab administration needs to be 4 weeks apart. C3D1 will be 4 weeks after C2D15. 
10 The durvalumab PK sample should be taken before durvalumab dose administration. 
11Cycle 3. 
 


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1 Introduction and Background 
1.1 Non-Hodgkin Lymphoma and CD-19 
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 US and will account for an estimated 4.3% 
(n=72,240) of new cancer cases in 2017 (Siegel et al., 2017). In the United States, tumors of 
B-cell origin make up 85% to 90% of non-Hodgkin lymphoma. 
Human CD19 antigen is a 95 kDa 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 and Racila, 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 
DLBCL 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 ~50-70% of patients with relapsed or refractory DLBCL, with ~30-50% 
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 relapsed or refractory DLBCL 
(Coiffier and Sarkozy, 2016; Epperla and Hamadani, 2017). 
1.1.2 Mantle Cell Lymphoma 
Mantle cell lymphoma (MCL) is a rare and aggressive form of non-Hodgkin lymphoma 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 
(80-90%) 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 
relapsed or refractory MCL (Campo and Rule, 2015). 
1.1.3 Follicular Lymphoma 
Follicular lymphoma (FL) is the most common type of indolent NHL, accounting for 
approximately 22% of all patients with NHL. Standard first-line therapy uses 
immuno-chemotherapy. Although current front-line regimens for Stages III and IV such as 
R-CHOP or R-bendamustine are associated with high response rates, most patients still relapse. 
There 
are 
a 
number 
of 
agents 
available 
for 
second-line 
therapy, 
including 
cytarabine-containing regimens and idelalisib (Zydelig®). It has been reported idelalisib is 
effective in patients with high-risk FL and early relapse after initial immune-chemotherapy, 
with 56.8% ORR, 13.5% CR rate, and 11.8 months duration of response (DOR) 
(Gopal et al., 2017). However, FL is characterized by successive lines of therapy resulting in 
progressively shorter periods of disease-free survival followed ultimately by the development 
of either chemo-refractoriness, large cell transformation, or death from treatment-related 
toxicities (Cheah and Fowler, 2018). Thus, there remains unmet medical need for novel drugs 
for patients with relapsed or refractory FL. 


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1.2 Loncastuximab Tesirine and Durvalumab 
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.  
It is anticipated to become a component of combination therapies that increase the response 
rate and durability of treatment. 
The schematic representation of loncastuximab tesirine is presented in Figure 1. 
Figure 1 
Schematic Representation and Chemical Structure of Loncastuximab 
Tesirine 
Abbreviations: Ala, alanine; PABA, para-aminobenzoic acid; PEG, polyethylene glycol; RB4v1.2, humanized anti-CD19 
monoclonal antibody; Val, valine.
Loncastuximab tesirine binds with picomolar affinity to human CD19. After binding and 
internalization, loncastuximab tesirine traffics 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).  


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1.2.2 Safety and Efficacy of Loncastuximab Tesirine 
ADCT-402-101 (NCT02669017) is a first-in-human Phase 1 dose escalation study of 
loncastuximab tesirine in relapsed or refractory B-cell NHL patients, who 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 were 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 was to evaluate the safety and tolerability of 
the dose(s) determined in Part 1. The secondary objectives include evaluating the clinical 
activity of loncastuximab tesirine as measured by ORR, DOR, progression--free survival 
(PFS), and overall survival (OS). 
As of data cut-off date of 03 December 2017, a total of 144 patients with relapsed or refractory 
B-cell NHL received at least one infusion of loncastuximab tesirine. The median age was 
63.5 years (range: 23-86). The median number of previous chemotherapy regimens was 
3 (range: 1-10) with 24.3% of patients having prior stem cell transplant. 
Treatment-emergent adverse events (TEAEs) were reported in 137 (95.1%) out of 144 patients 
treated with loncastuximab tesirine. The most common TEAEs (observed in at least in 15% of 
patients), regardless of relationship to study treatment, were fatigue (42.4%); nausea (27.1%); 
gamma-glutamyltransferase (GGT) increased (26.4%); anemia (25.7%); edema peripheral 
(25.0%); dyspnea (18.8%); neutrophil count decreased, platelet count decreased, and 
thrombocytopenia (18.1% each); rash (17.4%); abdominal pain (16.0%); neutropenia (16.0%); 
and constipation (15.3%). Grade ≥3 TEAEs were reported in 92 (63.9%) patients. The most 
common Grade ≥3 TEAEs (observed in at least in 5% of patients) were neutrophil count 
decreased (16.0%); GGT increased (14.6%); anemia (12.5%); platelet count decreased 
(11.8%); neutropenia (11.1); and thrombocytopenia (8.3%). 
The following events were considered non-serious adverse drug reactions (ADRs): 
GGT increased, edema (includes peripheral and facial), neutrophil count decreased, 
platelet count decreased, thrombocytopenia, neutropenia, and skin-related events (such as rash, 
maculopapular rash, and erythema). 
TEAEs in 16 (11.1%) patients led to treatment discontinuation.   
Dose-limiting toxicity (DLT) was reported in 3 patients (2 thrombocytopenia and 1 febrile 
neutropenia). 
Serious adverse events (SAEs) were reported in 54 (37.5%) out of 144 patients. 
Of these, 24 patients experienced an SAE(s) considered at least possibly related to study drug. 
Six of the possibly related events were observed in multiple patients (febrile neutropenia in 
5 patients, pyrexia in 3 patients, dyspnea in 2 patients, lung infection in 2 patients, 
pleural effusion in 2 patients, and sepsis in 2 patients). Preliminary data indicate an acceptable 
safety profile. Febrile neutropenia and pleural effusion have been classified as expected serious 
ADRs. 


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Out of 126 evaluable patients, 33 (26.2%) achieved CR and 25 (19.8%) achieved partial 
response (PR), for an ORR of 58/126 (46.0%).   
Out of 92 evaluable patients with DLBCL, 22 (23.9%) achieved CR and 16 (17.4%) 
achieved PR, for an ORR of 38/92 (41.3%). 
The MTD was not formally established, but the recommended maximum Phase 2 dose was 
determined to be 150 µg/kg based on tolerability and antitumor efficacy. 
Additional details may be found in the current loncastuximab tesirine Investigator’s Brochure. 
1.2.3 Durvalumab Description 
Durvalumab is a human monoclonal antibody (mAb) of the immunoglobulin G (IgG) 
1 kappa subclass that blocks the interaction of programmed death-ligand 1 (PD-L1) 
[but not programmed cell death ligand-2] with PD-1 on T cells and CD80 (B7.1) on other 
immune cells. Blockade of PD-L1/PD-1 and PD-L1/CD80 interactions releases the inhibition 
of immune responses, including those that may result in tumor elimination. In vitro studies 
demonstrate that durvalumab antagonizes the inhibitory effect of PD-L1 on primary human 
T cells resulting in the restored proliferation of interferon gamma (IFN-γ) (Stewart et al., 2015). 
In vivo studies have shown that durvalumab inhibits tumor growth in xenograft models via a 
T-cell-dependent mechanism (Stewart et al., 2015). Based on these data, durvalumab is 
expected to stimulate the patient’s antitumor immune response by binding to PD-L1 and 
shifting the balance toward an antitumor response. Durvalumab has been engineered to reduce 
antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity. 
To date, durvalumab has been given either as monotherapy or in combination with other 
anticancer agents to more than 6000 patients as part of ongoing studies. 
Checkpoint activation is an immune-evasion strategy that is operative in various tumors, 
both solid and hematological. There is pre-clinical evidence suggesting that the combination 
of an antibody-drug conjugate (ADC) and a checkpoint inhibitor (such as a PD-L1 blocker) 
may be more potent than either of the respective monotherapies (Müller et al., 2015). 
Early results from clinical trials combining ADCs and checkpoint inhibitors show potential 
increased effectiveness of the combination (Diefenbach et al., 2015; Diefenbach et al., 2016). 
1.2.4 Safety and Efficacy of Durvalumab 
Risks with durvalumab include, but are not limited to, diarrhea/colitis, pneumonitis/ interstitial 
lung disease (ILD), endocrinopathies (i.e., events of hypophysitis, adrenal insufficiency, 
hyperthyroidism and hypothyroidism, and Type 1 diabetes mellitus), hepatitis/increases in 
transaminases, nephritis/increases in creatinine, pancreatitis/increases in amylase and lipase, 
rash/dermatitis, myocarditis, myositis/polymyositis, and other rare or less frequent 
inflammatory events including neurotoxicities, infusion-related reactions, hypersensitivity 
reactions, and infections/serious infections. 


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In monotherapy clinical studies, adverse events (AEs) reported very commonly include events 
such as fatigue, diarrhea, nausea and vomiting, decreased appetite, and muscle and joint pain. 
A total of 5% to 10% of patients discontinued the drug due to an AE. The majority of 
treatment-related AEs were manageable, with dose delays, symptomatic treatment, and in the 
case of events suspected to have an immune basis, the use of established treatment guidelines 
for immune-mediated toxicity (see Section 13.3, Appendix 3). 
Additional details may be found in the current version of the durvalumab IB. 
 


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2 Study Rationale 
While both loncastuximab tesirine and durvalumab have shown antitumor activity as single 
agents, a substantial proportion of patients will not have a complete response to either agent, 
and many 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 PD-L1 inhibitor, such as 
durvalumab, represents a rational approach for study in the clinic.  
2.1 Rationale for Study Design 
As loncastuximab tesirine and durvalumab represent a novel combination, the study will have 
dose finding using a standard 3+3 dose escalation design, followed by a dose expansion. 
As toxicity seemed similar across histologies in the Phase 1 study of loncastuximab tesirine, 
the dose escalation will enroll all histologies. To ensure adequate number of patients for the 
less common histologies of MCL and FL, the dose expansion will have individual cohorts for 
each histology. 
2.2 
Rationale for Dose Selection 
Durvalumab will be administered as a fixed dose based on a population pharmacokinetic (PK) 
analysis that indicated only a minor impact of body weight on the PK of durvalumab. The dose 
of 1500 mg corresponds to a dose of 20 mg/kg, which was the highest dose tested in clinical 
trials and was well tolerated. As this is a novel combination, loncastuximab tesirine will be 
administered starting with a dose of 90 µg/kg, which is 60% of the recommended Phase 2 dose. 
In treatment cycles where both drugs are given, they will be administered sequentially 1 week 
apart, with loncastuximab tesirine being given first in the initial 2 treatment cycles to allow for 
potential immunogenic cell death, which could enhance the activity of durvalumab. 
 
 


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3 
 Study Objectives and Endpoints 
Table 2 
Study Objectives and Endpoints  
Objectives 
Endpoints 
Primary 
• To characterize the safety 
and tolerability of 
loncastuximab tesirine in 
combination with 
durvalumab, and to identify 
the recommended dose and 
schedule for future studies  
• Frequency and severity of adverse events (AEs and serious adverse 
events (SAEs 
• 
Incidence of dose-limiting toxicities (DLTs) in the 21 days after the 
first durvalumab dose (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) 
Secondary 
• To evaluate the antitumor 
effect of the combination of 
loncastuximab tesirine with 
durvalumab 
• To characterize the 
pharmacokinetic (PK profile 
of loncastuximab tesirine 
when given in combination 
with durvalumab 
• To evaluate the 
immunogenicity of 
loncastuximab tesirine when 
given in combination with 
durvalumab 
• Overall response rate (ORR according to the 2014 Lugano 
classification as determined by the Investigator. ORR is the proportion 
of patients with a best overall response (BOR) of complete response 
(CR or partial response (PR 
• Duration of response (DOR defined as the time from the documentation 
of first tumor response to disease progression or death  
• CR rate defined as the percentage of patients with a BOR of CR 
• Relapse-free survival (RFS) defined as the time from the documentation 
of CR to disease progression or death 
• Progression free survival (PFS) defined as the time between start of 
treatment and the first documentation of progression, or death  
• Overall survival (OS) defined as the time between the start of treatment 
and death from any cause 
• Concentrations and PK parameters of loncastuximab tesirine 
(total antibody, PBD-conjugated antibody, and unconjugated cytotoxin 
SG3199) 
• Anti-drug antibody (ADA) titers and, if applicable, neutralizing activity 
to loncastuximab tesirine 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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4 Study Design 
4.1 Overview 
This is a Phase 1b, open-label, single-arm combination study with a dose escalation phase 
(Part 1) followed by a dose expansion phase (Part 2). The study will enroll approximately 
75 patients.  
A standard 3+3 dose escalation design will be used for Part 1. The DLT evaluation period will 
be 21 days after the first durvalumab dose. 
Part 2 will consist of up to 3 expansion cohorts, one for DLBCL, one for MCL, and one for 
FL. Each cohort will be approximately 20 patients treated at the dose determined in Part 1. 
The study will include a Screening Period (of up to 28 days), a Treatment Period (cycles of 3, 
6, and 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 may be used to satisfy screening requirements if they are performed in the 
screening window. 
The screening period is from 28 days to 1 day prior to the start of the study drug. The screening 
assessments should 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. 
4.3 Treatment Period 
The treatment period starts on the date when a patient receives the first dose of study drug and 
continues until the End of Treatment (EOT) visit.   
The treatment will start with Cycle 1, which will be 3 weeks long (i.e., 21 days), Cycle 2 will 
be 6 weeks long because durvalumab administration needs to be 4 weeks apart, and all other 
subsequent cycles will be 4 weeks long. Loncastuximab tesirine will be administered as an 
intravenous (IV) infusion over 30 minutes on Day 1 of Cycles 1 and 2. All patients will receive 
loncastuximab tesirine every 3 weeks (Q3W) for 2 cycles. Patients who have a response of 
PR or stable disease (SD) at the Week 15 assessment may receive an additional 2 doses of 
loncastuximab tesirine given on day 8 of Cycles 5 and 6.  


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Durvalumab will be administered as an IV infusion over 60 minutes on Day 8 of Cycle 1 and 
Day 15 of Cycle 2, then on Day 1 of 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.  
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. 
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, MCL, or FL 
3. Patients must have relapsed or refractory disease and have failed or been intolerant to 
standard therapy 
4. Patients who have received previous CD19-directed therapy must have a biopsy that 
shows CD19 expression after completion of the CD19-directed therapy 
5. Measurable disease as defined by the 2014 Lugano Classification  
6. Patients must be willing to undergo tumor biopsy 
7. ECOG performance status 0-1 
8. 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 ≥9.0 g/dL (5.59 mmol/L), transfusion allowed 
d. Alanine aminotransferase (ALT), aspartate aminotransferase (AST), and 
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-Gault equation 
Note: A laboratory assessment may be repeated a maximum of two times during the 
Screening period to confirm eligibility.  
9. Negative beta-human chorionic gonadotropin (β-HCG) pregnancy test within 3 days 
prior to start of study drug on C1D1 for women of childbearing potential 
10. Women of childbearing potential* must agree to use a highly effective** method of 
contraception from the time of giving informed consent until at least 16 weeks after the 
last dose of study therapy. 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 16 weeks after the patient receives his last dose 
of study therapy. 


