Clinical trial NCT02669264
Conditions: Acute Lymphoblastic Leukemia
Keywords: Loncastuximab tesirine
Sponsor: ADC Therapeutics S.A.
Start date: 2016-03-01; Completion date: 2018-07-03
Enrollment: 35 participants; Allocation: NON_RANDOMIZED; Intervention model: SINGLE_GROUP

Brief summary:
This study evaluates ADCT-402 in participants with relapsed or refractory B-cell lineage acute lymphoblastic leukemia (B-ALL). 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-402-102 is the first clinical study with ADCT-402 in participants with B-cell lineage acute lymphoblastic leukemia (B-ALL).

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 an infusion of ADCT-402 either on weekly administration or every 3-week administration. participants on weekly administration will receive an infusion of ADCT-402 on Days 1, 8, and 15 of each 3 week treatment cycle. Participants on 3-week administration will receive an infusion of ADCT-402 on Day 1, every 3 weeks. Dose escalation will continue until the maximum tolerated dose (MTD) is determined.

In Part 2 (expansion), all participants will be assigned to the recommended dose and/or schedule of ADCT-402 identified in Part 1 by the Dose Escalation Steering Committee.

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.

Arms: arm 1: Weekly administration - Participants will receive an intravenous (IV) infusion of ADCT-402, on Days 1, 8, and 15 of each 3-week (21-day) cycle.

3-week administration - Participants will receive an IV infusion of ADCT-402, on Day 1 of each 3-week (21-day) cycle.

The dose escalation will be conducted according to a 3+3 design. arm 2: All participants will be assigned to the recommended dose and/or schedule of ADCT-402 identified in Part 1 by the Dose Escalation Steering Committee
Interventions: intervention 1: ADCT-402
Intervention descriptions: intervention 1: Intravenous infusion

Protocol documents:
Prot_000.pdf: 
Protocol Number:  ADCT-402-102 
 
Official Title:     A Phase 1, Open-label, Dose-Escalation, Multicenter Study to Evaluate the 
Tolerability, Safety, Pharmacokinetics, and Anti-tumor Activity of ADCT-402 
in Patients with Relapsed or Refractory B-cell Lineage Acute Lymphoblastic 
Leukemia (B-ALL) 
 
NCT Number:  NCT02669264 
 
Document Date:  19 April 2017   


ADC Therapeutics
ADCT-402
ADCT-402-102
Protocol Amendment 3
Date of Protocol: 19 April 2017 
Page 1
CLINICAL STUDY PROTOCOL
IND: 126138
A Phase 1, Open-label, Dose-Escalation, Multicenter Study to Evaluate the 
Tolerability, Safety, Pharmacokinetics, and Anti-tumor Activity of ADCT-402 
in Patients with Relapsed or Refractory B-cell Lineage Acute Lymphoblastic 
Leukemia (B-ALL)
PROTOCOL NO.: ADCT-402-102
EudraCT Number: 2016-000953-10
Sponsor:
ADC Therapeutics SA
 
Sponsor Contact:
Medical Monitor:
Date of Original Protocol: 
18 September 2015
Date of Protocol Amendment 1:
8 December 2015
Date of Protocol Amendment 2:
14 March 2016
Date of Protocol Amendment 3:
19 April 2017
Confidentiality Statement
All financial and non-financial 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 
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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.
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ADC Therapeutics 
ADCT -402-1 02 
ADCT-402 
Protocol Amendment 3 
Protocol Approval- Sponsor Signatory 
Study Title 
Protocol Number 
Date of Original 
Protocol: 
Protocol Amendment 1: 
Protocol Amendment 2: 
Protocol Amendment 3: 
A Phase 1, Open-label, Dose-Escalation, Multicenter Study to 
Evaluate the Tolerability, Safety, Pharmacokinetics, and 
Anti-tumor Activity of ADCT-402 in Patients with Relapsed or 
Refractory B-cell Lineage Acute Lymphoblastic Leukemia 
(B-ALL) 
ADCT -402-1 02 
18 September 20 15 
8 December 20 15 
14 March 2016 
19 April 2017 
Date of Protocol: 19 April 2017 
Page 3 
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Declaration of Investigator
I have read and understood all sections of the protocol entitled “A Phase 1, Open-label, 
Dose-Escalation, Multicenter Study to Evaluate the Tolerability, Safety, Pharmacokinetics, and 
Anti-tumor Activity of ADCT-402 in Patients with Relapsed or Refractory B-cell Lineage Acute 
Lymphoblastic Leukemia (B-ALL)” 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 Amendment 3, dated 19 April 2017, the International Conference 
on Harmonisation (ICH) harmonised tripartite guideline E6 (R1): Good Clinical Practice and all 
applicable governmental regulations. I will not make changes to the protocol before consulting 
with ADC Therapeutics SA or implement protocol changes without independent ethics 
committee approval except to eliminate an immediate risk to patients. I agree to administer study 
treatment only to patients under my personal supervision or the supervision of a subinvestigator.
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 .......................................................................................................................5
List of Tables..............................................................................................................................8
List of Figures............................................................................................................................9
Protocol Synopsis.....................................................................................................................10
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
Non-clinical Efficacy and Safety of ADCT-402.......................................25
1.3
Safety of Commercially Available Antibodies Directed against CD19.................26
2
Study Objectives..............................................................................................................27
2.1
Primary Objectives.................................................................................................27
2.2
Secondary Objectives.............................................................................................27
3
Investigational Plan and Patient Selection ......................................................................28
3.1
Study Design..........................................................................................................28
3.2
Dose-Escalation .....................................................................................................28
3.3
Selection of Study Population................................................................................31
3.3.1
Inclusion Criteria ......................................................................................31
3.3.2
Exclusion Criteria.....................................................................................32
4
Study Procedures.............................................................................................................35
4.1
Procedures by Study Day – Every 3-Week (Q3W) Dosing Schedule ...................35
4.1.1
Screening Period (Day –28 to –1) ............................................................35
4.1.2
Day 1 (+ 3 days) of Each Cycle................................................................36
4.1.3
Day 2 (Cycles 1 and 2) .............................................................................39
4.1.4
Day 3 (Cycles 1 and 2) .............................................................................39
4.1.5
Day 5 (Cycles 1 and 2) .............................................................................39
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4.1.6
Day 8 (± 2 days) of Each Cycle................................................................39
4.1.7
Day 15 (± 2 days) of Cycles 1 and 2 ........................................................40
4.1.8
End of Treatment Visit..............................................................................40
4.1.9
12-week Follow-up Visit ..........................................................................41
4.1.10
Long-term Follow-up................................................................................41
4.2
Withdrawal of Patients from the Study..................................................................41
4.2.1
Reasons for Withdrawal/Discontinuation.................................................41
4.2.2
Handling of Withdrawals..........................................................................42
4.2.3
Patient Replacements................................................................................43
5
Study Treatments.............................................................................................................44
5.1
Method of Assigning Patients to Treatment...........................................................44
5.2
Prophylactic Treatments for Hypersensitivity .......................................................44
5.3
Treatments Administered .......................................................................................45
5.4
Dose Delays and Modifications.............................................................................46
5.5
Identity of Investigational Product.........................................................................46
5.5.1
ADCT-402 Drug Product..........................................................................46
5.6
Management of Clinical Supplies..........................................................................47
5.6.1
Study Drug Packaging and Storage..........................................................47
5.6.2
Study Drug Preparation and Administration.............................................47
5.6.3
Study Drug Accountability .......................................................................47
5.7
Overdose Management ..........................................................................................47
5.8
Treatment Compliance...........................................................................................47
5.9
Concomitant Treatment..........................................................................................48
5.9.1
Prohibited During Study...........................................................................48
5.9.2
Permitted During Study............................................................................48
6
Study Assessments and Procedures.................................................................................50
6.1
Efficacy Assessments.............................................................................................50
6.2
Pharmacokinetic, Pharmacodynamic and 
.....................51
6.2.1
Pharmacokinetic Assessments ..................................................................51
6.2.2
Pharmacodynamic and Other Assessments ..............................................51
6.3
Safety and Tolerability Assessments......................................................................52
6.3.1
Definition of Dose-Limiting Toxicities ....................................................52
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6.3.2
Safety Oversight by the Dose-Escalation Steering Committee................52
6.3.3
Adverse Events .........................................................................................53
6.3.4
Pregnancy .................................................................................................56
6.3.5
Clinical Laboratory Analyses ...................................................................56
6.3.6
Electrocardiograms...................................................................................57
6.3.7
Physical Examination ...............................................................................57
6.3.8
Vital Sign Measurements..........................................................................57
6.3.9
Weight.......................................................................................................57
6.3.10
Eastern Cooperative Oncology Group Performance Status......................57
6.4
Sample Handling, Storage and Shipment ..............................................................58
7
Statistical and Analytical Plan.........................................................................................59
7.1
Safety Endpoints....................................................................................................59
7.2
Endpoints ...............................................................................................................59
7.2.1
Primary Endpoints ....................................................................................59
7.2.2
Secondary Endpoints ................................................................................59
7.3
Sample Size Calculations.......................................................................................59
7.4
Analysis Sets..........................................................................................................60
7.5
Description of Subgroups to be Analyzed .............................................................60
7.6
Statistical Analysis Methodology ..........................................................................60
7.6.1
Safety Analyses.........................................................................................60
7.6.2
Efficacy Analysis......................................................................................61
7.6.3
Pharmacokinetic and Pharmacodynamic Analyses ..................................62
7.6.4
Study Drug Exposure................................................................................63
7.7
Data Quality Assurance..........................................................................................63
7.7.1
Data Management.....................................................................................63
8
Ethics ...............................................................................................................................65
8.1
Independent Ethics Committee or Institutional Review Board .............................65
8.2
Ethical Conduct of the Study.................................................................................65
8.3
Patient Information and Consent ...........................................................................65
9
Investigator’s Obligations ...............................................................................................66
9.1
Confidentiality .......................................................................................................66
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9.2
Financial Disclosure and Obligations....................................................................66
9.3
Adverse Events and Study Report Requirements..................................................66
9.4
Investigator Documentation...................................................................................67
9.5
Study Conduct........................................................................................................67
9.6
Adherence to Protocol............................................................................................67
9.7
Investigator’s Final Report ....................................................................................67
9.8
Records Retention..................................................................................................67
10
Study Management..........................................................................................................69
10.1 Monitoring .............................................................................................................69
10.1.1
Monitoring of the Study............................................................................69
10.1.2
Inspection of Records ...............................................................................69
10.2 Management of Protocol Amendments and Deviations.........................................69
10.2.1 Modification of the Protocol.....................................................................69
10.2.2
Protocol Deviations ..................................................................................70
10.3 Study Termination..................................................................................................70
10.4 Final Report ...........................................................................................................70
11
Reference List..................................................................................................................71
12
Appendices ......................................................................................................................74
12.1 Appendix: Schedule of Events ..............................................................................74
12.2 Appendix: CTCAE Immune System Hypersensitivity Grades..............................84
List of Tables
Table 1.
Planned Dose Levels for ADCT-402 (Q3W Administration) ..........................29
Table 2.
Planned Dose Levels for ADCT-402 (QW Administration) ............................29
Table 3.
Definition of Severity Grades for Common Terminology Criteria 
for Adverse Events (CTCAE)..........................................................................55
Table 4.
Definition of Eastern Cooperative Oncology Group (ECOG) 
Performance Status Grades..............................................................................58
Table 5.
Schedule of Study Procedures: Every 3-Week (Q3W) Dosing........................75
Table 6.
Central Laboratory Sample Collection Schedule: Every 3-Week 
(Q3W) Dosing..................................................................................................78
Table 7.
Schedule of Study Procedures: Weekly (QW) Dosing ....................................79
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Table 8.
Central Laboratory Sample Collection Schedule: Weekly (QW) 
Dosing, Cycle 1................................................................................................82
Table 9.
Central Laboratory Sample Collection Schedule: Weekly (QW) 
Dosing, Cycle 2+ .............................................................................................83
Table 10.
CTCAE Immune System Hypersensitivity Grades..........................................84
List of Figures
Figure 1. Schematic Representation and Chemical Structure of ADCT-402 ..........................23
Figure 2. Schematic Representation for Dose-Escalation (3+3) Design .................................30
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Protocol Synopsis
Protocol Number:
ADCT-402-102
Title:
A Phase 1, Open-label, Dose-Escalation, Multicenter Study to Evaluate the 
Tolerability, Safety, Pharmacokinetics, and Anti-tumor Activity of ADCT-402 
in Patients with Relapsed or Refractory B-lineage Acute Lymphoblastic 
Leukemia (B-ALL).
Sponsor:
ADC Therapeutics SA
Study Phase:
1
Study Sites:
Approximately 10 sites during dose-escalation (Part 1) and 25 sites during dose 
expansion (Part 2).
Indication:
Patients with relapsed or refractory B-cell lineage acute lymphoblastic
leukemia (B-ALL) 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.
Rationale:
More than 6,000 new cases of ALL are diagnosed yearly in the U.S., with more 
than half (58%) occurring in patients <20 years of age. Children younger than
15 years have the best prognosis, with an expected 5-year survival rate of 88%, 
compared with 61% for adolescents and young adults and 40 to 45% for adults 
>40 years of age. ALL in older patients is more often associated with poor 
prognostic factors, including a higher relapse rate, higher incidence of minimal 
residual disease (MRD), and poorer tolerance to induction therapy. 
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-ALL.
 
