Clinical trial NCT02432235
Conditions: Hodgkin Lymphoma Non-Hodgkin Lymphoma
Keywords: Camidanlumab tesirine
Sponsor: ADC Therapeutics S.A.
Start date: 2015-10-05; Completion date: 2019-10-24
Enrollment: 133 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
This study evaluates camidanlumab tesirine in participants with relapsed/refractory Non-Hodgkin or Hodgkin lymphoma.

Detailed description:
This is a Phase I, first in human clinical study with camidanlumab tesirine to evaluate the safety and tolerability and pharmacokinetics of camidanlumab tesirine in participants with relapsed/refractory lymphoma.

Camidanlumab tesirine 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: Part 1 (dose escalation) and Part 2 (expansion).

Arms: arm 1: Participants received an intravenous (IV) infusion of camidanlumab tesirine (3 μg/kg) on Day 1 of each 3-week treatment cycle, for a maximum of 2 cycles. arm 2: Participants received an intravenous (IV) infusion of camidanlumab tesirine (5 μg/kg) on Day 1 of each 3-week treatment cycle, for a maximum of 4 cycles. arm 3: Participants received an intravenous (IV) infusion of camidanlumab tesirine (8 μg/kg) on Day 1 of each 3-week treatment cycle, for a maximum of 3 cycles. arm 4: Participants received an intravenous (IV) infusion of camidanlumab tesirine (13 μg/kg) on Day 1 of each 3-week treatment cycle, for a maximum of 15 cycles. arm 5: Participants received an intravenous (IV) infusion of camidanlumab tesirine (20 μg/kg) on Day 1 of each 3-week treatment cycle, for a maximum of 3 cycles. arm 6: Participants received an intravenous (IV) infusion of camidanlumab tesirine (30 μg/kg) on Day 1 of each 3-week treatment cycle, for a maximum of 10 cycles. arm 7: Participants received an intravenous (IV) infusion of camidanlumab tesirine (45 μg/kg) on Day 1 of each 3-week treatment cycle, for a maximum of 10 cycles. arm 8: Participants received an intravenous (IV) infusion of camidanlumab tesirine (60 μg/kg) on Day 1 of each 3-week treatment cycle, for a maximum of 8 cycles. arm 9: Participants received an intravenous (IV) infusion of camidanlumab tesirine (80 μg/kg) on Day 1 of each 3-week treatment cycle, for a maximum of 7 cycles. arm 10: Participants received an intravenous (IV) infusion of camidanlumab tesirine (100 μg/kg) on Day 1 of each 3-week treatment cycle, for a maximum of 5 cycles. arm 11: Participants received an intravenous (IV) infusion of camidanlumab tesirine (150 μg/kg) on Day 1 of each 3-week treatment cycle, for a maximum of 2 cycles. arm 12: A single participant received by error an intravenous (IV) infusion of camidanlumab tesirine (300 μg/kg) on Day 1 of Cycle 1 (planned dose was 30 μg/kg). Dosing in the subsequent cycles was 30 μg/kg (for 2 more cycles).
Interventions: intervention 1: Camidanlumab tesirine
Intervention descriptions: intervention 1: Intravenous (IV) infusion.

Protocol documents:
Prot_000.pdf: 
Protocol Number:  ADCT-301-001 
 
Official Title:  A Phase 1 Adaptive Dose-Escalation Study to Evaluate the Tolerability, Safety, 
Pharmacokinetics, and Antitumor Activity of ADCT-301 in Patients with 
Relapsed or Refractory Hodgkin Lymphoma and Non-Hodgkin Lymphoma 
 
NCT Number: NCT02432235 
 
Document Date:  04 January 2019 


ADC Therapeutics 
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Page 1 
CLINICAL STUDY PROTOCOL 
IND: 121912 
EudraCT Number: 2015‐005272‐25 
A Phase 1 Adaptive Dose-Escalation Study to Evaluate the Tolerability, Safety, 
Pharmacokinetics, and Antitumor Activity of ADCT-301 in Patients with 
Relapsed or Refractory Hodgkin Lymphoma and Non-Hodgkin Lymphoma 
PROTOCOL NO.:  ADCT-301-001 
Sponsor: 
ADC Therapeutics SA 
 
 
 
Sponsor Contact: 
 
 
 
Medical Monitor: 
 
 
 
 
 
 
Date of Original Protocol:  
22 January 2015 
Date of Amendment 1: 
17 April 2015 
Date of Amendment 2: 
18 December 2015 
Date of Amendment 3: 
8 April 2016 
Date of Amendment 4: 
8 November 2016 
Date of Amendment 5: 
4 May 2017 
Date of Amendment 6: 
31 August 2017 
Date of Amendment 7: 
19 January 2018 
Date of Amendment 8: 
31 October 2018 
Date of Amendment 9: 
04 January 2019 
Confidentiality Statement 
All financial and nonfinancial support for this study will be provided by  
ADC Therapeutics SA. The concepts and information contained in this document or generated during the study 
are considered proprietary and may not be disclosed in whole or in part without the express, written consent of 
ADC Therapeutics SA. The study will be conducted according to the current version of International Council 
for Harmonisation harmonised tripartite guideline E6, Good Clinical Practice. 


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Protocol Approval  Sponsor Signatory
Study Title: 
A Phase 1 Adaptive Dose-Escalation Study to 
Evaluate the Tolerability, Safety, Pharmacokinetics, 
and Antitumor Activity of ADCT-301 in Patients with 
Relapsed or Refractory Hodgkin Lymphoma and 
Non-Hodgkin Lymphoma 
Protocol Number: 
ADCT-301-001 
Date of Original Protocol: 
22 January 2015 
Date of Amendment 1: 
17 April 2015 
Date of Amendment 2: 
18 December 2015 
Date of Amendment 3: 
8 April 2016 
Date of Amendment 4: 
8 November 2016 
Date of Amendment 5: 
4 May 2017 
Date of Amendment 6: 
31 August 2017 
Date of Amendment 7: 
19 January 2018 
Date of Amendment 8: 
31 October 2018 
Date of Amendment 9: 
04 January 2019 


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Declaration of Investigator 
I have read and understood all sections of the protocol entitled “A Phase 1 Adaptive 
Dose-Escalation Study to Evaluate the Tolerability, Safety, Pharmacokinetics, and Antitumor 
Activity of ADCT-301 in Patients with Relapsed or Refractory Hodgkin Lymphoma and 
Non-Hodgkin Lymphoma” 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 9, dated 04 January 2019, the current version of 
International Council for Harmonisation (ICH) harmonised tripartite guideline E6: Good 
Clinical Practice and all applicable governmental regulations.  I will not make changes to the 
protocol before consulting with ADC Therapeutics 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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Table of Contents 
Table of Contents ...................................................................................................................... 4 
List of Figures ........................................................................................................................... 8 
Protocol Synopsis...................................................................................................................... 9 
List of Abbreviations............................................................................................................... 19 
1 
Introduction .................................................................................................................... 21 
2 
Study Rationale and Justification for Dose Level Selection .......................................... 23 
3 
Study Objectives ............................................................................................................. 24 
3.1 
Primary Objectives .................................................................................................24 
3.2 
Secondary Objectives .............................................................................................24 
 
