Conditions: Relapsed Follicular Lymphoma Refractory Follicular Lymphoma
Keywords: Relapsed Follicular Lymphoma Refractory Follicular Lymphoma Loncastuximab Tesirine Follicular Lymphoma Lymphoma
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 6
Healthy volunteers: no

Brief summary:
This study aims to evaluate the efficacy of single agent loncastuximab tesirine compared to idelalisib in participants with relapsed or refractory follicular lymphoma.

Detailed description:

Arms:
arm 1: Participants will be administered loncastuximab tesirine as an intravenous (IV) infusion on Day 1 of each cycle, where 1 cycle is 3 weeks. Loncastuximab tesirine will be administered at a dose of 150 μg/kg for 2 cycles, then at a dose of 75 μg/kg for subsequent cycles. arm 2: Participants will be administered 150 mg idelalisib, orally, twice a day throughout each cycle, where 1 cycle is 4 weeks.

Interventions: intervention 1: Loncastuximab Tesirine intervention 2: Idelalisib
Intervention descriptions: intervention 1: IV infusion intervention 2: Oral tablet

Protocol document:
Prot_SAP_000.pdf: 
 
 
 
 
Title: A Phase 2 Randomized Study of Loncastuximab Tesirine 
Versus Idelalisib in Patients with Relapsed or Refractory Follicular 
Lymphoma (LOTIS 6) 
 
 
 
 
Protocol Number: ADCT-402-202 
 
 
 
 
NCT Number: NCT04699461 
 
 
 
 
Protocol Version & Date: Version 3.0 
7th April 2021 






ADC Therapeutics 
Loncastuximab Tesirine (ADCT-402) 
ADCT-402-202 (LOTIS 6) 
Protocol Amendment 3.0 
Confidential 
Page 3 of 99 
Declaration of Investigator 
 
I have read and understood all sections of the protocol entitled: “A Phase 2 Randomized 
Study of Loncastuximab Tesirine Versus Idelalisib in Patients with Relapsed or Refractory 
Follicular Lymphoma (LOTIS 6)” and the accompanying Investigator’s Brochure (IB). 
I agree to supervise all aspects of the protocol and to conduct the clinical investigation in 
accordance with Protocol Amendment 3.0, dated 07 Apr 2021, the current version of 
International Council for Harmonisation (ICH) harmonised tripartite guideline E6: 
Good Clinical Practice, and all applicable governmental regulations. I will not make changes 
to the protocol before consulting with ADC Therapeutics or implement protocol changes 
without independent ethics committee approval except to eliminate an immediate risk to 
patients. I agree to administer the study treatment only to patients under my personal 
supervision or the supervision of a sub-Investigator. 
I will not supply the study treatment 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 
 
 
 
 
 
ADCT Document Number: CLIN-0185


ADC Therapeutics 
Loncastuximab Tesirine (ADCT-402) 
ADCT-402-202 (LOTIS 6) 
Protocol Amendment 3.0 
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Page 4 of 99 
Summary of Changes for Protocol Amendment 3.0 
The primary reason for Protocol Amendment 3 is to align the frequency of laboratory 
evaluations for patients treated with idelalisib with the idelalisib Summary of Product 
Characteristics (SmPC); to exclude patients with history of hypersensitivity to any of the 
excipients of study drugs; to align contraception guidance for women of childbearing potential 
(WOCBP) receiving idelalisib treatment with the idelalisib SmPC; and to extend SAE 
reporting duration to at least 5 half-lives after the last loncastuximab tesirine dose based on 
regulatory authority request.  
The summary of changes and the rationale in Protocol Amendment 3.0 is as follows: 

Changed treatment cycle length for the idelalisib arm from 3 weeks to 4 weeks and
added hematology tests every 2 weeks (Q2W) for the initial 6 months (cycles 1 to 7)
and ALT/AST/total bilirubin tests Q2W for the initial 3 months (cycles 1 to 4) of
idelalisib treatment.
o
Section 4.1 Overview & Section 4.2.3 Treatment Period: Amended the
idelalisib treatment cycle length from 3 weeks to 4 weeks.
o
Schedule of Events: Split Schedule of Events (SoE) table (Table 1) to Table 1
Schedule of Events for Loncastuximab Tesirine Arm and Table 2 Schedule of
Events for Idelalisib Arm for a better clarity.
o
Added hematology tests on day 15 for cycles 1 to 7 and AST/ALT /total
bilirubin tests on day 15 for cycles 1 to 4 for patients in idelalisib arm in Table 2.
o
PRO-CTCAE questionnaire for patients in the idelalisib arm ends in cycle 7 to
correspond to 6-month treatment duration compared to loncastuximab tesirine.
Updated the schedule for PRO-CTCAE questionnaire in SoE (Table 2).
o
Section 7 Study Assessments and Procedures was revised to reference
Table 1 and Table 2 for the study events, where applicable.

Section 5.2 Exclusion Criteria: Added an exclusion criterion: History of
hypersensitivity to any of the excipients of loncastuximab tesirine or idelalisib.

Section 6.8.4 Contraceptive Guidance: Added “If WOCBP use hormonal
contraceptives such as birth control pills, a second barrier method of contraception
(e.g., condoms) must be used during idelalisib treatment until 1 month after last dose
of idelalisib.”

Section 8.2 Eliciting and Reporting Adverse Events/Serious Adverse Events: Amended
to extend collection of SAEs to at least 76 days after the last dose of loncastuximab
tesirine or until initiation of new anticancer treatment, whichever is earlier, to ensure
appropriate surveillance of any late onset events while eliminating the confounding
influence of other anti-cancer therapies based on updated conjugated loncastuximab
tesirine Ab half-life (15.2 days). As idelalisib is a comparator, SAE follow-up duration
for idelalisib was also updated to align with loncastuximab tesirine. Table 1 and Table 2
were updated to reflect the change.
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ADC Therapeutics 
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ADCT-402-202 (LOTIS 6) 
Protocol Amendment 3.0 
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In addition, non-substantial clarifications/corrections for inconsistencies, as well as 
administrative and editorial changes were included; revisions to the protocol text have also 
been applied to the synopsis section. 
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ADC Therapeutics 
Loncastuximab Tesirine (ADCT-402) 
ADCT-402-202 (LOTIS 6) 
Protocol Amendment 3.0 
Confidential 
Page 6 of 99 
List of Prior Protocol Versions  
Document 
Version Date 
Rationale for Changes  
Protocol Amendment 2.0 19 Feb 2021 
The primary reason for Protocol Amendment 2 was to 
extend the contraception duration post loncastuximab 
tesirine for female participants with childbearing 
potential from 6 to 9 months to align with current 
regulatory guidance.  
Protocol Amendment 1.0 25 Nov 2020 
The primary reason for Protocol Amendment 1 was to 
incorporate the changes in response to the US FDA 
feedback. 
This 
amendment 
combines 
changes 
regarding safety monitoring, study stratification, and 
statistical analysis. In addition, updates include 
removal of QTcF eligibility criteria and dexamethasone 
equivalent as premedication, assigning ORR as key 
secondary endpoint, as well as modifications on PRO 
schedules. 
Protocol Original 
26 Aug 2020 
 
 
ADCT Document Number: CLIN-0185


ADC Therapeutics 
Loncastuximab Tesirine (ADCT-402) 
ADCT-402-202 (LOTIS 6) 
Protocol Amendment 3.0 
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Table of Contents 
 
Summary of Changes for Protocol Amendment 3.0 ................................................................. 4 
List of Prior Protocol Versions .................................................................................................. 6 
Table of Contents ...................................................................................................................... 7 
List of Tables ........................................................................................................................... 11 
List of Figures ......................................................................................................................... 11 
List of Abbreviations............................................................................................................... 12 
Protocol Synopsis.................................................................................................................... 15 
Schedule of Events .................................................................................................................. 24 
1 
Introduction and Background ......................................................................................... 31 
1.1 Disease Background ......................................................................................................31 
1.2 Description of the Study Drugs .....................................................................................32 
1.2.1 
Loncastuximab tesirine (ADCT-402) ..................................................................32 
1.2.2 
Idelalisib ..............................................................................................................33 
1.2.3 
Clinical Study Data for Loncastuximab Tesirine and Idelalisib ..........................33 
1.3 Benefit/Risk Assessment ...............................................................................................34 
2 
Study Rationale .............................................................................................................. 35 
2.1 Rationale for Study Design ...........................................................................................35 
2.2 Rationale for Dose Selection .........................................................................................35 
3 
Study Objectives and Endpoints ..................................................................................... 37 
4 
Study Design .................................................................................................................. 39 
4.1 Overview .......................................................................................................................39 
4.2 Study Periods ................................................................................................................39 
4.2.1 
Screening Period ..................................................................................................39 
4.2.2 
Randomization .....................................................................................................39 
4.2.3 
Treatment Period .................................................................................................39 
4.2.4 
End of Treatment .................................................................................................40 
4.2.5 
Follow-up Period .................................................................................................40 
4.2.6 
End of Study ........................................................................................................40 
4.3 Study Stopping Rules ....................................................................................................40 
5 
Patient Population ........................................................................................................... 41 
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ADCT-402-202 (LOTIS 6) 
Protocol Amendment 3.0 
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5.1 Inclusion Criteria ...........................................................................................................41 
5.2 Exclusion Criteria..........................................................................................................42 
5.3 Screening Failures .........................................................................................................44 
5.4 Re-screening Procedures ...............................................................................................44 
5.5 Discontinuation .............................................................................................................44 
5.5.1 
Discontinuation from Study Treatment ...............................................................44 
5.5.2 
Discontinuation from the Study ...........................................................................45 
5.5.3 
Lost to Follow-Up ...............................................................................................46 
5.5.4 
Patient Replacements ...........................................................................................46 
6 
Study Treatment .............................................................................................................. 47 
6.1 Study Drugs ...................................................................................................................47 
6.1.1 
Loncastuximab tesirine ........................................................................................47 
6.1.2 
Idelalisib ..............................................................................................................47 
6.2 Management of Clinical Supplies .................................................................................47 
6.2.1 
Packaging and Storage ........................................................................................48 
6.2.2 
Preparation and Administration ...........................................................................48 
6.3 Study Treatment Assignment and Dosing .....................................................................49 
6.4 Premedication ................................................................................................................49 
6.5 Treatment Compliance ..................................................................................................49 
6.6 Definition and Management of Overdose .....................................................................49 
6.7 Dose Delays and Modifications ....................................................................................50 
6.7.1 
Dose Delays and Modifications for Loncastuximab Tesirine and Idelalisib .......50 
6.8 Supportive Care .............................................................................................................53 
6.8.1 
Management of Edema and Serosal Effusion ......................................................53 
6.8.2 
Prevention and Management of Infusion-related Hypersensitivity Reactions ....53 
6.8.3 
Prevention and Management of Skin Toxicity ....................................................53 
6.8.4 
Contraceptive Guidance ......................................................................................54 
6.8.5 
Other Supportive Care .........................................................................................55 
6.9 Concomitant Medications and Procedures ....................................................................55 
6.9.1 
Permitted During Study .......................................................................................55 
6.9.2 
Prohibited During Study ......................................................................................55 
7 
Study Assessments and Procedures ................................................................................ 56 
7.1 Informed Consent ..........................................................................................................56 
7.2 Demographics and Baseline Characteristics .................................................................56 
7.3 Efficacy Assessments ....................................................................................................56 
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ADCT-402-202 (LOTIS 6) 
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7.4 Safety Assessments .......................................................................................................57 
7.4.1 
Physical Examination ..........................................................................................57 
7.4.2 
ECOG Performance Status ..................................................................................58 
7.4.3 
Height and Weight ...............................................................................................58 
7.4.4 
Vital Signs ...........................................................................................................58 
7.4.5 
Laboratory Tests ..................................................................................................58 
7.4.6 
Pregnancy Test .....................................................................................................59 
7.4.7 
Electrocardiograms ..............................................................................................59 
7.5 Pharmacokinetics, Pharmacodynamics, and Immunogenicity ......................................60 
7.5.1 
Pharmacokinetics .................................................................................................60 
7.5.2 
Immunogenicity ...................................................................................................62 
 
 
 
 
 
 
7.6 Patient Reported Outcomes ...........................................................................................63 
7.6.1 
EuroQol-5 Dimensions-5 Levels (EQ-5D-5L) ....................................................64 
7.6.2 
Functional Assessment of Cancer Therapy - Lymphoma (FACT-Lym) ..............64 
7.6.3 
FACT-Lym GP5 ...................................................................................................65 
7.6.4 
Patient-Reported Outcomes version of the Common Terminology Criteria for 
Adverse Events (PRO-CTCAE™) – Selected Items ...........................................65 
8 
Adverse Events ............................................................................................................... 66 
8.1 Definition of Adverse Events and Serious Adverse Events ..........................................66 
8.1.1 
Adverse Events ....................................................................................................66 
8.1.2 
Serious Adverse Events .......................................................................................66 
8.1.3 
Clinical Laboratory Abnormalities and Other Abnormal Assessments as Adverse 
Events or Serious Adverse Events .......................................................................67 
8.2 Eliciting and Reporting Adverse Events/Serious Adverse Events ................................67 
8.3 Assessment of Severity .................................................................................................68 
8.4 Assessment of Causality ...............................................................................................68 
8.5 Special Situations Reports.............................................................................................69 
8.5.1 
Definitions of Special Situations .........................................................................69 
8.5.2 
Reporting Pregnancy ...........................................................................................69 
8.5.3 
Reporting Overdose .............................................................................................70 
8.5.4 
Reporting Other Special Situations .....................................................................70 
9 
Statistical Considerations ............................................................................................... 71 
9.1 Sample Size Determination ...........................................................................................71 
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ADCT-402-202 (LOTIS 6) 
Protocol Amendment 3.0 
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9.2 Analysis Populations .....................................................................................................72 
9.3 Interim Analysis ............................................................................................................72 
9.4 Final Analysis ................................................................................................................72 
9.5 Demographics and Baseline Characteristics .................................................................73 
9.6 Exposure to Treatments .................................................................................................73 
9.7 Efficacy Analyses ..........................................................................................................73 
9.7.1 
Complete Response Rate .....................................................................................73 
9.7.2 
Overall Response Rate ........................................................................................74 
9.7.3 
Progression-Free Survival ...................................................................................74 
9.7.4 
Overall Survival ...................................................................................................74 
9.7.5 
Duration of Response ..........................................................................................75 
9.7.6 
Subgroup analysis ................................................................................................75 
9.8 Safety Analyses .............................................................................................................75 
9.8.1 
Adverse Events ....................................................................................................75 
9.8.2 
Clinical Laboratory Results .................................................................................75 
9.8.3 
Additional Safety Assessments ............................................................................76 
9.9 Pharmacokinetic and Pharmacodynamic Analyses .......................................................76 
9.10 Immunogenicity Analyses .............................................................................................76 
9.11 PROs Data Analyses .....................................................................................................77 
 
10 
Regulatory, Ethical, and Study Oversight/Management Considerations ....................... 79 
10.1 Regulatory and Ethical Considerations .........................................................................79 
10.2 Financial Disclosure and Obligations ...........................................................................79 
10.3 Patient Information and Consent ...................................................................................79 
10.4 Data Protection ..............................................................................................................80 
10.5 Data Quality Assurance .................................................................................................80 
10.6 Source Documents ........................................................................................................81 
10.7 Study and Site Closure ..................................................................................................81 
10.8 Monitoring of the Study ................................................................................................82 
10.9 Publications ...................................................................................................................82 
11 
References ...................................................................................................................... 83 
 
 
 
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ADCT-402-202 (LOTIS 6) 
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List of Abbreviations 
Abbreviation 
Definition 
ADA 
anti-drug antibody 
ADC 
antibody-drug conjugate 
ADL 
activities of daily living 
AE 
adverse event 
AIDS 
Acquired Immuno-deficiency Syndrome 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count 
AST 
aspartate aminotransferase 
BID 
twice daily 
β-HCG 
human chorionic gonadotropin 
BOR 
best overall response 
C1D1 
Cycle 1 Day 1 
CAR-T 
chimeric antigen receptor T-cell 
CD 
cluster of differentiation 
 
 
CMH 
Cochran–Mantel–Haenszel test 
CI 
confidence interval 
CMV 
cytomegalovirus 
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 
DLBCL 
diffuse large B-cell lymphoma 
DNA 
deoxyribonucleic acid 
DOR 
duration of response 
ECG 
electrocardiogram(s) 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 
EDC 
electronic data capture 
EMA 
European Medicines Agency 
EOI 
end of infusion 
EOS 
end of study 
EOT 
end of treatment 
EQ-5D-5L 
EuroQoL–5 Dimensions–5 Levels 
EWB 
emotional well-being 
EZH2 
enhancer of zeste homolog 2 
FACT-Lym 
Functional Assessment of Cancer Therapy-Lymphoma 
FDA 
Food and Drug Administration 
FFPE 
formalin-fixed paraffin-embedded 
FL 
follicular lymphoma 
FLIPI 
Follicular Lymphoma International Prognostic Index 
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ADCT-402-202 (LOTIS 6) 
Protocol Amendment 3.0 
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Abbreviation 
Definition 
FSH 
follicle stimulating hormone 
FWB 
functional well-being 
GCP 
Good Clinical Practice 
 