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* 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.  
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 ADA to a CD19 
antibody 
2. Previous therapy with any checkpoint inhibitor 
3. Autologous stem cell transplant within 100 days prior to start of study drug (C1D1) 
4. History of allogenic stem cell transplant 
5. History of solid organ transplant 
6. Active 
or 
prior 
documented 
autoimmune 
or 
inflammatory 
disorders 
(including inflammatory bowel disease [e.g., colitis or Crohn’s disease], diverticulitis 
[with the exception of diverticulosis], systemic lupus erythematosus, Sarcoidosis 
syndrome, or Wegener syndrome [granulomatosis with polyangiitis, Graves’ disease, 
rheumatoid arthritis, hypophysitis, uveitis, etc.]). The following are exceptions to this 
criterion: 
a. Patients with vitiligo or alopecia 
b. Patients with hypothyroidism (e.g., following Hashimoto syndrome) stable on 
hormone replacement  
c. Any chronic skin condition that does not require systemic therapy 
d. Patients without active disease in the last 5 years may be included but only after 
consultation with the Study Physician 
e. Patients with celiac disease controlled by diet alone 
7. Active infection including tuberculosis (clinical evaluation that includes clinical 
history, physical examination and radiographic findings, and tuberculosis testing in line 
with local practice) 
8. Known seropositive and requiring anti-viral therapy for human immunodeficiency 
virus (HIV), hepatitis B virus (HBV), or hepatitis C virus (HCV)  


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9. History of Stevens-Johnson syndrome or toxic epidermal necrolysis 
10. Lymphoma with active central nervous system involvement at the time of screening, 
including leptomeningeal disease 
11. 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) 
12. Breastfeeding or pregnant 
13. Significant medical comorbidities, including but not limited to, uncontrolled 
hypertension (blood pressure [BP] ≥160/100 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, or severe chronic pulmonary disease 
14. Radiotherapy, chemotherapy, or other anti-neoplastic therapy within 14 days prior to 
start of study drug (C1D1), except shorter if approved by the Sponsor  
15. Major surgery within 28 days prior to start of study drug (C1D1), except shorter if 
approved by the Sponsor. Note: Local surgery of isolated lesions for palliative intent is 
acceptable 
16. Use of any other experimental medication within 14 days prior to start of study drug 
(C1D1) 
17. Planned live vaccine administration after starting study drug (C1D1)  
18. 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 
19. Congenital long QT syndrome or a corrected QTcF interval of >470 ms at screening 
(unless secondary to pacemaker or bundle branch block) 
20. History of another primary malignancy except for: 
a. Malignancy treated with curative intent and with no known active disease 
≥5 years before the first dose of investigational product and of low potential 
risk for recurrence 
b. Adequately treated non-melanoma skin cancer or lentigo maligna without 
evidence of disease 
c. Adequately treated carcinoma in situ without evidence of disease 
21. History of active primary immunodeficiency 
22. Any other significant medical illness, abnormality, or condition that would, in the 
Investigator’s judgement, make the patient inappropriate for study participation or put 
the patient at risk. 


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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 
- 
SAE 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 formulation 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. 
6.1.2 Durvalumab 
Durvalumab will be supplied as a 500-mg vial solution for infusion after dilution. The solution 
contains 50 mg/mL durvalumab, 26 mM histidine/histidine hydrochloride, 275 mM trehalose 
dihydrate, and 0.02% weight/volume (w/v) polysorbate 80; it has a pH of 6.0. The nominal fill 
volume is 10.0 mL. Durvalumab vials are stored at 2°C to 8°C (36°F to 46°F) and must not be 
frozen. Drug product should be kept in secondary packaging until use to prevent excessive 
light exposure. 
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 in a secure area. 
• Loncastuximab tesirine liquid formulation: loncastuximab tesirine should be protected 
from light and stored frozen (-65°C or below). Loncastuximab tesirine should be 
thawed under ambient conditions. 
• Unopened vials of durvalumab must be stored at 2°C to 8°C (36°F to 46°F) and must 
not be frozen. 


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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 loncastuximab tesirine to be administered 
will depend on the dose level and the weight of the patient. 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 deviation. 
Durvalumab will be given as a fixed dose of 1500 mg administered as a 60 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 deviation. 
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 
drugs are 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 Part 1, loncastuximab tesirine will be administered on Day 1 of Cycle 1 and Cycle 2 
per the dose escalation plan as shown below. 
Loncastuximab tesirine will be given initially for 2 doses, 3 weeks apart.  
Loncastuximab Tesirine Dose Escalation 
Dose Level 
Loncastuximab tesirine 
Durvalumab 
1 
90 µg/kg IV on Day 1 Q3W × 2 
1500 mg IV Q4W 
2 
120 µg/kg IV on Day 1 Q3W × 2 
1500 mg IV Q4W 
3 
150 µg/kg IV on Day 1 Q3W × 2 
1500 mg IV Q4W 
Patients who have a response of PR or SD at the 15 week assessment may receive two 
additional doses of loncastuximab tesirine given 4 weeks apart. 


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Patients with a body mass index (BMI) ≥35 kg/m2 will have their loncastuximab tesirine dose 
calculated based on an adjusted body weight as follows: 
• Adjusted body weight (ABW) in kg = 35 kg/m2 * (height in meters)2 
• Dose to administer (mg) = dosage (µg/kg) * ABW/1000 
During Part 2, patients will receive loncastuximab tesirine on Day 1 of Cycle 1 and Cycle 2 at 
the recommended dose determined in Part 1. Patients who have a response of PR or SD at the 
15 week assessment may receive 2 additional doses of loncastuximab tesirine given 4 weeks 
apart. 
Refer to Section 6.7 for premedication and supportive care. 
6.3.2 Durvalumab Dosing 
Administration of durvalumab will be performed by the Investigator or a qualified designee. 
Durvalumab will be administered at a fixed dose of 1500 mg every 4 weeks. Durvalumab will 
be administered on Day 8 of Cycle 1, Day 15 of Cycle 2, and Day 1 of subsequent cycles. 
6.4 Dose Escalation 
6.4.1 Dose Escalation Design 
The dose escalation of loncastuximab tesirine in Part 1 will follow a standard 3+3 design using 
the dose levels defined in Section 6.3.1. 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 
experience a DLT, then 3 additional patients will be treated at that dose level. If 0 of 3 
additional patients experience a DLT, then the following cohort will be treated at the next 
higher dose level. If 1 or more of 3 additional patients experience a DLT, then the preceding 
dose level will be determined as the MTD. 
Patients in Part 1 without a DLT who discontinue from the study prior to completion of the 
DLT period will be replaced. 
6.4.2  Dose Limiting Toxicity Period 
For patients in Part 1, the DLT period will be the 21 days after the first durvalumab dose. 
Any treatment-related toxicities that first occurred during the DLT period must be followed 
for resolution to determine if they qualify as a DLT as specified in the DLT criteria below. 


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6.4.3 Dose Limiting Toxicity Definition 
A DLT defined as any of the following events, which occur during the 21-day DLT evaluation 
period of Part 1, 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 toxicity ≥ Grade 3 with the exception of the following: 
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 or symptoms of pancreatitis. 
o Grade 3 electrolyte abnormalities that normalize within 48 hours (with or without 
medical intervention) and that 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. 


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• In addition, the following will be considered DLTs: 
o Grade 2 noninfectious pneumonitis that does not resolve to ≤Grade 1 within 3 days 
of the initiation of maximal supportive care 
o Any grade of immune-mediated rash with bullous formation 
o Grade 
2 
or 
3 
immune-mediated 
peripheral 
neuromotor 
syndrome 
(such as Guillain-Barre and myasthenia gravis) that does not resolve to Grade ≤1 
within 30 days or that exhibits signs of respiratory insufficiency or autonomic 
instability 
o Grade 2 immune-mediated myocarditis that does not resolve to Grade ≤1 within 
3 days of initiating optimal medical management, including systemic 
corticosteroids 
o Grade 2 or 3 immune-mediated myositis/polymyositis that does not resolve to 
Grade ≤1 within 30 days of initiating optimal medical management, including 
systemic corticosteroids, or that exhibits signs of respiratory insufficiency 
regardless of optimal medical management 
o Immune-mediated increase in creatinine >3 × ULN, or >3 × baseline for patients 
with a baseline creatinine elevated above ULN 
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 Dose Escalation Steering Committee (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, which will be 
distributed to DESC members. 


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6.5 Dose Delays and Modifications 
6.5.1 Loncastuximab Tesirine 
If a patient experiences any Grade ≥3 (≥2 for edema, effusion, or increased AST/ALT/GGT) 
toxicity, loncastuximab tesirine must be held until the toxicity resolves to Grade 1 or less 
(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%.   
In addition, the Investigator may reduce the dose of loncastuximab tesirine by 50% for any 
Grade ≥3 (≥2 for edema, effusion, or increased AST/ALT/GGT) 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. 
6.5.2 Durvalumab 
If a patient experiences any Grade ≥3 toxicity, durvalumab must be held until the toxicity 
resolves to Grade 1 or less (Grade 1 or baseline for peripheral neuropathy).  
In addition, durvalumab must be held for the following Grade ≥2 specific immune-mediated 
toxicities: 
• Pneumonitis/ILD 
• Diarrhea/Colitis 
• Hepatitis (elevated liver function tests) 
• Nephritis or renal dysfunction 
• Persistent rash (>1-2 weeks) 
• Endocrinopathy (except isolated hypothyroidism or Type 1 diabetes mellitus) 
• Neurotoxicity 
• Peripheral neuromotor syndromes 
• Myocarditis 
• Myositis/polymyositis 
See Section 13.3, Appendix 3 for guidelines regarding management and resumption of 
durvalumab therapy after specific immune-mediated toxicities. 
For all other toxicities, durvalumab must be held until the toxicity resolves to Grade 1 or less 
(Grade 1 or baseline for peripheral neuropathy). 
Durvalumab will be given at full dose when resumed after being held for toxicity, i.e., there 
will be no dose reduction. 


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6.6 Overdose Management 
An overdose is any dose of study drug(s) given to a patient that exceeds 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 durvalumab 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 
Unless contraindicated, administer dexamethasone 4 mg PO or IV 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. 
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.  


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6.7.3 Treatment and Prophylaxis of Infusion-related Hypersensitivity 
Reactions 
Medications for the treatment of severe hypersensitivity reactions, including anaphylaxis, 
should be available for immediate use and may be administered according to institutional 
standard of care.  
Any patient who experiences an infusion-related hypersensitivity reaction should receive 
prophylactic treatment in subsequent cycles according to the guidelines below or as per 
institutional standard of care: 
• On Day 1 of each cycle, patients should receive dexamethasone 20 mg PO or IV 12 and 
6 hours before the start of the loncastuximab tesirine infusion.  When necessary, 12 and 
6 hours before the first infusion may be defined as “immediately before sleeping” and 
“immediately after waking up.” 
• On Day 1 of each cycle, patients will be given diphenhydramine hydrochloride 50 mg IV 
30 minutes before the start of the loncastuximab tesirine infusion. 
• On Day 1 of each cycle, patients will be given ranitidine (or equivalent) 50 mg IV 
30 minutes before the start of the loncastuximab tesirine infusion. 
• For 2 days following administration of loncastuximab tesirine on Day 1, patients are to 
take dexamethasone 4 mg PO or IV twice daily (BID). 
6.7.4 Skin Rash 
Skin rash has been reported with loncastuximab tesirine, as well as with another investigational 
agent containing the same PBD warhead (Rudin et al., 2017). The rash has been reported in 
areas at risk for sun exposure; it is therefore recommended that precautions are taken to avoid 
prolonged exposure of skin to sunlight. 
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. 


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6.7.6 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. 
6.7.7 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 6.7.8.  
Hematopoietic growth factors are permitted as per American Society of Clinical Oncology 
guidelines (Smith et al., 2006). 
6.7.8 Prohibited During Study 
• Other anticancer therapy with the exception of hormonal therapy for maintenance treatment 
of breast and prostate cancer. 
• Other investigational agents. 
• Live vaccines including for 30 days after the last dose of durvalumab. 
• Current or prior use of immunosuppressive medication within 14 days before the first dose 
of durvalumab. The following are exceptions to this criterion: 
o Intranasal, inhaled, topical steroids, or local steroid injections (e.g., intra-articular 
injection) 
o Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone 
or its equivalent 
o Steroids as premedication for hypersensitivity reactions (e.g., computed tomography 
[CT] scan premedication) 
 
 


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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 
• 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. 


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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). 
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 SoE (Table 1) until progression.  Disease assessments 
should take place at the timepoints 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 timepoints. 
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 until they achieve CR. Patients who achieve CR may have CT with 
contrast for subsequent disease assessments. If disease is not PET-avid at baseline, CT with 
contrast or magnetic resonance imaging (MRI) may be used for all subsequent disease 
assessments. 
Screening (Baseline) imaging must be performed within 4 weeks prior to C1D1. 
During the treatment period, imaging will be performed 6 weeks and 15 weeks after C1D1, 
then every 8 weeks until EOT. Week 6 imaging should be performed prior to C3D1. 
Week 15 imaging should be performed prior to C5D1. All other imaging should be performed 
within ± 2 weeks of the scheduled time point. 
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.   
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. 
The patient’s response to treatment will be determined according to the 2014 Lugano 
Classification Criteria (Section 13.2, Appendix 2) as CR, PR, SD, or progressive disease (PD). 
Images will be obtained according to local site imaging protocols 


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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 examination, 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.  
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 initiation of new 
anti-cancer therapy, whichever occurs earlier; thereafter, only related SAEs will be reported.  
Whenever possible, AEs should be reported as a diagnosis rather than individual signs and 
symptoms. If no diagnosis is available or has been identified, then the primary symptom is 
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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. 
8.2.3 Assessment of Severity 
AEs will be graded according to CTCAE v4.0 (or more recent). For events not included in the 
CTCAE criteria, the severity of the AE is graded on a scale of 1 to 5 as shown in Table 3.  
Table 3 
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 rationale for the causality assessment.   


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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 durvalumab. 
SUSARs will be reported to competent authorities and the Independent Ethics Committee 
(IEC) in accordance with current legislation. 
8.2.6 Pregnancy 
Any pregnancy in a participant or partner that occurs during the study must be reported using 
the Pregnancy Report Form. 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 from the time the patient signs the ICF until 90 days after the last dose of study 
drug(s) 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 participant, 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. AE/SAE collection 
and reporting is 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 examination will be performed according to institutional standards and will include a 
whole body skin examination. Physical examinations will occur at the timepoints shown on 
Table 1. 
8.3.2 ECOG Performance Status 
ECOG performance status grades are presented in Section 13.1, Appendix 1 and will be 
captured as per SoE (Table 1).  


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8.3.3 Height and Weight 
Height and weight will be measured as per SoE (Table 1). 
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 blood pressure (systolic and diastolic), 
heart rate, respiratory rate, and body temperature and should be performed according to the 
institutional standards, see timepoints shown on Table 1. Vital signs should be measured before 
and after each loncastuximab tesirine infusion and each durvalumab infusion. 
8.3.5 Laboratory Tests 
Samples will be collected at the time points specified as per SoE (Table 1).  
Hematology: white blood cells (WBCs) 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/ 
phosphorus, calcium, magnesium, blood urea nitrogen or urea, carbon dioxide/bicarbonate, 
creatinine, creatine phosphokinase, total protein, albumin, glucose and lactate dehydrogenase.  
Coagulation: partial thromboplastin time and International Normalized Ratio. 
Urinalysis: pH, specific gravity, protein, WBC, red blood cell (RBCs), 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: TSH, (reflex free T3 or free T4). Hepatitis B, C, and HIV. 


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8.3.6 Pregnancy Test 
A highly sensitive β-HCG test in urine or blood β-HCG test must be performed in women of 
childbearing potential (WOCBP) for eligibility (see Section 5.1) and throughout the study as 
per SoE.  
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 2 consecutive pregnancy tests no more than 6 weeks. 
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 
timepoints throughout the study as per SoE (Table 1). Refer to Table 4 for the detailed schedule 
of ECGs. 
ECGs should be performed after the patient is resting for at least 5 minutes. 
Where applicable, at timepoints coinciding with blood sample collection including PK, ECGs 
should be taken prior to blood collection and before vital sign measurements.  
If a patient experiences Torsade de Pointes, additional concomitant PK samples 
(i.e., unscheduled) should be collected. 
Table 4 
Schedule for Triplicate ECG Collection  
Cycle 
Day 
ECG timepoint (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 timepoint is counted from start of Loncastuximab tesirine infusion.  
 