 
4 
Investigational Plan and Patient Selection ..................................................................... 25 
4.1 
Study Design ..........................................................................................................25 
4.1.1 
Dose Escalation and Determination of the Maximum Tolerated Dose 
(Part 1) ......................................................................................................26 
4.1.2 
Dose Expansion (Part 2) ...........................................................................26 
4.2 
Selection of Study Population ................................................................................27 
4.2.1 
Inclusion Criteria ......................................................................................27 
4.2.2 
Exclusion Criteria .....................................................................................28 
5 
Study Procedures ............................................................................................................ 31 
5.1 
Procedures by Study Day .......................................................................................31 
5.1.1 
Screening Period (Day –28 to –1) ............................................................31 
5.1.2 
Day 1 (± 3 days) of Each Cycle ................................................................33 
5.1.3 
Day 8 (± 1 day) of Each Cycle .................................................................34 
5.1.4 
Day 15 (± 1 day) .......................................................................................35 
5.1.5 
End of Treatment Visit ..............................................................................36 
5.1.6 
Long-term Follow-up ................................................................................37 
5.2 
Withdrawal of Patients from the Study ..................................................................37 
5.2.1 
Reasons for Withdrawal/Discontinuation .................................................37 
5.2.2 
Handling of Withdrawals ..........................................................................38 
5.2.3 
Patient Replacements ................................................................................38 
6 
Study Treatments ............................................................................................................ 39 
6.1 
Method of Assigning Patients to Treatment Groups ..............................................39 
6.2 
Prophylactic Treatments for Hypersensitivity .......................................................39 


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6.3 
Treatments Administered .......................................................................................40 
6.4 
Dose Delays and Modifications .............................................................................41 
6.5 
Study Stopping Rules .............................................................................................42 
6.6 
Identity of Investigational Product .........................................................................43 
6.6.1 
ADCT-301 Drug Product ..........................................................................43 
6.7 
Management of Clinical Supplies ..........................................................................43 
6.7.1 
Study Drug Packaging and Storage ..........................................................43 
6.7.2 
Study Drug Accountability .......................................................................44 
6.8 
Overdose Management ..........................................................................................44 
6.9 
Treatment Compliance ...........................................................................................44 
6.10 Concomitant Treatment ..........................................................................................44 
6.10.1 Prohibited During Study ...........................................................................44 
6.10.2 Permitted During Study ............................................................................45 
6.10.3 Diagnostic, Work-up, and Management of 
Polyradiculopathy/Guillain-Barré Syndrome ...........................................46 
7 
Study Assessments and Procedures ................................................................................ 47 
7.1 
Efficacy Assessments .............................................................................................47 
7.2 
Pharmacokinetic and Pharmacodynamic Assessments ..........................................47 
7.3 
Safety and Tolerability Assessments ......................................................................48 
7.3.1 
Dose-Limiting Toxicities and Dose-Escalation Scheme ..........................49 
7.3.1.1 
Definition of Dose-Limiting Toxicities ................................. 49 
7.3.1.2 
Safety Oversight by the Dose Escalation Steering Committee
 ............................................................................................... 50 
7.3.2 
Adverse Events .........................................................................................51 
7.3.2.1 
Definitions of Adverse Events ............................................... 51 
7.3.2.2 
Eliciting and Documenting Adverse Events .......................... 51 
7.3.2.3 
Reporting Adverse Events ..................................................... 52 
7.3.2.4 
Assessment of Severity .......................................................... 53 
7.3.2.5 
Assessment of Causality ........................................................ 53 
7.3.2.6 
Follow-up of Patients Reporting Adverse Events .................. 53 
7.3.3 
Pregnancy .................................................................................................54 
7.3.4 
Clinical Laboratory Analyses ...................................................................54 
7.3.4.1 
Hematology ............................................................................ 54 
7.3.4.2 
Biochemistry .......................................................................... 54 


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7.3.4.3 
Urinalysis ............................................................................... 54 
7.3.4.4 
Additional Renal Function Studies ........................................ 55 
7.3.4.5 
Additional Microbiological Serological studies .................... 55 
7.3.5 
Electrocardiograms ...................................................................................55 
7.3.6 
Physical Examination ...............................................................................55 
7.3.7 
Vital Sign Measurements ..........................................................................56 
7.3.8 
Eastern Cooperative Oncology Group Performance Status ......................56 
7.4 
Sample Handling, Storage, and Shipment .............................................................56 
8 
Statistical and Analytical Plan ........................................................................................ 58 
8.1 
Safety Endpoints ....................................................................................................58 
8.2 
Study Endpoints .....................................................................................................58 
8.2.1 
Primary Endpoints ....................................................................................58 
8.2.2 
Secondary Endpoints ................................................................................58 
 
 
8.3 
Sample Size Calculations .......................................................................................59 
8.4 
Analysis Sets ..........................................................................................................59 
8.5 
Description of Subgroups to be Analyzed .............................................................60 
8.6 
Statistical Analysis Methodology ..........................................................................60 
8.6.1 
Efficacy Analysis ......................................................................................60 
8.6.1.1 
Overall Response Rate ........................................................... 60 
8.6.1.2 
Duration of Response ............................................................ 60 
8.6.1.3 
Overall Survival ..................................................................... 60 
8.6.1.4 
Progression-Free Survival ..................................................... 60 
8.6.2 
Safety Analyses .........................................................................................61 
8.6.2.1 
Analyses of Adverse Events .................................................. 61 
8.6.2.2 
Clinical Laboratory Results ................................................... 61 
8.6.2.3 
Additional Safety Assessments .............................................. 62 
8.6.3 
Pharmacokinetic and Pharmacodynamic Analyses ..................................62 
8.6.4 
Study Drug Exposure ................................................................................63 
8.7 
Data Quality Assurance ..........................................................................................63 
8.7.1 
Data Management .....................................................................................63 
9 
Ethics .............................................................................................................................. 64 
9.1 
Independent Ethics Committee or Institutional Review Board .............................64 
9.2 
Ethical Conduct of the Study .................................................................................64 