 
GGT 
gamma glutamyl transferase 
HBV 
hepatitis B virus 
HCV 
hepatitis C virus 
HIV 
human immunodeficiency virus 
HSCT 
hematopoietic stem cell transplant 
IB 
Investigator’s Brochure 
ICF 
informed consent form 
ICH 
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use 
IEC 
independent ethics committee 
IRB 
institutional review board 
IV 
Intravenous 
ITT 
intent-to-treat 
MRI 
magnetic resonance imaging 
NHL 
non-Hodgkin's lymphoma 
ORR 
overall response rate 
OS 
overall survival 
PBD 
pyrrolobenzodiazepine 
PCR 
polymerase chain reaction 
PD 
progressive disease 
PET-CT 
positron emission tomography-computed tomography 
PFS 
progression-free survival 
PI3K 
phosphatidylinositol 3-kinase 
PJP 
Pneumocystis jirovecii pneumonia 
PK 
pharmacokinetic(s) 
PR 
partial response 
PWB 
physical well-being 
R/R 
relapsed or refractory 
Q2W 
every 2 weeks 
Q3W 
every 3 weeks 
QoL 
quality of life 
QT 
measure between Q wave and T wave in the electrocardiogram 
QTcF 
Fridericia correction of the QT measure 
RBC 
red blood cell 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SD 
stable disease 
SOC 
standard of care 
SoE 
schedule of events 
SJS 
Stevens-Johnson syndrome 
SmPC 
Summary of Product Characteristics 
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ADCT-402-202 (LOTIS 6) 
Protocol Amendment 3.0 
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Abbreviation 
Definition 
SWB 
social/family well-being 
TEAE 
treatment-emergent adverse event 
TEN 
toxic epidermal necrolysis 
TLS 
tumor lysis syndrome 
ULN 
upper limit of normal 
US 
United States 
VAS 
visual analog scale 
WBC 
white blood cell 
WOCBP 
women of childbearing potential 
 
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ADCT-402-202 (LOTIS 6) 
Protocol Amendment 3.0 
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Protocol Synopsis 
Protocol Number: 
ADCT-402-202 
Title: 
A Phase 2 Randomized Study of Loncastuximab Tesirine Versus 
Idelalisib in Patients with Relapsed or Refractory Follicular 
Lymphoma (LOTIS 6) 
Sponsor: 
ADC Therapeutics SA 
Study Phase: 
Phase 2 
Indication: 
Follicular lymphoma (FL) 
Rationale: 
Non-Hodgkin Lymphoma (NHL) is ranked as the 5th to 9th most 
common cancer in most countries worldwide, with almost 510,000 
new cases estimated in 2018. Follicular lymphoma represents the 
2nd most common subtype of NHL and ~20–25% of all new NHL 
diagnoses in western countries. While the majority of patients with 
FL will respond to initial therapy, almost all of them will relapse; 
thus, FL is considered incurable and is an area of significant unmet 
medical need. 
Loncastuximab tesirine (ADCT-402) is an antibody-drug conjugate 
(ADC) that has been designed to target and kill cluster of 
differentiation (CD)19-expressing malignant B-cells. CD19 is 
highly expressed in B-cell NHL, including FL. Data from a Phase 1 
study of loncastuximab tesirine in relapsed or refractory (R/R) B-
cell NHL shows significant activity of loncastuximab tesirine in 
heavily pretreated patients with R/R FL, with an overall response 
rate (ORR) of 78.6% and a complete response rate (CRR) of 64.3%. 
Median duration of response and median progression free survival 
were both not reached. 
Idelalisib is an inhibitor of phosphatidylinositol 3-kinase (PI3K). 
There are several PI3K inhibitors which are used in later-line 
treatment of R/R FL. The approved PI3K inhibitors have ORRs 
ranging from 42% to 59%, with substantially lower CRRs of 1% to 
14%. Idelalisib was chosen as the comparator for this study as it is 
the PI3K inhibitor with the widest range of use. 
Objectives: 
Primary Objective 
To evaluate the efficacy of single agent loncastuximab tesirine 
compared to idelalisib in patients with relapsed or refractory 
follicular lymphoma. 
Secondary Objectives 
• To further evaluate the additional efficacy of single agent 
loncastuximab tesirine compared to idelalisib in patients 
with relapsed or refractory follicular lymphoma. 
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3. Relapsed or refractory disease following two or more 
treatment regimens, at least one of which must have contained 
an anti-CD20 therapy. 
4. Patients who have received previous CD19-directed therapy 
must have a biopsy which shows CD19 expression after 
completion of the CD19-directed therapy. 
5. Measurable disease as defined by the 2014 Lugano 
Classification as assessed by positron emission tomography-
computed tomography (PET-CT) or, if not FDG-avid, CT or 
magnetic resonance imaging (MRI). 
6. Availability of formalin-fixed paraffin-embedded (FFPE) 
tumor tissue block (or minimum 10 freshly cut unstained 
slides if block is not available). 
Note: Any biopsy since initial diagnosis is acceptable, but if 
several samples are available, the most recent sample is 
preferred. 
7. ECOG performance status 0 to 2. 
8. Adequate organ function as defined by screening laboratory 
values within the following parameters: 
a. Absolute neutrophil count (ANC) ≥1.0 × 103/µL (off 
growth factors at least 72 hours), 
b. Platelet count ≥75 × 103/µL without transfusion in 
the past 2 weeks, 
c. Alanine aminotransferase (ALT), aspartate 
aminotransferase (AST), and gamma glutamyl 
transferase (GGT) ≤2.5 × the upper limit of normal 
(ULN), 
d. Total bilirubin ≤1.5 × ULN (patients with known 
Gilbert’s syndrome may have a total bilirubin up to 
≤3 × ULN). 
e. Calculated creatinine clearance ≥30 mL/min by the 
Cockcroft and Gault equation. 
Note: A laboratory assessment may be repeated a maximum 
of two times during the Screening period to confirm 
eligibility 
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9. Women of childbearing potential must agree to use a highly 
effective method of contraception from the time of giving 
informed consent until at least 9 months after the last dose of 
study treatment. Men with female partners who are of 
childbearing potential must agree to use a condom when 
sexually active or practice total abstinence from the time of 
giving informed consent until at least 6 months after the 
patient receives his last dose of study treatment. 
Exclusion Criteria: 
1. Previous treatment with loncastuximab tesirine. 
2. Previous treatment with idelalisib. 
3. History of hypersensitivity to any of the excipients of 
loncastuximab tesirine or idelalisib.  
4. Follicular lymphoma which has transformed to diffuse large 
B-cell lymphoma (DLBCL) or other aggressive lymphoma. 
5. Requires treatment or prophylaxis with a strong cytochrome 
P450 (CYP) 3A inhibitor, inducer, or sensitive substrate. 
6. History of or ongoing drug-induced pneumonitis. 
7. History of or ongoing inflammatory bowel disease. 
8. Any condition that could interfere with the absorption or 
metabolism of idelalisib including malabsorption syndrome, 
disease significantly affecting gastrointestinal function, or 
resection of the stomach or small bowel. 
9. Active second primary malignancy other than non-melanoma 
skin cancers, non-metastatic prostate cancer, in situ cervical 
cancer, ductal or lobular carcinoma in situ of the breast, or 
other malignancy that the Sponsor’s medical monitor and 
Investigator agree and document should not be exclusionary. 
10. Autologous transplant within 30 days prior to start of study 
treatment (C1D1). 
11. Allogenic transplant within 60 days prior to start of study 
treatment (C1D1). 
12. Active graft-versus-host disease. 
13. Post-transplantation lymphoproliferative disorders. 
14. Human immunodeficiency virus (HIV) seropositive with any 
of the following: 
a. CD4+ T-cell counts <350 cells/µL. 
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ADCT-402-202 (LOTIS 6) 
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b. Acquired immuno-deficiency syndrome (AIDS)-
defining opportunistic infection within 12 months 
prior to screening. 
c. Not on anti-retroviral therapy, or on anti-retroviral 
therapy for <4 weeks at the time of screening. 
d. HIV viral load ≥400 copies/mL. 
15. Serologic evidence of chronic hepatitis B infection and 
unable or unwilling to receive standard prophylactic anti-viral 
therapy or with detectable hepatitis B virus (HBV) viral load. 
16. Serologic evidence of hepatitis C infection without 
completion of curative treatment or with detectable hepatitis 
C virus (HCV) viral load. 
17. History of Stevens-Johnson syndrome or toxic epidermal 
necrolysis. 
18. Lymphoma with active central nervous system involvement, 
including leptomeningeal disease. 
19. 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). 
20. Breastfeeding or pregnant. 
21. Significant medical comorbidities, including but not limited 
to, uncontrolled hypertension (BP ≥160/100 mm Hg 
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. 
22. Any Grade ≥3 active infection which requires IV antibiotics, 
IV antiviral, or IV antifungal treatment. 
23. Major surgery, radiotherapy, chemotherapy or other anti-
neoplastic therapy within 14 days prior to start of study 
treatment (C1D1), except shorter if approved by the Sponsor. 
24. Use of any other experimental medication within 30 days 
prior to start of study treatment (C1D1). 
25. Live vaccine administration within 4 weeks prior to Cycle 1 
Day 1. 
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ADCT-402-202 (LOTIS 6) 
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26. Failure to recover to ≤ Grade 1 (Common Terminology 
Criteria for Adverse Events [CTCAE] v5.0) from acute non-
hematologic toxicity (except ≤ Grade 2 neuropathy or 
alopecia) due to previous therapy prior to screening. 
27. Any other significant medical illness, abnormality, or 
condition that would, in the Investigator’s judgment, make 
the patient inappropriate for study participation or put the 
patient at risk. 
Estimated 
Duration of 
Patient 
Participation and 
Study Duration: 
The duration of the study participation for each patient is defined as 
the time from the date of signed written informed consent to the 
completion of the follow-up period, withdrawal of consent, loss to 
follow-up, or death, whichever occurs first. 
The study will include a screening period (up to 28 days), a 
treatment period (cycles of 3 weeks for loncastuximab treatment 
arm and cycles of 4 weeks for idelalisib treatment arm), and a 
follow-up period (for up to 3 years after the end of treatment). 
Patients may continue treatment until disease progression, 
unacceptable toxicity, or other discontinuation criteria, whichever 
occurs first. 
The overall 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 will be performed using PET-CT, as per 
Schedule of Events (SoE) until tumor progression. Additional 
disease assessments may be obtained, if clinically indicated. 
Note: If disease is not FDG-avid at baseline, CT or MRI may be 
used for 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, CMV 
tests, urinalysis) 
• Pregnancy test, if applicable 
• 12-Lead ECG (triplicate) 
• AEs/SAEs, graded according to CTCAE version 5.0 
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O’Brien-Fleming spending function as the non-binding lower bound 
(futility) will be used. 
Final analysis of the primary endpoint will take place 12 months 
after the last patient is randomized. The same method will be used. 
If CRR is significantly different between two arms, the key 
secondary endpoint ORR will be tested sequentially using the same 
approach as CRR. 
PFS, OS analysis will be performed using PROC LIFETEST, 
adjusting for stratification factor. Kaplan-Meier plot for PFS, OS, 
and DOR will be presented by treatment. 
Subgroup analyses with age, gender, region, and other important 
baseline characteristics will be conducted for efficacy endpoint if 
proper. 
 
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Schedule of Events 
Table 1. 
Schedule of Events for Loncastuximab Tesirine Arm 
 
Protocol 
Section Screening 
Treatment Period 
EOT 
Follow-up Period 
(up to 3 years from EOT) Every 
12 weeks 
(1 Cycle = 3 weeks) 
 
 
Cycle 1  
Cycle 2  
Cycle 3 & 
Beyond 
 
Day (D) 
 
-28 to -1 
1 
1 
1 
 
 
Informed consent 
7.1 
X 
 
 
 
 
 
Randomization 
4.2.2 
 
X (D-1) 
 
 
 
 
Eligibility criteria 
5 
X 
 
 
 
 
 
Demography 
7.2 
X 
 
 
 
 
 
Medical/Cancer history 
7.2 
X 
 
 
 
 
 
Physical examination 
7.4.1 
X 
X 
X 
X 
X 
 
ECOG performance status 
7.4.2 
X 
X 
X 
X 
X 
 
Height 
7.4.3 
X 
 
 
 
 
 
Weight 
7.4.3 
X 
X 
X 
X 
X 
 
Vital signs2 (BP, HR, RR, Temp) 
7.4.4 
X 
X 
X 
X 
X 
 
Disease assessment3,4 
7.3 
Screening, 6 weeks and 12 weeks after C1D1, then every 12 weeks until 2 years from C1D1, then every 6 months. 
Hematology and Chemistry5 
7.4.5 
X 
X 
X 
X 
X 
 
Coagulation and Urinalysis  
7.4.5 
X 
 
 
 
 
 
HBV, HCV tests 
7.4.5 
X 
  
 
CMV IgG, Antigen or PCR test 
(all patients)6 
7.4.5 
X 
 
 
 
 
 
HIV tests 
7.4.5 
X 
 
 
 
 
 
Pregnancy test7, if applicable 
7.4.6 
X 
X 
X 
X 
X 
X7 at ≥ 9 months post last 
loncastuximab tesirine dose 
12-lead ECG (Triplicate)  
7.4.7 
X 
X 
(Pre-dose) 
X (Pre-dose), EOI-
only for 
loncastuximab 
tesirine arm 
  
X  
 
Pre-medication  
6.4 
 
D-1 to D2 
D-1 to D2 
D-1 to D2 
 
 
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Protocol 
Section Screening 
Treatment Period 
EOT 
Follow-up Period 
(up to 3 years from EOT) Every 
12 weeks 
(1 Cycle = 3 weeks) 
 
 
Cycle 1  
Cycle 2  
Cycle 3 & 
Beyond 
 
Day (D) 
 
-28 to -1 
1 
1 
1 
 
 
Loncastuximab tesirine 
Administration (IV infusion)  
6.2.2 
 
X 
 
X 
 
X 
 
 
 
PK sample  
7.5.1 
 
X 
(Pre-dose and 
EOI) 
X 
(Pre-dose and EOI) 
X 
(C3-C6: Pre-
dose and EOI; 
C7, then every 
other cycle: 
Pre-dose) 
X  
 
ADA sample  
7.5.2 
 
X 
 (Pre-dose) 
 
X  
(C3, then every 
other cycle: 
Pre-dose) 
X 
X8 
Patient Reported Outcomes 
(EQ-5D-5L) 
7.6.1 
 
X 
X 
X 
X 
X10 
Up to 1 year from EOT 
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Protocol 
Section Screening 
Treatment Period 
EOT 
Follow-up Period 
(up to 3 years from EOT) Every 
12 weeks 
(1 Cycle = 3 weeks) 
 
 
Cycle 1  
Cycle 2  
Cycle 3 & 
Beyond 
 
Day (D) 
 
-28 to -1 
1 
1 
1 
 
 
Patient Reported Outcomes 
(FACT-Lym) 
7.6.2 
 
X 
X 
X 
C3-C18 only  
X (only if 
EOT occurs 
prior to 
C19)  
 
PROs (GP-5 and items selected 
from PRO-CTCAE) (Complete 
at home except C1D1) 
7.6.3 
7.6.4 
 
X9 
Day 1 
 & Day 10 
X9 
Day 10 
X9 
C3 – C9 only 
Day 10 
 
 
Concomitant medications 
6.9 
From ICF signature date or Day -14 whichever is earlier, until at least 30 days after last dose of study treatment 
Adverse events 
8 
AEs from ICF signature date until at least 30 days after last dose of study treatment; SAEs from ICF signature 
date until at least 76 days after last dose of study treatment or initiation of new anticancer therapy, whichever is 
earlier; thereafter only related SAEs 
1st new anticancer treatment 
 
 
 
 
 
 
X 
Survival 
 
 
 
 
 
 
X 
Abbreviations: ADA: anti-drug antibody; AE: adverse events; BP: blood pressure; β-HCG: β subunit of Human chorionic gonadotropin; C: cycle; 
C1D1: cycle 1 day 1; 
 CMV: cytomegalovirus; CT: computerized tomography; ECG: electrocardiogram; ECOG: Eastern 
Cooperative Oncology Group; EOI: end of infusion; EOT: end of treatment; FACT-Lym: The Functional Assessment of Cancer Treatment-Lymphoma 
questionnaire; FDG: (18)F-fluorodeoxyglucose; 
; HBV: hepatitis B virus; HCV: hepatitis C virus; HIV: human immunodeficiency virus; 
HR: heart rate; ICF: informed consent form; IV: Intravenous; MRI: Magnetic resonance imaging; PCR: polymerase chain reaction; PK: pharmacokinetics; PRO-
CTCAE: Patient-Reported Outcomes Version of the Common Terminology Criteria for Adverse Events; RR: respiratory rate; SAE: serious AEs; Temp: 
temperature;. 
 