 
 
 
 
 
 
 
 
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Objectives:
Primary objectives:

Evaluate the safety and tolerability and determine the maximum tolerated 
dose (MTD) of ADCT-402 in patients with relapsed or refractory B-ALL
(Part 1). 

Determine the recommended dose of ADCT-402 for Part 2 (expansion).

Evaluate the safety and tolerability of ADCT-402 in Part 2 (expansion) at 
the dose level recommended in Part 1.
Secondary objectives:

Evaluate the clinical activity of ADCT-402, based on the patient’s response 
to treatment (complete response [CR], CR with incomplete blood count 
recovery [CRi], partial response [PR], progressive disease [PD], no 
response [NR]) and determination of the 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) against ADCT-402 in serum before, 
during, and after treatment with ADCT-402.
 
 
 
 
 
 
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Patient Selection:
Inclusion Criteria:
1. Male or female patients, ages 12 years and older, with relapsed or refractory 
B-ALL 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. 
Note: Diagnosis and classification as per World Health Organization (WHO) 
classification of B-ALL (Swerdlow, 2008). 
2. Eastern Cooperative Oncology Group (ECOG) performance status 0-2.
3. Serum/plasma creatinine ≤1.5 mg/dL. If the patient has a serum/plasma
creatinine >1.5 mg/dL, creatinine clearance must be >60 mL/min/1.73 m2, 
as calculated by the Cockcroft and Gault equation (Cockcroft and 
Gault, 1976). 
4. Serum/plasma 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.
5. Total serum/plasma bilirubin ≤1.5 times ULN. Patients with known 
Gilbert’s syndrome may have a total bilirubin up to ≤3 times ULN).
6. Negative urine or serum beta-human chorionic gonadotropin (β-HCG) 
pregnancy test within 7 days prior to the Cycle 1, Day 1 visit, for women of 
child-bearing potential.
7. Women of child-bearing 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 child-bearing 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.
* 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.
** Defined as: 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 
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interruptus), lactational amenorrhea method, and spermicide-only are not 
acceptable as highly effective methods of contraception.
8. WBC value of <15,000 cells/µL prior to Cycle 1 Day 1.
Exclusion Criteria:
1. Patients who, in the opinion of the Investigator, have an option for other 
treatment for B-ALL at the current state of disease. 
2. Known active central nervous system (CNS) leukemia, defined as 
morphologic evidence of lymphoblasts in the cerebrospinal fluid (CSF), use 
of CNS-directed intrathecal treatment for active disease within 28 days 
prior to Screening, or symptomatic CNS leukemia (i.e., cranial nerve 
palsies or other significant neurologic dysfunction) within 28 days prior to 
Screening. 
Note: Patients may have a history of CNS leukemic involvement if they have 
received prior treatment for CNS involvement and no evidence of active 
disease (defined as ≥2 consecutive spinal fluid assessments with no 
evidence of disease) is present at Screening. Prophylactic intrathecal 
chemotherapy is not a criterion for exclusion.
3. Patients with Burkitt’s leukemia/lymphoma.
4. Active graft-versus-host disease.
5. Autologous or allogenic transplant within the 60 days prior to Screening.
6. Known history of immunogenicity or hypersensitivity to a CD19 antibody.
7. Known history of positive serum human ADA.
8. 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). 
9. 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). 
10. History of Stevens-Johnson syndrome or toxic epidermal necrolysis 
syndrome.
11. Pregnant or breastfeeding women.
12. Significant medical comorbidities, including uncontrolled hypertension 
(diastolic blood pressure >115 mm Hg), unstable angina, congestive heart 
failure (greater than New York Heart Association class II), severe 
uncontrolled ventricular arrhythmias, electrocardiographic evidence of 
acute ischemia, poorly controlled diabetes, severe chronic pulmonary 
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disease, coronary angioplasty, myocardial infarction within 6 months prior 
to Screening, or uncontrolled atrial or ventricular cardiac arrhythmias.
13. Use of any other experimental medication(s) within 14 days or 5 half-lives 
but, in no case <14 days prior to start of study treatment on Cycle 1, Day 1, 
except if approved by the Sponsor.
14. Major surgery, chemotherapy, systemic therapy (excluding 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. 
15. Failure to recover (to Common Terminology Criteria for Adverse Events 
[CTCAE Version 4.0] Grade 0 or Grade 1) from acute non-hematologic 
toxicity (except all grades of alopecia or Grade 2 or lower neuropathy), due 
to previous therapy, prior to the Screening visit. 
16. Isolated extramedullary relapse (i.e. testicular, CNS).
17. Congenital long QT syndrome or a corrected QTc interval of ≥450 ms at 
the Screening visit (unless secondary to pacemaker or bundle branch 
block). 
18. 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 the Investigator agree and document should not be 
exclusionary. 
19. 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.
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-ALL. The study will determine the MTD, 
as well as evaluate the preliminary activity, PK, pharmacodynamics (PD), and 
 of ADCT-402.
In Part 1, patients will be assigned to treatment according to a 3+3 
dose-escalation design (see below) and oversight by a Dose-Escalation Steering 
Committee (DESC). In Part 2 (expansion), all patients will be assigned to the 
dose level of ADCT-402 identified in Part 1.
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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 
anti-cancer 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:
The Investigator’s assessment of response to treatment will be based on bone 
marrow samples (aspirate or biopsy if aspirate unattainable) obtained during the 
study. Determination of ORR, DOR, OS, and PFS will be determined based on 
the Investigator’s assessment of the patient’s response to ADCT-402 as CR, 
CRi, PR, PD, or NR.
Complete response is defined as achieving each of the following:
o Bone marrow differential showing ≤5% blast cells.
o Absolute neutrophil count (ANC) ≥1.0 x 109/L and platelet count 
≥100 x 109/L.
o Absence of extramedullary disease.
o Patient is independent of red blood cell transfusions.
Complete response with incomplete blood count recovery is defined as 
achieving all CR criteria except that values for ANC may be <1.0 x 109/L 
and/or values for platelets may be <100 x 109/L. 
Partial response is defined as achieving each of the following:
o ANC ≥1.0 x 109/L and platelet count ≥100 x 109/L.
o Bone marrow differential showing a ≥50% decrease from baseline in the 
percentage of bone marrow blast cells to a level >5% and ≤25%, 
or
bone marrow differential showing <5% blast cells.
No response is defined as not achieving CR, CRi, or PR.
PD is defined as: 
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o For patients with CR or CRi, the first date of reappearance of blast cells 
in bone marrow and/or peripheral blood to a level ≥5%, or development 
of extramedullary disease.
o For patients with PR, the first date of an increase in blast cells in bone 
marrow and/or peripheral blood such that the patient does not continue to 
meet the criteria for PR.
DOR and ORR will be defined among responders (CR, CRi, PR); OS and PFS 
will also be determined.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Safety 
Assessments:
Safety will be assessed based on the evaluation of adverse events (AEs), 
serious AEs (SAEs), treatment discontinuations due to AEs, dose-limiting 
toxicities (DLTs), periodic 12-lead electrocardiogram (ECG) recordings, 
physical examinations, vital signs measurements, ECOG performance status, 
and hematology, coagulation panel, biochemistry, pregnancy (for women of 
child-bearing potential), and urinalysis test results obtained at various 
timepoints during the study. Adverse events will be graded according to 
CTCAE Version 4.0. 
Definition of DLT:
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 higher event of neutropenia or thrombocytopenia, or a Grade 4 
anemia, with a hypocellular bone marrow lasting for 6 weeks or more 
after the start of a cycle, in the absence of residual leukemia (i.e., with 
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<5% blasts). In case of a normocellular bone marrow with <5% blasts, 
8 weeks with ≥Grade 3 pancytopenia will be considered a DLT. 

