Clinical trial NCT02588092
Conditions: Acute Myeloid Leukemia Acute Lymphoblastic Leukemia
Keywords: Camidanlumab tesirine
Sponsor: ADC Therapeutics S.A.
Start date: 2016-02-01; Completion date: 2018-08-29
Enrollment: 35 participants; Allocation: NON_RANDOMIZED; Intervention model: SINGLE_GROUP

Brief summary:
This study evaluates ADCT-301 in participants with Acute Myeloid Leukemia (AML) or Acute Lymphoblastic Leukemia (ALL). Participants will participate in a dose-escalation phase (Part 1) and receive ADCT-301 either weekly or once every 3 weeks.

In Part 2 of the study, participants will receive a recommended dose of ADCT-301 as determined by a Dose Escalation Steering Committee.

Detailed description:
This is a Phase 1 study with ADCT-301 to evaluate the safety, tolerability and pharmacokinetics of ADCT-301 in participants with Acute Myeloid Leukemia (AML) or Acute Lymphoblastic Leukemia (ALL).

ADCT-301 is a human monoclonal antibody attached via a cleavable linker to a pyrrolobenzodiazepine (PBD) warhead which, when internalized by antigen expressing cells, covalently cross links deoxyribonucleic acid (DNA) preventing replication.

The study will be conducted in 2 parts: In Part 1 (dose escalation) participants will either be on weekly administration or every 3-week administration. Participants on weekly administration will receive an infusion of ADCT-301 on Days 1, 8, and 15 of each 3 week treatment cycle. Participants on 3-week administration will receive an infusion of ADCT-301 on Day 1, every 3 weeks. Dose escalation will continue until the maximum tolerated dose (MTD) is determined.

In Part 2 (expansion), participants will be assigned to receive a recommended dose and/or schedule of ADCT-301 as determined by a Dose Escalation Steering Committee.

For each participant, the study will include a screening period (up to 28 days), a treatment period, and a follow-up period to assess disease progression and survival for up to 12 months after the last dose of study drug. The total study duration will be dependent on overall participant tolerability to the study drug and response to treatment. It is anticipated that the entire study (Parts 1 and 2) will enroll a maximum of 80 participants and could last approximately 3 years from first participant treated to last participant completed.

Arms: arm 1: Weekly administration - Participants will receive an IV infusion of ADCT-301, on Days 1, 8, and 15 of each 3-week (21-day) cycle.

3-week administration - Participants will receive an IV infusion of ADCT-301, on Day 1 of each 3-week (21-day) cycle.

The dose escalation will be conducted according to a 3+3 design. arm 2: Participants will be assigned to receive the recommended dose and/or schedule of ADCT-301 as determined by the Dose Escalation Steering Committee.
Interventions: intervention 1: ADCT-301
Intervention descriptions: intervention 1: Intravenous infusion

Protocol documents:
Prot_000.pdf: 
Protocol Number:  ADCT-301-002 
 
Official Title:    A Phase 1, Open-label, Dose-escalation, Multicenter Study to Evaluate the 
Tolerability, Safety, Pharmacokinetics, and Activity of ADCT-301 in Patients 
with Relapsed or Refractory CD25-positive Acute Myeloid Leukemia or 
CD25-positive Acute Lymphoblastic Leukemia 
 
NCT Number:  NCT02588092 
 
Document Date:  19 January 2018 


ADC Therapeutics
ADCT-301
ADCT-301-002
Protocol Amendment 5
Date of Amendment: 19 January 2018
Page 1
CLINICAL STUDY PROTOCOL
IND: 121912
A Phase 1, Open-label, Dose-escalation, Multicenter Study to Evaluate the 
Tolerability, Safety, Pharmacokinetics, and Activity of ADCT-301 in Patients 
with Relapsed or Refractory CD25-positive Acute Myeloid Leukemia or
CD25-positive Acute Lymphoblastic Leukemia
PROTOCOL NO.: ADCT-301-002
Sponsor:
ADC Therapeutics SA
 
 
Sponsor Contact:
Medical Monitor:
Date of Original Protocol:
6 July 2015
Date of Amendment 1:
17 December 2015
Date of Amendment 2:
5 February 2016
Date of Amendment 3:
8 November 2016
Date of Amendment 4:
03 April 2017
Date of Amendment 5:
19 January 2018
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 Council for Harmonisation (ICH) harmonised tripartite guideline E6(R1),
Good Clinical Practice
.
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ADC Therapeutics 
ADCT-301 
ADCT-30 1-002 
Protocol Amendment 5 
Protocol Approval - Sponsor Signatory 
Study Title 
Protocol Number 
Date of Original Protocol: 
Date of Amendment 1: 
Date of Amendment 2 
Date of Amendment 3: 
Date of Amendment 4: 
Date of Amendment 5: 
A Phase I, Open-label, Dose-escalation, Multicenter Study 
to Evaluate the Tolerability, Safety, Phannacokinetics, and 
Activity of ADCT-301 in Patients with Relapsed or 
Refractory CD25-positive Acute Myeloid Leukemia or 
CD25-positive Acute Lymphoblastic Leukemia 
ADCT-301-002 
6 July 2015 
17 December 2015 
5 February 2016 
8 November 2016 
03 April 2017 
19 January 2018 
Protocol accepted and approved by: 
Date of Amendment: 19 January 2018 
Page 2 
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ADCT-301
ADCT-301-002
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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 
Activity of ADCT-301 in Patients with Relapsed or Refractory CD25-positive Acute Myeloid 
Leukemia or CD25-positive Acute Lymphoblastic Leukemia” and the accompanying
Investigator Brochure. 
I agree to supervise all aspects of the protocol and to conduct the clinical investigation in 
accordance with Protocol Amendment 5, dated 19 January 2018, the International Council for
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 sub-Investigator.
I will not supply the investigational drug to any person not authorized to receive it. 
Confidentiality will be protected. Patient identity will not be disclosed to third parties or appear 
in any study reports or publications.
I will not disclose information regarding this clinical investigation or publish results of the 
investigation without authorization from ADC Therapeutics SA.
Signature of Principal Investigator
Date
Printed Name of Principal Investigator
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ADCT-301-002
Protocol Amendment 5
Date of Amendment: 19 January 2018
Page 4
Table of Contents
Table of Contents ............................................................................................................................ 4
List of Tables................................................................................................................................... 8
List of Figures................................................................................................................................. 8
Protocol Synopsis............................................................................................................................ 9
List of Abbreviations..................................................................................................................... 22
1
Introduction .......................................................................................................................... 25
2
Study Rationale and Justification for Dose Level Selection ................................................ 27
2.1
Clinical Background ....................................................................................................27
2.2
Non-clinical Efficacy and Safety of ADCT-301..........................................................28
2.3
Safety of Commercially Available Antibodies Directed against CD25.......................29
3
Study Objectives................................................................................................................... 30
3.1
Primary Objectives.......................................................................................................30
3.2
Secondary Objectives...................................................................................................30
4
Investigational Plan and Patient Selection ........................................................................... 32
4.1
Study Design................................................................................................................32
4.1.1
Dose-escalation (Part 1) and Determination of Maximum Tolerated    Dose.33
4.1.2
Dose Expansion (Part 2).................................................................................35
4.2
Selection of Study Population......................................................................................35
4.2.1
Inclusion Criteria ............................................................................................35
4.2.2
Exclusion Criteria...........................................................................................36
5
Study Procedures .................................................................................................................. 39
5.1
Procedures by Study Day – Every 3-Week Dosing Schedule (Q3W) .........................39
5.1.1
Screening Period (Day –28 to –1) ..................................................................39
5.1.2
Day 1 (± 3 days) of Each Cycle......................................................................41
5.1.3
Day 2 (Cycles 1 and 2) ...................................................................................42
5.1.4
Day 3 (Cycles 1 and 2) ...................................................................................42
5.1.5
Day 5 (Cycles 1 and 2) ...................................................................................43
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5.1.6
Day 8 (± 1 day) of Each Cycle .......................................................................43
5.1.7
Day 19 (±3 days) of Each Cycle.....................................................................43
5.1.7.1
Bone Marrow Aspirate or Biopsy................................................ 44
5.1.8
End of Treatment Visit....................................................................................44
5.1.9
12-Week Follow-up Visit................................................................................45
5.1.10
Long-term Follow-up......................................................................................45
5.2
Withdrawal of Patients from the Study........................................................................45
5.2.1
Reasons for Withdrawal/Discontinuation.......................................................45
5.2.2
Handling of Withdrawals................................................................................46
5.2.3
Patient Replacements......................................................................................46
6
Study Treatments .................................................................................................................. 47
6.1
Method of Assigning Patients to Treatment.................................................................47
6.2
Prophylactic Treatments for Hypersensitivity .............................................................47
6.3
Treatments Administered .............................................................................................48
6.4
Dose Delays and Modifications...................................................................................49
6.5
Study Stopping Rules...................................................................................................50
6.6
Identity of Investigational Product...............................................................................50
6.6.1
ADCT-301 Drug Product................................................................................51
6.7
Management of Clinical Supplies................................................................................51
6.7.1
Study Drug Packaging and Storage ................................................................51
6.7.2
Study Drug Preparation and Administration...................................................51
6.7.3
Study Drug Accountability .............................................................................51
6.8
Overdose Management ................................................................................................52
6.9
Treatment Compliance.................................................................................................52
6.10 Concomitant Treatment................................................................................................52
6.10.1
Prohibited During Study.................................................................................52
6.10.2
Permitted During Study..................................................................................52
6.10.3 Diagnostic, Work-up and Management of Polyradiculopathy / Guillain-Barré 
Syndrome .......................................................................................................53
7
Study Assessments and Procedures ...................................................................................... 55
7.1
Efficacy Assessments...................................................................................................55
7.2
Pharmacokinetic, Pharmacodynamic and 
...........................56
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7.2.1
Pharmacokinetic Profile Assessments ............................................................56
7.2.2
................................................................................56
7.3
Safety and Tolerability Assessments............................................................................57
7.3.1
Dose-Limiting Toxicities and Dose-Escalation Scheme ................................57
7.3.1.1
Definition of Dose-Limiting Toxicities ....................................... 57
7.3.1.2
Safety Oversight by the Dose-Escalation Steering Committee ... 58
7.3.2
Adverse Events ...............................................................................................58
7.3.2.1
Definitions of Adverse Events..................................................... 58
7.3.2.2
Eliciting and Documenting Adverse Events................................ 59
7.3.2.3
Reporting Adverse Events ........................................................... 59
7.3.2.4
Assessment of Severity................................................................ 60
7.3.2.5
Assessment of Causality.............................................................. 60
7.3.2.6
Follow-Up of Patients Reporting Adverse Events....................... 61
7.3.3
Pregnancy .......................................................................................................61
7.3.4
Clinical Laboratory Analyses .........................................................................61
7.3.4.1
Hematology.................................................................................. 61
7.3.4.2
Biochemistry................................................................................ 61
7.3.4.3
Urinalysis..................................................................................... 62
7.3.4.4
Additional Renal Function Studies.............................................. 62
7.3.4.5
Additional Microbiological Serological studies.......................... 62
7.3.5
Electrocardiograms.........................................................................................62
7.3.6
Physical Examination .....................................................................................62
7.3.7
Vital Sign Measurements................................................................................63
7.3.8
Eastern Cooperative Oncology Group Performance Status............................63
7.4
Sample Handling, Storage and Shipment ....................................................................63
8
Statistical and Analytical Plan.............................................................................................. 65
8.1
Safety Endpoints..........................................................................................................65
8.2
Endpoints .....................................................................................................................65
8.2.1
Primary Endpoints ..........................................................................................65
8.2.2
Secondary Endpoints ......................................................................................65
8.3
Sample Size Calculations.............................................................................................66
8.4
Analysis Sets................................................................................................................66
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8.5
Description of Subgroups to be Analyzed ...................................................................66
8.6
Statistical Analysis Methodology ................................................................................67
8.6.1
Safety Analyses...............................................................................................67
8.6.1.1
Analyses of Adverse Events ........................................................ 67
8.6.1.2
Clinical Laboratory Results......................................................... 67
8.6.1.3
Additional Safety Assessments.................................................... 67
8.6.2
Efficacy Analysis............................................................................................68
8.6.2.1
Duration of Response .................................................................. 68
8.6.2.2
Overall Response Rate................................................................. 68
8.6.2.3
Overall Survival........................................................................... 68
8.6.2.4
Progression-Free Survival ........................................................... 68
8.6.3
Pharmacokinetic and 
...................................................69
8.6.4
Study Drug Exposure......................................................................................69
8.7
Data Quality Assurance................................................................................................69
8.7.1
Data Management...........................................................................................70
9
Ethics .................................................................................................................................... 71
9.1
Independent Ethics Committee or Institutional Review Board ...................................71
9.2
Ethical Conduct of the Study.......................................................................................71
9.3
Patient Information and Consent .................................................................................71
10
Investigator’s Obligations..................................................................................................... 72
10.1 Confidentiality .............................................................................................................72
10.2 Financial Disclosure and Obligations..........................................................................72
10.3 Investigator Documentation.........................................................................................72
10.4 Study Conduct..............................................................................................................73
10.5 Adherence to Protocol..................................................................................................73
10.6 Adverse Events and Study Report Requirements ........................................................73
10.7 Investigator’s Final Report ..........................................................................................73
10.8 Records Retention........................................................................................................74
10.9 Publications..................................................................................................................74
11
Study Management............................................................................................................... 75
11.1 Monitoring ...................................................................................................................75
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11.1.1
Monitoring of the Study..................................................................................75
11.1.2
Inspection of Records .....................................................................................75
11.2 Management of Protocol Amendments and Deviations...............................................75
11.2.1
Modification of the Protocol...........................................................................75
11.2.2
Protocol Deviations ........................................................................................76
11.3 Study Termination........................................................................................................76
11.4 Final Report .................................................................................................................76
12
Reference List....................................................................................................................... 77
13
Appendices ........................................................................................................................... 80
13.1 Appendix: Schedule of Events.....................................................................................80
13.2 Appendix: CTCAE Immune System Hypersensitivity Grades....................................90
13.3 Appendix: Clinical case definitions: Level 1 of diagnostic certainty for Guillain-Barré 
syndrome......................................................................................................................93
13.4 Appendix: Guillain–Barré Syndrome Disability Scale................................................94
List of Tables
Table 1: Schedule of Study Procedures: Every 3-Week (Q3W) Dosing....................................... 81
Table 2: Central Laboratory Sample Collection Schedule: Every 3-Week (Q3W) Dosing.......... 84
Table 3: Schedule of Study Procedures: Weekly (QW) Dosing ................................................... 85
Table 4: Central Laboratory Sample Collection Schedule: QW Dosing Cycle 1......................... 88
Table 5: Central Laboratory Sample Collection Schedule: QW Dosing: Cycle 2+...................... 89
Table 6: CTCAE* Immune System Hypersensitivity Grades ....................................................... 90
List of Figures
Figure 1. Schematic Representation and Chemical Structure of ADCT-301................................ 25
Figure 2. Schematic Representation for Dose-escalation (3+3) Design....................................... 33
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ADCT-301
ADCT-301-002
Protocol Amendment 5
Date of Amendment: 19 January 2018
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Protocol Synopsis
Protocol Number:
ADCT-301-002
Title:
A Phase 1, Open-label, Dose-escalation, Multicenter Study to Evaluate the 
Tolerability, Safety, Pharmacokinetics, and Activity of ADCT-301 in 
Patients with Relapsed or Refractory CD25-positive Acute Myeloid 
Leukemia or CD25-positive Acute Lymphoblastic Leukemia
Sponsor:
ADC Therapeutics SA
Study Phase:
Phase 1
Study Sites:
Approximately 10 sites during dose-escalation (Part 1) and 10 sites during 
dose expansion (Part 2)
Indication:
Patients with relapsed or refractory cluster of differentiation 25 
(CD25)-positive acute myeloid leukemia (AML) or CD25-positive acute 
lymphoblastic leukemia (ALL) who have failed, or are intolerant to, any 
established therapy known to provide clinical benefit at current state of 
disease. Patients with myelodysplastic syndrome who have received 
treatment with hypomethylating agents and subsequently present with 
CD25+ AML and who failed, or are ineligible for standard induction 
therapy, are eligible for treatment with ADCT-301.
Rationale:
Acute myeloid leukemia is the most common leukemia in adults and results 
in the largest number of deaths due to leukemia in the USA. The overall 
5-year survival rate for AML is 26%, with younger patients (age <45 years) 
having a higher survival rate (>50%) compared with older patients 
(~10% for patients 65-74 years). Cytotoxic induction therapy is associated 
with high rates of complete response/remission, especially for younger 
patients who are able to tolerate treatment. However, the majority of 
patients with AML will eventually relapse or develop refractory disease.
More than 6,000 new cases of ALL are diagnosed yearly in the US, 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. Acute lymphoblastic leukemia 
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, CD25 expression is mainly limited to activated 
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ADCT-301-002
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T- and B-cells. Expression of CD25 by AML and ALL blast cells is 
associated with adverse outcomes, including induction failure, relapse, and
shortened overall survival.
ADCT-301 is an antibody-drug conjugate, composed of the human 
monoclonal antibody, HuMax®-TAC, directed against CD25, and 
conjugated through a 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. After binding to the cell surface and 
internalization, ADCT-301 is transported to the lysosomes, where the 
protease-sensitive linker is cleaved and free PBD dimers are released inside 
the target cell. 
The potential for ADCT-301 in treating hematological malignancies, which 
demonstrate CD25 over-expression, has been shown by complete responses 
in mouse xenograft models following single, low-dose administration. The
efficacy of ADCT-301 in these models is due to targeted delivery of the 
PBD cytotoxin SG3199.
The safety of ADCT-301 has been assessed in non-clinical testing. In mice, 
ADCT-301 is well tolerated at doses up to 9 mg/kg. A repeat-dose Good 
Laboratory Practice (GLP) toxicology study in cynomolgus monkeys 
investigated doses ranging from 0.15 to 0.9 mg/kg. Toxicities included 
body weight loss, nephrotoxicity, and cutaneous adverse events (AEs). The
highest non-severe toxic dose was determined to be 0.15 mg/kg. 
Objectives:
Primary objectives:
The primary objectives for Part 1 (dose-escalation) and Part 2 (expansion) 
of the study are: 