Visit Scheduling Windows:  
• Treatment Period: Visit day ± 3 days (excluding C1D1 which is the reference day). 
• EOT: As soon as possible after decision to discontinue the study treatment but preferably at least 30 days after last dose of study treatment 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. 
 
2 Vitals should be taken at pre-dose and EOI for every loncastuximab tesirine dosing visit.  
3 Positron-emission tomography-computed tomography will be used to perform imaging study. If disease is not FDG-avid at baseline, CT or MRI may be used. 
Screening imaging must be performed within 4 weeks prior to C1D1 and the same assessment method must be used throughout the study. Week 6 and Week 12 
imaging should be performed within ±5 days of the scheduled timepoint. All other imaging for disease assessment should be performed within ±2 weeks of the 
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scheduled time point. Imaging for disease assessment should be performed at the scheduled timepoint even if drug dosing is delayed. Additional disease 
assessments may be obtained, if clinically indicated. 
4 During follow-up period disease assessments to be performed in patients who discontinued study treatment for reasons other than disease progression or initiation 
of other anti-cancer therapy (except for hematopoietic stem cell transplant). 
5 ≤3days prior to administration of study treatment for loncastuximab tesirine arm patients.  
6 CMV tests include CMV IgG and CMV antigen or PCR test at screening visit for all patients.  
7 Serum or urine β-HCG test to be done on every visit at local lab if applicable. If the urine pregnancy test is positive, a serum β-HCG test is required for confirmation. 
Remote pregnancy test is acceptable when patient has no required site visit planned during follow-up period. Additional tests may be obtained, if needed. 
8 Only patients who test positive for ADAs may be asked to provide additional ADA samples every 12 weeks until the ADA titer falls to the baseline level. 
9 Patients will complete PRO-CTCAE items and GP-5 at study site on C1D1; at home on Day 10 (± 2 day) of each cycle for up to Cycle 9.  
10 In the event that patients complete follow up visit at home instead of being on site, EQ-5D-5L will be completed on Visit day (+2 days). 
 
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Table 2. 
Schedule of Events for Idelalisib Arm 
 
Protocol 
Section Screening 
Treatment Period 
EOT 
Follow-up Period 
(up to 3 years from EOT) Every 
12 weeks 
(1 Cycle = 4 weeks) 
 
 
Cycle 1 to Cycle 7  
 
Cycle 8 & 
Beyond 
 
Day (D) 
 
-28 to -1 
1 
15 
1 
 
 
Informed consent 
7.1 
X 
 
 
 
 
 
Randomization 
4.2.2 
 
X  
C1 only (D-1) 
 
 
 
 
Eligibility criteria 
5 
X 
 
 
 
 
 
Demography 
7.2 
X 
 
 
 
 
 
Medical/Cancer history 
7.2 
X 
 
 
 
 
 
Physical examination 
7.4.1 
X 
X 
 
X 
X 
 
ECOG performance status 
7.4.2 
X 
X 
 
X 
X 
 
Height 
7.4.3 
X 
 
 
 
 
 
Weight 
7.4.3 
X 
X 
 
X 
X 
 
Vital signs2 (BP, HR, RR, Temp) 
7.4.4 
X 
X 
 
X 
X 
 
Disease assessment3,4 
7.3 
Screening, 6 weeks and 12 weeks after C1D1, then every 12 weeks until 2 years from C1D1, then every 6 months. 
Hematology5 
7.4.5 
X 
X 
X 
X 
X 
 
Chemistry5 
7.4.5 
X 
X 
AST/ALT/total 
bilirubin - C1 to C4 
only 
X 
X 
 
Coagulation and Urinalysis  
7.4.5 
X 
 
 
 
 
 
HBV, HCV tests 
7.4.5 
X 
  
 
CMV IgG, Antigen or PCR test 
(all patients)6 
7.4.5 
X 
 
 
 
 
 
CMV Antigen or PCR test (for 
patients with positive CMV tests 
or history of CMV infection)7 
7.4.5 
 
X 
 
X 
X 
 
HIV tests 
7.4.5 
X 
 
 
 
 
 
Pregnancy test8, if applicable 
7.4.6 
X 
X 
 
X 
X 
 
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Protocol 
Section Screening 
Treatment Period 
EOT 
Follow-up Period 
(up to 3 years from EOT) Every 
12 weeks 
(1 Cycle = 4 weeks) 
 
 
Cycle 1 to Cycle 7  
 
Cycle 8 & 
Beyond 
 
Day (D) 
 
-28 to -1 
1 
15 
1 
 
 
12-lead ECG (Triplicate)  
7.4.7 
X 
X  
C1-C2 only 
(Pre-dose) 
 
  
X  
 
Idelalisib Administration 
 
6.2.2 
 
Twice daily orally  
 
 
 
Patient Reported Outcomes 
(EQ-5D-5L) 
7.6.1 
 
X 
 
X  
X 
X10 
Up to 1 year from EOT 
Patient Reported Outcomes 
(FACT-Lym) 
7.6.2 
 
X 
 
X 
C8-C18 
only  
 
X (only if 
EOT occurs 
prior to 
C19)  
 
PROs (GP-5 and items selected 
from PRO-CTCAE) (Complete 
at home except C1D1) 
7.6.3 
7.6.4 
 
X9 
Day 1 
 & Day 10 for 
C1, then D10 
for C2-C7 
 
 
 
 
Concomitant medications 
6.9 
From ICF signature date or Day -14 whichever is earlier, until at least 30 days after last dose of study treatment 
Adverse events 
8 
AEs from ICF signature date until at least 30 days after last dose of study treatment; SAEs from ICF signature 
date until at least 76 days after last dose of study treatment or initiation of new anticancer therapy, whichever is 
earlier; thereafter only related SAEs 
1st new anticancer treatment 
 
 
 
 
 
 
X 
Survival 
 
 
 
 
 
 
X 
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Abbreviations: AE: adverse events; BP: blood pressure; β-HCG: β subunit of Human chorionic gonadotropin; C: cycle; C1D1: cycle 1 day 1; 
 
; CMV: cytomegalovirus; CT: computerized tomography; ECG: electrocardiogram; ECOG: Eastern Cooperative Oncology Group; EOI: end of 
F-fluorodeoxyglucose;
infusion; EOT: end of treatment; FACT-Lym: The Functional Assessment of Cancer Treatment-Lymphoma questionnaire; FDG: (18)
; HBV: hepatitis B virus; HCV: hepatitis C virus; HIV: human immunodeficiency virus; HR: heart rate; ICF: informed consent form; 
IV: Intravenous; MRI: Magnetic resonance imaging; PCR: polymerase chain reaction; PRO-CTCAE: Patient-Reported Outcomes Version of the Common 
Terminology Criteria for Adverse Events; RR: respiratory rate; SAE: serious AEs; Temp: temperature. 
Visit Scheduling Windows: 
• Treatment Period: Visit day ± 3 days (excluding C1D1 which is the reference day).
• EOT: As soon as possible after decision to discontinue the study treatment but preferably at least 30 days after last dose of study treatment 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.
 
2 Vitals could be taken regardless of dosing time on the visit day. 
3 Positron-emission tomography-computed tomography will be used to perform imaging study. If disease is not FDG-avid at baseline, CT or MRI may be used. 
Screening imaging must be performed within 4 weeks prior to C1D1 and the same assessment method must be used throughout the study. Week 6 and Week 12 
imaging should be performed within ±5 days of the scheduled timepoint. All other imaging for disease assessment should be performed within ±2 weeks of the 
scheduled time point. Imaging for disease assessment should be performed at the scheduled timepoint even if drug dosing is delayed. Additional disease 
assessments may be obtained, if clinically indicated. 
4 During follow-up period disease assessments to be performed in patients who discontinued study treatment for reasons other than disease progression or initiation 
of other anti-cancer therapy (except for hematopoietic stem cell transplant). 
5 Safety lab sample collection on visit days may occur at any time during the visit.  
6 CMV tests include CMV IgG and CMV antigen or PCR test at screening visit for all patients.  
7 CMV antigen or PCR test for patients with positive CMV serology or history of CMV infection who are receiving treatment with idelalisib. 
8 Serum or urine β-HCG test to be done on every visit at local lab if applicable. If the urine pregnancy test is positive, a serum β-HCG test is required for confirmation. 
Additional tests may be obtained, if needed. 
9 Patients will complete PRO-CTCAE items and GP-5 at study site on C1D1; at home on Day 10 (± 2 day) of each cycle for up to Cycle 7. 
10 In the event that patients complete follow up visit at home instead of being on site, EQ-5D-5 will be completed on Visit day (+2 days). 
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1 Introduction and Background 
1.1 
Disease Background 
Non-Hodgkin Lymphoma (NHL) is ranked as the 5th to 9th most common cancer in most 
countries worldwide, with almost 510,000 new cases estimated in 2018 (Miranda-Filho, 2019). 
Follicular lymphoma (FL) represents the 2nd most common subtype of NHL and ~20–25% of 
all new NHL diagnoses in western countries (Carbone, 2019). In the United States (US), the 
annual incidence of FL was 2.7 per 100,000 on 2017 (Howlader N, 2020). In Western Europe, 
the annual incidence of FL has rapidly increased during recent decades and has risen from 2–
3/100,000 during the 1950s to 5/100,000 recently (Mounier M, 2015). While the majority of 
patients with FL will respond to initial therapy, almost all of them will relapse; thus, FL is 
considered incurable (Hiddeman, 2014) and is an area of significant unmet medical need. 
Currently approved therapies for relapsed/refractory (R/R) FL include lenalidomide combined 
with rituximab and obinutuzumab combined with bendamustine, both of which have full 
approval in second line, and the phosphatidylinositol 3-kinase (PI3K) inhibitors (idelalisib, 
copanlisib, and duvelisib), all of which have accelerated approval in third line in US. Idelalisib 
is only PI3K inhibitor received accelerated approval by Europe Medicines Agency (EMA). In 
addition, the enhancer of zeste homolog 2 (EZH2) inhibitor tazemetostat received US Food 
and Drug Administration (FDA) accelerated approval for adult patients with R/R FL whose 
tumors are positive for an EZH2 mutation and who have received at least 2 prior systemic 
therapies, and for adult patients with R/R FL who have no satisfactory alternative treatment 
options. Standard first-line therapy uses immuno-chemotherapy. Although current front-line 
regimens for Stages III and IV FL such as CHOP (cyclophosphamide, doxorubicin, 
vincristine, prednisone) plus obinutuzumab or rituximab, or bendamustine plus obinutuzumab 
or rituximab are associated with high response rates, most patients still relapse. The approved 
second line therapies have overall response rates (ORRs) ranging from 59% to 80%, with 
complete response rates (CRRs) ranging from 16% to 46% (Gazyva® US- Prescribing 
Information; Revlimid® US-Prescribing Information; Andorsky 2019; Leonard 2019). The 
approved PI3K inhibitors have ORRs ranging from 42% to 59%, with substantially lower 
CRRs of 1% to 14% (Zydelig® US- Prescribing Information; Aliqopa™ US- Prescribing 
Information; Copiktra® US- Prescribing Information). The approved EZH2 inhibitor 
tazemetostat has ORR 69% with CRR 12% for patients with EZH2 mutant, and ORR 34% 
with CRR 4% for patients with EZH2 wild-type (TAZVERIK™ US- Prescribing Information). 
There 
are 
a 
number 
of 
agents 
available 
for 
second-line 
therapy, 
including 
cytarabine-containing regimens and idelalisib. 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% CRR, 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 
chemotherapy refractoriness, large cell transformation, or death from treatment-related 
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toxicities (Cheah, 2018). Thus, there remains unmet medical needs for novel drugs for patients 
with R/R FL. 
1.2 
Description of the Study Drugs 
1.2.1 Loncastuximab tesirine (ADCT-402) 
Loncastuximab tesirine (ADCT-402) is an antibody drug conjugate (ADC), composed of a 
humanized monoclonal antibody (RB4v1.2) directed against human cluster of differentiation 
19 
(CD19) 
conjugated 
through 
a 
cathepsin-cleavable 
linker 
to 
SG3199, 
a pyrrolobenzodiazepine (PBD) dimer cytotoxin. The toxin SG3199 attached to the linker is 
designated as SG3249.  
The schematic representation of loncastuximab tesirine is presented in Figure 1. 
Figure 1. 
Schematic Representation and Chemical Structure of Loncastuximab 
Tesirine  
 
Abbreviations: 
Ala=alanine; 
HC=heavy 
chain; 
LC=light 
chain; 
PABA=para-aminobenzoic 
acid; 
PBD=Pyrrolobenzodiazepine; PEG=polyethylene glycol; RB4v1.2=human monoclonal antibody being studied; 
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 DNA and form potent cytotoxic DNA 
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interstream 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, 2017; Beck et al, 2017). 
More detailed information about loncastuximab tesirine may be found in the Investigator’s 
brochure (Loncastuximab tesirine IB). 
1.2.2 Idelalisib 
Idelalisib is a small molecule, an inhibitor of PI3K. Idelalisib induced apoptosis and inhibited 
proliferation in cell lines derived from malignant B-cells and in primary tumor cells. Idelalisib 
inhibits several cell signaling pathways, including B-cell receptor signaling and the CXCR4 
and CXCR5 signaling, which are involved in trafficking and homing of B-cells to the lymph 
nodes and bone marrow. Treatment of lymphoma cells with idelalisib resulted in inhibition of 
chemotaxis and adhesion, and reduced cell viability. 
More detailed information about idelalisib may be found in the idelalisib prescribing 
information or Summary of Product Characteristics (Idelalisib® US- Prescribing Information; 
Idelalisib-SmPC). 
1.2.3 Clinical Study Data for Loncastuximab Tesirine and Idelalisib 
Loncastuximab tesirine  
ADCT-402-101 (NCT02669017, https://clinicaltrials.gov/ct2/show/NCT02669017), was a 
first-in-human Phase 1 dose-escalation study of loncastuximab tesirine in R/R B-cell NHL 
patients. The data from this study showed loncastuximab tesirine exhibits significant anti-
tumor activity in heavily pretreated patients with R/R FL, with an ORR of 78.6% and a CRR 
of 64.3%. Median duration of response and median progression free survival (PFS) were both 
not reached.  
Toxicity was manageable, with the most common Grade ≥3 treatment-emergent adverse events 
(TEAEs) being Gamma-glutamyl transferase (GGT) increased (21.3%); neutropenia (16.9%); 
anemia (15.3%); neutrophil count decreased (14.8%); thrombocytopenia (12.0%); platelet 
count decreased (10.4%); blood alkaline phosphatase (ALP) increased (6.6%); lymphocyte 
count decreased (6.6%); disease progression (6.0%); febrile neutropenia (5.5%); and 
hypokalemia (5.5%) (Loncastuximab tesirine IB)  
Idelalisib 
Idelalisib is the only PI3K inhibitor approved by FDA and EMA as monotherapy for the 
treatment of adult patients with FL that is R/R to two prior lines of treatment. 
In 
Study 
101-09 
(NCT01282424, 
https://clinicaltrials.gov/ct2/show/NCT01282424), 
72 patients with FL received 150 mg of idelalisib orally twice (BID) daily until evidence of 
disease progression or unacceptable toxicity. The ORR was 55.6% and CRR was 16.7%. The 
median PFS was 11.0 months (range 8.0–14.0), and the median DOR was 11.8 months 
(range 6.2- 26.9) (Idelalisib -SmPC). 
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The most common Grade ≥3 TEAEs in 125 adults with indolent non-Hodgkin lymphoma 
treated with idelalisib 150 mg BID in clinical trials were elevated transaminases (21%), 
diarrhea (13%), neutropenia (27%), pneumonia (7%), and thrombocytopenia (6%) 
(Gopal et al, 2014). 
1.3 
Benefit/Risk Assessment 
The primary benefit for this study is that of effective treatment for lymphoma, although this 
benefit is not guaranteed. The primary risk of this study is the toxicities from the treatment; for 
loncastuximab tesirine, the most common adverse reactions are gamma-glutamyl transferase 
increased, neutropenia, thrombocytopenia, fatigue, anemia, nausea, cough, edema, and blood 
ALP increased, and for idelalisib the most common adverse reactions are diarrhea, fatigue, 
nausea, cough, pyrexia, abdominal pain, pneumonia, and rash and the most common laboratory 
abnormalities are neutropenia, alanine aminotransferase (ALT) elevations, and aspartate 
aminotransferase (AST) elevations. It is expected that the potential benefit of effective 
treatment will outweigh the potential toxicities, providing a positive risk/benefit ratio. 
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2 Study Rationale 
Non-Hodgkin Lymphoma is ranked as the 5th to 9th most common cancer in most countries 
worldwide, with almost 510,000 new cases estimated in 2018. Follicular lymphoma represents 
the 2nd most common subtype of NHL and ~20–25% of all new NHL diagnoses in western 
countries. While the majority of patients with FL will respond to initial therapy, almost all of 
them will relapse; thus, FL is considered incurable and is an area of significant unmet medical 
need. 
Loncastuximab tesirine (ADCT-402) is an antibody drug conjugate (ADC) that has been 
designed to target and kill CD19-expressing malignant B-cells. CD19 is highly expressed in 
B-cell NHL, including follicular lymphoma. Data from a Phase 1 study of loncastuximab 
tesirine in relapsed or refractory B-cell NHL showed significant activity of loncastuximab 
tesirine in heavily pretreated patients with relapsed/refractory follicular lymphoma, with an 
ORR of 78.6% and a CRR of 64.3%. Median DOR and median PFS were both not reached. 
Data from loncastuximab tesirine studies demonstrated an acceptable safety profile to date and 
a positive risk-benefit for further evaluation in R/R FL. 
2.1 
Rationale for Study Design 
This is a Phase 2, randomized, 2-arm, and open-label study and will enroll approximately 150 
patients. Eligible patients will be randomly assigned to treatment with loncastuximab tesirine 
or idelalisib in a 2:1 ratio. The randomization will be stratified based on time since last systemic 
therapy (≤2 years vs >2 years). A randomized trial design was chosen as this is a well-
recognized standard for evaluating new treatments. The study is an open label trial as the 
primary endpoint is tumor response as determined by central review, which is unlikely to be 
affected by investigator or subject knowledge of treatment assignment. The sample size is 
driven by a regulatory agency request to have safety data on ~100 FL patients treated with 
loncastuximab tesirine. With 100 patients treated in the loncastuximab tesirine arm and 
complete response rate as the primary endpoint, the study would be substantially overpowered 
with a standard 1:1 randomization scheme, so a 2:1 randomization is used to limit the number 
of patients required to complete the study, which still results in a power of >99%.  
Idelalisib was chosen as the comparator for this study as it is the only PI3K inhibitor currently 
approved for treatment of R/R FL in both the US and Europe. 
2.2 
Rationale for Dose Selection 
Loncastuximab tesirine will be administered intravenously (IV) at a dose of 150 µg/kg every 
3 weeks for 2 doses, then at a dose of 75 µg/kg every 3 weeks at the subsequent doses.  
The initial dose of 150 µg/kg every 3 weeks (Q3W) was based on the observation that response 
rate in patients treated in the Phase 1 trial appeared to increase with increasing exposure, but 
toxicity was substantially increased at 200 µg/kg compared to lower dose levels. Thus, 
150 µg/kg was chosen as the highest initial dose with acceptable toxicity. The dose reduction 
after 2 cycles was based on the fact that a substantial portion of patients treated on the Phase 1 
trial required dose reduction after 2 or more cycles, usually as a result of prolonged dose delays 
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because of adverse events (AEs). Decreasing the dose after 2 cycles was intended to reduce 
the incidence of dose delay and reduce the need for further dose reduction. This dosing regimen 
has been used in 145 patients in a Phase 2 study of loncastuximab tesirine in patients with R/R 
diffuse large B-cell lymphoma (R/R DLBCL) and appears to be well-tolerated with a 
manageable toxicity profile and comparable efficacy to that achieved in a similar patient 
population in Phase 1. 
 
