Clinical trial NCT02669017
Conditions: Non-Hodgkin Lymphoma Burkitt's Lymphoma Chronic Lymphocytic Leukemia Lymphoma, Large B-Cell, Diffuse Lymphoma, Follicular Lymphoma, Mantle-Cell Lymphoma, Marginal Zone Waldenstrom Macroglobulinemia Primary Mediastinal B-cell Lymphoma
Keywords: Loncastuximab tesirine
Sponsor: ADC Therapeutics S.A.
Start date: 2016-03-01; Completion date: 2019-02-21
Enrollment: 183 participants; Allocation: NON_RANDOMIZED; Intervention model: SINGLE_GROUP

Brief summary:
This study evaluates ADCT-402 in participants with Relapsed or Refractory B-cell Lineage Non Hodgkin Lymphoma (B-NHL). Participants will participate in a dose escalation phase (Part 1) and dose expansion (Part 2). In Part 2, participants will receive the dose level identified in Part 1.

Detailed description:
Study ADCT-402-101 is the first clinical study with ADCT-402 in participants with B-cell Non Hodgkin Lymphoma (NHL).

ADCT-402 is an antibody drug conjugate (ADC) composed of a humanized antibody directed against human cluster of differentiation 19 (CD19), stochastically conjugated via a valine-alanine cleavable, maleimide linker to a pyrrolobenzodiazepine (PBD) dimer cytotoxin.

The study will be conducted in 2 parts. In Part 1 (dose escalation) participants will receive infusions of ADCT-402, at escalating doses. Part 1 will continue until the maximum tolerated dose is determined. In Part 2 (expansion), participants will be assigned to the recommended dose level(s) and schedule(s) of ADCT-402 identified in Part 1 by the Dose Escalation Steering Committee.

For each participant, the study will include a screening period (up to 28 days), a treatment period (until withdrawal), and a follow-up period to assess disease progression and survival for up to 12 months after the last dose of study drug. The total study duration will be dependent on overall participant tolerability to the study drug and response to treatment. It is anticipated that the duration of the entire study (Parts 1 and 2) could be approximately 3 years from first participant treated to last participant completed.

Arms: arm 1: In Part 1 (dose escalation) participants will receive intravenous (IV) infusions of ADCT-402 at escalating doses, according to a 3+3 study design. Doses will be escalated from 15 µg/kg to 200 µg/kg on Day 1 of each cycle, with cycle lengths of 3 or 6 weeks. arm 2: In Part 2 (expansion), participants will be assigned to the recommended dose level(s) and schedule(s) of ADCT-402 identified in Part 1 by the Dose Escalation Steering Committee.

Participants will receive intravenous (IV) infusions of ADCT-402 at either 120 μg/kg or 150 μg/kg on Day 1 of each 3 week cycle (Q3W).
Interventions: intervention 1: ADCT-402
Intervention descriptions: intervention 1: intravenous infusion

Protocol documents:
Prot_000.pdf: 
Protocol Number:  ADCT-402-101 
 
Official Title:     Phase 1 Dose-escalation Study to Evaluate the Tolerability, Safety, 
Pharmacokinetics, and Antitumor Activity of ADCT-402 in Patients with 
Relapsed or Refractory B-cell Lineage Non Hodgkin Lymphoma (B-NHL)  
 
NCT Number:  NCT02669017 
 
Document Date:  16 October 2017   


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CLINICAL STUDY PROTOCOL
IND: 126138
EudraCT Number: 2016-000952-92
A Phase 1 Dose-escalation Study to Evaluate the Tolerability, Safety, 
Pharmacokinetics, and Antitumor Activity of ADCT-402 in Patients with 
Relapsed or Refractory B-cell Lineage Non Hodgkin Lymphoma (B-NHL)
PROTOCOL NO.:  ADCT-402-101
Sponsor:
ADC Therapeutics SA
Sponsor Contact:
Medical Monitor:
Date of Original Protocol: 
21 September 2015
Protocol Amendment 1:
8 December 2015
Protocol Amendment 2:
8 March 2016
Protocol Amendment 3:
Protocol Amendment 4:
Protocol Amendment 5:
Protocol Amendment 6:
Protocol Amendment 7:
01 July 2016
01 November 2016
10 April 2017
24 July 2017
16 October 2017
Confidentiality Statement
All financial and nonfinancial support for this study will be provided by ADC Therapeutics SA. The 
concepts and information contained in this document or generated during the study are considered 
proprietary and may not be disclosed in whole or in part without the express, written consent of ADC 
Therapeutics SA. The study will be conducted according to the current version of International Council
for Harmonisation harmonised tripartite guideline E6, Good Clinical Practice.




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Declaration of Investigator
I have read and understood all sections of the protocol entitled “A Phase 1, Dose-escalation 
Study to Evaluate the Tolerability, Safety, Pharmacokinetics, and Antitumor Activity of ADCT-
402 in Patients with Relapsed or Refractory B-cell Lineage Non Hodgkin Lymphoma (B-NHL)” 
and the accompanying Investigator Brochure.
I agree to supervise all aspects of the protocol and to conduct the clinical investigation in 
accordance with the Protocol, dated 16 October 2017 , 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 study 
treatment only to patients under my personal supervision or the supervision of a sub-Investigator.
I will not supply the investigational drug to any person not authorized to receive it. 
Confidentiality will be protected. Patient identity will not be disclosed to third parties or appear 
in any study reports or publications.
I will not disclose information regarding this clinical investigation or publish results of the 
investigation without authorization from ADC Therapeutics SA.
Signature of Principal Investigator
Date
Printed Name of Principal Investigator


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Table of Contents
Table of Contents ............................................................................................................................ 4
List of Tables................................................................................................................................... 8
List of Figures................................................................................................................................. 8
Protocol Synopsis............................................................................................................................ 9
List of Abbreviations..................................................................................................................... 20
1
Introduction and Study Rationale......................................................................................... 23
1.1
Description of ADCT-402............................................................................................23
1.2
Study Rationale............................................................................................................24
1.2.1
Clinical Background .......................................................................................24
1.2.2
Biology of CD19.............................................................................................24
1.2.3
Nonclinical Efficacy and Safety of ADCT-402 ..............................................25
1.2.4
Safety of Commercially Available Antibodies Directed against CD19..........25
2
Study Objectives................................................................................................................... 26
2.1
Primary Objectives.......................................................................................................26
2.2
Secondary Objectives...................................................................................................26
3
Investigational Plan and Patient Selection ........................................................................... 27
3.1
Study Design................................................................................................................27
3.2
Dose Escalation............................................................................................................28
3.3
Selection of Study Population......................................................................................30
3.3.1
Inclusion Criteria ............................................................................................30
3.3.2
Exclusion Criteria...........................................................................................32
4
Study Procedures .................................................................................................................. 34
4.1
Procedures by Study Day.............................................................................................34
4.1.1
Screening Period (Day –28 to –1) ..................................................................34
4.1.2
Day 1 of Each Cycle.......................................................................................35
4.1.3
Day 2 (Cycles 1 and 2) ...................................................................................37
4.1.4
Day 3 (Cycles 1 and 2) ...................................................................................37
4.1.5
Day 5 (Cycles 1 and 2) ...................................................................................37
4.1.6
Day 8 (± 2 days) of Each Cycle......................................................................37
4.1.7
Day 15 (± 2 days) of Cycles 1 and 2 ..............................................................38
4.1.8
Day 28 (± 3 days) ...........................................................................................38


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4.1.9
End of Treatment Visit....................................................................................39
4.1.10
12-week Follow-up Visit ................................................................................39
4.1.11
Long-term Follow-up......................................................................................40
4.2
Withdrawal of Patients from the Study........................................................................40
4.2.1
Reasons for Withdrawal/Discontinuation.......................................................40
4.2.2
Handling of Withdrawals................................................................................41
4.2.3
Patient Replacements......................................................................................41
5
Study Treatments .................................................................................................................. 42
5.1
Method of Assigning Patients to Treatment Groups....................................................42
5.2
Prophylactic Treatments for Hypersensitivity .............................................................42
5.3
Treatments Administered .............................................................................................43
5.4
Dose Delays and Modifications...................................................................................44
5.5
Identity of Investigational Product...............................................................................44
5.5.1
ADCT-402 Drug Product................................................................................44
5.6
Management of Clinical Supplies................................................................................45
5.6.1
Study Drug Packaging and Storage ................................................................45
5.6.2
Study Drug Preparation and Administration...................................................45
5.6.3
Study Drug Accountability .............................................................................45
5.7
Overdose Management ................................................................................................45
5.8
Treatment Compliance.................................................................................................45
5.9
Concomitant Treatment................................................................................................45
5.9.1
Prohibited During Study.................................................................................46
5.9.2
Permitted During Study..................................................................................46
6
Study Assessments and Procedures ...................................................................................... 48
6.1
Efficacy Assessments...................................................................................................48
6.2
Pharmacokinetic and Pharmacodynamic Assessments................................................48
6.2.1
Pharmacokinetic Assessments ........................................................................49
6.2.2
Pharmacodynamic and Other Assessments ....................................................49
6.3
Safety and Tolerability Assessments............................................................................49
6.3.1
Definition of Dose-Limiting Toxicities ..........................................................50
6.3.1.1
Safety Oversight by the Dose Escalation Steering Committee.....50
6.3.2
Adverse Events ...............................................................................................51
6.3.2.1
Definitions of Adverse Events......................................................51
6.3.2.2
Eliciting and Documenting Adverse Events.................................51
6.3.2.3
Reporting Adverse Events ............................................................52


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6.3.2.4
Assessment of Severity.................................................................52
6.3.2.5
Assessment of Causality...............................................................53
6.3.2.6
Follow-Up of Patients Reporting Adverse Events........................53
6.3.3
Pregnancy .......................................................................................................53
6.3.4
Clinical Laboratory Analyses .........................................................................54
6.3.4.1
Hematology...................................................................................54
6.3.4.2
Biochemistry.................................................................................54
6.3.4.3
Urinalysis......................................................................................54
6.3.4.4
Additional Renal Function Studies...............................................54
6.3.5
Electrocardiograms.........................................................................................54
6.3.6
Physical Examination .....................................................................................55
6.3.7
Vital Sign Measurements................................................................................55
6.3.8
Weight.............................................................................................................55
6.3.9
Eastern Cooperative Oncology Group Performance Status............................55
6.4
Sample Handling, Storage and Shipment ....................................................................55
7
Statistical and Analytical Plan.............................................................................................. 58
7.1
Safety Endpoints..........................................................................................................58
7.2
Primary Endpoints .......................................................................................................58
7.2.1
Primary Endpoints ..........................................................................................58
7.2.2
Secondary Endpoints ......................................................................................58
7.3
Sample Size Calculations.............................................................................................59
7.4
Analysis Sets................................................................................................................59
7.5
Description of Subgroups to be Analyzed ...................................................................59
7.6
Statistical Analysis Methodology ................................................................................60
7.6.1
Safety Analyses...............................................................................................60
7.6.1.1
Analyses of Adverse Events .........................................................60
7.6.1.2
Clinical Laboratory Results..........................................................60
7.6.1.3
Additional Safety Assessments.....................................................60
7.6.2
Efficacy Analysis............................................................................................61
7.6.2.1
Overall Response Rate..................................................................61
7.6.2.2
Duration of Response ...................................................................61
7.6.2.3
Overall Survival............................................................................61
7.6.2.4
Progression-Free Survival ............................................................61
7.6.3
Pharmacokinetic and Pharmacodynamic Analyses ........................................61
7.6.4
Study Drug Exposure......................................................................................62
7.7
Data Quality Assurance................................................................................................62


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7.7.1
Data Management...........................................................................................62
8
Ethics .................................................................................................................................... 64
8.1
Independent Ethics Committee or Institutional Review Board ...................................64
8.2
Ethical Conduct of the Study.......................................................................................64
8.3
Patient Information and Consent .................................................................................64
9
Investigator’s Obligations..................................................................................................... 65
9.1
Confidentiality .............................................................................................................65
9.2
Financial Disclosure and Obligations..........................................................................65
9.3
Adverse Events and Study Report Requirements ........................................................65
9.4
Investigator Documentation.........................................................................................66
9.5
Study Conduct..............................................................................................................66
9.6
Adherence to Protocol..................................................................................................66
9.7
Investigator’s Final Report ..........................................................................................66
9.8
Records Retention........................................................................................................67
10
Study Management............................................................................................................... 68
10.1 Monitoring ...................................................................................................................68
10.1.1
Monitoring of the Study..................................................................................68
10.1.2
Inspection of Records .....................................................................................68
10.2 Management of Protocol Amendments and Deviations...............................................68
10.2.1 Modification of the Protocol...........................................................................68
10.2.2
Protocol Deviations ........................................................................................69
10.3 Study Termination........................................................................................................69
10.4 Final Report .................................................................................................................69
11
Reference List....................................................................................................................... 70
12
Appendices ........................................................................................................................... 73
12.1 Appendix: Schedule of Events.....................................................................................73
12.1.1
Schedule of Study Procedures ........................................................................74
12.1.2
Timings for ECG, PK, PD, and Exploratory Assessments..............................78
12.2 Appendix: Response Assessment of Hodgkin and Non-Hodgkin Lymphoma (Lugano 
Classification) ..............................................................................................................79
12.3 Appendix: CTCAE Immune System Hypersensitivity Grades....................................82


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List of Tables
Table 1.
Planned Dose Levels for ADCT-402 .................................................................... 29
Table 2.
Definition of Severity Grades for Common Terminology Criteria for Adverse 
Events (CTCAE)................................................................................................... 53
Table 3.
Definition of Eastern Cooperative Oncology Group (ECOG) Performance Status 
Grades ................................................................................................................... 55
List of Figures
Figure 1  Schematic Representation and Chemical Structure of ADCT-402................................ 23
Figure 2. Schematic Representation for Dose Escalation (3+3) Design....................................... 29


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Protocol Synopsis
Protocol 
Number:
ADCT-402-101
Title:
A Phase 1, Dose-escalation Study to Evaluate the Tolerability, Safety, 
Pharmacokinetics, and Antitumor Activity of ADCT-402 in Patients with 
Relapsed or Refractory B-cell Lineage Non Hodgkin Lymphoma 
(B-NHL)
Sponsor:
ADC Therapeutics SA
Study Phase:
Phase 1
Study Sites:
Approximately 11 sites during dose escalation (Part 1) and12 sites during 
dose expansion (Part 2)
Indication:
Patients with relapsed or refractory B-cell lineage non-Hodgkin 
Lymphoma (B-NHL) who have failed, or are intolerant to, any established 
therapy; or for whom no other treatment options are available, in the 
opinion of the Investigator.
The DESC will determine which histologic sub-types will be investigated 
in Part 2 of the study based on the emerging efficacy and tolerability 
profile from part 1.
B-cell NHL defined as:

Diffuse large B-cell lymphoma (DLBCL)

Follicular lymphoma (FL)

Chronic lymphocytic leukemia (CLL)

Mantle cell lymphoma (MCL)

Marginal Zone B-cell Lymphoma (MZBCL)

Burkitt’s lymphoma (BL)

Lymphoplasmacytic lymphoma (Waldenstrom macroglobulinemia 
[WM]).
Rationale:
Non-Hodgkin Lymphoma is the seventh most common type of cancer in 
the U.S., and will account for an estimated 4.3% (n=71,850) of new 
cancer cases in 2015. It is most commonly a disease of older individuals 
with approximately 75% of new cases diagnosed in individuals 55 years 
of age or older (median age at diagnosis = 66 years). Response to initial 


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treatment generally exceeds 50% and the overall 5-year survival rate in the 
U.S. is 70%. However, a significant proportion of patients will relapse. 
The poor prognosis for relapsed patients, especially those with chemo-
refractory disease with a short interval between remission and relapse, or 
those who relapse after high-dose therapy and autologous stem cell 
transplant (ASCT), highlights the need for new forms of treatment for 
NHL.
In normal human tissue, expression of cluster of differentiation 19 (CD19) 
is limited to the developmental stages of the B cell and is lost in terminally 
differentiated plasma cells. Expression of CD19 is maintained in 
hematologic B-cell malignancies, including B-NHL.
ADCT-402 is an antibody drug conjugate (ADC) composed of a 
humanized monoclonal antibody, directed against human CD19, 
conjugated to SG3199, a pyrrolobenzodiazepine (PBD) dimer cytotoxin, 
through a protease-cleavable valine-alanine linker. The PBD dimer
cytotoxin (SG3199) attached to the linker is designated as SG3249.
The potential for ADCT-402 in treating B-cell malignancies was tested in 
mouse xenograft models of human-derived B-cell leukemias and 
lymphomas. Complete responses were observed in mice after receiving a 
single low dose of ADCT-402. The efficacy of ADCT-402 in these 
models is due to targeted delivery of the PBD cytotoxin, SG3199.
ADCT-402 is not pharmacologically cross-reactive (active) in any 
standard species used for nonclinical safety assessment. In the absence of 
CD19 target engagement, it was not possible to nonclinically evaluate the 
safety consequences associated with possible B-cell depletion. However, 
the impact and overall safety of B-cell depletion has been investigated 
clinically and nonclinically with other B-cell depleting agents and has 
been shown to be safe and well tolerated. The safety studies therefore
assessed the potential off-target effects of ADCT-402 and the impact of 
ADCT-402 on the tissues normally associated with antibody clearance.
In rats, ADCT-402 is well tolerated at doses up to 2 mg/kg. A repeat-
dose Good Laboratory Practice (GLP) toxicology study in cynomolgus 
monkeys investigated doses from 0.3 to 0.6 mg/kg with the 0.6 mg/kg 
dose identified as the highest nonsevere toxic dose (HNSTD). Toxicity 
in the monkey was characterized by reversible dose-dependent skin 
changes (hyperpigmentation with hyperplasia / hyperkeratosis), 
reversible dose-dependent anemia associated with some bone marrow 
hypocellularity, reversible dose-dependent nephropathy and 
dose-dependent testicular toxicity (atrophy with reduced 
spermatogenesis, expected to be reversible).
Objectives:
Primary Objectives

Evaluate the safety and tolerability, and determine, as appropriate, the 
maximum tolerated dose (MTD) of ADCT-402 in patients with 
relapsed or refractory B-cell lineage NHL (Part 1).


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
Determine the recommended dose(s) of ADCT-402 for Part 2 
(expansion).

Evaluate the safety and tolerability of ADCT-402 in Part 2 
(expansion) at the dose level(s) recommended in Part 1.
Secondary Objectives

Evaluate the clinical activity of ADCT-402 as measured by overall 
response rate (ORR), duration of response (DOR), progression-free 
survival (PFS), and overall survival (OS).

Characterize the pharmacokinetic (PK) profile of ADCT-402 (total 
antibody; drug to-antibody ratio [DAR] ≥0), PBD-conjugated 
antibody (DAR ≥1), and free warhead SG3199.

Evaluate anti-drug antibodies (ADAs) in blood before, during, and 
after treatment with ADCT-402.
 
 
 
 
 
 
 
 
 
Patient
Selection:
Inclusion Criteria
1. Part 1: Male or female patients, ages 18 years or older with 
pathologically-confirmed relapsed or refractory B-cell lineage NHL 
who have failed or are intolerant to established therapy, or for whom 
no other treatment options are available, in the opinion of the 
Investigator.
Refractory or relapsed B-cell NHL (per World health Organization 
[WHO] Classification system) defined as: 

Diffuse large B-cell lymphoma (DLBCL),

Follicular lymphoma (FL),

Chronic lymphocytic leukemia (CLL),

Mantle cell lymphoma (MCL),

Marginal Zone B-cell Lymphoma (MZBCL),


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
Burkitt’s lymphoma (BL),

Lymphoplasmacytic lymphoma (Waldenstrom macroglobulinemia 
[WM]).
Part 2: Eligible histologic sub-types to be investigated in part 2 of the 
study will be determinded by the DESC based on evolving efficacy 
and safety information from Part 1. Patients enrolled in part 2 of the 
study will have failed or are intolerant to established therapy, or have 
no other treatment options are available, in the opinion of the 
Investigator.
The DESC may establish specific patient populations within each 
hitological subtype to be investigated such as specific prior treatments.
2. Availability of formalin-fixed paraffin-embedded (FFPE) tumor tissue 
block. An FFPE block from a current biopsy is preferred; however,
archival tissue taken at initial diagnosis or any prior relapse is 
acceptable. If tissue block is not available, slides from a FFPE block 
may be acceptable for eligibility upon consultation with the Sponsor.
3. Measurable disease, as defined by the 2014 Lugano Classification.
4. Eastern Cooperative Oncology Group (ECOG) performance status
0 to 2.
5. Absolute neutrophil count (ANC) ≥1000/µL.
6. Platelet count of ≥75000/µL.
7. Hemoglobin ≥9.0 g/dL without transfusion within the 2 weeks prior to 
Day 1.
8. Serum/plasma creatinine ≤1.5 mg/dL. If the patient has a creatinine 
> 1.5mg/dL, a measured creatinine clearance must be >60mL/min as 
calculated by the Cockcroft and Gault equation.
9. Serum/plasma alkaline phosphatase, alanine aminotransferase (ALT), 
and aspartate aminotransferase (AST) ≤2 times the upper limit of 
normal (ULN); ≤ 5 times ULN if there is liver or bone involvement.
10. Total serum/plasma bilirubin ≤1.5 times ULN (patients with known 
Gilbert’s syndrome may have a total bilirubin up to ≤3 times ULN).
11. Negative serum or urine beta-human chorionic gonadotropin (β-HCG)
pregnancy test within 7 days prior to Day 1 for women of childbearing 
potential.
12.Women of childbearing potential* must agree to use a highly 
effective** method of contraception from the time of giving informed 
consent until at least 16 weeks after the last dose of ADCT-402. Men 
with female partners who are of childbearing potential must agree that 
they or their partners will use a highly effective method of 
contraception from the time of giving informed consent until at least 
16 weeks after the patient receives his last dose of ADCT-402.
*
Women of childbearing potential are defined as sexually mature 


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women who have not undergone bilateral tubal ligation, bilateral 
oophorectomy, or hysterectomy; or who have not been 
postmenopausal (i.e., who have not menstruated at all) for at least 1 
year.
** Highly effective forms of birth control are methods which achieve a 
failure rate of less than 1% per year when used consistently and 
correctly. Highly effective forms of birth control include: Hormonal 
contraceptives (oral, injectable, patch, intrauterine devices), male 
partner sterilization, or total abstinence from heterosexual intercourse, 
when this is the preferred and usual lifestyle of the patient. 
Note: The double-barrier method (e.g., synthetic condoms, diaphragm, 
or cervical cap with spermicidal foam, cream, or gel), periodic 
abstinence (such as calendar, symptothermal, post-ovulation), 
withdrawal (coitus interruptus), lactational amenorrhea method, and 
spermicide-only are not acceptable as highly effective methods of 
contraception.
Exclusion Criteria
1. Patients who, in the opinion of the Investigator, have any option for 
other treatment for B-cell NHL at the current state of disease.
2. Active graft-versus-host disease.
3. Autologous or allogenic transplant within the 60 days prior to the 
Screening visit.
4. Known history of immunogenicity or hypersensitivity to a CD19 
antibody.
5. Evidence of myelodysplasia or myeloid leukemia by morphology, 
immunostains, flow cytometry, or cytogenetics on a bone marrow 
aspirate or biopsy.
6. Known history of positive serum human ADA.
7. Active autoimmune disease, motor neuropathy considered of 
autoimmune origin, and other central nervous system (CNS)
autoimmune disease. Known seropositive for human 
immunodeficiency (HIV) virus, hepatitis B surface antigen (HBsAg), 
or antibody to hepatitis C virus (anti-HCV) with confirmatory testing 
and requiring anti-viral therapy.
Note: Testing is not mandatory to be eligible. Testing for HCV should 
be considered if the patient is at risk for having undiagnosed HCV 
(e.g., history of injection drug use).
8. History of Steven's Johnson's syndrome or toxic epidermal necrolysis 
syndrome.
9. Pregnant or breastfeeding women.
10. Significant medical comorbidities, including uncontrolled 
hypertension (diastolic blood pressure greater than 115 mm Hg), 
unstable angina, congestive heart failure (greater than New York Heart 


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Association class II), severe uncontrolled ventricular arrhythmias, or 
electrocardiographic evidence of acute ischemia, poorly controlled 
diabetes, severe chronic pulmonary disease, coronary angioplasty, or 
myocardial infarction within 6 months prior to screening, or 
uncontrolled atrial or ventricular cardiac arrhythmias.
11. Use of any other experimental medication(s) within 14 days or 
5 half-lives but in no case less than 14 days prior to start of study 
treatment on Cycle 1, Day 1, except if approved by Sponsor.
12. Steroid use equivalent to greater than 20 mg of prednisone within 
4 weeks (28 days) prior to Day 1, except for the use of short course 
systemic corticosteroids (≤ 7 days), with a wash-out period of 1 week 
prior to start of study treatment on Day 1.
13. Major surgery, chemotherapy, systemic therapy (excluding steroids
hydroxyurea steroids, and any targeted small molecules or biologics), 
or radiotherapy, within 14 days or 5 half-lives (whichever is 
shorter) prior to Cycle 1, Day 1 treatment, except if approved by the 
Sponsor.
14. Failure to recover (to Common Terminology Criteria for Adverse 
Events [CTCAE] Grade 0 or Grade 1) from acute non hematologic 
toxicity (except all grades alopecia or Grade 2 or lower neuropathy ), 
due to previous therapy, prior to Screening.
15. Congenital long QT syndrome or a corrected QTc interval ≥450 ms at 
the Screening visit (unless secondary to pacemaker or bundle branch 
block).
16. 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. 
17. 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.