Evaluate the safety and tolerability and determine the maximum 
tolerated dose (MTD) of ADCT-301 in patients with CD25-positive 
relapsed or refractory AML and CD25-positive ALL (Part 1).

Determine the recommended dose of ADCT-301 for Part 2.

Evaluate the safety and tolerability of ADCT-301 in Part 2 at the dose 
level recommended in Part 1.
Secondary objectives:
The secondary objectives for Part 1 and Part 2 of the study are:

Evaluate the clinical activity of ADCT-301, based on the patient’s 
response to treatment (complete response [CR], CR with incomplete 
blood count recover [CRi], partial response [PR], progressive disease 
[PD], no response [NR]) and determination of the overall duration of 
response (DOR), overall response rate (ORR), overall survival (OS), 
and progression-free survival (PFS).
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
Characterize the pharmacokinetic (PK) profile of ADCT-301 (total 
antibody, drug-to-antibody ratio [DAR] ≥0), PBD-conjugated antibody 
(DAR ≥1), and free warhead SG3199.

Evaluate anti-drug antibodies (ADAs) to ADCT-301 in blood before, 
during, and after treatment with ADCT-301.
 
 
 
 
 
 
 
 
 
 
 
Patient Selection:
Inclusion Criteria:
1. Male or female age 18 years or older.
2. Patients with:

Relapsed or refractory CD25-positive* AML** who have failed, or are 
intolerant to, any established therapy known to provide clinical benefit 
at current state of disease.

Myelodysplastic syndrome who have received treatment with 
hypomethylating agents and subsequently present with CD25-positive*
AML and who failed, or are ineligible for standard induction therapy.

Relapsed or refractory CD25-positive* 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.
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Note: *CD25-positive is defined as determination of CD25 expression by 
≥5% of blast cells within bone marrow (aspirate or biopsy), assessed
at an approved clinical laboratory. **Diagnosis and classification as 
per World Health Organization (WHO) classification of acute 
leukemias.34
3.
Eastern Cooperative Oncology Group (ECOG) performance status 0-2.
4.
Serum/plasma creatinine ≤1.5mg/dL, or 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.9
5.
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.
6.
Total serum/plasma bilirubin ≤1.5 times the ULN. Patients with 
known Gilbert’s syndrome may have a total bilirubin up to ≤3 times 
ULN.
7.
Women of child-bearing potential must have a negative urine or serum 
beta-human chorionic gonadotropin (β-HCG) pregnancy test within 
7 days prior to the Day 1 visit.
8.
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-301. 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-301. 
*   Defined as: Sexually mature women who have not undergone bilateral 
tubal ligation, bilateral oophorectomy, or hysterectomy; or who have 
not been post-menopausal (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.
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9. WBC count value of <15,000 cells/µL prior to C1D1.
Exclusion Criteria:
1. Patients who have an option for any treatment with proven clinical 
benefit for CD25-positive AML or CD25-positive ALL at current state 
of disease.
2. Known active central nervous system (CNS) leukemia, defined as 
morphologic evidence of leukemic blasts 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. Active graft-versus-host disease.
4. Autologous or allogenic transplant within the 60 days prior to 
Screening.
5. Known history of immunogenicity or hypersensitivity to a CD25 
antibody.
6. Known history of positive serum human ADA, or known allergy to any 
component of ADCT-301.
7. History of symptomatic autoimmune disease (e.g., rheumatoid arthritis, 
systemic progressive sclerosis [scleroderma], systemic lupus 
erythematosus, Sjögren's syndrome, autoimmune vasculitis [e.g., 
Wegener's granulomatosis]).
8. History of neuropathy considered of autoimmune origin (e.g., 
polyradiculopathy including Guillain-Barré syndrome and myasthenia 
gravis); other CNS autoimmune disease (e.g., poliomyelitis, multiple 
sclerosis). 
9. History of recent infection (within 4 weeks of C1D1) considered to be 
caused by one of the pathogens listed in section 7.3.4.5: HSV1, HSV2, 
VZV, EBV, CMV, measles, Influenza A, Zika virus, Chikungunya 
virus, mycoplasma pneumonia, Campylobacter jejuni, or enterovirus 
D68.
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10. Known seropositive for human immunodeficiency virus (HIV), 
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). 
11. History of Stevens-Johnson syndrome or toxic epidermal necrolysis 
syndrome.
12. Pregnant or breastfeeding women.
13. 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.
14. Use of any other experimental medication(s) within 14 days or 
5 half-lives, but in no case <14 days prior to start of the study treatment 
on Cycle 1, Day 1, except if approved by the Sponsor.
15. 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.
16. 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 Screening.
17. Isolated extramedullary relapse (i.e., testicular, CNS).
18. Congenital long QT syndrome or a QTc interval ≥450 ms at Screening 
(unless secondary to pacemaker or bundle branch block). 
19. Active second primary malignancy other than non-melanoma skin 
cancers, nonmetastatic prostate cancer, in situ cervical cancer, ductal or 
lobular carcinoma in situ of the breast, or other malignancy that the 
Sponsor’s Medical Monitor and the Investigator agree and document 
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should not be exclusionary. 
20. 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-301, used as 
monotherapy, in patients with relapsed or refractory CD25-positive AML
or CD25-positive ALL. The study will determine the MTD, as well as 
evaluate the preliminary activity, PK, and pharmacodynamics (PD) of 
ADCT-301.
In Part 1, patients will be assigned to treatment according to a 3+3 
dose-escalation design and oversight by a Dose-Escalation Steering 
Committee (DESC). In Part 2, all patients will be assigned to the dose level 
of ADCT-301 identified in Part 1.
Estimated Duration 
of Patient 
Participation and 
Study Duration:
For each patient, the study will include a Screening period (up to 28 days), 
a treatment period (until withdrawal), and a follow-up period to assess 
disease progression and survival for up to 12 months after the last dose of 
study drug. The total study duration will be dependent on overall patient 
tolerability to the study drug and response to treatment. It is anticipated that 
the duration of the entire study (Parts 1 and 2) could be approximately 
3 years from first patient treated to last patient completed.
Patients who discontinue treatment for any reason other than disease 
progression will continue to be followed approximately every 12 weeks 
from the last disease assessment until disease progression or initiation of 
new anti-cancer treatment. After documentation of disease progression or 
start of new anti-cancer 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 treatment at any time and for any reason, 
without prejudice to their future medical care. Patients may also be 
withdrawn by the Investigator or others at the study site.
A patient may be withdrawn from treatment for any of the following 
reasons:

Disease progression.

AE.

Withdrawal of consent.

Major protocol deviation.

Required treatment delay >21 days (except in case of potential patient 
benefit, which must be approved by the Sponsor).
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
Non-compliance, including lost to follow-up.

Other (e.g., pregnancy, development of contraindications).

The Investigator determines 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.
Note: Patient enrollment will be halted, pending a safety analysis and 
review with the appropriate regulatory authority(ies):
if any patient in Part 1 or Part 2 experiences a CTCAE Grade 5 AE, 
or 2 non-hematologic CTCAE Grade 4 AEs, which are not 
attributable to the underlying disease, and for which relationship 
to ADCT-301 cannot be ruled out, within 30 days of their last 
dose of ADCT-301.
in the event of another single case of GBS. Patients currently on 
trial having clinical benefit or not yet having reached first bone 
marrow assessment can continue on study once informed and 
they consent to continue treatment.
Note: Patients who experience a dose-limiting toxicity (DLT) during
Cycle 1 are to be permanently discontinued from the study.
Efficacy 
Assessments:
Assessment of response to treatment with ADCT-301 will be based on 
bone marrow samples (aspirate or biopsy, if aspirate unattainable). The
activity of ADCT-301 will be evaluated based on the Investigator’s 
evaluation of the patient’s response to ADCT-301 as CR, CRi, PR, PD, or 
NR.8,11
Complete response is defined as achieving each of the following:

Bone marrow differential showing ≤5% blast cells and absence of blast 
cells with Auer rods.

Absolute neutrophil count (ANC) ≥1.0 x 109/L and platelet count 
≥100 x 109/L.

Absence of extramedullary disease.

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:

ANC ≥1.0 x 109/L and platelet count ≥100 x 109/L.

Bone marrow differential showing a ≥50% decrease from baseline in 
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the percentage of bone marrow blast cells to a level >5% and ≤25%, 
or
bone marrow differential showing <5% blast cells and presence of Auer 
rods. 
No response is defined as not achieving CR, CRi, or PR.
Progressive disease 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.
DOR and ORR will be defined among responders (CR, CRi, or PR); OS 
and PFS will also be determined.
Pharmacokinetic, 
Pharmacodynamic,
and 
 
Assessments:
The PK profile of ADCT-301 (total antibody; drug-to-antibody ratio 
[DAR] ≥0), PBD-conjugated antibody (DAR ≥1), and free warhead 
SG3199 will be assessed. Additional PK, ADA, cytokines, and serum 
CD25 (sCD25); blood samples will be collected at the discretion of the 
Investigator during any visit where toxicity is observed. A PK, ADA, 
cytokines, and sCD25 sample will also be collected concurrently with any 
other blood draw to assess safety (e.g., Unscheduled Visit), if possible. 
The PK profile will include determination of standard PK parameters (e.g.,
maximum concentration [Cmax], time to Cmax [Tmax], AUC0-last, AUC0-τ, 
AUC0-∞, AI, Vss, MRT, λz, t1/2, CL, and Vz.).
 