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 grades of alopecia). 
o CTCAE Grade 3 or higher hypersensitivity reaction (regardless of 
premedication).
o CTCAE Grade 3 or higher skin ulceration. 
The protocol-defined DLT observation period for dose-escalation will be 
1 cycle. 
Note: Patients who experience a DLT during Cycle 1 are to be permanently 
discontinued from the study.
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 single-use, 
glass vials containing approximately 16 mg ADCT-402 per vial (deliverable 
volume 3.2 mL, with an additional 0.3 mL overfill at 5 mg/mL).
Patients will receive a 1-hour intravenous (IV) infusion of ADCT-402 on Day 1 
of Cycle 1. If ADCT-402 is well tolerated after the first infusion, the infusion 
duration may be shortened to 30 minutes for subsequent cycles for that patient, 
at the Investigator’s discretion.
Every 3-Week (Q3W) Administration 
Patients will be given ADCT-402 on Day 1 of each 3-week (21-day) treatment 
cycle.
Weekly (QW) Administration
Patients will be given ADCT-402 QW on Days 1, 8, and 15 of each 3-week 
(21-day) treatment cycle. 
A patient will maintain the same treatment schedule throughout the duration of 
the trial.
Once a patient achieves CR/CRi, frequency or dose may be adjusted by the 
DESC based on emerging safety, efficacy and PK profile.
The trial will be continuously monitored for emerging safety, efficacy and/or 
PK profile, and the DESC will determine if it is appropriate to maintain a QW 
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schedule, revert to an every 3-week (Q3W) schedule, or test other dosing 
regimens. 
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 600 µg/kg.
The DLT observation period for dose-escalation is 1 cycle. Patients will be 
entered sequentially to each dose level.
The first dose level for the QW dosing will be based on the safety and 
tolerability of patients who have been treated on the Q3W schedule. The first 
3 patients will be given a cumulative dose each cycle that is comparable to (but 
not higher than) the highest dose tested at the Q3W dosing schedule at which 
3 patients completed the DLT observation period without a DLT. For example, 
if the highest Q3W dose tested at which 3 patients did not experience a DLT 
was cohort 150 µg/kg, the first cohort to receive QW dosing will receive 
50 µg/kg each week for 3 weeks. 
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; therefore, is 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.
During Part 1, the DESC may expand enrollment at doses below the current 
dose level as part of the dose-escalation process. Additional patients may only 
be added at a lower dose level provided there is at least 1 patient who has 
achieved a PR (or better). 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, 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.
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Sample Size:
This is a Phase 1 study with a maximum sample size of approximately 
70 patients. It is estimated that Part 1 (dose-escalation) will enroll up to 
approximately 40 patients and Part 2 (dose expansion) will enroll up to 
approximately 30 patients.
Date of Protocol:
18 September 2015
Date of Protocol 
Amendment 1:
8 December 2015
Date of Protocol 
Amendment 2:
14 March 2016
Date of Protocol 
Amendment 3:
19 April 2017
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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
ALL
acute lymphoblastic leukemia
ALT
alanine aminotransferase
ANC
absolute neutrophil count
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
B-ALL
B-cell lineage acute lymphoblastic leukemia
β-HCG
beta human chorionic gonadotropin
BMA
bone marrow aspirate
BSA
body surface area
BSI
before start of infusion
CBC
complete blood count
CD
cluster of differentiation
CFR
Code of Federal Regulations
CL
clearance
Cmax
maximum concentration
CNS
central nervous system
CR
complete response
CRi
complete response with incomplete blood count recovery
CRO
contract research organization
CSF
cerebrospinal fluid
CTCAE
Common Terminology Criteria for Adverse Events
D5W
5% dextrose in water
DAR
drug-to-antibody ratio
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Abbreviation
Definition
DESC
Dose-Escalation Steering Committee
DLT
dose-limiting toxicity
DOR
duration of response
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
EWOC
escalation with overdose control
eCRF
electronic case report form
EOI
end of infusion
EOT
end of treatment
FDA
Food and Drug Administration
GCP
Good Clinical Practice
GLP
Good Laboratory Practice
HBsAg
hepatitis B surface antigen
HCV
hepatitis C virus
HIV
human immunodeficiency virus
HNSTD
highest non-severe toxic dose
ICF
informed consent form
ICH
International Conference on Harmonisation
IEC
independent ethics committee
INR
International Normalized Ratio
IP
investigational product
IRB
institutional review board
IV
intravenous
IVF
intravenous fluid
kDa
kilodalton
MNC
mononuclear cells
MRD
minimal residual disease
MRI
magnetic resonance imaging
MRT
mean residence time
MTD
maximum tolerated dose
NR
no response
ORR
overall response rate
OS
overall survival
PABA
para-aminobenzoic acid
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Abbreviation
Definition
PBD
pyrrolobenzodiazepine
PD
pharmacodynamics
PEG
polyethylene glycol
PFS
progression-free survival
PK
pharmacokinetic
PR
partial response
PT
prothrombin time
PTT
partial thromboplastin time
Q3W
every 3-week
QTc
corrected QT interval
QW
every week
QWBA
quantitative whole-body autoradiography
RBC
red blood cell
SAE
serious adverse event
SAP
statistical analysis plan
SUSAR
suspected unexpected serious adverse reactions
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
Vss
volume of distribution at steady-state
Val
valine
VZ
volume of distribution
WB
whole blood
WBC
white blood cell
WHO
World Health Organization
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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 anti-cancer 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 directed against human CD19; 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.
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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 
them hidden to repair mechanisms, allowing for a longer effective period (Adair, 2012) and 
making them effective in multiple cancer cell lines resistant to other chemotherapy. 
1.2 Study Rationale
Study ADCT-402-102 is the first clinical study with ADCT-402 in patients with B-cell lineage 
acute lymphoblastic leukemia (B-ALL).
1.2.1 Clinical Background
Acute lymphoblastic leukemia is a hematologic malignancy characterized by the clonal 
expansion of lymphoid blast cells (B- or T-cell lineage) in the peripheral blood, bone marrow, 
and/or other tissues. As per the US Surveillance Epidemiology and End Results (SEER)
statistical fact sheets, an estimated 6,250 new cases of ALL will be diagnosed in the U.S. in 2015 
(0.4% of all cancer cases). It is the most common leukemia diagnosed in children with more than 
half (58%) of all new cases occurring in patients younger than 20 years of age. The expected 
overall 5-year survival rate for ALL is approximately 68% (National Cancer Institute, 2015). 
Due to advances in therapy and supportive care, survival rates for ALL have been improving 
across all age groups. Children younger than 15 years have the best prognosis, with an expected 
5-year survival rate of 88%. However, survival rates for older patients have not improved to the 
same extent. The expected 5-year survival for adolescents and young adults (ages 15 to <20 
years) with ALL is approximately 61%, which decreases to approximately 40 to 45% for adults 
older than 40 years of age (National Cancer Institute, 2015).
Compared with children, ALL in older patients is more often associated with poor prognostic 
factors, including a higher relapse rate, cell markers associated with poor outcomes, 
low incidence of favorable subtypes, higher incidence of minimal residual disease (MRD), and 
poorer tolerance to induction therapy (Inaba, 2013; Moorman, 2007; Schafer and Hunger, 2011).
1.2.2 Biology of CD19 
Human CD19 is a 95 kilodalton (kDa) type I transmembrane glycoprotein belonging to the 
immunoglobin 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 it 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 
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extent observed with other CD antigens1 (Cooper et al, 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 hematologic malignancies of B-cell lineage (e.g., B-ALL, 
hairy cell leukemia, Burkitt’s lymphoma, follicular lymphoma, diffuse large B-cell lymphoma) 
(Anderson, 1984; Scheuermann and Racila, 1995; Wang, 2012). It is not expressed in most cases 
of chronic myelogenous leukemia, acute myelogenous leukemia, T-cell ALL, or multiple 
myeloma (Wang, 2012).
1.2.3 Non-clinical 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 
non-clinical safety assessment (Blanc, 2011). In the absence of CD19 target engagement in the 
rat and monkey, it is not possible to non-clinically 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 non-clinically with other B-cell deleting agents and been shown 
to be generally safe and well tolerated (Chen and Cohen, 2012; Kimby, 2005).
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
 
 
 
 
 
 
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 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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1.3 Safety 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 the maximum tolerated dose (MTD) of 
ADCT-402 in patients with relapsed or refractory B-ALL in Part 1. 

Determine the recommended dose of ADCT-402 for Part 2 (expansion).

Evaluate the safety and tolerability of ADCT-402 in Part 2 (expansion) at the dose level 
recommended in Part 1.
2.2 Secondary Objectives

Evaluate the clinical activity of ADCT-402, based on the patient’s response to treatment 
(complete response [CR], CR with incomplete blood count recovery [CRi], partial response 
[PR], progressive disease [PD], no response [NR]) and determination of the 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-ALL. The study will determine the MTD, as well as evaluate the preliminary activity, PK, 
pharmacodynamics (PD), and 
 for ADCT-402.
Patients will receive a 1-hour intravenous (IV) infusion of ADCT-402 on Day 1 of Cycle 1. If 
ADCT-402 is well tolerated after the first infusion, the infusion duration may be shortened to 
30 minutes for subsequent cycles for that patient, at the Investigator’s discretion. Weekly (QW)
administration will be evaluated as described in Section 3.2. Additional treatment schedules may 
be considered based on emerging data.
For each patient, the study will include a Screening period (up to 28 days), a treatment period 
(until withdrawal, Section 4.2.1), 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.
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 6.3.2). In 
Part 2, (expansion), all patients will be assigned to the dose level of ADCT-402 identified in 
Part 1.
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 anti-cancer 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 
600 µg/kg. The potential dose levels are described in Table 1 and Table 2.
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Table 1.
Planned Dose Levels for ADCT-402 (Q3W Administration)
Dose Level
Dose of ADCT-402
Dose Level
Dose of ADCT-402
1
2
3
15 µg/kg 
30 µg/kg
60 µg/kg
9
10
11
300 µg/kg
350 µg/kg
400 µg/kg
4
90 µg/kg
12
450 µg/kg 
5
120 µg/kg
13
500 µg/kg 
6
7
8
150 µg/kg
200 µg/kg
250 µg/kg
14
15
550 µg/kg 
600 µg/kg
Table 2.
Planned Dose Levels for ADCT-402 (QW Administration)
Dose Level
Dose of ADCT-402
Dose Level
Dose of ADCT-402
1
5 µg/kg 
7
75 µg/kg
2
10 µg/kg
8
100 µg/kg
3
20 µg/kg
9
125 µg/kg
4
5
6
30 µg/kg
40 µg/kg
50 µg/kg
10
11
12
150 µg/kg
175 µg/kg
200 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 adverse events (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; 
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therefore, is 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.
The number of dose levels will depend on the emergent toxicity profile of ADCT-402 and will 
be decided by the DESC (Section 6.3.2); PK, and PD evaluations may also inform decision 
making.
Every 3 Week (Q3W) Administration
Patients will be given ADCT-402 on Day 1 of each 3-week treatment cycle.
Weekly (QW) Administration
Patients will be given ADCT-402 QW on Days 1, 8 and 15 of each 3-week (21-day) treatment 
cycle.
The first dose level for the QW dosing will be based on the safety and tolerability of patients 
who have been treated on the every 3-week (Q3W) schedule. The first 3 patients will be given a 
cumulative dose each cycle that is comparable to (but not higher than) the highest dose tested at 
the Q3W dose schedule at which 3 patients completed the DLT observation period without a 
DLT. For example, if the highest Q3W dose tested at which 3 patients did not experience a DLT 
was cohort 150 µg/kg, the first cohort to receive QW dosing will receive 50 µg/kg each week for 
3 weeks. 
A patient will maintain the same treatment schedule throughout the duration of the trial.
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Weekly dosing will be implemented at the discretion of the DESC (and in accordance with local 
ethics committee approvals). Once a patient achieves CR/CRi, frequency or dose may be 
adjusted by the DESC based on emerging safety, efficacy and PK profile.
The trial will be continuously monitored for emerging safety, efficacy and/or PK profile and the 
DESC will determine if it is appropriate to maintain a QW schedule, revert to a Q3W schedule, 
or test other dosing regimens.
During Part 1, the DESC may expand enrollment at doses below the current dose level as part of 
the dose-escalation process. Additional patients may only be added at a lower dose level 
provided there is at least 1 patient who has achieved a PR (Section 6.1) or better. 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, 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 70 patients. It is estimated that Part 1 
(dose-escalation) will enroll approximately 40 patients at 10 sites and Part 2 (dose expansion) 
will enroll approximately 30 patients at 25 sites. Patients will be assigned to a study treatment 
only if they meet all of the inclusion criteria and none of the exclusion criteria.
3.3.1 Inclusion Criteria
1.
Male or female patients, ages 12 years and older, with relapsed or refractory B-ALL 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.
Note: Diagnosis and classification as per World Health Organization (WHO) classification of B-
ALL (Swerdlow, 2008).
2.
Eastern Cooperative Oncology Group (ECOG) performance status 0-2.
3.
Serum/plasma creatinine ≤1.5mg/dL. If the patient has a serum/plasma creatinine 
>1.5mg/dL, creatinine clearance must be >60 mL/min/1.73 m2, as calculated by the 
Cockcroft and Gault equation (Cockcroft and Gault, 1976). 
4.
Serum/plasma 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.
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5.
Total serum/plasma bilirubin ≤1.5 times ULN. Patients with known Gilbert’s syndrome 
may have a total bilirubin up to ≤3 times ULN).
6.
Negative urine or serum beta-human chorionic gonadotropin (β-HCG) pregnancy test 
within 7 days prior to the Cycle 1, Day 1 visit for women of child-bearing potential.
7.
Women of child-bearing 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 child-bearing 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.
* 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.
** Defined as: 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.
8.
WBC value of <15,000 cells/µL prior to Cycle 1 Day 1.
3.3.2 Exclusion Criteria
1.
Patients who, in the opinion of the Investigator, have an option for other treatment for B-
ALL at the current state of disease. 
2.
Known active central nervous system (CNS) leukemia, defined as morphologic evidence of 
lymphoblasts in the cerebrospinal fluid (CSF), use of CNS-directed intrathecal treatment 
for active disease within 28 days prior to Screening, or symptomatic CNS leukemia (i.e., 
cranial nerve palsies or other significant neurologic dysfunction) within 28 days prior to 
Screening. 
Note: Patients may have a history of CNS leukemic involvement if they have received prior 
treatment for CNS involvement and no evidence of active disease (defined as 
≥2 consecutive spinal fluid assessments with no evidence of disease) is present at 
Screening. Prophylactic intrathecal chemotherapy is not a criterion for exclusion.
3.
Patients with Burkitt’s leukemia/lymphoma.
4.
Active graft-versus-host disease.
5.
Autologous or allogenic transplant within the 60 days prior to the Screening visit.
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6.
Known history of immunogenicity or hypersensitivity to a CD19 antibody.
7.
Known history of positive serum human ADA.
8.
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).
9.
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).
10.
History of Stevens-Johnson syndrome or toxic epidermal necrolysis syndrome.
11.
Pregnant or breastfeeding women.
12.
Significant medical comorbidities, including uncontrolled hypertension (diastolic blood 
pressure >115 mm Hg), unstable angina, congestive heart failure (greater than New York 
Heart Association class II), severe uncontrolled ventricular arrhythmias, 
electrocardiographic evidence of acute ischemia, poorly controlled diabetes, severe chronic 
pulmonary disease, coronary angioplasty, myocardial infarction within 6 months prior to 
Screening, or uncontrolled atrial or ventricular cardiac arrhythmias.
13.
Use of any other experimental medication(s) within 14 days or 5 half-lives, but in no case 
<14 days prior to the start of study treatment on Cycle 1, Day 1, except if approved by the 
Sponsor.
14.
Major surgery, chemotherapy, systemic therapy (excluding 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. 
15.
Failure to recover (to [CTCAE Version 4.0] Grade 0 or Grade 1) from acute 
non-hematologic toxicity (except all grades of alopecia or Grade 2 or lower neuropathy), 
due to previous therapy, prior to Screening. 
16.
Isolated extramedullary relapse (i.e., testicular, CNS).
17.
Congenital long QT syndrome, or a corrected QTc interval of ≥450 ms, at the Screening
visit (unless secondary to pacemaker or bundle branch block).
18.
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 the Investigator agree and 
document should not be exclusionary.
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19.
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 – Every 3-Week (Q3W) Dosing Schedule 
The following procedures will be performed during the study. Regardless of dosing schedule, all 
patients will complete the same Screening procedures described in Section 4.1.1, as well as the 
same procedures described for End of Treatment (EOT; Section 4.1.8), 12-Week Follow-up Visit 
(Section 4.1.9) and Long-term Follow-up (Section 4.1.10).
Visit procedures described in Sections 4.1.2 - 4.1.7 are for patients on the Q3W dosing schedule. 
The Schedule of Events for the Q3W and QW dosing schedules are shown in Table 5 and 
Table 7, respectively, in Appendix 12.1.
 