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Study Design:
This is a Phase 1, open-label, dose escalation (Part 1) and expansion 
(Part 2) study of the safety and tolerability of ADCT-402, used as 
monotherapy, in patients with relapsed or refractory B-NHL. The study 
will determine the MTD, as well as evaluate the preliminary activity, PK, 
pharmacodynamics (PD), and other exploratory assessments of 
ADCT-402.
In Part 1, patients will be assigned to treatment according to a 3+3 dose 
escalation design (see below) and with oversight by a Dose Escalation 
Steering Committee (DESC). 
In Part 2, (expansion), all patients will be assigned to the recommended 
dose level(s) and schedule(s) of ADCT-402 identified in Part 1.
Estimated 
Duration of 
Patient 
Participation 
and Study 
Duration:
For each patient, the study will include a screening period (up to 28 days), 
a treatment period (until withdrawal), and a follow-up period to assess 
disease progression and survival for up to 12 months after the last dose of 
study drug. The total study duration will be dependent on overall patient 
tolerability to the study drug and response to treatment. It is anticipated 
that the duration of the entire study (Parts 1 and 2) could be approximately 
3 years from first patient treated to last patient completed.
Patients who discontinue treatment for any reason other than disease 
progression will continue to be followed approximately every 12 weeks 
from the last disease assessment until disease progression, or initiation of 
new anticancer treatment. After documentation of disease progression or 
start of new treatment, patients will be followed (by telephone contact or 
chart review) approximately every 12 weeks for up to 12 months after the 
last dose of study drug to collect survival information.
Patients may withdraw from the study at any time and for any reason, 
without prejudice to their future medical care, by the Investigator or others 
at the study site. 
Efficacy 
Assessments:
Disease assessments will be conducted within 6 days prior to Day 1 of 
Cycles 3 and 5 and thereafter every third cycle (i.e., Cycles 8, 11, 14, etc.), 
until disease progression, or more frequently, if clinically indicated. The 
same methods used at Screening which identify sites of disease should be 
used uniformly for all subsequent assessments. If PET-CT is positive, 
subsequent diagnostic CT and MRI are not needed unless clinically 
indicated. PET-CT is not required if a PET-CT examination at Screening 
was negative.
For patients who have reduced dosing frequency and are following a 
6 week schedule, disease assessments should occur approximately 6 
weeks and 12 weeks after Cycle 1 Day 1, and thereafter at least every 12 
weeks. It is understood that there will be a ± 6 day window for restaging 
of these patients.
The patient’s response to treatment will be determined by the Investigator 
as complete response (CR), partial response (PR), stable disease (SD), or 
progressive disease (PD), based on the 2014 Lugano Classification 


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Criteria.
Pharmacokinetic
and Anti-drug
Antibody 
Assessments:
The PK profile of ADCT-402 (total antibody; DAR ≥0), PBD-conjugated 
antibody (DAR ≥1), and free warhead SG3199 will be assessed using 
measures from validated bioanalytical methods . The PK profile will 
include determination of standard PK parameters (e.g., maximum 
concentration [Cmax], time to Cmax [Tmax]).
The following pharmacodynamic and other exploratory assessments will 
be performed at various time points in the study:
 

Level of ADAs against ADCT-402 in serum. 
 

Serum concentrations of ADCT-402 and free warhead SG3199 will 
be determined. The QTc interval will also be measured.
Safety 
Assessments:
Safety will be assessed based on the evaluation of adverse events (AEs), 
serious AEs (SAEs), treatment discontinuations due to AEs, dose limiting 
toxicity(s) (DLTs), periodic 12-lead electrocardiogram (ECG) recordings, 
physical examinations, vital signs measurements, ECOG performance 
status, and hematology, coagulation panel and pregnancy testing (for 
women of child-bearing potential), biochemistry, and urinalysis test 
results obtained at various timepoints during the study. Adverse events 
will be graded according to CTCAE Version 4.0.


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Definition of 
DLT
A dose-limiting toxicity (DLT) is defined as any of the following events, 
except those that are clearly due to underlying disease or extraneous 
causes.
A hematologic DLT is defined as:

Grade 3 or 4 febrile neutropenia or neutropenic infection.

Grade 4 neutropenia lasting >7 days.

Grade 4 thrombocytopenia.

Grade 3 thrombocytopenia with clinically significant bleeding, or 
Grade 3 thrombocytopenia requiring a platelet transfusion.

Grade 4 anemia.
A non-hematologic DLT is defined as:

Grade 4 tumor lysis syndrome (Grade 3 TLS will not constitute DLT 
unless it leads to irreversible end-organ damage).

Grade 3 or higher AE (including nausea, vomiting, diarrhea, and 
electrolyte imbalances lasting more than 48 hours despite optimal 
therapy; excluding all grades of alopecia).

Grade 3 or higher hypersensitivity reaction (regardless of 
premedication).

Grade 2 or higher skin ulceration.
The DLT period for dose escalation will be 1 cycle.
Investigational 
Product, Dosage, 
and Mode of 
Administration:
ADCT-402 is a sterile formulation containing PBD-conjugated humanized 
monoclonal IgG1 antibody (DAR ≥1), humanized monoclonal IgG1 
antibody (DAR = 0), and SG3249. It is provided pre-formulated in 10 mL 
glass vials containing approximately 16 mg ADCT-402 per vial 
(deliverable volume 3.2 mL at 5 mg/mL).
Patients will receive a 1-hour intravenous (IV) infusion of ADCT-402, at 
escalating doses, on Day 1 of each cycle. If ADCT-402 is well tolerated 
after the first cycle, the infusion duration may be shortened to 30 minutes 
for subsequent cycles for that patient, at the Investigator’s discretion.


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Dose-Escalation 
Design:
In Part 1, patients will be assigned to treatment with ADCT-402 at 
escalating doses according to a 3+3 study design. The initial dose of 
ADCT-402 will be 15 µg/kg (Dose Level 1), and the highest allowed dose 
will be 300 µg/kg. 
Further dose levels and schedules evaluated include the following:

120 µg/kg:  Dosing every 3 weeks for 2 cycles. Patients with at least 
SD after the second cycle continue treatment at a reduced dose of 
60 µg/kg q6weeks, beginning 6 weeks after Cycle 2 infusion.  

150 µg/kg: Dosing every 3 weeks for 2 cycles. Patients with at least 
SD after the second cycle continue treatment at a reduced dose of 
60 µg/kg q6weeks, beginning 6 weeks after Cycle 2 infusion.  

200 µg/kg: Dosing every 6 weeks for 2 cycles.  For patients with at 
least SD 6 weeks after Cycle 2, continue treatment at a reduced dose 
of 60 µg/kg q6weeks, beginning 6 weeks after Cycle 2 infusion.

200 µg/kg: Dosing every 6 weeks.  For patients with at least SD 
6 weeks after Cycle 1, continue treatment at a reduced dose of 
60 µg/kg every 6 weeks beginning 6 weeks after Cycle 1 infusion.
The first patient enrolled into the study at 15 µg/kg (Dose Level 1) must 
be observed for 7 days for occurrence of AEs prior to treating the second 
patient in the study. The DLT observation period for dose escalation is 
1 cycle.
For each dose level, if none of the first 3 patients at that level experiences 
a DLT, new patients may be entered at the next higher dose level. If 1 of 
3 patients experiences a DLT, up to 3 more patients are to be treated at 
that same dose level. If none of the additional 3 patients at that dose level 
experiences a DLT, new patients may then be entered at the next higher 
dose level. However, if 1 or more of the additional 3 patients experiences 
a DLT, then no further patients are to be started at that dose level and the 
preceding dose is identified as the MTD. The MTD is therefore defined as 
the highest dose level at which none of the first 3 treated patients, or no 
more than 1 of the first 6 treated patients, experiences a DLT.
The study will be continuously monitored for safety and early stopping for 
successful identification of the MTD.


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Dose-Expansion 
Design:
In Part 2, (expansion), patients will be assigned to the recommended dose 
level(s) and schedule(s) of ADCT-402 identified in Part 1 based on 
evolving safety, efficacy and pharmacokinetic data.
The population in Part 2 expansion may be restricted to specific 
histologies based on both signals of activity and the safety observed in 
Part 1.  
Further, dose levels and schedules evaluated in Part 2 may include but are 
not limited to the following:
90, 120, 150, 200 µg/kg:  Dosing every 3 weeks.
120 µg/kg:  Dosing every 3 weeks for 2 cycles. Patients with at least SD 
after the second cycle continue treatment at a reduced dose of 60 µg/kg 
q6weeks, beginning 6 weeks after Cycle 2 infusion.  
150 µg/kg: Dosing every 3 weeks for 2 cycles. Patients with at least SD 
after the second cycle continue treatment at a reduced dose of 60 µg/kg 
q6weeks, beginning 6 weeks after Cycle 2 infusion.  
200 µg/kg: Dosing every 6 weeks for 2 cycles.  For patients with at least 
SD 6 weeks after Cycle 2, continue treatment at a reduced dose of 60 
µg/kg q6weeks, beginning 6 weeks after Cycle 2 infusion.
200 µg/kg: Dosing every 6 weeks.  For patients with at least SD 6 weeks
after Cycle 1, continue treatment at a reduced dose of 60 µg /kg every 6 
weeks beginning 6 weeks after Cycle 1 infusion.
Sample Size:
This is a Phase 1 study with a maximum sample size of up to 
approximately 200 patients. It is estimated that approximately 90 patients 
will enroll at 11 sites in Part 1, and approximately 110 patients will enroll 
at 12 sites in Part 2.


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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
AI
accumulation index
Ala
alanine
ALT
alanine aminotransferase
ANC
absolute neutrophil count
ASCT
autologous stem cell transplant
AST
aspartate aminotransferase
AUC0-∞
area under the concentration-time curve from time zero to infinity
AUC0-last
area under the concentration-time curve from time zero to the last 
quantifiable concentration
AUC0-τ
area under the concentration-time curve from time zero to the end of the
dosing interval
BSA
body surface area
CBC
complete blood count
CD
cluster of differentiation
CFR
Code of Federal Regulations
CI
confidence interval
CL
clearance
Cmax
maximum concentration
CNS
central nervous system
CR
complete response
CRO
contract research organization
CT
computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
D5W
5% dextrose in water
DAR
drug-to-antibody ratio
DESC
Dose Escalation Steering Committee
DLT
dose-limiting toxicity
DOR
duration of response
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic case report form
EOI
end of infusion


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Abbreviation
Definition
EOT
End of treatment
EWOC
escalation with overdose control
FDA
Food and Drug Administration
FDG
18F-fluorodeoxyglucose
FFPE
formalin-fixed paraffin-embedded
GCP
Good Clinical Practice
GLP
Good Laboratory Practice
HBsAg
hepatitis B surface antigen
β-HCG
human chorionic gonadotropin
HCV
hepatitis C virus
HIV
human immunodeficiency virus
HNSTD
highest nonsevere toxic dose
hr
hour
ICF
informed consent form
ICH
International Council for Harmonisation
IEC
independent ethics committee
IHC
immunohistochemistry
INR
international Normalized Ratio
IV
intravenous
IRB
institutional review board
mos
months
MRI
magnetic resonance imaging
MRT
mean residence time
MTD
maximum tolerated dose
NHL
non-Hodgkin Lymphoma
NSAID
non-steroidal anti-inflammatory drug
ORR
overall response rate
OS
overall survival
PABA
para-aminobenzoic acid
PBD
pyrrolobenzodiazepine
PD
progressive disease
pharmacodynamics
PEG
polyethylene glycol
PET
positron emission tomography
PFS
progression free survival
PK
pharmacokinetic
PR
partial response


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Abbreviation
Definition
PT
prothrombin time
PTT
partial thromboplastin time
QWBA
Quantitative whole-body autoradiography
q6weeks
Every 6 weeks
RB4v1.2
human monoclonal antibody being studied
SAE
serious adverse event
SAP
statistical analysis plan
SCID
Severely combined immunodeficiency
SD
stable disease
TEAE
treatment-emergent adverse event
TLS
tumor lysis syndrome
λz
terminal elimination phase rate constant
Tmax
time to maximum concentration
T1/2
terminal half-life
ULN
upper limit of normal
Val
valine
Vss
volume of distribution at steady-state
VZ
volume of distribution
WBC
white blood cell
WHO
World Health Organization
wk
week


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1
Introduction and Study Rationale
1.1 Description of ADCT-402
ADCT-402 is an antibody drug conjugate (ADC) composed of a humanized antibody (RB4v1.2) 
directed against human cluster of differentiation 19 (CD19), attached with a cathepsin-cleavable 
linker to SG3199, a pyrrolobenzodiazepine (PBD) dimer cytotoxin. 
The PBD dimers are highly efficient anticancer drugs that bind in the minor groove of DNA and 
form highly cytotoxic DNA interstrand cross-links. The schematic representation of ADCT-402 
is presented in Figure 1.
Figure 1  Schematic Representation and Chemical Structure of ADCT-402
Abbreviations: Ala, alanine; PABA, para-aminobenzoic acid; PEG, polyethylene glycol; RB4v1.2, human 
monoclonal antibody being studied; Val, valine. 
The make-up of ADCT-402 includes:

RB4v1.2: A humanized monoclonal antibody specific for human CD19 of the immunoglobin 
G1 (IgG1), kappa isotype, generated by the variable domain resurfacing of the murine 
monoclonal anti-B4 (anti-CD19) antibody (Roguska, 1996).

SG3249:  A PBD linker that comprises the PBD dimer SG3199 and all linker components, 
including the maleimide, 8-polyethylene glycol, a protease-sensitive valine-alanine linker 
and a para-aminobenzoic acid (PABA) self-immolative group.
ADCT-402 binds with picomolar affinity to human CD19. After binding and internalization, 
ADCT-402 is transported to the lysosomes, where the protease sensitive linker is cleaved and 
free PBD dimers are released inside the target cell. The released PBD dimers bind into the minor 
groove of DNA and form highly cytotoxic DNA interstrand cross-links (Hartley, 2011a). The 
cross-links formed by PBD dimers are relatively non-distorting of the DNA structure, making 


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them hidden to repair mechanisms, allowing for a longer effective period (Adair, 2012) and 
effectiveness in tumor cell lines resistant to other forms of chemotherapy.
1.2 Study Rationale
Study ADCT-402-101 is the first- clinical study with ADCT-402 in patients with B-cell
non-Hodgkin Lymphoma (NHL).
1.2.1Clinical Background
Non-Hodgkin Lymphoma represents a biologically and clinically diverse group of hematologic 
malignancies arising from precursor and mature B, T, and natural killer cells. It is the seventh 
most common type of cancer in the U.S., and will account for an estimated 4.3% (n=71,850) of 
new cancer cases in 2015. It is most commonly a disease of older individuals with approximately
75% of new cases diagnosed in individuals 55 years of age or older (median age at diagnosis = 
66 years) (National Cancer Institute 2015). The two most common types of NHL, diffuse large 
B-cell lymphoma (DLBCL) and follicular lymphoma (FL), together account for more than half 
of all NHL cases (The Non-Hodgkin's Lymphoma Classification Project, 1997; Swerdlow, 
2008).
Combination chemotherapy or chemo-immunotherapy, with or without radiotherapy, is the most 
common initial treatment for most types of NHL (Ansell, 2015; Evens et al, 2015). Response to 
initial treatment generally exceeds 50% and the overall 5-year survival rate in the U.S. is 70% 
(National Cancer Institute 2015). However, a significant proportion of patients will relapse. The 
current standard of care for relapsed NHL is additional chemotherapy, which can be followed by 
allogeneic stem cell transplantation (ASCT). The poor prognosis for relapsed patients, especially 
those with chemo-refractory disease with a short interval between remission and relapse, or those 
who relapse after high-dose therapy and ASCT, highlights the need for new forms of treatment 
for NHL (Chao, 2013; Mounier and Gisselbrecht, 2011).
1.2.2Biology of CD19
Human CD19 is a 95 kilodalton (kDa) type I transmembrane glycoprotein belonging to the 
immunoglobulin Ig super family (Carter and Barrington, 2004; Tedder, 2009). In normal human 
tissue, expression of CD19 is restricted to the various stages of B cell development, from early 
pre B stage to mature B cells, but is lost in terminally differentiated plasma cells (Haas and 
Tedder, 2005; Scheuermann and Racila, 1995). Once bound to an antibody, CD19 is rapidly 
internalized by the cell (Gerber, 2009; Blanc, 2011). It is not shed into the circulation to the 
extent observed with other CD antigens0F1 (Cooper, 2004), therefore low to no levels of soluble 
CD19 are present to compete with binding at the target tissue. 
Expression of CD19 is maintained in B-cell malignancies, including DLBCL, Burkitt’s 
lymphoma, and FL. Additionally, CD19 expression is maintained in B-cell tumors which have 
1 Note:  A report of soluble CD19 detected in the cerebrospinal fluid of patients with certain types of B-cell lymphoma was 
recently published (Muniz, 2014).


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lost expression of CD20 after anti-CD20 monoclonal antibody treatment (Anderson, 1984, 
Scheuermann and Racila, 1995; Wang, 2012).
1.2.3Nonclinical Efficacy and Safety of ADCT-402
The potential for ADCT-402 in treating B-cell hematologic malignancies expressing CD19 has 
been shown by complete responses in mouse xenograft models of human-derived B-cell 
leukemias and lymphomas following single, low-dose administration. The efficacy of ADCT-
402 in these models is due to targeted delivery 
 
ADCT-402 is not pharmacologically cross-reactive (active) in any standard species used for 
nonclinical safety assessment (Blanc, 2011). In the absence of CD19 target engagement in the rat 
and monkey, it is not possible to evaluate the safety consequences associated with likely B-cell 
depletion. However, the impact and overall safety of B-cell depletion has been investigated 
clinically and nonclinically with other B-cell deleting agents and been shown to be safe and well 
tolerated (Kimby, 2005; Chen and Cohen, 2012).
Therefore, the safety studies performed assess the potential off-target effects of ADCT-402 and 
the impact of ADCT-402 on the tissues associated with ‘normal’ antibody clearance. In rats, 
ADCT-402 is well tolerated at doses up to 2 mg/kg.
 
 
 
 
As per guidance from the Food and Drug Administration (FDA), the starting dose of ADCT-402 
chosen for this study is 15 µg/kg.
See the Investigator Brochure for ADCT-402 for additional information, including guidance for 
the Investigator. 
1.2.4Safety of Commercially Available Antibodies Directed against CD19
Although several antibodies targeted against CD19 are currently in clinical development with 
different manufacturers (Jabbour, 2015), only one is commercially available in the U.S. 
Blinatumomab (Blincyto, Amgen, Thousand Oaks, CA) is a bispecific CD19-directed CD3 T-
cell engager indicated for the treatment of Philadelphia chromosome-negative, relapsed or 
refractory B-ALL. The antibody binds to CD19 on B-lineage cells and to CD3 on T cells. The 
most commonly reported adverse reactions reported with its use include pyrexia, headache, 
peripheral edema, febrile neutropenia, nausea, hypokalemia, and constipation (Amgen, 2014).


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2
Study Objectives
2.1 Primary Objectives

Evaluate the safety and tolerability, and determine, as appropriate, the maximum tolerated 
dose (MTD) of ADCT-402 in patients with relapsed or refractory B-cell lineage NHL in 
Part 1.

Determine the recommended dose(s) of ADCT-402 for Part 2 (expansion).

Evaluate the safety and tolerability of ADCT-402 in Part 2 (expansion) at the dose level(s)
recommended in Part 1.
2.2 Secondary Objectives

Evaluate the clinical activity of ADCT-402 as measured by overall response rate (ORR),
duration of response (DOR), overall survival (OS), and progression-free survival (PFS).

Characterize the pharmacokinetic (PK) profile of ADCT-402 (total antibody; drug to-
antibody ratio [DAR] ≥0), PBD-conjugated antibody (DAR ≥1), and free warhead SG3199.