 
 
 
 
 
 
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Safety Assessments:
Safety will be assessed based on AEs, serious AEs (SAEs), treatment 
discontinuations due to AEs, DLTs, measurements of cytokines in 
serum, periodic 12-lead electrocardiogram (ECG) recordings, physical 
examinations, vital signs measurements, ECOG performance status, and 
hematology, biochemistry, coagulation panel, pregnancy testing (for 
women of child-bearing potential) and urinalysis test results. 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 and/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 AEs (including nausea, vomiting, diarrhea, and 
electrolyte imbalances lasting more than 48 hours despite optimal 
therapy; excluding all grades of alopecia). 
o
Grade 3 or higher hypersensitivity reaction (regardless of 
premedication).
o
Grade 3 or higher skin ulceration.
o
Peripheral sensory or motor neuropathy ≥ Grade 2.
The DLT observation period for dose-escalation will be 1 cycle. Patients
who experience a DLT during Cycle 1 are to be permanently discontinued 
from the study.
Investigational 
Product, Dosage, 
and Mode of 
Administration:
ADCT-301 is a sterile formulation containing PBD-conjugated 
HuMax®-TAC (DAR ≥1), HuMax®-TAC (DAR = 0), and SG3249. It is 
provided pre-formulated in 10-mL glass vials containing approximately 
30 mg of ADCT-301 per vial (deliverable volume 5.4 mL at 6 mg/mL).
The appropriate quantity of ADCT-301 will be diluted in 50 mL of 5% 
dextrose in water (D5W).
Patients will receive a 1-hour intravenous (IV) infusion of ADCT-301 on 
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Day 1 of Cycle 1. If ADCT-301 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.
The investigational product administration schedule is as follows:
Every 3-Week Administration 
Patients will be given ADCT-301 on Day 1 of each 3-week (21-day)
treatment cycle.
Weekly Administration
Patients will be given ADCT-301 (weekly [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 schedule, revert to an every 3-week (Q3W) schedule, or 
test other dosing regimens. 
Dose-Escalation 
Design:
Dose-escalation (Part 1) will be conducted according to a 3+3 design. The 
initial dose of ADCT-301 will be 3 µg/kg (Dose Level 1), and the highest 
allowed dose will be 150 µg/kg every three weeks (50 µg/kg every week). 
The DLT observation period for dose-escalation will be 1 cycle. The first 
patient at each new dose level must be observed for 7 days for occurrence 
of AEs prior to treating the second patient at that dose level. 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 experience 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. 
No intra-patient dose-escalation is allowed.
The number of dose levels will depend on the emergent toxicity profile of 
ADCT-301 and will be decided by the DESC; PK and PD evaluations may 
also inform decision making. 
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During Part 1 (dose-escalation), the DESC may expand enrollment at doses 
below the current dose level as part of the dose-escalation process. 
No more than 9 additional patients (e.g., 3 cohorts of 3 patients) will be 
enrolled in the remaining dose escalation portion of this study (max. dose 
level 50 µg/kg/week) from the date of protocol amendment number 5, 
unless 2 additional patients attain a PR, CR or CRi, in which case 
additional patients will be treated at a dose patients have cleared the DLT
period, to determine if there is sufficient evidence of clinical activity to 
continue the study.
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 (Section 7.1). 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.
Every 3-Week Administration
Patients will be given ADCT-301 on Day 1 of each 3-week treatment cycle.
When the dose is escalated, the dose may increase by 100% if no DLTs are 
observed at the current level (e.g., at 6 μg/kg, the dose increase is 6 μg/kg). 
Once a DLT is observed at a given dose level, the next dose may only 
increase by 50% (e.g., at 6 μg/kg, the dose increase is 3 μg/kg). The dose 
may never increase by more than 100%, or more than an absolute value of 
20 µg/kg at dose levels below 100 µg/kg and 50 µg/kg for dose levels 
between 100 and 150 µg/kg, whichever is less. A patient will maintain the 
same treatment schedule throughout the duration of the trial.
Weekly Administration
Patients will be given ADCT-301 (QW) on Days 1, 8 and 15 of each 
3-week 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 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 92 µg/kg, the first cohort to 
receive QW dosing will receive 30 µg/kg each week for 3 weeks. 
When the dose is escalated, the dose may increase by 50% if no DLTs are 
observed at the current level. Once a DLT is observed at a given dose level, 
the next dose may only increase by 25%. The dose may never increase by 
more than 50%, or more than an absolute value of 20 µg/kg/week, 
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whichever is less. 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 partial response (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 Part 2 (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.
Sample Size:
A maximum of 80 patients (up to 50 patients in Part 1 and up to 30 patients 
in Part 2) may be enrolled at approximately 10 study sites in Part 1 and 
10 study sites in Part 2.
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List of Abbreviations
Abbreviation
Definition
ADA
anti-drug antibody
ADC
antibody-drug conjugate
ADL
activities of daily living
AE
adverse event
AI
accumulation index
Ala
alanine
ALL
acute lymphoblastic leukemia
ALT
alanine aminotransferase
AML
acute myeloid leukemia
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
β-HCG
Beta-human chorionic gonadotropin
BMA
bone marrow aspirate
BSA
BSI
body surface area
before-start of infusion
CBC
complete blood count
CD
cluster of differentiation
sCD
serum cluster of differentiation
CFR
Code of Federal Regulations
CL
Clearance
Cmax
maximum concentration
CMV
cytomegalovirus
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
DESC
Dose-Escalation Steering Committee
DLT
dose-limiting toxicity
DOR
duration of response
EBV
Epstein-Barr virus
ECG
electrocardiogram
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Abbreviation
Definition
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic case report form
EOI
end of infusion
EOT
end of treatment
FDA
Food and Drug Administration
FLT3-ITD
FMS-like tyrosine kinase 3 internal tandem duplications
GBS
Guillain-Barré syndrome
GCP
Good Clinical Practice
GLP
Good Laboratory Practice
HbsAg
hepatitis B surface antigen
HSV1 / 2
Herpes Simplex Virus Type 1 / Type 2
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
IL-2R
interleukin-2 receptor
INR
International Normalized Ratio
IP
investigational product 
IRB
institutional review board
IV
IVF
intravenous
intravenous fluid
kDa
kilodalton
LSC
leukemic stem cell
MNC
mononuclear cells
MRT
mean residence time
MTD
maximum tolerated dose
NR
no response
ORR
overall response rate
OS
overall survival
PABA
para-aminobenzoic acid
PBD
pyrrolobenzodiazepine
PBMC
peripheral blood mononuclear cell
PD
pharmacodynamics or progressive disease
PEG
polyethylene glycol
PFS
progression-free survival
Ph
Philadelphia chromosome
PK
PLEX
pharmacokinetic
plasma exchange
PR
partial response
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Abbreviation
Definition
PT
prothrombin time
PTT
partial thromboplastin time
RBC
Q3W
red blood cell
every 3 weeks
QTc
QW
corrected QT interval
every week
QWBA
quantitative whole-body autoradiography
SAE
serious adverse event
SAP
statistical analysis plan
SEER
US Surveillance Epidemiology and End Results
SUSAR
suspected unexpected serious adverse reaction
TAC
t-cell activation antigen
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
US
United States
Vss
volume of distribution at steady-state
Val
valine
VZ
volume of distribution
VZV
varicella zoster virus
WB
whole blood
WBC
white blood cell
WHO
World Health Organization
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1
Introduction
ADCT-301 is an antibody-drug conjugate (ADC), composed of the human monoclonal antibody, 
HuMax®-TAC, directed against human cluster of differentiation 25 (CD25), and conjugated 
through a 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.16 The schematic representation of ADCT-301,
and the different components that may be formed following the administration of this ADC to 
humans, are presented in Figure 1.
Figure 1. Schematic Representation and Chemical Structure of ADCT-301
Abbreviations: Ala, alanine; PABA, para-aminobenzoic acid; PEG, polyethylene glycol; HuMax®-TAC, human 
monoclonal antibody being studied; Val, valine. 
The make-up of ADCT-301 includes:

HuMax®-TAC: A human monoclonal antibody of the IgG1, kappa isotype, specific for 
human CD25.

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.

SG3199: A PBD dimer cytotoxin, which is a highly efficient anti-cancer drug due to its
interstrand cross-linking, a consequence of its specifically designed strong binding to the 
minor groove of DNA.
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The interleukin-2 receptor (IL-2R) is made up of 3 subunits: α (CD25), β (CD122) and γ 
(CD132). CD25, or T-cell activation antigen (TAC), is the alpha-chain of IL-2R.5,6 ADCT-301
binds with picomolar affinity to human CD25. After binding and internalization, ADCT-301 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 
in a sequence-selective manner, and form highly cytotoxic DNA interstrand cross-links.16
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.1
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2
Study Rationale and Justification for Dose Level Selection 
2.1 Clinical Background
Acute myeloid leukemia (AML) is a heterogeneous hematologic malignancy characterized by 
the clonal expansion of myeloid blasts in the peripheral blood, bone marrow, and/or other tissues. 
It is the most common leukemia in adults and results in the largest number of deaths due to 
leukemia in the USA. The diagnosis will account for 38% of an estimated 54,270 new cases of 
leukemia and 42% of estimated deaths due to leukemia in 2015.2 It is more common in older 
adults (median age at onset, 67 years), with 72% of cases diagnosed at ages 55 years and older. 
The overall 5-year survival rate for AML is 26%, with younger patients (age <45 years) having a 
higher survival rate (>50%) compared with older patients (~10% for patients 65-74 years). 23
Cytotoxic induction therapy is associated with high rates of complete response/remission, 
especially for younger patients who are able to tolerate treatment. The discrepancy between the 
high response rates achieved with induction therapy and poor long-term survival is due to the 
inability to prevent or overcome disease relapse.4,14 The majority of patients with AML will 
eventually relapse or develop refractory disease. The prognosis for these patients is poor and 
most patients will die from progressive disease (PD).
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 US 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%.24
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.24
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.17,21,30
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There are specific subtypes of ALL associated with specific cytogenetic changes and expression 
of certain cell surface markers that confer a poor prognosis. While the addition of tyrosine kinase 
inhibitors to the treatment protocols of patients with Philadelphia chromosome (Ph)+ and Ph-like 
ALL have improved remission rates and disease-free survival, patients unable to undergo 
hematopoietic stem cell transplantation still have a poor prognosis with a 3-year overall survival 
(OS) of 14%.18
CD25, or TAC, is the 55-kilodalton (kDa) alpha-chain of IL-2R.6 In normal human tissue, 
expression of CD25 is mainly limited to activated T- and B-cells.5,6 It is not expressed on normal 
human hematopoietic stem cells,29 but has been demonstrated in subpopulations of 
chemotherapy-resistant human leukemic stem cells (LSC).10 Survival of quiescent, 
chemotherapy-resistant LSCs may play a role in the development of relapsed or refractory 
disease in AML.10,19
CD25 expression has been demonstrated in newly diagnosed and relapsed AML 7,13,33 and in 
late-stage myelodysplastic syndrome related AML.20 Expression of CD25 by AML blast cells is 
associated with adverse outcomes, including induction failure, relapse, and shortened OS.7,13,20,33
Expression of cluster of differentiation 25 (CD25) independently confers a poor prognosis for 
patients with ALL and is commonly found in patients with Ph+ ALL.22
It is not yet understood what biological role, if any, CD25 may play in the development of 
adverse outcomes. However, the availability of treatment specifically targeted to cells expressing 
CD25 may provide additional therapeutic options for these patients.
2.2 Non-clinical Efficacy and Safety of ADCT-301
The potential for ADCT-301 in treating hematological malignancies, which demonstrate CD25
over-expression, has been shown by complete responses in mouse xenograft models following 
single, low-dose administration. The efficacy of ADCT-301 in these models is due to targeted 
delivery of the PBD cytotoxin SG3199.
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The safety of ADCT-301 has been assessed in non-clinical testing. In mice, ADCT-301 is well 
tolerated at doses up to 9 mg/kg. A repeat-dose Good Laboratory Practice (GLP) toxicology 
study in cynomolgus monkeys investigated doses ranging from 0.15 to 0.9 mg/kg. Systemic 
exposure to total ADCT-301 was consistent with the intravenous (IV) infusion route and
increased in a generally dose-proportional manner. No marked sex-related differences in 
exposure were noted. No evidence of accumulation or changes in median time to maximum 
concentration (Tmax) and in mean terminal half-life (t1/2), clearance (CL), and volume of 
distribution (Vz) estimates were observed with increasing dose or on repeat dosing (where total 
ADCT-301 was sufficiently quantifiable). The average Day 1 ADCT-301 maximum 
concentration (Cmax) (N = 2 at each dose level) at 0.3 mg/kg, 0.6 mg/kg, and 0.9 mg/kg was 
4,520 ng/mL, 12,450 ng/mL and 15,950 ng/mL, respectively. The t1/2 value for ADCT-301
ranged from 4.25 days to 7.54 days for doses 0.3 mg/kg to 0.9 mg/kg.
Toxicities included body weight loss, nephrotoxicity, and cutaneous adverse events (AEs). 
The highest non-severe toxic dose (HNSTD) in the GLP-compliant study in cynomolgus 
monkeys was determined to be 0.15 mg/kg. As per guidance from the Food and Drug 
Administration (FDA), a starting dose of 10 µg/kg (1/6 of the HNSTD, based on body surface 
area [BSA]) could be proposed for this first study in patients with AML. However, based on 
anomalous exposure data observed on some dosing days at the 0.15 mg/kg dose level (no 
explanation in the formulation or dosing records), a lower starting dose of 3 µg/kg was chosen 
for this study to offset any uncertainty associated with the 0.15 mg/kg dose level and to increase 
the margin of safety.
See the Investigator Brochure for ADCT-301 for additional information, including guidance for 
the Investigator.
2.3 Safety of Commercially Available Antibodies Directed against CD25
The safety profiles of monoclonal antibodies directed against CD25 (IL2-Rα), such as Simulect®
(basiliximab, Novartis Pharmaceuticals, NJ, USA) and Zenapax® (daclizumab, Roche 
Pharmaceuticals, NJ, USA), have been well characterized. Both products are indicated for 
prophylaxis of acute organ transplant rejection in patients receiving renal transplant. The most 
frequently reported AEs identified in the prescribing information for both products are 
gastrointestinal disorders, including abdominal pain, constipation, diarrhea, nausea, and 
vomiting.25,27
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3
Study Objectives
3.1 Primary Objectives
The primary objectives for Part 1 (dose-escalation) and Part 2 (expansion) of the study are:

Evaluate the safety and tolerability and determine the maximum tolerated dose (MTD) of 
ADCT-301 in patients with CD25-positive relapsed or refractory AML or CD25-positive 
ALL (Part 1).

Determine the recommended dose of ADCT-301 for Part 2.

Evaluate the safety and tolerability of ADCT-301 in Part 2 at the dose level recommended in 
Part 1.
3.2 Secondary Objectives
The secondary objectives for Part 1 and Part 2 of the study are:

Evaluate the clinical activity of ADCT-301, based on the patient’s response to treatment 
(complete response [CR], CR with incomplete blood count recovery [CRi], partial response 
[PR], PD, no response [NR]) and determination of the overall duration of response (DOR), 
overall response rate (ORR), OS, and progression-free survival (PFS).

Characterize the pharmacokinetic (PK) profile of ADCT-301 (total antibody,
drug-to-antibody ratio [DAR] ≥0), PBD-conjugated antibody (DAR ≥1), and free warhead 
SG3199.

Evaluate anti-drug antibodies (ADAs) to ADCT-301 in blood before, during, and after 
treatment with ADCT-301.
 