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3 Study Objectives and Endpoints 
Table 3. 
Study Objectives and Endpoints 
Objectives 
Endpoints 
Primary 
To evaluate the efficacy of single agent loncastuximab 
tesirine compared to idelalisib in patients with relapsed or 
refractory follicular lymphoma. 
Complete response rate (CRR) according to the 2014 Lugano classification as 
determined by central review in patients with FL. Complete response rate is the 
proportion of patients with a best overall response (BOR) of complete response 
(CR) assessed prior to any subsequent anticancer treatment. 
Secondary 
To further evaluate the additional efficacy of single agent 
loncastuximab tesirine compared to idelalisib in patients 
with relapsed or refractory follicular lymphoma. 
Key Secondary Endpoint 
• 
Overall response rate (ORR) defined as the percentage of patients with a 
BOR of CR or partial response (PR) by central review assessed prior to any 
subsequent anticancer treatment.  
Other Secondary Endpoints 
• 
Progression free survival (PFS) defined as the time between the 
randomization date and the first documentation of recurrence, progression, or 
death. 
• 
Overall survival (OS) defined as the time between the randomization date 
and death from any cause. 
• 
Duration of response (DOR) defined as the time from the documentation of 
tumor response to disease progression or death. 
To assess the safety profile of loncastuximab tesirine in 
patients with relapsed or refractory follicular lymphoma. 
• 
Incidence and severity of adverse events (AEs) and serious adverse events 
(SAEs). 
• 
Changes from baseline of safety laboratory values, vital signs, 12-lead 
electrocardiogram (ECG), and Eastern Cooperative Oncology Group 
(ECOG) performance status.  
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4 Study Design 
4.1 
Overview 
This is a prospective, randomized, 2-arm, multi-center, and open-label Phase 2 study in patients 
with R/R FL. The study will enroll approximately 150 patients. Eligible patients will be 
randomly assigned to treatment with loncastuximab tesirine or idelalisib in a 2:1 ratio. A block 
randomization with stratification based on time since last systemic therapy (≤2 years vs >2 
years) will be used. A non-binding futility analysis on the primary endpoint of CRR will be 
performed for the first 60 patients around 12 weeks after the 60th patient is randomized (enough 
time for 2 disease assessments). The duration of the study participation for each patient is 
defined as the time from the date of signed written informed consent to the completion of the 
follow-up period, withdrawal of consent, loss to follow-up, or death, whichever occurs first. 
The study will include a screening period (up to 28 days), a treatment period (cycles of 3 weeks 
for loncastuximab tesirine treatment and cycles of 4 weeks for idelalisib treatment), and a 
follow-up period (approximately every 12 weeks visits) for up to 3 years from treatment 
discontinuation (Section 4.2, study periods). 
4.2 
Study Periods 
4.2.1 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 
SOC may be used to satisfy screening requirements if they are performed in the appropriate 
window. 
The screening period is from 28 days to 1 day prior to the start of the study drug. 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. 
4.2.2 Randomization 
Patients who are eligible will be randomized via Interactive Response Technology 
(see Interactive Response Technology manual for details). The randomization will be stratified 
based on time since last systemic therapy (≤2 years vs >2 years). Block randomization with 
size of 3 will be used to generate the randomization list. Approximately 150 patients will be 
randomized (2:1 ratio) to receive either loncastuximab tesirine or idelalisib. For details on 
randomization steps and for treatment assignment, see Section 6.3. 
4.2.3 Treatment Period 
The treatment period will start on the date when a patient is administered the first dose of study 
treatment and continues until the end of treatment (EOT) visit (see below).  
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A treatment cycle is defined as 3 weeks (i.e., 21 days) for patients assigned to loncastuximab 
tesirine treatment. A treatment cycle is defined as 4 weeks (i.e., 28 days) for patients assigned 
to idelalisib treatment. Patients will receive either IV loncastuximab tesirine on Day 1 of each 
cycle, or idelalisib 150 mg BID orally Days 1-28 every cycle. Patients may continue treatment 
until disease progression, unacceptable toxicity, death, or other discontinuation criteria, 
whichever occurs first. 
4.2.4 End of Treatment 
An EOT visit should be performed as soon as possible after the decision to discontinue the 
study treatment, but preferably at least 30 days after last dose of study treatment 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. 
When EOT coincides with a scheduled visit, the scheduled visit will become EOT. 
4.2.5 Follow-up Period 
All patients, regardless of disease status, will be followed every 12 weeks for up to 3 years 
from the EOT, or until withdrawal of consent, loss to follow-up, or death, whichever occurs 
first. 
When disease assessments or blood draw are not planned for a follow-up visit, the visit can be 
done by phone. 
4.2.6 End of Study 
The end of study (EOS) occurs at the last scheduled visit/procedure for the last patient, unless 
the study is terminated earlier by Sponsor. The death date will be considered as the EOS date 
for an individual patient whose survival status was informed at any later contact date. 
4.3 
Study Stopping Rules 
Once at least 15 patients have been treated with idelalisib, study enrollment will be paused for 
safety evaluation if any of the following occur: 
1. The number of patients with reported Grade 5 toxicity in the loncastuximab tesirine 
arm is more than twice the number of patients with reported Grade 5 toxicity in the 
idelalisib arm. 
2. Grade 4 skin toxicity is reported in >2 patients treated with loncastuximab tesirine and 
the incidence of Grade 4 skin toxicity in patients treated with loncastuximab tesirine is 
>5% and the incidence is at least 50% higher than the incidence in patients treated with 
idelalisib. 
3. Grade 4 toxicity of edema or effusion is reported in >2 patients treated with 
loncastuximab tesirine and the incidence of Grade 4 toxicity of edema or effusion in 
patients treated with loncastuximab tesirine is >5% and at least 50% higher than the 
incidence in patients treated with idelalisib. 
Safety evaluation will be performed by ADCT. 
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5 Patient Population 
Patients must meet all inclusion criteria and none of the exclusion criteria to be eligible for the 
study. All criteria have to be assessed during Screening, unless otherwise specified. 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known 
as protocol waivers or exemptions, is not permitted. 
5.1 
Inclusion Criteria  
1. Written informed consent must be obtained prior to any study procedures. 
2. Male or female patients aged 18 years or older, with pathologic diagnosis of FL 
(Grade 1, 2, 3A) in the most recent tumor biopsy. 
3. Relapsed or refractory disease following two or more treatment regimens, at least one 
of which must have contained an anti-CD20 therapy. 
4. Patients who have received previous CD19-directed therapy must have a biopsy which 
shows CD19 expression after completion of the CD19-directed therapy. 
5. Measurable disease as defined by the 2014 Lugano Classification as assessed by 
PET-CT or, if not FDG avid, CT or magnetic resonance imaging (MRI). 
6. Availability of formalin-fixed paraffin-embedded (FFPE) tumor tissue block (or 
minimum 10 freshly cut unstained slides if block is not available). 
Note: Any biopsy since initial diagnosis is acceptable, but if several samples are 
available, the most recent sample is preferred. 
7. Eastern Cooperative Oncology Group (ECOG) performance status 0 to 2. 
8. Adequate organ function as defined by screening laboratory values within the following 
parameters: 
a. Absolute neutrophil count (ANC) ≥1.0 × 103/µL (off growth factors at least 
72 hours), 
b. Platelet count ≥75 × 103/µL without transfusion in the past 2 weeks, 
c. Alanine aminotransferase, AST, and GGT ≤2.5 × the upper limit of normal 
(ULN), 
d. Total bilirubin ≤1.5 × ULN (patients with known Gilbert’s syndrome may have a 
total bilirubin up to ≤3 × ULN). 
e. Calculated creatinine clearance ≥30 mL/min by the Cockcroft and Gault 
equation. 
Note: A laboratory assessment may be repeated a maximum of two times during the 
Screening period to confirm eligibility 
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9. Women of childbearing potential (WOCBP)* must agree to use a highly effective 
method** of contraception from the time of giving informed consent until at least 
9 months after the last dose of study treatment. Men with female partners who are of 
childbearing potential must agree to use a condom when sexually active or practice 
total abstinence from the time of giving informed consent until at least 6 months after 
the patient receives his last dose of study treatment. 
* 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. A postmenopausal state is defined as no menses 
for 12 months without an alternative medical cause. A high follicle stimulating 
hormone (FSH) level in the postmenopausal range may be used to confirm a 
postmenopausal state in women not using hormonal contraception or hormonal 
replacement therapy. However, in the absence of 12 months of amenorrhea, a single 
FSH measurement is insufficient. 
** Highly effective forms of birth control are methods that achieve a failure rate of less 
than 1% per year when used consistently and correctly. Highly effective forms of 
birth control include hormonal contraceptives associated with inhibition of ovulation 
(oral, injectable, patch, 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. Previous treatment with loncastuximab tesirine. 
2. Previous treatment with idelalisib. 
3. History of hypersensitivity to any of the excipients of loncastuximab tesirine or 
idelalisib.  
4. Follicular lymphoma which has transformed to DLBCL or other aggressive 
lymphomas. 
5. Requires treatment or prophylaxis with a strong cytochrome P450 (CYP) 3A inhibitor, 
inducer, or sensitive substrate. 
6. History of or ongoing drug-induced pneumonitis. 
7. History of or ongoing inflammatory bowel disease. 
8. Any condition that could interfere with the absorption or metabolism of idelalisib 
including malabsorption syndrome, disease significantly affecting gastrointestinal 
function, or resection of the stomach or small bowel. 
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9. Active second primary malignancy other than non-melanoma skin cancers, non-
metastatic prostate cancer, in situ cervical cancer, ductal or lobular carcinoma in situ 
of the breast, or other malignancy that the Sponsor’s medical monitor and Investigator 
agree and document should not be exclusionary. 
10. Autologous transplant within 30 days prior to start of study treatment (C1D1). 
11. Allogenic transplant within 60 days prior to start of study treatment (C1D1). 
12. Active graft-versus-host disease. 
13. Post-transplantation lymphoproliferative disorders. 
14. Human immunodeficiency virus (HIV) seropositive with any of the following: 
a. CD4+ T-cell counts <350 cells/µL. 
b. Acquired immuno-deficiency syndrome (AIDS)-defining opportunistic infection 
within 12 months prior to screening. 
c. Not on anti-retroviral therapy, or on anti-retroviral therapy for < 4 weeks at the 
time of screening. 
d. HIV viral load ≥400 copies/mL. 
15. Serologic evidence of chronic hepatitis B infection and unable or unwilling to receive 
standard prophylactic anti-viral therapy or with detectable hepatitis B virus (HBV) viral 
load. 
16. Serologic evidence of hepatitis C infection without completion of curative treatment or 
with detectable hepatitis C virus (HCV) viral load. 
17. History of Stevens-Johnson syndrome or toxic epidermal necrolysis. 
18. Lymphoma with active central nervous system involvement, including leptomeningeal 
disease. 
19. 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). 
20. Breastfeeding or pregnant. 
21. Significant medical comorbidities, including but not limited to, uncontrolled 
hypertension (BP ≥160/100 mm Hg 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. 
22. Any Grade ≥3 active infection which requires IV antibiotics, IV antiviral, or IV 
antifungal treatment. 
23. Major surgery, radiotherapy, chemotherapy or other anti-neoplastic therapy within 
14 days prior to start of study treatment (C1D1), except shorter if approved by the 
Sponsor. 
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24. Use of any other experimental medication within 30 days prior to start of study 
treatment (C1D1). 
25. Live vaccine administration within 4 weeks prior to Cycle(C) 1 Day (D) 1. 
26. Failure to recover to ≤ Grade 1 (Common Terminology Criteria for Adverse Events 
[CTCAE] version 5.0) from acute non-hematologic toxicity (except ≤Grade 2 
neuropathy or alopecia) due to previous therapy prior to screening. 
27. Any other significant medical illness, abnormality, or condition that would, in the 
Investigator’s judgment, make the patient inappropriate for study participation or put 
the patient at risk.  
5.3 
Screening Failures  
Patients who signed the ICF but were found not eligible for the study prior to receiving study 
treatment are defined as screening failures. 
For these patients, only limited information will be collected in the electronic case report form 
(eCRF): 
- 
Informed consent 
- 
Demographics 
- 
Inclusion/exclusion criteria 
- 
Serious adverse event (SAE) and/or death occurring during the Screening Period 
- 
Screen fail (documenting primary reason for screen failure) 
5.4 
Re-screening Procedures  
A patient who did not meet the eligibility criteria (screen failure) may be considered for 
re-screening. Decision for re-screening must be confirmed by the Sponsor/Medical monitor. A 
re-screened patient should be assigned a new patient number. 
Participants who are rescreened are required to sign a new ICF. 
5.5 
Discontinuation 
The reason for discontinuation, whether it is from study treatment or from study, and the date 
of discontinuation will be collected for all patients. 
Note: Once discontinued from the study for any reason, patients are not permitted to be 
re-enrolled. 
5.5.1 Discontinuation from Study Treatment 
A patient may be discontinued from the study treatment for any of the following reasons: 
• Disease Progression 
• Adverse events 
• Patient decision 
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• Physician decision 
• Major protocol deviation 
• Lost to follow-up 
• Study termination by the Sponsor 
A patient must discontinue from the study drug for any of the following reasons: 
• Pregnancy 
• Death  
The reason(s) patients initiate subsequent anti-lymphoma therapy should be captured. 
IMPORTANT: Study treatment discontinuation is not equivalent to discontinuation from the 
study. Patients discontinuing the study treatment will be asked to perform an EOT visit 
(Section 4.2.4) and continue with the Follow-up period (Section 4.2.5) 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. 
5.5.2 Discontinuation from the Study  
A patient may be discontinued from the study for any of the following reasons: 
• Study completion 
• Withdrawal of consent 
• Physician decision 
• Lost to follow-up 
• Study termination by the Sponsor 
• Death 
If a patient withdraws informed consent for study participation, no additional study data will 
be collected. 
The Sponsor may continue to use previously collected medical research data prior to the 
withdrawal consistent with the original authorization. If a patient withdraws from the study, 
he/she may request destruction of any samples taken and not tested, and the investigator must 
document this in the site study records. 
The study may be terminated at any time, for any reason, by the Sponsor. 
Patients still receiving study treatment should have an EOT visit as described in Section 4.2.4 
and Schedule of Events (SoE) (Table 1 or Table 2). 
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5.5.3 Lost to Follow-Up 
Patients who fail to return for protocol follow-up are to be contacted by the investigative site. 
Following a minimum of two documented unsuccessful telephone calls, the investigative site 
should send a registered letter to the patient in a final attempt to ensure protocol compliance. 
5.5.4 Patient Replacements 
Any patient who is randomized will not be replaced. 
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6 Study Treatment 
6.1 
Study Drugs 
Loncastuximab tesirine is an investigational medicinal product for this trial. It will be supplied 
by the study sponsor. Idelalisib is the comparator regimen in the study. Idelalisib will be 
supplied by the Sponsor when required by applicable local laws and regulations. 
6.1.1 Loncastuximab tesirine  
Loncastuximab tesirine will be provided as a lyophilized white to off-white powder in glass 
vials (10 mg loncastuximab tesirine per vial) and stored at 2-8°C. The lyophilized 
loncastuximab tesirine is formulated in 20 mM histidine, 175 mM sucrose, and 0.02% 
polysorbate 20, at pH 6.0. Prior to use, this study drug is reconstituted with 2.2 mL of Sterile 
Water for Injection to deliver 2.0 mL at a concentration of 5 mg/mL. Sterile Water for Injection 
is to be provided by study sites. See the Pharmacy Manual for additional details on dose 
handling and administration.  
6.1.2 Idelalisib 
Idelalisib tablets are for oral administration. Each tablet contains either 100 mg or 150 mg of 
idelalisib with the following inactive ingredients: microcrystalline cellulose, hydroxypropyl 
cellulose, croscarmellose sodium, sodium starch glycolate, magnesium stearate, and a tablet 
coating. The tablet coating consists of polyethylene glycol, talc, polyvinyl alcohol, and 
titanium dioxide and of FD&C Yellow #6/Sunset Yellow FCF Aluminum Lake (for the 100 mg 
tablet) and red iron oxide (for the 150 mg tablet). See the Pharmacy Manual/ idelalisib 
Prescribing Information/SmPC for additional details on dose handling and administration. 
6.2 
Management of Clinical Supplies 
The investigator or designee must confirm appropriate temperature conditions have been 
maintained for study drug(s) received and any discrepancies are reported as instructed in the 
pharmacy manual.  
Study drug(s) must be stored in a secure, monitored (manual or automated) area in accordance 
with the storage conditions specified in the pharmacy manual with access limited to authorized 
site staff. 
The investigator or designee is responsible for study drug accountability, reconciliation, and 
record maintenance (ie, receipt, reconciliation, and final disposition records). 
Detailed instructions regarding study treatment shipment, handling, storage, preparation, 
administration, and final disposition of unused study treatment are included in the study 
pharmacy manual and in the prescribing information or SmPC for idelalisib. 
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6.2.1 Packaging and Storage 
The study drugs will be supplied by the Sponsor through the designated packaging, labeling, 
and 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. 
Study drugs must be stored according to the pharmacy manual/prescribing information or 
SmPC, in a secure area.  
Loncastuximab tesirine will be provided as a refrigerated lyophilized formulation, and stored 
at 2-8°C. Loncastuximab tesirine should be stored in the original box to protect from long-term 
exposure to light. Light protection is not required for dose preparation and during 
administration of the diluted drug in the IV bag. 
Refer to the IB (loncastuximab tesirine), prescribing information or SmPC (idelalisib), and 
pharmacy manual for storage instructions. 
6.2.2 Preparation and Administration 
Loncastuximab tesirine  
Loncastuximab tesirine solution at the concentration of 5 mg/mL will be the basis for the 
preparation of the infusion solution. The amount of the product to be diluted will depend on 
the dose level and the body mass of the patient. The weight of the patient at C1 D1 can be used 
for calculating the dose. If the patient’s weight measured on subsequent dosing days has 
changed by 10% or more compared to C1 D1, then the dose should be recalculated. Additional 
details are included in the pharmacy manual. 
Administration of loncastuximab tesirine will be performed by the Investigator or a qualified 
designee according to the pharmacy manual. 
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. 
Extravasation of loncastuximab tesirine may be associated with local irritation, swelling, pain, 
or tissue damage. The IV infusion site should be monitored for signs of IV infiltration or drug 
extravasation, and patients should be instructed to report immediately any signs of IV 
infiltration or drug extravasation during or after the infusion. Suspected extravasation of 
loncastuximab tesirine should be managed according to institutional protocol for management 
of extravasation of cytotoxic chemotherapy. For patients who have a central line, 
administration of loncastuximab tesirine via this central line should be considered. 
Idelalisib 
Idelalisib is available as 100 mg and 150 mg oval-shaped tablets in a high-density polyethylene 
bottle with a polyester fiber coil, capped with a child-resistant closure. Each bottle contains 
60 film-coated tablets and is to be dispensed only in original container.  
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If supplied through the study sufficient idelalisib will be dispensed until the next visit. 
6.3 
Study Treatment Assignment and Dosing 
• Patients who are eligible will be randomized via Interactive Response Technology to 
either of the study treatment arms, loncastuximab tesirine or idelalisib in a 2:1 ratio. 
Loncastuximab Tesirine Arm: Administration of loncastuximab tesirine will be 
performed by the Investigator or a qualified designee. Patients will receive a 30 minutes 
IV infusion of loncastuximab tesirine on Day 1 of each cycle (150 µg/kg Q3W for 
2 cycles, then 75 µg/kg Q3W for subsequent cycles).  
Refer to Section 6.4 for premedication and Section 6.8 for supportive care. 
• Idelalisib Arm: Patients will receive 150 mg idelalisib tablet orally BID. Please refer to 
idelalisib prescribing information or idelalisib SmPC for detailed instructions.  
6.4 
Premedication 
Unless contraindicated, administer dexamethasone 4 mg orally BID, the day before 
loncastuximab tesirine administration (if possible), the day of loncastuximab tesirine 
administration (give at least 2 hours prior to administration when not given the day before; 
otherwise any time prior to administration), and the day after loncastuximab tesirine 
administration. Dexamethasone may be given IV if clinically indicated. 
Patients who experience an infusion-related hypersensitivity reaction will receive the 
alternative premedication regimen specified in Section 6.8.2 for more details. 
6.5 
Treatment Compliance 
The Investigator or his/her designated and qualified representatives will administer/dispense 
the study treatments only to patients enrolled in the study in accordance with the protocol. 
Compliance will be verified by the study treatment administration information recorded in the 
electronic data capture (EDC).  
Home administration of idelalisib will be documented in a patient diary, which will be 
reviewed by the Investigator or designee at each study visit. 
6.6 
Definition and Management of Overdose 
An overdose is any dose of study drug administered to the patient that exceeds the maximum 
dose described in the protocol by 15% or more. Any overdose, with or without associated AEs, 
must be promptly reported to the Sponsor (see Section 8.5.3). There are no data available to 
determine what the effects of overdose of loncastuximab tesirine and idelalisib are and whether 
they can be reversed. Symptomatic treatment and standard supportive care measures for the 
management of any observed toxicity should be applied. 
If feasible, a sample for pharmacokinetic (PK) analysis should be taken as close as possible to 
the overdose event. 
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6.7 
Dose Delays and Modifications  
6.7.1 Dose Delays and Modifications for Loncastuximab Tesirine and 
Idelalisib  
The criteria and guidance for dose delay and dose modifications of loncastuximab tesirine and 
idelalisib are summarized in Table 4 and Table 5, respectively. 
Table 4. 
Criteria for Dose Delay or Dose Modification of Loncastuximab Tesirine 
Toxicity 
Loncastuximab Tesirine 
Grade ≥3 non-
hematologic adverse 
events  
• Hold until the toxicity resolves to Grade ≤1, (Grade 1 or 
baseline for peripheral neuropathy) 
• If dosing is delayed by more than 3 weeks and the toxicity is 
considered at least possibly related to loncastuximab tesirine, 
then subsequent doses must be reduced by 50%. If the toxicity 
recurs, subsequent doses must be reduced by an additional 
50% 
• A maximum of 2 dose reductions are allowed 
• Note: Patients who have a toxicity meeting the criteria for 
dose reduction following Cycle 2 will receive the protocol-
specified dose of 75 µg/kg for Cycle 3, i.e., they will not have 
an additional dose reduction for Cycle 3 
Grade ≥2 edema, 
effusion 
 