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9.3 
Patient Information and Consent ...........................................................................64 
10 
Investigator’s Obligations ............................................................................................... 66 
10.1 Confidentiality .......................................................................................................66 
10.2 Financial Disclosure and Obligations ....................................................................66 
10.3 Investigator Documentation ...................................................................................67 
10.4 Study Conduct ........................................................................................................67 
10.5 Adherence to Protocol............................................................................................67 
10.6 Adverse Events and Study Report Requirements ..................................................68 
10.7 Investigator’s Final Report ....................................................................................68 
10.8 Records Retention ..................................................................................................68 
10.9 Publications ............................................................................................................68 
11 
Study Management ......................................................................................................... 69 
11.1 Monitoring .............................................................................................................69 
11.1.1 Monitoring of the Study ............................................................................69 
11.1.2 Inspection of Records ...............................................................................69 
11.2 Management of Protocol Amendments and Deviations .........................................69 
11.2.1 Modification of the Protocol .....................................................................69 
11.2.2 Protocol Deviations ..................................................................................70 
11.3 Study Termination ..................................................................................................70 
11.4 Final Report ...........................................................................................................70 
12 
Reference List ................................................................................................................. 71 
13 
Appendices ..................................................................................................................... 73 
13.1 Appendix: Schedule of Events ...............................................................................73 
13.1.1 Schedule of Study Procedures ..................................................................74 
13.1.2 Timing of ECG and Sample Collection for PK, ADA,
 
 and PBMCs ..................................................................78 
13.2 Appendix: Response Assessment of Hodgkin and Non-Hodgkin Lymphoma 
(Lugano Classification) ..........................................................................................79 
13.3 Appendix: Global Response Score Grading Scales for Modified 
Severity-weighted Assessment Tool (mSWAT) for CTCL ....................................83 
13.3.1 Skin Scoring ..............................................................................................83 
13.3.1.1 
Total Body Surface Area (TBSA) Involvement by Skin 
Disease ................................................................................... 83 


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13.3.1.2 
Severity Weighting Factor ..................................................... 83 
13.3.1.3 
Calculating Skin Scores ......................................................... 83 
13.3.1.4 
Response Definitions ............................................................. 85 
13.3.2 Global Response Score .............................................................................86 
13.4 Appendix: CTCAE Immune System Hypersensitivity Grades ..............................87 
13.5 Appendix: Dose Escalation Scheme Report ..........................................................90 
13.5.1 Overview................................................................................................. 90 
13.5.2 Continual Reassessment Method ..............................................................91 
13.5.3 Dose Escalation Rules ..............................................................................92 
13.5.3.1 
Starting Dose and Entry into the Study ................................. 92 
13.5.3.2 
Assignment of Dose Level ..................................................... 92 
13.5.4 Interim Monitoring ...................................................................................93 
13.5.4.1 
Safety Monitoring .................................................................. 93 
13.5.4.2 
Success in Identifying the MTD ............................................ 93 
13.5.5 Operating Characteristics ..........................................................................93 
13.5.5.1 
All Doses Safe ....................................................................... 94 
13.5.5.2 
MTD is the Highest Dose (0.30 mg/kg) ................................ 95 
13.5.5.3 
MTD is a Middle Dose (0.15 mg/kg) .................................... 96 
13.5.5.4 
MTD is a Middle Dose (0.10 mg/kg) .................................... 97 
13.5.5.5 
MTD is a Low Dose (0.05 mg/kg) ......................................... 98 
13.5.5.6 
MTD is a Low Dose (0.02 mg/kg) ......................................... 99 
13.5.5.7 
No Doses Safe ...................................................................... 100 
13.6 Appendix: Clinical Case Definitions: Level 1 of Diagnostic Certainty for 
Guillain-Barré Syndrome .....................................................................................101 
13.7 Appendix: Guillain–Barré Syndrome Disability Scale ........................................102 
List of Figures 
Figure 1.  Schematic Representation and Chemical Structure of ADCT-301 ......................... 21 


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Protocol Synopsis 
Protocol Number: 
ADCT-301-001 
Title: 
A Phase 1 Adaptive Dose-Escalation Study to Evaluate the Tolerability, 
Safety, Pharmacokinetics, and Antitumor Activity of ADCT-301 in 
Patients with Relapsed or Refractory Hodgkin Lymphoma and 
Non-Hodgkin Lymphoma 
Sponsor: 
ADC Therapeutics SA 
Study Phase: 
Phase 1 
Study Sites: 
Approximately 10 sites during dose-escalation (Part 1) and 13 sites during 
dose expansion (Part 2) 
Indication: 
Refractory or relapsed lymphoma (per WHO Classification) defined as:  
• 
Non-Hodgkin lymphoma (NHL): Patients with histologically 
confirmed NHL (including stage ≥Ib cutaneous T-cell lymphoma 
[CTCL]) who have failed or are intolerant to any established therapy 
known to provide clinical benefit at current state of disease. 
• 
Hodgkin lymphoma: Patients with histologically confirmed classical 
Hodgkin lymphoma who have failed or are intolerant to any 
established therapy known to provide clinical benefit at current state 
of disease. 
Rationale: 
Lymphoma cells have been reported to express cluster of differentiation 
(CD) 25 on their cell surface.  Expression of CD25 is positive (≥20% 
tumor cells) in approximately 58% to 78% of Hodgkin lymphoma, 42% to 
50% of peripheral T-cell lymphoma, 54% of cutaneous T-cell lymphoma, 
and 40% of diffuse large B-cell lymphoma cases. 
ADCT-301 is an antibody drug conjugate (ADC), composed of the human 
monoclonal antibody, HuMax®-TAC, directed against CD25, and 
conjugated 
through 
a 
cleavable 
linker 
to 
SG3199, 
a 
pyrrolobenzodiazepine (PBD) dimer cytotoxin.  PBD dimers are highly 
efficient anticancer drugs that bind in the minor groove of DNA and form 
highly cytotoxic DNA interstrand cross-links.  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 potential for ADCT-301 in treating hematological malignancies that 
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 


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targeted delivery of the PBD cytotoxin SG3199. 
The safety of ADCT-301 has been assessed in nonclinical 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 
relapsed/refractory lymphoma (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 activity of ADCT-301 measured by overall response rate, 
duration of response, progression-free survival, and overall survival. 
• Characterize the pharmacokinetic (PK) profile of HuMax-TAC 
(total antibody; drug-to-antibody ratio [DAR] ≥0), PBD-conjugated 
HuMax-TAC (DAR ≥1), and free warhead SG3199. 
• Evaluate anti-drug antibodies (ADAs) in blood before, during, and 
after treatment with ADCT-301. 
 