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Eligibility and clinical decisions may be made based on the local ECG assessment. 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, Pharmacodynamics, and Immunogenicity 
PK, ADA, and 
 samples will be collected as per SoE (Table 1). 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, 
pharmacodynamics, and/or 
testing.   
When multiple samples are required at the same timepoint, collection of safety samples should 
be first followed by PK, and 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 concentrations 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 5.  
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.  
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 5 
Sampling Schedule for Loncastuximab Tesirine PK and ADA  
Cycle 
Day 
PK timepoint (window) 
ADA timepoint (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 2h 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 
(preferably within 2 h prior to start of 
infusion) 
 
Pre-dose 
(preferably within 2 h prior to start of 
infusion) 
 
C5, C6, C7** 
D1 
Pre-dose 
(preferably within 2 h prior to start of 
infusion) 
 
Pre-dose 
(preferably within 2 h prior to start of 
infusion) 
 
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 timepoint is counted from start of loncastuximab tesirine infusion. 
**Only for patients who receive loncastuximab tesirine during Cycles 5 and 6. 
Blood samples for determination of durvalumab concentration in serum will be obtained 
according to the SoE, Table 1. The PK concentration of durvalumab prior to the C2D15 dose 
will also be assessed by a central laboratory designated by the Sponsor using a validated 
bioanalytical method. 
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 (MSD-ECL) platform.  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 5. 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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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 75 patients. Part 1 (dose escalation) will enroll 
approximately 15 patients and Part 2 (dose expansion) will enroll approximately 60 patients 
(20 patients per cohort for up to 3 expansion cohorts, one for DLBCL, one for MCL and one 
for FL). 
9.2 Analysis Populations 
• The Safety analysis set consists of all patients who receive study drug. 
• The DLT-evaluable analysis set consists of all patients in Part 1 who receive study drugs 
and excludes patients who discontinue from the study during the DLT period without 
experiencing a DLT. 
• The Efficacy analysis set will consist of all patients who receive at least 1 dose of study 
drug, have valid baseline disease assessment(s), and 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. 
• PK Population: All patients with at least 1 pre- (C1D1) and 1 post-dose valid assessment. 
• Pharmacodynamics Population: All patients with at least 1 valid pharmacodynamics/ 
 assessment.  
9.3 Interim Analysis for Futility 
No formal interim analysis is planned.    
9.4 Final Analysis 
All efficacy and safety endpoints will be analyzed and reported in the clinical study report 
(CSR). 
9.5 Demographics and Baseline Characteristics 
Demographics and baseline characteristics, such as cancer history and medical history, will be 
summarized for the Safety analysis set.  


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9.6 Exposure to Treatments 
Exposure to study drug and prior and concomitant medications will be summarized for the 
Safety analysis set. Dose interruptions, reductions, and relative dose intensity will also be 
summarized. 
9.7 Efficacy Analyses 
9.7.1 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, as determined by the Investigator. 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% confidence interval (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 non-evaluable for BOR if no assessment after this time period is 
available.   
9.7.2 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 duration of response and 95% CI will be presented. Further details will 
be outlined in the SAP. 
9.7.3 Complete Response Rate 
Complete response rate (CRR) will be defined as the proportion of patients with a BOR of CR, 
according to the 2014 Lugano classification, as determined by the Investigator. The percentage 
of CRR with its 95% CI will be presented. 
9.7.4 Relapse-free Survival 
RFS will be defined among CR patients as the time from the earliest date of first complete 
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 RFS and 95% CI will be presented. Further details will be outlined in the 
SAP. 


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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 
Median 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. 
9.8 Safety Analyses 
Safety analyses will be presented descriptively.   
9.8.1 Adverse Events 
The focus of AE summarization will be on TEAEs. A TEAE is defined as an AE that occurs 
or worsens in the period extending from the first dose of study drug to 30 days after the last 
dose of study drug or initiation of new anti-cancer therapy (whichever occurs earlier). 
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 [SOC]) is counted 
only once for that Preferred Term (or SOC) 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; serious AEs; 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. 


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9.8.3 Additional Safety Assessments 
The results of scheduled assessments of vital signs, physical examinations, ECOG performance 
status, and 12-lead ECGs will be summarized. All data will be reported according to the 
nominal visit date for which it was recorded (i.e., no visit windows will be applied). 
Unscheduled data will be included in “worst case” summaries, which will capture a worst case 
across all scheduled and unscheduled visits after the first dose of study drug. All data will be 
listed. Further details will be provided in the SAP. 
9.9 Pharmacokinetic Analyses 
The PK profile for loncastuximab tesirine in serum will include determination of maximum 
concentration (Cmax), time to Cmax (Tmax), and area under the concentration-time curve from 
time zero to the last quantifiable concentration (AUC0-last). 
 
PK parameters will be determined for all PK-evaluable patients using either a compartmental 
(population) 
or 
non-compartmental 
analysis 
method 
with 
Phoenix 
WinNonlin 
 or other appropriate software and may be reported 
separately. 
Demographic data for the PK population will be summarized. Potential correlations of 
PK parameters to baseline characteristics and safety observations will be assessed but may be 
reported separately. In addition, the influence of loncastuximab tesirine PBD-conjugated 
antibody and unconjugated warhead SG3199 concentrations, if appropriate on the QTc interval 
will be assessed but 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 new FDA Draft Guidance for Industry 
(April 2016): ‘Assay Development and Validation for Immunogenicity testing of 
Therapeutic Protein Products’. 
 
 


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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. 
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 case, 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 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 SUSARSs) 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, 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 
Adair JR, Howard PW, Hartley JA, et al. Antibody-drug conjugates - a perfect synergy. Expert 
Opin Biol Ther 2012;12(9):1191-1206. 
Al-Hamadani M, Habermann TM, Cerhan JR, et al. Non-Hodgkin lymphoma subtype 
distribution, 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. 
Campo E., Rule S. Mantle cell lymphoma: evolving management strategies. 
Blood 2015;125:48-55 
Cheah CY, Fowler NH. Novel agents for relapsed and refractory follicular lymphoma. 
Best Pract Res Clin Haematol 2018;31(1):41-48. 
Cheson BD, Fisher RI, Barrington SF, et al. Recommendations for initial evaluation, staging, 
and response assessment of Hodgkin and non-Hodgkin lymphoma: The Lugano classification. 
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. 
Diefenbach CS, Hong F, Cohen JB, et al. Preliminary safety and efficacy of the combination 
of brentuximab vedotin and ipilimumab in relapsed/refractory Hodgkin lymphoma: A Trial of 
the ECOG-ACRIN Cancer Research Group (E4412). Blood 2015; 126:585 
Diefenbach CS, Hong F, David KA, et al. A phase I study with an expansion cohort of the 
combination of ipilimumab and nivolumab and brentuximab vedotin in patients with 
relapsed/refractory Hodgkin lymphoma: a trial of the ECOG-ACRIN Cancer Research Group 
(E4412 Arms D and E). Blood 2016; 128:1106 
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. 
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. 
Gopal AK, Kahl BS, Flowers CR, Martin P, Ansell SM, Abella-Dominicis E, et al. Idelalisib 
is effective in patients with high-risk follicular lymphoma and early relapse after initial 
chemoimmunotherapy. Blood 2017;22:3037-3039. 
Hartley JA. The development of pyrrolobenzodiazepines as antitumour agents. Expert Opin 
Investig Drugs 2011;20(6):733-744. 


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Müller P, Kreuzaler M, Khan T, et al. Trastuzumab emtansine (T-DM1) renders HER2+ breast 
cancer highly susceptible to CTLA-4/PD-1 blockade. Science Translational Medicine 2015 
Nov 25;7(315):315ra188. 
Oken MM, Creech RH, Tormey DC, et al. Toxicity and response criteria of the 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-label, phase 1 study. Lancet Oncol 2017;18(1):42-51. 
Scheuermann RH, Racila E. CD19 antigen in leukemia and lymphoma diagnosis and 
immunotherapy. Leuk Lymphoma 1995;18(5-6):385-397. 
Siegel RL, Miller KD, Jemal A. Cancer statistics, 2017. CA Cancer J Clin 2017;67(1):7-30. 
Smith TJ, Khatcheressian J, Lyman GH, et al. 2006 update of recommendations for the use of 
white blood cell growth factors: an evidence-based clinical practice guideline. J Clin Oncol 
2006;24(19):3187-3205. 
Stewart, et al. Identification and Characterization of MEDI4736, an Antagonistic Anti–PD-L1 
Monoclonal Antibody. Cancer Immunology Research 2015; (3)(9)1052-1062  


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13 Appendices 
13.1 Appendix 1 Eastern Cooperative Oncology Group Performance 
Status 
Performance status will be assessed using the ECOG performance status grades as indicated 
below: 
Grade 
Definition 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature, e.g., light house work, office work 
2 
Ambulatory and capable of all self-care but unable to carry out any work activities; 
up and about more than 50% of waking hours 
3 
Capable of only limited self-care; confined to bed or chair more than 50% of 
waking hours 
4 
Completely disabled; cannot carry on any self-care; totally confined to bed or chair 
5 
Dead 
Oken et al., 1982 
 
 
 


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13.2 Appendix 2 Response Assessment of Hodgkin and Non-Hodgkin 
Lymphoma (Lugano Classification) 
Response / Site 
PET-CT-Based Response 
CT-Based Response 
Complete 
Complete metabolic response 
Complete radiologic response  
(all of the following) 
Lymph nodes and 
extralymphatic 
sites 
• Score 1, 2, or 3* with or without a 
residual mass on 5PS** 
Note: Uptake may be greater than 
normal mediastinum and/or liver in 
Waldeyer’s ring or extranodal sites 
with high physiologic uptake or with 
activation within spleen or marrow 
(e.g., with chemotherapy or myeloid 
colony-stimulating factors). In this 
circumstance, complete metabolic 
response may be inferred if uptake at 
sites of initial involvement is no 
greater than surrounding normal 
tissue even if the tissue has high 
physiologic uptake 
• Target nodes/nodal masses must 
regress to ≤1.5 cm in LD 
• No extralymphatic sites of disease 
Nonmeasured 
lesion 
• Not applicable 
• Absent 
Organ enlargement 
• Not applicable 
• Regress to normal 
New lesions 
• None 
• None 
Bone marrow 
• No evidence of FDG-avid disease 
in marrow 
• Normal by morphology; if 
indeterminate,
 
Partial 
Partial metabolic response 
Partial remission  
(all of the following) 


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Response / Site 
PET-CT-Based Response 
CT-Based Response 
Lymph nodes and 
extralymphatic 
sites 
• Score 4 or 5** with reduced uptake 
compared with baseline and 
residual mass(es) of any size. 
• At interim, these findings suggest 
responding disease. 
• At end of treatment, these findings 
indicate residual disease. 
• ≥50% decrease in SPD of up to 6 
target measurable nodes and 
extranodal sites 
• When a lesion is too small to 
measure on CT, assign 5 mm × 5 
mm as the default value 
• When no longer visible, 0 × 0 mm 
• For a node >5 mm × 5 mm, but 
smaller than normal, use actual 
measurement for calculation 
Nonmeasured 
lesion 
• Not applicable 
• Absent/normal, regressed, but no 
increase 
Organ enlargement 
• Not applicable 
• Spleen must have regressed by 
>50% in length beyond normal 
New lesions 
• None 
• None 
Bone marrow 
• Residual uptake higher than uptake 
in normal marrow but reduced 
compared with baseline (diffuse 
uptake compatible with reactive 
changes from chemotherapy 
allowed). If there are persistent 
focal changes in the marrow in the 
context of a nodal response, 
consideration should be given to 
further evaluation with MRI or 
biopsy or an interval scan 
• Not applicable 
No response or 
stable disease 
No metabolic response 
 
Stable disease 


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Response / Site 
PET-CT-Based Response 
CT-Based Response 
Target nodes/nodal 
masses, extranodal 
lesions 
• Score 4 or 5 with no significant 
change in FDG update from 
baseline at interim or end of 
treatment 
• <50% decrease from baseline in 
SPD of up to 6 dominant, 
measurable nodes and extranodal 
sites; no criteria for progressive 
disease are met 
Nonmeasured 
lesions 
• Not applicable 
• No increase consistent with 
progression 
Organ enlargement 
• Not applicable 
• No increase consistent with 
progression 
New lesions 
• None 
• None 
Bone marrow 
• No change from baseline 
• Not applicable 
Progressive 
disease 
Progressive metabolic disease 
Progressive disease  
(requires at least 1 of the following) 
Individual target 
nodes/nodal 
masses 
• Score 4 or 5 with an increase in 
intensity of uptake from baseline 
and/or 
• PPD progression 
Extranodal lesions 
• New FDG-avid foci consistent with 
lymphoma at interim or end of 
treatment assessment 
An individual node/lesion must be 
abnormal with: 
• LDi > 1.5 cm and 
• Increase by ≥50% from PPD nadir 
and  
• An increase in LDi or SDi from 
nadir 
0.5 cm for lesions ≤ 2 cm 
1.0 cm for lesions > 2 cm 
• In the setting of splenomegaly, the 
splenic length must increase by > 
50% of the extent of its prior 
increase beyond baseline (e.g., a 
15-cm spleen must increase to > 16 


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Response / Site 
PET-CT-Based Response 
CT-Based Response 
cm). If no prior splenomegaly, 
must increase by at least 2 cm from 
baseline 
• New or recurrent splenomegaly 
Nonmeasured 
lesions 
• None 
• New or clear progression of 
preexisting nonmeasured lesions 
New lesions 
• New FDG-avid foci consistent with 
lymphoma rather than another 
etiology (e.g., infection, 
inflammation). If uncertain 
regarding etiology of new lesions, 
biopsy or interval scan may be 
considered 
• Regrowth of previously resolved 
lesions 
• A new node > 1.5 cm in any axis 
• A new extranodal site > 1.0 cm in 
any axis; if < 1.0 cm in any axis, its 
presence must be unequivocal and 
must be attributable to lymphoma 
• Assessable disease of any size 
unequivocally attributable to 
lymphoma 
Bone marrow 
• New or recurrent FDG-avid foci 
• New or recurrent involvement 
Abbreviations: 
5PS, 
5-point 
scale; 
CT, 
computed 
tomography; 
FDG, 
fluorodeoxyglucose; 
; LDi, longest transverse diameter of a lesion; MRI, magnetic resonance imaging; 
PET, positron emission tomography; PPD, cross product of the LDi and perpendicular diameter; SDi, shortest 
axis perpendicular to the LDi; SPD, sum of the product of the perpendicular diameters for multiple lesions. 
 