• Hold until the toxicity resolves to Grade ≤1 
• If dosing is delayed by more than 3 weeks and the toxicity is 
considered at least possibly related to loncastuximab tesirine, 
then subsequent doses must be reduced by 50%. If the toxicity 
recurs, subsequent doses must be reduced by an additional 
50% 
• A maximum of 2 dose reductions are allowed 
• Note: Patients who have a toxicity meeting the criteria for 
dose reduction following Cycle 2 will receive the protocol-
specified dose of 75 µg/kg for Cycle 3, i.e., they will not have 
an additional dose reduction for Cycle 3 
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Toxicity 
Loncastuximab Tesirine 
Grade ≥3 neutropenia or 
thrombocytopenia 
• Hold until toxicity resolves to Grade ≤2  
• If dosing is delayed by more than 3 weeks and the toxicity is 
considered at least possibly related to loncastuximab tesirine, 
then subsequent doses must be reduced by 50%. If the toxicity 
recurs, subsequent doses must be reduced by an additional 
50% 
• A maximum of 2 dose reductions are allowed 
• Note: Patients who have a toxicity meeting the criteria for 
dose reduction following Cycle 2 will receive the 
protocol-specified dose of 75 µg/kg for Cycle 3, i.e., they will 
not have an additional dose reduction for Cycle 3  
Grade 4 infusion related 
reaction 
• Permanently discontinue loncastuximab tesirine 
Hy’s law (AST and/or 
ALT > 3 × ULN and 
bilirubin > 2 × ULN)) 
• Permanently discontinue loncastuximab tesirine. 
Hy’s law defined as: AST and/or ALT > 3 × ULN and 
bilirubin > 2 × ULN, and without initial findings of 
cholestasis (ALP activity < 2 × ULN) and no other reason that 
could explain the combination of increased transaminases and 
serum total bilirubin, such as viral hepatitis A, B, or C, 
preexisting or acute liver disease, or another drug capable of 
causing the observed injury 
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Table 5. 
Criteria for Dose Delay or Dose Modification of Idelalisib 
Toxicity 
Idelalisib 
Grade ≥2 symptomatic 
pneumonitis of any severity 
Permanently discontinue idelalisib 
Grade 2 increased 
ALT/AST/bilirubin or diarrhea 
Maintain idelalisib dose. Monitor at least weekly until 
normal 
Grade 3 increased 
ALT/AST/bilirubin or diarrhea 
Withhold idelalisib. Monitor at least weekly until normal, 
then may resume idelalisib at 100 mg BID. 
Grade 4 increased 
ALT/AST/bilirubin or diarrhea 
Discontinue idelalisib permanently 
Grade 3 neutropenia and/or 
thrombocytopenia 
Maintain Idelalisib dose. Monitor ANC and/or platelet 
count at least weekly 
Grade 4 neutropenia and/or 
thrombocytopenia 
Withhold idelalisib. Monitor ANC and/or platelet count 
at least weekly. When neutropenia and 
thrombocytopenia are Grade 3 or less, may resume 
idelalisib at 100 mg BID 
Grade ≥3 sepsis or pneumonia 
Withhold idelalisib until infection has resolved. 
Active CMV infection of any 
grade or viremia (positive PCR 
or antigen test) 
Withhold idelalisib until the infection and viremia have 
resolved. If idelalisib is resumed, monitor by PCR or 
antigen for CMV reactivation at least monthly.  
Suspected PJP infection of any 
grade. 
Withhold idelalisib. Permanently discontinue idelalisib if 
PJP infection is confirmed. 
Other Grade ≥3 non-
hematologic toxicities 
Withhold idelalisib until resolved, then may resume 
idelalisib at 100 mg BID. If the same grade ≥3 toxicity 
recurs after resuming idelalisib, permanently discontinue 
idelalisib 
Anaphylaxis, Intestinal 
Perforation, Stevens-Johnson 
syndrome (SJS) and toxic 
epidermal necrolysis (TEN) 
Permanently discontinue idelalisib 
Abbreviations: 
ALT=alanine 
aminotransferase; 
ANC= 
Absolute 
neutrophil 
count; 
AST=aspartate 
aminotransferase; 
BID=twice 
daily; 
CMV=cytomegalovirus; 
PCR=polymerase 
chain 
reaction; 
PJP=Pneumocystis jirovecii pneumonia. 
 