 
 
 
 
 
 
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Investigational Plan and Patient Selection
4.1 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-301, used as monotherapy, in patients with relapsed or refractory 
CD25-positive AML or CD25-positive ALL. The study will determine the MTD, as well as 
evaluate the preliminary activity, PK, and pharmacodynamics (PD) of ADCT-301.
Patients will receive a 1-hour IV infusion of ADCT-301 on Day 1 of Cycle 1. If ADCT-301 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 4.1.1. 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 5.2.1), 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 4.1.1) and oversight of a Dose-Escalation Steering Committee (DESC) (Section 7.3.1.2). 
In Part 2, (expansion), all patients will be assigned to the dose level of ADCT-301 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 anti-cancer 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.
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4.1.1
Dose-escalation (Part 1) and Determination of Maximum Tolerated    
Dose
Dose-escalation will be conducted according to a 3+3 design (Figure 2). The initial dose of 
ADCT-301 will be 3 µg/kg (Dose Level 1), and the highest allowed dose will be 150 µg/kg every 
three weeks (50 µg/kg every week).
The DLT (see Section 7.3.1.1 for further details) observation period for dose-escalation will be 
1 cycle. The first patient at each new dose level must be observed for 7 days for occurrence of 
AEs prior to treating the second patient at that dose level. 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,
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
* For every 3 weeks (Q3W) administration, the dose increase will never exceed 100% or 20 µg/kg at dose levels below 100 
µg/kg and 50 µg/kg for dose levels between 100 and 150 µg/kg, whichever is less. Dose adjustment for other treatment schedules, 
such as QW dosing are included below. Abbreviations: DLT, dose-limiting toxicity; MTD, maximum tolerated dose; <, less than; 
≥ greater than or equal to.
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The number of dose levels will depend on the emergent toxicity profile of ADCT-301 and will 
be decided by the DESC (Section 7.3.1.2); PK and PD evaluations may also inform decision 
making.
During Part 1 (dose-escalation), 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 (Section 7.1). 
No more than 9 additional patients (e.g., 3 cohorts of 3 patients) will be enrolled in the remaining 
dose escalation portion of this study (max. dose level 50 µg/kg/week) from the date of protocol 
amendment number 5, unless 2 additional patients attain a PR, CR, or CRi, in which case additional 
patients will be treated at a dose patients have cleared the DLT period, to determine if there is 
sufficient evidence of clinical activity to continue the study.
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.
Every 3-Week Administration
Patients will be given ADCT-301 on Day 1 of each 3-week treatment cycle.
When the dose is escalated, the dose may increase by 100% if no DLTs are observed at the 
current level (e.g., at 6 μg/kg, the dose increase is 6 µg/kg). Once a DLT is observed at a given 
dose level, the next dose may only increase by 50% (e.g., at 6 μg/kg, the dose increase is
3 μg/kg). The dose may never increase by more than 100%, or more than an absolute value of 
20 µg/kg at dose levels below 100 µg/kg and 50 µg/kg for dose levels between 100 and 
150 µg/kg, whichever is less.
Weekly Administration
Patients will be given ADCT-301 (QW) on Days 1, 8, and 15 of each 3-week 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 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 92 µg/kg, 
the first cohort to receive (QW) dosing will receive 30 µg/kg each week for 3 weeks.  
When the dose is escalated, the dose may increase by 50% if no DLTs are observed at the current 
level. Once a DLT is observed at a given dose level, the next dose may only increase by 25%. 
The dose may never increase by more than 50%, or more than an absolute value of 
20 µg/kg/week, whichever is less.  
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.   
4.1.2
Dose Expansion (Part 2) 
During Part 2 (dose expansion), patients will be monitored for safety using the same DLT criteria 
employed during Part 1 (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.
4.2 Selection of Study Population
A maximum of 80 patients (up to 50 patients in Part 1 and up to 30 patients in Part 2) may be 
enrolled at approximately 10 study sites in Part 1 and 10 study sites in Part 2. Patients will be 
assigned to a study treatment only if they meet all of the inclusion criteria and none of the 
exclusion criteria.
4.2.1
Inclusion Criteria
1.
Male or female age 18 years or older.
2.
Patients with:

Relapsed or refractory CD25-positive* AML** who have failed, or are intolerant to, any 
established therapy known to provide clinical benefit at current state of disease.

Myelodysplastic syndrome who have received treatment with hypomethylating agents and 
subsequently present with CD25-positive* AML** and who failed, or are ineligible for 
standard induction therapy.

Relapsed or refractory CD25-positive *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: *CD25-positive is defined as determination of CD25 expression by ≥5% of blast cells 
within bone marrow (aspirate or biopsy), assessed at an approved clinical laboratory. 
**Diagnosis and classification as per World Health Organization (WHO) classification of 
acute leukemias.34
3.
Eastern Cooperative Oncology Group (ECOG) performance status 0-2.
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4.
Serum/plasma creatinine ≤1.5mg/dL, or if the patient has a serum/plasma creatinine 
>1.5mg/dL, creatinine clearance must be >60 mL/min/1.73m2, as calculated by the 
Cockcroft and Gault equation.9
5.
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.
6.
Total serum/plasma bilirubin ≤1.5 times the ULN. Patients with known Gilbert’s syndrome 
may have a total bilirubin up to ≤3 times ULN.
7.
Women of child-bearing potential must have a negative urine or serum beta-human 
chorionic gonadotropin (β-HCG) pregnancy test within 7 days prior to the Day 1 visit.
8.
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-301. 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-301.
*
Defined as: Sexually mature women who have not undergone bilateral tubal ligation, 
bilateral oophorectomy, or hysterectomy; or who have not been post-menopausal (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.
9.
White blood cell count value of <15,000 cells/µL prior to C1D1.
4.2.2
Exclusion Criteria
1.
Patients who have an option for any treatment with proven clinical benefit for 
CD25-positive AML or CD25-positive ALL at current state of disease.
2.
Known active central nervous system (CNS) leukemia, defined as morphologic evidence of 
leukemic blasts 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.
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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.
Active graft-versus-host disease.
4.
Autologous or allogenic transplant within the 60 days prior to Screening.
5.
Known history of immunogenicity or hypersensitivity to a CD25 antibody.
6.
Known history of positive serum human ADA, or known allergy to any component of 
ADCT-301.
7.
History of symptomatic autoimmune disease (e.g., rheumatoid arthritis, systemic 
progressive sclerosis [scleroderma], systemic lupus erythematosus, Sjögren’s syndrome, 
autoimmune vasculitis [e.g., Wegener’s granulomatosis]).
8.
History of neuropathy considered of autoimmune origin (e.g., polyradiculopathy including 
Guillain-Barré syndrome and myasthenia gravis); other CNS autoimmune disease 
(e.g., poliomyelitis, multiple sclerosis).
9.
History of recent infection (within 4 weeks of C1D1) considered to be caused by one of the 
pathogens listed in section 7.3.4.5: HSV1, HSV2, VZV, EBV, CMV, measles, Influenza A, 
Zika virus, Chikungunya virus, mycoplasma pneumonia, Campylobacter jejuni, or enterovirus 
D68.
10.
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).
11.
History of Stevens-Johnson syndrome or toxic epidermal necrolysis syndrome.
12.
Pregnant or breastfeeding women.
13.
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.
14.
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.
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15.
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.
16.
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 Screening.
17.
Isolated extramedullary relapse (i.e., testicular, CNS).
18.
Congenital long QT syndrome or a QTc interval ≥450 ms at Screening (unless secondary to 
pacemaker or bundle branch block).
19.
Active second primary malignancy other than non-melanoma skin cancers, nonmetastatic 
prostate cancer, in situ cervical cancer, ductal or lobular carcinoma in situ of the breast, or 
other malignancy that the Sponsor’s Medical Monitor and the Investigator agree and 
document should not be exclusionary.
20.
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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5
Study Procedures
5.1 Procedures by Study Day – Every 3-Week Dosing Schedule (Q3W)
The following procedures will be performed during the study. Regardless of dosing schedule, all 
patients will complete the same Screening procedures described in Section 5.1.1, as well as the 
same procedures described for the End of Treatment (EOT; Section 5.1.8), 12-Week Follow-up 
Visit (Section 5.1.9) and Long-term Follow-up (Section 5.1.10).
Visit procedures described in Section 5.1.2 – Section 5.1.7 are for patients on the Q3W Schedule.  
The Schedule of Procedures for the Q3W and QW dosing schedules are shown in Table 1 and 
Table 3, respectively, in Appendix 13.1. Timings for sample collections for assessment of PK, 
and other parameters for the Q3W dosing schedule are shown in Table 2, and 
Cycle 1 and Cycle 2+ of the QW dosing schedule in Table 4 and Table 5, respectively, in
Appendix 13.1.
For QW dosing, most of the assessments will remain uniform with the Q3W dosing assessments, 
with the following exceptions:

Study drug administration will occur at Days 1, 8, and 15

The Q3W Day 19 assessments will be performed on Day 15 (concurrently with the 3rd QW
dose) for the QW patients 
o
Note: Bone marrow aspirate (BMA) or biopsy for QW patients is still performed at 
Day 19 ± 3 days but must be performed prior to the first dose of the next cycle.

Pharmacokinetic and Pharmacodynamics, ADA, serum CD25 (sCD25), WBC population, 
cytokines, and additional renal function studies sampling schedule is adjusted according to 
the prescribed dosing schedule.  
5.1.1
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.
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
Medical history (to include a complete history of all surgeries, significant diagnoses, all 
cancer treatment [including surgery, radiation therapy, chemotherapy, etc.], and FLT3-ITD 
status, if available).

Serum or urine β-HCG pregnancy testing (women of child-bearing potential only).

Physical examination, including neurological examination and 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. The examination must include a determination if the 
patient has had any infection. At the discretion of the investigator, evaluation of any reported 
infection must be conducted to rule out infection with a microorganism that may be 
associated with autoimmune or neurological disease(s) as specified in the exclusion criteria.
o
Neurological assessment (as part of the physical examination) including strength, 
sensation, and deep-tendon reflexes throughout; examination does not need to be 
conducted by neurologist unless there are abnormal findings not explained by 
previous medical history (e.g., a patient with left sided weakness known to be a result 
of a previous CVA would not need to see a neurologist as part of this study) and that 
could be linked to or may be an early indicator of polyradiculopathy/GBS, such as 
ascending (bilateral) sensory loss or motor weakness.

Vital signs (arterial blood pressure, heart rate, respiratory rate, body temperature), height and 
weight measurements.

ECOG performance status.

Collection of information on disease related mutations, including FLT-3, if available.

Bone marrow aspirate (or biopsy if aspirate unattainable):
o
Evaluation of CD25 expression on blast cells, assessed at an approved local clinical 
laboratory (see Inclusion Criterion 2, Section 4.2.1).
o
Confirmation of disease, as per the WHO classification of acute leukemias,34 at an 
approved local clinical laboratory.

 

 
 
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
Hematology, coagulation panel, biochemistry, and urinalysis parameters.
o
Patients with a WBC value >15,000 cells/μL may receive treatment with hydroxyurea 
and/or leukopheresis, to lower the WBC value to <15,000 cells/μL prior to Day 1, 
Cycle 1 dosing. Hydroxyurea may be used during the first cycle to control WBC count at 
Investigator discretion.
o
Collection of mononuclear cells (MNC) sample.

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.
5.1.2
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-301 infusion at each cycle, unless otherwise specified. Timing for sample collections and 
procedures is provided in Appendix 13.1.

Serum or urine 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 neurological examination and including whole-body skin 
assessment, unless a physical examination was performed within 3 days prior to Day 1.
The examination must include a determination if the patient has had any infection. At the 
discretion of the investigator, evaluation of any reported infection must be conducted to rule 
out infection with a microorganism that may be associated with autoimmune or neurological 
disease(s) as specified in the exclusion criteria.

On Day 1 of Cycle 1, vital signs are to be measured before the start of the infusion, every 
30 minutes during the infusion, and at the end of infusion. If no clinically significant changes 
occur during this first infusion, vital sign measurements are to be obtained prior to infusion 
start and end of infusion for all subsequent infusions. For Cycles 1 and 2, patients will also 
have vital signs measured 1 hour after the end of infusion and at discharge.
Note: Timing of measurements is ± approximately 5 minutes.

Weight, unless an assessment was performed within 3 days prior to Day 1.

ECOG performance status, unless an assessment was performed within 3 days prior to Day 1.

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-301 infusion on Day 1 of Cycle 1, or
o
<72 hours before the start of ADCT-301 infusion on Day 1 of Cycle 2 and subsequent 
cycles. 
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
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-301 infusion on Day 1 of Cycle 1, or
o
<72 hours before the start of ADCT-301 infusion on Day 1 of Cycle 2 and subsequent 
cycles.

12-lead ECG (Cycles 1 and 2), before the start of infusion, at end of infusion, and at 3 hours 
after the end of infusion (Section 7.3.5).

Sample collection for central laboratory analysis of soluble CD25 and ADA (all cycles). 

Sample collection for central laboratory analysis of PK parameters for Q3W is before the 
start of the ADCT-301 infusion, at the end of the infusion, and at 1, 3, and 6 hours after the 
end of the ADCT-301 infusion (Cycles 1 and 2). In all subsequent cycles, samples will be 
collected before the start of the ADCT-301 infusion and at the end of the infusion.

Sample collection and shipment for central laboratory analysis of peripheral WBC
populations (Part 2).

Sample collection for cytokine analysis before the start of the ADCT-301 infusion and at 
6 hours after the end of the infusion in Cycles 1 and 2.

Collection of AE information.

Collection of concomitant medication information. 

Premedication administration, if applicable (Section 6.2).

ADCT-301 administration.
5.1.3
Day 2 (Cycles 1 and 2)
The following procedures will be performed 24 hours after the end of infusion:

12-lead ECG.

Sample collection for central laboratory analysis of PK parameters.

Sample collection for cytokine analysis.
5.1.4
Day 3 (Cycles 1 and 2)
The following procedures will be performed 48 hours after the end of infusion:

Sample collection for central laboratory analysis of PK parameters.

Sample collection and shipment for central laboratory analysis of peripheral WBC 
populations (Part 2).
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5.1.5
Day 5 (Cycles 1 and 2)
The following procedures will be performed 96 hours after the end of infusion:

Sample collection for central laboratory analysis of PK parameters.

Sample collection and shipment for central laboratory analysis of peripheral WBC 
populations (Part 2).
5.1.6
Day 8 (± 1 day) of Each Cycle

Physical examination, including neurological examination and including whole-body skin 
assessment (Cycles 1 and 2). The examination must include a determination if the patient has 
had any infection.  At the discretion of the investigator, evaluation of any reported infection 
must be conducted to rule out infection with a microorganism that may be associated with 
autoimmune or neurological disease(s) as specified in the exclusion criteria.

Weight (Cycles 1 and 2).

Vital signs.

Hematology and biochemistry parameters.

Urinalysis and sample collection for additional renal function studies.

Sample collection for central laboratory analysis of PK (Cycles 1 and 2).

Sample collection for central laboratory analysis of peripheral WBC populations (Part 2). 

Collection of AE information.

Collection of concomitant medication information.
5.1.7
Day 19 (±3 days) of Each Cycle
NOTE: If the timing of the assessments required at the Day 1 visit for the next cycle coincides 
with the Day 19 visit, assessments that are included at both Day 19 and Day 1 are to be 
performed only once. 