Evaluate anti-drug antibodies (ADAs) to ADCT-402 in blood before, during, and after 
treatment with ADCT-402.
 
 
 
 
 


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3
Investigational Plan and Patient Selection
3.1 Study Design
This is a Phase 1, open-label, dose escalation (Part 1) and expansion (Part 2) study of the safety 
and tolerability of ADCT-402, used as monotherapy, in patients with relapsed or refractory 
B-cell NHL. The study will determine the MTD, as well as evaluate the preliminary activity, PK, 
pharmacodynamics, and other exploratory assessments of
ADCT-402.
Patients will receive a 1-hour intravenous (IV) infusion of ADCT-402, at escalating doses, 
on Day 1 of each cycle. If ADCT-402 is well tolerated after the first cycle, the infusion duration 
may be shortened to 30 minutes for subsequent cycles for that patient, at the Investigator’s 
discretion.
For each patient, the study will include a screening period (up to 28 days), a treatment period 
(until withdrawal, Section 4.2), and a follow-up period to assess disease progression and survival 
for up to 12 months after the last dose of study drug. The total study duration will depend on 
overall patient tolerability to the study drug and response to treatment. It is anticipated that the 
duration of the entire study (Parts 1 and 2) could be approximately 3 years from first patient 
treated to last patient completed.
Part 1
In Part 1, patients will be assigned to treatment according to a 3+3 dose escalation design 
(Section 3.2) and oversight of a Dose Escalation Steering Committee (DESC)
(Section 6.3.1.1). 
During the conduct of Part 1, and prior to implementation of Amendment 5, alternative dosing 
schedules are being evaluated at the discretion of the DESC as described below:. 

120 µg/kg:  Dosing every 3 weeks for 2 cycles. Patients with at least SD after the second 
cycle continue treatment at a reduced dose of 60 µg/kg q6weeks, beginning 6 weeks after Cycle 2 
infusion.  

150 µg/kg: Dosing every 3 weeks for 2 cycles. Patients with at least SD after the second 
cycle continue treatment at a reduced dose of 60 µg/kg q6weeks, beginning 6 weeks after Cycle 2 
infusion.  

200 µg/kg: Dosing every 6 weeks for 2 cycles.  For patients with at least SD 6 weeks after 
Cycle 2, continue treatment at a reduced dose of 60 µg/kg q6weeks, beginning 6 weeks after 
Cycle 2 infusion.

200 µg/kg: Dosing every 6 weeks.  For patients with at least SD 6 weeks after Cycle 1, 
continue treatment at a reduced dose of 60 µg /kg every 6 weeks beginning 6 weeks after Cycle 1
infusion.
Changes described in part 2 resulted from requests based on DESC decisions.


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Part 2
In Part 2, (expansion), patients will be assigned to the recommended dose level(s) and 
schedule(s) of ADCT-402 identified in Part 1 based on evolving safety, efficacy and 
pharmacokinetic data.
The population in Part 2 expansion may be restricted to specific histologies based on both 
signals of activity and the safety observed in Part 1.  
Further, dose levels and schedules evaluated in Part 2 may include but are not limited to the 
following:
A.
90, 120, 150, and/or 200 µg/kg:  Dosing every 3 weeks.
B.
120 µg/kg:  Dosing every 3 weeks for 2 cycles. Patients with at least SD after the second 
cycle continue treatment at a reduced dose of 60 µg/kg q6weeks, beginning 6 weeks after Cycle 2 
infusion.  
C.
150 µg/kg: Dosing every 3 weeks for 2 cycles. Patients with at least SD after the second 
cycle continue treatment at a reduced dose of 60 µg/kg q6weeks, beginning 6 weeks after Cycle 2 
infusion.  
D.
200 µg/kg: Dosing every 6 weeks for 2 cycles.  For patients with at least SD 6 weeks after 
Cycle 2, continue treatment at a reduced dose of 60 µg/kg q6weeks, beginning 6 weeks after 
Cycle 2 infusion.
E.
200 µg/kg: Dosing every 6 weeks.  For patients with at least SD 6 weeks after Cycle 1,
continue treatment at a reduced dose of 60 µg /kg every 6 weeks beginning 6 weeks after Cycle 1 
infusion.
The continuation of each patient’s treatment will be based on an independent verification of local 
response assessments, unless otherwise approved by the sponsor.  
The DESC will determine and document the dose levels, schedules, and disease subtypes to be 
evaluated in Part 2. These determinations by the DESC will be provided in writing.  
Based on emerging safety and efficacy profile, the DESC may add additional cohorts to part 2 of the 
study with the same or different dosing regimens and for the same or different B-cell NHL 
histologies. The dose will not exceed the highest dose tested in part 1 at which 3 patients cleared the 
DLT observation period.
Patients who discontinue treatment for any reason other than disease progression will continue to 
be followed approximately every 12 weeks from the last disease assessment until disease 
progression, or initiation of new anticancer treatment. 
After documentation of disease progression or start of new treatment, patients will be followed 
(by telephone contact or chart review) approximately every 12 weeks for up to 12 months after 
the last dose of study drug to collect survival information.
3.2 Dose Escalation
In Part 1, dose escalation will be conducted according to a 3+3 design (Figure 2). The initial dose 
of ADCT-402 will be 15 µg/kg (Dose Level 1), and the highest allowed dose will be 300 µg/kg.
The potential dose levels are described in Table 1.


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Table 1.
Planned Dose Levels for ADCT-402
Dose Level
Dose of ADCT-402
Dose Level
Dose of ADCT-402
1
15 µg/kg 
6
150 µg/kg
2
30 µg/kg
7
200 µg/kg
3
60 µg/kg
8
250 µg/kg
4
90 µg/kg
9
300 µg/kg
5
120 µg/kg
The dose-limiting toxicity (DLT, Section 6.3.1) observation period for dose escalation is 1 cycle. 
The first patient enrolled into the study at 15 µg/kg (Dose Level 1) must be observed for 7 days 
for occurrence of AEs prior to treating the second patient in the study. Patients will be entered 
sequentially to each dose level.
For each dose level, if none of the first 3 patients at that level experiences a DLT, new patients 
may be entered at the next higher dose level. If 1 of 3 patients experiences a DLT, up to 3 more 
patients are to be treated at that same dose level. If none of the additional 3 patients at that dose 
level experiences a DLT, new patients may then be entered at the next higher dose level. 
However, if 1 or more of the additional 3 patients experiences a DLT, then no further patients are 
to be started at that dose level and the preceding dose is identified as the MTD. The MTD is 
therefore defined as the highest dose level at which none of the first 3 treated patients, or no 
more than 1 of the first 6 treated patients, experiences a DLT.
No intra-patient dose escalation is allowed. 
Figure 2. Schematic Representation for Dose Escalation (3+3) Design
Abbreviations:  DLT, dose-limiting toxicity; MTD, maximum tolerated dose; <, less than; ≥ greater than or equal to.


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The number of dose levels will depend on the emergent toxicity profile of ADCT-402 and will 
be decided by the DESC (Section 6.3.1.1); PK, and PD evaluations may also inform decision 
making.
The trial will be continuously monitored for safety. If the maximum allowed dose (300 μg/kg) is 
reached and the MTD is not identified, no further dose escalation will be allowed pending a 
safety analysis and review and accordingly, an amendment to the protocol.
During Part 1, the DESC may expand enrollment at any dose level in which 3 patients have 
completed the DLT observation period if at least 1 patient in the study has achieved a partial 
response (PR, Section 6.1) or better, or if further evaluation of PK or PD data is deemed 
necessary to characterize pharmacology in humans. No more than 10 patients in total can be 
treated at any dose level unless ≥3 of the 10 patients have achieved a PR or better.
During dose expansion (part 2), patients will be monitored for safety using the same DLT criteria 
employed during dose-escalation. If during the treatment period, > 30% of patients experience 
safety events that would meet the criteria that define a DLT in the dose-escalation phase of the 
study, enrollment in the expansion cohort(s) may be paused and the study data reviewed to 
determine whether additional monitoring or other action (such as alternate dose levels) should be 
evaluated prior to further enrollment.
3.3 Selection of Study Population
This is a Phase 1 study with a sample size of up to 200 patients. It is estimated that 
approximately 90 patients will enroll at 11 sites in Part 1, and approximately 110 patients will 
enroll at 12 sites in Part 2. Patients will be assigned to a study treatment only if they meet all of 
the inclusion criteria and none of the exclusion criteria.
3.3.1Inclusion Criteria
1. Part 1: Male or female patients, ages 18 years or older with pathologically-confirmed 
relapsed or refractory B-cell lineage NHL who have failed or are intolerant to established 
therapy, or for whom no other treatment options are available, in the opinion of the
Investigator.
Refractory or relapsed B-cell NHL (per WHO Classification system; Swerdlow, 2008) 
defined as: 

Diffuse large B-cell lymphoma (DLBCL),

Follicular lymphoma (FL),

Chronic lymphocytic leukemia (CLL),

Mantle cell lymphoma (MCL),

Marginal Zone B-cell Lymphoma (MZBCL),

Burkitt’s lymphoma (BL),

Lymphoplasmacytic lymphoma (Waldenstrom macroglobulinemia [WM]).


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Part 2: 
Eligible histologic sub-types to be investigated in part 2 of the study will be determined by 
the DESC based on evolving efficacy and safety information from Part 1. Patients enrolled in 
part 2 of the study will have failed or are intolerant to established therapy, or have no other 
treatment options are available, in the opinion of the Investigator.
2. Availability of formalin-fixed paraffin-embedded (FFPE) tumor tissue block. An FFPE block 
from a current biopsy is preferred; however, archival tissue taken at initial diagnosis or any 
prior relapse is acceptable. If tissue block is not available, slides from a FFPE block may be 
acceptable for eligibility upon consultation with the Sponsor (Section 6.4).
3. Measurable disease, as defined by the 2014 Lugano Classification (Appendix 12.2). 
4. Eastern Cooperative Oncology Group (ECOG) performance status 0 to 2.
5. Absolute neutrophil count (ANC) ≥1000/µL.
6. Platelet count of ≥75000/µL.
7. Hemoglobin ≥9.0 g/dL without transfusion within the 2 weeks prior to Day 1.
8. Serum/plasma creatinine ≤1.5 mg/dL. If the patient has a creatinine > 1.5mg/dL, a measured 
creatinine clearance must be >60mL/min as calculated by the Cockcroft and Gault equation
(Cockcroft and Gault 1976).
9. Serum/plasma alkaline phosphatase, alanine aminotransferase (ALT), and aspartate
aminotransferase (AST) ≤2 times the upper limit of normal (ULN); ≤5 times ULN if there is 
liver or bone involvement.
10. Total serum/plasma bilirubin ≤1.5 times ULN (patients with known Gilbert’s syndrome may 
have a total bilirubin up to ≤3 times ULN).
11. Negative blood or urine beta-human chorionic gonadotropin (β-HCG) pregnancy test within
7 days prior to Day 1 for women of childbearing potential.
12. Women of childbearing potential* must agree to use a highly effective** method of 
contraception from the time of giving informed consent until at least 16 weeks after the last 
dose of ADCT-402. Men with female partners who are of childbearing potential must agree 
that they or their partners will use a highly effective method of contraception from the time 
of giving informed consent until at least 16 weeks after the patient receives his last dose of
ADCT-402.
* Women of childbearing potential are defined as sexually mature women who have not 
undergone bilateral tubal ligation, bilateral oophorectomy, or hysterectomy; or who have not 
been postmenopausal (i.e., who have not menstruated at all) for at least 1 year.
** Highly effective forms of birth control are methods which achieve a failure rate of less 
than 1% per year when used consistently and correctly. Highly effective forms of birth 
control include: Hormonal contraceptives (oral, injectable, patch, intrauterine devices), male 
partner sterilization, or total abstinence from heterosexual intercourse, when this is the 


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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.
3.3.2Exclusion Criteria
1. Patients who, in the opinion of the Investigator, have any option for other treatment for B-cell 
NHL at the current state of disease. 
2. Active graft-versus-host disease.
3. Autologous or allogenic transplant within the 60 days prior to the Screening visit.
4. Known history of immunogenicity or hypersensitivity to a CD19 antibody.
5. Evidence of myelodysplasia or myeloid leukemia by morphology, immunostains,
flow cytometry, or cytogenetics on a bone marrow aspirate or biopsy.
6. Known history of positive serum human ADA.
7. Active autoimmune disease (e.g., rheumatoid arthritis, systemic progressive sclerosis 
[scleroderma], systemic lupus erythematosus, Sjögren's syndrome, autoimmune vasculitis 
[e.g., Wegener's granulomatosis]); motor neuropathy considered of autoimmune origin (e.g., 
Guillain-Barré syndrome and myasthenia gravis); other CNS autoimmune disease (e.g., 
poliomyelitis, multiple sclerosis). Known seropositive for human immunodeficiency (HIV) 
virus, hepatitis B surface antigen (HBsAg), or antibody to hepatitis C virus (anti-HCV) with 
confirmatory testing and requiring anti-viral therapy. 
Note: Testing is not mandatory to be eligible. Testing for HCV should be considered if the 
patient is at risk for having undiagnosed HCV (e.g., history of injection drug use).
8.
History of Steven's Johnson's syndrome or toxic epidermal necrolysis syndrome.
9. Pregnant or breastfeeding women.
10. Significant medical comorbidities, including uncontrolled hypertension (diastolic blood 
pressure greater than 115 mm Hg), unstable angina, congestive heart failure (greater than 
New York Heart Association class II), severe uncontrolled ventricular arrhythmias, or 
electrocardiographic evidence of acute ischemia, poorly controlled diabetes, severe chronic 
pulmonary disease, coronary angioplasty, or myocardial infarction within 6 months prior to 
screening, or uncontrolled atrial or ventricular cardiac arrhythmias.
11. Use of any other experimental medication(s) within 14 days or 5 half-lives but in no case less 
than 14 days prior to start of study treatment on Cycle 1, Day 1.
12. Steroid use equivalent to greater than 20 mg of prednisone within 4 weeks (28 days) prior to 
Day 1, except for the use of short course systemic corticosteroids (≤ 7 days), with a wash-out 
period of 1 week prior to start of study treatment on Day 1.


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13. Major surgery, chemotherapy, systemic therapy (excluding steroids; and any targeted small 
molecules or biologics),), radiotherapy, within 14 days or 5 half-lives (whichever is shorter) 
prior to Cycle 1, Day 1 treatment, except if approved by the Sponsor.
14. Failure to recover (to Common Terminology Criteria for Adverse Events [CTCAE] Grade 0 
or Grade 1) from acute non hematologic toxicity (except all grades alopecia or grade 2 or 
lower neuropathy), due to previous therapy, prior to Screening.
15. Congenital long QT syndrome, or a corrected QTc interval of ≥450 ms, at the Screening visit
(unless secondary to pacemaker or bundle branch block).
16. Active second primary malignancy other than non-melanoma skin cancers, nonmetastatic 
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.
17. 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.


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4
Study Procedures
4.1 Procedures by Study Day
The following procedures will be performed during the study. Timings for sample collections 
and procedures are provided in Appendix 12.1.
4.1.1Screening Period (Day –28 to –1)
The following procedures will be performed within 28 days prior to the Day 1 visit of Cycle 1, 
unless otherwise specified:

A signed and dated Institutional Review Board (IRB) /Independent Ethics Committee (IEC)
approved informed consent form (ICF) obtained prior to performing any study evaluations.
Results (e.g., from laboratory tests or radiographic evaluations, etc.) obtained prior to the 
date of informed consent but within the allowed timeframe for screening may be used for 
determination of patient eligibility only if obtained as part of the patient’s standard of care.

Demographic characteristics.

Medical history (to include a complete history of all surgeries and significant diagnoses and 
all cancer treatment [including surgery, radiation therapy, chemotherapy, etc.]).

Blood or urine β-HCG pregnancy testing (women of childbearing potential only).

Physical examination including whole body skin assessment. The whole body skin 
assessment does not have to be performed by a dermatologist. However, any unexplained 
lesion is to be referred to a dermatologist for further evaluation and skin biopsy, if clinically 
warranted.

Vital signs (arterial blood pressure, heart rate, respiratory rate, body temperature), height and 
weight measurements.

ECOG performance status.
 
 
 
 

Disease assessment: Positron emission tomography - computed tomography (PET-CT) and 
diagnostic CT of the neck/chest/abdomen/pelvis and other areas of known disease or newly 
suspected disease with a clinical examination for lymphoma. Contrast should be used unless 
contraindicated. Magnetic resonance imaging (MRI) is permitted if diagnostic CT is 
contraindicated. The same assessments methods used at Screening which identify sites of 
disease should be used uniformly for all subsequent assessments. 
Note: PET-CT is only required at screening for 18F-fluorodeoxyglucose (FDG) avid, nodal 


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lymphomas (defined as per the Lugano Classification criteria as essentially all eligible 
histologies except small lymphocytic lymphoma, lymphoplasmacytic 
lymphoma/Waldenstrom’s macroglobulinemia, mycosis fungoides, and marginal zone NHLs, 
unless there is a suspicion of aggressive transformation). If PET-CT examination is negative 
at Screening, subsequent PET-CT is not required.  If PET-CT is positive, subsequent 
diagnostic CT and MRI are not needed unless clinically indicated.

Hematology, coagulation panel, biochemistry, and urinalysis parameters.

12-lead electrocardiogram (ECG).

Collection of adverse event (AE) information.

Collection of information on medications used (including prescription or over-the-counter 
medication, herbal or naturopathic products) within the 14 days prior to the Day 1 visit.
4.1.2Day 1 of Each Cycle
The following procedures will be performed prior to ADCT-402 infusion (unless otherwise 
indicated) at each cycle, unless otherwise specified.  

Blood or urine β-HCG pregnancy test required if the pregnancy test was obtained >7 days 
prior to Day 1 (every other cycle).

Physical examination including whole body skin assessment, unless an assessment was 
performed within 3 days prior to Day 1.

Vital signs:  On Day 1 of Cycles 1 and 2, vital signs are to be measured before the start of the 
ADCT-402 infusion, every 30 minutes during the infusion, at the end of infusion, and at 1, 3, 
and 6 hours after the end of infusion. If no clinically significant changes occur during Cycles 
1 and 2, vital sign measurements are to be obtained prior to infusion start and end of infusion 
for all subsequent infusions. If clinically significant changes in vital signs are observed at 
Cycle 1 and/or 2 infusion, that patient will be required to have vital signs measured before 
the start of the ADCT-402 infusion, every 30 minutes during the infusion, at the end of 
infusion, and at 1, 3, and 6 hours after the end of the ADCT-402 infusion for all subsequent 
cycles.

Weight.

ECOG performance status.

Samples for hematology, coagulation panel, biochemistry parameters, will be measured prior 
to dosing unless the last sample was collected:
o
<24 hours before the start of ADCT-402 infusion on Day 1 of Cycle 1, or
o
<72 hours before the start of ADCT-402 infusion on Day 1 of Cycle 2 and subsequent 
cycles.


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
Sample collection for additional renal function studies.

Sample collection for urinalysis
Prior to dosing unless the last sample was collected:
o
<24 hours before the start of ADCT-402 infusion on Day 1 of Cycle 1, or
o
<72 hours before the start of ADCT-402 infusion on Day 1 of Cycle 2 and subsequent
cycles.

Disease assessment:
Patients Initially Treated Every 3 weeks 
o
To be conducted within 6 days prior to Day 1 of Cycles 3 and 5 and thereafter every third 
cycle (i.e., Cycles 8, 11, 14, etc.), until disease progression, or more frequently, 
if clinically indicated.
o
Patients who initially follow a three-week dose schedule and then transition to a six-week 
schedule following Cycle 2 should have disease assessments ~6 weeks after Cycle 1
Day 1, and ~12 weeks after Cycle 1 Day 1, and thereafter at least every 12 weeks.  
Patients Initially Treated Every 6 weeks 
o
For patients who have reduced dosing frequency and are following a 6 week schedule, 
disease assessments should occur approximately 6 weeks and 12 weeks after Cycle 1 
Day 1, and thereafter at least every 12 weeks. It is understood that there will be a ± 6 day 
window for restaging of these patients.
o
For patients in Part 2: Treatment continuation will require independent verification of the 
local response assessment unless otherwise approved by the sponsor.  
In case of dose delays, please refer to Section 6.1 for the frequency of disease assessments.
The same methods used at Screening which identify sites of disease should be used uniformly 
for all subsequent assessments.  If PET-CT is positive, subsequent diagnostic CT and MRI are 
not needed unless clinically indicated.
If PET-CT examination is negative at Screening, subsequent PET-CT is not required.

12-lead ECG (Cycles 1 and 2) before the start of the ADCT-402 infusion, within 30 minutes 
of the end of infusion, and at 3 hours (± 30 minutes) and 24 (± 2.4) hours after the end of 
infusion. For Cycle 3 and subsequent cycles, a 12-lead ECG is to be performed before the 
start of ADCT-402 infusion.

Sample collection for central laboratory analysis of ADA (all cycles).

Sample collection (Cycles 1 and 2) for central laboratory analysis of PK parameters before 
the start of the ADCT-402 infusion, at the end of the infusion, and at 1, 3, and 6 hours after 
the end of the ADCT-402 infusion. For Cycle 3 and subsequent cycles, samples will be 
collected before the start of the ADCT-402 infusion and at the end of the infusion.


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
Collection of AE information.

Collection of concomitant medication information.

Premedication administration, if applicable (Section 5.2).

ADCT-402 administration.
4.1.3Day 2 (Cycles 1 and 2)
The following procedures will be performed 24 hours (± 10%) after the end of the ADCT-402 
infusion:

12-lead ECG.

Vital signs

Sample collection for central laboratory analysis of PK parameters.

Collection of AE information.

Collection of concomitant medication information.
4.1.4Day 3 (Cycles 1 and 2)
The following procedures will be performed 48 hours (± 10%) after the end of the ADCT-402 
infusion:

Vital signs.

Sample collection for central laboratory analysis of PK parameters.

Collection of AE information.

Collection of concomitant medication information.
4.1.5Day 5 (Cycles 1 and 2)
The following procedures will be performed 96 hours (± 1 day) after the end of the ADCT-402 
infusion:

Sample collection for central laboratory analysis of PK parameters.

Vital signs.

Collection of AE information.

Collection of concomitant medication information.
4.1.6Day 8 (± 2 days) of Each Cycle

Physical examination (Cycles 1 and 2) including whole body skin assessment.


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
Weight 

Vital signs.

Hematology and biochemistry parameters.

Urinalysis and sample collection for additional renal function studies.

Sample collection for central laboratory analysis of PK parameters (Cycles 1-4).

Collection of AE information.