Reference: Idelalisib® Prescribing Information For additional information on management of 
toxicities, please refer to the Investigator Brochure for loncastuximab tesirine and to the 
prescribing information or SmPC for idelalisib. 
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6.8 
Supportive Care 
Supportive care specific to loncastuximab tesirine are detailed in below subsections. 
Additional information is available in the loncastuximab tesirine IB. Supportive care for 
idelalisib should be provided based on the idelalisib prescribing information or SmPC, and/or 
according to institutional SOC. 
6.8.1 Management of Edema and Serosal Effusion 
Spironolactone at standard doses should be administered for patients with weight gain greater 
than 1 kg from Cycle 1 Day 1, new or worsening edema, and/or new or worsening serosal 
(pleural, pericardial, or ascitic) effusion. The dose of spironolactone may be titrated as 
clinically indicated. Additional diuretic support may be added if there is further increase in 
weight, edema, or effusion. Additionally, patients should be advised to monitor their weight 
daily, at around the same time (preferably in the morning), and to notify the study site if they 
gain >1 kg (2.2 pounds) over baseline. 
6.8.2 Prevention and Management of Infusion-related Hypersensitivity 
Reactions 
Medications for the treatment of severe hypersensitivity reactions, including anaphylaxis, 
should be available for immediate use and may be administered according to site standard 
treatment protocols.  
Any patient who experiences an infusion-related hypersensitivity reaction should receive 
prophylactic treatment in subsequent cycles according to the guidelines below or institutional 
SOC: 
• On Day 1 of each cycle, patients will be instructed to take dexamethasone 20 mg PO or 
equivalent 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 BID. 
6.8.3 Prevention and Management of Skin Toxicity 
Skin toxicity has been reported in patients receiving loncastuximab tesirine for hematologic 
malignancies. Often, the toxicities manifested as rash were reported in sun exposed areas; it is 
therefore recommended that precautions are taken to avoid exposure of skin to sunlight, even 
through glass (e.g., use of sun protective clothing and sunglasses, sunscreen with a sun 
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protection factor ≥30 applied every 2 hours. Also, fragrance-free detergents and soaps are 
recommended. 
Treatment recommendations for skin toxicities include topical treatment to affected areas: 
• Maculopapular rash or photosensitivity rash: high potency topical steroid cream (e.g., 
clobetasol propionate 0.05%, halobetasol propionate 0.05%) 
• Pruritus: high potency topical steroid cream (e.g., clobetasol propionate 0.05%, 
halobetasol propionate 0.05%) and consider oral antipruritic. 
• Xerosis or hyperpigmentation: consider ammonium lactate 12% or urea 20% BID; and 
triamcinolone 0.1% and triamcinolone 0.1% cream BID. 
• Blistering rash: silvadene 1% cream BID and consider laboratory testing for blistering 
disorder (Varicella Zoster Virus (VZV)/Herpes Simplex Virus (HSV) and bacterial 
infection; bullous pemphigoid; pemphigus) 
Consideration should be given to corticosteroid therapy in patients who develop clinically 
significant skin toxicity. Also, for grade ≥2 skin toxicities consider a dermatology consult. 
6.8.4 Contraceptive Guidance 
Women of childbearing potential* must agree to use a highly effective method of contraception, 
and men with female partners who are of childbearing potential must agree to use a condom 
when sexually active or practice total abstinence from the time of giving informed consent 
until the study drug is safely cleared from the body. Please refer to Section 5.1 Inclusion 
Criterion #9 for information on the definition of WOCBP and recommended highly effective 
methods of contraception.  
• For patients with loncastuximab tesirine treatment, if applicable, the highly effective 
birth control must be followed from the date of signing the ICF until at least 9 months 
after last dose of loncastuximab tesirine administration for WOCBP, and at least 
6 months after the last dose of loncastuximab tesirine for male patients with female 
partners of reproductive potential.  
• For patients with idelalisib treatment, if applicable, the highly effective birth control 
mut be followed from the date of signing the ICF until 1 month after the last dose of 
idelalisib for WOCBP, and 3 months after the last dose of idelalisib for male patients 
with female partners of reproductive potential. 
• If WOCBP use hormonal contraceptives such as birth control pills, a second barrier 
method of contraception (e.g., condoms) must be used during idelalisib treatment until 
1 month after last dose of idelalisib. 
Please refer to Section 7.4.6 for pregnancy test, and Section 8.5.2 for reporting pregnancy.  
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6.8.5 Other Supportive Care 
• Patients receiving idelalisib treatment should receive Pneumocystis jirovecii pneumonia 
(PJP) prophylaxis based on institutional standard of care. 
• Patients receiving idelalisib and who have positive CMV serology or a history of CMV 
infection should be monitored for CMV viremia using CMV antigen or PCR. Patients who 
develop CMV viremia should have idelalisib held and CMV treatment based on 
institutional standard of care. 
• Although the study patient population has a low risk for development of tumor lysis 
syndrome (TLS) compared to patients with acute disease (Cairo et al, 2010), patients 
should be observed for development of TLS and treated according to site standard 
treatment protocols. 
• As testing in animals showed testicular toxicity (atrophy with reduced spermatogenesis), 
male patients are advised to consider cryopreservation of sperm prior to treatment with 
loncastuximab tesirine, where applicable. 
6.9 
Concomitant Medications and Procedures 
Medications (except for the study treatment) and procedures will be recorded in the eCRF 
starting from the ICF signature date or from 14 days prior to C1D1, whichever is earlier, and 
continuing until at least 30 days after last dose of study treatment. 
6.9.1 Permitted During Study 
Medications or procedures for the clinical care of the patient, including management of AEs, 
are permitted during the study, except for those listed in Section 6.9.2.  
6.9.2 Prohibited During Study 
The following treatments are prohibited during study treatment but are allowed in the 
follow-up period. 
• Other anticancer therapy with the exception of hormonal therapy for maintenance treatment 
of breast and prostate cancer. 
• Other investigational agents 
• Live vaccines until 3 months after last dose of study drug. 
• In patient receiving idelalisib, strong CYP3A inducers/inhibitors and sensitive substrates 
should be avoided. Information on strong CYP3A inducers, inhibitors and sensitive 
substrates 
may 
be 
found 
in 
Section 12.3 
(Appendix 3) 
or 
at 
http://medicine.iupui.edu/clinpharm/ddis/main-table/ 
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7 Study Assessments and Procedures 
Study assessments and procedures are to be completed as described below; however, there may 
be situations (e.g., safety issues) preventing their completion. In such case, the Investigator 
should take all actions necessary to ensure the safety and well-being of the patient and 
document the reason for not performing the assessment.  
The Schedule of Events (SoE) tables are listed per treatment arm for the study. Table 1 is for 
loncastuximab tesirine arm and Table 2 is for idelalisib arm.   
7.1 
Informed Consent 
Informed consent, as documented by a signed and dated ICF, must be obtained prior to 
performing any study procedures. Results (e.g., from laboratory tests or radiographic 
evaluations, etc.) obtained prior to the date of informed consent but within the allowed 
timeframe may be used for determination of patient eligibility only if obtained as part of 
standard care. For additional details, please refer to Section 10.3. 
7.2 
Demographics and Baseline Characteristics 
These assessments include: 
• Demographic information such as age, gender, ethnicity, and race; to the extent allowed by 
local regulations. 
• Cancer medical history, which includes a complete history of all surgeries and significant 
diagnoses, and all cancer treatments, including surgery, radiation therapy, chemotherapy, 
etc. 
• Any significant medical history.  
• Collection of information on prior medications used from ICF signature date or at least 
within 14 days prior to study drug administration, whichever is earlier. 
7.3 
Efficacy Assessments 
Disease assessment will occur as per SoE (Table 1 or Table 2). 
Screening (Baseline) imaging should be performed within 4 weeks prior to C1D1. 
During the treatment period, imaging will be performed 6 weeks and 12 weeks after C1D1, 
then every 12 weeks until 2 years from C1D1, then every 6 months. Imaging for disease 
assessment will continue until disease progression or initiation of other anti-cancer therapy 
(except for hematopoietic stem cell transplant). Week 6 and Week 12 imaging should be 
performed within ±5 days of the scheduled time point; all other imaging should be performed 
within ±2 weeks of the scheduled time point. Disease assessments should take place at the 
timepoints specified even if study drug dosing is delayed. Additional disease assessments may 
be obtained, if clinically indicated. 
Response data from investigators may be collected for patients who receive chimeric antigen 
receptor T cells (CAR-T) therapy until 90 days after receiving CAR-T therapy. 
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Positron emission tomography-computed tomography (PET-CT) of the neck/chest/abdomen/ 
pelvis and other areas of known disease or newly suspected disease, as well as a clinical 
examination for lymphoma, will be performed. If it is known that the tumor is FDG-avid, the 
baseline CT as part of the PET-CT does not have to be performed with contrast medium; 
however, if the baseline PET-CT shows that the tumor is not FDG-avid, diagnostic CT with 
IV contrast will need to be obtained as a baseline examination. For this reason, if it is known 
that the tumor is not FDG-avid on previous imaging, consideration should be given to obtaining 
a diagnostic quality CT with IV contrast as part of the initial PET-CT examination. Patients 
who have a contraindication to CT IV contrast medium should have MRI examinations 
performed instead. The assessment method determined to identify sites of disease at Baseline 
(i.e., PET-CT, CT, MRI) should be used for all subsequent assessments. 
Patients whose tumor is not FDG-avid should have a bone marrow biopsy as part of their 
baseline staging and disease assessment if clinically appropriate. 
The patient’s response to treatment will be determined according to the 2014 Lugano 
Classification Criteria (Appendix 2) as CR, PR, stable disease (SD), or progressive disease 
(PD). Patients with clinical progression should have a radiographic disease assessment to 
confirm progression unless contraindicated. Radiographic disease assessment modality should 
be the same as that used to identify sites of disease at Baseline. 
Images will be obtained according to imaging requirements as outlined in the imaging manual 
and will be submitted for a central/independent review. Central imaging review will be 
performed using two blinded independent reviewers with adjudication by a third blinded 
independent reviewer in cases of discordance. Submission instructions for the 
central/independent review will be provided in a separate manual. 
7.4 
Safety Assessments  
Safety will be assessed based on the procedures in the subsection below. Adverse events/SAEs 
collection and reporting is described in Section 8. 
Unless otherwise specified, all safety assessments on dosing days will be done prior to study 
treatment administration. Additional safety assessments may be performed by the Investigator 
when clinically indicated. 
7.4.1 Physical Examination 
Planned time points for physical examination are provided in the SoE (Table 1 or Table 2). 
A complete physical examination will be performed at screening. 
Limited, symptom-directed physical examinations should be performed at specified post 
baseline visits and as clinically indicated. 
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7.4.2 ECOG Performance Status 
Eastern Cooperative Oncology Group performance status grades are presented in Section 12.1, 
Appendix 1 and will be captured at the planned timepoints provided in the SoE (Table 1 or 
Table 2). 
7.4.3 Height and Weight 
Planned time points for height and weight are provided in the SoE (Table 1 or Table 2). 
7.4.4 Vital Signs 
Planned time points for vital signs are provided in the SoE (Table 1 or Table 2). 
Vital signs include the measurements of arterial blood pressure (systolic and diastolic), 
heart rate, respiratory rate, and body temperature and will be performed according to the 
institutional standards. 
For Day 1 of each cycle, vital signs are to be measured before the start of the infusion and at 
the end of infusion for patients on the loncastuximab tesirine arm; vital signs will be measured 
once during visit for patients on the idelalisib arm. 
7.4.5 Laboratory Tests 
Samples will be collected at the time points specified as per SoE (Table 1 or Table 2). 
Additional sample(s) may be collected and analyzed if clinically indicated. The C1D1 
laboratory tests do not need to be repeated if the laboratory tests for eligibility were done within 
3 days of C1D1. 
Hematology: red blood cell (RBC), white blood cells (WBC) with 5-part differential 
(neutrophils, eosinophils, basophils, lymphocytes, and monocytes), platelet count, hemoglobin, 
and hematocrit.  
Chemistry: ALT, AST, GGT, ALP, amylase, lipase, total bilirubin (conjugated and 
unconjugated bilirubin only when total bilirubin is abnormal), sodium, potassium, chloride, 
phosphorus/phosphate, calcium, magnesium, blood urea nitrogen or urea, carbon 
dioxide/bicarbonate, creatinine, creatinine clearance, creatine phosphokinase, total protein, 
albumin, glucose, and lactate dehydrogenase, uric acid.  
Coagulation: partial thromboplastin time (PTT)/activated PTT (aPTT) and International 
Normalized Ratio (INR). 
Urinalysis: pH, specific gravity, protein, WBC, RBC, ketones, glucose, and bilirubin. 
Urinalysis may be performed by dipstick. Abnormal findings will be followed up with a 
microscopic evaluation and/or additional assessments as clinically indicated. A microscopic 
evaluation consists at a minimum of WBC and RBC quantitation per high power field, as well 
as semi-quantitative assessment of other cells and substances, if present, such as epithelial cells, 
bacteria, and crystals (“few,” “moderate,” “many”). Other evaluations depending on 
microscopic findings may be added. 
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Other tests:  
HBV and/or HCV serology tests, and viral load test if clinically indicated. 
HIV serology tests, and HIV viral load and /or CD4+ T cell count if clinically indicated. 
CMV screening tests: CMV IgG test, and CMV antigen or PCR test for all patients during 
screening period. 
CMV monitoring tests: CMV antigen or PCR test for patients with positive CMV serology or 
history of CMV infection who are receiving treatment with idelalisib. 
7.4.6 Pregnancy Test 
A highly sensitive β subunit of Human chorionic gonadotropin (β-HCG) test in blood or urine 
will be performed in WOCBP for eligibility (see Section 5.1) and throughout the study as per 
SoE (Table 1 or Table 2) and as needed. 
When possible, for WOCBP patients treated with loncastuximab tesirine, a final pregnancy 
test should be performed ≥9 months post last drug dose, however, remote pregnancy test is 
acceptable. 
Pregnancy test must be negative prior to study drug infusion. 
If a urine pregnancy test is positive, the study treatment must be held pending pregnancy 
confirmation. If the pregnancy is confirmed by serum β-HCG test, study treatment will be 
discontinued permanently for the patient. Refer to Section 8.5.2 for the handling of the patient 
and reporting the event. 
7.4.7 Electrocardiograms 
Three consecutive (also called triplicate) 12-lead electrocardiograms (ECGs) will be conducted 
at defined timepoints as per SoE (Table 1 or Table 2) and Table 6. The 12-lead ECGs will be 
performed after the patient is resting for at least 5 minutes. 
At timepoints coinciding with blood sample collection, including PK, ECGs should be taken 
prior to blood collection, and, when applicable, before vital signs measurements. For 
loncastuximab tesirine arm a preferred sequence for triplicate ECG, vital signs, and PK sample 
assessments at End of Infusion (EOI) is demonstrated in Figure 2. 
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. Eligibility and clinical decisions 
may be made based on the local ECG assessment. 
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Figure 2. 
Preferred Sequence for Triplicate Electrocardiogram (ECG), Vital Signs, 
and Pharmacokinetic (PK) Sample Assessments at End of Infusion (EOI) 
 
 
7.5 
Pharmacokinetics, Pharmacodynamics, and Immunogenicity 
The PK, anti-drug antibody (ADA), and
 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, 
 
When multiple samples are required at the same timepoint, collection of safety samples should 
be first, followed by PK, then ADA, 
. 
In order to better understand the disease, metabolic disposition, and pharmacologic behavior 
of loncastuximab tesirine in humans, samples remaining after primary analyses may be utilized 
for further analysis. 
Biological samples may be retained for up to 10 years to further address scientific questions as 
new information in regard to the disease or the study drug becomes available. 
For detailed instructions related to central laboratory sample collection, labeling, processing, 
storage, or shipment refer to the appropriate laboratory manual(s). 
7.5.1 Pharmacokinetics  
The concentration in serum of loncastuximab tesirine (total antibody), PBD-conjugated 
antibody, and unconjugated warhead SG3199 for samples taken prior to and immediately after 
dosing on Cycles 1 through 6, and end of treatment in patients on loncastuximab tesirine will 
be assessed by a central laboratory designated by the Sponsor using validated bioanalytical 
methods. In addition, matching PK samples will be drawn at ADA collection time points from 
Cycle 7 and beyond during study treatment. 
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Approximately 6 mL of whole blood will be collected as per Table 1 and Table 6. Blood should 
be drawn from a vein away from the one used for study drug infusion. 
PK samples must be stored at ≤ -70°C. Please refer to the laboratory manual for detailed 
instructions regarding specimen handling and shipment. 
At timepoints coinciding with ECG collection, PK blood collection should occur immediately 
after the end of the ECG recording and, when applicable, after vital signs. 
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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Table 6. 
Sampling Schedule for ECG, PK, ADA and 
 
Cycle 
Day 
ECG timepoint  PK timepoint 
loncastuximab 
tesirine 
arm 
only 
ADA timepoint 
loncastuximab 
tesirine arm only 
 
Screening 
-28 to 
-1 
X 
 
 
C1-C6 
D1 C1: Pre-dose 
only 
C2: Pre-dose for 
all subjects & 
EOI (Within 10 
min prior to EOI) 
for 
loncastuximab 
tesirine arm only 
X 
Pre-dose & 
EOI: Within 
10 min post 
EOI  
C1, C3, and C5 
only: Pre-dose  
C7 & 
Beyond 
D1  
C7, then 
every other 
cycle 
Pre-dose 
C7, then every 
other cycle 
Pre-dose 
EOT 
 
Anytime during 
EOT visit  
 
X 
 
X 
Follow-Up 
 
 
 
If ADA positive 
is detected, 
additional ADA 
samples may be 
requested for 
testing every 12 
weeks until the 
ADA titer falls to 
the baseline level  
**Pre-dose: preferably within 2 h prior to start of infusion 
Abbreviations: ADA=anti-drug antibody; C=cycle; D=day; ECG=electrocardiogram; EOI=end of infusion; 
EOT=end-of-treatment; h=hour; min=minute; PK=pharmacokinetics; 
; 
 IP=Investigational Product 
 