 
 
 
 
  
 
 
 
 
 
 
 
 


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Patient Selection: 
Inclusion Criteria: 
1. Male or female age 18 years or older. 
2. Refractory or relapsed lymphoma (per WHO Classification system) 
defined as:  
• 
Non-Hodgkin 
lymphoma 
(NHL): 
Patients 
with 
histologically 
confirmed NHL (including stage ≥ Ib cutaneous T-cell lymphoma 
[CTCL]) who have failed or are intolerant to any established therapy 
known to provide clinical benefit at current state of disease.  There is 
no upper limit to the number of prior therapies. 
• Hodgkin lymphoma: Patients with histologically confirmed classical 
Hodgkin lymphoma who have failed or are intolerant to brentuximab 
vedotin. Patients must have received a checkpoint inhibitor. There is 
no upper limit to the number of prior therapies.  
3. Pathologically confirmed relapsed or refractory lymphoma; a biopsy at 
any relapse is acceptable. 
4. Availability of formalin-fixed paraffin-embedded (FFPE) tumor tissue 
block.  An FFPE block from a current biopsy is preferred; however, 
archival tissue taken at any prior relapse is acceptable.  If tissue block 
is not available, slides from a FFPE block may be acceptable for 
eligibility upon consultation with the Sponsor. 
5. Measurable disease, defined by the 2014 Lugano Classification 
Criteria (including CTCL patients without evidence of skin disease).  
CTCL patients with skin disease and modified Severity-Weighted 
Assessment Tool (mSWAT) criteria > 0, or absolute Sézary count 
≥1000 cells/µL are eligible. 
6. Eastern Cooperative Oncology Group (ECOG) performance status 0 to 
2. 
7. Absolute neutrophil count (ANC) ≥1500/µL. Criterion not applicable 
to adult T cell leukemia/lymphoma (ATLL) patients.  
8. Platelet count of ≥75000/µL. Criterion not applicable to ATLL 
patients. 
9. Hemoglobin ≥9.0 g/dL without transfusion within the 2 weeks prior to 
Day 1. Criterion not applicable to ATLL patients. 
10. Serum/plasma creatinine ≤1.5 mg/dL, or if the patient has a creatinine 
>1.5 mg/dL, a measured creatinine clearance must be >80 mL/min as 
calculated by the Cockcroft and Gault equation. 
11. Serum/plasma alkaline phosphatase, alanine aminotransferase, and 
aspartate aminotransferase ≤2 times the upper limit of normal (ULN); 
≤5 times ULN if there is liver or bone involvement. 


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12. Total serum/plasma bilirubin ≤1.5 times ULN (patients with known 
Gilbert’s syndrome may have a total bilirubin up to ≤3 times ULN). 
13. Women of childbearing potential must have a negative blood 
beta-human chorionic gonadotropin (β-HCG) pregnancy test within 
7 days prior to Day 1. 
14. Women of childbearing potential* must agree to use a highly 
effective** method of contraception from the time of giving informed 
consent until at least 16 weeks after the last dose of ADCT-301.  
Men with female partners who are of childbearing potential must agree 
that they or their partners will use a highly effective method of 
contraception from the time of giving informed consent until at least 
16 weeks after the patient receives his last dose of ADCT-301.   
*Defined as: Sexually mature women who have not undergone 
bilateral tubal ligation, bilateral oophorectomy, or hysterectomy; or 
who have not been postmenopausal (i.e., who have not menstruated at 
all) for at least 1 year. 
**Defined as: Hormonal contraceptives (oral, injectable, patch, 
intrauterine devices), male partner sterilization, or total abstinence 
from heterosexual intercourse, when this is the preferred and usual 
lifestyle 
of 
the 
patient. 
Note: 
The 
double-barrier 
method 
(e.g., synthetic condoms, diaphragm, or cervical cap with spermicidal 
foam, cream, or gel), periodic abstinence (such as calendar, 
symptothermal, post-ovulation), withdrawal (coitus interruptus), 
lactational amenorrhea method, and spermicide-only are not 
acceptable as highly effective methods of contraception. 
Exclusion Criteria: 
1. Patients who have an option for any treatment with proven clinical 
benefit for their lymphoid malignancy at current state of disease.  
2. Active graft-versus-host disease. 
3. Autologous or allogenic transplant within the 60 days prior to Cycle 1 
Day 1 
4. Evidence of myelodysplasia or myeloid leukemia by morphology, 
immunostains, flow cytometry, or cytogenetics on a bone marrow 
aspirate or biopsy. 
5. Known history of positive serum human ADA or known allergy to 
any component of ADCT-301. 
6. 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]). 


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7. History 
of 
neuropathy 
considered 
of 
autoimmune 
origin 
(e.g., polyradiculopathy including Guillain-Barré syndrome (GBS) and 
myasthenia gravis); other central nervous system autoimmune disease 
(e.g., poliomyelitis, multiple sclerosis). 
8. 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. 
9. 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.  If patient is at risk for 
having undiagnosed HCV (e.g., history of injection drug use), 
HCV testing should be considered.  
10. History of Steven's Johnson's syndrome or toxic epidermal necrolysis 
syndrome. 
11. Pregnant or breastfeeding women. 
12. Significant medical comorbidities, including uncontrolled hypertension 
(diastolic blood pressure > 115 mm Hg), unstable angina, congestive 
heart failure (greater than New York Heart Association class II), severe 
uncontrolled ventricular arrhythmias, or electrocardiographic evidence 
of acute ischemia, poorly controlled diabetes, severe chronic 
pulmonary disease, coronary angioplasty, or myocardial infarction 
within 6 months prior to screening, or uncontrolled atrial or ventricular 
cardiac arrhythmias. 
13. Use of any other experimental medication(s) within 14 days or 
5 half-lives, but in no case < 14 days prior to the start of study 
treatment on Cycle 1, Day 1, except if approved by the Sponsor. 
14. Major surgery, radiotherapy, chemotherapy, or other anti-neoplastic 
therapy (including prednisone ≥ 40 mg/day or equivalent) within 
14 days or 5 half-lives (whichever is shorter) prior to Cycle 1, Day 1 
treatment, or shorter if approved by the Sponsor. 
15. Failure to recover (to Common Terminology Criteria for Adverse 
Events [CTCAE Version 4.0] Grade 0 or Grade 1) from acute 
non-hematologic toxicity (except all grades of alopecia or Grade 2 or 
lower neuropathy), due to previous therapy, prior to Screening. 
16. Congenital long QT syndrome or a corrected QTc interval ≥ 450 ms at 
screening (unless secondary to pacemaker or bundle branch block).  
17. 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 