Collection of concomitant medication information.
4.1.7Day 15 (± 2 days) of Cycles 1 and 2
The Day 15 visit will be conducted during Cycles 1 and 2 only; the following procedures will be 
performed at this visit:

Physical examination including whole body skin assessment.

Weight.

Vital signs.

Hematology and biochemistry parameters.

Urinalysis and sample collection for additional renal function studies.

Sample collection for central laboratory analysis of PK parameters.

Collection of AE information.

Collection of concomitant medication information.
4.1.8Day 28 (± 3 days) 
For patients who have transitioned to a reduced dosing frequency (see Section 3.1) this visit will 
be required for Safety/PK Monitoring. Assessments required for Safety/PK Monitoring are 
indicated below.  For patients in Part 1 this visit will be done approximately 21 days after 
infusion.  

Physical examination 

Vital signs

Weight

ECOG

12-lead ECG

Sample collection for hematology, coagulation panel, and biochemistry parameters

Sample collection for urinalysis


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
Sample collection for additional renal function studies.

Sample collection for central laboratory analysis of PK parameters and ADA.

Collection of AE information

Collection of concomitant medication information
4.1.9End of Treatment Visit
The following procedures will be performed within 30 days after study treatment discontinuation
and prior to initiation of new anticancer treatment:

Physical examination including whole body skin assessment.

Weight and vital signs.

ECOG performance status.

Disease assessments:
o
Patients who already have documented objective disease progression do not need to have 
assessments repeated.
o
Patients who do not already have documented objective disease progression will have 
assessments performed at the end of treatment visit if the most recent disease assessment 
was >9 weeks prior to the end of treatment visit.

Blood or urine pregnancy test

Hematology, coagulation panel, and biochemistry parameters.

Urinalysis and sample collection for additional renal function studies.

12-lead ECG.

Sample collection for central laboratory analysis of PK parameters and ADA.
 

Collection of AE information

Collection of concomitant medication information.
When EOT coincides with a scheduled visit, the scheduled visit will become EOT.
4.1.1012-week Follow-up Visit
Each patient will have a blood sample taken for assessment of PK and ADA at 12 (±1) weeks 
after their last dose of ADCT-402, unless a new anticancer treatment has been initiated.
Blood Sample Collection and Adverse Event Monitoring During Long-Term Follow-up
Patients who test positive for ADAs may be requested to supply additional ADA samples.


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For all patients, collection of AEs and SAEs will continue for 12 weeks after the last dose of 
study drug or initiation of new anticancer treatment (see Section 6.3.2.2).
4.1.11Long-term Follow-up
Patients who discontinue treatment for any reason other than objective disease progression will 
continue to be followed with scans approximately every 12 weeks from the last tumor 
assessment until disease progression, or initiation of new anticancer treatment. If a patient 
discontinues treatment for a hematopoietic stem cell transplant, the frequency of imaging will be 
as per the transplant center standard of care.
After documentation of disease progression or start of new treatment, patients will be contacted
by telephone approximately every 12 weeks for up to 12 months after the last dose of study drug 
to collect survival information.
4.2 Withdrawal of Patients from the Study
The duration of the study participation for each patient is defined as the time from the date of 
signed written informed consent through the completion of the follow-up period or withdrawal of 
consent.
4.2.1Reasons for Withdrawal/Discontinuation
Patients may withdraw from the study at any time and for any reason without prejudice to their
future medical care by the Investigator or others at the study site.
A patient may be withdrawn from treatment with ADCT-402 for any of the following reasons:

Disease progression.

AE.

Withdrawal of consent.

Major protocol deviation.

Required treatment delay >21 days (except in case of potential patient benefit, which must be 
approved by the Sponsor).

Following a dose delay due to toxicity, if the same toxicity recurs after second dose reduction, 
study drug must be discontinued permanently.

Non-compliance, including lost to follow-up.

Pregnancy.

Other (e.g., development of contraindications with use of the study drug).

The Investigator determines that it is in the best interest of the patient to discontinue the 
patient’s participation in the study.

Discontinuation of the study by the Sponsor.


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
Death.
Patients experiencing other significant toxicities must be immediately and permanently 
withdrawn from treatment with ADCT-402 as follows:

Any patient who experiences a Grade 3 or higher hypersensitivity (Appendix 12.3) reaction, 
regardless of premedication, during any cycle of treatment. 

Any patient who experiences a recurrent Grade 3 or 4 toxicity, excluding hematological 
toxicity.

Any patient who requires a dosing delay >21 consecutive days from the planned Day 1 
dosing at any time during treatment (except in case of potential patient benefit, which must 
be approved by the Sponsor).
4.2.2Handling of Withdrawals
The Investigator will confer with the Sponsor if a patient experiences a serious or intolerable AE. 
If a patient discontinues from the study because of an AE, the patient will be followed to 
satisfactory resolution, until the Investigator deems the event to be chronic or not clinically 
significant, or until the patient is considered to be stable (Section 6.3.2.6).
For each patient who discontinues study treatment and withdraws from the study, the 
Investigator will record the reason(s) for discontinuation on the relevant page of the electronic 
case report form (eCRF). Whenever possible, each patient who discontinues study treatment will 
undergo an EOT visit and all EOT assessments (Section 4.1.9). Patients who fail to return for 
final assessments are to be contacted by the investigative site. Following a minimum of 2 
documented unsuccessful telephone calls, the investigative site will send a registered letter to the 
patient in a final attempt to ensure protocol compliance.
Note: Once discontinued from the study, for any reason, patients are not permitted to be 
re-enrolled into the study.
4.2.3Patient Replacements
Any patient in Part 1 who discontinues before completion of the first treatment cycle, for any 
reason other than a DLT, is to be replaced.


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5
Study Treatments
5.1 Method of Assigning Patients to Treatment Groups
In Part 1 (dose escalation), patients will receive an IV infusion of ADCT-402  on Day 1 of each 
3-week (21-day) cycle. The first patient receiving the first dose of ADCT-402 in the study must 
be observed for 7 days for occurrence of AEs prior to treating a second patient. The dose 
escalation procedure is described in Section 3.2. If the highest allowed dose (300 μg/kg) is 
reached and the MTD is not identified, no further dose escalation will be allowed, pending a 
safety analysis and an amendment to the protocol.
In Part 2 (expansion), patients will be assigned to the recommended dose level(s) and schedule(s) 
of ADCT-402 identified in Part 1 by the DESC. Once the recommended Part 2 dose(s) and 
schedule(s) is/are determined, patients receiving lower or higher dose levels of ADCT-402 may 
be offered continued treatment at the recommended dose(s) and schedule(s).
5.2 Prophylactic Treatments for Hypersensitivity
If 1 patient experiences a Grade 2 or higher (Appendix 12.3) infusion-related hypersensitivity 
reaction at any time during Part 1 (dose escalation), all subsequent patients must receive 
prophylactic treatment, as described below or as per the institution’s standard of care, to reduce 
the risk of hypersensitivity reactions.

On Day 1 of each cycle, patients will be instructed to take 20 mg orally of dexamethasone at 
12 and 6 hours before the start of ADCT-402 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 50 mg IV of diphenhydramine hydrochloride
at 30 minutes before the start of ADCT-402 infusion.

On Day 1 of each cycle, patients will be given 50 mg of ranitidine (or equivalent) IV at 30 
minutes before the start of ADCT-402 infusion.

For 2 days following administration of ADCT-402 on Day 1, all patients are to take 
dexamethasone 4 mg orally, twice per day.
Other medications for prophylaxis and treatment of hypersensitivity or infusion reactions may be 
administered, according to standard treatment center protocols. Medications for the treatment of 
severe hypersensitivity reactions, including anaphylaxis, should be available for immediate use.
If a patient experiences a Grade 1 or 2 hypersensitivity reaction (Appendix 12.3), the following 
medications (or equivalent) should be administered for 48 hours after ADCT-402 infusion:

Ranitidine 150 mg orally, 2 times per day.

Diphenhydramine hydrochloride 50 mg orally, 3 times per day.
Any patient who experiences a Grade 3 or higher hypersensitivity (Appendix 12.3) reaction 
should be discontinued from the study and immediately treated according to institutional 


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standard of care and determined by the treating investigator. These patients must be carefully 
observed after the treatment. Additional therapy, as per the institution’s standard of care, should 
also be followed.
5.3 Treatments Administered
In Part 1 (dose escalation), each patient will be assigned a dose level and schedule as described 
in Section 3.1 and Section 3.2. In Part 2 (expansion), all patients will be assigned to the 
recommended dose level(s) and schedule(s) of ADCT-402 identified in Part 1 by the DESC.
ADCT-402 will be administered on Day 1 of each cycle as a 1-hour IV infusion. If ADCT-402 is 
well tolerated after the first cycle, the infusion duration may be shortened to 30 minutes for 
subsequent cycles, on an individual patient basis, at the Investigator’s discretion. 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.
Prophylactic antiemetic medications, electrolyte supplementation, and other standard supportive 
care measures may also be administered according to standard treatment center protocols, or as 
in Section 5.2 and Section 5.9.2.
Although the study patient population has a low risk for development of tumor lysis syndrome 
(TLS) compared to patients with acute disease (Cairo, 2010), patients should be observed for 
development of TLS and treated according to standard treatment center protocols.
Because of non-clinical observations related to nephropathy, adequate patient hydration (e.g., 8
to 10 glasses of water or equivalent per day) is recommended for patients receiving ADCT-402.
Additionally, because new or worsening edema and / or new or worsening pleural effusion have 
been observed, patients are advised to monitor their weight on a daily basis (Section 6.3.8 and 
5.9.2) 
As non-clinical testing indicates testicular toxicity (atrophy with reduced spermatogenesis), male 
patients are advised to consider cryopreservation of sperm prior to treatment with ADCT-402, 
where applicable.
Available pre-clinical data on ADCT-402 does not suggest a photosensitivity concern, based on 
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However, skin rash has been reported in the ADTC 402-101 study, as well as with another 
investigational agent containing the same pyrollobenzodiazepine warhead (Rudin, 2016).  The 
rash has been limited to areas at risk for sun exposure, it is therefore recommended that 
precautions are taken to avoid prolonged exposure of skin to direct sunlight. 
5.4 Dose Delays and Modifications
The Investigator may suspend ADCT-402 dosing for up to 21 days for any patient who 
experiences a protocol-defined DLT after Cycle 1 (the defined DLT observation period). At the 
discretion of the Investigator, the dose may also be delayed for up to 21 days for any toxicity that 
does not meet DLT criteria. Resumption of dosing with ADCT-402 after suspension is at the 
discretion of the Investigator, based on assessment of the patient’s clinical condition and whether 
or not the patient is deriving potential clinical benefit from treatment with ADCT-402. Following 
recovery to Grade 1 or to baseline grade, treatment with ADCT-402 may resume at the 
Investigator’s discretion.
Patients who resume treatment following a dose delay may, at the discretion of the DESC, have 
their dose of study drug reduced by 50%. If toxicity occurs again at the reduced dose, the patient 
will be discontinued from the study.  
During part 2, dose delay due to toxicity may extend beyond 21 days at the discretion of the 
investigator, in consultation with the Sponsor, based on assessment of the patient’s clinical 
condition and whether or not the patient is deriving potential clinical benefit from treatment with 
ADCT-402. When dosing is resumed, the dose may be decreased by 50% at the discretion of the 
Investigator, in consultation with the Sponsor.
If the dose is reduced and the toxicity recurs, the dose will be further reduced by 50%.
If toxicity recurs after second dose reduction, study drug must be discontinued permanently.
If dose is held for six weeks or more, restaging scans must be done prior to restarting dosing to 
rule out disease progression.
5.5 Identity of Investigational Product
ADC Therapeutics will provide and distribute adequate supplies of ADCT-402 to the study sites. 
The following drug supplies will be used in the study: 
Product
Supplied As:
ADCT-402
10-mL single-use glass vial with overfill to allow for up to 3.2 mL to 
deliver a total of 16 mg per vial (overfill deliverable volume 3.5 mL 
at 5 mg/mL). (equivalent to 16 mg ADCT-402)
5.5.1ADCT-402 Drug Product
ADCT-402 is a sterile formulation containing PBD-conjugated RB4v1.2 (DAR ≥1), RB4v1.2 
(DAR = 0), and SG3249. It is provided pre-formulated in 10-mL glass vials containing 
approximately 16 mg ADCT-402 per vial (deliverable volume 3.2 mL at 5 mg/mL).


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5.6 Management of Clinical Supplies
5.6.1Study Drug Packaging and Storage
ADCT-402 will be supplied in a labeled 10-mL stoppered glass vial shipped to the 
investigational site. Once the package arrives, the receiving site pharmacy will complete the 
enclosed procedures to acknowledge receipt. 
All study drugs must be stored in a secure area (e.g., a locked cabinet). ADCT-402 should be 
protected from light and stored frozen (–65°C or below). ADCT-402 should be thawed under 
ambient conditions.
5.6.2Study Drug Preparation and Administration
After the vials have been completely thawed, they should be gently mixed by swirling to ensure 
homogeneity and visually inspected before use. The appropriate quantity of ADCT-402 will be 
removed from the vial with a syringe and diluted into a 50 mL IV bag containing 5% dextrose in 
water (D5W)/Glucose. The amount of the product to be diluted will depend on the dose level and 
the body mass of the patient. Once the ADCT-402 has been transferred, the bag should be mixed 
to ensure homogeneity of the dosing solution. The contents of the IV bag will then be 
administered to the patient with a dosing pump per institutional guidelines for intravenous fluid. 
Additional instructions regarding study drug handling, storage, and preparation are included in 
the pharmacy manual.
5.6.3Study Drug Accountability
The Investigator will maintain accurate records of receipt of all study drugs, including dates of 
receipt. In addition, accurate records will be kept regarding when and how much study drug is 
dispensed and used by each patient in the study. Reasons for departure from the expected 
dispensing regimen must also be recorded. All study drugs will be reconciled and retained or 
destroyed according to applicable regulations.
5.7 Overdose Management
An overdose is any dose of study treatment given to a patient that exceeds the dose described in 
the protocol. Any overdose, with or without associated AEs, must be promptly reported to the 
Sponsor. There are no data available to determine what the effects of overdose are and whether 
they can be reversed. Symptomatic treatment and standard supportive care measures for the 
management of any observed toxicity should be applied.
5.8 Treatment Compliance
Administration of the study treatments will be performed by the Investigator or a qualified 
designee; therefore, compliance will be verified by the study drug administration information. 
5.9 Concomitant Treatment
All medications used within 14 days prior to Day 1 and during the treatment period are recorded 
in the eCRF. This will include all prescription drugs, herbal products, vitamins, minerals, and 


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over-the-counter medications. Any changes in concomitant medications will also be recorded in 
the patient’s eCRF.
5.9.1Prohibited During Study

Other anticancer therapy with the exception of hormonal therapy for maintenance treatment 
of breast and prostate cancer.

Radiation therapy is prohibited during the first cycle of therapy. After the first cycle, 
radiation is permitted for palliative use only if documented radiographic disease progression 
is ruled out first.

Other investigational agents.

Chronic treatment with corticosteroids (prednisone ≥12.5 mg/day or dexamethasone
≥2 mg/day, excluding inhaled steroids).

Live vaccines.
5.9.2Permitted During Study
After confirmation and documentation of eligibility, supportive care treatments 
(transfusions, etc.) can be prescribed as medically appropriate.
Hematopoietic growth factors are permitted as per American Society of Clinical Oncology 
guidelines (Smith, 2006); however, prophylactic use of growth factors is not allowed during the 
first treatment cycle.
If a Grade 2 or higher infusion-related hypersensitivity (Appendix 12.3) reaction is observed in 
1 patient at any time during Part 1 of the study, all subsequent patients must receive prophylactic 
treatment (Section 5.2).
Concomitant steroid use is permitted as follows:

Replacement doses of steroids for patients with adrenal insufficiency

Intranasal, inhaled, topical steroids, or local steroid injections (e.g., intra-articular injection)
During Part 1, the DESC agreed to evaluate the potential for the addition of dexamethasone to 
mitigate toxicity.  The recommendation was communicated (February 2017) as follows: 
Dexamethasone 8 mg PO BID

Day -1 (day prior to dosing) [if possible]

Day 1 (day of dosing, pre-dose)

Day 2 (day after dosing)
It is further recommended that patients in Part 2 have receive dexamethasone as follows:

Dexamethasone 4 mg PO BID the day before IP administration (if possible), the day of IP 
administration (given at least 2 hours prior to IP administration, if not given the day before), 


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and the day after IP administration (Week 1/Day 1 of each cycle only, regardless of treatment 
schedule).
In addition, spironolactone, at standard doses, may be instituted at any time for patients with 
weight gain greater than 1 kg (2.2 pounds) from Cycle 1 Day 1, new or worsening edema and/or 
new or worsening pleural effusion.  The dose of spironolactone may be titrated as clinically 
indicated.  Additional diuretic support may be added if there is further increase in weight, edema 
or pleural effusion.
Any concomitant medication deemed necessary for the welfare of the patient during the study 
may be given at the discretion of the Investigator.


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6
Study Assessments and Procedures
Patients will undergo the procedures at the time points specified in schedule of events
(Appendix 12.1).
6.1 Efficacy Assessments
Disease assessments will occur every other cycle for the first 2 evaluations (6 weeks [end of 
Cycle 2 ±1 week] and 12 weeks [end of Cycle 4 ±1 week]), and every third cycle
(every 9 weeks [e.g., end of Cycles 7, 10, 13, etc., ±1 week]) thereafter until progression, or 
more frequently, if clinically indicated. 
Patients Initially Treated Every 3 weeks 

To be conducted within 6 days prior to Day 1 of Cycles 3 and 5 and thereafter every third 
cycle (i.e., Cycles 8, 11, 14, etc.), until disease progression, or more frequently, if clinically 
indicated.
Patients who initially follow a three week dose schedule and then transition to a six week 
schedule following cycle 2 should have disease assessments ~6 weeks after Cycle 1 Day 1, 
~12 weeks after Cycle 1 Day 1, and thereafter at least every 12 weeks.
Patients Initially Treated Every 6 weeks 

For patients who have reduced dosing frequency and are following a 6 week schedule, 
disease assessments should occur approximately 6 weeks and 12 weeks  after Cycle 1 Day 1, 
and thereafter at least every 12 weeks. It is understood that there will be a ± 6 day window 
for restaging of these patients.
For patients in Part 2: Treatment continuation will require independent verification of the local 
response assessment unless otherwise approved by the sponsor.  
Assessments may be performed within ± 1 week of the required timepoint and response 
assessment must be available prior to initiation of dosing at the subsequent cycle.
In case of dose delays, disease assessment should be maintained at the frequencies defined above 
and response assessment is required prior to resumption of ADCT-402 dosing (only if the 
interval from last scan is ≥ 6/9/12 weeks, as applicable) to rule out disease progression.
The patient’s response to treatment will be determined by the Investigator as complete response 
(CR), partial response (PR), stable disease (SD), or progressive disease (PD), based on the 2014 
Lugano Classification Criteria (Appendix 12.2). Images will be obtained according to local site 
imaging requirements and may be required to be submitted for a central/independent review.
Submission instructions for the central/independent review will be provided in a separate manual.
6.2 Pharmacokinetic and Pharmacodynamic Assessments
Blood (5-mL draw) samples will be collected for assessment and will be processed according to 
the instructions provided by the bioanalytical laboratory to the study sites. All PK and 


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pharmacodynamic assessments will be conducted using measures from validated bioanalytical 
methods. Timing and timing windows for sample collection are shown in Appendix 12.1.
6.2.1Pharmacokinetic Assessments
The PK profile of ADCT-402 (total antibody; DAR ≥0), PBD-conjugated antibody (DAR ≥1), 
and free warhead SG3199 will be assessed by a central laboratory. Additional PK blood samples 
will be collected, at the discretion of the Investigator, during any visit where toxicity is observed. 
A PK and ADA sample will also be collected concurrently with any other blood draw to assess 
safety (e.g., Unscheduled Visit), if possible. All PK samples will be evaluable as long as actual 
collection times are recorded.
To understand the metabolic disposition of ADCT-402 in humans, samples remaining after PK 
analysis is complete may be pooled among patients for potential metabolite identification.
The PK profile will include determination of: maximum concentration (Cmax), time to Cmax (Tmax), 
area under the concentration-time curve from time zero to the last quantifiable concentration 
(AUC0-last), area under the concentration-time curve (AUC) from time zero to the end of the 
dosing interval (AUC0-τ), area under the concentration-time curve from time zero to infinity 
(AUC0-∞), accumulation index (AI), volume of distribution at steady-state (Vss), mean residence 
time (MRT), terminal elimination phase rate constant (λz), terminal half-life (T1/2), clearance 
(CL), and volume of distribution (Vz).
6.2.2Pharmacodynamic and Other Assessments
The following pharmacodynamic/exploratory assessments will be performed at varying 
timepoints in the study:
 

Level of ADAs against ADCT-402 in serum.
 
6.3 Safety and Tolerability Assessments
Safety will be assessed based on AEs, SAEs, periodic 12-lead ECG recordings, physical 
examinations, vital signs measurements, ECOG performance status, and hematology, coagulation 
panel, biochemistry, pregnancy testing (for women of child-bearing potential) and urinalysis test 
results. Adverse events will be graded according to CTCAE version 4.0. A schedule of safety 
assessments is provided in Appendix 12.1.


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6.3.1Definition of Dose-Limiting Toxicities
A DLT is defined as any of the following events, except those that are clearly due to underlying 
disease or extraneous causes.

A hematologic DLT is defined as:
o
Grade 3 or 4 febrile neutropenia or neutropenic infection.
o
Grade 4 neutropenia lasting >7 days.
o
Grade 4 thrombocytopenia.
o
Grade 3 thrombocytopenia with clinically significant bleeding, or Grade 3 
thrombocytopenia requiring a platelet transfusion.
o
Grade 4 anemia.

A non-hematologic DLT is defined as:
o
Grade 4 tumor lysis syndrome (Grade 3 TLS will not constitute DLT unless it leads to 
irreversible end-organ damage).
o
Grade 3 or higher AE (including nausea, vomiting, diarrhea, and electrolyte imbalances 
lasting more than 48 hours despite optimal therapy; excluding all grade ofalopecia).
o
Grade 3 or higher hypersensitivity (Appendix 12.3) reaction (regardless of premedication).
o
Grade 2 or higher skin ulceration.
The DLT period for dose escalation will be 1 cycle.
6.3.1.1
Safety Oversight by the Dose Escalation Steering Committee
A DESC will be responsible for safety monitoring and overall supervision of the study. 
Membership of the DESC will include:

Medical monitor(s)/Pharmacovigilance representative(s) (Sponsor and/or designee)

Investigator(s) from each participating site

Biostatistician(s)

Ad-hoc members (e.g., project manager, study coordinators, regulatory representatives, etc.)
In general, the DESC will make any substantial decisions regarding the conduct of the study, 
such as:

Monitor the safety of the study and review its progress at monthly intervals or more frequent 
intervals as required.