7.5.2 Immunogenicity 
Detection of ADAs will be performed by using a screening assay for identification of antibody-
positive samples/patients, a confirmation assay, and titer assessment and will be performed 
using the Meso-Scale Discovery Electrochemiluminescence platform. If an ADA is confirmed, 
a functional assay for the assessment of the neutralizing capacity of the ADA will be performed.  
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Blood samples for ADA testing will be collected pre-dose on C1D1, then Day 1 of every other 
cycles from patients assigned to loncastuximab tesirine arm only. Up to 6 mL of whole blood 
will be collected each time as per Table 1 and Table 6. 
Blood should be drawn from a vein away from the one used for study drug infusion. 
For patients who test positive for ADA, additional ADA samples may be requested for testing 
every 12 weeks following the EOT visit until the ADA titer falls to the baseline level 
ADA samples must be stored at ≤ -70°C. Please refer to the laboratory manual for detailed 
instructions regarding specimen handling and shipment. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
. 
7.6 
Patient Reported Outcomes 
The impact of study treatment on disease- related symptoms, symptomatic adverse events, as 
well as various aspects of patient’s health-related quality of life (HRQoL), will be assessed by:  
• EuroQoL-5 Dimensions-5 Levels (EQ-5D-5L) (Appendix 4). 
• Functional Assessment of Cancer Therapy – Lymphoma (FACT-Lym) (Appendix 5). 
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• GP5 item of FACT-Lym (Appendix 6) 
• Selected symptomatic adverse events from the PRO-CTCAE library, including fatigue, 
swelling, rash, nausea, diarrhea, abdominal pain, and cough (Appendix 7). 
Questionnaires will be completed in the respondent’s native language, at the scheduled time 
points as per Table 1 or Table 2. Responses to PRO questionnaires will be collected 
electronically. 
1. Both EQ-5D-5L and FACT-Lym will be completed at study site with the exception of 
EQ-5D-5L follow -up assessments, which may be completed by phone (see Table 1 or 
Table 2). 
2. Both GP5 item of FACT-Lym and selected PRO-CTCAE items will be completed by 
patients at home, with the exception of the PRO-CTCAE items at baseline (Cycle 1 
Day1), which will be answered at study site (see Table 1 or Table 2). 
Questionnaires should always be administered prior to clinical assessment if applicable. The 
patient should be given instructions, space, time, and privacy to complete the questionnaires 
by themselves and without any assistance from anyone else. The study coordinator should 
encourage the patient to complete the questionnaires without any missing responses. 
7.6.1 EuroQol-5 Dimensions-5 Levels (EQ-5D-5L) 
EQ-5D-5L is a standardized, generic instrument for describing health status as the patient 
experiences 
them 
“today.” 
It 
is 
used 
for 
clinical 
and 
economic 
evaluation 
(EuroQol Research Foundation, 2019). The EQ-5D-5L consists of two parts:  
• The descriptive system: consists of five single-item dimensions: mobility, self-care, usual 
activities, pain/discomfort, and anxiety/depression. Each dimension comprises five levels 
of perceived problems (e.g., none, slight, moderate, severe, extreme/unable to). 
• The visual analog scale (VAS): patients are asked to rate their current health on a 100-point 
scale, ranging from ‘the best health you can imagine’ (score 100) and ‘the worst health you 
can imagine’ (score 0). Patients are asked to mark an “X” on the VAS to indicate their own 
health and then to report the score in a text box. If there is a discrepancy between where 
the patient has placed the X and the number, he/she has written in the box, the number in 
the box is to be entered in the CRF together with a comment indicating the discrepancy. 
Patients will complete this questionnaire as per the SoE (Table 1 or Table 2). 
7.6.2 Functional Assessment of Cancer Therapy - Lymphoma (FACT-Lym) 
FACT-Lym (Version 4) is a HRQoL questionnaire validated in patients with B-cell and other 
types of NHL (Cella et al., 2005; Hlubocky et al., 2013). It has been widely used in NHL trials, 
for example, the phase III GADOLIN study in patients with rituximab-refractory indolent NHL 
including FL (Cheson et al., 2017), the phase III GALLIUM study in previously untreated, 
advanced indolent NHL including FL (Thielen et al., 2019), and the RESORT E4402 study in 
patients with low–tumor burden NHL including FL (Wagner et al., 2015). FACT-Lym consists 
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of a general HRQoL assessment (FACT-G) and a disease-specific subscale (Lymphoma 
subscale, LymS). FACT-G (27 items) measures four functional dimensions: physical well-
being (PWB), social/family well-being (SWB), emotional well-being (EWB), and functional 
well-being (FWB). The LymS (15 items) addresses symptoms and functional limitations that 
are important to patients with NHL, such as pain, lump or swelling, fatigue, fever, night sweats, 
itching, and weight loss. All items use a 0-4 ordinal measurement where 0 = not at all, 1 = a 
little bit, 2 = somewhat, 3 = quite a bit, and 4 = very much. The summary scores for PWB, 
SWB, EWB, FWB and LymS are computed as the sum of corresponding items (after reversed 
coding for the negatively stated items) with higher values indicating better quality of life. Three 
composite scores are also derived: Trial Outcome Index (TOI: sum of PWB, FWB, LymS), 
FACT-G total (sum of PWB, SWB, EWB, FWB), and FACT-Lym total (sum of FACT-G total 
and LymS). Patients will complete this questionnaire as per the SoE (Table 1 or Table 2). 
7.6.3 FACT-Lym GP5  
A single item from the FACT-Lym, GP5, will be administered to assess the extent of perceived 
bother due to symptomatic AEs. Evidence exists for the validity of this item and its usefulness 
as an overall summary measure of burden due to symptomatic treatment toxicities 
(Pearman, 2018). Patients will complete this question as per the SoE (Table 1 and Table 2). 
7.6.4 Patient-Reported Outcomes version of the Common Terminology 
Criteria for Adverse Events (PRO-CTCAE™) – Selected Items 
PRO-CTCAE is a patient-reported outcome measurement system developed to evaluate 
symptomatic toxicity in patients on cancer clinical trials. The PRO-CTCAE Item Library 
contains 124 items representing 78 symptomatic toxicities drawn from the Common 
Terminology Criteria for Adverse Events (CTCAE). PRO-CTCAE items assess the symptom 
attributes of frequency, severity, interference, amount, presence/absence. Each symptomatic 
AE is evaluated by 1-3 attributes. The PRO-CTCAE has been developed as a standardized 
measurement that can provide a flexible fit-for-purpose approach to assess relevant 
symptomatic AEs for the trial (Kluetz 2016). The PRO-CTCAE Measurement System are 
validated in accordance with well-established PRO instruments (Dueck 2015). The PRO-
CTCAE items included in this study are fatigue, swelling, rash, nausea, diarrhea, abdominal 
pain, and cough. These AEs are selected in an unbiased manner based on the symptomatic 
adverse events reported in Loncastuximab tesirine 402-201 trial of patients with R/R DLBCL 
(Carmelo Carlo-Stella, EHA 2020) and Idelalisib package insert for FL indication. Specifically, 
symptomatic AEs with occurrence in at least 20% of patients treated with either therapy are 
selected. Patients will complete these questions as per the SoE (Table 1 or Table 2). 
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8 Adverse Events 
Reporting 
of 
AEs 
to 
competent 
authorities 
and 
Independent 
Review 
Boards 
(IRBs)/Independent Ethics Committees (IECs) will be consistent with current laws, regulations, 
and guidelines. 
8.1 
Definition of Adverse Events and Serious Adverse Events 
8.1.1 Adverse Events 
An AE is defined as any untoward medical occurrence in a patient or clinical investigation 
subject administered a pharmaceutical product, which does not necessarily have to have a 
causal relationship with this treatment.  
An AE does not include the following: 
• Medical or surgical procedures such as surgery, endoscopy, tooth extraction, and 
transfusion. The condition that led to the procedure may be an adverse event and must be 
reported. 
• Pre-existing diseases, conditions, or laboratory abnormalities present or detected before the 
screening visit that do not worsen. 
• Situations where an untoward medical occurrence has not occurred (e.g., hospitalization 
for elective surgery, social and/or convenience admissions) 
Test results collected during the study (e.g., laboratory values, physical examination, ECGs, 
etc.) or identified from review of other documents may constitute AEs if deemed clinically 
significant.  
8.1.2 Serious Adverse Events 
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. 
• an important medical event that does not meet the preceding criteria but based on 
appropriate medical judgment may jeopardize the patient or may require medical or 
surgical intervention to prevent any of the outcomes listed above. 
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8.1.3 Clinical Laboratory Abnormalities and Other Abnormal Assessments 
as Adverse Events or Serious Adverse Events 
Laboratory abnormalities (e.g., clinical chemistry, hematology, and urinalysis) or other 
abnormal assessments (e.g., electrocardiogram, x-rays, vital signs) without clinical 
significance are not recorded as AEs or SAEs. However, laboratory abnormalities/other 
abnormal assessments that require medical or surgical intervention or lead to pharmaceutical 
product interruption, modification, or discontinuation must be recorded as an AE, as well as 
an SAE, if applicable. If the laboratory abnormality/other abnormal assessment is consistent 
with a clinical diagnosis, report the adverse event using the diagnosis (i.e., anemia), not the 
laboratory result (i.e., decreased hemoglobin). 
8.2 
Eliciting and Reporting Adverse Events/Serious Adverse Events 
Patients will be instructed to contact the Investigator at any time after ICF signature if any 
symptoms develop. At each study visit, patients will be asked a nonleading question to elicit 
any medically related changes in their well-being. Patients may also report AEs voluntarily 
and they will be instructed to contact the Investigator between visits if any symptoms develop 
or worsen.  
AEs will be reported starting when the patient provides written informed consent. Clinically 
significant medical conditions present at the time of ICF signature will be reported as medical 
history. Clinically significant medical conditions that start or worsen after ICF signature will 
be reported as AEs. 
All AEs, regardless of relationship to study treatment, will be reported from the time the patient 
signs the ICF until 30 days after the last dose of study treatment.  
All SAEs, regardless of relationship to study treatment, will be reported from the date patient 
signs the ICF until at least 76 days after last dose of study drug, or start of new anticancer 
therapy, whichever is earlier; thereafter, only related SAEs will be reported. 
Whenever possible, AEs should be reported as a diagnosis rather than individual signs and 
symptoms. If no diagnosis is available or has been identified, then the primary symptom is 
reported.  
In general, the term ‘disease progression’ should not be used for reporting an AE/SAE. 
However, AEs/SAEs that are complications of disease progression should be reported. 
All AEs reported or observed during the study will be recorded on the AE page of the 
eCRF.  Information to be collected will include event term, date of onset, assessment of 
severity (Section 8.3), seriousness (Section 8.1), relationship to study treatment (Section 8.4), 
action taken with study treatment, 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 
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research organization [CRO]) within 24 hours after the time site personnel first learn about the 
event. Reporting will occur through the EDC system. 
8.3 Assessment of Severity 
The AEs will be graded according to CTCAE v5.0. For events not included in the CTCAE 
criteria, the severity of the AE is graded on a scale of 1 to 5 as shown in Table 7.  
Table 7. 
Definition of Severity Grades for CTCAE 
Grade 
Definition 
1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated. 
2 
Moderate; minimal, local or noninvasive intervention indicated; limiting 
age-appropriate instrumental activities of daily living (ADL).a 
3 
Severe or medically significant but not immediately life threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting 
self-care ADL.b 
4 
Life-threatening consequences; urgent intervention indicated. 
5 
Death related to adverse event. 
a ADL refers to preparing meals, shopping for groceries or clothes, using the telephone, managing money, etc. 
b Self-care ADL refers to bathing, dressing and undressing, feeding self, using the toilet, taking medications, and 
not bedridden.  
 
The AEs characterized as intermittent do not require documentation of onset and duration of 
each episode. 
8.4 
Assessment of Causality 
The Investigator’s assessment of an AE’s relationship to study treatment is an important part 
of safety reporting, but is not a factor in determining whether an AE is reported. An AE will 
be assessed as related to study treatment if there is a reasonable possibility of causal 
relationship with the use of the study treatment. For SAEs, whenever possible, the Investigator 
should provide a rationale for the causality assessment. 
The investigator or qualified subinvestigator is responsible for providing an assessment of the 
relationship to the study drug(s) using clinical judgment and the following considerations: 
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Causality 
Definition 
Not related 
An adverse event is not related to the study drug 
Unlikely related 
An adverse event where evidence exits for an alternative 
explanation other than the study drug e.g concomitant 
medication(s), concomitant disease(s), or time to onset suggests 
unlikely relationship. 
Possibly related 
An adverse event that might be due to study drug. An alternative 
explanation (e.g concomitant medication(s), concomitant disease(s), 
or time to onset) is inconclusive, where a causal relationship with 
study drug cannot be ruled out. 
Probably related 
An adverse event that might be due to study drug. An alternative 
explanation 
(e.g 
concomitant 
medication(s), 
concomitant 
disease(s)) is less likely, and where a causal relationship with study 
drug 
is 
more 
suggestive 
(ie 
time 
to 
onset, 
positive 
dechallenge/rechallenge). 
Related 
An adverse event where an alternative explanation cannot be 
explained and, therefore, considered related to study drug. 
 
8.5 
Special Situations Reports 
8.5.1 Definitions of Special Situations 
Any special situation occurring in a participant that may require expedited reporting or safety 
review may include the following with the study drug: 
• Pregnancy reports (see Section 8.5.2) 
• Overdose reports (see Section 8.5.3) 
• Other special situations (see Section 8.5.4), such as: 
o Suspected misuse or abuse  
o Accidental exposure 
o Medication error 
o Exposure to the study drug from breast-feeding  
o Adverse events associated with product complaints 
8.5.2 Reporting Pregnancy 
Any pregnancy in a participant that occurs from the time the patient signs the ICF up to 
9 months after discontinuation of loncastuximab tesirine or up to 1 months after terminating 
idelalisib treatment during the study must be reported using the Pregnancy Report Form. Any 
pregnancy in a partner of a male participant that occurs from signing the ICF up to 6 months 
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post last loncastuximab tesirine or up to 3 months post last idelalisib during the study must be 
reported. Pregnancy must be reported within 24 hours after the site personnel first learn of the 
pregnancy. The pregnancy itself is not considered an AE. However, the pregnancy must be 
followed to determine outcome (including spontaneous miscarriage, elective termination, 
normal birth, or congenital abnormality) and status of mother and child, even if the patient 
discontinued from the study. Abortions (elective or spontaneous) occurring during the 
pregnancy reporting period must be reported as an SAE. 
Any SAE occurring in association with a pregnancy that is brought to the Investigator’s 
attention after the patient has completed the study and considered by the Investigator as 
possibly related to the study treatment must be promptly reported in the same manner. 
Once pregnancy is confirmed in a study participant, study treatment will be discontinued, 
see Section 7.4.6 for additional information. 
8.5.3 Reporting Overdose 
An overdose of the study drug(s) is defined under Section 6.6. 
An overdose itself is not considered an AE. However, if such an overdose occurs during the 
study, with or without any signs or symptoms, it must be reported to ADC Therapeutics within 
24 hours after the time site personnel first learn about the event.  
8.5.4 Reporting Other Special Situations 
All other special situation reports must be reported within 24 hours after the time site personnel 
first become aware of the situation. 
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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 Determination 
Approximately 150 patients will be enrolled and randomly assigned to treatment with 
loncastuximab tesirine or idelalisib in a 2:1 ratio. The study is over-powered for the primary 
efficacy endpoint when a 55% of CRR in loncastuximab tesirine (compared to observed 64.3% 
CRR in Phase 1 trial) and 15% from idelalisib (Salles G, 2017) are assumed. The purpose of a 
larger sample size and 2:1 randomization ratio is to provide a more robust safety data set (~100 
FL patients treated with loncastuximab tesirine). Table 8 and Table 9 summarizes the study 
power when different CRR and ORR are expected.  
Table 8. 
Power for Primary Endpoint CRR with 2-Sided Significance Level 0.05 
Expected CRR from loncastuximab tesirine 
arm* 
55% 
45% 
40% 
CRR from idelalisib arm** 
15% 
15% 
15% 
Power*** 
99% 
96.1% 
87.3 
* Data from Phase 1 trial (ADCT-402-101) shows that CRR is approximately 64%, lower CRRs are assumed 
in this study 
** CRR from idelalisib is assumed to be 15% (Salles G, 2017) 
*** Based on nquery fisher’s exact test 
Table 9. 
Power for Key Secondary Endpoint ORR with 2-Sided Significance 
Level 0.05 
Expected ORR from loncastuximab tesirine 
arm* 
79% 
75% 
70% 
ORR from idelalisib arm** 
54% 
54% 
54% 
Power*** 
84.1% 
67.3% 
41.7% 
* Data from Phase 1 trial (ADCT-402-101) shows that ORR is approximately 79%. 
**ORR from idelalisib is assumed to be 54% (Idelalisib® US- Prescribing Information).  
*** Based on nquery fisher’s exact test 
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9.2 
Analysis Populations 
• Intent-to-treat (ITT) Population: All patients who are randomized. This population will 
be used in the primary analyses of efficacy. 
• All-Treated Population: All patients who receive at least 1 dose of loncastuximab 
tesirine or idelalisib. This population will be used in the primary analyses of safety. 
• Per-Protocol Population: All patients in the all-treated population without important 
protocol deviations, which will be further described in detail in the SAP. 
• The PK Population: All patients who receive loncastuximab tesirine and have at least 
1 pre-(C1D1) and 1 post dose valid assessment. 
• The Immunogenicity Population: All patients who receive loncastuximab tesirine and 
have at least 1 valid ADA assessment. 
• The Pharmacodynamic Population: All patients who receive study drug and have at least 
1 valid pharmacodynamics/
  