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Sponsor medical monitor and Investigator agree and document should 
not be exclusionary.  
18. 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, first-in-human (FIH), open-label study of ADCT-301 in 
patients with relapsed and refractory lymphoma that will be conducted in 
2 parts.  
In Part 1 (dose-escalation), patients will receive a 1-hour intravenous (IV) 
infusion of ADCT-301 on Day 1 every 3 weeks (21-day cycle) and the 
MTD will be determined. If ADCT-301 is well tolerated after the first 
cycle, the infusion duration may be shortened to 30 minutes for 
subsequent cycles for that patient, at the Investigator’s discretion. The 
starting dose of ADCT-301 will be 3 µg/kg (Dose Level 1) and dose 
escalation will be conducted according to a continual reassessment 
method (CRM).    
The first patient to be treated at each new dose will be monitored for any 
AEs for 7 days before proceeding with dosing for a second patient. 
In Part 2 (expansion), patients will be assigned to receive the 
recommended 
dose(s) 
of 
ADCT-301 
as 
determined 
by 
the 
Dose Escalation Steering Committee (DESC) during Part 1 of the study. 
The following dosing regimen(s) may be investigated based on safety and 
PK emerging information: 
• 
45 µg/kg every 3 weeks for 3 cycles followed by 30 µg/kg every 
3 weeks for patients who have not progressed.   
• 
45 µg/kg every 3 weeks for 3 cycles followed by 20 µg/kg every 
3 weeks for patients who have not progressed.   
• 
45 µg/kg every 3 weeks for 4 cycles followed by 30 µg/kg every 
3 weeks for patients who have not progressed. 
• 
45 µg/kg every 3 weeks for 4 cycles followed by 20 µg/kg every 
3 weeks for patients who have not progressed. 
The initial dose level for Part 1 will be 3 µg/kg (Dose Level 1).  
The highest allowed dose will be 300 µg/kg.  The MTD will be the highest 
safe dose that has at least a 60% probability that the dose-limiting-toxicity 
(DLT) rate is < 30%.  The dose escalation design is described below. 
After discontinuation of treatment, patients without documented objective 
disease progression will be followed until progression of disease or 
initiation of new anticancer therapy for up to 12 months.  All patients will 
be followed for survival (by telephone contact or retrospective chart 
review) until a new anticancer therapy is initiated or for up to 12 months 
after treatment discontinuation. 


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A DESC will be responsible for safety monitoring and overall supervision 
of the study.   
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, see below), 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 entire study (Parts 1 and 2) could last 
approximately 3 years from first patient treated to last patient completed. 
A patient may be withdrawn from the treatment for any of the following 
reasons: 
• Objective disease progression 
• Clinical 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 with use of the study 
dug) 
• The Investigator determines if 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 


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Efficacy 
Assessments: 
Response to ADCT-301 will be assessed through the evaluation of 
complete response (CR), partial response (PR), progressive disease (PD), 
and stable disease (SD) determined by the Investigator based on the 
Lugano Classification Criteria (2014) and Global Response Score Grading 
Scales for CTCL.  Disease assessments will occur every other cycle for 
the first 2 evaluations (6 and 12 weeks), and every third cycle (every 9 
weeks) thereafter until progression or more frequently, if clinically 
indicated.  
Patients who discontinue treatment for any reason other than objective 
disease progression will continue to be followed with scans approximately 
every 12 weeks from the last tumor assessment until disease progression, 
or initiation of a new anticancer treatment.  If a patient discontinues 
treatment for a hematopoietic stem cell transplant, the frequency of 
imaging will be as per the transplant center standard of care.  
After documentation of disease progression or start of a new anticancer 
treatment, patients will be contacted by telephone approximately every 
12 weeks for up to 12 months after the last dose of study drug to collect 
survival information. 
Pharmacokinetic 
and Anti-drug 
Antibody 
Assessments: 
The concentration versus time profile of total antibody HuMax-TAC, 
PBD-conjugated HuMax-TAC and free warhead SG3199 in serum will be 
determined centrally in Cycles 1 and 2.  
In Cycles 1 and 2, sample collection for analysis of PK parameters will be 
performed before the start of the ADCT-301 infusion, end of the infusion, 
and at 1, 3, 6, 24, 48, 96, 168 (Day 8), and 336 hours (Day 15) after the 
end of the ADCT-301 infusion.  In all subsequent cycles, PK blood 
samples will be collected before the start of the ADCT-301 infusion, 
at end of the infusion, at End of Treatment (EOT), and at 12 weeks 
following the last ADCT-301 infusion.  
Antidrug (ADCT-301) antibodies in serum will be measured centrally 
before the start of each ADCT-301 infusion, at EOT, at 12 weeks 
following the last ADCT 301 infusion, and optionally in PK samples if 
needed. 
 
 
 
 
 
 
 
 
 
 


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•
 
 
 
 
 
 
 
 
 
 
Safety 
Assessments: 
Safety will be assessed based on the evaluation of AEs, serious AEs 
(SAEs), treatment discontinuations due to AEs, DLTs, periodic 12-lead 
electrocardiogram (ECG) recordings, physical examinations, vital signs 
measurements, ECOG performance status, hematology, coagulation panel, 
biochemistry, pregnancy testing (for women of child-bearing potential) 
and urinalysis test results obtained at various time points during the study.  
Adverse events will be graded according to CTCAE Version 4.0.  
Definition of DLT 
A DLT is defined as any of the following events, except those that are 
clearly due to underlying disease or extraneous causes: 
• A hematologic DLT is defined as (not applicable for ATLL patients): 
o Grade 3 or 4 febrile neutropenia or neutropenic infection. 
o Grade 4 neutropenia lasting > 7 days. 
o Grade 4 thrombocytopenia. 
o Grade 3 thrombocytopenia with clinically significant bleeding, or 
Grade 3 thrombocytopenia requiring a platelet transfusion. 
o Grade 4 anemia. 
• For ATLL patients, a hematologic DLT is defined as: 
o Any Grade 4 neutropenia lasting ≥ 42 days from the start of the 
cycle in the absence of evidence of residual leukemia. 
o Grade 3 or higher event of thrombocytopenia or a Grade 4 anemia, 
with a hypocellular bone marrow lasting for ≥ 42 days from the start 
of the cycle, in the absence of evidence of residual leukemia (i.e., 
with <5% malignant cells).  
• 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 (including nausea, vomiting, diarrhea, and 
electrolyte imbalances lasting ≥ 48 hours despite optimal therapy 
[excluding all grades of alopecia]).  
o Grade 3 or higher hypersensitivity reaction (regardless of 
premedication). 