* A score of 3 in many patients indicates a good prognosis with standard treatment, especially if at the time of an 
interim scan. However, in trials involving PET where de-escalation is investigated, it may be preferable to 
consider a score of 3 as inadequate response (to avoid undertreatment). Measured dominant lesions: Up to six of 
the largest dominant nodes, nodal masses, and extranodal lesions selected to be clearly measurable in two 
diameters. Nodes should preferably be from disparate regions of the body and should include, where applicable, 
mediastinal and retroperitoneal areas. Non-nodal lesions include those in solid organs (e.g., liver, spleen, kidneys, 
lungs), GI involvement, cutaneous lesions, or those noted on palpation. Nonmeasured lesions: Any disease not 
selected as measured, dominant disease and truly assessable disease should be considered not measured. 
These sites include any nodes, nodal masses, and extranodal sites not selected as dominant or measurable or that 
do not meet the requirements for measurability but are still considered abnormal, as well as truly assessable 
disease, which is any site of suspected disease that would be difficult to follow quantitatively with measurement, 
including pleural effusions, ascites, bone lesions, leptomeningeal disease, abdominal masses, and other lesions 
that cannot be confirmed and followed by imaging. In Waldeyer’s ring or in extranodal sites (e.g., GI tract, liver, 
bone marrow), FDG uptake may be greater than in the mediastinum with complete metabolic response, but should 
be no higher than surrounding normal physiologic uptake (e.g., with marrow activation as a result of 
chemotherapy or myeloid growth factors).  


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** PET 5PS: 1, no uptake above background; 2, uptake ≤ mediastinum; 3, uptake > mediastinum but ≤ liver; 
4, uptake moderately > liver; 5, uptake markedly higher than liver and/or new lesions; X, new areas of uptake 
unlikely to be related to lymphoma. 
Cheson et al., 2014 
 
 
 


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13.3 Appendix 3 Guidelines for Durvalumab Dose Modification for 
Specific Immune-mediated Reactions 
 
Adverse Events 
Severity 
grade of the 
Event (NCI 
CTCAE 
version 4.03) 
Dose 
modifications 
Toxicity management 
 
 
 
 
 
 
 
Pneumonitis/Interstitial 
Lung Disease (ILD) 
Any Grade 
General Guidance 
For Any Grade: 
− 
Monitor patients for signs and 
symptoms of pneumonitis or ILD 
(new onset or worsening 
shortness of breath or cough). 
Patients should be evaluated with 
imaging and pulmonary function 
tests, including other diagnostic 
procedures as described below. 
− 
Initial work-up may include 
clinical evaluation, monitoring of 
oxygenation via pulse oximetry 
(resting and exertion), laboratory 
work-up, and high- resolution CT 
scan. 
Grade 1 
(asymptomatic, 
clinical or 
diagnostic 
observations 
only; 
intervention not 
indicated) 
No dose modifications 
required. However, 
consider holding study 
drug/study regimen dose 
as clinically appropriate 
and during diagnostic 
work-up for other 
etiologies. 
For Grade 1 (radiographic changes 
only): 
− 
Monitor and closely follow up in 
2 to 4 days for clinical symptoms, 
pulse oximetry (resting and 
exertion), and laboratory work-up 
and then as clinically indicated. 
− 
Consider Pulmonary and 
Infectious disease consult. 
Grade 2 
(symptomatic; 
medical 
intervention 
indicated; 
limiting 
instrumental 
ADL) 
Hold study drug/study 
regimen dose until Grade 
2 resolution to Grade ≤1. 
• 
If toxicity worsens, 
then treat as Grade 3 
or Grade 4. 
• 
If toxicity improves 
to Grade ≤1, then the 
decision to reinitiate 
study drug/study 
regimen will be 
based upon treating 
For Grade 2 (mild to moderate new 
symptoms): 
− 
Monitor symptoms daily and 
consider hospitalization. 
− 
Promptly start systemic steroids 
(e.g., prednisone 1 to 
2 mg/kg/day PO or IV 
equivalent). 
− 
Reimage as clinically indicated. 
− 
If no improvement within 3 to 5 
days, additional workup should 
be considered and prompt 


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physician’s clinical 
judgment and after 
completion of 
steroid taper. 
treatment with IV 
methylprednisolone 2 to 
4 mg/kg/day started. 
− 
If still no improvement within 3 
to 5 days despite IV 
methylprednisolone at 2 to 
4 mg/kg/day, promptly start 
immunosuppressive therapy such 
as TNF inhibitors 
(e.g., infliximab at 5 mg/kg every 
2 weeks). Caution: It is important 
to rule out sepsis and refer to 
infliximab label for general 
guidance before using infliximab. 
− 
Once the patient is improving, 
gradually taper steroids over ≥28 
days and consider prophylactic 
antibiotics, antifungals, or anti-
PJP treatment (refer to current 
NCCN guidelines for treatment 
of cancer-related infections 
[Category 2B recommendation])a 
− 
Consider pulmonary and 
infectious disease consult. 
− 
Consider, as necessary, 
discussing with study physician. 
Grade 3 or 4 
(Grade 3: severe 
symptoms; 
limiting self-
care ADL; 
oxygen 
indicated) 
 
(Grade 4: life-
threatening 
respiratory 
compromise; 
urgent 
intervention 
indicated [e.g., 
tracheostomy or 
intubation]) 
Permanently discontinue 
study drug/study 
regimen. 
For Grade 3 or 4 (severe or new 
symptoms, new/worsening hypoxia, life-
threatening): 
− 
Promptly initiate empiric IV 
methylprednisolone 1 to 
4 mg/kg/day or equivalent. 
− 
Obtain Pulmonary and Infectious 
disease consult; consider, as 
necessary, discussing with study 
physician. 
− 
Hospitalize the patient. 
− 
Supportive care (e.g., oxygen). 
− 
If no improvement within 3 to 5 
days, additional workup should 
be considered and prompt 
treatment with additional 
immunosuppressive therapy such 
as TNF inhibitors 
(e.g., infliximab at 5 mg/kg every 
2 weeks’ dose) started. Caution: 
rule out sepsis and refer to 


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infliximab label for general 
guidance before using infliximab. 
− 
Once the patient is improving, 
gradually taper steroids over ≥28 
days and consider prophylactic 
antibiotics, antifungals, and, in 
particular, anti-PJP treatment 
(refer to current NCCN 
guidelines for treatment of 
cancer-related infections 
[Category 2B 
recommendation]).a 
Diarrhea/Colitis 
Any Grade 
General Guidance 
For Any Grade: 
− 
Monitor for symptoms that may 
be related to 
diarrhea/enterocolitis (abdominal 
pain, cramping, or changes in 
bowel habits such as increased 
frequency over baseline or blood 
in stool) or related to bowel 
perforation (such as sepsis, 
peritoneal signs, and ileus). 
− 
Patients should be thoroughly 
evaluated to rule out any 
alternative etiology (e.g., disease 
progression, other medications, 
or infections), including testing 
for clostridium difficile toxin, 
etc. 
− 
Steroids should be considered in 
the absence of clear alternative 
etiology, even for low-grade 
events, in order to prevent 
potential progression to higher 
grade event. 
− 
Use analgesics carefully; they 
can mask symptoms of 
perforation and peritonitis. 
Grade 1 
(Diarrhea: stool 
frequency of <4 
over baseline per 
day) 
(Colitis: 
asymptomatic; 
clinical or 
diagnostic 
No dose modifications. 
For Grade 1: 
− 
Monitor closely for worsening 
symptoms. 
− 
Consider symptomatic treatment, 
including hydration, electrolyte 
replacement, dietary changes 
(e.g., American Dietetic 
Association colitis diet), and 
loperamide. Use probiotics as per 


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observations 
only) 
treating physician’s clinical 
judgment. 
Grade 2 
(Diarrhea: stool 
frequency of 4 
to 6 over 
baseline per day) 
(Colitis: 
abdominal pain; 
mucus or blood 
in stool) 
Hold study drug/study 
regimen until resolution 
to Grade ≤1 
• 
If toxicity worsens, 
then treat as Grade 3 
or Grade 4. 
• 
If toxicity improves 
to Grade ≤1, then 
study drug/study 
regimen can be 
resumed after 
completion of 
steroid taper. 
For Grade 2: 
− 
Consider symptomatic treatment, 
including hydration, electrolyte 
replacement, dietary changes 
(e.g., American Dietetic 
Association colitis diet), and 
loperamide and/or budesonide. 
− 
Promptly start prednisone 1 to 2 
mg/kg/day PO or IV equivalent. 
− 
If event is not responsive within 
3 to 5 days or worsens despite 
prednisone at 1 to 2 mg/kg/day 
PO or IV equivalent, GI consult 
should be obtained for 
consideration of further workup, 
such as imaging and/or 
colonoscopy, to confirm colitis 
and rule out perforation, and 
prompt treatment with IV 
methylprednisolone 2 to 4 
mg/kg/day started. 
− 
If still no improvement within 3 
to 5 days despite 2 to 4 mg/kg IV 
methylprednisolone, promptly 
start immunosuppressives such as 
infliximab at 5 mg/kg once every 
2 weeksa. Caution: it is 
important to rule out bowel 
perforation and refer to 
infliximab label for general 
guidance before using infliximab. 
− 
Consider, as necessary, 
discussing with study physician if 
no resolution to Grade ≤1 in 3 to 
4 days. 
− 
Once the patient is improving, 
gradually taper steroids over ≥28 
days and consider prophylactic 
antibiotics, antifungals, and anti-
PJP treatment (refer to current 
NCCN guidelines for treatment 
of cancer-related infections 
[Category 2B 
recommendation]).a 


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Grade 3 or 4 
(Grade 3 
diarrhea: stool 
frequency of ≥7 
over baseline per 
day; 
Grade 4 
diarrhea: life 
threatening 
consequences) 
(Grade 3 colitis: 
severe 
abdominal pain, 
change in bowel 
habits, medical 
intervention 
indicated, 
peritoneal signs; 
Grade 4 colitis: 
life-threatening 
consequences, 
urgent 
intervention 
indicated) 
 
Grade 3 
Permanently discontinue 
study drug/study regimen 
for Grade 3 if toxicity 
does not improve to 
Grade ≤1 within 14 days; 
study drug/study regimen 
can be resumed after 
completion of steroid 
taper. 
 
Grade 4 
Permanently discontinue  
study drug/study 
regimen.  
For Grade 3 or 4: 
− 
Promptly initiate empiric IV 
methylprednisolone 2 to 
4 mg/kg/day or equivalent. 
− 
Monitor stool frequency and 
volume and maintain hydration. 
− 
Urgent GI consult and imaging 
and/or colonoscopy as 
appropriate. 
− 
If still no improvement within 3 
to 5 days of IV 
methylprednisolone 2 to 4 
mg/kg/day or equivalent, 
promptly start further 
immunosuppressives (e.g., 
infliximab at 5 mg/kg once every 
2 weeks). Caution: Ensure GI 
consult to rule out bowel 
perforation and refer to 
infliximab label for general 
guidance before using infliximab. 
− 
Once the patient is improving, 
gradually taper steroids over ≥28 
days and consider prophylactic 
antibiotics, antifungals, and anti-
PJP treatment (refer to current 
NCCN guidelines for treatment 
of cancer-related infections 
[Category 2B 
recommendation]).a 
Hepatitis  
(elevated LFTs) 
Infliximab should not be 
used for management of 
immune-related hepatitis. 
Any Grade 
General Guidance 
For Any Grade: 
− 
Monitor and evaluate liver 
function test: AST, ALT, ALP, 
and TB. 
− 
Evaluate for alternative etiologies 
(e.g., viral hepatitis, disease 
progression, concomitant 
medications). 
Grade 1 
(AST or ALT 
>ULN and 
≤3.0×ULN 
and/or TB 
>ULN and 
≤1.5×ULN) 
• 
No dose 
modifications. 
• 
If it worsens, then 
treat as Grade 2 
event. 
For Grade 1: 
− 
Continue LFT monitoring per 
protocol. 


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Grade 2 
(AST or  
ALT >3.0×ULN 
and ≤5.0×ULN 
and/or  
TB >1.5×ULN 
and ≤3.0×ULN) 
• 
Hold study 
drug/study regimen 
dose until Grade 2 
resolution to Grade 
≤1. 
• 
If toxicity worsens, 
then treat as Grade 3 
or Grade 4. 
• 
If toxicity improves 
to Grade ≤1 or 
baseline, resume 
study drug/study 
regimen after 
completion of steroid 
taper. 
For Grade 2: 
− 
Regular and frequent checking of 
LFTs (e.g., every 1 to 2 days) 
until elevations of these are 
improving or resolved. 
− 
If no resolution to Grade ≤1 in 1 
to 2 days, consider, as necessary, 
discussing with study physician. 
− 
If event is persistent (>3 to 5 
days) or worsens, promptly start 
prednisone 1 to 2 mg/kg/day PO 
or IV equivalent. 
− 
If still no improvement within 3 
to 5 days despite 1 to 
2 mg/kg/day of prednisone PO or 
IV equivalent, consider 
additional work up and start 
prompt treatment with IV 
methylprednisolone 2 to 
4 mg/kg/day. 
− 
If still no improvement within 3 
to 5 days despite 2 to 
4 mg/kg/day of IV 
methylprednisolone, promptly 
start immunosuppressives (i.e., 
mycophenolate mofetil).a Discuss 
with study physician if 
mycophenolate mofetil is not 
available. Infliximab should 
NOT be used. 
− 
Once the patient is improving, 
gradually taper steroids over ≥28 
days and consider prophylactic 
antibiotics, antifungals, and anti-
PJP treatment (refer to current 
NCCN guidelines for treatment 
of cancer-related infections 
[Category 2B 
recommendation]).a 
Grade 3 or 4 
(Grade 3: AST 
or  
ALT >5.0×ULN 
and ≤20.0×ULN 
and/or  
TB >3.0×ULN 
For Grade 3: 
For elevations in 
transaminases ≤8 × ULN, 
or elevations in bilirubin 
≤5 × ULN: 
• Hold study 
drug/study regimen 
dose until resolution 
For Grade 3 or 4: 
− 
Promptly initiate empiric IV 
methylprednisolone at 1 to 
4 mg/kg/day or equivalent. 
− 
If still no improvement within 3 
to 5 days despite 1 to 
4 mg/kg/day methylprednisolone 
IV or equivalent, promptly start 


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and 
≤10.0×ULN) 
 
(Grade 4: AST 
or  
ALT >20×ULN 
and/or  
TB >10×ULN) 
to Grade ≤1 or 
baseline 
• Resume study 
drug/study regimen 
if elevations 
downgrade to Grade 
≤1 or baseline within 
14 days and after 
completion of steroid 
taper. 
• Permanently 
discontinue study 
drug/study regimen 
if the elevations do 
not downgrade to 
Grade ≤1 or baseline 
within 14 days 
For elevations in 
transaminases >8 × ULN 
or elevations in bilirubin 
>5 × ULN, discontinue 
study drug/study 
regimen. 
Permanently discontinue 
study drug/study regimen 
for any case meeting 
Hy’s law criteria (AST 
and/or ALT >3 × ULN + 
bilirubin >2 × ULN 
without initial findings of 
cholestasis (i.e., elevated 
alkaline P04) and in the 
absence of any 
alternative cause.b 
 
For Grade 4: 
Permanently discontinue 
study drug/study 
regimen. 
treatment with 
immunosuppressive therapy (i.e., 
mycophenolate mofetil). Discuss 
with study physician if 
mycophenolate is not available. 
Infliximab should NOT be 
used. 
− 
Perform hepatology consult, 
abdominal workup, and imaging 
as appropriate. 
− 
Once the patient is improving, 
gradually taper steroids over ≥28 
days and consider prophylactic 
antibiotics, antifungals, and anti-
PJP treatment (refer to current 
NCCN guidelines for treatment 
of cancer-related infections 
[Category 2B 
recommendation]).a 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Nephritis or renal 
dysfunction 
(elevated serum 
creatinine) 
Any Grade 
General Guidance 
For Any Grade: 
− 
Consult with nephrologist. 
− 
Monitor for signs and symptoms 
that may be related to changes in 
renal function (e.g., routine 
urinalysis, elevated serum BUN 
and creatinine, decreased 
creatinine clearance, electrolyte 


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imbalance, decrease in urine 
output, or proteinuria). 
− 
Patients should be thoroughly 
evaluated to rule out any 
alternative etiology (e.g., disease 
progression or infections). 
− 
Steroids should be considered in 
the absence of clear alternative 
etiology even for low-grade 
events (Grade 2), in order to 
prevent potential progression to 
higher grade event. 
 