Physical examination, including neurological examination and including whole-body skin 
assessment for Cycles 1 and 2. The examination must include a determination if the patient 
has had any infection. At the discretion of the investigator, evaluation of any reported 
infection must be conducted to rule out infection with a microorganism that may be 
associated with autoimmune or neurological disease(s) as specified in the exclusion criteria.

Weight and vital signs measurements (Cycles 1 and 2).

Hematology and biochemistry parameters.

Urinalysis and sample collection for additional renal function studies.

Sample collection for central laboratory analysis of PK (Cycles 1 and 2).

Sample collection for central laboratory analysis of peripheral WBC populations (Part 2).

Collection of AE information.
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
Collection of concomitant medication information.
5.1.7.1 Bone Marrow Aspirate or Biopsy
A BMA (or biopsy if aspirate unattainable) will be obtained at the Day 19 visit (±3 days) of each 
cycle, beginning with Cycle 2, and repeated at each subsequent cycle, until disease progression,
CR (Section 7.1), or CRi is achieved. Once CR/CRi is achieved, sampling will be repeated at 
least every 3 cycles, or, as clinically indicated.
A bone marrow sample (aspirate or biopsy if aspirate unattainable) will also be collected at the 
EOT Visit (Section 5.1.8) 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.
Response to treatment with ADCT-301 (Section 7.1) is to be performed by an approved clinical 
laboratory.
5.1.8
End of Treatment Visit
The following procedures will be performed within 30 days (+ 7 days) after treatment 
discontinuation:

Serum or urine pregnancy test.

Physical examination, including neurological examination and including whole-body skin 
assessment. The examination must include a determination if the patient has had any 
infection. At the discretion of the investigator, evaluation of any reported infection must be 
conducted to rule out infection with a microorganism that may be associated with 
autoimmune or neurological disease(s) as specified in the exclusion criteria.

Weight and vital signs measurements.

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, soluble CD25, ADA, and 
cytokines. 

Sample collection for central laboratory analysis of peripheral WBC populations (Part 2).

Collection of AE information.

Collection of concomitant medication information.

Bone marrow sample (see Section 5.1.7.1).
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5.1.9
12-Week Follow-up Visit
Each patient will have a sample taken for assessment of PK and ADA at 12 weeks (±1 week)
after their last dose of ADCT-301.
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-301.
For all patients, collection of AEs and SAEs will continue for 84 days (12 weeks) after the last 
dose of study drug or initiation of new anti-cancer treatment (see Section 7.3.2.2).
5.1.10
Long-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 anti-cancer 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.
5.2 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.
5.2.1
Reasons for Withdrawal/Discontinuation
Patients may withdraw from treatment at any time and for any reason, without prejudice to their
future medical care. Patients may also be withdrawn by the Investigator or others at the study site.
A patient may be withdrawn from treatment for any of the following reasons:

Disease progression.

AE.

Withdrawal of consent.

Major protocol deviation.

Required treatment delay >21 days (except in case of potential patient benefit, which must be 
approved by the Sponsor).

Non-compliance, including lost to follow-up.

Pregnancy.

Other (e.g., development of contraindications).
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
The Investigator determines 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.
Note: Patient enrollment will be halted, pending a safety analysis and review with the 
appropriate regulatory authority(ies), if any patient in Part 1 or Part 2 experiences a CTCAE 
Grade 5 AE, or 2 non-hematologic CTCAE Grade 4 AEs, which are not attributable to the 
underlying disease, and for which relationship to ADCT-301 cannot be ruled out, within 30 days 
of their last dose of ADCT-301. 
Note: Patients who experience a DLT during Cycle 1 are to be permanently discontinued from 
the study.
5.2.2
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 7.3.2.6).
For each patient who discontinues study treatment and withdraws from the study, the 
Investigator will record the reason(s) for discontinuation on the relevant page of the electronic 
case report form (eCRF). Whenever possible, each patient who discontinues study treatment will 
undergo an EOT Visit and all EOT assessments (Section 5.1.8). Patients who fail to return for 
final assessments are to be contacted by the investigative site. Following a minimum of two
documented unsuccessful telephone calls, the investigative site will send a registered letter to the 
patient in a final attempt to ensure protocol compliance.
Note: Once discontinued from the study, for any reason, patients are not permitted to be 
re-enrolled into the study.
5.2.3
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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6
Study Treatments
6.1 Method of Assigning Patients to Treatment
In Part 1 (dose-escalation), patients will receive an IV infusion of ADCT-301 according to their 
assigned schedule.
The first patient at each new dose level must be observed for 7 days for occurrence of AEs prior 
to treating the second patient at that dose level. Patients will be entered sequentially to each dose 
level. The dose-escalation procedure is described in Section 4.1.1.
In Part 2, (expansion), all patients will be assigned to the dose level of ADCT-301 identified in 
Part 1 by the DESC. Once the recommended Part 2 dose is determined, patients receiving lower 
dose levels of ADCT-301 may be offered continued treatment at the recommended dose. 
6.2 Prophylactic Treatments for Hypersensitivity
If 1 patient experiences a CTCAE Grade 2 or higher infusion-related hypersensitivity reaction
(Appendix 13.2) 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-301 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-301 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-301 infusion.

For 2 days following administration of ADCT-301 on Day 1, all patients are to take 
dexamethasone 4 mg orally, twice per day.
Other doses and 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.
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If a patient experiences a CTCAE Grade 1 or 2 hypersensitivity reaction, the following 
medications (or equivalent) should be administered for 48 hours after ADCT-301 infusion:

Ranitidine 150 mg orally, 2 times per day.

Diphenhydramine hydrochloride 50 mg orally, 3 times per day.
Any patient who experiences a CTCAE Grade 3 or higher hypersensitivity reaction
(Appendix 13.2) should be discontinued from the study 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.
6.3 Treatments Administered
In Part 1 (dose-escalation), each patient will be assigned a dose level as described in 
Section 4.1.1. In Part 2 (expansion), all patients will be assigned to the dose level identified in 
Part 1 by the DESC.
Patients will receive a 1-hour IV infusion of ADCT-301 on Day 1 of Cycle 1. If ADCT-301 is 
well tolerated after the first infusion, the infusion duration may be shortened to a 30-minute
IV infusion for subsequent cycles, on an individual patient basis, at the Investigator’s discretion.
Variations in infusion times due to minor differences in IV bag overfill/underfill and the
institution’s procedure for flushing chemotherapy lines will not result in protocol deviation.
Prophylactic antiemetic medications, electrolyte supplementation, and other standard supportive 
care measures may also be administered according to standard treatment center protocols, or as 
in Section 6.2.
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-301.
Available pre-clinical data on ADCT-301 does not suggest a photosensitivity concern, based on 
the lack of any signals in the rat and monkey toxicology studies with ADCT-301 and the 
non-clinical experience with SG3199, including a QWBA (quantitative whole-body 
autoradiography) study indicating no specific accumulation to melanin containing tissues, skin or 
eyes.
However, skin rash has been reported in the ADCT-301 program, as well as with another 
investigational agent containing the same pyrollobenzodiazepine warhead.28 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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6.4 Dose Delays and Modifications
Patients will receive the first 2 cycles, 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] >0.5 x109/L and/or platelets >50 x109/L).
The Investigator should suspend ADCT-301 dosing for up to 21 days for any patient who
experiences a protocol-defined DLT during any treatment cycle. 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-301 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-301. Following recovery 
to CTCAE Grade 1 or to baseline grade, treatment with ADCT-301 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.
Dosing frequency may be adjusted according to individual patient response as described in 
Section 4.1.1.
Patients experiencing certain types of infection during the course of participation in this clinical 
study also must delay further dosing, as stipulated in Section 7.3.4.5.
Patients experiencing any autoimmune toxicities (e.g., endocrinopathies) ≥ grade 1 need to be 
followed at least weekly to quickly detect deterioration and modify dosing as per DLT criteria 
(can be done by telephone unless symptoms worsen).
Patients who experience a DLT (Section 7.3.1.1) during Cycle 1 are to be permanently 
withdrawn from the study. Patients who experience the following significant toxicities will be 
immediately and permanently withdrawn from treatment with ADCT-301:

Any patient who experiences a CTCAE Grade 3 or higher hypersensitivity reaction, 
regardless of premedication, during any cycle of treatment (Appendix 13.2).

Any patient who experiences a recurrent CTCAE Grade 3 or 4 toxicity, excluding 
hematological toxicity.

Any patient who requires a dosing delay >21 consecutive days from the planned Day 1 
dosing at any time during treatment (except in case of potential patient benefit, which must 
be approved by the Sponsor).
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Neurological toxicities: dose delay/permanent discontinuation 
Patients experiencing any new neurological toxicities ≥ Grade 1, not explained by previous 
medical history, that could be linked to or may be an early indicator of polyradiculopathy/GBS, 
such as ascending (bilateral) sensory loss or motor weakness, need to be immediately evaluated 
by a neurologist and dosing of ADCT-301 needs to be delayed until polyradiculopathy/GBS is 
ruled out. Should further clinical, radiologic, or laboratory evidence support the diagnosis of 
polyradiculopathy/GBS with the level 1 of diagnostic certainty (Appendix 13.3), treatment with 
ADCT-301 must be stopped and patient must be permanently discontinued.
Patients with Grade ≥ 3 neurologic toxicities, defined as peripheral sensory and peripherally 
motor neuropathies, must be permanently discontinued.
Other new neurological findings not explained by previous medical history increase of ≥ 1 grade 
over baseline will result in dose delay; dosing may be resumed after resolution to baseline, at the 
investigator’s discretion. The patient must be carefully monitored at least weekly until such 
resolution (can be done by telephone unless symptoms worsen).
6.5 Study Stopping Rules
The study will be stopped if any of the following circumstances occur:

Two additional patients (from date of December 14, 2017) develop 
polyradiculopathy/GBS (Level 1 of diagnostic certainty; Appendix 13.3). Continuation of 
patients who have shown clinical benefit will be discussed with the relevant regulatory 
authority(ies) if this stopping rule is applied.

≥30% of patients experience a specific Grade 4 or higher non-hematologic treatment-
emergent AE.
Furthermore, patient enrollment will be halted, pending a safety analysis and review with the 
relevant regulatory authority(ies):

if any patient in Part 1 or Part 2 experiences a CTCAE Grade 5 AE, or 2 non-hematologic 
CTCAE Grade 4 AEs, which is not attributable to the underlying disease, and for which 
relationship to ADCT-301 cannot be ruled out, within 30 days of their last dose of 
ADCT-301.

in the event of another single case of GBS. Patients currently on trial having clinical 
benefit or not yet having reached first bone marrow assessment can continue on study 
once informed and they consent to continue treatment.
6.6 Identity of Investigational Product
ADC Therapeutics will provide and distribute adequate supplies of ADCT-301 to the study sites. 
The following drug supplies will be used in the study: 
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Product
Supplied As
ADCT-301
10-mL glass vial at a deliverable volume of 5.4 mL at 6 mg/mL 
(equivalent to 30 mg ADCT-301)
6.6.1
ADCT-301 Drug Product
ADCT-301 is a sterile formulation containing PBD-conjugated HuMax®-TAC (DAR ≥1),
HuMax®-TAC (DAR = 0), and SG3249. It is provided pre-formulated in 10-mL glass vials 
containing approximately 30 mg ADCT-301 per vial (deliverable volume 5.4 mL at 6 mg/mL).
6.7 Management of Clinical Supplies
6.7.1
Study Drug Packaging and Storage
ADCT-301 will be supplied in a labeled 10-mL stoppered glass vial and shipped by Fisher
Clinical Services to the investigational site. Once the package arrives, the receiving site 
pharmacy will complete the enclosed procedures to acknowledge receipt.
All study drugs must be stored in a secure area (e.g., a locked cabinet). ADCT-301 should be 
protected from light and stored frozen (-65C or below). ADCT-301 should be thawed under 
ambient conditions.
6.7.2
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-301 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-301 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.
6.7.3
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.
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6.8 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.
6.9 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. 
6.10 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-301. 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.
6.10.1
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.
6.10.2
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;31 however, prophylactic 
use of growth factors is not allowed during the first treatment cycle.
Patients with a WBC value >15,000 cells/μL at the Screening Visit may receive 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 study drug administration on Day 1, Cycle 1 (Section 5.1.1).
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If CTCAE Grade 2 or higher infusion-related hypersensitivity reactions are observed in 1 patient 
at any time during Part 1 of the study, all subsequent patients must receive prophylactic 
treatment (Section 6.2).
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:
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.
6.10.3
Diagnostic, Work-up and Management of Polyradiculopathy /
Guillain-Barré Syndrome
It is recommended starting management of polyradiculopathy/GBS with either IVIg 0.4 g/kg/day 
for 5 days or plasma exchange (PLEX) once diagnosis of polyradiculopathy/GBS has been 
considered by a neurologist; this would be at CTCAE Grade 2 symptoms for neuropathy or 
Score 1 as per GBS disability scale (Appendix 13.4).
Diagnostic workup should include:

Neurology consultation

MRI spine with and without contrast to rule out compressive lesion and evaluate for 
nerve root enhancement or thickening

Electrodiagnostic studies (nerve conduction studies)

Pulmonary function tests

Lumbar puncture: CSF typically has albuminocytologic dissociation with protein 
elevation disproportionate to WBC—although note that CSF WBC are often elevated in 
GBS associated with immune checkpoint inhibitors

Serum antibody testing for GBS (ganglioside antibodies) when possible
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Management includes:

IVIg or PLEX as above 

If IVIg and/or PLEX do not result in improvement, consider using steroids (Gu 2017)15

Admission to inpatient unit with capability for rapid transfer to ICU-level monitoring

Frequent focused neurological examination (at least twice daily)

Frequent pulmonary function monitoring

Monitoring for autonomic dysfunction

Non-opioid management of neuropathic pain

Treatment of constipation/ileus

Anticoagulation

Physical therapy
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7
Study Assessments and Procedures
Patients will undergo the procedures at the time points specified in schedule of events
(Appendix 13.1).
7.1 Efficacy Assessments
Assessment of response to treatment with ADCT-301 will be based on bone marrow samples
(aspirate or biopsy if aspirate unattainable). Bone marrow samples will be obtained as described 
in Section 5.1.7.1 and Table 1 and Table 3 for the Q3W and QW dosing schedules, respectively.
The activity of ADCT-301 will be evaluated based on the Investigator’s evaluation of the 
patient’s response to ADCT-301 as CR, CRi, PR, PD or NR.8,11

Complete response is defined as achieving each of the following:
o
Bone marrow differential showing ≤5% blast cells and absence of blast cells with Auer
rods.
o
Absolute neutrophil count ≥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 (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
Absolute neutrophil count ≥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 and presence of Auer rods.