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o Skin ulceration ≥ Grade 2. 
o Peripheral sensory or motor neuropathy ≥ Grade 2. 
Note: The DLT observation period for dose escalation will be 1 cycle; 
however, the adaptive dose-escalation algorithm will incorporate 
cumulative DLTs occurring through Cycle 3.  
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 ADCT-301 per vial (deliverable volume 5.4 mL at 6 mg/mL). 
Patients will receive ADCT-301 administered initially as a 1-hour IV 
infusion on Day 1 of each 3-week cycle.  If ADCT-301 is well tolerated 
after the first cycle, the infusion duration may be shortened to 30 minutes 
for subsequent cycles at the Investigator’s discretion. 
Dose-Escalation 
Design: 
Dose levels from 3 to 300 μg/kg are possible. 
Dose escalation will be conducted according to a CRM.  Non-DLT 
toxicity events (i.e., Grade 2 or higher toxicities) will inform the 
probability of DLT at each dose level.  Dose escalation is also conducted 
according to a set of rules that govern entry into the study and assignment 
of dose level.  These rules allow that untried dose levels may be skipped.  
The trial is continuously monitored for safety and early stopping for 
successfully identifying the MTD. 
The final number of doses will be dependent on the emergent toxicity 
profile and will be decided by a DESC; PK and pharmacodynamic 
evaluations may also inform decision making.  
The DLT observation period for dose escalation will be 1 cycle; however, 
the adaptive dose-escalation algorithm will incorporate cumulative DLTs 
occurring through Cycle 3.  No intra-patient dose escalation will be 
allowed during the study.  However, once the recommended Part 2 dose(s) 
is determined, patients receiving lower or higher dose levels of 
ADCT-301 may be offered continued treatment at the recommended dose. 
During Part 1, the DESC may expand enrollment at doses below the 
current dose level being evaluated 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 with documented stable disease.  Not more than 
10 patients in total can be treated at any dose level unless at least 3 of the 
10 patients have documented partial response or better using the 
2014 Lugano Classification criteria2 or other appropriate measures of 
response. 
Sample Size: 
This is a Phase 1 study with a total sample size of approximately 
140 patients.  Part 1 may enroll approximately 80 patients and Part 2 will 
enroll approximately 60 patients. 


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List of Abbreviations 
Abbreviation 
Definition 
ADA 
ADC 
anti-drug antibody 
antibody drug conjugate 
AE 
adverse event 
AI 
accumulation index 
ANC 
ATLL 
absolute neutrophil count 
adult T cell leukemia/lymphoma 
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 
BSA 
body surface area 
CBC 
complete blood count 
CD 
cluster of differentiation 
CFR 
Code of Federal Regulations 
CL 
clearance 
Cmax 
maximum concentration 
CMV 
cytomegalovirus 
CR 
complete response 
CRM 
continual reassessment method 
CRO 
contract research organization 
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTCL 
cutaneous T-cell lymphoma 
D5W 
5% dextrose in water 
DAR 
drug-to-antibody ratio 
DESC 
Dose Escalation Steering Committee 
DLT 
dose-limiting toxicity 
EBV 
Epstein-Barr virus 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 
EOT 
End of Treatment 
FDA 
Food and Drug Administration 
FDG 
18F-fluorodeoxyglucose 
FIH 
first-in-human 
FFPE 
formalin-fixed paraffin-embedded 
GBS 
Guillain-Barré syndrome 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practice 
HCV 
hepatitis C virus 


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Abbreviation 
Definition 
HIV 
human immunodeficiency virus  
HbsAg 
hepatitis B surface antigen (HbsAg) 
HSV1 / 2 
Herpes Simplex Virus Type 1 / Type 2 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
IEC 
independent ethics committee 
IL-2R 
Interleukin 2 receptor 
INR 
International Normalized Ratio 
IRB 
institutional review board 
IV 
intravenous 
IVF 
intravenous fluid 
IVIg 
intravenous immunoglobulin 
MRI 
magnetic resonance imaging 
mSWAT 
modified Severity-Weighted Assessment Tool 
MRT 
mean residence time 
MTD 
maximum tolerated dose 
NHL 
non-Hodgkin lymphoma 
PBD 
pyrrolobenzodiazepine 
PBMC 
peripheral blood mononuclear cell 
PD 
Progressive Disease 
PET 
positron emission tomography 
PK 
PLEX 
pharmacokinetic 
plasma exchange 
PR 
partial response 
PT 
prothrombin time 
PTT 
Partial prothrombin time 
QWBA 
Quantitative Whole Body Autoradiography 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SD 
stable disease 
SPD 
sum of the product of the perpendicular diameters 
TAC 
T-cell activation antigen 
TBSA 
total body surface area 
TEAE 
treatment-emergent adverse event 
TLS 
tumor lysis syndrome 
λz 
terminal elimination phase rate constant 
Tmax 
time to maximum concentration 
T1/2 
terminal half-life 
ULN 
upper limit of normal 
Vss 
volume of distribution at steady-state 
VZ 
volume of distribution 
VZV 
varicella zoster virus 
WBC 
white blood cell 


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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.  PBD dimers are highly efficient anticancer drugs that bind in the minor groove of 
DNA and form highly cytotoxic DNA interstrand cross-links.  The schematic representation 
of ADCT-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: PABA, para-aminobenzoic acid; PEG, polyethylene glycol. 
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 self-immolative group. 
• SG3199:  A PBD dimer cytotoxin, which is a highly efficient anticancer 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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CD25 or T-cell activation antigen (TAC) is the 55 kDa alpha chain of the interleukin-2 
receptor (IL-2R).  The IL-2R is made up of three subunits:  α (CD25), β (CD122) and 
γ (CD132).  Lymphoma cells have been reported to express CD25 on their cell surface.  
Expression of CD25 as detected by flow cytometry is positive (≥20% tumor cells) in 
approximately 58% to 78% of Hodgkin lymphoma, 42% to 50% of peripheral T-cell 
lymphoma, 54% of cutaneous T-cell lymphoma, and 40% of diffuse large B-cell lymphoma 
cases.12, 7, 10, 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.  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.  


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2 Study Rationale and Justification for Dose Level Selection  
Study ADCT-301-001 is the first-in-human (FIH) clinical study with ADCT-301.  
The potential for ADCT-301 in treating hematological malignancies that 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 profiles of monoclonal antibodies directed against CD25 (IL-2Rα), 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 adverse events (AEs) identified in the prescribing 
information for both products are gastrointestinal disorders, including abdominal pain, 
constipation, diarrhea, nausea, and vomiting.8,11  
The safety of ADCT-301 has been assessed in nonclinical 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 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 half-life 
(T1/2) of 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 AEs.  The highest 
non-severe toxic dose 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 (one-sixth of the highest non-severe 
toxic dose based on body surface area [BSA]) could be proposed for the FIH study.  
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 (Dose Level 1) 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.  
 


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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 relapsed/refractory lymphoma (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 activity of ADCT-301 measured by overall response rate, duration of 
response, progression-free survival, and overall survival. 
• Characterize the pharmacokinetic (PK) profile of HuMax-TAC (total antibody; 
drug-to-antibody ratio [DAR] ≥0), PBD-conjugated HuMax-TAC (DAR ≥1), and free 
warhead SG3199. 
• Evaluate anti-drug antibodies (ADAs) in blood before, during, and after treatment with 
ADCT-301. 
 