 
Grade 1 
(Serum 
creatinine > 1 to 
1.5 × baseline; > 
ULN to 1.5 × 
ULN) 
No dose modifications. 
For Grade 1: 
− 
Monitor serum creatinine weekly 
and any accompanying 
symptoms. 
• 
If creatinine returns to 
baseline, resume its 
regular monitoring per 
study protocol. 
• 
If creatinine worsens, 
depending on the 
severity, treat as Grade 
2, 3, or 4. 
− 
Consider symptomatic treatment, 
including hydration, electrolyte 
replacement, and diuretics. 
Grade 2 
(serum 
creatinine >1.5 
to 3.0 × 
baseline; >1.5 to 
3.0 × ULN) 
Hold study drug/study 
regimen until resolution 
to Grade ≤1 or baseline.  
• 
If toxicity worsens, 
then treat as Grade 3 
or 4. 
• 
If toxicity improves 
to Grade ≤1 or 
baseline, then 
resume study 
drug/study regimen 
after completion of 
steroid taper. 
For Grade 2: 
− 
Consider symptomatic treatment, 
including hydration, electrolyte 
replacement, and diuretics. 
− 
Carefully monitor serum 
creatinine every 2 to 3 days and 
as clinically warranted. 
− 
Consult nephrologist and 
consider renal biopsy if clinically 
indicated. 
− 
If event is persistent (>3 to 5 
days) or worsens, promptly start 
prednisone 1 to 2 mg/kg/day PO 
or IV equivalent. 
− 
If event is not responsive within 
3 to 5 days or worsens despite 


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prednisone at 1 to 2 mg/kg/day 
PO or IV equivalent, additional 
workup should be considered and 
prompt treatment with IV 
methylprednisolone at 2 to 
4 mg/kg/day started. 
− 
Once the patient is improving, 
gradually taper steroids over ≥28 
days and consider prophylactic 
antibiotics, antifungals, and anti-
PJP treatment (refer to current 
NCCN guidelines for treatment 
of cancer-related infections 
[Category 2B 
recommendation]).a 
− 
When event returns to baseline, 
resume study drug/study regimen 
and routine serum creatinine 
monitoring per study protocol. 
Grade 3 or 4 
(Grade 3: serum 
creatinine 
>3.0 × baseline; 
>3.0 to 
6.0 × ULN; 
 
Grade 4: serum 
creatinine >6.0 × 
ULN) 
Permanently discontinue 
study drug/study 
regimen. 
For Grade 3 or 4: 
− 
Carefully monitor serum 
creatinine on daily basis. 
− 
Consult nephrologist and 
consider renal biopsy if clinically 
indicated. 
− 
Promptly start prednisone 1 to 2 
mg/kg/day PO or IV equivalent. 
− 
If event is not responsive within 
3 to 5 days or worsens despite 
prednisone at 1 to 2 mg/kg/day 
PO or IV equivalent, additional 
workup should be considered and 
prompt treatment with IV 
methylprednisolone 2 to 
4 mg/kg/day started. 
− 
Once the patient is improving, 
gradually taper steroids over ≥28 
days and consider prophylactic 
antibiotics, antifungals, and anti-
PJP treatment (refer to current 
NCCN guidelines for treatment 
of cancer-related infections 
[Category 2B 
recommendation]).a 
 
 


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Rash 
(excluding bullous skin 
formations) 
Any Grade 
(refer to NCI 
CTCAE v 4.03 
for definition of 
severity/grade 
depending on 
type of skin 
rash) 
General Guidance 
For Any Grade: 
− 
Monitor for signs and symptoms 
of dermatitis (rash and pruritus). 
− 
IF THERE IS ANY BULLOUS 
FORMATION, THE STUDY 
PHYSICIAN SHOULD BE 
CONTACTED AND STUDY 
DRUG DISCONTINUED. 
Grade 1 
No dose modifications. 
For Grade 1: 
− 
Consider symptomatic treatment, 
including oral antipruritics (e.g., 
diphenhydramine or 
hydroxyzine) and topical therapy 
(e.g., urea cream). 
Grade 2 
For persistent (>1 to 2 
weeks) Grade 2 events, 
hold scheduled study 
drug/study regimen until 
resolution to Grade ≤1 or 
baseline. 
• 
If toxicity worsens, 
then treat as 
Grade 3. 
• 
If toxicity improves 
to Grade ≤1 or 
baseline, then 
resume drug/study 
regimen after 
completion of 
steroid taper. 
For Grade 2: 
− 
Obtain dermatology consult. 
− 
Consider symptomatic treatment, 
including oral antipruritics (e.g., 
diphenhydramine or 
hydroxyzine) and topical therapy 
(e.g., urea cream). 
− 
Consider moderate-strength 
topical steroid. 
− 
If no improvement of rash/skin 
lesions occurs within 3 to 5 days 
or is worsening despite 
symptomatic treatment and/or use 
of moderate strength topical 
steroid, consider, as necessary, 
discussing with study physician 
and promptly start systemic 
steroids such as prednisone 1 to 2 
mg/kg/day PO or IV equivalent. 
− 
Consider skin biopsy if the event 
is persistent for >1 to 2 weeks or 
recurs. 
 
 
Grade 3 or 4 
For Grade 3: 
Hold study drug/study 
regimen until resolution 
to Grade ≤1 or baseline. 
If temporarily holding the 
study drug/study regimen 
does not provide 
For Grade 3 or 4: 
− 
Consult dermatology. 
− 
Promptly initiate empiric IV 
methylprednisolone 1 to 
4 mg/kg/day or equivalent. 
− 
Consider hospitalization. 


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improvement of the 
Grade 3 skin rash to 
Grade ≤1 or baseline 
within 30 days, then 
permanently discontinue 
study drug/study 
regimen. 
 
For Grade 4: 
Permanently discontinue 
study drug/study 
regimen. 
 
− 
Monitor extent of rash [Rule of 
Nines]. 
− 
Consider skin biopsy (preferably 
more than 1) as clinically 
feasible. 
− 
Once the patient is improving, 
gradually taper steroids over ≥28 
days and consider prophylactic 
antibiotics, antifungals, and anti-
PJP treatment (refer to current 
NCCN guidelines for treatment 
of cancer-related infections 
[Category 2B 
recommendation]).a 
− 
Consider, as necessary, 
discussing with study physician. 
Endocrinopathy 
(e.g., hyperthyroidism, 
hypothyroidism, Type 1 
diabetes mellitus, 
hypophysitis, 
hypopituitarism, and 
adrenal insufficiency; 
exocrine event of 
amylase/lipase increased 
also included in this 
section) 
 
Any Grade 
(depending on 
the type of 
endocrinopathy, 
refer to NCI 
CTCAE v4.03 
for defining the 
CTC 
grade/severity) 
General Guidance 
For Any Grade: 
− 
Consider consulting an 
endocrinologist for endocrine 
events. 
− 
Consider, as necessary, 
discussing with study physician. 
− 
Monitor patients for signs and 
symptoms of endocrinopathies. 
Non-specific symptoms include 
headache, fatigue, behavior 
changes, changed mental status, 
vertigo, abdominal pain, unusual 
bowel habits, polydipsia, 
polyuria, hypotension, and 
weakness. 
− 
Patients should be thoroughly 
evaluated to rule out any 
alternative etiology (e.g., disease 
progression including brain 
metastases, or infections). 
− 
Depending on the suspected 
endocrinopathy, monitor and 
evaluate thyroid function tests: 
TSH, free T3 and free T4 and 
other relevant endocrine and 
related labs (e.g., blood glucose 
and ketone levels, HgA1c). 
− 
For modest asymptomatic 
elevations in serum amylase and 
lipase, corticosteroid treatment is 
not indicated as long as there are 


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no other signs or symptoms of 
pancreatic inflammation. 
− 
If a patient experiences an AE 
that is thought to be possibly of 
autoimmune nature (e.g., 
thyroiditis, pancreatitis, 
hypophysitis, or diabetes 
insipidus), the investigator should 
send a blood sample for 
appropriate autoimmune antibody 
testing. 
 
Grade 1 
No dose modifications. 
For Grade 1 (including those with 
asymptomatic TSH elevation): 
− 
Monitor patient with appropriate 
endocrine function tests. 
− 
For suspected 
hypophysitis/hypopituitarism, 
consider consultation of an 
endocrinologist to guide 
assessment of early-morning 
ACTH, cortisol, TSH and free 
T4; also consider gonadotropins, 
sex hormones, and prolactin 
levels, as well as cosyntropin 
stimulation test (though it may 
not be useful in diagnosing early 
secondary adrenal insufficiency). 
− 
If TSH < 0.5 × LLN, or TSH >2 
× ULN, or consistently out of 
range in 2 subsequent 
measurements, include free T4 at 
subsequent cycles as clinically 
indicated and consider 
consultation of an 
endocrinologist. 
Grade 2 
For Grade 2 
endocrinopathy other 
than hypothyroidism and 
Type 1 diabetes mellitus, 
hold study drug/study 
regimen dose until 
patient is clinically 
stable. 
• 
If toxicity worsens, 
then treat as Grade 
3 or Grade 4. 
For Grade 2 (including those with 
symptomatic endocrinopathy): 
− 
Consult endocrinologist to guide 
evaluation of endocrine function 
and, as indicated by suspected 
endocrinopathy and as clinically 
indicated, consider pituitary scan. 
− 
For all patients with abnormal 
endocrine work up, except those 
with isolated hypothyroidism or 
Type 1 DM, and as guided by an 


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Study drug/study regimen 
can be resumed once 
event stabilizes and after 
completion of steroid 
taper. 
Patients with 
endocrinopathies who 
may require prolonged or 
continued steroid 
replacement (e.g., adrenal 
insufficiency) can be 
retreated with study 
drug/study regimen on 
the following conditions: 
1. 
The event stabilizes 
and is controlled. 
2. 
The patient is 
clinically stable as 
per investigator or 
treating physician’s 
clinical judgement. 
3. 
Doses of 
prednisone are 
≤10 mg/day or 
equivalent. 
endocrinologist, consider 
short-term corticosteroids (e.g., 1 
to 2 mg/kg/day 
methylprednisolone or IV 
equivalent) and prompt initiation 
of treatment with relevant 
hormone replacement (e.g., 
hydrocortisone, sex hormones). 
− 
Isolated hypothyroidism may be 
treated with replacement therapy, 
without study drug/study regimen 
interruption, and without 
corticosteroids. 
− 
Isolated Type 1 diabetes mellitus 
(DM) may be treated with 
appropriate diabetic therapy, 
without study drug/study regimen 
interruption, and without 
corticosteroids. 
− 
Once patients on steroids are 
improving, gradually taper 
immunosuppressive steroids 
(as appropriate and with guidance 
of endocrinologist) over ≥28 days 
and consider prophylactic 
antibiotics, antifungals, and anti-
PJP treatment (refer to current 
NCCN guidelines for treatment 
of cancer-related infections 
[Category 2B 
recommendation]).a 
− 
For patients with normal 
endocrine workup (laboratory 
assessment or MRI scans), repeat 
laboratory assessments/MRI as 
clinically indicated. 
Grade 3 or 4 
For Grade 3 or 4 
endocrinopathy other 
than hypothyroidism and 
Type 1 diabetes mellitus, 
hold study drug/study 
regimen dose until 
endocrinopathy 
symptom(s) are 
controlled.  
Study drug/study regimen 
can be resumed once 
event stabilizes and after 
For Grade 3 or 4: 
− 
Consult endocrinologist to guide 
evaluation of endocrine function 
and, as indicated by suspected 
endocrinopathy and as clinically 
indicated, consider pituitary scan. 
Hospitalization recommended. 
− 
For all patients with abnormal 
endocrine work up, except those 
with isolated hypothyroidism or 
Type 1 DM, and as guided by an 
endocrinologist, promptly initiate 


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completion of steroid 
taper. 
Patients with 
endocrinopathies who 
may require prolonged or 
continued steroid 
replacement (e.g., adrenal 
insufficiency) can be 
retreated with study 
drug/study regimen on 
the following conditions: 
1. 
The event stabilizes 
and is controlled. 
2. 
The patient is 
clinically stable as 
per investigator or 
treating physician’s 
clinical judgement. 
3. 
Doses of prednisone 
are ≤10 mg/day or 
equivalent. 
empiric IV methylprednisolone 1 
to 2 mg/kg/day or equivalent, as 
well as relevant hormone 
replacement (e.g., 
hydrocortisone, sex hormones). 
− 
For adrenal crisis, severe 
dehydration, hypotension, or 
shock, immediately initiate IV 
corticosteroids with 
mineralocorticoid activity. 
− 
Isolated hypothyroidism may be 
treated with replacement therapy, 
without study drug/study regimen 
interruption, and without 
corticosteroids. 
− 
Isolated Type 1 diabetes mellitus 
may be treated with appropriate 
diabetic therapy, without study 
drug/study regimen interruption, 
and without corticosteroids. 
− 
Once patients on steroids are 
improving, gradually taper 
immunosuppressive steroids (as 
appropriate and with guidance of 
endocrinologist) over ≥28 days 
and consider prophylactic 
antibiotics, antifungals, and anti-
PJP treatment (refer to current 
NCCN guidelines for treatment 
of cancer-related infections 
[Category 2B 
recommendation]).a 
 
Neurotoxicity 
(to include but not be 
limited to limbic 
encephalitis and 
autonomic neuropathy, 
excluding Myasthenia 
Gravis and Guillain-
Barre) 
Any Grade 
(depending on 
the type of 
neurotoxicity, 
refer to NCI 
CTCAE v4.03 
for defining the 
CTC 
grade/severity) 
General Guidance 
For Any Grade: 
− 
Patients should be evaluated to 
rule out any alternative etiology 
(e.g., disease progression, 
infections, metabolic syndromes, 
or medications). 
− 
Monitor patient for general 
symptoms (headache, nausea, 
vertigo, behavior change, or 
weakness). 
− 
Consider appropriate diagnostic 
testing (e.g., electromyogram and 
nerve conduction investigations). 


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− 
Perform symptomatic treatment 
with neurological consult as 
appropriate. 
− 
 
Grade 1 
No dose modifications. 
For Grade 1: 
− 
See “Any Grade” 
recommendations above. 
Grade 2 
For acute motor 
neuropathies or 
neurotoxicity, hold study 
drug/study regimen dose 
until resolution to Grade 
≤1. 
For sensory 
neuropathy/neuropathic 
pain, consider holding 
study drug/study regimen 
dose until resolution to 
Grade ≤1. 
If toxicity worsens, 
then treat as Grade 3 
or 4. 
Study drug/study regimen 
can be resumed once 
event improves to Grade 
≤1 and after completion 
of steroid taper. 
For Grade 2: 
− 
Consider, as necessary, 
discussing with the study 
physician. 
− 
Obtain neurology consult. 
− 
Sensory neuropathy/neuropathic 
pain may be managed by 
appropriate medications (e.g., 
gabapentin or duloxetine). 
− 
Promptly start systemic steroids 
prednisone 1 to 2 mg/kg/day PO 
or IV equivalent. 
− 
If no improvement within 3 to 5 
days despite 1 to 2 mg/kg/day 
prednisone PO or IV equivalent, 
consider additional workup and 
promptly treat with additional 
immunosuppressive therapy (e.g., 
IV IG). 
Grade 3 or 4 
For Grade 3: 
Hold study drug/study 
regimen dose until 
resolution to Grade ≤1. 
Permanently discontinue 
study drug/study regimen 
if Grade 3 imAE does not 
resolve to Grade ≤1 
within 30 days. 
 