For QW dosing, most assessments remain uniform, with the following exceptions:

Study Drug Administration occurs at Days 1, 8, and 15.

Note: Bone Marrow Aspirate (BMA) or Biopsy for QW patients is still performed within 
6 days prior to the first dose of the next cycle.

Pharmacokinetic and Pharmacodynamics, ADA, WBC population, and additional renal 
function studies sampling schedule is adjusted according to the prescribed dosing 
schedule. 
4.1.1 Screening 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) is to be obtained prior to performing any study 
evaluations. Results (clinical laboratory, 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, significant diagnoses, and all 
cancer treatment [including surgery, radiation therapy, chemotherapy, etc.]).

Serum or urine β-HCG pregnancy testing (women of child-bearing potential only).

Physical examination, including whole body skin assessment. 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.
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
Vital signs (arterial blood pressure, heart rate, respiratory rate, body temperature).

Height.

Weight.

ECOG performance status.

Bone marrow samples:
o
Bone marrow aspirate (or biopsy if aspirate is unattainable) for confirmation of disease,
as per the WHO classification of ALL (Swerdlow, 2008), at an approved local clinical
laboratory.

Mononuclear cell (MNC) samples:
o
Whole blood (WB) sample collection with subsequent MNC isolation for retrospective
central laboratory evaluation of CD19 and other CD markers (e.g., CD20, CD21, CD22).
o

Hematology, coagulation panel, biochemistry, and urinalysis parameters.

Patients with a WBC value >15,000 cells/μL may receive cytoreduction treatment with
steroids (up to 4 days) or hydroxyurea, and/or leukopheresis, to lower the WBC value to
<15,000 cells/μL prior to Cycle 1, Day 1 dosing (Section 5.3). Hydroxyurea may be used
during Cycle 1 to control WBC count at Investigator discretion.
Note: Patients are not to receive treatment with study drug until their WBC value is
≤15,000 cells/μL.

12-lead electrocardiogram (ECG).

Collection of 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.
4.1.2 Day 1 (+ 3 days) of Each Cycle 
Day 1 of each cycle occurs on infusion day. The following procedures will be performed prior to 
ADCT-402 infusion (unless otherwise indicated) at each cycle. 

Serum or urine β-HCG pregnancy test (women of child-bearing potential, Cycle 1 only)
required if the screening pregnancy test was obtained >7 days prior to Day 1.

Physical examination, including whole body skin assessment, unless an assessment was
performed within 3 days prior to Day 1.
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
Vital signs: On Day 1 of Cycles 1 and 2, vital signs are to be measured before the start of 
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 the
Cycles 1 and 2, vital sign measurements are to be obtained prior to the start of and at the end 
of ADCT-402 infusion for all subsequent cycles. 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, unless an assessment was performed within 3 days prior to Day 1.

ECOG performance status.

Hematology, coagulation panel, and 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.

Sample collection for
o
Additional renal function studies
o
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.

12-lead ECG (Cycles 1 and 2) before the start of the ADCT-402 infusion, within 30 minutes 
of the end of infusion, and 3 hours (± 30 minutes) and 24 (± 2.4) hours after the end of 
infusion (Table 5 and Table 7 in Appendix 12.1). 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.

Whole blood sample collection for central laboratory analysis of peripheral WBC populations 
and evaluation of CD19 and other CD markers (e.g., CD20, CD21, CD22) before the start of,
and 3 hours after, ADCT-402 infusion on Day 1 (Cycles 1 and 2). 
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
MNC samples:
o
 
 
 

Urine sample collection for central laboratory assessment of additional renal function studies.

Collection of AE information. 

Collection of concomitant medication information. 

Premedication administration, if applicable (Section 5.2). 

ADCT-402 administration.
4.1.2.1
Bone Marrow Sample
Within 6 days prior to Day 1 of Cycle 3, a bone marrow sample (aspirate or biopsy if aspirate 
unattainable) will be obtained for assessment of response to treatment and determination of 
MRD (via flow cytometry) by an approved clinical laboratory. Results must be available to the 
Investigator before the next dose of study drug is administered.
A bone marrow sample will then be obtained within 6 days prior to the Day 1 visit of Cycle 5 
and at each subsequent cycle until CR or CRi (Section 6.1) is achieved or until disease 
progression. Once CR/CRi is achieved, sampling will be repeated at least every 3 cycles, or as 
clinically indicated.
A bone marrow sample will also be collected at the EOT visit (Section 4.1.8) for those patients 
who have not demonstrated disease progression and if their most recent sample was obtained 
more than 12 (± 1) weeks prior to the EOT visit.
Bone marrow aspirate sample collection with subsequent MNC isolation should follow the same 
collection schedule as above. Mononuclear cells from BMA will be used for retrospective central 
laboratory evaluation of CD19 and other CD markers (e.g., CD20, CD21, CD22). 
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Samples obtained during treatment and at the EOT visit are to be saved for biobanking (see 
Laboratory Manual). Additionally, when available, results from other analyses conducted as part 
of the institution’s standard of care will also be collected.
4.1.3 Day 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.
4.1.4 Day 3 (Cycles 1 and 2)
The following procedures will be performed 48 hours (±10%) after the end of infusion:

Vital signs.

Sample collection for central laboratory analysis of PK parameters.

Collection of AE information.

Collection of concomitant medication information.
4.1.5 Day 5 (Cycles 1 and 2)
The following procedures will be performed 96 hours (±1 day) after the end of infusion:

Sample collection for central laboratory analysis of PK parameters.

Vital signs.

Collection of AE information.

Collection of concomitant medication information.
4.1.6 Day 8 (± 2 days) of Each Cycle 
The following procedures will be performed at this visit:

Physical examination including whole body skin assessment (Cycles 1 and 2). 

Weight (Cycles 1 and 2).

Vital signs.

Hematology and biochemistry parameters.

Urinalysis. 

Urine sample collection for central laboratory assessment of additional renal function studies.

Sample collection for central laboratory analysis of PK parameters (Cycles 1 and 2).
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
Collection of AE information.

Collection of concomitant medication information.
4.1.7 Day 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.

Urine sample collection for central laboratory assessment of additional renal function studies.

Sample collection for central laboratory analysis of PK.

Collection of AE information.

Collection of concomitant medication information.
4.1.8 End of Treatment Visit
The following procedures will be performed within 30 days (+ 7 days) after study treatment 
discontinuation:

Serum or urine pregnancy test.

Physical examination including whole body skin assessment. 

Weight and vital signs.

ECOG performance status.

Hematology, coagulation panel, and biochemistry parameters.

Urinalysis and sample collection for assessment of additional renal function studies.

12-lead ECG.

Sample collection for central laboratory assessment of PK and ADA. 

Whole blood sample collection for central laboratory analysis of peripheral WBC populations
and evaluation of CD19 and other CD markers (e.g., CD20, CD21, CD22).

MNC) samples:
o
Whole blood (WB) sample collection with subsequent MNC isolation for retrospective 
central laboratory evaluation of CD19 and other CD markers (e.g., CD20, CD21, CD22).
o
 
 
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
Collection of AE information.

Collection of concomitant medication information.

Bone marrow sample for disease assessment (see Section 4.1.2.1).
4.1.9 12-week Follow-up Visit
Each patient will have a sample taken for assessment of PK and ADA at 12 (±1) weeks after their 
last dose of ADCT-402.
Blood Sample Collection and Adverse Event Monitoring During Long-Term Follow-up
For all patients, a PK and ADA blood sample collection will be performed 12 weeks (± 1 week) 
following the last dose of ADCT-402.
For all patients, collection of AEs and SAEs will continue for up to 84 days (12 weeks) after the 
last dose of study drug or initiation of new anti-cancer treatment (see Section 6.3.3.2). 
4.1.10Long-term Follow-up
Patients who discontinue treatment for any reason other than disease progression will continue to 
be followed by telephone contact approximately every 12 weeks from the last disease assessment 
until disease progression, or initiation of new anti-cancer 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.
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.
4.2.1 Reasons 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.
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
Withdrawal of consent.

Major protocol deviation.

Required treatment delay of >21 days (except in case of potential patient benefit, which must 
be approved by the Sponsor).

Non-compliance, including lost to follow-up.

Pregnancy.

Other (e.g., development of contraindications).

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.

Death.
Patients who experience the following significant toxicities will be immediately and permanently 
withdrawn from treatment with ADCT-402:

Any patient who experiences a Grade 3 or higher hypersensitivity reaction (Appendix 12.2), 
regardless of premedication, during any cycle of treatment 

Any patient who experiences a protocol-defined DLT beyond Cycle 1 (except in the case of 
potential patient benefit, which must be approved by the Sponsor).

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).
4.2.2 Handling 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 6.3.3.6).
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For each patient who is withdrawn from treatment with ADCT-402 and withdraws from the 
study, the Investigator will record the reason(s) for discontinuation on the relevant page of the 
eCRF. Whenever possible, each patient who discontinues study treatment will undergo an EOT 
visit and all EOT assessments (Section 4.1.8). 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 withdrawn from the study, for any reason, patients are not permitted to be
re-enrolled into the study.
4.2.3 Patient 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
In Part 1 (dose-escalation), patients will receive an IV infusion of ADCT-402, according to their 
assigned schedule. 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. Patients will be 
entered sequentially to each dose level. The dose-escalation procedure is described in 
Section 3.2. If the highest allowed dose (600 μg/kg) is reached and the MTD is not identified, no 
further dose-escalation will be allowed, pending a safety analysis and accordingly, an 
amendment to the protocol
In Part 2 (expansion), all patients will be assigned to the dose level of ADCT-402 identified in 
Part 1 by the DESC. Once the recommended Part 2 dose is determined, patients receiving lower 
dose levels of ADCT-402 may be offered continued treatment at the recommended dose.
5.2 Prophylactic Treatments for Hypersensitivity
If 1 patient experiences a Grade 2 or higher infusion-related hypersensitivity reaction
(Appendix 12.2) 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, 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.
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Any patient who experiences a Grade 3 or higher hypersensitivity reaction (Appendix 12.2)
should be withdrawn from treatment with ADCT-402 and immediately treated according to 
institutional 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 as described in Section 3.2. 
In Part 2 (expansion), all patients will be assigned to the dose level identified in Part 1 by the 
DESC.
ADCT-402 will be administered on investigational product (IP) administration day of each cycle 
as a 1-hour IV infusion. If ADCT-402 is well tolerated after the first infusion, the infusion 
duration may be shortened to 30 minutes for subsequent infusions, 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.
Because of non-clinical observations related to nephropathy and adrenal gland changes, adequate 
patient hydration (e.g., 8 to 10 glasses of water or equivalent per day) is recommended for 
patients receiving ADCT-402.
New or worsening edema and / or new or worsening pleural effusion have been observed. 
Therefore patients are advised to monitor their weight on a daily basis (Sections 5.9.2 and 6.3.8).
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 
the lack of any signals in the rat and monkey toxicology studies with ADCT-402 and the 
 