 
 
 
 
 
 
 
 
 
 
 
 


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4 Investigational Plan and Patient Selection 
4.1 Study Design  
This is a Phase 1, FIH, open-label, dose-escalation (Part 1) and expansion (Part 2) study of 
ADCT-301 in patients with relapsed and refractory lymphoma.  The study will evaluate the 
safety and tolerability of ADCT-301 as monotherapy, as well as the preliminary activity, PK, 
pharmacodynamics, and formation of ADAs of ADCT-301 in patients.  
For each patient, the study will include a screening period (up to 28 days), a treatment period 
(until progressive disease, intolerable toxicity, or withdrawal of consent), 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 entire study (Parts 1 and 2) 
could last approximately 3 years from first patient treated to last patient completed. 
In Part 1, patients will receive ADCT-301 administered as a 1-hour IV infusion on Day 1 of 
each 3-week (21-day) cycle.  If ADCT-301 is well tolerated after the first cycle, the infusion 
duration may be shortened to 30 minutes for subsequent cycles at the Investigator’s 
discretion.   
The first patient at each dose level will be monitored for any AEs for 7 days before 
proceeding with dosing for the second patient. 
The initial dose level for Part 1 will be 3 µg/kg (Dose Level 1).  The highest allowed dose 
will be 300 µg/kg.  The MTD will be the highest safe dose that has at least a 60% probability 
that the dose-limiting toxicity (DLT) rate is < 30%.   
After discontinuation of treatment, patients without documented objective disease 
progression will be followed until progression of disease or initiation of new anticancer 
therapy for up to 12 months.  All patients will be followed for survival (by telephone contact 
or retrospective chart review) until a new anticancer therapy is initiated or for up to 
12 months after treatment discontinuation. 


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4.1.1 Dose Escalation and Determination of the Maximum Tolerated Dose 
(Part 1) 
Dose escalation will be conducted according to a continual reassessment method (CRM) 
(Section 13.5).  Dose levels from 3 to 300 μg/kg are possible. 
However, the final number of doses will be dependent on the emergent toxicity profile and 
will be decided by a Dose Escalation Steering Committee (DESC) (Section 7.3.1.2).  
Pharmacokinetic and pharmacodynamic evaluations may also inform decision making. 
The DLT observation period for dose escalation will be 1 cycle; however, the adaptive 
dose-escalation algorithm will incorporate cumulative DLTs occurring through Cycle 3.  
No intra-patient dose escalation will be allowed during the study.  However, once the 
recommended Part 2 dose(s) is determined, patients receiving lower or higher dose levels of 
ADCT-301 in Part 1 may be offered continued treatment at the recommended dose. 
During Part 1, the DESC may expand enrollment at doses below the current dose level being 
evaluated 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 with documented stable disease.  
Not more than 10 patients in total can be treated at any dose level unless at least 3 of the 10 
patients have documented partial response or better using the 2014 Lugano Classification 
criteria2 or other appropriate measures of response (Appendix 13.3).  
4.1.2 Dose Expansion (Part 2) 
In Part 2 (expansion), patients will be assigned to receive the recommended dose(s) of 
ADCT-301, as determined by the DESC during Part 1 of the study.   
The following dosing regimen(s) may be investigated based on safety and PK emerging 
information: 
• 
45 µg/kg every 3 weeks for 3 cycles followed by 30 µg/kg every 3 weeks for patients who 
have not progressed.   
• 
45 µg/kg every 3 weeks for 3 cycles followed by 20 µg/kg every 3 weeks for patients who 
have not progressed.   
• 
45 µg/kg every 3 weeks for 4 cycles followed by 30 µg/kg every 3 weeks for patients who 
have not progressed. 
• 
45 µg/kg every 3 weeks for 4 cycles followed by 20 µg/kg every 3 weeks for patients who 
have not progressed. 
The patient population (e.g., disease subtypes) to be enrolled in Part 2 (expansion) may be 
refined based on results and observations from Part 1. 


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4.2 Selection of Study Population 
It is estimated that approximately 140 patients (approximately 80 patients in Part 1 and 
approximately 60 patients in Part 2) will be enrolled at approximately 10 sites in Part 1 and 
13 sites in Part 2 of the study.  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. Refractory or relapsed lymphoma (per WHO Classification system) defined as:  
• Non-Hodgkin lymphoma (NHL): Patients with histologically confirmed NHL 
(including stage ≥ Ib cutaneous T-cell lymphoma [CTCL]) who have failed or are 
intolerant to any established therapy known to provide clinical benefit at current state 
of disease.  There is no upper limit to the number of prior therapies. 
• Hodgkin lymphoma: Patients with histologically confirmed classical Hodgkin 
lymphoma who have failed or are intolerant to brentuximab vedotin. Patients must 
have received a checkpoint inhibitor. There is no upper limit to the number of prior 
therapies. 
3. Pathologically confirmed relapsed or refractory lymphoma; a biopsy at any relapse is 
acceptable. 
4. Availability of formalin-fixed paraffin-embedded (FFPE) tumor tissue block. 
An FFPE block from a current biopsy is preferred; however, archival tissue taken at any 
prior relapse is acceptable.  If tissue block is not available, slides from a FFPE block may 
be acceptable for eligibility upon consultation with the Sponsor. 
5. Measurable disease, defined by the 2014 Lugano Classification Criteria (including CTCL 
patients without evidence of skin disease) (Appendix 13.2).  CTCL patients with skin 
disease and modified Severity-Weighted Assessment Tool (mSWAT) criteria >0, or 
absolute Sézary count ≥ 1000 cells/µL are eligible (Appendix 13.3). 
6. ECOG performance status 0 to 2. 
7. Absolute neutrophil count (ANC) ≥1500/µL. Criterion not applicable to adult T cell 
leukemia/lymphoma (ATLL) patients.  
8. Platelet count of ≥75000/µL. Criterion not applicable to ATLL patients. 
9. Hemoglobin ≥9.0 g/dL without transfusion within the 2 weeks prior to Day 1. 
Criterion not applicable to ATLL patients. 
10. Serum/plasma creatinine ≤1.5 mg/dL, or if the patient has a creatinine > 1.5 mg/dL, 
a measured creatinine clearance must be > 80 mL/min as calculated by the Cockcroft and 
Gault equation.4 