For Grade 4: 
Permanently discontinue 
study drug/study 
regimen. 
For Grade 3 or 4: 
− 
Consider, as necessary, 
discussing with study physician. 
− 
Obtain neurology consult. 
− 
Consider hospitalization. 
− 
Promptly initiate empiric IV 
methylprednisolone 1 to 
2 mg/kg/day or equivalent. 
− 
If no improvement within 3 to 5 
days despite IV corticosteroids, 
consider additional workup and 
promptly treat with additional 
immunosuppressants (e.g., IV 
IG). 
− 
Once stable, gradually taper 
steroids over ≥28 days. 
Any Grade 
General Guidance 
For Any Grade: 


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Peripheral neuromotor 
syndromes 
(such as Guillain-Barre 
and myasthenia gravis) 
− 
The prompt diagnosis of 
immune-mediated peripheral 
neuromotor syndromes is 
important, since certain patients 
may unpredictably experience 
acute decompensations that can 
result in substantial morbidity or 
in the worst case, death. Special 
care should be taken for certain 
sentinel symptoms that may 
predict a more severe outcome, 
such as prominent dysphagia, 
rapidly progressive weakness, 
and signs of respiratory 
insufficiency or autonomic 
instability. 
− 
Patients should be evaluated to 
rule out any alternative etiology 
(e.g., disease progression, 
infections, metabolic syndromes 
or medications). It should be 
noted that the diagnosis of 
immune-mediated peripheral 
neuromotor syndromes can be 
particularly challenging in 
patients with underlying cancer, 
due to the multiple potential 
confounding effects of cancer 
(and its treatments) throughout 
the neuraxis. Given the 
importance of prompt and 
accurate diagnosis, it is essential 
to have a low threshold to obtain 
a neurological consult. 
− 
Neurophysiologic diagnostic 
testing (e.g., electromyogram and 
nerve conduction investigations, 
and “repetitive stimulation” if 
myasthenia is suspected) are 
routinely indicated upon 
suspicion of such conditions and 
may be best facilitated by means 
of a neurology consultation. 
− 
It is important to consider that the 
use of steroids as the primary 
treatment of Guillain-Barre is not 
typically considered effective. 
Patients requiring treatment 
should be started with IV IG and 


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followed by plasmapheresis if not 
responsive to IV IG. 
 
Grade 1 
No dose modifications. 
For Grade 1: 
− 
Consider, as necessary, 
discussing with the study 
physician. 
− 
Care should be taken to monitor 
patients for sentinel symptoms of 
a potential decompensation as 
described above. 
− 
Obtain a neurology consult. 
Grade 2 
Hold study drug/study 
regimen dose until 
resolution to Grade ≤1. 
Permanently discontinue 
study drug/study regimen 
if it does not resolve to 
Grade ≤1 within 30 days 
or if there are signs of 
respiratory insufficiency 
or autonomic instability. 
For Grade 2: 
− 
Consider, as necessary, 
discussing with the study 
physician. 
− 
Care should be taken to monitor 
patients for sentinel symptoms of 
a potential decompensation as 
described above. 
− 
Obtain a neurology consult 
− 
Sensory neuropathy/neuropathic 
pain may be managed by 
appropriate medications (e.g., 
gabapentin or duloxetine). 
MYASTHENIA GRAVIS: 
o 
Steroids may be 
successfully used to 
treat myasthenia gravis. 
It is important to 
consider that steroid 
therapy (especially 
with high doses) may 
result in transient 
worsening of 
myasthenia and should 
typically be 
administered in a 
monitored setting under 
supervision of a 
consulting neurologist. 
o 
Patients unable to 
tolerate steroids may be 
candidates for 
treatment with 
plasmapheresis or IV 


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Loncastuximab Tesirine in Combination with Durvalumab 
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Date of Protocol Amendment 1: 14-January-2019 
 
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IG. Such decisions are 
best made in 
consultation with a 
neurologist, taking into 
account the unique 
needs of each patient. 
o 
If myasthenia gravis-
like neurotoxicity is 
present, consider 
starting AChE inhibitor 
therapy in addition to 
steroids. Such therapy, 
if successful, can also 
serve to reinforce the 
diagnosis. 
GUILLAIN-BARRE: 
o 
It is important to 
consider here that the 
use of steroids as the 
primary treatment of 
Guillain-Barre is not 
typically considered 
effective. 
o 
Patients requiring 
treatment should be 
started with IV IG and 
followed by 
plasmapheresis if not 
responsive to IV IG. 
 
Grade 3 or 4 
For Grade 3: 
Hold study drug/study 
regimen dose until 
resolution to Grade ≤1. 
Permanently discontinue 
study drug/study regimen 
if Grade 3 imAE does not 
resolve to Grade ≤1 
within 30 days or if there 
are signs of respiratory 
insufficiency or 
autonomic instability. 
 
For Grade 4: 
For Grade 3 or 4 (severe or life-
threatening events): 
− 
Consider, as necessary, 
discussing with study physician. 
− 
Recommend hospitalization. 
− 
Monitor symptoms and obtain 
neurological consult. 
MYASTHENIA GRAVIS: 
o 
Steroids may be 
successfully used to 
treat myasthenia gravis. 
They should typically 
be administered in a 
monitored setting under 
supervision of a 
consulting neurologist. 


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ADCT-402-104 Clinical Protocol 
Protocol Amendment 1 
 
Date of Protocol Amendment 1: 14-January-2019 
 
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Permanently discontinue 
study drug/study 
regimen. 
o 
Patients unable to 
tolerate steroids may be 
candidates for 
treatment with 
plasmapheresis or IV 
IG. 
o 
If myasthenia gravis-
like neurotoxicity 
present, consider 
starting AChE inhibitor 
therapy in addition to 
steroids. Such therapy, 
if successful, can also 
serve to reinforce the 
diagnosis. 
GUILLAIN-BARRE: 
o 
It is important to 
consider here that the 
use of steroids as the 
primary treatment of 
Guillain-Barre is not 
typically considered 
effective. 
o 
Patients requiring 
treatment should be 
started with IV IG and 
followed by 
plasmapheresis if not 
responsive to IV IG. 
 
Myocarditis 
Any Grade 
General Guidance 
Discontinue drug 
permanently if biopsy-
proven immune-mediated 
myocarditis. 
For Any Grade: 
− 
The prompt diagnosis of 
immune-mediated myocarditis is 
important, particularly in patients 
with baseline cardiopulmonary 
disease and reduced cardiac 
function.  
− 
Consider, as necessary, 
discussing with the study 
physician. 
− 
Monitor patients for signs and 
symptoms of myocarditis (new 
onset or worsening chest pain, 
arrhythmia, shortness of breath, 
peripheral edema). As some 
symptoms can overlap with lung 
toxicities, simultaneously 


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Loncastuximab Tesirine in Combination with Durvalumab 
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Date of Protocol Amendment 1: 14-January-2019 
 
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evaluate for and rule out 
pulmonary toxicity as well as 
other causes (e.g., pulmonary 
embolism, congestive heart 
failure, malignant pericardial 
effusion). A Cardiology 
consultation should be obtained 
early, with prompt assessment of 
whether and when to complete a 
cardiac biopsy, including any 
other diagnostic procedures. 
− 
Initial work-up should include 
clinical evaluation, BNP, cardiac 
enzymes, ECG, echocardiogram 
(ECHO), monitoring of 
oxygenation via pulse oximetry 
(resting and exertion), and 
additional laboratory work-up as 
indicated. Spiral CT or cardiac 
MRI can complement ECHO to 
assess wall motion abnormalities 
when needed. 
− 
Patients should be thoroughly 
evaluated to rule out any 
alternative etiology (e.g., disease 
progression, other medications, 
or infections). 
 
Grade 1 
(asymptomatic 
with laboratory 
(e.g., BNP) or 
cardiac imaging 
abnormalities) 
No dose modifications 
required unless clinical 
suspicion is high, in 
which case hold study 
drug/study regimen dose 
during diagnostic work-
up for other etiologies. If 
study drug/study regimen 
is held, resume after 
complete resolution to 
Grade 0. 
For Grade 1 (no definitive findings): 
- 
Monitor and closely follow up in 
2 to 4 days for clinical symptoms, 
BNP, cardiac enzymes, ECG, 
ECHO, pulse oximetry (resting 
and exertion), and laboratory 
work-up as clinically indicated. 
- 
Consider using steroids if clinical 
suspicion is high. 
 
Grade 2, 3 or 4 
(Grade 2: 
Symptoms with 
mild to moderate 
activity or 
exertion) 
 
 (Grade 3: 
Severe with 
symptoms at rest 
- If Grade 2 -- Hold 
study drug/study 
regimen dose until 
resolution to Grade 0. 
If toxicity rapidly 
improves to Grade 0, 
then the decision to 
reinitiate study 
drug/study regimen 
For Grade 2-4: 
− 
Monitor symptoms daily, 
hospitalize. 
− 
Promptly start IV 
methylprednisolone 2 to 
4 mg/kg/day or equivalent after 
Cardiology consultation has 
determined whether and when to 


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Loncastuximab Tesirine in Combination with Durvalumab 
ADCT-402-104 Clinical Protocol 
Protocol Amendment 1 
 
Date of Protocol Amendment 1: 14-January-2019 
 
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or with minimal 
activity or 
exertion; 
intervention 
indicated) 
 
(Grade 4: Life-
threatening 
consequences; 
urgent 
intervention 
indicated (e.g., 
continuous IV 
therapy or 
mechanical 
hemodynamic 
support)) 
 
will be based upon 
treating physician’s 
clinical judgment and 
after completion of 
steroid taper. If 
toxicity does not 
rapidly improve, 
permanently. 
discontinue study 
drug/study regimen. 
If Grade 3-4, 
permanently discontinue 
study drug/study 
regimen. 
complete diagnostic procedures 
including a cardiac biopsy. 
− 
Supportive care (e.g., oxygen). 
− 
If no improvement within 3 to 5 
days despite IV 
methylprednisolone at 2 to 
4 mg/kg/day, promptly start 
immunosuppressive therapy such 
as TNF inhibitors 
(e.g., infliximab at 5 mg/kg every 
2 weeks). Caution: It is important 
to rule out sepsis and refer to 
infliximab label for general 
guidance before using infliximab. 
− 
Once the patient is improving, 
gradually taper steroids over ≥28 
days and consider prophylactic 
antibiotics, antifungals, or anti-
PJP treatment (refer to current 
NCCN guidelines for treatment 
of cancer-related infections 
[Category 2B 
recommendation]).a 
Myositis/Polymyositis 
(“Poly/myositis”) 
Any Grade 
General Guidance 
For Any Grade: 
− 
Monitor patients for signs and 
symptoms of poly/myositis. 
Typically, muscle weakness/pain 
occurs in proximal muscles 
including upper arms, thighs, 
shoulders, hips, neck and back, 
but rarely affects the extremities 
including hands and fingers; also 
difficulty breathing and/or 
trouble swallowing can occur and 
progress rapidly. Increased 
general feelings of tiredness and 
fatigue may occur, and there can 
be new-onset falling, difficulty 
getting up from a fall, and trouble 
climbing stairs, standing up from 
a seated position, and/or reaching 
up. 
− 
If poly/myositis is suspected, a 
Neurology consultation should be 
obtained early, with prompt 
guidance on diagnostic 
procedures. Myocarditis may co-
occur with poly/myositis; refer to 


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Loncastuximab Tesirine in Combination with Durvalumab 
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Date of Protocol Amendment 1: 14-January-2019 
 
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guidance under Myocarditis. 
Given breathing complications, 
refer to guidance under 
Pneumonitis/ILD.  
Given possibility of an existent 
(but previously unknown) 
autoimmune disorder, consider 
Rheumatology consultation. 
− 
Consider, as necessary, 
discussing with the study 
physician. 
− 
Initial work-up should include 
clinical evaluation, creatine 
kinase, aldolase, LDH, 
BUN/creatinine, erythrocyte 
sedimentation rate or C-reactive 
protein level, urine myoglobin, 
and additional laboratory work-
up as indicated, including a 
number of possible 
rheumatological/antibody tests 
(i.e., consider whether a 
rheumatologist consultation is 
indicated and could guide need 
for rheumatoid factor, antinuclear 
antibody, anti-smooth muscle, 
antisynthetase [such as anti-Jo-1], 
and/or signal-recognition particle 
antibodies). Confirmatory testing 
may include electromyography, 
nerve conduction studies, MRI of 
the muscles, and/or a muscle 
biopsy. Consider Barium 
swallow for evaluation of 
dysphagia or dysphonia. 
Patients should be thoroughly evaluated to 
rule out any alternative etiology (e.g., 
disease progression, other medications, or 
infections). 
 
Grade 1 
(mild pain) 
- No dose 
modifications. 
For Grade 1: 
− 
Monitor and closely follow up in 
2 to 4 days for clinical symptoms 
and initiate evaluation as 
clinically indicated. 
− 
Consider Neurology consult. 


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Loncastuximab Tesirine in Combination with Durvalumab 
ADCT-402-104 Clinical Protocol 
Protocol Amendment 1 
 
Date of Protocol Amendment 1: 14-January-2019 
 
Page 96 
− 
Consider, as necessary, 
discussing with the study 
physician. 
 
Grade 2 
(moderate pain 
associated with 
weakness; pain 
limiting 
instrumental 
activities of 
daily living 
[ADLs]) 
Hold study drug/study 
regimen dose until 
resolution to Grade ≤1. 
- Permanently 
discontinue study 
drug/study regimen if 
it does not resolve to 
Grade ≤1 within 30 
days or if there are 
signs of respiratory 
insufficiency. 
For Grade 2: 
− 
Monitor symptoms daily and 
consider hospitalization. 
− 
Obtain Neurology consult, and 
initiate evaluation. 
− 
Consider, as necessary, 
discussing with the study 
physician. 
− 
If clinical course is rapidly 
progressive (particularly if 
difficulty breathing and/or 
trouble swallowing), promptly 
start IV methylprednisolone 2 to 
4 mg/kg/day systemic steroids 
along with receiving input from 
Neurology consultant.  
− 
If clinical course is not rapidly 
progressive, start systemic 
steroids (e.g., prednisone 1 to 
2 mg/kg/day PO or IV 
equivalent); if no improvement 
within 3 to 5 days, continue 
additional work up and start 
treatment with IV 
methylprednisolone 2 to 
4 mg/kg/day 
− 
If after start of IV 
methylprednisolone at 2 to 
4 mg/kg/day there is no 
improvement within 3 to 5 days, 
consider start of 
immunosuppressive therapy such 
as TNF inhibitors 
(e.g., infliximab at 5 mg/kg every 
2 weeks). Caution: It is important 
to rule out sepsis and refer to 
infliximab label for general 
guidance before using infliximab. 
− 
Once the patient is improving, 
gradually taper steroids over ≥28 
days and consider prophylactic 
antibiotics, antifungals, or anti-
PJP treatment (refer to current 
NCCN guidelines for treatment 
of cancer-related infections 


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Loncastuximab Tesirine in Combination with Durvalumab 
ADCT-402-104 Clinical Protocol 
Protocol Amendment 1 
 
Date of Protocol Amendment 1: 14-January-2019 
 
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[Category 2B 
recommendation]).a 
 
Grade 3 or 4 
(pain associated 
with severe 
weakness; 
limiting self-
care ADLs) 
For Grade 3: 
Hold study drug/study 
regimen dose until 
resolution to Grade ≤1. 
Permanently discontinue 
study drug/study regimen 
if Grade 3 imAE does not 
resolve to Grade ≤1 
within 30 days or if there 
are signs of respiratory 
insufficiency. 
 