 
However, skin rash has been reported in another program conducted by this Sponsor, 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.
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5.4 Dose Delays and Modifications
Patients will receive the first 2 cycles of ADCT-402, irrespective of blood count recovery. For 
patients achieving a CR/CRi, the subsequent cycle would be delayed until peripheral blood count 
recovery (absolute neutrophil count [ANC] >500 x109/L and/or platelets >50 x109/L).
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 Investigator, 
have their dose reduced by 1 dose level. If toxicity recurs at a severity that would mandate a dose 
delay, then the dose may be further reduced 1 dose level. If toxicity recurs at such level, then the 
patient is to be discontinued from treatment. Dose re-escalation is allowed at the Investigator’s 
discretion, at maximum to the dose level the patient was initially assigned to.
Dose frequency may be adjusted according to individual patient response as described in 
Section 3.2.
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 at a deliverable volume of 3.2 mL (with an 
additional 0.3 mL overfill) at 5 mg/mL (equivalent to 16 mg ADCT-402)
5.5.1 ADCT-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 single-use, glass vials 
containing approximately 16 mg ADCT-402 per vial (deliverable volume 3.2 mL, with an 
additional 0.3 mL overfill, at 5 mg/mL).
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5.6 Management of Clinical Supplies
5.6.1 Study Drug Packaging and Storage
ADCT-402 will be supplied in a labeled 10-mL stoppered glass vial and shipped to the
investigational site. Once the package arrives, the receiving site pharmacy will complete the 
enclosed forms 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. 
5.6.2 Study 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). 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 (IVF) 
administration. 
Additional instructions regarding study drug handling, storage, and preparation are included in 
the pharmacy manual.
5.6.3 Study 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 effects and whether effects of an 
overdose can be reversed. Symptomatic treatment and standard supportive care measures for the 
management of this 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. 
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5.9 Concomitant Treatment
All medications used within 14 days prior to the Day 1 visit and during the treatment period are
to be recorded in the eCRF. Concomitant medication information will be collected for 30 days 
following the patient’s last dose of ADCT-402.  This will include all prescription drugs, herbal 
products, vitamins, minerals, and over-the-counter medications. Any changes in concomitant 
medications will also be recorded in the patient’s eCRF.
5.9.1 Prohibited During Study

Other anti-cancer therapy, with the exception of hormonal therapy for maintenance treatment 
of breast and prostate cancer.

Hydroxyurea is not permitted after Cycle 1 unless approved by the Sponsor.

Other investigational agents.

Chronic treatment with corticosteroids (prednisone ≥12.5 mg/day or dexamethasone
≥2 mg/day, excluding inhaled steroids).

Live vaccines.
5.9.2 Permitted 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 the American Society of Clinical Oncology guidelines (Smith, 2006); however, 
prophylactic use of growth factors is not allowed during the first treatment cycle.
Patients with a WBC value >15,000 cells/μL may receive cytoreduction treatment with steroids 
(up to 4 days) or hydroxyurea prior to and during the first cycle of treatment, and/or 
leukopheresis, to lower the WBC value to <15,000 cells/μL prior to Cycle 1, Day 1 dosing. 
Note: Patients are not to receive treatment with study drug until their WBC value is 
≤15,000 cells/μL.
If a Grade 2 or higher infusion-related hypersensitivity 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).

Intrathecal medication for CNS prophylaxis (not for active disease) per institutional standard 
of care practices.

Prophylactic treatment with dexamethasone as follows may be instituted by the DESC based 
on emerging safety and PK profile:
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o
Dexamethasone 4 mg oral BID the day before investigational product (IP) administration, 
the day of IP administration, and the day after IP administration (Week 1/Day 1 of each cycle 
only, regardless of treatment schedule).
o
A 2-day course of dexamethasone 4 mg PO BID will be given (Week 1/Days 1 and 2 of 
each cycle). If possible, the first dose should be given at least 2 hours prior to IP 
administration. Any concomitant medication deemed necessary for the welfare of the patient 
during the study may be given at the discretion of the Investigator.

Spironolactone, at standard doses, may be instituted at any time for patients with weight gain 
greater than 1 kg (2.2 lbs) 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 Section 4.1 and the Schedule 
of Procedures and Central Laboratory Sample Collection for the Q3W and QW dosing schedules 
(Table 5 through Table 9) in Appendix 12.1.
6.1 Efficacy Assessments
Assessment of response to treatment with ADCT-402 will be based on bone marrow samples
(aspirate, or biopsy if aspirate unattainable). Bone marrow samples will be obtained as described 
in Section 4.1.2.1. 
The activity of ADCT-402 will be evaluated based on the Investigator’s evaluation of the 
patient’s response to ADCT-402 as CR, CRi, PR, PD, or NR (Cheson, 2003; Döhner, 2010).

Complete response is defined as achieving each of the following:
o
Bone marrow differential showing ≤5% blast cells,
o
Absolute neutrophil count ≥1.0 x 109/L and platelet count ≥100 x 109/L,
o
Absence of extra-medullary disease,
o
Patient is independent of red blood cell (RBC) transfusions.

Complete response with incomplete blood count recovery is defined as achieving all 
CR criteria except that values for ANC may be <1.0 x 109/L and/or values for platelets may 
be <100 x 109/L.

Partial response is defined as achieving each of the following:
o
ANC ≥1.0 x 109/L and platelet count ≥100 x 109/L,
o
Bone marrow differential showing a ≥50% decrease from baseline in the percentage of 
bone marrow blast cells to a level >5% and ≤25%.

No response is defined as not achieving CR, CRi, or PR.

PD is defined as:
o
For patients with CR or CRi, the first date of reappearance of blast cells in bone marrow 
and/or peripheral blood to a level ≥5%, or development of extramedullary disease.
o
For patients with PR, the first date of an increase in blast cells in bone marrow and/or 
peripheral blood such that the patient does not continue to meet the criteria for PR.
As defined in Section 7.6.2, DOR and ORR will be defined among responders (CR, CRi, PR); 
OS and PFS will also be determined.
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6.2.1 Pharmacokinetic 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 in Cycles 1 and 2. Additional 
PK and ADA 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 the 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). 
6.2.2 Pharmacodynamic and Other Assessments
The following assessments will be performed at varying time points in the study:

Flow cytometric assessment of CD19 and other CD marker expression in MNCs isolated 
from BMA and WB, tested retrospectively by a central laboratory in samples collected before 
treatment with ADCT-402.

Level of ADAs against ADCT-402 in serum before, during, and after treatment with 
ADCT-402.

Analysis of peripheral WBC populations and CD marker panel expression (e.g., CD19, 
CD20, CD21 and CD22) before, during, and after treatment with ADCT-402 (Cycles 1 and 2)
by flow cytometry in WB.

Serum concentrations of ADCT-402 and free warhead SG3199, QTc interval.

Evaluation of MRD, by flow cytometry in bone marrow.
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6.3 Safety and Tolerability Assessments
Safety will be assessed based on AEs, serious AEs (SAEs), treatment discontinuation due to 
AEs, DLTs, periodic 12-lead ECG recordings, physical examinations, vital signs measurements, 
ECOG performance status, and hematology, coagulation panel, biochemistry, pregnancy (for 
women of child-bearing potential), and urinalysis test results. Adverse events will be graded 
according to CTCAE Version 4.0. The Schedule of Events for the Q3W and QW dosing 
schedules are shown in Table 5 and Table 7, respectively, in Appendix 12.1.
6.3.1 Definition 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 higher event of neutropenia or thrombocytopenia, or a Grade 4 anemia, with a 
hypocellular bone marrow lasting for 6 weeks or more after the start of a cycle, in the 
absence of residual leukemia (i.e., with <5% blasts). In case of a normocellular bone 
marrow with <5% blasts, 8 weeks with ≥Grade 3 pancytopenia will be considered a DLT. 

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 grades of alopecia). 
o
CTCAE Grade 3 or higher hypersensitivity reaction (regardless of premedication).
o
CTCAE Grade 3 or higher skin ulceration. 
The DLT observation period for dose-escalation will be 1 cycle. 
Note: Patients who experience a DLT during Cycle 1 are to be permanently discontinued from 
the study.
6.3.2 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.)
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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.

Determine if it is appropriate to maintain a QW schedule, revert to a Q3W schedule, or test 
other dosing regimens. 
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. 
6.3.3 Adverse Events
6.3.3.1
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 assignment to the treatment group 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.
An 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 
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or convulsions that do not result in inpatient hospitalization, or the development of drug 
dependency or drug abuse.
6.3.3.2
Eliciting and Documenting Adverse Events
Adverse events will be assessed from the time the patient signs the ICF up to 84 days (12 weeks)
days after the last dose of study drug or initiation of new anti-cancer treatment.
Any SAEs that occur > 84 days (12 weeks) after the last dose of study drug do not need to be 
reported unless the Investigator considers them to be related to study drug.
At every study visit, patients will be asked a standard non-leading 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, 
ECG changes, etc.) or identified from review of other documents that are relevant to patient
safety.
6.3.3.3
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. CTCAE Version 4.0 will be used to grade all AEs (Section 6.3.3.4). 
Any AE that meets SAE criteria (Section 6.3.3.1) 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:
Pharmacovigilance Department 
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6.3.3.4
Assessment of Severity
Adverse events will be 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 3.
Table 3. 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 non-invasive 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.
6.3.3.5
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 AEs, 
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).
6.3.3.6
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.
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6.3.4 Pregnancy
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 6.3.3.3, 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 
withdrawn from the study. The outcome of the pregnancy will be reported on the Pregnancy 
Outcome Form. Spontaneous miscarriages must be reported as an SAE.
Any SAE occurring in association with a pregnancy 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 6.3.3.3).
6.3.5 Clinical Laboratory Analyses
Samples will be collected at the time points specified in the Schedule of Events for the Q3W and 
QW dosing schedules (Table 5 and Table 7, respectively) Appendix 12.1. 
Any clinically significant abnormal laboratory test results are to be recorded as AEs or SAEs, per 
CTCAE Version 4.0.
6.3.5.1
Hematology
The complete blood count (CBC) includes WBC with a 5-part differential, platelet count, 
hemoglobin, hematocrit, and ANC. Peripheral blasts will be included in the hematology analysis 
for Part 2 only. If the WBC value is <400 x 106/L, a differential is not required. 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. 
6.3.5.2
Biochemistry
Tests for clinical biochemistry include 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).
6.3.5.3
Urinalysis
Urinalysis analytes will include pH, specific gravity, protein, glucose, ketones, bilirubin, nitrites 
and occult blood. The urinalysis may be performed using a urine dipstick.
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6.3.5.4
Additional Renal Function Studies
Urine will be collected for central laboratory 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 the Laboratory Manual).
6.3.6 Electrocardiograms
A 12-lead ECG is to be performed at the time points identified in the Schedule of Events for the 
Q3W and QW dosing schedules (Table 5 and Table 7, respectively) 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.
Measurement of the QTc interval may be obtained according to the formula used by the 
institution, however, the Fridericia formula is preferred (Fridericia, 1920). The same formula 
used to confirm eligibility must be applied within a patient for the duration of the study.
6.3.7 Physical 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 is to 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.
6.3.8 Vital Sign Measurements
Vital signs 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.
6.3.9 Weight
If possible, patients are advised to monitor their weight daily starting Cycle 1 Day 1 and inform 
their investigator if their weight increase more than 1 kg (2.2 lbs) from Cycle 1 Day 1.
6.3.10Eastern Cooperative Oncology Group Performance Status
The patient’s performance status will be assessed according to the time points in the Schedule of 
Events for the Q3W and QW dosing schedules (Table 5 and Table 7, respectively) in 
Appendix 12.1 using ECOG performance status grades (Table 4; Oken, 1982).
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Table 4. 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 central laboratory sample collection, labeling, processing, storage, and 
shipping will be provided to the site in the Laboratory Manual. 
Samples will be collected for PK, ADA, peripheral WBC population, CD marker expression,and 
additional renal function studiesFor PK and ADA, WB is to be collected with subsequent serum 
isolation. Serum samples should be aliquoted and transferred as frozen (–20°C or below, -70°C
preferred), according to the Laboratory Manual. 
 
For the analysis of peripheral WBC populations and cell surface markers, WB is to be collected 
and shipped (ambient), as per the Laboratory Manual, directly to the selected vendor for 
immediate processing.
 