No response is defined as not achieving CR, CRi, or PR.

Progressive disease 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 8.6.2, DOR and ORR will be defined among responders (CR, CRi, PR); 
OS and PFS will also be determined.
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7.2.1
Pharmacokinetic Profile Assessments
The PK profile of ADCT-301 (total antibody; DAR ≥0), PBD-conjugated antibody (DAR ≥1), 
and free warhead SG3199 will be assessed. 
Additional PK, ADA, cytokines, and sCD25 blood samples will be collected, at the discretion of 
the Investigator, during any visit where toxicity is observed. A PK, ADA, cytokines, and sCD25
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.
The PK profile will include determination of standard PK parameters: Cmax, Tmax, area under the 
concentration-time curve (AUC) from time zero to the last quantifiable concentration (AUC0-last), 
area under the concentration-time curve 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), and terminal 
elimination phase rate constant (λz), t1/2, CL, and Vz.
 
 
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7.3 Safety and Tolerability Assessments
Safety will be assessed based on AEs, SAEs, treatment discontinuations due to AEs, DLTs, 
measurements of cytokines in serum, periodic 12-lead ECG recordings, physical examinations, 
vital signs measurements, ECOG performance status, and hematology, biochemistry, coagulation 
panel, pregnancy testing (for women of child-bearing potential) and urinalysis test results.
Adverse events will be graded according to CTCAE Version 4.0. A schedule of the safety 
assessments is provided in Appendix 13.2 (Table 6).
7.3.1
Dose-Limiting Toxicities and Dose-Escalation Scheme
7.3.1.1
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 and/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 AEs (including nausea, vomiting, diarrhea, and electrolyte imbalances 
lasting more than 48 hours despite optimal therapy; excluding all grades of alopecia).
o
Grade 3 or higher hypersensitivity reaction (regardless of premedication).
o
Grade 3 or higher skin ulceration.
o
Peripheral sensory or motor neuropathy ≥ Grade 2.
Note: The DLT observation period for dose-escalation will be 1 cycle. Patients who experience a 
DLT during Cycle 1 are to be permanently discontinued from the study.
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7.3.1.2
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.)
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.
7.3.2
Adverse Events
7.3.2.1
Definitions of Adverse Events
The Investigator is responsible for reporting all AEs that are observed or reported during the 
study, regardless of their relationship to study drug or their clinical significance.
An AE is defined as any untoward medical occurrence in a patient enrolled into this study 
regardless of its causal relationship to study drug. Patients will be instructed to contact the 
Investigator at any time after 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.
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A serious adverse event (SAE) is defined as any event that results in death, is immediately 
life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, 
results in persistent or significant disability/incapacity, or is a congenital anomaly/birth defect. 
Hospitalization for elective procedures or for protocol compliance is not considered an SAE.
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered SAEs when, based upon appropriate medical judgment, they 
may jeopardize the patient or may require medical or surgical intervention to prevent 1 of the 
outcomes listed in this definition. Examples of such medical events include allergic 
bronchospasm requiring intensive treatment in an emergency room or at home, blood dyscrasias 
or convulsions that do not result in inpatient hospitalization, or the development of drug 
dependency or drug abuse.
7.3.2.2
Eliciting and Documenting Adverse Events
Adverse events will be assessed from the time the patient signs the ICF up to 84 days (12 weeks) 
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 the event 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.
7.3.2.3
Reporting Adverse Events
All AEs reported or observed during the study will be recorded on the AE page of the eCRF. 
Information to be collected includes drug treatment, dose, event terminology, date of onset, 
CTCAE Version 4.0 assessment of severity, 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. The CTCAE includes 
5 grades (1 to 5), with Grade 5 being death.
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Any AE that meets SAE criteria (Section 7.3.2.1) must be reported to the contract research 
organization (CRO) immediately (i.e., within 24 hours after the time site personnel first learn 
about the event). The following contact information is to be used for SAE reporting:
Pharmacovigilance Department
7.3.2.4
Assessment of Severity
Adverse events are graded according to CTCAE Version 4.0. For events not included in the 
CTCAE criteria, the severity of the AE is graded on a scale of 1 to 5 as follows:
1:
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated
2:
Moderate; minimal, local or noninvasive intervention indicated; limiting 
age-appropriate instrumental ADLa
3:
Severe or medically significant but not immediately life-threatening; hospitalization or 
prolongation of hospitalization indicated; disabling; limiting self-care ADLb
4:
Life-threatening consequences; urgent intervention indicated
5:
Death related to adverse event
a Instrumental activities of daily living (ADL) refer to preparing meals, shopping for groceries or clothes, 
using the telephone, managing money, etc.
b Self-care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking medications, 
and not bedridden.
Changes in the severity of an AE should be documented to allow an assessment of the duration 
of the event at each level of intensity to be performed. Adverse events characterized as 
intermittent do not require documentation of onset and duration of each episode.
7.3.2.5
Assessment of Causality
The Investigator’s assessment of an AE’s relationship to study drug is part of the documentation 
process, but it is not a factor in determining what is or is not reported in the eCRF.
All 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).
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7.3.2.6
Follow-Up of Patients Reporting Adverse Events
All AEs must be reported in detail on the appropriate page of the eCRF and followed to 
satisfactory resolution, until the Investigator deems the event to be chronic or not clinically 
significant, or until the patient is considered to be stable.
7.3.3
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 7.3.2.3, upon learning of its occurrence. The pregnancy must be 
followed to determine outcome (including spontaneous miscarriage, elective termination, normal 
birth, or congenital abnormality) and status of mother and child, even if the patient was 
discontinued from the study. The outcome of the pregnancy will be reported on the Pregnancy
Outcome Form. Spontaneous miscarriages must be reported as an SAE.
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 7.3.2.3).
7.3.4
Clinical Laboratory Analyses
Samples will be collected at the time points specified in Appendix 13.1. 
Any clinically significant abnormal laboratory test results are to be recorded as AEs or SAEs per 
CTCAE Version 4.0.
7.3.4.1
Hematology
The complete blood count (CBC) includes WBC with 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 includes prothrombin time (PT), International Normalized Ratio (INR), and partial 
thromboplastin time (PTT). Patients taking coumarin-derivative anticoagulants should be 
monitored closely and their anticoagulant dose adjusted as needed. 
7.3.4.2
Biochemistry
Tests for clinical biochemistry include ALT, AST, 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 include creatinine clearance9..
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7.3.4.3
Urinalysis
Urinalysis will include pH, specific gravity, protein, occult blood, glucose, ketones, nitrites and 
bilirubin. The urinalysis may be performed using a urine dipstick.
7.3.4.4
Additional Renal Function Studies
Urine will be collected for testing of biomarkers suggestive of potential renal injury (aquaporin-2, 
calbindin D28, and clusterin). Analysis of this additional urine sample will be performed at a 
central laboratory (instructions provided in the Laboratory Manual).
7.3.4.5
Additional Microbiological Serological studies
Patients will be regularly examined and asked whether they have been suffering from an 
infection during their participation in the trial. If there is a reasonable suspicion that such 
infection could have been caused by one of the pathogens listed below, appropriate 
microbiological workup must be conducted. Should such workup indicate that infection was 
indeed caused by one of those microorganisms, re-dosing must be delayed so that there is at least 
a four-week window between symptom resolution and the next dose of ADCT-301.
Pathogens of interest are: HSV1, HSV2, VZV, EBV, CMV, measles, Influenza A, Zika virus, 
Chikungunya virus, mycoplasma pneumonia, Campylobacter jejuni, and enterovirus D68.
7.3.5
Electrocardiograms
On Day 1 of Cycles 1 and 2, a 12-lead ECG is to be performed before the start of the ADCT-301
infusion, within 30 minutes of the end of infusion, and 3 (±30 minutes) and 24 (±2.4) hours after 
the end of infusion. On Day 1 of Cycle 3 and subsequent cycles, a 12-lead ECG is to be 
performed before the start of ADCT-301 infusion. 
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.12 The same formula used to confirm 
eligibility must be applied within a patient for the duration of the study. 
7.3.6
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. Physical examination will also include a neurological examination 
of strength, sensation, and deep tendon reflexes; unexpected findings will be referred to a 
neurologist for further evaluation. Height will be measured at the Screening Visit (Day -28 to -1) 
and weight will be assessed before treatment as follows:
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Every 3-Week Schedule: Day 1 of each cycle, Days 8 and 19 of Cycles 1 and 2, and at the EOT 
Visit.
Weekly Schedule: Days 1, 8, 15 of each cycle and at the EOT Visit.
The examination must include a determination if the patient has had any infection. At the 
discretion of the investigator, evaluation of any reported infection must be conducted to rule out 
infection with a microorganism that may be associated with autoimmune or neurological 
disease(s) as specified in the exclusion criteria.
Any clinically significant abnormalities, including those that worsen from baseline, are to be 
recorded as AEs or SAEs.
7.3.7
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.
7.3.8
Eastern Cooperative Oncology Group Performance Status
The patient’s performance status will be assessed according to the time points in the schedule of 
events (Appendix 13.1) using the ECOG performance status grades below:26
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
7.4 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.
During the study, whole blood samples will be collected for PK, ADA, cytokines, CD25 
expression, PD (soluble CD25 [sCD25], analysis of peripheral WBC populations), CD34 
expression (and other CD markers), and safety analyses (clinical chemistry, cytokine and 
hematology). MNCs isolated from BMA and MNCs isolated from whole blood samples will be 
collected for screening and disease assessment.
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For PK, ADA, cytokines, sCD25 and cytokine, whole blood samples are to be collected and 
processed on site. The resulting serum samples should be aliquoted and stored until shipment. 
Each sample must be clearly labeled with the following information: study number, study center 
number, patient number, tube identification, and the sample collection time point (by day and 
hour), when necessary.
The central laboratory samples are to be packed in sufficient dry ice and shipped from the study 
center to the central laboratory. Where possible, samples should be stored at -70°C or below. 
Samples should be shipped according to the sample shipment schedule provided in Laboratory 
Manual.
 
.
Clinical chemistry and hematology samples, which should not be frozen, are to be transferred at
ambient temperature to local laboratories.
For the analysis of peripheral WBC populations, whole blood is to be collected and shipped, as 
per the Central Laboratory Manual, directly to the testing central laboratory for immediate 
processing.
Bone marrow samples and whole blood samples for Screening and disease assessment are to be 
taken and processed on site according to local clinical procedures. At Screening, any remaining 
sample material is then to be processed and frozen according to the Laboratory Manual. 
The resulting MNC cell preparation should be transferred as frozen samples (-70°C or below) to 
the testing central laboratory.
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8
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).
8.1 Safety Endpoints
Safety will be assessed based on AEs, SAEs, treatment discontinuations due to AEs, DLTs, 
measurements of cytokines in serum, periodic 12-lead ECG recordings, physical examinations, 
vital signs measurements, ECOG performance status, and hematology, coagulation panel,
biochemistry, pregnancy testing (for women of child-bearing potential) and urinalysis test results.
8.2 Endpoints
8.2.1
Primary Endpoints
The primary objectives for Part 1 (dose-escalation) and Part 2 (expansion) of the study are:

Assessment of DLTs (Section 7.3.1.1) and determination of the MTD (Section 4.1.1) for
ADCT-301 during Part 1.

Determination of the recommended dose of ADCT-301 for Part 2 by the DESC.

Assessment of safety parameters in Parts 1 and Part 2 (Section 8.6.1), schedule of safety 
assessments in the Schedule of Procedures for the Q3W and QW dosing schedules in Table 1
and Table 3, respectively (Appendix 13.1).
8.2.2
Secondary Endpoints
The following secondary endpoints will be determined in Part 1 and Part 2:

Determination of DOR, ORR, OS, and PFS (Section 8.6.2).

Determination of PK parameters (Section 7.2) for ADCT-301 (total antibody; DAR ≥0), 
PBD-conjugated antibody (DAR ≥1), and free warhead SG3199.

Measurement of ADAs to ADCT-301 before, during, and after treatment with ADCT-301
(Section 8.6.3).
 
 
 
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8.3 Sample Size Calculations
This is a Phase 1 study with a maximum total sample size of 80 patients. It is expected that Part 1 
will enroll up to 50 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. The cohorts will 
be enrolled at the dose level recommended in Part 1. 
The DESC will make recommendations with regard to the intended differences between these 
cohorts, e.g. tumor subtypes, dosing regimen or dose levels, as well as the number of these 
cohorts, taking into account the limit on the overall number of patients as specified above and 
safety/efficacy data observed up to that decision point.
8.4 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 during the first 21-day cycle 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.

 
8.5 Description of Subgroups to be Analyzed
Subgroup analyses, if planned, will be described in the SAP.
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8.6 Statistical Analysis Methodology
8.6.1
Safety Analyses
8.6.1.1
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.
Other AE analyses of interest will be specified in the SAP.
The incidence of deaths and the primary cause of death will be summarized.
8.6.1.2
Clinical Laboratory Results
Clinical hematology, biochemistry, coagulation panel, 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.
8.6.1.3
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.
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8.6.2
Efficacy Analysis
Determination of DOR and ORR will be based on the Investigator’s evaluation of the patient’s 
response to ADCT-301 (Section 7.1). Overall survival and PFS will also be determined.
8.6.2.1
Duration of Response
Duration of response will be defined among responders (CR, CRi, or PR) as the time from the 
earliest date of first response until the first date of either disease progression or death due to any 
cause. The date of disease progression is defined for patients with CR or CRi as the first date of 
reappearance of blast cells in bone marrow and/or peripheral blood to a level ≥5%, or 
development of extramedullary disease. In patients with PR, it is defined as 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 (Section 7.1). 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 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. Further details on censoring rules will 
be outlined in the SAP.
8.6.2.2
Overall Response Rate
The ORR is 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-301.
8.6.2.3
Overall Survival
Overall survival is 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. Further details on censoring 
rules will be outlined in the SAP.
8.6.2.4
Progression-Free Survival
Progression-free survival is defined as the time from first dose of study drug until the first date of 
either disease progression or death due to any cause. The date of disease progression is defined 
for patients with CR or CRi as the first date of reappearance of blast cells in bone marrow and/or 
peripheral blood to a level ≥5%, or development of extramedullary disease. In patients with PR, 
PFS is defined as 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 (Section 7.1). 
Patients without disease progression or patients who died after an extended loss to follow-up will 
be censored at the date of the last adequate disease assessment prior to the extended loss to 
follow-up. Further details on censoring rules will be outlined in the SAP.
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8.6.4
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.
8.7 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; 
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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.
8.7.1
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 
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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9
Ethics
9.1 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.
9.2 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.
9.3 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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10 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.
10.1 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.
10.2 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.
10.3 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 or 
equivalent, where applicable.
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
Curriculum vitae for the Investigator and each sub-Investigator listed on Form FDA 1572 or 
equivalent, where applicable.