For Grade 4: 
- Permanently 
discontinue study 
drug/study regimen. 
For Grade 3 or 4 (severe or life-
threatening events): 
− 
Monitor symptoms closely; 
recommend hospitalization. 
− 
Obtain Neurology consult, and 
complete full evaluation. 
− 
Consider, as necessary, 
discussing with the study 
physician. 
− 
Promptly start IV 
methylprednisolone 2 to 
4 mg/kg/day systemic steroids 
along with receiving input from 
Neurology consultant. 
− 
If after start of IV 
methylprednisolone at 2 to 
4 mg/kg/day there is no 
improvement within 3 to 5 days, 
consider start of 
immunosuppressive therapy such 
as TNF inhibitors 
(e.g., infliximab at 5 mg/kg every 
2 weeks). Caution: It is important 
to rule out sepsis and refer to 
infliximab label for general 
guidance before using infliximab. 
− 
Consider whether patient may 
require IV IG, plasmapheresis. 
− 
Once the patient is improving, 
gradually taper steroids over ≥28 
days and consider prophylactic 
antibiotics, antifungals, or anti-
PJP treatment (refer to current 
NCCN guidelines for treatment 
of cancer-related infections 
[Category 2B 
recommendation]).a 
aASCO Educational Book 2015 “Managing Immune Checkpoint Blocking Antibody Side Effects” by Michael Postow MD. 
bFDA Liver Guidance Document 2009 Guidance for Industry: Drug Induced Liver Injury – Premarketing Clinical 
Evaluation.  AChE Acetylcholine esterase; ADL Activities of daily living; AE Adverse event; ALP Alkaline 
phosphatase test; ALT Alanine aminotransferase; AST Aspartate aminotransferase; BUN Blood urea nitrogen; CT 
Computed tomography; CTCAE Common Terminology Criteria for Adverse Events; ILD Interstitial lung disease; 
imAE immune-mediated adverse event; IG Immunoglobulin; IV Intravenous; GI Gastrointestinal; LFT Liver function 
tests; LLN Lower limit of normal; MRI  Magnetic resonance imaging; NCI  National Cancer Institute; NCCN  
National Comprehensive Cancer Network; PJP Pneumocystis jirovecii pneumonia (formerly known as Pneumocystis 
carinii pneumonia); PO  By mouth; T3  Triiodothyronine; T4 Thyroxine; TB Total bilirubin; TNF Tumor necrosis 
factor; TSH Thyroid-stimulating hormone; ULN Upper limit of normal. 
 


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Protocol Amendment 1 
 
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Infusion-Related Reactions 
Severity Grade of 
the Event (NCI 
CTCAE 
version 4.03) 
Dose Modifications 
Toxicity Management 
Any Grade 
General Guidance 
For Any Grade: 
− 
Manage per institutional standard at the 
discretion of investigator. 
− 
Monitor patients for signs and symptoms of 
infusion-related reactions (e.g., fever and/or 
shaking chills, flushing and/or itching, 
alterations in heart rate and blood pressure, 
dyspnea or chest discomfort, or skin rashes) 
and anaphylaxis (e.g., generalized urticaria, 
angioedema, wheezing, hypotension, or 
tachycardia). 
Grade 1 or 2 
For Grade 1: 
The infusion rate of study drug/study 
regimen may be decreased by 50% or 
temporarily interrupted until resolution 
of the event. 
 
For Grade 2: 
The infusion rate of study drug/study 
regimen may be decreased 50% or 
temporarily interrupted until resolution 
of the event. 
Subsequent infusions may be given at 
50% of the initial infusion rate. 
For Grade 1 or 2: 
− 
Acetaminophen and/or antihistamines may 
be administered per institutional standard at 
the discretion of the investigator. 
− 
Consider premedication per institutional 
standard prior to subsequent doses. 
− 
Steroids should not be used for routine 
premedication of Grade ≤2 infusion 
reactions. 
Grade 3 or 4 
For Grade 3 or 4: 
Permanently discontinue study 
drug/study regimen. 
For Grade 3 or 4: 
− 
Manage severe infusion-related reactions 
per institutional standards (e.g., IM 
epinephrine, followed by IV 
diphenhydramine and ranitidine, and IV 
glucocorticoid). 
CTCAE Common Terminology Criteria for Adverse Events; IM intramuscular; IV intravenous; NCI National Cancer 
Institute. 
 
 


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Non–Immune-Mediated Reactions 
Severity Grade of the 
Event (NCI CTCAE 
version 4.03) 
Dose Modifications 
Toxicity Management 
Any Grade 
Note: Dose modifications are not required 
for AEs not deemed to be related to study 
treatment (i.e., events due to underlying 
disease) or for laboratory abnormalities not 
deemed to be clinically significant. 
Treat accordingly, as per institutional 
standard. 
Grade 1 
No dose modifications. 
Treat accordingly, as per institutional 
standard. 
Grade 2 
Hold study drug/study regimen until 
resolution to ≤Grade 1 or baseline. 
Treat accordingly, as per institutional 
standard. 
Grade 3 
Hold study drug/study regimen until 
resolution to ≤Grade 1 or baseline. 
For AEs that downgrade to ≤Grade 2 within 
7 days or resolve to ≤Grade 1 or baseline 
within 14 days, resume study drug/study 
regimen administration. Otherwise, 
discontinue study drug/study regimen. 
Treat accordingly, as per institutional 
standard. 
Grade 4 
 
Discontinue study drug/study regimen (Note: 
For Grade 4 labs, decision to discontinue 
should be based on accompanying clinical 
signs/symptoms, the Investigator’s clinical 
judgment, and consultation with the 
Sponsor.). 
Treat accordingly, as per institutional 
standard. 
Note: As applicable, for early phase studies, the following sentence may be added: “Any event greater than or equal to 
Grade 2, please discuss with Study Physician.” 
AE Adverse event; CTCAE Common Terminology Criteria for Adverse Events; NCI National Cancer Institute. 
 

SAP_001.pdf: 
Protocol Number:  ADCT-402-104 
 
Official Title:    A Phase 1 Open-Label Study to Evaluate the Safety and Antitumor Activity 
of Loncastuximab Tesirine and Durvalumab in Patients with Advanced 
Diffuse Large B-Cell Lymphoma, Mantle Cell Lymphoma, or Follicular 
Lymphoma 
 
NCT Number:  NCT03685344 
 
Document Date:  02-Nov-2020 


ADC Therapeutics 
ADCT-402 
ADCT-402-104 
SAP Final Version No. 1.0  
Page 1 of 18 
 
 
 
 
 
 
Statistical Analysis Plan 
 
 
 
 
A Phase 1 Open-Label Study to Evaluate the Safety and Antitumor Activity 
of Loncastuximab Tesirine and Durvalumab in Patients with Advanced 
Diffuse Large B-Cell Lymphoma, Mantle Cell Lymphoma, or Follicular 
Lymphoma 
 
PROTOCOL NO.:  ADCT-402-104  
 
 
 
SAP Version No./ Date: Final 1.0/ Nov. 02, 2020 
 
Statistician: 
 
 
 
 
 
  
Confidentiality Statement 
All financial and nonfinancial support for this study will be provided by ADC Therapeutics 
SA. 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 
expressed, written consent of ADC Therapeutics SA. The study will be conducted according 
to the International Conference on Harmonisation harmonised tripartite guideline E6(R1), 
Good Clinical Practice. 
 


ADC Therapeutics 
ADCT-402 
ADCT-402-104 
SAP Final Version No. 1.0  
Page 2 of 18 
 
 
 
SAP Approval – Sponsor Signatory 
 
 
 
Study Title 
A Phase 1 Open-Label Study to Evaluate the Safety and 
Antitumor Activity of Loncastuximab Tesirine and 
Durvalumab in Patients with Advanced Diffuse Large B-Cell 
Lymphoma, Mantle Cell Lymphoma, or Follicular 
Lymphoma 
 
Protocol Number 
ADCT-402-104 
Version Number 
Date: 
Version No. 1.0 
02 Nov 2020 
 
 
 
 
 
 
SAP accepted and approved by: 
 
 
Head of Early Clinical Development 
ADC Therapeutics 
 
Date 
 
 
 
 
Head of Biometrics  
ADC Therapeutics 
 
Date 
 
13 November 2020
Nov 13, 2020


ADC Therapeutics 
ADCT-402 
ADCT-402-104 
SAP Final Version No. 1.0  
Page 3 of 18 
 
Table of Contents 
Table of Contents ...................................................................................................................... 3 
1 Introduction ............................................................................................................................ 5 
2 Study Objectives .................................................................................................................... 6 
2.1 Primary Objectives ......................................................................................................6 
2.2 Secondary Objectives ..................................................................................................6 
 
3 Study Design .......................................................................................................................... 7 
3.1 Sample Size Consideration ..........................................................................................7 
3.2 Randomization .............................................................................................................7 
3.3 Modifications to the statistical section of the protocol ................................................7 
4 Statistical methods ................................................................................................................. 8 
4.1 Analysis Sets ................................................................................................................8 
4.1.1 Safety Analysis Set .........................................................................................8 
4.1.2 DLT-evaluable Analysis Set (Part 1) ...............................................................8 
4.1.3 Efficacy Analysis Set ......................................................................................8 
4.2 Patient Disposition .......................................................................................................8 
4.3 Protocol Deviations .....................................................................................................9 
4.4 Demographic and Baseline Characteristics .................................................................9 
4.5 Cancer History and Medications History ....................................................................9 
4.6 Prior or Concomitant Medications (other than anticancer therapies) ........................10 
4.7 Exposure to Treatment ............................................................................................... 11 
4.7.1 Extent of ADCT-402 Exposure ..................................................................... 11 
4.7.2 Extent of Durvalumab Exposure ................................................................... 11 
4.7.3 Prophylactic Medications for Hypersensitivity ............................................ 11 
4.7.4 Subsequent Anticancer Therapy or Procedure ..............................................12 
4.8 Safety Analyses .........................................................................................................12 
4.8.1 Dose-limiting Toxicities (Part 1)...................................................................12 
4.8.2 Adverse Events, Serious Adverse Events, and Deaths ..................................12 
4.8.2.1 Analyses of adverse events .......................................................... 12 
4.8.2.2 Deaths .......................................................................................... 13 
4.8.3 Laboratory Data ............................................................................................14 
4.8.4 Electrocardiogram .........................................................................................14 
4.8.5 Vital Signs .....................................................................................................15 


ADC Therapeutics 
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ADCT-402-104 
SAP Final Version No. 1.0  
Page 4 of 18 
 
4.8.6 ECOG Performance Status ...........................................................................15 
4.8.7 Physical Examinations and Body Weight .....................................................15 
4.9 Efficacy Analyses ......................................................................................................15 
5 Interim Analyses .................................................................................................................. 15 
6 Data handling conventions ................................................................................................... 16 
6.1 General conventions ..................................................................................................16 
6.1.1 Missing data ..................................................................................................16 
6.1.2 Unscheduled visits ........................................................................................17 
6.1.3 Duplicated visits............................................................................................17 
Appendix 1 Glossary of Abbreviations ................................................................................... 18 
 


ADC Therapeutics 
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1 Introduction 
This statistical analysis plan (SAP) describes the statistical methods to be used during the 
reporting and analyses of data collected under ADC Therapeutics Protocol ADCT-402-104. 
This SAP should be read in conjunction with the study protocol and case report form (CRF).  
 


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2  Study Objectives 
2.1 Primary Objectives  
 To characterize the safety and tolerability of loncastuximab tesirine in combination 
with durvalumab, and to identify the recommended dose and schedule for future 
studies. 
2.2 Secondary Objectives 
 To evaluate the antitumor effect of the combination of loncastuximab tesirine with 
durvalumab. 
 To characterize the pharmacokinetic (PK) profile of loncastuximab tesirine when given 
in combination with durvalumab. 
 To evaluate the immunogenicity of loncastuximab tesirine when given in combination 
with durvalumab. 
 
 
 
 
 
 
 
 
 


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3 Study Design 
Refer to the corresponding section in the protocol. 
3.1 Sample Size Consideration 
Refer to the corresponding section in the protocol. 
3.2 Randomization 
This study is not randomized. 
3.3 Modifications to the statistical section of the protocol  
The trial was terminated early. Therefore, only dose escalation (Part 1) data for enrolled 
patients will be analyzed and a selected or modified analysis from the statistical section of 
the protocol will be performed.  


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4 Statistical methods  
All analyses use 
 
or higher. Summary tables will be organized by each dose 
level; if some dose levels have few patients, then dose levels could be combined into dose 
ranges. All available data will be used in the analyses, and important data will be included in 
data listings, sorted by dose level, patient, and by visit within patient. Missing data will not be 
imputed, except via censoring in survival analyses and as otherwise specified. 
Unless otherwise noted, categorical data will be presented using counts and percentages, with 
the number of patients in the analysis set by treatment group as the denominator for percentages. 
Percentages will be rounded to one decimal place, except 100% will be displayed without any 
decimal places and percentages will not be displayed for zero counts. Continuous data, unless 
otherwise noted, 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.  
No hypothesis testing will be performed in this study. 
4.1 Analysis Sets  
4.1.1 Safety Analysis Set 
The safety analysis set consists of all patients who receive any study drug. 
4.1.2 DLT-evaluable Analysis Set (Part 1) 
The DLT-evaluable analysis set consists of all patients in Part 1 who received study drugs and 
excludes patients who discontinue from the study during the DLT evaluation period without 
experiencing a DLT. The patients with completed DLT information will be included even if 
they discontinue early before the end of DLT evaluation period. The DLT evaluation period 
will be the 21 days after the first durvalumab dose. 
4.1.3 Efficacy Analysis Set 
The efficacy analysis set consists of patients who receive at least one dose of study drug with 
a valid baseline and at least one valid post-baseline disease assessment or patients who have 
documented progression of disease or death at any time after the first dose of study. 
4.2 Patient Disposition 
For the enrolled patients, the number and percentage of enrolled and treated patients who were 
on treatment as well as reason for screen failure will be tabulated. For the safety analysis set, 
the number and percentage of patients who discontinued from study treatment and who 
discontinued the study for each reason will be tabulated for each dose level.  
Patient disposition data will be listed.  