 
 
Each sample tube should be clearly labeled with : 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, pregnancy (for 
women of child-bearing potential), and urinalysis test results.
7.2 Endpoints
7.2.1 Primary 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 7.6.1).
7.2.2 Secondary Endpoints

Determination of ORR, DOR, 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).
 
7.3 Sample Size Calculations
This is a Phase I study with a maximum total sample size of 70 patients. It is expected that Part 1 
will enroll up to 40 patients and Part 2 will enroll up to 30 patients. Patients will be enrolled in 
Part 2 of the study in cohorts of approximately 10. Based on a true AE rate of 15%, there is 80% 
confidence that one AE will be observed for the 10 patients enrolled. The DESC will make 
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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
Six 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 from the study drug during Cycle 1 without 
experiencing a DLT.

The Efficacy analysis set will consist of 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.

The PK analysis set will consist of all patients who receive study drug and have sufficient
concentration data for PK analysis.

The PD analysis set will consist of all patients who receive study drug and have sufficient 
data available for analysis.
 
7.5 Description of Subgroups to be Analyzed
Subgroup analyses, if planned, will be described in the SAP.
7.6 Statistical Analysis Methodology
7.6.1 Safety 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 the patient’s first 
study medication dose date and before the last dose date up to 84 days (12 weeks). Planned 
summaries of TEAEs will be detailed in the SAP 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.
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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 cytokine levels, 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.
7.6.2 Efficacy Analysis
Determination of DOR and ORR will be based on the Investigator’s evaluation of the patient’s 
response to ADCT-402 (Section 6.1). Overall survival and PFS will also be determined.
7.6.2.1
Overall Response Rate
The ORR will be defined as the proportion of patients with a best overall response of CR, CRi or 
PR at the time each patient discontinues treatment with 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, CRi, 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 is defined for patients with CR or CRi as the first date of 
reappearance of blast cells in bone marrow to a level ≥5%, or development of extramedullary 
disease. In patients with PR, this is defined as the first date of an increase in blast cells in bone 
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marrow such that the patient does not continue to meet the criteria for PR (Section 6.1). 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 DOR 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 first dose of study drug treatment until the 
date of 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. 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.
7.6.3 Pharmacokinetic and Pharmacodynamic Analyses
Pharmacokinetic endpoints (Section 6.2) for RB4v1.2, PBD-conjugated RB4v1.2, and free 
warhead SG3199 will be calculated for all patients using non-compartmental analysis. Data for 
PK will be summarized in tables and individual data will be listed.
 
 
 
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7.6.4 Study 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.
7.7.1 Data 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).
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 
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Regulatory Activities Version 18.0. Concomitant medications will be coded using WHO Drug
Dictionary 01 June 2015.
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 Conference on Harmonisation (ICH) guidelines require 
that approval be obtained from an IRB/IEC before participation of human patients in research 
studies. Before study onset, the protocol, informed consent, advertisements to be used for the 
recruitment of study patients, and any other written information regarding this study 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 ICH harmonised
tripartite guideline E6(R1): 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 ICF, in compliance with US Title 21 Code of Federal Regulations (CFR) Part 50, 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 study 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 active participating patients must sign the 
revised form.
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 
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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, regulatory authorities (e.g., 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. 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 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 ICH E6(R1) 8.2 and 
Title 21 of the CFR 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 
ICH E6(R1). 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 ICH 
E6(R1) 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.
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 IP. These documents should be retained for a longer period, 
however, if required by the applicable regulatory requirements or by an agreement with the 
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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
10.1.1 Monitoring 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.
10.1.2 Inspection 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
10.2.1 Modification 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 a 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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10.2.2 Protocol 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 EOT visit 
to the study site.
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
Adair JR, Howard PW, Hartley JA, Williams DG, and Chester KA (2012). Antibody-drug 
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.
Blanc V, Bousseau A, Caron A, Carrez C, Lutz RJ, and Lambert JM (2011). SAR3419: an anti-
CD19-maytansinoid immunoconjugate for the treatment of B-cell malignancies. Clin Cancer Res 
17(20):6448-6458.
Carter RH and Barrington RA (2004). Signaling by the CD19/CD21 complex on B cells. Curr 
Dir Autoimmun. 7:4–32.
Chen DR and Cohen PL (2012). Living life without B cells: is repeated B-cell depletion a safe 
and effective long-term treatment plan for rheumatoid arthritis? Int J Clin Rheumtol 7(2): 159-
166.
Cheson BD, Bennett JM, Kopecky KJ, Buchner T, Willman CL, Estey EH, et al, (2003). Revised 
recommendations of the international working group for diagnosis, standardization of response 
criteria, treatment outcomes, and reporting standards for therapeutic trials in acute myeloid 
leukemia. Clin Oncol 21:4642-4649.
Cockcroft DW and Gault MH (1976). Prediction of creatinine clearance from serum creatinine. 
Nephron 16(1):31-41.
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.
Döhner H, EH Estey, S Amadori, FR Appelbaum, T Büchner, AK Burnett, et al, (2010). 
Diagnosis and management of acute myeloid leukemia in adults:  recommendations from an 
international expert panel, on behalf of the European LeukemiaNet. Blood 115(3):453-474. 
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.
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.
Haas KM and Tedder TF, (2005). Role of the CD19 and CD21/35 receptor complex in innate 
immunity, host defense and autoimmunity. Adv Exp Med Biol.;560:125–139.
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Hartley JA (2011a). The development of pyrrolobenzodiazepines as antitumour agents. Expert 
Opin Investig Drugs 20(6): 733-744.
Inaba H, Greaves M, and Mullighan CG (2013). Acute lymphoblastic leukaemia. Lancet June 1; 
381(9881): doi:10.1016/S0140-6736(12)62187-4.
Jabbour E, O’Brien S, Ravandi F, and Kantarjian H (2015). Monoclonal antibodies in acute 
lymphoblastic leukemia. Blood 125(26):4010-4015.
Kimby E (2005). Tolerability and safety of rituximab (MabThera). Cancer Treat Rev 31(6):456-
473.
Moorman AV, Harrison CJ, Buck GA, Richards SM, Secker-Walker LM, Martineau M, et al, 
(2007). Karyotype is an independent prognostic factor in adult acute lymphoblastic leukemia 
(ALL): analysis of cytogenetic data from patients treated on the Medical Research Council 
(MRC) UKALLXII/Eastern Cooperative Oncology Group (ECOG) 2993 trial. Blood Apr 
15;109(8):3189-97. Epub 2006 Dec 14.
Muniz C, Martin-Martin L, Lopez A, Sanchez-Gonzalez B, Salar A, Almeida J, et al (2014). 
Contribution of cerebrospinal fluid sCD19 levels to the detection of CNS lymphoma and its 
impact on disease outcome. Blood 123(12): 1864-1869.
National Cancer Institute (2015). SEER Cancer Statistics Factsheets: Acute Lymphocytic 
Leukemia (ALL) 2015. Accessed on 1 July 2015, at 
http://seer.cancer.gov/statfacts/html/alyl.html.
Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, and Carbone PP (1982). 
Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol
5(6):649-55.
Roguska MA, Pedersen JT, Henry AH, Searle SM, Roja CM, Avery B, et al, (1996). A 
comparison of two murine monoclonal antibodies humanized by CDR-grafting and variable 
domain resurfacing. Protein Eng 9(10): 895-904.
Rudin CM, Pietanza MC, Bauer TM, Spigel DR, Ready N, Morgansztern D, et al. Safety and 
efficacy of single-agent rovolpituzumab tesirine (SC16LD6.5), a delta-like protein 3 (DLL3)-
targeted antibody-drug conjugate (ADC) in recurrent or refractory small cell lung cancer 
(SCLC). J Clin Oncol 34 (2016) (suppl: abstr LBA8505).
Schafer ES and Hunger SP, (2011). Optimal therapy for acute lymphoblastic leukemia in 
adolescents and young adults. Nat Rev Clin Oncol 8:417-24, published online 31 May 2011; 
doi:10.1038/nrclinonc.2011.77
Scheuermann RH and Racila E (1995). CD19 antigen in leukemia and lymphoma diagnosis and
immunotherapy. Leuk Lymphoma 18(5-6): 385-397.
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2006 Update of recommendations for the use of white blood cell growth factors: an evidence-
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Swerdlow SH, Campo E, Harris NL, et al, eds. (2008) WHO Classification of Tumours of 
Haematopoietic and Lymphoid Tissues. Lyon, France: IARC.
Tedder TF (2009). CD19: a promising B cell target for rheumatoid arthritis . Nat. Rev. 
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diagnosis and therapy. Exp Hematol Oncol 1(1): 36.
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12 Appendices
12.1 Appendix: Schedule of Events 
The Schedule of Events for the Q3W and QW dosing schedules are shown in (Table 5 and 
Table 7, respectively) of this appendix. Timings for sample collections for assessment of PK,
PD, and other parameters for the Q3W dosing schedule are shown in Table 6, and for the QW 
dosing schedule in Table 8 and Table 9.
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Table 5.
Schedule of Study Procedures: Every 3-Week (Q3W) Dosing 
Procedure
Screening
D-28 to -1
Cycle 1
Cycle 2
Cycle 3
until PD/DC
EOT
30
(+7)days3
12 Week 
Follow 
Up Visit
(±1) week4
Follow-
Up
12 (± 1) 
week
D1
D21
D3&52
D8
D15
D1
D21
D3&52
D8
D15
D1
D8
±3d
±2d
±2d
±3d
±2d
±2d
±3d
±2d
Informed consent
X
Demography
X
Medical history5
X
Serum or urine β-HCG 
pregnancy test
X
X6
X
Physical examination7
X
X
X
X
X
X
X
X
X
Vital signs8
X
X9
X
X
X
X
X9
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
Bone marrow 
aspirate/biopsy10
X
X11
X12
Hematology13
X
X14
X
X
X14
X
X
X14
X
X
Coagulation Panel15
X
X14
X14
X14
X
Biochemistry16
X
X14
X
X
X14
X
X
X14
X
X
Urinalysis17
X
X14
X
X
X14
X
X
X14
X
X
12-lead ECG
X
X18
X
X18
X
X19
X
Concomitant 
Medications20
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Premedication21
X
X
X
ADCT-402 
Administration22
X
X
X
Adverse events 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X23
Survival information
X24
X24
New anti-cancer 
treatment information
X25
X25
Abbreviations: D = Day(s); d = day(s); DC = discontinue; PD, progressive disease; ECG, electrocardiogram; ECOG, Eastern Cooperative Oncology Group;
EOT, end of treatment visit; β-HCG, beta-human chorionic gonadotropin.
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Refer to Table 6 for Central Lab Sample Collection Schedule. 
1.
Day 2 to occur 24 hours (±10%) after EOI.
2.
Day 3 to occur 48 hours (± 10%) after EOI. Day 5 to occur 96 (± 24) hours after EOI. 
3.
After last dose of ADCT-402. EOT window is + 7 days.
4.
Follow-up to occur 12 (± 1) week after last dose of ADCT-402. 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 anti-cancer 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.
5.
Medical history: To include a complete history of all surgeries, significant diagnoses, cancer history, immunophenotyping and all cancer treatments.
6.
Serum or urine pregnancy test: For women of child-bearing potential. Not required if negative screening β-HCG pregnancy test was obtained within 7 days 
prior to Cycle 1, Day 1.
7.
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 repeated on Day 1, 
if last performed within 3 days prior to dosing with ADCT-402.
8.
Vital signs to include arterial blood pressure, heart rate, respiratory rate, and body temperature. 
9.
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 the 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. Note: Timing of 
measurements is approximately ±15 minutes.
10. A bone marrow sample, via aspirate or biopsy if an aspirate is unattainable, will be obtained at Screening for confirmation of disease (as per WHO 
classification of ALL [Swerdlow, 2008]), at an approved clinical laboratory. 
11. A bone marrow sample will be obtained within 6 days prior to the Day 1 visit of Cycles 3 and 5 and at each subsequent cycle until CR or CRi is achieved or 
until disease progression. Assessment of response to treatment and determination of MRD (via flow cytometry) are to be done by an approved clinical 
laboratory. Results must be available to the Investigator before the next dose of study drug is administered. Once CR/CRi is achieved, sampling will be 
repeated at least every 3 cycles, or, as clinically indicated.
12. A bone marrow sample will be obtained at the EOT visit for those patients who have not demonstrated disease progression and if their most recent sample 
was obtained more than 12 (± 1) weeks prior to the EOT visit.
13. Hematology: CBC to include WBC with a 5-part differential, platelet count, hemoglobin, hematocrit, and ANC. Peripheral blasts will be included in the 
hematology analysis for Part 2 only. If WBC is < 400 x 106/L differential is not required.
14. Samples for hematology, coagulation panel, biochemistry, and urinalysis will be collected prior to dosing unless the last sample was 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.
15. Coagulation panel: PTT and INR; PT expressed in seconds is optional. 
16. Biochemistry: 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]).
17. Urinalysis to include: pH, specific gravity, protein, glucose, ketones, nitrites, occult blood and bilirubin. The urinalysis may be performed using a urine 
dipstick.
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18. 12-lead ECG: On Days 1 and 2 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 hours (± 30 minutes) and 24 (± 2.4) hours after the end of infusion. 
19. 12-lead ECG: On Day 1 of Cycle 3 and subsequent cycles, a 12-lead ECG is to be performed before the start of ADCT-402 infusion.
20. 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, during the study and 30 days following the patient’s last dose of ADCT-402.
21. Premedication to be performed if a CTCAE Grade 2 or higher infusion-related hypersensitivity reaction is 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 
(Section 5.2).
22. ADCT-402: Patients will receive a 1-hour IV infusion of ADCT-402, at escalating doses, each 3-week (21-day) cycle. If ADCT-402 is well tolerated after 
the first infusion, the infusion duration may be shortened to 30 minutes for subsequent infusions for that patient, 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. The IP window is +15 minutes.
23. For all patients, collection of AEs and SAEs will continue for up to 12 weeks (84 days) after the last dose of study drug or initiation of new anti-cancer
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.
24. After documentation of disease progression or start of new anti-cancer 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.
25. Information on anti-cancer treatment initiated after discontinuation of ADCT-402 to be recorded in the eCRF.
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Table 7.
Schedule of Study Procedures: Weekly (QW) Dosing
Procedure
Screen
Cycle 1
Cycle 2
Cycles 3 
until PD/DC
EOT
30 (+7) 
days3
12 Week 
Follow-
Up Visit
(± 1) week4
Follow-
Up
12 (± 1) 
week
D1
D21
D3&2
D8
D15
D1
D21
D3&52
D8
D15
D1
D8
D15
±3d
±2d
±2d
±3d
±2d
±2d
±3d
±2d
±2d
Informed consent
X
Demography
X
Medical history5
X
Serum or urine β-HCG 
pregnancy test
X
X6
X
Physical examination7
X
X
X
X
X
X
X
X
X
Vital signs8
X
X9
X
X
X
X
X9
X
X
X
X
X
X
X
X
Height
X
Weight
X
X
X
X
X
X
X
X
X
X
X
ECOG performance 
status
X
X
X
X
X
Bone marrow 
aspirate/biopsy10
X
X11
X12
Hematology13
X
X14
X
X
X14
X
X
X14
X
X
X
Coagulation Panel15
X
X14
X14
X14
X
Biochemistry16
X
X14
X
X
X14
X
X
X14
X
X
X
Urinalysis17
X
X14
X
X
X14
X
X
X14
X
X
X
12-lead ECG
X
X18
X
X18
X
X19
X
Concomitant 
medications20
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Premedication21
X
X
X
X
X
X
X
X
X
ADCT-402 
administration22
X
X
X
X
X
X
X
X
X
Adverse events 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X23
Survival information
X24
X24
New anti-cancer 
treatment information
X25
X25
Abbreviations: D = day(s); d = day(s); ECG, electrocardiogram; ECOG, Eastern Cooperative Oncology Group; EOT, end of treatment visit; β-HCG, beta-
human chorionic gonadotropin.
Refer to Table 8 and Table 9 for Central Lab Sample Collection Schedule.
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1.
Day 2 to occur 24 hours (±10%) after EOI.
2.
Day 3 to occur 48 hours (± 10%) after EOI. Day 5 to occur 96 (± 24) hours after EOI. 
3.
After last dose of ADCT-402. EOT window is + 7 days.
4.
Follow-up to occur 12 (± 1) week after last dose of ADCT-402. 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 anti-cancer 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.
5.
Medical history: To include a complete history of all surgeries, significant diagnoses, cancer history, immunophenotyping and all cancer treatments.
6.
Serum or urine pregnancy test: For women of child-bearing potential. Not required if negative screening β-HCG pregnancy test was obtained within 7 days 
prior to Cycle 1, Day 1.
7.
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 repeated on Day 1, 
if last performed within 3 days prior to dosing with ADCT-402.
8.
Vital signs to include arterial blood pressure, heart rate, respiratory rate, and body temperature. 
9.
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 the 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. Note: Timing of 
measurements is approximately ±15 minutes. 
10. A bone marrow sample, via aspirate or biopsy if an aspirate is unattainable, will be obtained at Screening for confirmation of disease (as per WHO 
classification of ALL [Swerdlow, 2008]), at an approved clinical laboratory. 
11. A bone marrow sample will be obtained within 6 days prior to the Day 1 visit of Cycles 3 and 5 and at each subsequent cycle until CR or CRi is achieved or 
until disease progression, .Assessment of response to treatment and determination of MRD (via flow cytometry) are to be done by an approved clinical 
laboratory. Results must be available to the Investigator before the next dose of study drug is administered. Once CR/CRi is achieved, sampling will be 
repeated at least every 3 cycles, or, as clinically indicated.
12. A bone marrow sample will be obtained at the EOT visit for those patients who have not demonstrated disease progression and if their most recent sample 
was obtained more than 12 (± 1) weeks prior to the EOT visit.
13. Hematology: CBC to include WBC with a 5-part differential, platelet count, hemoglobin, hematocrit, and ANC. Peripheral blasts will be included in the 
hematology analysis for Part 2 only. If WBC is < 400 x 106/L differential is not required.
14. Samples for hematology, coagulation panel, biochemistry, and urinalysis will be collected prior to dosing unless the last sample was 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.
15. Coagulation panel: PTT and INR; PT expressed in seconds is optional. 
16. Biochemistry: 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, 
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ADCT-402-102
Protocol Amendment 3
Date of Protocol: 19 April 2017 
Page 81
albumin, glucose, triglycerides, total cholesterol, phosphorus, and lactate dehydrogenase. At Days 1, 8 and 15 of each cycle, biochemistry will include 
creatinine clearance (calculated using the Cockcroft and Gault formula [Cockcroft and Gault, 1976]).
17. Urinalysis to include: pH, specific gravity, protein, glucose, ketones, nitrites, occult blood and bilirubin. The urinalysis may be performed using a urine 
dipstick.
18. 12-lead ECG: On Days 1 and 2 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 hours (± 30 minutes) and 24 (± 2.4) hours after the end of infusion. 
19. 12-lead ECG: On Day 1 of Cycle 3 and subsequent cycles, a 12-lead ECG is to be performed before the start of ADCT-402 infusion.
20. 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, during the study, and 30 days following the patient’s last dose of ADCT-402.
21. Premedication to be performed if a CTCAE Grade 2 or higher infusion-related hypersensitivity reaction is observed in 1 patient at any time during Part 1 of 
the study. All subsequent patients must receive prophylactic treatment on Days 1, 8 and 15 of each cycle thereafter to reduce the risk of hypersensitivity 
reaction (Section 5.2).
22. ADCT-402: Patients will receive a 1-hour IV infusion of ADCT-402, at escalating doses, on Days 1, 8 and 15 of each 3-week (21-day) cycle. If ADCT-402 
is well tolerated after the first infusion, the infusion duration may be shortened to 30 minutes for subsequent infusions for that patient, 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. The IP window is +15 minutes.
23. For all patients, collection of AEs and SAEs will continue for up to 12 weeks (84 days) after the last dose of study drug or initiation of new anti-cancer
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.
24. After documentation of disease progression or start of new anti-cancer 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.
25. Information on anti-cancer treatment initiated after discontinuation of ADCT-402 to be recorded in the eCRF.
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ADCT-402-102
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Date of Protocol: 19 April 2017 
Page 82
 