Determine dose levels to be administered and the MTD based on assessment of safety 
findings and determination of DLTs.

Approve any amendments or administrative changes to the protocol, when required.


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Each DESC meeting and the decisions made will be documented in writing and provided to all 
participating DESC members and Investigators. Meeting documents may be submitted to 
IRBs/IECs or competent authorities according to institutional or local requirements.
The DESC will be maintained during Part 2 (expansion) of the study to continue to monitor and 
evaluate patient safety.
6.3.2Adverse Events
6.3.2.1
Definitions of Adverse Events
The Investigator is responsible for reporting all AEs that are observed or reported during the 
study, regardless of their relationship to study drug or their clinical significance.
An AE is defined as any untoward medical occurrence in a patient enrolled into this study 
regardless of its causal relationship to study drug. Patients will be instructed to contact the 
Investigator at any time after ICF signature if any symptoms develop.
A treatment-emergent AE (TEAE) is defined as any event not present before exposure to study 
drug or any event already present that worsens in either intensity or frequency after exposure to 
study drug.
A serious adverse event (SAE) is defined as any event that results in death, is immediately life 
threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results 
in persistent or significant disability/incapacity, or is a congenital anomaly/birth defect. 
Hospitalization for elective procedures or for protocol compliance is not considered an SAE.
Important medical events that may not result in death, are life threatening, or require 
hospitalization may be considered SAEs when, based upon appropriate medical judgment, the 
event may jeopardize the patient or may require medical or surgical intervention to prevent any 
of the outcomes listed in this definition. Examples of such medical events include allergic 
bronchospasm requiring intensive treatment in an emergency room or at home, blood dyscrasias 
or convulsions that do not result in inpatient hospitalization, or the development of drug 
dependency or drug abuse.
6.3.2.2
Eliciting and Documenting Adverse Events
All AEs will be assessed from the time the patient signs the ICF until 84 days (12 weeks) after 
the last dose of study drug or initiation of new anticancer treatment.
Any SAEs that occur more than 84 days after the last dose of study drug do not need to be 
reported unless the Investigator considers them related to study drug.
At every study visit, patients will be asked a standard nonleading question to elicit any medically 
related changes in their well-being. They will also be asked if they have been hospitalized, had 
any accidents, used any new medications, or changed concomitant medication regimens (both 
prescription and over-the-counter medications).
In addition to patient observations, AEs will be documented from any data collected on the AE
page of the eCRF (e.g., clinically significant changes in laboratory values, physical examination, 


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ECG changes, etc.) or identified from review of other documents that are relevant to patient
safety.
6.3.2.3
Reporting Adverse Events
All AEs reported or observed during the study will be recorded on the AE page of the eCRF. 
Information to be collected includes drug treatment, dose, event terminology, date of onset, 
CTCAE version 4.0 assessment of severity and relationship to study drug, date of resolution of 
the event, seriousness, any required treatment or evaluations, and outcome. With the exception of 
disease progression, AEs resulting from concurrent illnesses, reactions to concurrent illnesses, 
and reactions to concurrent medications also must be reported. All AEs will be followed to 
adequate resolution.
Any AE that meets SAE criteria (Section 6.3.2.1) must be reported to the contract research 
organization (CRO) immediately (i.e., within 24 hours after the time site personnel first learn 
about the event). The following contact information is to be used for SAE reporting:
6.3.2.4
Assessment of Severity
Adverse events are graded according to CTCAE version 4.0. 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 2.


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Table 2. Definition of Severity Grades for Common Terminology Criteria for Adverse 
Events (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 ADLa
3
Severe or medically significant but not immediately life threatening; hospitalization or 
prolongation of hospitalization indicated; disabling; limiting self-care ADLb
4
Life-threatening consequences; urgent intervention indicated
5
Death related to adverse event
a Instrumental activities of daily living (ADL) refer to preparing meals, shopping for groceries or clothes, 
using the telephone, managing money, etc.
b Self-care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking medications, 
and not bedridden.
Changes in the severity of an AE should be documented to allow an assessment of the duration 
of the event at each level of intensity to be performed. Adverse events characterized as 
intermittent do not require documentation of onset and duration of each episode.
6.3.2.5
Assessment of Causality
The Investigator’s assessment of an AE’s relationship to study drug is part of the documentation 
process, but it is not a factor in determining what is or is not reported in the eCRF. All adverse 
events, regardless of assessment of causality, are reported in the eCRF.
All SAEs considered at least possibly related to the study drug will be considered unexpected;
and therefore, reported as Suspected Unexpected Serious Adverse Reactions (SUSARs).
6.3.2.6
Follow-Up of Patients Reporting Adverse Events
All AEs must be reported in detail on the appropriate page of the eCRF and followed to 
satisfactory resolution, until the Investigator deems the event to be chronic or not clinically 
significant, or until the patient is considered to be stable.
6.3.3Pregnancy
Any pregnancy that occurs during study participation must be reported using a clinical study
Pregnancy Report Form. To ensure patient safety, each pregnancy must be reported as described 
for reported AEs in Section 6.3.2.3, upon learning of its occurrence. 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 was 
discontinued from the study. The outcome of the pregnancy will be reported on the Pregnancy 
Outcome Form. Spontaneous miscarriages must be reported as an SAE.


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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 (Section 6.3.2.3).
6.3.4Clinical Laboratory Analyses
Samples will be collected at the time points specified in Appendix 12.1. 
Any clinically significant abnormal laboratory test results are to be recorded as AEs or SAEs per 
CTCAE version 4.0.
6.3.4.1
Hematology
Complete blood count (CBC) includes WBC with 5-part differential, platelet count, hemoglobin, 
hematocrit, and ANC. The coagulation panel must include partial thromboplastin time (PTT) and 
International Normalized Ratio (INR); prothrombin time (PT) expressed in seconds is optional ).
Patients taking coumarin-derivative anticoagulants should be monitored closely and their 
anticoagulant dose adjusted as needed. 
6.3.4.2
Biochemistry
Biochemistry includes alanine aminotransferase, aspartate aminotransferase, gamma-glutamyl 
transferase, alkaline phosphatase, amylase, lipase, total bilirubin, sodium, potassium, calcium, 
magnesium, blood urea nitrogen or urea, carbon dioxide/bicarbonate, chloride, creatinine, 
creatine phosphokinase, total protein, albumin, glucose, triglycerides, total cholesterol, 
phosphorus, and lactate dehydrogenase. Biochemistry will also include creatinine clearance 
(Cockcroft and Gault, 1976) on Day 1 of each cycle.
6.3.4.3
Urinalysis
Urinalysis includes  pH, specific gravity, protein, glucose, bilirubin, nitrites and occult blood.
The urinalysis may be performed by dipstick.
6.3.4.4
Additional Renal Function Studies
Urine will be collected for testing of biomarkers suggestive of potential renal injury (aquaporin-2, 
calbindin D28, and clusterin). Analysis of this additional urine sample will be performed at a 
central laboratory (instructions provided in laboratory manual).
6.3.5Electrocardiograms
A 12-lead electrocardiogram is to be performed at the time points shown in Appendix 12.1.
Any abnormalities, including those that worsen from baseline, believed to be clinically 
significant in the medical and scientific judgment of the Investigator are to be recorded as AEs or 
SAEs.
During Part 1, measurement of the QTc interval may be obtained according to the formula used 
by the institution, however, the Fridericia formula is preferred (Fridericia, 1920). During Part 2, 
the Fridericia formula should be used for all patients.


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The same formula used to confirm eligibility must be applied within a patient for the duration of 
the study.
6.3.6Physical Examination 
Physical examinations will include a complete review of body systems, including whole body 
skin assessment. Whole body skin assessment does not have to be performed by a dermatologist; 
however, any unexplained lesion will be referred to a dermatologist for further evaluation and 
biopsy if clinically warranted. Any clinically significant abnormalities, including those that 
worsen from baseline, are to be recorded as AEs or SAEs.
6.3.7Vital Sign Measurements
Vital sign measurements will include arterial blood pressure, heart rate, respiratory rate, and 
temperature. Any clinically significant abnormalities, including those that worsen from baseline, 
are to be recorded as AEs or SAEs.
6.3.8Weight
If possible, patients are advised to monitor their weight daily starting cyle 1 day 1 and inform 
their investigator if their weight increases more than 1 kg (2.2 pounds) from Cycle 1 Day 1.
6.3.9Eastern Cooperative Oncology Group Performance Status
The patient’s performance status will be assessed according to the time points in the schedule of 
events (Appendix 12.1) using the ECOG performance status grades (Table 3; Oken, 1982).
Table 3. Definition of Eastern Cooperative Oncology Group (ECOG) Performance Status 
Grades
Grade
Definition
0
Fully active, able to carry on all predisease performance without restriction
1
Restricted in physically strenuous activity but ambulatory and able to carry out work of a 
light or sedentary nature, e.g., light house work, office work
2
Ambulatory and capable of all self-care but unable to carry out any work activities. 
Up and about more than 50% of waking hours
3
Capable of only limited self-care, confined to bed or chair more than 50% of waking 
hours
4
Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair
5
Dead
As per Oken, 1982.
6.4 Sample Handling, Storage and Shipment
Detailed instructions for sample collection, labeling, processing, storage, and shipping will be 
provided to the site in the Laboratory Manual.


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For the tissue sample provided at screening, blocks and slides should be packed in ice or cold 
packs prior to priority overnight shipping. If available, a copy of the original pathology report 
containing the histopathological diagnosis should accompany each specimen. Refer to the 
Laboratory Manual for further information. Desired specimen characteristics are:

Tissues fixed in neutral buffered formalin (NBF);

Blocks preferable to slides;

If slides are supplied, sections must be:
o
Mounted on positively charged slides of the correct type,
o
Transferred to the slide in a water bath (not by tape),
o
Not have been baked,
o
Not be paraffin coated (the slide containing the mounted specimen should not have been 
dipped in paraffin),
o
Stored at 4°C in an airtight container prior to shipment.
During the study, blood samples will be collected for PK, ADA, 
 
 and safety analyses (clinical chemistry and hematology).
 
 
For PK and ADA, blood samples are to be collected and processed on site according to the 
Laboratory Manual. The resulting serum samples should be aliquoted and stored frozen at 
≤-70C until shipment. Each sample tube should be clearly labeled with the following 
information: study number, study center number, patient number, tube identification, and the 
scheduled sampling time by day (and hour, when necessary).
Serum and urine samples are to be packed in sufficient dry ice and shipped from the study center 
to the central laboratory. Once labeled, samples should be stored at ≤-70°C until shipment . 
Samples should be shipped according to the sample shipment schedule provided in Laboratory 
Manual.  Samples may be retained at the central laboratory for up to 5 years after the end of the 
study, and may be used for additional analyses. Samples will not be destroyed until 5 years after 
the end of the study, or unless a specific authorization is given by ADC Therapeutics.
The clinical chemistry and hematology samples, which should not be frozen, are transferred at
ambient temperature to local laboratories.
 


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Each sample tube should be clearly labeled with the following information: Study number, study 
center number, patient number, tube identification, and the scheduled sampling time by day (and 
hour, when necessary).


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7
Statistical and Analytical Plan
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).
7.1 Safety Endpoints
Safety will be assessed based on AEs, SAEs, treatment discontinuations due to AEs, DLTs, 
periodic 12-lead ECG recordings, physical examinations, vital signs measurements, ECOG 
performance status, and hematology, coagulation panel, biochemistry, and urinalysis test results.
7.2 Primary Endpoints
7.2.1Primary Endpoints

Assessment of DLTs (Section 6.3.1) and determination of the MTD (Section 3.2)
for ADCT-402 during Part 1.

Determination of the recommended dose of ADCT-402 for Part 2 by the DESC.

Assessment of safety parameters for Part 1 and Part 2 (Section 6.3).
7.2.2Secondary Endpoints

Determination of DOR, ORR, OS, and PFS (Section 7.6.2).

Determination of PK parameters (Section 7.6.3) for ADCT-402 (total antibody; DAR ≥0), 
PBD-conjugated antibody (DAR ≥1), and free warhead SG3199.

Measurement of ADAs to ADCT-402 before, during, and after treatment with ADCT-402 
(Section 7.6.3).
 


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7.3 Sample Size Calculations
This is a Phase 1 study with a maximum total sample size of 200 patients. It is expected that 
Part 1 will enroll up to 90 patients and Part 2 will enroll up to 110 patients.
Patients will be enrolled in Part 2 of the study in cohorts of approximately 10 to 20.
The DESC will make recommendations with regard to the intended differences between these 
cohorts, e.g. tumor subtypes, dosing regimen or dose levels, as well as the number of these 
cohorts, taking into account the limit on the overall number of patients as specified above and 
safety/efficacy data observed up to that decision point.
7.4 Analysis Sets
Five analysis sets will be used in this study:

The Safety analysis set will consist of all patients who receive study drug

The DLT-evaluable analysis set will consist of all patients in Part 1 who receive study drug 
and excludes patients who discontinue study drug during Cycle 1 without experiencing a 
DLT.

The Efficacy analysis set will consist of all patients with valid baseline data who receive who 
receive at least 2 doses of study drug or who have documented progression of disease at any 
time after the first dose of study drug.

The PK analysis set will consist of all patients who receive study drug and have sufficient 
concentration data for PK analysis.

The Pharmacodynamic analysis set will consist of all patients who receive study drug and 
have sufficient concentration data for analysis.
 
7.5 Description of Subgroups to be Analyzed
Subgroup analyses, if planned, will be described in the SAP.


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7.6 Statistical Analysis Methodology
7.6.1Safety Analyses
7.6.1.1
Analyses of Adverse Events
An AE will be considered to be a TEAE if it begins or worsens on or after first dose date and 
before last dose date + 84 days. Planned summaries of TEAEs are detailed in the statistical 
analysis plan and will include:

All TEAEs.

All serious TEAEs.

All treatment-related TEAEs.

All treatment-related serious TEAEs.

All TEAEs resulting in study drug discontinuation.

All DLTs.

Other AE analyses of interest will be specified in the SAP. 
The incidence of deaths and the primary cause of death will be summarized.
7.6.1.2
Clinical Laboratory Results
Clinical hematology, coagulation panel, biochemistry, and urinalysis data will be summarized at 
each scheduled assessment. Numeric hematology and biochemistry results will be summarized 
using change from baseline. All results will be summarized using shift from baseline. Shifts for 
clinical laboratory results that can be graded according to CTCAE version 4.0 will be 
summarized by CTCAE grade. Shifts for other numeric laboratory results will be by 
high/normal/low flag. Shifts for all other laboratory results will be by normal/abnormal flag.
Summaries by visit will include data from scheduled assessments, and all data will be reported 
according to the nominal visit date for which it was recorded. Unscheduled data will be included 
in “worst case post baseline” summaries, which will capture a worst case across all scheduled 
and unscheduled visits after the first dose of study treatment. Further details will be provided in 
the SAP.
7.6.1.3
Additional Safety Assessments
The results of scheduled assessments of vital signs, physical examinations, ECOG performance 
status, and 12-lead ECGs will be summarized. All data will be reported according to the nominal 
visit date for which it was recorded (i.e., no visit windows will be applied). Unscheduled data 
will be included in “worst case” summaries, which will capture a worst case across all scheduled 
and unscheduled visits after the first dose of study treatment. All data will be listed. Further 
details will be provided in the SAP.


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7.6.2Efficacy Analysis
7.6.2.1
Overall Response Rate
Overall response rate will be defined as the proportion of patients with a best overall response of 
CR or PR at the time each patient discontinues ADCT-402. Percentage of ORR with its 95% 
confidence interval (CI) will be presented.
7.6.2.2
Duration of Response
Duration of response 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 as 
assessed by the Investigator using the 2014 Lugano Classification for response (Appendix 12.2).
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. In addition, patients with disease 
progression or death after an extended loss to follow-up will be censored at the date of the last 
valid disease assessment prior to the extended loss to follow-up. The data will be analyzed by 
Kaplan-Meier method. The median duration of response and 95% CI will be presented. Further 
details will be outlined in the SAP.
7.6.2.3
Overall Survival
Overall survival will be defined as the time from the beginning of study drug treatment until 
death due to any cause. For patients who have not died at the time of the analysis, censoring will 
be performed using the date the patient was last known to be alive. The data will be analyzed by 
Kaplan-Meier method. The median survival time and 95% CI will be presented. Further details 
will be outlined in the SAP.
7.6.2.4
Progression-Free Survival
Progression-free survival will be defined among the efficacy population (Section 7.4) as the time 
from first dose of study drug until the first date of either disease progression or death due to any 
cause. The date of disease progression will be defined as the earliest date of radiological disease 
progression as assessed by the Investigator using the 2014 Lugano Classification for response 
(Appendix 12.2). For patients whose disease has not progressed or who have not died at the time 
of the analysis, censoring will be performed using the date of the last valid disease assessment. In 
addition, patients with disease progression or who have died after an extended loss to follow-up 
by the investigative site will be censored at the date of the last disease assessment prior to the 
extended loss to follow-up. The data will be analyzed by Kaplan-Meier method. The median PFS
time and 95% CI will be presented. Further details will be outlined in the SAP.
7.6.3Pharmacokinetic and Pharmacodynamic Analyses
Pharmacokinetic endpoints for RB4v1.2, PBD-conjugated RB4v1.2, and free warhead SG31999 
will be evaluated for all patients using noncompartmental analysis. Data for PK parameters will 
be summarized in tables and individual data will be listed.


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7.6.4Study Drug Exposure
Study drug exposure will be summarized by dose level and overall. Duration of treatment, total 
number of cycles dosed, and total dose received will be summarized. The number of patients 
dosed by cycle will also be summarized using frequency counts and percentages.
Duration of treatment will be calculated as date of last dose of study drug – date of first dose of 
study drug + 1.
7.7 Data Quality Assurance
Steps to be taken to ensure the accuracy and reliability of data include the selection of a qualified 
Investigator and appropriate study site, review of protocol procedures with the Investigator and 
associated personnel before the study and periodic monitoring visits by the clinical research 
associate. Written instructions will be provided for collection, preparation, and shipment of 
blood and plasma samples.
The eCRFs will be provided to the clinical contact and the clinical research associate will review 
them with site personnel.
The clinical research associate will review eCRFs for accuracy and completeness by remote 
monitoring, during on-site monitoring visits, and after transmission to the Sponsor; any 
discrepancies will be resolved with the Investigator or designee, as appropriate. After entry of the 
data into the clinical study database they will be verified for accuracy.
7.7.1Data Management
As part of the responsibilities assumed by participating in the study, the Investigator agrees to 
maintain adequate case histories for the patients treated as part of the research under this protocol. 
The Investigator agrees to maintain accurate eCRFs and source documentation as part of the case 
histories. These source documents may include laboratory reports, ECG strips, and patient 
diaries.
Investigative site personnel will enter patient data into Medidata Rave. The analysis data sets 
will be a combination of these data and data from other sources (e.g., laboratory data).


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Clinical data management will be performed in accordance with applicable CRO standards and 
data cleaning procedures to ensure the integrity of the data (e.g., removing errors and 
inconsistencies in the data). Adverse events will be coded using the Medical Dictionary for 
Regulatory Activities Version 16.0. Concomitant medications will be coded using WHO Drug
Dictionary 01 June 2013.
After database lock, each study site will receive information about all of their site-specific eCRF 
data as entered into electronic data capture system for the study, including full discrepancy and 
audit history. Additionally, a copy of all of the study site’s data from the study will be created 
and sent to the Sponsor for storage. The CRO will maintain a duplicate copy for its records. In all 
cases, patient initials will not be collected or transmitted to the Sponsor.


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8
Ethics
8.1 Independent Ethics Committee or Institutional Review Board
Federal regulations and the International Council for Harmonisation (ICH) guidelines require 
that approval be obtained from an institutional review board (IRB)/independent ethics committee 
(IEC) before participation of human patients in research studies. Before study onset, the protocol,
informed consent, advertisements to be used for the recruitment of study patients, and any other 
written information regarding this study to be provided to the patient or the patient’s legal 
guardian must be approved by the IRB/IEC. Documentation of all IRB/IEC approvals and of the 
IRB/IEC compliance with the current version of ICH harmonised tripartite guideline E6: Good 
Clinical Practice (GCP) will be maintained by the site and will be available for review by the 
Sponsor or its designee.
All IRB/IEC approvals should be signed by the IRB/IEC chairman or designee and must identify 
the IRB/IEC name and address, the clinical protocol by title or protocol number or both, and the 
date approval or a favorable opinion was granted.
The Investigator is responsible for obtaining continued review of the clinical research at intervals 
not exceeding 1 year or otherwise specified by the IRB/IEC. The Investigator must supply the 
Sponsor or its designee with written documentation of continued review of the clinical research.
8.2 Ethical Conduct of the Study
The study will be performed in accordance with the ethical principles that have their origin in the 
Declaration of Helsinki, ICH GCP, and all applicable regulations.
8.3 Patient Information and Consent
A written informed consent in compliance with IRB/IEC and local regulations shall be obtained 
from each patient before entering the study or performing any unusual or non-routine procedure 
that involves risk to the patient. An informed consent template may be provided by the Sponsor
to investigative sites. If any institution-specific modifications to study-related procedures are 
proposed or made by the site, the consent should be reviewed by the Sponsor or its designee or 
both before IRB/IEC submission. Once reviewed, the consent will be submitted by the 
Investigator to his or her IRB/IEC for review and approval before the start of the study. If the 
ICF is revised during the course of the study, all patients on-study must sign the revised form, 
unless otherwise indicated by the IRB/IEC (local or global, as applicable). In such case, the 
reason for not re-consenting the patient should be documented.
Before recruitment and enrollment, each prospective patient or his or her legal guardian will be 
given a full explanation of the study and be allowed to read the approved ICF. Once the 
Investigator is assured that the patient/legal guardian understands the implications of 
participating in the study, the patient/legal guardian will be asked to give consent to participate in 
the study
 


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9
Investigator’s Obligations
The following administrative items are meant to guide the Investigator in the conduct of the 
study but may be subject to change based on industry and government standard operating 
procedures, working practice documents, or guidelines. Changes will be reported to the IRB/IEC 
but will not result in protocol amendments.
9.1 Confidentiality
All laboratory specimens, evaluation forms, reports, and other records will be identified in a 
manner designed to maintain patient confidentiality. All records will be kept in a secure storage 
area with limited access. Clinical information will not be released without the written permission 
of the patient (or the patient’s legal guardian), except as necessary for monitoring and auditing 
by the Sponsor, its designee, the FDA, or the IRB/IEC.
The Investigator and all employees and coworkers involved with this study may not disclose or 
use for any purpose other than performance of the study any data, record, or other unpublished, 
confidential information disclosed to those individuals for the purpose of the study. Prior written 
agreement from the Sponsor or its designee must be obtained for the disclosure of any said 
confidential information to other parties.
9.2 Financial Disclosure and Obligations
Investigators are required to provide financial disclosure information to allow the Sponsor to 
submit the complete and accurate certification or disclosure statements required under 21 CFR 
54 and local regulations. In addition, the Investigator must provide to the Sponsor a commitment 
to promptly update this information if any relevant changes occur during the course of the 
investigation and for 1 year following the completion of the study.
Neither the Sponsor nor the CRO is financially responsible for further testing or treatment of any 
medical condition that may be detected during the screening process. In addition, in the absence 
of specific arrangements, neither the Sponsor nor the CRO is financially responsible for further 
treatment of the patient’s disease.
9.3
Adverse Events and Study Report Requirements
By participating in this study the Investigator agrees to submit reports of SAEs to the Sponsor
according to the time line and method outlined in the protocol. In addition, the Investigator 
agrees to submit annual reports to the study site IRB/IEC as appropriate.
The Sponsor will ensure that all relevant safety information (SAEs and SUSARSs) is reported to 
the FDA and competent authorities of EU Member States, and to the IEC, in accordance with 
current legislation (US 21CFR.316 and EU Directive 2001/20/EC).