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4.3 Protocol Deviations 
The number and percentage of patients with any important clinical study report (CSR) 
reportable protocol deviation will be summarized overall and by type of deviation. The pre-
defined important CSR reportable protocol deviations are listed below; in addition, any other 
protocol deviations deemed by ADCT medical to be important CSR reportable deviations 
will be included in the summary.  
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 received the wrong treatment or incorrect dose. For example, 
- Actual dose of study drug was more than 15% off the protocol defined planned dose 
level.  
- Lonca dosing interval is less than 18 days.  
Important protocol deviations will be listed. 
4.4 Demographic and Baseline Characteristics 
Demographic and baseline characteristics will be tabulated for the safety analysis set by dose 
level. Variables include the following: 
 Sex (female, male) 
 Race (white, black or African American, Asian, American Indian or Alaska native, 
native Hawaiian or other Pacific Islander, other) 
 Ethnicity (Hispanic or Latino, not Hispanic or Latino) 
 Age (years) 
 Age group (< 65, ≥ 65 - < 75, ≥ 75 years) 
 Height (cm) 
 Weight (kg) 
 Body mass index (kg/m2) 
 Eastern Cooperative Oncology Group (ECOG) performance status 
 Country (Spain, USA) 
Demographic and baseline characteristics data will be listed. 
4.5 Cancer History and Medications History 
Cancer history will be presented for the safety analysis set by dose level. Cancer history will 
include the following variables: 
 Duration since diagnosis 
 Non-Hodgkin lymphoma (NHL) subtype (diffuse large B-cell lymphoma, mantle cell 
lymphoma, follicular lymphoma)  
 Disease staging (Stage I, II, III, IV; Subtype E, X, S; Extra-nodal involvement at study 
entry and number of sites of involvement) 
 Cytogenetic analysis (cytogenetic abnormalities: t (2;3), t (2;18), t (3;14), t (3;22), t 
(8;14), t (8;22], t (11q), t (11;14), del (11q), +12, del (13q), t (14;18), del (17p), t 
(18;22), BCL2 rearrangement, BCL6 rearrangement, MYC rearrangement, other) 


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 Immunophenotypic analysis (IgVH status: mutated, unmutated, not applicable; Results 
of negative, positive or not done for expression BCL2, BCL6, CD3, CD5, CD10, 
CD19, CD20, CD21, CD23, CD43, CD45, CYCLIN D1, IRF4/MUM1, Ki-67, MYC, 
and ZAP70 ) 
Prior anticancer procedure or therapy will include the following variables: 
 Number of lines of therapy/ regimens per patient 
 Any prior surgeries for the current malignancy (yes, no) 
 Any prior radiotherapy for the current malignancy (yes, no) 
 Reason for stopping prior systemic treatment (progression, toxicity, Completed 
Treatment, other) 
 Best response while on regimen for prior systemic treatment (complete response [CR], 
partial response [PR], stable disease [SD], progressive disease [PD], not evaluable 
[NE]) 
 Any prior stem cell transplant (yes, no) 
 Type of transplant (allogenic, autologous, both, other) 
 Conditioning therapy (yes, no) 
Bone marrow evaluation (bone marrow aspirate and/or bone marrow biopsy) at screening may 
be listed if applicable. Medical and cancer history data will be listed. Results of cytogenetic 
analysis and immunophenotypic analysis will be listed. CD19 expression level data will be 
listed if available. Tumor tissue biopsy collection will not be listed, but will be contained in 
datasets. 
Prior anticancer surgery, radiotherapy, systemic treatment, and stem cell transplant data will 
be listed. 
4.6 Prior or Concomitant Medications (other than anticancer therapies) 
All medications taken from ICF signature date or from 14 days before dosing and continuing 
until 30 days after last dose of study drug are to be reported in the CRF pages. 
All medications will be coded using the World Health Organization-Drug Dictionary (WHO-
DD) and presented by dose level for the safety analysis set. 
 Prior medications are those the patient used prior to first investigational product (IP) 
intake. Prior medications can be discontinued before first dosing or can be ongoing 
during the treatment phase.   
 Concomitant medications are any treatments received by the patient concomitantly to 
any IP(s), from first dose (or start of the observation period) to the last dose + 30 days. 
A given medication can be classified both as a prior medication and as a concomitant 
medication. Concomitant medications do not include medications started 30 days after 
the last dose.  
Any technical details related to computation, dates, and imputation for missing dates are 
described in Section 6.  
Prior medications will be listed together with concomitant medications. Premedication for 
dosing will be listed separately. 


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4.7 Exposure to Treatment 
4.7.1 Extent of ADCT-402 Exposure 
ADCT-402 exposure will be summarized for the safety analysis set by dose level. The 
following items will be tabulated. 
 Duration of treatment (in days) = last dose date – first dose date +1 
 Total number of cycles dose administered 
 Total dose administered (in µg and µg/kg)  
 Average dose per cycle (in µg and µg/kg)  
When actual weight adjusted dose is needed, the last available weight before each infusion 
will be used. Patients with a BMI ≥35 kg/m2 will have their dose calculated based on an 
adjusted body weight as follows: 
Adjusted body weight in kg = 35 kg/m2 * (height in meters)2. 
Dose administered at each infusion (µg) is calculated by concentrated IP volume (in mL)* 5 
mg/mL *1000 or serially diluted IP volume (in mL)/50* 5 mg/mL *1000; for partial infusion, 
multiply by (1- volume of dosing solution not administered [in mL]/ 50 mL). 
4.7.2 Extent of Durvalumab Exposure 
Durvalumab exposure will be summarized for the safety analysis set by dose level. The 
following items will be tabulated. 
 Duration of treatment (in days) = last dose date – first dose date +1 
 Total number of cycles dose administered 
 Total dose administered (in mg)  
 Average dose per cycle (in mg)  
For partial infusion, dose administered at each infusion (mg) is calculated as 1500 mg*(1- 
volume of dosing solution not administered [in mL]/ total volume of dosing solution 
prepared [in mL]). 
Dose delays and dose reductions could also be analyzed if relevant. A cycle is delayed if it 
starts more than 3 days post-scheduled date. Durvalumab will be given at full dose when 
resumed after being held for toxicity, i.e., there will be no dose reduction. 
Exposure data and infusion details will be listed together. 
4.7.3 Prophylactic Medications for Hypersensitivity  
Prophylactic medications for hypersensitivity will be listed only. 


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4.7.4 Subsequent Anticancer Therapy or Procedure 
Patients’ subsequent anticancer therapies or procedures including systemic therapy, radiation, 
transplant, or other, along with the start date of new anticancer therapy or procedure will be 
listed only. 
4.8 Safety Analyses 
The summary of safety results will be presented by treatment group.  
General common rules 
All safety analyses will be performed on the safety analysis set, unless otherwise specified, 
using the following common rules: 
 The baseline value is defined as the last non-missing value or measurement taken up to 
the first dose in the study. 
 The analyses of the safety variables will be essentially descriptive and no systematic 
testing is planned. 
 The toxicity grade according to the Common Terminology Criteria for Adverse Events 
(CTCAE) version 4.0 will be taken into account in the summary. For patients with 
multiple occurrences of the same event, the maximum grade is used. If a patient has 
both missing and non-missing severity grades for treatment-emergent adverse events 
(TEAEs) within the same preferred term (PT), the patient will be counted under the 
non-missing severity grade. 
4.8.1 Dose-limiting Toxicities (Part 1) 
DLT data will be listed for Part 1 of the study. 
4.8.2 Adverse Events, Serious Adverse Events, and Deaths 
4.8.2.1 Analyses of adverse events 
The primary focus of adverse event reporting will be on TEAEs. An adverse event (AE) will 
be considered to be a TEAE if it begins or worsens on or after first dose date and until 30 days 
after the last dose date, or start of a new anticancer therapy/procedure, whichever comes earlier. 
An AE occurring before the first dose or more than 30 days after last dose date or after the start 
of a new anticancer therapy/procedure will not be included in TEAE displays, but will be listed 
as non-TEAEs. 
If an AE date/time of onset (occurrence, worsening, or becoming serious) is incomplete, an 
imputation algorithm will be used to classify the AE as pre-treatment, TEAE, or post-treatment. 
The algorithm for imputing date/time of onset will be conservative and will classify an AE as 
a treatment-emergent unless there is definitive information to determine it is a non-TEAE (pre- 
or post-treatment).  
Details on classification of AEs with missing or partial onset dates are provided in Section 6. 


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Analysis of all TEAE(s):  
The following TEAE summaries will be generated for the safety analysis set in each dose level. 
 Overview of TEAEs, summarizing number of TEAE and number (%) of patients with 
any 
- 
TEAE 
- 
Related TEAE (including possibly related, probably related, or related) 
- 
Any TEAE ≥Grade 3  
- 
Serious TEAE  
- 
TEAE leading to death 
- 
TEAE leading to permanent treatment discontinuation 
- 
TEAE leading to ADCT-402 delay or reduction or interruption 
- 
TEAE with at least one infusion related reaction 
For related TEAE and TEAE leading to dose modification (treatment 
discontinuation, dose delay/reduction/interruption), summary will be broken up for 
each study drug respectively. 
 All TEAEs by PT and all TEAEs with CTCAE Grade ≥ 3 by PT, showing number (%) 
of patients with at least one TEAE, sorted by decreasing incidence of PTs 
 All TEAEs by primary System Organ Class (SOC) and PT, showing number (%) of 
patients with at least one TEAE, sorted by SOC in alphabetic order and decreasing 
incidence of PTs within SOC. This sorting order will be applied to all other tables, 
unless otherwise specified. 
 All TEAEs by primary SOC, PT and Maximal CTCAE grade, showing number (%) of 
patients with at least one TEAE, sorted by SOC and PT in alphabetic order. This sorting 
order will be applied to all other tables, unless otherwise specified. 
 All TEAEs with CTCAE Grade ≥ 3 by primary SOC, PT and Maximal CTCAE grade 
 All related TEAEs by primary SOC, PT and Maximal CTCAE grade (including 
possibly related, probably related, or related) 
 All Serious TEAEs by primary SOC, PT and Maximal CTCAE grade 
All TEAEs, all serious adverse events (SAEs), all TEAEs leading to treatment discontinuation, 
all TEAEs leading to dose reduction, all TEAEs leading to dose delay, all TEAEs leading to 
infusion interruption, all TEAEs considered infusion related reactions, all TEAEs with fatal 
outcome and non-TEAEs will be listed. 
4.8.2.2 Deaths 
The following death summaries will be generated on the safety analysis set. 
 Number (%) of patients who died during the study and reasons for death 


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 Number (%) of patients who died within 30 days after last dose of study drug except 
deaths occurred after taking any subsequent anticancer therapy/procedure and reasons 
for death 
All deaths will be listed. 
4.8.3 Laboratory Data 
Laboratory data of hematology, chemistry, and coagulation will be reported in SI units. 
Descriptive statistics (mean, standard deviation, median, and range) will be calculated for the 
raw data and for their changes from baseline at each scheduled assessment. 
All results will be summarized using shift from baseline. Shifts for clinical laboratory results 
that can be graded according to CTCAE version 4.0 will be summarized by CTCAE grade. 
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 treatment. 
Summary analyses will include data up to the start of subsequent anticancer therapy/procedure. 
All laboratory data, including urinalysis, will be listed. Pregnancy test results will not be listed, 
but will be included in datasets. 
4.8.4 Electrocardiogram 
Electrocardiogram (ECG) parameters (e.g., corrected QT interval [QTc] in ms) will not be 
converted or derived, but will be reported as provided by investigational sites. 
Descriptive statistics (mean, standard deviation, median, and range) will be calculated for the 
raw data and for their changes from baseline at each scheduled assessment. 
The following abnormal QTc (including QTcF, QTcB and QTc with unspecified method) will 
be reported: 
 At any post-baseline with absolute value 
>450 - <=480 ms 
>480 - <=500 ms 
> 500 ms 
Change from Baseline 
 >30 – <=60 ms 
 >60 ms 
For patients with unspecified QTc method at either baseline or post-baseline, consistent 
correction method is assumed within a patient when calculating the change from baseline.  
Summary analyses will include data up to the start of subsequent anticancer therapy/procedure. 
All ECG data will be listed, both for quantitative data and for overall impression. 


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4.8.5 Vital Signs 
Descriptive statistics (mean, standard deviation, median, and range) for vital signs data, 
including systolic and diastolic blood pressure, heart rate, respiration rate, and body 
temperature will be calculated for the raw data and for their changes from baseline at each 
scheduled assessment. 
Summary analyses will include data up to the start of subsequent anticancer therapy/procedure. 
All vital signs data will be listed together with body weight and ECOG performance score. 
4.8.6 ECOG Performance Status 
ECOG results will be summarized using shift from baseline. ECOG performance score data 
will be listed together with vital signs and body weight. 
4.8.7 Physical Examinations and Body Weight 
Physical examination will be performed according to protocol. Clinically significant findings 
from the physical examinations will be recorded as medical history (prior to first administration 
of study drug) or AEs (subsequent to first administration of study drug). 
Body weight will be listed together with vital signs and ECOG performance score. 
4.9 Efficacy Analyses 
Due to the early termination of the trial, efficacy data will be listed only. Lesion assessment 
data (target lesions, non-target lesions, and new lesions) and overall disease assessment will 
be listed. 
5 Interim Analyses  
NA. 


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6 Data handling conventions 
6.1 General conventions 
6.1.1 Missing data 
Handling of missing/partial dates   
In general, imputation of missing dates will be made for AE onset date, AE resolution date, 
date of death, medication start/end dates, start and end dates of prior and subsequent therapies, 
and date of initial diagnosis for reporting. No imputation should be done at the data level. 
 If dates are completely missing, no imputation will be made.  
 For any partial date with missing year, no imputation will be made. 
  For missing initial diagnosis date and subsequent therapies, if only day is missing, then 
the 15th of the month will be used; if only year is present, then June 30th will be used. 
If such imputed date for initial diagnosis is on or after date of first dose, then date of 
first dose - 1 will be used. If such imputed date for subsequent therapies is before date 
of last dose, then date of last dose +1 will be used.  
 If the imputed date is for an AE start date and is in the same year and month as but 
before the first dose date, then the first dose date will be used, or if the imputed AE 
start date is after the AE end date, then the AE end date will be used. If the imputed 
date is for an AE start date and is in the same year and month as but after the last dose 
date + 30 days, then the last dose date + 30 days will be used. 
 If a medication date or time is missing or partially missing, so it cannot be determined 
whether it was taken prior or concomitantly, it will be considered as a prior and 
concomitant medication. 
 If the imputed date is for a date of death and is before the last date that the patient is 
known to be alive, the latter date will be used. 
Handling of missing relationship to investigational product of TEAEs 
If the assessment of the relationship to investigational product is missing, then the relationship 
to investigational product has to be assumed and the TEAE considered as such in the frequency 
tables of possibly related TEAEs, but no imputation should be done at the data level. 
Handling of missing severity/grades of AEs 
If the severity/grade is missing for one of the treatment emergent occurrences of an AE, the 
maximal severity of the remaining occurrences will be considered. If the severity is missing 
for all the occurrences a “missing” category will be added in summary table. 
No other imputation of values for missing data will be performed. 


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6.1.2 Unscheduled visits 
Unscheduled visit measurements of laboratory data, vital signs, and ECG will be used for 
computation of baseline and worst values and/or grades. Re-windowing for unscheduled visits 
will not be performed  
6.1.3 Duplicated visits 
Depending on the statistical analysis method, single values may be required for each analysis 
window. For example, change from baseline by visit usually requires a single value per visit. 
Unless otherwise noted throughout the rest of this document, when a single value is needed, 
the following rule(s) will be used: 
 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. 
 
 


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Appendix 1 Glossary of Abbreviations 
Glossary of Abbreviations: 
AE 
Adverse event 
CI 
Confidence interval 
CR 
Complete response 
CRF 
Case report form 
CSR 
Clinical study report 
CTCAE 
Common Terminology Criteria for Adverse Events 
DLT 
Dose-limiting toxicity 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
EOS 
End of study 
EOT 
End of treatment 
IP 
Investigational product 
MedDRA 
Medical Dictionary for Regulatory Activities 
NE 
Not evaluable 
NHL 
Non-Hodgkin lymphoma 
PD 
Pharmacodynamics, progressive disease 
PK 
Pharmacokinetic 
PR 
Partial response 
PT 
Preferred term 
QTc 
Corrected QT interval (ms) 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SD 
Stable disease 
SOC 
System organ class 
std 
Standard deviation 
TEAE 
Treatment-emergent adverse event 
TFLs 
Tables, figures, and listings 
WHO-DD 
World Health Organization-Drug Dictionary