 
 
 
 
 
 
 
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ADC Therapeutics 
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ADCT-402-102
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ADC Therapeutics 
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ADCT-402-102
Protocol Amendment 3
Date of Protocol: 19 April 2017 
Page 84
12.2 Appendix: CTCAE Immune System Hypersensitivity Grades
Table 10. 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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Date of Protocol: 19 April 2017 
Page 85
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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Date of Protocol: 19 April 2017 
Page 86
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 non-invasive 
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.
Page 349 of 368

SAP_001.pdf: 
Protocol Number:  ADCT-402-102 
 
Official Title:     A Phase 1, Open-label, Dose-Escalation, Multicenter Study to Evaluate the 
Tolerability, Safety, Pharmacokinetics, and Anti-tumor Activity of ADCT-402 
in Patients with Relapsed or Refractory B-cell Lineage Acute Lymphoblastic 
Leukemia (B-ALL) 
 
NCT Number:  NCT02669264 
 
Document Date:  19 April 2017   


Abbreviated Clinical Study Report 
ADCT-402-102 
Confidential
ADC Therapeutics ADCT-402 
 
 
 
 Documentation of Statistical Methods 
ADCT-402-102 SAP final version 1.0, 13 Sep 2018 
 
Page 1 of 16


ADC Therapeutics 
ADCT-402 
ADCT-402-102 
 SAP version 1.0 
 
 
 
 
 
Statistical Analysis Plan 
 
 
 
 
A Phase 1, Open-label, Dose-Escalation, Multicenter Study to Evaluate the 
Tolerability, Safety, Pharmacokinetics, and Anti-tumor Activity of ADCT-
402 in Patients with Relapsed or Refractory B-cell Lineage Acute 
Lymphoblastic Leukemia (B-ALL) 
 
PROTOCOL NO.:  ADCT-402-102  
 
 
 
SAP Version No./ Date: 1.0/ Sep 13, 2018 
 
Statistician: 
 
 
 
 
 
  
Confidentiality Statement 
All financial and nonfinancial support for this study will be provided by ADC Therapeutics 
SA. The concepts and information contained in this document or generated during the study 
are considered proprietary and may not be disclosed in whole or in part without the 
expressed, written consent of ADC Therapeutics SA. The study will be conducted according 
to the International Conference on Harmonisation harmonised tripartite guideline E6(R1), 
Good Clinical Practice. 
 
Page 2 of 16


Page 3 of 16
<\I)(" Thcrupcuuc, 
:\DC:T-402-I02 
Study Title 
Protocol 
umber 
Original SAP Version 
Dute: 
SAP Approval - Sponsor Signatory 
ADCT-J01 
SAP sor,1011 I 0 
A Phase I. Open-label. D0sc-Escala1ion, Multicen1cr Study to 
Evaluate the Tolerability. Safety, Phurii1ncokinc1ics. and Anti· 
tumor Activity of A DCT-402 in Pati.:nts with Rclaps.:<l or 
R.:fracior> £3-ccll Lineage Acute L.yrnphoblastic J.cukcrni.1 
(B-/\1.L) 
A DCT-402-102 
13SEP2018 
SA r acccpti;d and a ppr,)\ cd by: 


ADC Therapeutics 
ADCT-402 
ADCT-402-102 
 SAP version 1.0 
Table of Contents 
Table of Contents ...................................................................................................................... 3 
List of Tables ............................................................................................................................. 4 
List of Figures ........................................................................................................................... 4 
1 Introduction ............................................................................................................................ 5 
2 Study 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 
4.2 Subject Disposition ......................................................................................................8 
4.3 Demographic and Baseline Characteristics .................................................................9 
4.4 Pre-treatment disease characteristics and medical history ..........................................9 
4.5 Prior anticancer therapy .............................................................................................10 
4.6 Prior or Concomitant Medications (other than anticancer therapies) ........................10 
4.7 Exposure to Treatment ...............................................................................................10 
4.7.1 Extent of ADCT-402 Exposure .....................................................................10 
4.7.2 Subsequent Anticancer Therapy or Procedure .............................................. 11 
4.8 Safety Analyses ......................................................................................................... 11 
4.8.1 Dose-limiting Toxicities ................................................................................ 11 
4.8.2 Adverse Events, Serious Adverse Events, and Deaths .................................. 11 
4.8.2.1 Analyses of adverse events ...........................................................11 
4.8.2.2 Deaths .......................................................................................... 13 
4.8.3 Laboratory Data ............................................................................................13 
4.8.4 Electrocardiogram .........................................................................................13 
4.8.5 Vital Signs .....................................................................................................14 
4.8.6 ECOG Performance Status ...........................................................................14 
4.9 Efficacy Analyses ......................................................................................................14 
4.10 Pharmacokinetic Analyses and Pharmacodynamic Analyses ..................................14 
5 Interim Analyses .................................................................................................................. 15 
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ADC Therapeutics 
ADCT-402 
ADCT-402-102 
 SAP version 1.0 
6 Data handling conventions ................................................................................................... 15 
6.1 General conventions ..................................................................................................15 
6.1.1 Missing data ..................................................................................................15 
6.1.2 Unscheduled visits ........................................................................................15 
6.1.3 Duplicated visit .............................................................................................15 
 
List of Tables 
 
NA 
List of Figures 
 
NA 
 
 
 
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ADC Therapeutics 
ADCT-402 
ADCT-402-102 
 SAP version 1.0 
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 (ADCT) Protocol ADCT-
402-102. 
This SAP should be read in conjunction with the study protocol and case report form (CRF).  
 