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9.4 Investigator Documentation
Prior to beginning the study, the Investigator will be asked to comply with the current version of
ICH E6 8.2, Title 21 of the CFR, and local regulations by providing the following essential 
documents, including but not limited to:

IRB/IEC approval.

Original Investigator-signed Investigator agreement page of the protocol.

Form FDA 1572, fully executed, and all updates on a new fully executed Form FDA 1572.

Curriculum vitae for the Investigator and each sub-Investigator listed on Form FDA 1572.

Financial disclosure information to allow the Sponsor to submit complete and accurate 
certification or disclosure statements required under 21 CFR 54. In addition, the Investigators 
must provide to the Sponsor a commitment to promptly update this information if any 
relevant changes occur during the course of the investigation and for 1 year after the 
completion of the study.

IRB/IEC-approved informed consent, samples of site advertisements for recruitment for this 
study, and any other written information regarding this study that is to be provided to the 
patient or legal guardian.
9.5 Study Conduct
The Investigator agrees that the study will be conducted according to the principles of the current 
version of ICH E6. The Investigator will conduct all aspects of this study in accordance with all 
national, state, and local laws or regulations. Study information from this protocol will be posted 
on publicly available clinical study registers before enrollment of patients begins.
9.6 Adherence to Protocol
The Investigator agrees to conduct the study as outlined in this protocol in accordance with the 
current version of ICH E6 and all applicable guidelines and regulations.
9.7 Investigator’s Final Report
Upon completion of the study, where applicable, the Investigator should provide the IRB/IEC 
with a summary of the study outcome and the Sponsor and regulatory authority(ies) with any 
reports required.


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9.8 Records Retention
Essential documents should be retained until at least 2 years after the last approval of a 
marketing application in an ICH region and until there are no pending or contemplated marketing
applications in an ICH region or at least 2 years have elapsed since the formal discontinuation of 
clinical development of the investigational product. These documents should be retained for a 
longer period, however, if required by the applicable regulatory requirements or by an agreement 
with the Sponsor. It is the responsibility of the Sponsor to inform the Investigator/institution as to 
when these documents no longer need to be retained.
 
 
 


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10 Study Management
10.1 Monitoring
10.1.1Monitoring of the Study
The clinical monitor, as a representative of the Sponsor, has the obligation to follow the study 
closely. In doing so, the monitor will visit the Investigator and study site at periodic intervals, in 
addition to maintaining necessary telephone and written contact. The monitor will maintain 
current personal knowledge of the study through observation, review of study records and source 
documentation, and discussion of the conduct of the study with the Investigator and personnel.
All aspects of the study will be carefully monitored by the Sponsor or its designee for 
compliance with applicable government regulation with respect to current GCP and current 
standard operating procedures.
10.1.2Inspection of Records
Investigators and institutions involved in the study will permit study-related monitoring, audits, 
IRB/IEC review, and regulatory inspections by providing direct access to all study records. In the 
event of an audit, the Investigator agrees to allow the Sponsor, representatives of the Sponsor, or 
a regulatory agency access to all study records.
The Investigator should promptly notify the Sponsor and the CRO of any audits scheduled by 
any regulatory authorities and promptly forward copies of any audit reports received to the 
Sponsor.
10.2 Management of Protocol Amendments and Deviations
10.2.1Modification of the Protocol
Any change in the study plan requires a protocol amendment. An Investigator may not make any 
changes to the study without IRB/IEC and Sponsor approval, except those necessary to remove 
an apparent immediate hazard to the patient. A protocol change intended to eliminate an apparent 
immediate hazard to patient(s) may be implemented immediately, but the circumstances of the 
change must be documented and submitted to the IRB/IEC and to the Sponsor for further 
evaluation. If the protocol is in need of substantial changes, the Sponsor will amend the protocol 
and seek approval from the appropriate regulatory authority(ies) before implementation. All 
amendments to the protocol must be reviewed and approved following the same process as the 
original protocol before the amended protocol can be implemented.


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10.2.2Protocol Deviations
The Investigator will make every attempt to avoid deviations from the protocol, except in 
medical emergencies. In the event of a medical emergency, the Medical Monitor must be notified 
as soon as possible. The Investigator will inform the governing IRB/IEC of all protocol changes 
issued by the Sponsor in accordance with the IRB/IEC’s established procedure.
10.3 Study Termination
The Sponsor has every intention of completing the study; however, the Sponsor reserves the 
right to discontinue the study at any time for clinical or administrative reasons.
The end of the study is defined as the date on which the last patient completes the last visit to the 
study site (includes any end of treatment visit to the site and any visit to the site to obtain 
confirmatory scan of response).
10.4 Final Report
Whether the study is completed or prematurely terminated, the Sponsor will ensure that the 
clinical study reports are prepared and provided to regulatory agency(ies) as required by the 
applicable regulatory requirement(s). 
An Investigator will be identified to act as the signatory for the clinical study report. 
The Investigator will be provided access to statistical tables, figures, and relevant reports and 
will have the opportunity to review the complete study results.


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11 Reference List
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conjugates - a perfect synergy. Expert Opin Biol Ther 12(9):1191-1206.
Amgen, Thousand Oaks, California USA (2014). Prescribing information for blinatumomab 
(Blincyto), Accessed on 21 May 2015 at 
http://pi.amgen.com/united_states/blincyto/blincyto_pi_hcp_english.pdf.
Anderson KC, Bates MP, Slaughenhoupt BL, Pinkus GS, Schlossman SF, and Nadler LM (1984). 
Expression of human B cell-associated antigens on leukemias and lymphomas:  a model of 
human B cell differentiation. Blood 63(June):1424-1433.
Ansell SM (2015). Non-hodgkin lymphoma:  diagnosis and treatment. Mayo Clin Proc
90(8):1152-1163.
Blanc V, Bousseau A, Caron A, Carrez C, Lutz RJ, and Lambert JM (2011). SAR3419:  an anti-
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17(20):6448-6458.
Cairo MS. Coiffier B, Reiter A, and Younes A, on behalf of the TLS Expert Panel (2010). 
Recommendations for the evaluation of risk and prophylaxis of tumour lysis syndrome (TLS) in 
adults and children with malignant diseases: an expert TLS panel consensus. Br J Haem
149:578–586.
Carter RH and Barrington RA (2004). Signaling by the CD19/CD21 complex on B cells. Curr 
Dir Autoimmun 7:4–32.
Chao MP (2013). Treatment challenges in the management of relapsed or refractory 
non-Hodgkin’s lymphoma – novel and emerging therapies. Cancer Manag Res 5: 251–269. 
Published online 2013 Aug 23. doi:10.2147/CMAR.S34273
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166.
Cheson BD, Fisher RI, Barrington SF, Cavalli F, Schwartz H, and Lister T (2014).
Recommendations for initial evaluation, staging, and response assessment of Hodgkin and Non-
Hodgkin lymphoma: The Lugano classification. J Clin Onc 32(27):3059-3068
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Cooper LJ, Al-Kadhimi Z, DiGiusto D, Kalos M, Colcher D, Raubitschek A, et al (2004). 
Development and application of CD19-specific T cells for adoptive immunotherapy of B cell 
malignancies. Blood Cells Mol Dis 33(1):83-89.
Evens AM, Winter JN, Gordon LI, Chiu BCH, Tsang R, and Rosen ST (2015). Non-hodgkin 
lymphoma. Accessed 2 Aug 2015 on Cancer Network at http://www.cancernetwork.com.
Fridericia LS. The duration of systole in the electrocardiogram of normal subjects and of patients 
with heart disease. Act Med Scand 1920, 53:469–486.  Translation published in 2003 in Annals 
Noninvasive Electrocardiology 8(4):343-351.


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Gerber HP, Kung-Sutherland M, Stone I, Morris-Tilden C, Miyamoto J, McCormick R, et. al.
(2009). Potent antitumor activity of the anti-CD19 auristatin antibody drug conjugate hBU12-
vcMMAE against rituximab-sensitive and -resistant lymphomas. Blood 113(18):4352-4361.
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immunity, host defense and autoimmunity. Adv Exp Med Biol 560:125–139.
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Opin Investig Drugs 20(6): 733-744.
Hartley JM, Spanswick VJ, and Hartley JA (2011b). Measurement of DNA damage in individual 
cells using the single cell gel electrophoresis (comet) assay. Methods Mol Biol 731:309-320.
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lymphoblastic leukemia. Blood 125(26):4010-4015.
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473.
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lymphoma patients in the rituximab era. Curr Opin Oncol 23(2):209-213.
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Contribution of cerebrospinal fluid sCD19 levels to the detection of CNS lymphoma and its 
impact on disease outcome. Blood 123(12): 1864-1869.
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efficacy of single-agent rovolpituzumab tesirine (SC16LD6.5), a delta-like protein 3 (DLL3)-
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Rheumatol 5:572–577; doi:10.1038/nrrheum.2009.184.
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12 Appendices
12.1 Appendix: Schedule of Events 
Timings for study procedures are shown in Section 12.1.1 of this Appendix. Timings for sample 
collections for assessments of ECG, PK, PD, and exploratory parameters are shown in 
Section 12.1.2 of this Appendix.


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12.1.1 Schedule of Study Procedures
Procedure
Screen
Cycle 1
Cycle 2
Day –28
to –1
Day 
1
Day 
21
Days 
3 and 52
Day 8
(±2 days)
Day 15
(±2 days)
Day 283 (±
2 days)
Day 1
(±3 days)
Day 
21
Days 
3 and 52
Day 8
(±2 days)
Day 15
(±2 days)
Day 28343
(±2 days)
Informed consent
X
Demography
X
Medical history4
X
Blood or urine β-HCG 
X
X5
Physical examination7 F6
X
X
X
X
X
X
X
X
X
Vital signs8F7
X
X9F8
X
X
X
X
X
X
X
X
X
X
X
Height
X
Weight
X
X
X
X
X
X
X
X
X
ECOG performance status
X
X
X
X
X
Disease assessment10
X11F11
X
Hematology12F12
X
X13F13
X
X
X
X13
X
X
X
Coagulation Panel14F14
X
X13
X
X13
X
Biochemistry15F15
X
X13
X
X
X
X13
X
X
X
Urinalysis 16F16
X
X13
X
X
X
X13
X
X
X
Additional renal function studies17F17
X
X
X
X
X
X
X
X
12-lead ECG18
X
X18F
X
X
X
X
X
Sample for PK assessments19F19
X
X
X
X
X
X
X
X
X
X
X
X
Sample for ADA assessment19
X
X
X
X
 
 
Concomitant medications21F21
X
X
X
X
X
X
X
X
X
X
X
Premedication22F22
X
X
ADCT-402 administration23F23
X
X
Adverse events24
X
X
X
X
X
X
X
X
X24
X
X
Survival information
New anticancer treatment 
information


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Procedure
Cycles 3 until Progression/ Discontinuation
EOT
Within 30 days25F25
12-Week Follow-up Visit26F26
Long-term 
Follow-up27F
Day 1
(±3 days)
Day 827
(±2 days)
Day 283
(±3 days)
Informed consent
Demography
Medical history4
Blood or urine β-HCG5
X
X
Physical examination6
X
X
Vital signs7
X8
X
X
X
Height
Weight
X
X
X
X
ECOG performance status
X
X
X
Tumor tissue collection
Disease assessment
X28
X29F
X30F
Hematology12
X
X
X
X
Coagulation Panel14
X
X
X
Biochemistry15
X
X
X
X
Urinalysis16
X
X
X
X
Additional renal function 
studies17
X
X
X
X
12-lead ECG18
X
X
X
Sample for PK assessments19
X
X31F28
X
X
X29
Sample for ADA assessment
X
X
X
X32F29
 
 
Concomitant medications21
X
X
X
X
Premedication22
X
ADCT-402 administration23
X
Adverse events
X
X
X
X3324
Survival information
X
X
New anticancer treatment 
information
X
X


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Date of Protocol: 16 October 2017
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Abbreviations:  ADA, anti-drug antibody; 
; ECG, electrocardiogram; EOI, end of ADCT-402 infusion; EOT, end of treatment; 
ECOG, Eastern Cooperative Oncology Group; HCG, human chorionic gonadotropin; PK, pharmacokinetics; 
1
Day 2 to occur 24 hours (±10%) after EOI.
2
Day 3 to occur 48 (±10%) hours after EOI.  Day 5 to occur 96 hours (±1 day) after EOI.
3
For patients who have transitioned to a reduced dosing frequency based on response (see Section 3.1) this visit will be required for Safety/PK 
Monitoring.  For patients in Part 1, this visit will be done approximately 21 days after infusion.  
4
Medical history to include a complete history of all surgeries, significant diagnoses, and all cancer treatments.
5
Blood or urine pregnancy test for women of childbearing potential. Not to be repeated at Cycle 1 Day 1 if negative screening β-HCG pregnancy test was 
obtained within 7 days prior to Cycle 1, Day 1. Pregnancy test Day 1 (every 6 weeks) and at EOT.  
6
Physical examination to include whole body skin assessment. Whole body skin assessment does not have to be performed by a dermatologist. 
Any unexplained lesion is to be referred to a dermatologist for further evaluation and skin biopsy, if clinically warranted. Does not have to be done on 
Cycle 1, Day 1 if last performed within 3 days prior to dosing with ADCT-402.
7
Vital signs to include arterial blood pressure, heart rate, respiratory rate, and body temperature. Vital signs window is ±15 minutes.
8
Vital signs: On Day 1 of Cycles 1 and 2, vital signs are to be measured before the start of the ADCT-402 infusion, every 30 minutes during the infusion, 
at the end of infusion, and at 1, 3, and 6 hours after the end of infusion.  If no clinically significant changes occur during Cycles 1 and 2, vital sign
measurements are to be obtained prior to infusion start and end of infusion for all subsequent infusions. If clinically significant changes in vital signs are 
observed at Cycle 1 and/or 2 infusion, that patient will be required to have vital signs measured before the start of the ADCT-402 infusion, every 
30 minutes during the infusion, at the end of infusion, and at 1, 3, and 6 hours after the end of the ADCT-402 infusion for all subsequent cycles.
 
 
10
Modification to a patient’s treatment schedule will be based on an independent review of images unless otherwise approved by the sponsor. Therefore, 
the decision to delay treatment and/or reduce dose based on response will require independent verification of the local response assessment (see
Section 6.1). Refer to Sections 4.1.2 and 6.1 for timing of tumor assessments for patients who have reduced dosing frequency.
11
Assessment of Disease at Screening

Positron emission tomography - computed tomography (PET CT) and diagnostic CT of the neck/chest/abdomen/pelvis and other areas of known 
disease or newly suspected disease with a clinical examination for lymphoma. Contrast should be used unless contraindicated. Magnetic resonance 
imaging (MRI) is permitted if diagnostic CT is contraindicated. The same assessments methods used at Screening which identify sites of disease 
should be used uniformly for all subsequent assessments. If PET-CT is positive, subsequent diagnostic CT and MRI are not needed unless clinically 
indicated

PET-CT only required at Screening for 18F-fluorodeoxyglucose (FDG) avid, nodal lymphomas (defined as per the Lugano Classification criteria as 
essentially all eligible histologies except small lymphocytic lymphoma, lymphoplasmacytic lymphoma/WM, mycosis fungoides, and marginal zone 
NHLs, unless there is a suspicion of aggressive transformation). If PET-CT examination is negative at Screening, subsequent PET-CT is not 
required.
12  
Hematology: CBC to include WBC with 3- or 5-part differential, platelet count, hemoglobin, hematocrit, and ANC. 
13
Samples for hematology, coagulation panel, biochemistry, urinalysis, and additional renal function studies will be collected:
<24 hours before the start of ADCT 402 infusion on Day 1 of Cycle 1, or
<72 hours before the start of ADCT-402 infusion on Day 1 of Cycle 2 and subsequent cycles. 


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Date of Protocol: 16 October 2017
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14
The coagulation panel must include partial thromboplastin time (PTT) and International Normalized Ratio (INR);  prothrombin time (PT) is optional.
15
Biochemistry includes alanine aminotransferase, aspartate aminotransferase, gamma-glutamyl transferase, alkaline phosphatase, amylase, lipase, total 
bilirubin, sodium, potassium, calcium, magnesium, blood urea nitrogen or urea, carbon dioxide/bicarbonate, chloride, creatinine, creatine phosphokinase, 
total protein, albumin, glucose, triglycerides, total cholesterol, phosphorus, and lactate dehydrogenase. At Day 1 of each cycle, biochemistry will include 
creatinine clearance (calculated using the Cockcroft and Gault formula [Cockcroft and Gault, 1976]).
16
Urinalysis to include, pH, specific gravity, protein, glucose, ketones, nitrates, occult blood and bilirubin. The urinalysis can be done by dipstick.
17
Urine to be collected for testing of biomarkers suggestive of potential renal injury (aquaporin-2, calbindin D28, and clusterin).
18
12-lead ECG to be performed on Day 1 of Cycles 1 and 2, a 12-lead ECG is to be performed before the start of the ADCT 402 infusion, within
30 minutes of the end of infusion, and 3 (± 30 minutes) and 24 (± 2.4) hours after the end of infusion.
19
See Section 12.1.2 of this Appendix for sample timing. 
 
21
Concomitant medications to include prescription or over-the-counter medication, herbal or naturopathic products within the 14 days prior to the Cycle 1, 
Day 1 visit and during the study.
22
Premedication to be performed if grade 2 or higher infusion-related hypersensitivity reactions are observed in 1  patient at any time during Part 1 of the 
study, all subsequent patients must receive prophylactic treatment on Day 1 of each cycle thereafter to reduce the risk of hypersensitivity reaction.
23
ADCT-402:  Patients will receive a 1-hour IV infusion at escalating doses, on Day 1 of each 3-week (21-day) cycle. If ADCT-402 is well tolerated after 
the first cycle, the infusion duration may be shortened to 30 minutes for subsequent cycles for that patient, at the Investigator’s discretion. Variations in 
infusion times due to minor differences in IV bag overfill/under fill and the institution’s procedure for flushing chemotherapy lines will not result in 
protocol deviation.
24
For all patients, collection of AEs and SAEs will continue for 12 weeks after the last dose of study drug or initiation of new anticancer treatment. Any 
SAEs that occur more than 84 days after the last dose of study drug do not need to be reported unless the Investigator considers the event to be related to 
study drug.
25
End of Treatment to occur within 30 days after last dose of ADCT-402 and prior to the initiation of new anticancer treatment. When EOT coincides with 
a scheduled visit, the scheduled visit will become EOT.
26
Follow-up to occur 12 (±1) weeks after last dose of ADCT-402.
27
After completion of 6 treatment cycles (e.g., 6 infusions), the Day 8 visit is not required unless clinically indicated.
28
PK sample collection on Day 8 Cycles 1-4.  Refer to Section 6.1, Efficacy Assessments. 
29
Sample for assessment of PK and ADA to be obtained 12 weeks (± 1 week) after last dose of ADCT-402, unless a new anticancer treatment has been 
initiated.