Financial disclosure information to allow the Sponsor to submit complete and accurate 
certification or disclosure statements required under21 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.
10.4 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.
10.5 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.
10.6 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).
10.7 Investigator’s Final Report
Upon completion of the study, where applicable, the Investigator should provide the IRB/IEC 
with a summary of the study outcome and the Sponsor and regulatory authority(ies) with any 
reports required.
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10.8 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 Sponsor. It is 
the responsibility of the Sponsor to inform the Investigator/institution as to when these 
documents no longer need to be retained.
10.9 Publications
Following completion of the study, the results from the study may be reported at scientific 
meetings and/or published in scientific journals. The Sponsor will coordinate these activities and 
will work with the Investigator(s) to determine how the meeting abstracts, presentations and/or 
manuscripts are written and edited, the number and order of authors, the meeting and/or journal 
to which it will be submitted, and other related activities. The Sponsor acknowledges the right of 
the Investigator(s) to publish the results of this study after the entire study has completed, but 
also reserves the right to a 30-day window to review the publication for regulatory compliance as 
well as for protection of its intellectual property. 
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11 Study Management
11.1 Monitoring
11.1.1
Monitoring of the Study
The Medical 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.
11.1.2
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.
11.2 Management of Protocol Amendments and Deviations
11.2.1
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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11.2.2
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.
11.3 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.
11.4 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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12 Reference List
1.
Adair JR, PW Howard, JA Hartley, DG Williams, and KA Chester (2012). Antibody-drug 
conjugates - a perfect synergy. Expert Opin Biol Ther 12(9): 1191-1206.
2.
American Cancer Society, (2015). Cancer facts & figures 2015. Accessed on 20 May 2015 
at http://www.cancer.org/research/cancerfactsstatistics/cancerfactsfigures2015/.
3.
Angelini DF, T Ottone, G Guerrera, S Lavorgna, M Cittadini, F Buccisano, et al (2015). 
A leukemia-associated CD34/CD123/CD25/CD99-positive immunophenotype identifies 
FLT3-mutated clones in acute myeloid leukemia. Clin Cancer Res. May 8. 
pii:clincanres.3186.2014. 
4.
Breems DA, WL Van Putten, PC Huijgens, GJ Ossenkoppele, GE Verhoef, LF Verdonck, et 
al (2005). Prognostic index for adult patients with acute myeloid leukemia in first relapse. 
J Clin Oncol 23:1969–1978.
5.
Buckner, JH (2010). Mechanisms of impaired regulation by CD4(+)CD25(+)FOXP3(+) 
regulatory T cells in human autoimmune diseases. Nat Rev Immunol 10(12): 849-859. 
6.
Burchill MA, J Yang, KB Vang and MA Farrar (2007). Interleukin-2 receptor signaling in 
regulatory T cell development and homeostasis. Immunol Lett 114(1): 1-8. 
7.
Cerny J, H Yu, M Ramanathan, GD Raffel, WV Walsh, N Fortier, et al (2013). Expression 
of CD25 independently predicts early treatment failure of acute myeloid leukaemia (AML). 
Br J Haematol 160(2): 262-266.
8.
Cheson BD, JM Bennett, KJ Kopecky, T Buchner, CL Willman, EH Estey, 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.
9.
Cockcroft DW and MH Gault (1976). Prediction of creatinine clearance from serum 
creatinine. Nephron 16(1):31-41.
10. Ding L, TJ Ley, DE Larson, et al (2012). Clonal evolution in relapsed acute myeloid 
leukaemia revealed by whole-genome sequencing. Nature 481(7382):506-510.
11. 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. 
12. Fridericia LS (1920). The duration of systole in the electrocardiogram of normal subjects 
and of patients with heart disease. Act Med Scand 53:469–486.
13. Gönen M, Z Sun, ME Figueroa, JP Patel, O Abdel-Wahab, and J Racevskis, (2012). CD25 
expression status improves prognostic risk classification in AML independent of established 
biomarkers: ECOG phase 3 trial, E1900. Blood 120(11):2297-2306.
14. Grimwade D, H Walker, G Harrison, F Oliver, S Chatters, CJ Harrison, et al, for the 
Medical Research Council Adult Leukemia Working Party (2001). The predictive value of 
hierarchical cytogenetic classification in older adults with acute myeloid leukemia (AML): 
Analysis of 1065 patients entered into the United Kingdom Medical Research Council 
AML11 trial. Blood 98:1312–1320. 
15. Gu Y, Menzies AM, Long GV, Fernando SL, Herkes G (2017) Immune mediated 
neuropathy following checkpoint immunotherapy. J Clin Neurosci. Nov;45:14-17
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16. Hartley JA (2011[1]). The development of pyrrolobenzodiazepines as antitumour agents. 
Expert Opin Investig Drugs 20(6): 733-744.
17. Inaba H, Greaves M, and Mullighan CG (2013). Acute lymphoblastic leukaemia. Lancet 
June 1; 381(9881): doi:10.1016/S0140-6736(12)62187-4.
18. Jing Y, H Chen, M Liu, et al. (2014). Susceptibility of Ph-Positive ALL to TKI Therapy 
Associated with BCR-ABL Rearrangement Patterns: A Retrospective Analysis. PLoS ONE 
9(11):doi: 10.1371/journal.pone.0110431.
19. Ishikawa F, S Yoshida, Y Saito, A Hijikata, H Kitamura, S Tanaka, et al (2007). 
Chemotherapy-resistant human AML stem cells home to and engraft within the bone-
marrow endosteal region. Nat Biotechnol 25:1315–1321.
20. Miltiades P, E Lamprianidou, TP Vassilakopoulos, SG Papageorgaiou, AG Galanopoulos, 
and S Vakalopoulou, for the Hellenic MDS Study Group (2014). Expression of CD25 
antigen on CD34+ cells is an independent predictor of outcome in late-stage MDS patients 
treated with azacitidine. Blood Cancer Journal, 4, e187; doi:10.1038/bcj.2014.9 (Letter to 
the Editor).
21. 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.
22. Nakase K, K Kita, H Miwa, K Nishii, et al (2007). Clinical and prognostic significance of 
cytokine receptor expression in adult acute lymphoblastic leukemia: interleukin-2 receptor -
chain predicts a poor prognosis. Leukemia 21, 326–332.
23. National Cancer Institute (2015 [1]). SEER Stat Fact Sheets: Acute Myeloid Leukemia 
(AML), 2015. Accessed on 1 June 2015, at http://seer.cancer.gov/statfacts/html/amyl.html.
24. National Cancer Institute (2015 [2]). SEER Cancer Statistics Factsheets: Acute 
Lymphocytic Leukemia (ALL) 2015. Accessed on 1 July 2015, at 
http://seer.cancer.gov/statfacts/html/alyl.html.
25. Novartis, New Jersey, USA. Prescribing information for Simulect, 2005, accessed on 25 
May 2015 at https://www.pharma.us.novartis.com/product/pi/pdf/simulect.pdf. 
26. Oken MM, RH Creech, DC Tormey, et al, (1982). Toxicity and response criteria of the 
Eastern Cooperative Oncology Group. Am J Clin Oncol 5(6):649-55.
27. Roche Pharmaceuticals, New Jersey, USA. Prescribing Information for Zenapax, 2005, 
accessed on 25 May 2015 at http://www.gene.com/download/pdf/zenxapax_prescribing.pdf.
28. 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).
29. Saito Y, H Kitamura, A Hijikata, Tomizawa-Murasawa1, S Tanaka, S Takagi, et al, (2010). 
Identification of therapeutic targets M for quiescent, chemotherapy-resistant human 
leukemia stem cells. Sci Transl Med February 3; 2(17): 17ra9. 
doi:10.1126/scitranslmed.3000349.
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30. 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.
31. Sejvar JJ, Koohl KS, Gidudu J, Amato A, Bakshi N, Baxter R, et al, (2011) Guillain-Barre 
syndrome and Fisher syndrome: case definitions and guidelines for collection, analysis, and 
presentation of immunization safety data. Vaccine; 29(3): 599-612.
32. Smith TJ (Chair), J Khatcheressian, GH Lyman, H Ozer, JO Armitage, L Balducci, et al,
(2006). 2006 Update of recommendations for the use of white blood cell growth factors: an 
evidence-based clinical practice guideline. J Clin Onc 24(19):3187-3286.
33. Terwijn M, N Feller, A van Rhenen, A Kelder, G Westra, S Zweegman, G Ossenkoppele, 
and GJ Schuurhuis, (2009). Interleukin-2 receptor alpha-chain (CD25) expression on 
leukaemic blasts is predictive for outcome and level of residual disease in AML. Eur J 
Cancer Jun;45(9):1692-9. doi: 10.1016/j.ejca.2009.02.021. Epub 2009 Mar 25.
34. Vardiman J, J Thiel, D Arber, R Brunning, M Borowitz et al. (2009). The 2008 revision of 
the World Health Organization (WHO) classification of myeloid neoplasms and acute 
leukemia: rationale and important changes. Blood 114(5):937-951. doi: 10.1182/blood-
2009-03-209262. Epub 2009 Apr 8.
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13 Appendices
13.1 Appendix: Schedule of Events 
The Schedule of Procedures for the Q3W and QW dosing schedules are shown in Table 1 and 
Table 3, respectively. Timings for sample collections for assessment of PK, PD, 
, and 
other parameters for the Q3W dosing schedule are shown in Table 2, and Cycle 1 and Cycle 2+ 
of the QW dosing schedule in Table 4 and Table 5, respectively.
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13.2 Appendix: CTCAE Immune System Hypersensitivity Grades
Table 6: CTCAE* Immune System Hypersensitivity Grades
Adverse Event
Grade 1
Grade 2
Grade 3
Grade 4
Grade 5
Allergic reaction
Transient 
flushing or rash, 
drug fever 
<38C
(<100.4F); 
intervention not 
indicated
Intervention or 
infusion 
interruption 
indicated; 
responds 
promptly to 
symptomatic 
treatment (e.g.,
antihistamines, 
NSAIDS, 
narcotics); 
prophylactic 
medications 
indicated for 
≤24 hours
Prolonged (e.g.,
not rapidly 
responsive to 
symptomatic 
medication and/or 
brief interruption 
of infusion); 
recurrence of 
symptoms
following initial 
improvement; 
hospitalization 
indicated for 
clinical sequelae 
(e.g., renal 
impairment, 
pulmonary 
infiltrates)
Life-threatening 
consequences;
urgent 
intervention 
indicated
Death
Definition: A disorder characterized by an adverse local or general response from exposure to an allergen.
Anaphylaxis
-
-
Symptomatic 
bronchospasm, 
with or without 
urticaria; parenteral 
intervention 
indicated; allergy-
related 
edema/angioedema; 
hypotension
Life-threatening 
consequences;
urgent 
intervention 
indicated
Death
Definition: A disorder characterized by an acute inflammatory reaction resulting from the release of histamine 
and histamine-like substances from mast cells, causing a hypersensitivity immune response. Clinically, it 
presents with breathing difficulty, dizziness, hypotension, cyanosis, and loss of consciousness and may lead to 
death.
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Adverse Event
Grade 1
Grade 2
Grade 3
Grade 4
Grade 5
Autoimmune 
disorder
Asymptomatic; 
serologic or 
other evidence 
of autoimmune 
reaction, with 
normal organ 
function;
intervention not 
indicated
Evidence of 
autoimmune 
reaction 
involving a non-
essential organ 
or function (e.g.,
hypothyroidism)
Autoimmune 
reactions involving 
major organ (e.g.,
colitis, anemia, 
myocarditis, 
kidney)
Life-threatening 
consequences;
urgent 
intervention 
indicated
Death
Definition: A disorder resulting from loss of function or tissue destruction of an organ or multiple organs, 
arising from humoral or cellular immune responses of the individual to his own tissue constituents.
Cytokine release 
syndrome
Mild 
reaction; 
infusion 
interruption 
not 
indicated; 
intervention 
not 
indicated
Therapy or 
infusion 
interruption 
indicated but 
responds 
promptly to 
symptomatic 
treatment (e.g.,
antihistamines, 
NSAIDS, 
narcotics, 
intravenous 
fluids); 
prophylactic 
medications 
indicated for 
≤24 hours
Prolonged (e.g.,
not rapidly 
responsive to 
symptomatic 
medication and/or 
brief interruption 
of infusion); 
recurrence of 
symptoms 
following initial 
improvement; 
hospitalization 
indicated for 
clinical sequelae 
(e.g., renal 
impairment, 
pulmonary 
infiltrates)
Life-threatening 
consequences; 
pressor or 
ventilatory 
support indicated
Death
Definition: A disorder characterized by nausea, headache, tachycardia, hypotension, rash, and shortness of 
breath; it is caused by the release of cytokines from the cells.
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 
Asymptomatic or 
mild symptoms; 
Moderate; 
minimal, local 
Severe or 
medically 
Life-threatening 
Death
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Adverse Event
Grade 1
Grade 2
Grade 3
Grade 4
Grade 5
disorders -
Other, specify
clinical or 
diagnostic 
observations 
only; 
intervention not 
indicated
or noninvasive 
intervention 
indicated; 
limiting 
age-appropriate 
instrumental 
ADL
significant but not 
immediately 
life-threatening; 
hospitalization or 
prolongation of 
existing 
hospitalization 
indicated; 
disabling; limiting 
self-care ADL
consequences;
urgent 
intervention 
indicated
Abbreviations: ADL, Activities of daily living; NSAIDs, non-steroidal anti-inflammatory drugs.
* Adapted from CTCAE V4.0 – June 14, 2010, Immune system disorders.
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13.3 Appendix: Clinical case definitions: Level 1 of diagnostic certainty for 
Guillain-Barré syndrome

Bilateral AND flaccid weakness of the limbs1, 2, 3
AND

Decreased or absent deep tendon reflexes in weak limbs4
AND

Monophasic illness pattern5 AND interval between onset and nadir of weakness 
between 12 h and 28 days AND subsequent clinical plateau6
AND

Electrophysiologic findings consistent with GBS7
AND

Cytoalbuminologic dissociation (i.e., elevation of CSF protein level above laboratory 
normal value AND CSF total white cell count <50 cells/µL)8
AND