 
Page 6 of 16


ADC Therapeutics 
ADCT-402 
ADCT-402-102 
 SAP version 1.0 
2 Study Objectives 
Refer to the corresponding section in the protocol.  
 
 
 
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ADC Therapeutics 
ADCT-402 
ADCT-402-102 
 SAP version 1.0 
3 Study Design 
Refer to the corresponding section in the protocol.  
3.1 Sample Size Consideration 
Refer to the corresponding section in the protocol.  
3.2 Randomization 
This study is not randomized. 
3.3 Modifications to the statistical section of the protocol  
The trial was terminated early, prior to the completion of dose escalation (part 1).” Therefore, 
only Part 1 data will be analyzed and a selected or modified analysis from the statistical 
section of the protocol will be performed.  Please see details in each section. 
 
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ADC Therapeutics 
ADCT-402 
ADCT-402-102 
 SAP version 1.0 
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 only a few subjects, then dose levels can 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, subject, and by visit within subject. 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 subjects 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 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 subjects who receive ADCT-402. 
4.2 Subject Disposition 
For the Safety analysis set, the number and percentage of subjects who discontinued study 
treatment and discontinued the study for each reason will be tabulated for each dose level. 
Subject disposition data will be listed.  
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 an excluded concomitant treatment 
3. Patients who developed withdrawal criteria during the study but were not withdrawn. 
The withdrawal criteria include: 
- 
Grade 3 or higher hypersensitivity reaction 
- 
a recurrent Grade 3 or 4 toxicity, excluding hematological toxicity  
- 
a protocol-defined dose-limiting toxicity (DLT) beyond Cycle 1 (except in the case of 
potential patient benefit, which must be approved by the Sponsor)  
- 
a dosing delay >21 days (except in case of potential patient benefit, which must be 
approved by the Sponsor)  
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ADC Therapeutics 
ADCT-402 
ADCT-402-102 
 SAP version 1.0 
- 
toxicity recurs at the 2nd reduced dose level and at a severity that would mandate a 
treatment withdrawal    
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, at any of dose administration 
- 
patient started next cycle less than 18 days later after Day 1 of the most recent 
treatment cycle 
 
4.3 Demographic and Baseline Characteristics 
Demographic and baseline characteristics will be tabulated for the Safety analysis set. 
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) 
• ECOG PS 
Demographic and baseline characteristics data will be listed. 
4.4 Pre-treatment disease characteristics and medical history 
Cancer history will be summarized for the Safety analysis set. Cancer history will be listed 
and the following variables will be included: 
• Date of initial diagnosis of B-ALL 
• Current disease status (primary refractory, relapsed) 
• Extramedullary involvement and site of involvement  
Cytogenetic analysis data will be summarized, and the following variables will be included: 
• ALL with t(9;22)(q34;q11.2); BCR-ABL (Philadelphia chromosome)  
• ALL with t(v;11q23) (MLL rearranged)  
• ALL with t(1;19)(q23;p13.3); TCF3-PBX1 (E2A-PBX1)  
• ALL with t(12;21)(p13;q22); ETV6-RUNX1 (TEL-AML1)  
• Hyperdiploid > 50  
• Hypodiploid  
• t(5;14)(q31;q32); IL3-IGH 
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 SAP version 1.0 
All cytogenetic analysis data will be listed. 
Bone marrow evaluation (bone marrow aspirate and/or bone marrow biopsy) at screening will 
be listed. 
Medical history will be summarized by system organ class and preferred term. All medical 
history data will be listed. 
4.5 Prior anticancer therapy 
The number and percent of patients who had prior stem cell transplant and radiotherapy will 
be summarized.  
The number of lines of prior systemic therapies will be summarized. Number of lines is derived 
from the unique number of regimen number reported on the prior systemic treatment CRF page 
and the mobilization treatment and/or conditioning treatment from the prior stem cell 
transplant, if appropriate.   
Prior stem cell transplant, radiotherapy and systemic therapy data will be listed. 
4.6 Prior or Concomitant Medications (other than anticancer therapies) 
Prior and concomitant medications will be coded using the World Health Organization-Drug 
Dictionary (WHO-DD). 
Patient listing of all prior and concomitant medications will be provided. Pre-medication for 
dosing (for example, prophylaxis for hypersensitivity) will listed separately.  
4.7 Exposure to Treatment 
4.7.1 Extent of ADCT-402 Exposure 
ADCT-402 exposure will be summarized for the Safety analysis set by dose level.  The 
following items will be tabulated.  
• Duration of treatment (in weeks) = (date of last dose – date of first dose +1)/7 
• Number of infusions 
• Cumulative dose (in ug/kg) = sum of (dose administered at each infusion [ug] /last 
available weight before each infusion[kg]) 
where dose administered at each infusion[ug]= 
concentrated IP volume [ in mL]* 5 mg/mL *1000 or serially diluted IP volume[ in 
mL]/50* 5 mg/mL *1000; or  
for partial infusion, multiply by (1- volume of dosing solution not administered [in 
mL]/ 50 mL)  
• 
Relative dose intensity (%) = (Cumulative dose / (Duration of treatment + 6/7 for QW 
or + 20/7 for Q3W))/ planned weekly dose intensity *100% 
where planned weekly dose intensity =  
planned dose level at cycle 1 day 1 for QW, or  
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planned dose level at cycle 1 day 1 ÷3 for Q3W, for example, =10 ug/kg for 
30ug/kg Q3W planned dose level.    
Relative dose intensity will be additionally presented categorized (<60%, >=60 - <80%, 
>=80 - <90%, >=90 - <110%, >=110%) Exposure data and infusion details will be listed 
together. 
4.7.2 Subsequent Anticancer Therapy or Procedure 
Subjects’ subsequent anticancer therapy or procedure including systemic therapy, radiation, 
or other, along with the start date of subsequent anticancer therapy or procedure will be 
listed. 
4.8 Safety Analyses 
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 will be defined as the last non-missing value or measurement taken 
up to the first dose of the study drug 
• The analysis of the safety variables will be essentially descriptive and no systematic 
testing is planned. 
• If relevant, selected safety analyses may 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 subjects with 
multiple occurrences of the same event, the maximum grade will be used. If a subject 
has both missing and non-missing severity grades for treatment-emergent adverse 
events (TEAEs) within the same preferred term (PT), the missing severity of the TEAE 
will be treated as a lower severity grade (ie, the subject will be counted under the non-
missing severity grade).  
4.8.1 Dose-limiting Toxicities 
DLT data will be listed. 
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 the TEAEs. A TEAE is defined as an 
adverse event (AE) that occurs or worsens in the period from the first dose of study drug up 
to 84 days after the last dose of study drug, or start of new anti-cancer therapy, whichever is 
earlier. 
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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. 
For example, if only the day of the AE onset is missing, the year and month will be compared 
with the first dose and 84 days after the last dose of study drug, or start of new anti-cancer 
therapy, whichever is earlier. And if the month and day of the AE onset are missing, the year 
will be compared with the first dose and 84 days after the last dose of study drug, or start of 
new anti-cancer therapy, whichever is earlier. The algorithm for imputing TEAE will be 
conservative and will classify an AE as a treatment emergent unless there is definitive 
information to determine it is non-TEAEs.  
 
 
Analysis of all TEAE(s):  
The following TEAE summaries will be generated for the safety analysis set. 
• Overview of TEAEs, summarizing number of TEAEs and number (%) of subjects with 
any 
- 
TEAE 
- 
Related TEAE (including possibly related, probably related, or related) 
- 
Any ≥ grade 3 TEAE 
- 
Serious TEAE  
- 
TEAE leading to death 
- 
TEAE leading to permanent treatment discontinuation 
- 
TEAE leading to ADCT-402 delay or reduction or interruption 
- 
TEAE with at least one infusion related reaction 
• All TEAEs by PT, showing number (%) of subjects with at least one TEAE, sorted by 
decreasing incidence of PTs 
• All TEAEs by System Organ Class (SOC) and PT, showing number (%) of subjects 
with at least one TEAE, sorted by SOC in alphabetic order and decreasing incidence of 
PTs within SOC. This sorting order will be applied to all other AE tables, unless 
otherwise specified 
• All TEAEs by SOC, PT and Maximum CTCAE grade 
• All ≥ grade 3 TEAEs by SOC, PT and Maximum CTCAE grade 
• All related TEAEs by SOC, PT and Maximum CTCAE grade (including possibly 
related, probably related, or related)  
• All Serious TEAEs by SOC and PT by SOC, PT and Maximum CTCAE grade 
All AEs (including non-TEAEs), all SAEs (including non-TEAEs), all TEAEs leading to 
treatment discontinuation, all TEAEs leading to dose reduction, all TEAEs leading to dose 
delay, all TEAEs considered infusion related reactions, and all TEAEs with fatal outcome 
will be listed.  
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4.8.2.2 Deaths 
Reasons for deaths will be summarized separately for 1) all deaths, 2) death on therapy or 
within 30 days after last dose of study drug. 
4.8.3 Laboratory Data 
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. 
Laboratory data, including urinalysis, will be listed. Pregnancy test results will not be listed, 
but will be included in datasets. 
4.8.4 Electrocardiogram 
ECG parameters (e.g. corrected QT interval [QTcF (Fridericia) or QTcB(Bazett)]) will not be 
converted or derived, but will be reported as provided by investigational sites. 
Descriptive statistics (mean, standard deviation, median and range) for heart rate will be 
calculated 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 by a frequency table: 
 At any post-baseline with absolute value 
450 - 480 ms 
481 - 500 ms 
>= 501 ms 
Change from Baseline 
 31 – 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.  
All ECG data will be listed, both for quantitative data and for overall interpretation (normal, 
abnormal –clinically significant, abnormal –not clinically significant) reported by 
investigational sites. 
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4.8.5 Vital Signs 
Descriptive statistics (mean, standard deviation, median, and range) for vital signs data, 
including systolic and diastolic blood pressure, heart rate, respiration rate, and body 
temperature, will be calculated for the raw data and for their changes from baseline at each 
scheduled assessment. 
All vital signs data will be listed together with body weight. 
4.8.6 ECOG Performance Status 
ECOG results will be summarized using shift from baseline. All ECOG data will be listed. 
4.9 Efficacy Analyses 
Due to the early termination of the trial, efficacy data will be listed only. Disease assessment 
(CR, CRi, PR, PD, NR or NE) data will be listed.  
4.10 Pharmacokinetic Analyses and Pharmacodynamic Analyses 
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 will be analyzed using a noncompartmental analysis method. The PK 
parameters from analysis will include 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 
(AUC), accumulation index (AI), apparent terminal half-life (T1/2), apparent systemic 
clearance (CL), and volume of distribution at steady state (Vss).   
Data presentation by tables will include individual patient concentrations by nominal 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 reported. 
 
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5 Interim Analyses  
NA  
6 Data handling conventions 
6.1 General conventions 
6.1.1 Missing data 
Handling of missing relationship to investigational product of AEs 
If the assessment of the relationship to investigational product is missing, then the relationship 
to investigational product has to be assumed and the AE considered as such in the frequency 
tables of possibly related AEs, 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. 
 
6.1.2 Unscheduled visits 
Unscheduled visit measurements of laboratory data 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 visit 
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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