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12.2 Appendix: Response Assessment of Hodgkin and Non-
Hodgkin Lymphoma (Lugano Classification) 
Response Assessment of Hodgkin and Non-Hodgkin Lymphoma (Lugano Classification)
Response / Site
PET-CT-Based Response
CT-Based Response
Complete
Complete metabolic response
Complete radiologic response
(all of the following)
Lymph nodes and 
extralymphatic sites
Score 1, 2, or 3* with or without a residual 
mass on 5PS**
Note: Uptake may be greater than normal 
mediastinum and/or liver in Waldeyer’s ring 
or extranodal sites with high physiologic 
uptake or with activation within spleen or 
marrow (e.g., with chemotherapy or myeloid 
colony-stimulating factors). In this 
circumstance, complete metabolic response 
may be inferred if uptake at sites of initial 
involvement is no greater than surrounding 
normal tissue even if the tissue has high 
physiologic uptake
Target nodes/nodal masses must regress to
≤1.5 cm in LD
No extralymphatic sites of disease
Nonmeasured lesion
Not applicable
Absent
Organ enlargement
Not applicable
Regress to normal
New lesions
None
None
Bone marrow
No evidence of FDG-avid disease in marrow
Normal by morphology; if indeterminate, IHC 
negative
Partial
Partial metabolic response
Partial remission
(all of the following)
Lymph nodes and 
extralymphatic sites
Score 4 or 5** with reduced uptake compared 
with baseline and residual mass(es) of any 
size.
At interim, these findings suggest responding 
disease.
At end of treatment, these findings indicate 
residual disease.
≥50% decrease in SPD of up to 6 target 
measurable nodes and extranodal sites
When a lesion is too small to measure on CT, 
assign 5 mm × 5mm as the default value.
When no longer visible, 0 × 0 mm
For a node >5 mm × 5 mm, but smaller than 
normal, use actual measurement for 
calculation
Nonmeasured lesion
Not applicable
Absent/normal, regressed, but no increase
Organ enlargement
Not applicable
Spleen must have regressed by >50% in 
length beyond normal
New lesions
None
None


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Date of Protocol: 16 October 2017
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Response Assessment of Hodgkin and Non-Hodgkin Lymphoma (Lugano Classification)
Response / Site
PET-CT-Based Response
CT-Based Response
Bone marrow
Residual uptake higher than uptake in normal 
marrow but reduced compared with baseline 
(diffuse uptake compatible with reactive 
changes from chemotherapy allowed). If there 
are persistent focal changes in the marrow in 
the context of a nodal response, consideration 
should be given to further evaluation with 
MRI or biopsy or an interval scan
Not applicable
No response or stable 
disease
No metabolic response
Stable disease
Target nodes/nodal 
masses, extranodal 
lesions
Score 4 or 5 with no significant change in 
FDG update from baseline at interim or end of 
treatment
<50% decrease from baseline in SPD of up to 
6 dominant, measurable nodes and extranodal 
sites; no criteria for progressive disease are 
met
Nonmeasured lesions
Not applicable
No increase consistent with progression
Organ enlargement
Not applicable
No increase consistent with progression
New lesions
None
None
Bone marrow
No change from baseline
Not applicable
Progressive disease
Progressive metabolic disease
Progressive disease 
(requires at least 1 of the following)
Individual target 
nodes/nodal masses
Score 4 or 5 with an increase in intensity of 
uptake from baseline and/or
PPD progression
Extranodal lesions
New FDG-avid foci consistent with 
lymphoma at interim or end of treatment 
assessment
An individual node/lesion must be abnormal 
with:
LDi > 1.5 cm and
Increase by ≥50% from PPD nadir and 
An increase in LDi or SDi from nadir
0.5 cm for lesions ≤ 2 cm
1.0 cm for lesions > 2 cm
In the setting of splenomegaly, the splenic 
length must increase by > 50% of the extent of 
its prior increase beyond baseline (e.g., a 15-
cm spleen must increase to > 16 cm). If no 
prior splenomegaly, must increase by at least 
2 cm from baseline
New or recurrent splenomegaly
Nonmeasured lesions
None
New or clear progression of preexisting
nonmeasured lesions


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Response Assessment of Hodgkin and Non-Hodgkin Lymphoma (Lugano Classification)
Response / Site
PET-CT-Based Response
CT-Based Response
New lesions
New FDG-avid foci consistent with 
lymphoma rather than another etiology (e.g., 
infection, inflammation). If uncertain 
regarding etiology of new lesions, biopsy or 
interval scan may be considered
Regrowth of previously resolved lesions
A new node > 1.5 cm in any axis
A new extranodal site > 1.0 cm in any axis; if 
< 1.0 cm in any axis, its presence must be 
unequivocal and must be attributable to 
lymphoma
Assessable disease of any size unequivocally 
attributable to lymphoma
Bone marrow
New or recurrent FDG-avid foci
New or recurrent involvement
Abbreviations: 5PS, 5-point scale; CT, computed tomography; FDG, fluorodeoxyglucose; IHC, immunohistochemistry; LDi, 
longest transverse diameter of a lesion; MRI, magnetic resonance imaging; PET, positron emission tomography; PPD, cross 
product of the LDi and perpendicular diameter; SDi, shortest axis perpendicular to the LDi; SPD, sum of the product of the 
perpendicular diameters for multiple lesions.
* A score of 3 in many patients indicates a good prognosis with standard treatment, especially if at the time of an interim scan. 
However, in trials involving PET where de-escalation is investigated, it may be preferable to consider a score of 3 as inadequate 
response (to avoid undertreatment). Measured dominant lesions: Up to six of the largest dominant nodes, nodal masses, and 
extranodal lesions selected to be clearly measurable in two diameters. Nodes should preferably be from disparate regions of the 
body and should include, where applicable, mediastinal and retroperitoneal areas. Non-nodal lesions include those in solid organs 
(e.g., liver, spleen, kidneys, lungs), GI involvement, cutaneous lesions, or those noted on palpation. Nonmeasured lesions: Any 
disease not selected as measured, dominant disease and truly assessable disease should be considered not measured. These sites 
include any nodes, nodal masses, and extranodal sites not selected as dominant or measurable or that do not meet the 
requirements for measurability but are still considered abnormal, as well as truly assessable disease, which is any site of 
suspected disease that would be difficult to follow quantitatively with measurement, including pleural effusions, ascites, bone 
lesions, leptomeningeal disease, abdominal masses, and other lesions that cannot be confirmed and followed by imaging. In 
Waldeyer’s ring or in extranodal sites (e.g., GI tract, liver, bone marrow), FDG uptake may be greater than in the mediastinum 
with complete metabolic response, but should be no higher than surrounding normal physiologic uptake (e.g., with marrow 
activation as a result of chemotherapy or myeloid growth factors).
** PET 5PS: 1, no uptake above background; 2, uptake ≤ mediastinum; 3, uptake > mediastinum but ≤ liver; 4, uptake 
moderately > liver; 5, uptake markedly higher than liver and/or new lesions; X, new areas of uptake unlikely to be related to
lymphoma.
Reference:  Cheson BD, Fisher RI, Barrington SF, Cavalli F, Schwartz H, ListerTA. Recommendations for initial evaluation, 
staging, and response assessment of Hodgkin and Non-Hodgkin lymphoma:  The Lugano classification. J Clin Onc 2014, 
32(27):3059-3068


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Date of Protocol: 16 October 2017
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12.3 Appendix: CTCAE Immune System Hypersensitivity Grades
Adverse Event
Grade 1
Grade 2
Grade 3
Grade 4
Grade 5
Allergic reaction
Transient 
flushing or rash, 
drug fever 
<38C
(<100.4F); 
intervention not 
indicated
Intervention or 
infusion 
interruption 
indicated; responds 
promptly to 
symptomatic 
treatment (e.g.,
antihistamines, 
NSAIDS, 
narcotics); 
prophylactic 
medications 
indicated for ≤24
hours
Prolonged (e.g.,
not rapidly 
responsive to 
symptomatic 
medication 
and/or brief 
interruption of 
infusion); 
recurrence of 
symptoms 
following initial 
improvement; 
hospitalization 
indicated for 
clinical sequelae 
(e.g., renal 
impairment, 
pulmonary 
infiltrates)
Life-threatening 
consequences;
urgent intervention 
indicated
Death
Definition: A disorder characterized by an adverse local or general response from exposure to an allergen.
Anaphylaxis
-
-
Symptomatic 
bronchospasm, 
with or without 
urticaria; parenteral 
intervention 
indicated; 
allergy-related 
edema/angioedema
; hypotension
Life-threatening 
consequences;
urgent 
intervention 
indicated
Death
Definition: A disorder characterized by an acute inflammatory reaction resulting from the release of histamine 
and histamine-like substances from mast cells, causing a hypersensitivity immune response. Clinically, it 
presents with breathing difficulty, dizziness, hypotension, cyanosis, and loss of consciousness and may lead to 
death.


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Adverse Event
Grade 1
Grade 2
Grade 3
Grade 4
Grade 5
Autoimmune 
disorder
Asymptomatic; 
serologic or 
other evidence 
of autoimmune 
reaction, with 
normal organ 
function;
intervention not 
indicated
Evidence of 
autoimmune
reaction involving 
a non-essential 
organ or function 
(e.g.,
hypothyroidism)
Autoimmune 
reactions involving 
major organ (e.g.,
colitis, anemia, 
myocarditis, 
kidney)
Life-threatening 
consequences;
urgent intervention 
indicated
Death
Definition: A disorder resulting from loss of function or tissue destruction of an organ or multiple organs, 
arising from humoral or cellular immune responses of the individual to his own tissue constituents.
Cytokine release 
syndrome
Mild 
reaction; 
infusion 
interruption 
not 
indicated; 
intervention 
not 
indicated
Therapy or 
infusion 
interruption 
indicated but 
responds promptly 
to symptomatic 
treatment (e.g.,
antihistamines, 
NSAIDS, 
narcotics, 
intravenous fluids); 
prophylactic 
medications 
indicated for 
≤24 hours
Prolonged (e.g.,
not rapidly 
responsive to 
symptomatic 
medication 
and/or brief 
interruption of 
infusion); 
recurrence of 
symptoms 
following initial 
improvement; 
hospitalization 
indicated for 
clinical sequelae 
(e.g., renal 
impairment, 
pulmonary 
infiltrates)
Life-threatening 
consequences; 
pressor or 
ventilatory 
support indicated
Death
Definition: A disorder characterized by nausea, headache, tachycardia, hypotension, rash, and shortness of 
breath; it is caused by the release of cytokines from the cells.


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Adverse Event
Grade 1
Grade 2
Grade 3
Grade 4
Grade 5
Serum sickness
Asymptomatic; 
clinical or 
diagnostic 
observations 
only; 
intervention 
not indicated
Moderate 
arthralgia; fever, 
rash, urticaria, 
antihistamines 
indicated
Severe 
arthralgia or 
arthritis; 
extensive 
rash; steroids 
or intravenous 
fluids 
indicated
Life-threatening 
consequences; 
pressor or 
ventilatory 
support indicated
Death
Definition: A disorder characterized by a delayed-type hypersensitivity reaction to foreign proteins derived 
from an animal serum. It occurs approximately 6 to 21 days following the administration of the foreign 
antigen. Symptoms include fever, arthralgias, myalgias, skin eruptions, lymphadenopathy, chest marked 
discomfort, and dyspnea.
Immune 
system 
disorders -
Other, specify
Asymptomatic or 
mild symptoms; 
clinical or 
diagnostic 
observations 
only; 
intervention not 
indicated
Moderate; 
minimal, local or 
noninvasive 
intervention 
indicated; 
limiting 
age-appropriate 
instrumental 
ADL
Severe or 
medically 
significant but 
not immediately 
life-threatening; 
hospitalization 
or prolongation 
of existing 
hospitalization 
indicated; 
disabling;
limiting self-
care ADL
Life-threatening 
consequences;
urgent 
intervention 
indicated
Death
Abbreviations: ADL, Activities of daily living; NSAIDs, non-steroidal anti-inflammatory drugs.
Adapted from CTCAE 4.0 – June 14, 2010, Immune system disorders.

SAP_001.pdf: 
Protocol Number:  ADCT-402-101 
 
Official Title:     Phase 1 Dose-escalation Study to Evaluate the Tolerability, Safety, 
Pharmacokinetics, and Antitumor Activity of ADCT-402 in Patients with 
Relapsed or Refractory B-cell Lineage Non Hodgkin Lymphoma (B-NHL)  
 
NCT Number:  NCT02669017 
 
Document Date:  10 June 2019 


ADC Therapeutics 
ADCT-402 
ADCT-402-101 
SAP version 1.0 
Page 1 of 23 
 
 
 
 
 
 
Statistical Analysis Plan 
 
 
 
 
A Phase 1 Dose-escalation Study to Evaluate the Tolerability, Safety, 
Pharmacokinetics, and Antitumor Activity of ADCT-402 in Patients with 
Relapsed or Refractory B-cell Lineage Non-Hodgkin Lymphoma (B-NHL) 
 
PROTOCOL NO.:  ADCT-402-101  
 
 
 
SAP Version No./ Date: 1.0/ Jun 10, 2019 
 
Statistician: Luqiang Wang 
 
 
 
 
  
Confidentiality Statement 
All financial and nonfinancial support for this study will be provided by ADC Therapeutics 
SA. The concepts and information contained in this document or generated during the study 
are considered proprietary and may not be disclosed in whole or in part without the 
expressed, written consent of ADC Therapeutics SA. The study will be conducted according 
to the International Conference on Harmonisation harmonised tripartite guideline E6(R1), 
Good Clinical Practice. 
 




ADC Therapeutics 
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Table of Contents 
Table of Contents ...................................................................................................................... 3 
1 Introduction ............................................................................................................................ 5 
2 Study Objectives .................................................................................................................... 6 
2.1 Primary Objectives ......................................................................................................6 
2.2 Secondary Objectives ..................................................................................................6 
 
3 Study Design .......................................................................................................................... 7 
3.1 Sample Size Consideration ..........................................................................................7 
3.2 Randomization .............................................................................................................7 
3.3 Modifications to the statistical section of the protocol ................................................7 
4 Statistical methods ................................................................................................................. 8 
4.1 Analysis Sets ................................................................................................................8 
4.1.1 Safety Analysis Set .........................................................................................8 
4.1.2 DLT-evaluable Analysis Set (Part 1) ...............................................................8 
4.1.3 Efficacy Analysis Set ......................................................................................8 
4.1.4 Pharmacokinetics Analysis Set .......................................................................8 
 
 
4.2 Patient Disposition .......................................................................................................9 
4.3 Protocol Deviations .....................................................................................................9 
4.4 Demographic and Baseline Characteristics ...............................................................10 
4.5 Cancer History and Medications History ..................................................................10 
4.6 Prior or Concomitant Medications (other than anticancer therapies) ........................ 11 
4.7 Exposure to Treatment ............................................................................................... 11 
4.7.1 Extent of ADCT-402 Exposure ..................................................................... 11 
4.7.2 Prophylactic Medications for Hypersensitivity ............................................12 
4.7.3 Subsequent Anticancer Therapy or Procedure ..............................................12 
4.8 Safety Analyses .........................................................................................................12 
4.8.1 Dose-limiting Toxicities (Part 1)...................................................................12 
4.8.2 Adverse Events, Serious Adverse Events, and Deaths ..................................12 
4.8.2.1 Analyses of adverse events .......................................................... 12 
4.8.2.2 Deaths .......................................................................................... 14 
4.8.3 Laboratory Data ............................................................................................14 


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4.8.4 Electrocardiogram .........................................................................................15 
4.8.5 Vital Signs .....................................................................................................15 
4.8.6 ECOG Performance Status ...........................................................................15 
4.8.7 Physical Examinations and Body Weight .....................................................15 
4.9 Efficacy Analyses ......................................................................................................16 
4.9.1 Overall Response Rate ..................................................................................16 
4.9.2 Duration of Response ....................................................................................16 
4.9.3 Time to Response: .........................................................................................17 
4.9.4 Progression-free Survival..............................................................................17 
4.9.5 Overall Survival ............................................................................................17 
4.10 Pharmacokinetic/Pharmacodynamics Analyses ......................................................18 
4.10.1 PK Analysis Method ...................................................................................18 
 
 
5 Interim Analyses .................................................................................................................. 19 
6 Data handling conventions ................................................................................................... 20 
6.1 General conventions ..................................................................................................20 
6.1.1 Missing data ..................................................................................................20 
6.1.2 Unscheduled visits ........................................................................................21 
6.1.3 Duplicated visits............................................................................................21 
Appendix 1 Glossary of Abbreviations ................................................................................... 22 
 


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1 Introduction 
This statistical analysis plan (SAP) describes the statistical methods to be used during the 
reporting and analyses of data collected under ADC Therapeutics Protocol ADCT-402-101. 
This SAP should be read in conjunction with the study protocol and case report form (CRF). 
This version of the plan has been developed using the protocol Amendment 7 dated 16 
October 2017 and CRF version 5 dated 23 Jan 2018. 
 


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2  Study Objectives 
2.1 Primary Objectives  
 Evaluate the safety and tolerability, and determine, as appropriate, the maximum 
tolerated dose (MTD) of ADCT-402 in patients with relapsed or refractory B-cell 
lineage NHL in Part 1. 
 Determine the recommended dose(s) of ADCT-402 for Part 2 (expansion). 
 Evaluate the safety and tolerability of ADCT-402 in Part 2 (expansion) at the dose 
level(s) recommended in Part 1. 
2.2 Secondary Objectives 
 Evaluate the clinical activity of ADCT-402 measured by overall response rate (ORR), 
duration of response (DOR), overall survival (OS), and progression-free survival 
(PFS). 
 Characterize the pharmacokinetic (PK) profile of ADCT-402 (total antibody; drug-to-
antibody ratio [DAR] ≥0), pyrrolobenzodiazepine (PBD)-conjugated antibody (DAR ≥ 
1), and free warhead SG3199. 
 Evaluate anti-drug antibodies (ADAs) to ADCT-402 in blood before, during, and after 
treatment with ADCT-402. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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3 Study Design 
This is a Phase 1, open-label, dose escalation (Part 1) and expansion (Part 2) study of the safety 
and tolerability of ADCT-402, used as monotherapy, in patients with relapsed or refractory 
B-cell NHL. The study will determine the MTD, as well as evaluate the preliminary activity, 
PK, pharmacodynamics (PD), and other exploratory assessments of ADCT-402. 
In Part 1, patients will be assigned to treatment according to a 3+3 dose escalation design and 
oversight of a Dose Escalation Steering Committee (DESC). The initial dose of ADCT-402 
will be 15 µg/kg (Dose Level 1), and the highest allowed dose will be 300 µg/kg. The dose-
limiting toxicity (DLT) observation period for dose escalation is 1 cycle. Patients will be 
entered sequentially to each dose level. No intra-patient dose escalation is allowed. During Part 
1, the DESC may expand enrollment at any dose level in which 3 patients have completed the 
DLT observation period if at least 1 patient in the study has achieved a partial response (PR) 
or better, or if further evaluation of PK or PD data is deemed necessary to characterize 
pharmacology in humans. No more than 10 patients in total can be treated at any dose level 
unless ≥3 of the 10 patients have achieved a PR or better. 
In Part 2, (expansion), all patients will be assigned to the dose level(s) of ADCT-402 identified 
in Part 1. During dose expansion, patients will be monitored for safety using the same DLT 
criteria employed during dose-escalation. If during the treatment period, >30% of patients 
experience safety events that would meet the criteria that define a DLT in the dose-escalation 
phase of the study, enrollment in the expansion cohort(s) may be paused and the study data 
reviewed to determine whether additional monitoring or other action (such as alternate dose 
levels) should be evaluated prior to further enrollment. 
3.1 Sample Size Consideration 
This is a Phase 1 study with a maximum sample size of up to approximately 200 patients. It 
is estimated that approximately 90 patients will enroll in Part 1, and approximately 110 
patients will enroll in Part 2. 
3.2 Randomization 
This study is not randomized. 
3.3 Modifications to the statistical section of the protocol  
The efficacy analysis set was defined in the protocol as all patients with valid baseline data 
who receive at least 2 doses of study drug or who have documented progression of disease at 
any time after the first dose of study drug. However, a few patients received 200 µg/kg on an 
every 6 weeks (Q6W) schedule and their disease assessments were performed before the 
second dose. These patients should be considered as evaluable for efficacy analysis. 
Therefore, the efficacy analysis set is updated in the SAP to include all patients who have 
received at least one dose of ADCT-402 with a valid baseline and at least one valid post-
baseline disease assessment or patients who have documented progression of disease or death 
at any time after the first dose of study drug. 


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4 Statistical methods  
All analyses use SAS® version 9.4 or higher. Summary tables will be organized by each dose 
level; if some dose levels have few patients, then dose levels could be combined into dose 
ranges. All available data will be used in the analyses, and important data will be included in 
data listings, sorted by dose level, patient, and by visit within patient. Missing data will not be 
imputed, except via censoring in survival analyses and as otherwise specified. 
Unless otherwise noted, categorical data will be presented using counts and percentages, with 
the number of patients in the analysis set by treatment group as the denominator for percentages. 
Percentages will be rounded to one decimal place, except 100% will be displayed without any 
decimal places and percentages will not be displayed for zero counts. Continuous data, unless 
otherwise noted, will be summarized using the number of observations (n), mean, standard 
deviation (std), median, minimum, and maximum. Minima and maxima will be rounded to the 
precision of the original value, and means, medians, and 95% confidence intervals (CIs) if 
presented will be rounded to 1 decimal place greater than the precision of the original value. 
The std will be rounded to 2 decimal places greater than the precision of the original value, up 
to a maximum of 3 decimal places.  
No hypothesis testing will be performed in this study. 
4.1 Analysis Sets  
4.1.1 Safety Analysis Set 
The safety analysis set consists of all patients who receive ADCT-402. 
4.1.2 DLT-evaluable Analysis Set (Part 1) 
The DLT-evaluable analysis set consists of patients who complete one cycle of ADCT-402. 
The patients with completed DLT information will be included even if they discontinue early, 
before the end of cycle 1. 
4.1.3 Efficacy Analysis Set 
The efficacy analysis set consists of patients who receive at least one dose of ADCT-402 with 
a valid baseline and at least one valid post-baseline disease assessment or patients who have 
documented progression of disease or death at any time after the first dose of study drug and 
before the start of any subsequent anticancer therapy or procedure. 
4.1.4 Pharmacokinetics Analysis Set 
The PK analysis set includes all patients who receive at least 1 dose of ADCT-402 with 
evaluable and sufficient concentration-time data to permit reliable estimation of ADCT-402 
exposure, and with no major or critical protocol deviations related to ADCT-402 
administration. 


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4.2 Patient Disposition 
The number and percentage of patients enrolled and treated in the study will be presented along 
with the number and percentage of patients in each analysis set for each dose level. In addition, 
for the safety analysis set, the number and percentage of patients who withdrew from study 
treatment and who discontinued the study for each reason will be tabulated for each dose level. 
Patient disposition data will be listed.  
4.3 Protocol Deviations 
The number and percentage of patients with any important clinical study report (CSR) 
reportable protocol deviation will be summarized overall and by type of deviation. The pre-
defined important CSR reportable protocol deviations are listed below; in addition, any other 
protocol deviations deemed by ADCT medical to be important CSR reportable deviations 
will be included in the summary.  
1. Patient entered the study even though they did not satisfy the entry criteria 
2. Patient received a prohibited concomitant treatment during the study 
3. Patients who met criteria for mandatory withdrawal of study drug during the study 
but did not have study drug withdrawn. The criteria for mandatory withdrawal of 
study drug included: 
- Any patient who experiences a Grade 3 or higher hypersensitivity (Appendix 12.3 in 
the protocol) reaction, regardless of premedication, during any cycle of treatment.  
- Any patient who experiences a recurrent Grade 3 or 4 toxicity, excluding 
hematological toxicity. 
- Any patient who requires a dosing delay >21 consecutive days from the planned Day 
1 dosing at any time during treatment (except in case of potential patient benefit, 
which must be approved by the Sponsor).  