Absence of an identified alternative diagnosis for weakness9.
Reference: Sejvar 2011
1 Weakness is usually, but not always, symmetric in nature, and usually has a pattern of progression from legs to 
arms (ascending). However, other patterns of progression may occur (e.g., beginning in the arms). The degree 
of weakness can range from mild to moderate to severe, i.e., complete paralysis.
2 Respiratory or cranial nerve-innervated muscles may also be involved.
3 It is important that strength be assessed in a manner that takes into account subject age, sex, and level of 
functioning.
4 Decreased or absent tendon reflexes may also be seen in limbs without weakness. However, to meet case 
definition criteria, decreased or absent tendon reflexes must be observed in weak limbs.
5 Fluctuations in level of weakness, before reaching nadir, or during the plateau or improvement phases, occur 
in some cases, usually associated with the use of disease-modifying therapies. Such fluctuations usually occur 
within the first 9 weeks after onset and are followed by eventual improvement.
6 The eventual outcome is either stabilization at nadir OR subsequent improvement OR death.
7 Electrophysiologic patterns consistent with polyneuropathy of the types described for GBS. 
Electrophysiologic studies performed sooner than 7 days after weakness onset may be normal and should thus 
be repeated at a later time if possible, and “normal” studies may occur in otherwise typical cases of GBS. 
However, cases with persistently “normal” studies will not meet Level 1 criteria.
8 CSF (cerebrospinal fluid) protein concentrations should be elevated above what is considered normal 
reference values for the testing laboratory. CSF may be “normal” in otherwise typical cases of GBS; this is 
particularly true within the first week of illness. However, cases with persistently “normal” CSF, or CSF with 
≥50 WBC, will not meet Level 1 criteria.
9 If an alternative diagnosis explaining flaccid weakness/paralysis is present a diagnosis of Guillain–Barré 
syndrome is excluded. However, in many, if not most cases, a comprehensive documentation of testing for 
various other etiologies will either be incomplete or unavailable. These case definitions are provided to give 
guidance in the absence of detailed information on investigations for alternative etiologies of flaccid paralysis.
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13.4 Appendix: Guillain–Barré Syndrome Disability Scale
Score
Description
0
Healthy
1
Minor symptoms or signs of neuropathy but capable of manual work/capable of 
running
2
Able to walk without support of a stick (5m across an open space) but incapable 
of manual work/running
3
Able to walk with a stick, appliance, or support (5m across an open space)
4
Confined to bed or chair bound
5
Requiring assisted ventilation (for any part of the day or night)
6
Death
Reference: Sejvar 2011
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Clinical Protocol Amendment Summary of Changes
A Phase 1, Open-label, Dose-escalation, Multicenter Study to Evaluate the Tolerability, 
Safety, Pharmacokinetics, and Activity of ADCT-301 in Patients with Relapsed or 
Refractory CD25-positive Acute Myeloid Leukemia or CD25-positive Acute Lymphoblastic 
Leukemia
The basis for Protocol Amendment 5 (19 January 2018) is the reported cases of Guillain-Barré 
syndrome (GBS) and polyradiculopathy from patients treated with ADCT-301.
Inclusion and exclusion criteria have been modified taking into account possible predisposing or 
potential mitigating factors that may contribute to the risk of developing GBS.  Detailed safety 
monitoring specific for neurological and immune-related events have been added, as well as 
requiring a neurological examination as part of the physical examination. Treatment 
discontinuation and study stopping rules have also been modified.
Summary of Substantial Changes:

Specific study stopping rules for futility have been implemented for the remaining dose 
escalation portion of the study in Section 4.1.1, reducing the highest allowed dose for the study 
to 150 µg/kg every three weeks (50 µg/kg every week).

Exclusion criteria have been expanded to exclude polyradiculopathy (inclusive of Guillain-
Barré syndrome (GBS), which was already an exclusion for the study) and to provide more 
explicit restriction for entry of patients with a history of recent infection caused by a pathogen 
that may be associated with neurologic and immune-related disease(s): HSV1, HSV2, VZV, 
EBV, CMV, measles, Influenza A, Zika virus, Chikungunya virus, mycoplasma pneumonia, 
Campylobacter jejuni, or enterovirus D68; Section 4.2.2.

A neurological examination has been added as part of each complete physical examination, to 
include strength, sensation and deep-tendon reflexes throughout; Sections 5 and 7.3.6.

Requirements for physical examination have been expanded to mandate assessment for any 
infection and evaluation of such to rule out infection with a microorganism that may be 
associated with autoimmune or neurological disease(s) as specified in the exclusion criteria; 
Sections 5 and 7.3.6.
As part of evaluation for any infection, additional microbiological serological studies have 
been specified if there is suspicion that such infection could have been caused by HSV1, HSV2, 
VZV, EBV, CMV, measles, Influenza A, Zika virus, Chikungunya virus, mycoplasma 
pneumonia, Campylobacter jejuni, or enterovirus D68.
Should such workup indicate that infection was indeed caused by one of these microorganisms, 
re-dosing must be delayed so that there is at least a four-week window between symptom 
resolution and the next dose of ADCT-301; Section 7.3.4.5.

Requirement added for 
patients experiencing any autoimmune toxicities (e.g.,
endocrinopathies) ≥grade 1 to be followed at least weekly to quickly detect deterioration and 
modify dosing as per the dose limiting toxicity criteria; Section 6.4.
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
Requirement added for patients experiencing certain types of infection associated with 
neurologic and immune-related disease(s) during the course of participation in this clinical 
study also must delay further dosing; Section 6.4.

Recommendations pertaining to dose delay and modifications have been revised to include 
appropriate management of neurological toxicities, including polyradiculopathy/GBS; Section 
6.4. 

Specific study stopping criteria for excessive toxicity, including neurologic or autoimmune 
toxicity, were implemented in Section 6.5.

Specific treatment plans for the occurrence of Guillain-Barre and other neurologic toxicities
have been added in Section 6.10.3. 

The definition for non-hematologic DLTs has been expanded to include peripheral sensory or 
motor neuropathy ≥ Grade 2; Section 7.3.1.1.

In order to better evaluate the change in white blood cell populations (such as activated T cells), 
additional PBMC samples will be collected:
o
on Day 3 and Day 5 of Cycles 1 and 2 for the every 3 week dosing regimen.
o
on Day 3 and Day 5 of Cycle 1 and Day 8 of Cycle 2 for the weekly dosing regimen.
Section 5.1 and Tables 2, 4, and 5 of Appendix 13.1.

Because data collected so far were inconclusive, sample collection and evaluation of the DNA 
cross-linking (comet assay/γH2AX) will be discontinued; Sections 3.3, 5.1, 7.2.2, 7.4, 8.2.3, 
8.6.3, and Tables 2, 4, and 5 of Appendix 13.1.

Clinical definition of GBS and the GBS disability scale have been included in Appendices 13.3 
and 13.4.
In addition, administrative and editorial changes have been included, and revisions to the protocol 
text have also been applied to the synopsis section.
Page 548 of 548

SAP_001.pdf: 
Protocol Number:  ADCT-301-002 
 
Official Title:    A Phase 1, Open-label, Dose-escalation, Multicenter Study to Evaluate the 
Tolerability, Safety, Pharmacokinetics, and Activity of ADCT-301 in 
Patients with Relapsed or Refractory CD25-positive Acute Myeloid 
Leukemia or CD25-positive Acute Lymphoblastic Leukemia 
 
NCT Number:  NCT02588092 
 
Document Date:  September 14, 2018 
 


Abbreviated Clinical Study Report
ADCT-301-002 
Camidanlumab tesirine (ADCT-301) 
Confidential 
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16.1.9 Documentation of Statistical Methods 
ADCT-301-002 Statistical Analysis Plan FINAL version 1.0 September 14, 2018 


ADC Therapeutics 
ADCT-301 
ADCT-301-002 
SAP version 1.0 
 
 
 
 
 
Statistical Analysis Plan 
 
 
 
 
A Phase 1, Open-label, Dose-escalation, Multicenter Study to Evaluate the 
Tolerability, Safety, Pharmacokinetics, and Activity of ADCT-301 in 
Patients with Relapsed or Refractory CD25-positive Acute Myeloid 
Leukemia or CD25-positive Acute Lymphoblastic Leukemia 
 
PROTOCOL NO.:  ADCT-301-002  
 
 
 
SAP Version No./ Date: 1.0/ Sep 14, 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. 
 
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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 Medications History ..................................9 
4.5 Prior anticancer therapy .............................................................................................10 
4.6 Prior or Concomitant Medications (other than anticancer therapies) ........................10 
4.7 Exposure to Treatment ............................................................................................... 11 
4.7.1 Extent of ADCT-301 Exposure ..................................................................... 11 
4.7.2 Subsequent Anticancer Therapy or Procedure .............................................. 11 
4.8 Safety Analyses ......................................................................................................... 11 
4.8.1 Dose-limiting Toxicities ................................................................................12 
4.8.2 Adverse Events, Serious Adverse Events, and Deaths ..................................12 
4.8.2.1 Analyses of adverse events .......................................................... 12 
4.8.2.2 Autoimmune AE, based on an ADCT specific query (includes 
Preferred Terms (PTs) selected based on autoimmune 
mediated events) will be listed.  Deaths ................................ 13 
4.8.1 Laboratory Data ............................................................................................13 
4.8.1 Electrocardiogram .........................................................................................14 
4.8.1 Vital Signs .....................................................................................................14 
4.8.2 ECOG Performance Status ...........................................................................14 
4.9 Efficacy Analyses ......................................................................................................14 
4.10 Pharmacokinetic Analyses and Pharmacodynamic Measures .................................14 
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5 Interim Analyses .................................................................................................................. 16 
6 Data handling conventions ................................................................................................... 16 
6.1 General conventions ..................................................................................................16 
6.1.1 Missing data ..................................................................................................16 
6.1.2 Unscheduled visits ........................................................................................16 
6.1.3 Duplicated visit .............................................................................................16 
 
List of Tables 
 
NA 
List of Figures 
 
NA 
 
 
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1 Introduction 
This statistical analysis plan (SAP) describes the statistical methods to be used during the 
reporting and analyses of data collected under ADC Therapeutics (ADCT) Protocol ADCT-
301-002.
This SAP should be read in conjunction with the study protocol and case report form (CRF).
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2  Study Objectives  
See the planned study objectives in the corresponding section in the protocol. 
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3 Study Design 
Refer to the corresponding section in the protocol.   
3.1 Sample Size Consideration 
Refer to the corresponding section in the protocol.  
3.2 Randomization 
This study is not randomized. 
3.3 Modifications to the statistical section of the protocol  
The trial was terminated early, prior to the completion of dose escalation (part 1), therefore, 
only Part 1 data has been 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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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 study drug. 
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) during Cycle 1 
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- a dosing delay >21 (except in case of potential patient benefit, which must be 
approved by the Sponsor) or  
- diagnosis of polyradiculopathy/GBS with the level 1 of diagnostic certainty 
- Grade ≥ 3 neurologic toxicities, defined as peripheral sensory and peripherally motor 
neuropathies 
4. toxicity recurs at the 2nd reduced dose level and at a severity that would mandate a 
treatment withdrawal  Patient who received the wrong treatment or incorrect dose. 
For example, 
- actual dose of study drug was more than 15% greater than protocol defined planned 
dose level 
- patient started next cycle less than 18 days later after Day 1 of the most recent 
treatment cycle 
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 Medications History 
Cancer history will be presented for the Safety analysis set. Cancer history will include the 
following variables: 
• Disease diagnosis subtype (Acute myeloid leukemia (AML) or acute lymphoblastic leukemia 
(ALL)) 
• extramedullary involvement 
 
Cytogenetic analysis will include the following variables:  
For ALL: 
• 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 
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• Hypodiploid 
• t(5;14)(q31;q32); IL3-IGH 
• Other 
For AML: 
• AML with t(8;21)(q22;q22); RUNX1/RUNX1T1 
• AML with inv(16)(p13,1q22) or t(16;16)(p13.1;q22);]CBFB/MYH11 
• AML with t(15;17)(q22:q12)PML-RARA 
• AML with t(9;11)(p22:q23): MLLT3-MLL 
• AML with t(6;9)(p23:q34) DEK-NUP214 
• AML with inv(3)(q21q26.2) or t(3:3)(q21:q26);RPN1-EVI1 
• AML (megakaryoblastic) with t(1:22)(p13:q13): RBM15-MKL1 
• AML with mutated NPM1 
• AML with mutated CEBPA 
• Other 
All cytogenetic analysis data will be listed. 
Multilineage dysplasia syndrome 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 SOC 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.  
 
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4.7 Exposure to Treatment 
4.7.1 Extent of ADCT-301 Exposure 
ADCT-301 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]* 6 
mg/mL *1000 or serially diluted IP volume[ in mL]/50* 6 mg/mL *1000; 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 
planned dose level at cycle 1 day 1 ÷3 for Q3W, for example, =10 ug/kg for 30ug/kg 
Q3W planned dose level.  
For patients who switched from Q3W to QW or vice versa, the relative dose intensity 
is not calculated.   
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. 
Exposure data will be listed. 
4.7.2 Subsequent Anticancer Therapy or Procedure 
Subjects’ subsequent anticancer therapy or procedure including systemic therapy, radiation, 
transplant, 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. 
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• 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 that occurs or worsens in the period extending from the first dose of study drug 
to 84 days after the last dose of study drug, or start of new anti-cancer therapy, whichever is 
earlier. 
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 
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- 
TEAE leading to permanent treatment discontinuation 
- 
TEAE leading to ADCT-301 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 withdrawal, all TEAEs leading to dose reduction, all TEAEs leading to dose delay, 
infusion related reaction and all TEAEs with fatal outcome will be listed.  
In addition, neurologic AE (including the following Standardized MedDRA Queries (SMQ): 
Peripheral neuropathy (SMQ) [20000034], Guillain-Barre syndrome (SMQ) [20000131], and 
Demyelination (SMQ) [20000154]) will be listed. 
4.8.2.2 Autoimmune AE, based on an ADCT specific query (includes 
Preferred Terms (PTs) selected based on autoimmune mediated events) will 
be listed.  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. 
 
4.8.1 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. 
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4.8.1 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. 
4.8.1 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. 
4.8.2 ECOG Performance Status 
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 Measures 
The actual blood sampling time and actual amount of dose administered will be recorded and 
used in calculation of pharmacokinetic (PK) parameters.  All PK samples will be evaluable as 
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long as the actual collection times are recorded.  Analysis of the ADCT-301 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 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 patient PK parameters, statistical summaries (mean, standard deviation, median, 
range, geometric mean, geometric standard deviation, and n) of concentrations by dose cohort 
and nominal time, and statistical summary of PK parameters.1  Data presentation through 
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-301 
antidrug antibodies (ADA) were also collected concurrently with selected 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. 
 
 
 
 
 
 
 
 
 
 
 
__________ 
1 N.b.  statistical summarization for Tmax and T1/2 will include median, minimum and maximum values. 
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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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