• Patient-reported Outcomes Population: All patients who receive at least 1 dose of study 
treatment and complete at least one questionnaire at baseline and at one postbaseline 
visit. 
9.3 
Interim Analysis 
A non-binding futility analysis on the primary endpoint of CRR will be performed for the first 
60 patients (40% patients) around 12 weeks after the 60th patient is randomized (enough time 
for 2 disease assessments). O’Brien-Fleming spending function as the non-binding lower 
bound (futility) will be used. The details will be provided in SAP. 
9.4 
Final Analysis 
For primary and key secondary endpoint analyses, a database snapshot will be taken 12 months 
after last patient is randomized in order to allow approximately 9 months of duration of 
response follow up. All efficacy and safety endpoints will be analyzed and reported in the 
clinical study report (CSR). 
Results of the population PK analysis will be reported separately. 
The CR rate will be tested in the intent-to-treat population between two treatment arms by 
using Cochran–Mantel–Haenszel (CMH) method adjusted by stratification factors from 
randomization list. The point estimates for odds ratio and difference in CRR with 95% 
confidence interval (CI) will be presented. If CRR is significantly different between two arms, 
the key secondary endpoint ORR will be sequentially tested using the same approach as CRR. 
The PFS and OS analysis will be performed using PROC LIFETEST adjusted by stratification 
factor from randomization list. Kaplan-Meier plot for PFS, OS, and DOR will be presented by 
treatment.  
Follow-up analyses will be performed when all the patients complete the study per protocol. 
The results will be reported as CSR addendum. 
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9.5 
Demographics and Baseline Characteristics 
Demographics and Baseline characteristics, such as cancer history and medications history, 
will be summarized for the ITT Population. 
The Follicular Lymphoma International Prognostic Index (FLIPI) (Solal-Celigny P, 2004) will 
be calculated based on 5 clinical and laboratory parameters (age, Ann Arbor stage, number of 
nodal areas, LDH, and hemoglobin level) derived from baseline visit. In case required data 
point is missing for the baseline visit, then data from the screening visit will be used. 
9.6 
Exposure to Treatments 
Exposure to study treatment, prior, and concomitant medications will be summarized for the 
All-treated Population. Dose interruptions, reductions, and relative dose intensity will also be 
summarized. 
9.7 
Efficacy Analyses 
Efficacy analyses will be based on disease assessment by central review. The primary efficacy 
analysis will be CRR analysis, and ORR will be a key secondary endpoint. Additional 
secondary efficacy analyses will include analyses of PFS, OS, and DOR. 
Response reported by investigators (CRR, PFS, ORR, DOR) will be used for sensitivity 
analyses. 
When best overall response (BOR) is determined, 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 treatment. Any tumor assessment indicating SD before this time period will be 
considered as a non-evaluable for BOR if no assessment after this time period is available. 
9.7.1 Complete Response Rate 
Complete Response Rate assessed according to the 2014 Lugano classification will be defined 
as the proportion of patients with a BOR of CR, based on response assessments obtained prior 
to any subsequent cancer treatment. The percentage of CRR with its 95% CI will be presented. 
For the primary CRR and secondary ORR analysis in the ITT population, patients with missing 
response or not evaluable information will be counted as failures. 
The CR rate will be tested in the ITT population between two treatment arms by using CMH 
method adjusted for stratification factor in randomization list. The point estimates for odds 
ratio and difference in CRR with 95% CI will be presented. 
A sensitivity analysis using exact method for CRR without adjusting for the covariate will also 
performed. In addition, CRR will be analyzed using CMH method adjusted for prognostic 
baseline covariates (e.g., age, disease characteristics, FLIPI, region etc.) in the sensitivity 
analysis. If there are continuous variables, logistics regression may be used. 
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9.7.2 Overall Response Rate 
The ORR will be defined as the proportion of patients with a BOR of CR or PR. The overall 
response category will be derived based on response assessment performed on or before the 
start of subsequent anti-cancer therapy. For the primary ORR analysis in the all-treated 
population, patients with a CR or PR will be counted as successes and all other patients 
(including those with missing response information) will be counted as failures. The ORR will 
be tested in the ITT population by using the same approach as primary analysis and it will be 
tested only after primary analysis is significant. Similar sensitivity analyses will be performed 
for primary endpoint. 
9.7.3 Progression-Free Survival  
The PFS will be defined among ITT patients as the time from randomization date until the first 
date of either disease progression or death due to any cause. The date of disease progression 
will be defined as the earliest date of disease progression based on central review. 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 prior to initiation of a new anticancer therapy 
including Hematopoietic Stem Cell Transplantation (HSCT). Stratified Log-rank testing will 
be used to compare PFS between the 2 treatment arms. The hazard ratio along with the 95% 
confidence interval (CI; 2-sided) will be estimated using the stratified Cox model with 
treatment as the explanatory variable. The stratification factor from the randomization list will 
be used. The Kaplan-Meier (K-M) survival curves, 25th, 50th (median), 75th percentiles (if 
estimable), and survival probability at 0.5, 1, and 2 years along with the 2-sided 95% CIs will 
also be provided for each treatment group. Further details will be outlined in the SAP. 
A sensitivity analysis of PFS will be conducted in which the PFS for patients undergoing HSCT 
will not be censored at HSCT. 
In addition, a stratified Cox regression model may be used to further evaluate the treatment 
effects on PFS after adjusting for some prognostic factors. Besides treatment and the 
stratification factor from the randomization list, the following prognostic factors may be 
included in the model simultaneously: age, race (white, non-white), baseline ECOG score, 
FLIPI, baseline cancer stage. 
 
 
9.7.4 Overall Survival 
Median OS will be defined as the time from the randomization date until death due to any 
cause. For patients who have not died at the time of the analysis, censoring will be performed 
using the date the patient was last known to be alive. Stratified Log-rank testing will be used 
to compare OS between the 2 treatment arms. The hazard ratio along with the 95% confidence 
interval (CI; 2-sided) will be analyzed by using stratified Cox model with treatment as the 
explanatory variable. The stratification factors from randomization list will be used. The 
median OS time, The Kaplan-Meier (K-M) survival curves, 25th, 50th (median), 75th 
percentiles (if estimable), and survival probability at 0.5, 1, and 2 years along with the 2-sided 
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95% CIs will also be provided for each treatment group. Further details will be outlined in the 
SAP.  
A stratified Cox regression model may be used to further evaluate the treatment effects on OS 
after adjusting for some prognostic factors. Besides treatment and the stratification factors from 
the randomization list, the following prognostic factors may be included in the model 
simultaneously: age, race (white, non-white), baseline ECOG score, FLIPI, baseline cancer 
stage.
 
9.7.5 Duration of Response 
The DOR will be defined among responders (CR or PR) as the time from the earliest date of 
first response until the first date of either disease progression or death due to any cause. 
The date of disease progression will be defined as the earliest date of disease progression based 
on central review. 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 prior to 
initiation of a new anticancer therapy (including HSCT). The Kaplan-Meier plot, median DOR 
and 95% CI will be presented by treatment. Further details will be outlined in the SAP. 
A sensitivity analysis of DOR will be conducted in which the DOR for patients undergoing 
HSCT will not be censored at HSCT. 
9.7.6 Subgroup analysis 
Subgroup analyses such as age, gender, region and other important baseline characteristics may 
be conducted for CRR, ORR, PFS, OS and DOR. 
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 treatment until 30 days after the 
last dose of study treatment or start of new anti-cancer therapy, whichever is earlier. 
All TEAEs will be summarized. Summary tables will be presented to show the number of 
patients reporting TEAEs by severity grade and corresponding percentages. A patient who 
reports multiple TEAEs within the same Preferred Term (or System Organ Class) is counted 
only once for that Preferred Term (or System Organ Class) using the worst severity grade.  
Separate summaries will be prepared for TEAEs classified as severe or life-threatening 
(≥Grade 3); study treatment-related AEs; AEs leading to treatment interruption, modification, 
or discontinuation; SAEs; 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 v5.0 will be summarized by CTCAE grade. Shifts for other numeric laboratory 
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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 treatment. Further details will be 
provided in the SAP. 
9.8.3 Additional Safety Assessments 
The results of scheduled assessments of vital signs, physical examinations, 12-lead ECGs and 
ECOG performance status 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 treatment. All data will 
be listed. Further details will be provided in the SAP. 
9.9 
Pharmacokinetic and Pharmacodynamic Analyses 
The PK profile will include, but is not limited to, determination of clearance and volume of 
distribution. As appropriate, other parameters of exposure may be derived at the patient level 
for cross-study comparisons 
 
  
PK parameters for the typical patient will be determined using a population PK analysis 
approach. A subset of relevant intrinsic and extrinsic covariate factors will be identified prior 
to analysis and assessed for their influence on drug disposition. As appropriate, PK data from 
prior loncastuximab tesirine studies may be leveraged to support the population PK model. 
  
9.10 
Immunogenicity Analyses 
A tiered immunogenicity strategy (Figure 3) 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 FDA Immunogenicity Testing of Therapeutic 
Protein Products —Developing and Validating Assays for Anti-Drug Antibody Detection 
Guidance for Industry (Jan 2019). 
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Figure 3. 
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. For patients 
exhibiting a positive ADA, PK, safety and efficacy correlates will be assessed and reported. 
9.11 
PROs Data Analyses 
Patient-reported outcomes will be analyzed using PRO population. Completion rate of each 
PRO questionnaire (completed questionnaires as a proportion of the expected) will be 
calculated. Item level missing values will be imputed as per recommendation by the instrument 
developers. 
Changes from baseline (Cycle 1 Day 1) in PRO scores for physical well-being, LymS subscale, 
FACT-G total, TOI, and FACT-Lym total of FACT-Lym, as well as EQ-5D VAS will be 
estimated at each cycle for each treatment arm. The changes from baseline in these scores will 
be compared between the two treatment arms. Patients will be classified as 
improvement/deterioration based on the established minimally important differences for each 
measure. Proportion of patients with improvement/deterioration as well as time to 
improvement/deterioration will be estimated for each treatment arm and compared between 
the two treatment arms.  
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The occurrence, severity, and interference (per relevance) of specific symptomatic adverse 
events selected from PRO-CTCAE, as well as the proportion of patients reporting ‘quite a bit’ 
or ‘very much’ in GP5 item of FACT-Lym will be presented at approximately 3 months and 6 
months for each treatment arm, and compared between the two treatment arms. 
Full details will be further described in the SAP. 
 
 
 
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10 Regulatory, Ethical, and Study Oversight/Management Considerations 
10.1 
Regulatory and Ethical Considerations 
The study will be performed in accordance with the protocol and with the Consensus ethical 
principles derived from international guidelines including the Declaration of Helsinki and 
Council for International Organizations of Medical Sciences (CIOMS) International Ethical 
Guidelines, applicable International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use (ICH) Good Clinical Practice (GCP) Guidelines, and 
applicable laws and regulations. 
The protocol, protocol amendments, ICF, Investigator Brochure, and other relevant documents 
(e.g., advertisements) must be submitted to an IRB/IEC by the investigator and reviewed and 
approved by the IRB/IEC before the study is initiated.  
Any amendments to the protocol will require IRB/IEC approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an immediate 
hazard to study participants.  
The investigator will be responsible for the following: 
• Providing written summaries of the status of the study to the IRB/IEC annually or more 
frequently in accordance with the requirements, policies, and procedures established 
by the IRB/IEC 
• Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures 
• Providing oversight of the conduct of the study at the site and adherence to applicable 
laws and regulations. 
Study information from this protocol will be posted on publicly available clinical study 
registries before enrollment of patients begins. 
10.2 
Financial Disclosure and Obligations 
Investigators and sub-investigators will provide the sponsor with sufficient, accurate financial 
information as requested to allow the sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators are 
responsible for providing information on financial interests during the course of the study and 
for 1 year after completion of the study. 
10.3 
Patient Information and Consent 
The investigator or his/her representative will explain the nature of the study to the participant 
and answer all questions regarding the study. 
Participants must be informed that their participation is voluntary. Participants will be required 
to sign a statement of informed consent that meets the requirements of any applicable 
regulations, guidelines, and the IRB/IEC or study center. 
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The medical record must include a statement that written informed consent was obtained before 
the participant was enrolled in the study and the date the written consent was obtained. 
Participants must be re-consented to the most current version of the ICF(s) during their 
participation in the study, unless otherwise indicated by the IRB/IEC (local or global, as 
applicable). In such cases, the reason for not re-consenting the patient should be documented. 
A copy of the ICF(s) must be provided to the participant. 
10.4 
Data Protection 
Participants will be assigned a unique identifier. Any participant records or datasets that are 
transferred to the sponsor will contain the identifier only; participant names or any information 
which would make the participant identifiable will not be transferred. 
Sponsor maintains organizational and security measures (e.g. pseudonymisation, data 
protection policy, backups, network security, physical access control, monitoring network 
activity, etc.) to safeguard patient’s personal data that are transferred to Sponsor from loss, 
misuse, unauthorized access, disclosure, alteration or destruction and, when required, will 
cause third parties accessing your Personal Data to maintain the same and to assist Sponsor in 
complying with its obligations under applicable laws regarding personal data protection. 
The participant must be informed that his/her personal study-related data will be used by the 
sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the participant. 
The participant must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities. 
10.5 
Data Quality Assurance 
Study personnel involved in conducting this study will be qualified by education training and 
experience to perform their respective tasks. 
All participant data relating to the study will be recorded on printed or eCRF unless transmitted 
to the sponsor or designee electronically (e.g., central laboratory data). The Investigator is 
responsible for verifying that data entries are accurate and correct by physically or 
electronically signing the eCRF. 
The Investigator must maintain accurate documentation (source data) that supports the 
information entered in the eCRF. 
The Investigator must permit study-related monitoring, Sponsor/CRO audits, IRB/IEC review, 
and regulatory agency inspections and provide direct access to source data documents. 
The Sponsor or designee is responsible for the data management of this study including quality 
checking of the data. 
Study monitors will perform ongoing source data verification to confirm that data entered into 
the eCRF by authorized site personnel are accurate, complete, and verifiable from source 
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documents; that the safety and rights of participants are being protected; and that the study is 
being conducted in accordance with the currently approved protocol and any other study 
agreements, ICH GCP, and all applicable regulatory requirements. 
Upon completion of the study, the Sponsor shall prepare a summary of the study outcome in 
accordance with the ICH E3 guidelines for submission to the appropriate regulatory 
authority(ies). 
Records and documents, including signed ICFs, pertaining to the conduct of this study must 
be retained by the investigator for 15 years after study completion unless local regulations or 
institutional policies require a longer retention period. No records may be destroyed during the 
retention period without the written approval of the sponsor. No records may be transferred to 
another location or party without written notification to the sponsor. 
10.6 
Source Documents 
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. Source documents are filed at the investigator’s site. 
Data reported on the eCRF that are transcribed from source documents must be consistent with 
the source documents or the discrepancies must be explained. The Investigator may need to 
request previous medical records or transfer records, depending on the study. Also, current 
medical records must be available. 
Definition of what constitutes source data can be found in the Investigator Site File. 
10.7 
Study and Site Closure 
The Sponsor reserves the right to close the study site or terminate the study at any time for any 
reason. Study sites will be closed upon study completion. A study site is considered closed 
when all required documents and study supplies have been collected and a study-site closure 
visit has been performed. 
The Investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by the sponsor or investigator may include but are 
not limited to: 
• Failure of the investigator to comply with the protocol, the requirements of the IRB/IEC 
or local health authorities, the sponsor's procedures, or GCP guidelines 
• Inadequate recruitment of participants by the Investigator 
Discontinuation of further study intervention development 
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10.8 
Monitoring of the Study 
All aspects of the study will be carefully monitored by the Sponsor or designee for compliance 
with GCP and applicable government regulations. 
Monitoring details describing strategy (e.g., risk-based initiatives in operations and quality 
such as Risk Management and Mitigation Strategies and Analytical Risk-Based Monitoring), 
methods, responsibilities and requirements, including handling of noncompliance issues and 
monitoring techniques (central, remote, or on-site monitoring) are provided in the Monitoring 
Plan. 
Investigators and institutions involved in the study will permit study-related monitoring, 
Sponsor/CRO audits, IRB/IEC review, and regulatory inspections by providing direct access 
to source data and study records. 
The Investigator 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. 
10.9 
Publications 
Following completion of the study, the results from the study will be publicly disclosed through 
posting the results on appropriate registries such as ww.clinicaltrials.gov and may be reported 
publicly by making any oral public presentation and/or submitting or presenting a manuscript, 
abstract, or other materials relating to the Study at scientific meetings and/or to a publisher, 
reviewer, or other outside person in scientific journals (“Publication”), provided; however, that 
Publication of the results from an individual site shall not be made before the first multi-site 
Publication by Sponsor. The Sponsor shall coordinate the drafting, editing, authorship, and 
other activities related to study Publication and shall mutually agree with the Investigator(s) 
on the number, medium, forum, and timing for Publication. The Sponsor shall solicit input 
regarding contents of the Publication from all Investigators and in consultation with all sites. 
The Sponsor acknowledges the right of the Investigator(s) to publish the results of this study 
after the entire study has completed, but also reserves the right to a window to review the 
Publication for regulatory compliance as well as for protection of its intellectual property. 
In particular, the Sponsor may request to remove the Sponsor’s confidential information and 
suspend Publication for a certain period of time to protect the Sponsor’s intellectual property 
interest, as further set forth in the Clinical Trial Agreement with the clinical study site(s) and 
Investigator(s). 
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