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4. Patient who received the wrong treatment or incorrect dose. For example, 
- Actual dose of study drug was more than 15% greater than protocol defined planned 
dose level.  
- Patient started next cycle less than 18 days later after Day 1 of the most recent 
treatment cycle.  
Important protocol deviations will be listed. 
4.4 Demographic and Baseline Characteristics 
Demographic and baseline characteristics will be tabulated for the safety analysis set by dose 
level. Variables include the following: 
 Sex (female, male) 
 Race (white, black or African American, Asian, American Indian or Alaska native, 
native Hawaiian or other Pacific Islander, other) 
 Ethnicity (Hispanic or Latino, not Hispanic or Latino) 
 Age (years) 
 Age group (< 65, ≥ 65 - < 75, ≥ 75 years) 
 Height (cm) 
 Weight (kg) 
 Body mass index (kg/m2) 
 Eastern Cooperative Oncology Group (ECOG) performance status 
Demographic and baseline characteristics data will be listed. 
4.5 Cancer History and Medications History 
Cancer history will be presented for the safety analysis set by dose level. Cancer history will 
include the following variables: 
 Duration since diagnosis  
 non-Hodgkin lymphoma subtype (diffuse large B-cell lymphoma, follicular lymphoma, 
chronic lymphocytic leukemia, mantle cell lymphoma, marginal zone B-cell 
lymphoma, Burkitt’s lymphoma, lymphoplasmacytic lymphoma [Waldenstrom 
macroglobulinemia], other) 
 Stage of disease (Stage I, II, III, IV; constitutional symptoms A, B; Subtype E, X, S) 
 Cytogenetic analysis (results available yes, t(11;14), t(11q), +12, del(11q), del(13q), 
del(17p], t(14;18), t(8; 14), t(8;22), other) 
 Immunophenotypic analysis (results available yes; IgVH status mutated, unmutated, 
not applicable; CD5, CD10, CD19, CD20, CD21, CD23, CD43, CD79b, BCL1, BCL2, 
BCL6, CYCLIN D1, ZAP70 negative, positive, not done) 
Prior anticancer procedure or therapy will include the following variables: 
 Number of lines of therapy/ regimens per patient 
 Any prior radiotherapy for the current malignancy (yes, no) 
 Any prior systemic therapy for the current malignancy (yes, no) 
 Reason for stopping therapy (progression, toxicity, other) 


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 Best response (complete response [CR], partial response [PR], stable disease [SD], 
progressive disease [PD], not evaluable [NE]) 
 Any prior stem cell transplant (yes, no) 
 Type of transplant (allogenic, autologous, both, other) 
 Conditioning therapy (yes, no) 
Medical and cancer history data will be listed. 
 
 
 
Prior anticancer radiotherapy, systemic therapy, and stem cell transplant data will be listed. 
4.6 Prior or Concomitant Medications (other than anticancer therapies) 
All medications taken within 14 days before dosing and until the end of the study are to be 
reported in the CRF pages. 
All medications will be coded using the World Health Organization-Drug Dictionary (WHO-
DD) and presented by dose level for the safety analysis set. 
 Prior medications are those the patient used prior to first investigational product (IP) 
intake. Prior medications can be discontinued before first dosing or can be ongoing 
during the treatment phase.   
 Concomitant medications are any treatments received by the patient concomitantly to 
any IP(s), from first dose (or start of the observation period) to the last dose + 30 days. 
A given medication can be classified both as a prior medication and as a concomitant 
medication. Concomitant medications do not include medications started 30 days after 
the last dose.  
Any technical details related to computation, dates, and imputation for missing dates are 
described in Section 6.  
Prior medications will be listed together with concomitant medications. 
4.7 Exposure to Treatment 
4.7.1 Extent of ADCT-402 Exposure 
ADCT-402 exposure will be summarized for the safety analysis set by dose level. Duration 
of treatment, total number of cycles dosed, total dose received (in µg and µg/kg), and average 
dose per cycle (in µg and µg/kg) will be tabulated. When actual weight adjusted dose is 
needed, the last available weight before each infusion will be used. Dose administered at 
each infusion (µg) is calculated by concentrated IP volume (in mL)* 5 mg/mL *1000 or 
serially diluted IP volume (in mL)/50* 5 mg/mL *1000; for partial infusion, multiply by (1- 
volume of dosing solution not administered [in mL]/ 50 mL). 
Dose delays and dose reductions could also be analyzed if relevant. A cycle is delayed if it 
starts more than 3 days post- scheduled date. 
Exposure data and infusion details will be listed together. 


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4.7.2 Prophylactic Medications for Hypersensitivity  
Prophylactic medications for hypersensitivity will be listed only. 
4.7.3 Subsequent Anticancer Therapy or Procedure 
Patients’ subsequent anticancer therapies or procedures including systemic therapy, radiation, 
transplant, or other, along with the start date of new anticancer therapy or procedure will be 
collected and listed only. 
4.8 Safety Analyses 
The summary of safety results will be presented by treatment group.  
General common rules 
All safety analyses will be performed on the safety analysis set, unless otherwise specified, 
using the following common rules: 
 The baseline value is defined as the last non-missing value or measurement taken up to 
the first dose in the study. 
 The analyses of the safety variables will be essentially descriptive and no systematic 
testing is planned. 
 If relevant, selected safety analyses will be summarized by age, sex, racial subgroups, 
and any pertinent subgroups.  
 The toxicity grade according to the Common Terminology Criteria for Adverse Events 
(CTCAE) version 4.0 will be taken into account in the summary. For patients with 
multiple occurrences of the same event, the maximum grade is used. If a patient has 
both missing and non-missing severity grades for treatment-emergent adverse events 
(TEAEs) within the same preferred term (PT), the patient will be counted under the 
non-missing severity grade. 
4.8.1 Dose-limiting Toxicities (Part 1) 
DLT data will be listed for Part 1 of the study. 
4.8.2 Adverse Events, Serious Adverse Events, and Deaths 
4.8.2.1 Analyses of adverse events 
The primary focus of adverse event reporting will be on TEAEs. An adverse event (AE) will 
be considered to be a TEAE if it begins or worsens on or after first dose date and until 84 days 
(12 weeks) after the last dose date, or start of a new anticancer therapy/procedure, whichever 
comes earlier. 
An AE occurring before the first dose or more than 84 days (12 weeks) after last dose date or 
after the start of a new anticancer therapy/procedure will not be included in TEAE displays, 
but will be listed as non-TEAEs. 


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If an AE date/time of onset (occurrence, worsening, or becoming serious) is incomplete, an 
imputation algorithm will be used to classify the AE as pre-treatment, TEAE, or post-treatment. 
The algorithm for imputing date/time of onset will be conservative and will classify an AE as 
a treatment-emergent unless there is definitive information to determine it is a non-TEAE (pre- 
or post-treatment).  
Details on classification of AEs with missing or partial onset dates are provided in Section 6. 
Analysis of all TEAE(s):  
The following TEAE summaries will be generated for the safety analysis set in each dose level. 
 Overview of TEAEs, summarizing number of TEAE and number (%) of patients with 
any 
- 
TEAE 
- 
Related TEAE (including possibly related, probably related, or related) 
- 
Any TEAE ≥Grade 3  
- 
Serious TEAE  
- 
TEAE leading to death 
- 
TEAE leading to permanent treatment withdrawal 
- 
TEAE leading to ADCT-402 delay or reduction  
- 
TEAE with at least one infusion related reaction 
 All TEAEs ≥Grade 3 by PT, showing number (%) of patients with at least one TEAE, 
sorted by decreasing incidence of PTs 
 All TEAEs by primary System Organ Class (SOC) and PT, showing number (%) of 
patients with at least one TEAE, sorted by SOC in alphabetic agreed order and 
decreasing incidence of PTs within SOC. This sorting order will be applied to all other 
tables, unless otherwise specified. 
 All TEAEs by primary SOC, PT and Maximal CTCAE grade, showing number (%) of 
patients with at least one TEAE, sorted by SOC and PT in alphabetic order. This sorting 
order will be applied to all other tables, unless otherwise specified. 
 All TEAEs ≥Grade 3 by primary SOC, PT and Maximal CTCAE grade 
 All related TEAEs by primary SOC, PT and Maximal CTCAE grade (including 
possibly related, probably related, or related) 
 All TEAEs leading to treatment withdrawal by primary SOC, PT and Maximal CTCAE 
grade 
 All TEAEs leading to dose delay by primary SOC, PT and Maximal CTCAE grade 
 All TEAEs leading to dose reduction by primary SOC, PT and Maximal CTCAE grade 


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 All TEAEs leading to infusion interruption by primary SOC, PT and Maximal CTCAE 
grade 
 All TEAEs with fatal outcome by primary SOC, PT and Maximal CTCAE grade 
 All Serious TEAEs by primary SOC, PT and Maximal CTCAE grade 
 All infusion related reaction TEAEs by primary SOC, PT and Maximal CTCAE 
grade  
 Summary of grouped TEAEs selected by Standardised MedDRA Query (SMQ), 
ADCT modified SMQ will also be provided by primary Grouped term, PT and 
Maximal CTCAE grade. These group terms include: for effusion/edema, hepatic, 
fatigue, skin/nail, pain. 
 Summary of TEAEs will also be provided by demographic factors including: sex, age 
group, race, disease subtype if appropriate. 
All TEAEs, all serious adverse events (SAEs), all TEAEs leading to treatment withdrawal, 
all TEAEs leading to dose reduction, all TEAEs leading to dose delay, all TEAEs considered 
infusion related reactions, all TEAEs with fatal outcome and non-TEAEs will be listed. 
4.8.2.2 Deaths 
The following deaths summaries will be generated on the safety analysis set. 
 Number (%) of patients who died during the study and reasons for death 
 Number (%) of patients who died within 30 days after last dose of study drug except 
deaths occurred after taking any subsequent anticancer therapy/procedure and reasons 
for death 
All deaths will be listed. 
4.8.3 Laboratory Data 
Laboratory data of hematology, biochemistry, coagulation, and additional renal function 
studies up to 84 days after last dose of study drug or the end of treatment visit date, whichever 
is later, will be reported in SI units. Descriptive statistics (mean, standard deviation, median, 
and range) will be calculated for the raw data and for their changes from baseline at each 
scheduled assessment. 
All results will be summarized using shift from baseline. Shifts for clinical laboratory results 
that can be graded according to CTCAE version 4.0 will be summarized by CTCAE grade. 
Summaries by visit will include data from scheduled assessments, and all data will be reported 
according to the nominal visit date for which it was recorded. Unscheduled data will be 
included in “worst case post-baseline” summaries, which will capture a worst case across all 
scheduled and unscheduled visits after the first dose of study treatment. 
Summary analyses will include data up to the start of subsequent anticancer therapy/procedure. 
All laboratory data, including urinalysis, will be listed. Pregnancy test results will not be listed, 
but will be included in datasets. 


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4.8.4 Electrocardiogram 
Electrocardiogram (ECG) parameters (e.g., QTc in ms) will not be converted or derived, but 
will be reported as provided by investigational sites. 
Descriptive statistics (mean, standard deviation, median, and range) will be calculated for the 
raw data and for their changes from baseline at each scheduled assessment. 
The following abnormal QTc (including QTcF, QTcB and QTc with unspecified method) will 
be reported: 
 At any post-baseline with absolute value 
>450 - <=480 ms 
>480 - <=500 ms 
> 500 ms 
Change from Baseline 
 >30 – <=60 ms 
 >60 ms 
For patients with unspecified QTc method at either baseline or post-baseline, consistent 
correction method is assumed within a patient when calculating the change from baseline.  
Summary analyses will include data up to the start of subsequent anticancer therapy/procedure. 
All ECG data will be listed, both for quantitative data and for overall impression. 
4.8.5 Vital Signs 
Descriptive statistics (mean, standard deviation, median, and range) for vital signs data, 
including systolic and diastolic blood pressure, heart rate, respiration rate, and body 
temperature will be calculated for the raw data and for their changes from baseline at each 
scheduled assessment. 
Summary analyses will include data up to the start of subsequent anticancer therapy/procedure. 
All vital signs data will be listed together with body weight and ECOG performance score. 
4.8.6 ECOG Performance Status 
ECOG performance score data will be listed together with vital signs and body weight. 
4.8.7 Physical Examinations and Body Weight 
Physical examination will be performed according to protocol. Clinically significant findings 
from the physical examinations will be recorded as medical history (prior to first administration 
of ADCT-402) or AEs (subsequent to first administration of ADCT-402). 
Body weight will be listed together with vital signs and ECOG performance score. 


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4.9 Efficacy Analyses 
Disease assessment will be performed according to protocol. The endpoints described in this 
section use the investigator’s evaluation according to the Lugano Classification criteria and 
clinical progression from End of Treatment (EOT)/Study disposition page.  
Lesion assessment data (target lesions, non-target lesions, and new lesions) will be listed. A 
separate listing will contain derived data for DOR, PFS, and OS. 
4.9.1 Overall Response Rate 
Overall response rate is defined as the proportion of patients who achieve either CR or PR as 
best overall response as assessed by investigators according to the Lugano Classification 
criteria before the start of subsequent anticancer therapy or procedure.  
The order of overall response category is: CR, PR, SD, NE, PD (including disease recurrence/ 
relapse). The overall response category will be derived based on response assessment 
performed on or before the start of subsequent anticancer therapy/procedure. Patients without 
documented subsequent anticancer therapy and/or with missing start date of anticancer therapy 
will be considered as not having received subsequent anticancer therapy. If a patient only has 
one valid disease assessment which is SD, and the assessment is within 35 days after the first 
dose, the overall response for this patient will be considered as NE. 
The overall response rate and the corresponding 95% two-sided exact confidence interval at 
each dose level will be presented. Subgroup analysis may be provided for disease subtype, 
disease stage, double/triple hit (yes/no), bulky disease (yes/no), age group, sex, country, 
response to the first line and/or most recent line of prior systematic therapy (relapse: CR+PR 
vs. refractory: SD+PD vs. other: NE + missing), and other relevant variables. 
Percent change from baseline in the sum of product of diameters (SPD) for target lesions will 
be presented for available data in the efficacy analysis set by dose level. These data will also 
be displayed as a waterfall plot, with vertical bars representing the sorted values of best percent 
reduction for each patient.  
Tumor response and lesion measurement will be listed by assessment visit. 
4.9.2 Duration of Response 
Duration of response will be defined for patients with CR or PR only as the interval between 
the date of initial documentation of a response and the date of first documented evidence of 
progressive disease (based on radiographic or clinical progression at EOT/end of study [EOS]) 
or death. Patients who had the event after the start of subsequent anticancer therapy/procedure, 
or are progression-free and alive at the time of clinical cut-off, or have unknown status, will 
be censored at the last valid tumor assessment on or before the start of subsequent anticancer 
therapy/procedure or clinical cut-off time. When a subsequent anticancer therapy is used and 
progressive disease (based on radiographic or clinical progression at EOT/EOS) is observed 
within 6 days, they will be considered as the same visit (within the +/-6 days visit window) 
and the patient will be counted as having an event (losing the response).  


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Duration of response will be estimated and displayed by dose levels for the efficacy analysis 
set using Kaplan-Meier methods (SAS® PROC LIFETEST). A Kaplan-Meier plot will be 
presented. 
Subgroup analyses may be provided for disease subtype, disease stage, double/triple hit 
(yes/no), bulky disease (yes/no), age group, response to the first line and/or most recent line 
of prior systematic therapy (relapse: CR+PR vs. refractory: SD+PD vs. other: NE + missing), 
best response to ADCT-402 (CR/PR), and other relevant variables. 
4.9.3 Time to Response:  
Time to response (TTR) for the subset of patients who achieve a CR or PR will be summarized 
using descriptive statistics. 
4.9.4 Progression-free Survival 
Progression-free survival is defined as the interval between the date of first dose and the date 
of disease progression (based on radiographic or clinical progression at EOT/EOS) or death, 
whichever occurs first. Patients who have the event after the start of subsequent anticancer 
therapy/procedure, or who are progression-free and alive at the time of clinical cutoff, or have 
unknown status, will be censored at the time of their last valid disease assessment on or before 
the start of subsequent anticancer therapy/procedure or clinical cut-off. When a subsequent 
anticancer therapy was used and progressive disease (based on radiographic or clinical 
progression at EOT/EOS) were observed within 6 days, they will be considered as the same 
visit (within the +/-6 days window) and the patient will be counted as having an event. 
Patients with no post-baseline disease assessment will be censored on Day 1. 
PFS will be estimated and displayed by dose levels for the efficacy analysis set using Kaplan-
Meier methods (SAS® PROC LIFETEST). Patients who do not have a PFS event during or 
after the study will be censored. A Kaplan-Meier plot will be presented. 
4.9.5 Overall Survival 
Overall survival is defined as the interval between the date of first dose and the date of death 
from any cause. Patients who are known to be alive as of their last known status will be 
censored at their date of last contact. Patients who are lost to follow-up will be censored at the 
date the patient is last known to have been alive. The last confirmed alive date is the latest of 
the following: study visit date, telephone contact date, end of study last confirmed alive date, 
follow-up systemic (anticancer) therapy end date or start date (if ongoing or end date is 
missing), local or central radiologist scan date, or other date in the clinical database. 
OS will be estimated and displayed by dose levels for the efficacy analysis set using Kaplan-
Meier methods (SAS® PROC LIFETEST). A Kaplan-Meier plot will be presented. 


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4.10 Pharmacokinetic/Pharmacodynamics Analyses 
4.10.1  PK Analysis Method  
The actual blood sampling time and actual amount of dose administered will be recorded and 
used in calculation of PK parameters.  All PK samples will be evaluable as long as the actual 
collection times are recorded.  Analysis of the ADCT-402 total antibody [drug-to-antibody 
ratio (DAR≥0)], PBD-conjugated antibody (DAR≥1), and SG3199 (unconjugated warhead) 
concentrations in serum were analyzed using a noncompartmental (NCA) analysis method. 
The PK parameters from analysis included maximum concentration (Cmax), time to Cmax (Tmax), 
area under the concentration-time curve from time zero to the last quantifiable concentration 
(AUClast), area under the concentration-time curve (AUC) from time zero to the end of the 
dosing interval (AUCtau), area under the concentration-time curve from time zero to infinity 
(AUCinf), accumulation index (AI), terminal half-life (Thalf), systemic clearance (CL), 
clearance (CLss) and volume of distribution at steady state (Vss). 
Data presentation by tables will include individual patient concentrations by actual time, 
individual PK parameters, statistical summaries for concentrations by dose cohort and nominal 
time, and statistical summary for PK parameters. Data presentation by figures will include 
individual patient concentrations by actual time, and mean (standard error) of concentrations 
by nominal time. 
At selected times as indicated in the schedule of events tables, samples for ADCT-402 antidrug 
antibodies (ADA) were also collected concurrently with the PK samples.  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 instances in which a positive ADA titer is 
observed, results from testing for neutralizing antibody potential will be considered. 
 
 
  
 
  
   
 
 
 
 
 
 
   


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The results of all peripheral white blood cell populations, DNA cross-link formation, and renal 
functional tests will be listed by patient.  
 
 
 
  
 
 
  
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
  
 
   
5 Interim Analyses  
No formal interim analysis is planned. 


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6 Data handling conventions 
6.1 General conventions 
6.1.1 Missing data 
Handling of missing/partial dates   
In general, imputation of missing dates will be made for AE onset date, AE resolution date, 
date of death, medication start/end dates, start and end dates of prior and subsequent therapies, 
and date of initial diagnosis for reporting. No imputation should be done at the data level. 
 If dates are completely missing, no imputation will be made.  
 For any partial date with missing year, no imputation will be made. 
 For missing initial diagnosis date and subsequent therapies, if only day is missing, then 
the 15th of the month will be used; if only year is present, then June 30th will be used. 
If such imputed date for initial diagnosis is on or after date of first dose, then date of 
first dose - 1 will be used. If such imputed date for subsequent therapies is before date 
of last dose, then date of last dose +1 will be used. 
 If the imputed date is for an AE start date and is in the same year and month as but 
before the first dose date, then the first dose date will be used, or if the imputed AE 
start date is after the AE end date, then the AE end date will be used. If the imputed 
date is for an AE start date and is in the same year and month as but after the last dose 
date + 84 days, then the last dose date + 84 days will be used. 
 If a medication date or time is missing or partially missing, so it cannot be determined 
whether it was taken prior or concomitantly, it will be considered as a prior and 
concomitant medication. 
 If the imputed date is for a date of death and is before the last date that the patient is 
known to be alive, the latter date will be used. 
Handling of missing relationship to investigational product of TEAEs 
If the assessment of the relationship to investigational product is missing, then the relationship 
to investigational product has to be assumed and the TEAE considered as such in the frequency 
tables of possibly related TEAEs, but no imputation should be done at the data level. 
Handling of missing severity/grades of AEs 
If the severity/grade is missing for one of the treatment emergent occurrences of an AE, the 
maximal severity of the remaining occurrences will be considered. If the severity is missing 
for all the occurrences a “missing” category will be added in summary table. 
No other imputation of values for missing data will be performed. 


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6.1.2 Unscheduled visits 
Unscheduled visit measurements of laboratory data, vital signs, and ECG will be used for 
computation of baseline and worst values and/or grades. Re-windowing for unscheduled visits 
will not be performed  
6.1.3 Duplicated visits 
Depending on the statistical analysis method, single values may be required for each analysis 
window. For example, change from baseline by visit usually requires a single value per visit. 
Unless otherwise noted throughout the rest of this document, when a single value is needed, 
the following rule(s) will be used: 
 If more than 1 assessment occurs during the same nominal visit, select the record 
closest to the nominal day for that visit. 
 
If there are 2 assessments that are equidistant from the nominal day, the data of the 
assessment after the scheduled study day will be used. 
 The last measurement will be used if multiple measurements are taken on the same day. 
 
 


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Appendix 1 Glossary of Abbreviations 
Glossary of Abbreviations: 
ADA 
Anti-drug antibody 
AE 
Adverse event 
AI 
Accumulation index 
AUC 
Area under the concentration-time curve 
B-NHL 
B-cell lineage non-Hodgkin lymphoma 
CBC 
Complete blood count 
CD 
Cluster of differentiation  
CI 
Confidence interval 
CL 
Clearance 
Cmax 
Maximum concentration 
CR 
Complete response 
CRF 
Case report form 
CSR 
Clinical study report 
CTCAE 
Common Terminology Criteria for Adverse Events 
DAR 
Drug-to-antibody ratio 
DESC 
Dose Escalation Steering Committee 
DLT 
Dose-limiting toxicity 
DOR 
Duration of response 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
EOS 
End of study 
EOT 
End of treatment 
IP 
Investigational product 
MedDRA 
Medical Dictionary for Regulatory Activities 
MTD 
Maximum tolerated dose 
NCA 
Noncompartmental 
NE 
Not evaluable 
NHL 
Non-Hodgkin lymphoma 
ORR 
Overall response rate 


ADC Therapeutics 
ADCT-402 
ADCT-402-101 
SAP version 1.0 
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OS 
Overall survival 
PBD 
Pyrrolobenzodiazepine 
PD 
Pharmacodynamics, progressive disease 
PFS 
Progression-free survival 
PK 
Pharmacokinetic 
PR 
Partial response 
PT 
Preferred term 
Q6W 
Every 6 weeks 
QTc 
Corrected QT interval (ms) 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SD 
Stable disease 
SMQ 
Standardised MedDRA Query 
SOC 
System organ class 
SPD 
Sum of product of diameters  
std 
Standard deviation 
TEAE 
Treatment-emergent adverse event 
TFLs 
Tables, figures, and listings 
TTR 
Time to response 
ʎz 
Terminal elimination phase rate constant 
Tmax 
Time to maximum concentration 
t1/2 
Terminal half-life 
Vss 
Volume of distribution at steady-state 
Vz 
Volume of distribution 
WBC 
White blood cells 
WHO-DD 
World Health Organization-Drug Dictionary