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11. Serum/plasma 
alkaline 
phosphatase, 
alanine 
aminotransferase, 
and 
aspartate 
aminotransferase ≤2 times the upper limit of normal (ULN); ≤ 5 times ULN if there is 
liver or bone involvement. 
12. Total serum/plasma bilirubin ≤1.5 times ULN (patients with known Gilbert’s syndrome 
may have a total bilirubin up to ≤3 times ULN). 
13. Women of childbearing potential must have a negative blood beta-human chorionic 
gonadotropin (β-HCG) pregnancy test within 7 days prior to Day 1. 
14. Women of childbearing potential* must agree to use a highly effective** method of 
contraception from the time of giving informed consent until at least 16 weeks after the 
last dose of ADCT-301.  Men with female partners who are of childbearing potential must 
agree that they or their partners will use a highly effective method of contraception from 
the time of giving informed consent until at least 16 weeks after the patient receives his 
last dose of ADCT-301.   
*Defined as: Sexually mature women who have not undergone bilateral tubal ligation, 
bilateral oophorectomy, or hysterectomy; or who have not been postmenopausal (i.e., 
who have not menstruated at all) for at least 1 year. 
**Defined as: Hormonal contraceptives (oral, injectable, patch, intrauterine devices), 
male partner sterilization, or total abstinence from heterosexual intercourse, when this is 
the preferred and usual lifestyle of the patient.  Note: The double-barrier method (e.g., 
synthetic condoms, diaphragm, or cervical cap with spermicidal foam, cream, or gel), 
periodic abstinence (such as calendar, symptothermal, post-ovulation), withdrawal 
(coitus interruptus), lactational amenorrhea method, and spermicide-only are not 
acceptable as highly effective methods of contraception. 
4.2.2 Exclusion Criteria 
1. Patients who have an option for any treatment with proven clinical benefit for their 
lymphoid malignancy at current state of disease.  
2. Active graft-versus-host disease. 
3. Autologous or allogenic transplant within the 60 days prior to Cycle 1 Day 1 
4. Evidence of myelodysplasia or myeloid leukemia by morphology, immunostains, flow 
cytometry, or cytogenetics on a bone marrow aspirate or biopsy. 
5. Known history of positive serum human ADA or known allergy to any component of 
ADCT-301. 
6. 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]);  


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7. History of neuropathy considered of autoimmune origin (e.g., polyradiculopathy 
including Guillain-Barré syndrome and myasthenia gravis); other central nervous system 
autoimmune disease (e.g., poliomyelitis, multiple sclerosis). 
8. 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. 
9. 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.   
If patient is at risk for having undiagnosed HCV (e.g., history of injection drug use), 
HCV testing should be considered.  
10. History of Steven's Johnson's syndrome or toxic epidermal necrolysis syndrome. 
11. Pregnant or breastfeeding women. 
12. Significant medical comorbidities, including uncontrolled hypertension (diastolic blood 
pressure > 115 mm Hg), unstable angina, congestive heart failure (greater than New York 
Heart Association class II), severe uncontrolled ventricular arrhythmias, or 
electrocardiographic evidence of acute ischemia, poorly controlled diabetes, severe 
chronic pulmonary disease, coronary angioplasty, or myocardial infarction within 
6 months prior to screening, or uncontrolled atrial or ventricular cardiac arrhythmias. 
13. Use of any other experimental medication(s) within 14 days or 5 half-lives, but in no case 
< 14 days prior to the start of study treatment on Cycle 1, Day 1, except if approved by 
the Sponsor. 
14. Major 
surgery, 
radiotherapy, 
chemotherapy, 
or 
other 
anti-neoplastic 
therapy 
(including prednisone ≥ 40 mg/day or equivalent) within 14 days or 5 half-lives 
(whichever is shorter) prior to Cycle 1, Day 1 treatment, except if approved by the 
Sponsor. 
15. Failure to recover (to Common Terminology Criteria for Adverse Events 
[CTCAE Version 4.0] Grade 0 or Grade 1) from acute non-hematologic toxicity 
(except all grades of alopecia or Grade 2 or lower neuropathy), due to previous therapy, 
prior to Screening. 
16. Congenital long QT syndrome or a corrected QTc interval ≥ 450 ms at screening 
(unless secondary to pacemaker or bundle branch block). 
17. 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 Sponsor Medical Monitor and Investigator agree, and document 
should not be exclusionary.  


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18. 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 
The following procedures will be performed during the study. 
5.1.1 Screening Period (Day –28 to –1) 
The following procedures will be performed within 28 days prior to Day 1:  
• Signed and dated Institutional Review Board (IRB) /Independent Ethics Committee 
(IEC) approved informed consent form (ICF) obtained prior to performing any study 
evaluations.  Results (e.g., from laboratory tests or radiographic evaluations, etc.) 
obtained prior to the date of informed consent but within the allowed timeframe for 
screening may be used for determination of patient eligibility only if obtained as part of 
the patient’s standard of care. 
• Demography. 
• Medical history (to include a complete history of all surgeries and significant diagnoses 
and all cancer treatment [including surgery, radiation therapy, chemotherapy, etc.]) and 
assessment of cardiac risk factors (e.g., history of angina pectoris, coronary artery 
disease or cerebrovascular accident, transient ischemic attack, cardiac failure with 
known ejection fraction < 40%, or cardiac arrhythmia requiring medical therapy). 
• Pregnancy test (serum or urine, women of childbearing 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 will 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) 


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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 sign measurements.  
• Height. 
• Weight. 
• Eastern Cooperative Oncology Group (ECOG) performance status. 
• Disease assessments:  Assessed using positron emission tomography - computed 
tomography (PET-CT) and diagnostic CT of the neck/chest/abdomen/pelvis and other 
areas of known disease or newly suspected disease with a clinical examination for 
lymphoma.  Contrast should be used unless contraindicated. Magnetic resonance 
imaging (MRI) is permitted if diagnostic CT is contraindicated.  The same assessments 
methods used at Screening which identify sites of disease should be used uniformly for 
all subsequent assessments. 
Note: PET-CT is only required at screening for 18F-fluorodeoxyglucose (FDG) avid, 
nodal lymphomas (defined as per the Lugano Classification criteria as essentially all 
eligible histologies except small lymphocytic lymphoma, lymphoplasmacytic 
lymphoma/Waldenstrom’s macroglobulinemia, mycosis fungoides, and marginal zone 
NHLs, unless there is a suspicion of aggressive transformation). If PET-CT examination 
is negative at Screening, subsequent PET-CT is not required.  If PET-CT is positive, 
subsequent diagnostic CT and MRI are not needed, unless clinically indicated. 
• Hematology. 
• Coagulation panel. 
• Biochemistry. 
• Urinalysis. 
• 12-lead electrocardiogram (ECG). 
• AEs. 
• Concomitant medication use (including prescription or over-the-counter medication, 
herbal or naturopathic products) within the 14 days prior to Day 1. 


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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 unless otherwise specified: 
• Serum or urine pregnancy test (women of childbearing potential, Cycle 1 only) is not 
required if screening pregnancy test was performed using serum and was done < 7 days 
before dosing with negative result. 
• 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 (arterial blood pressure, heart rate, respiratory rate, 
temperature) are 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 
the first infusion, measurements are required prior to infusion start, hourly during 
infusion, and end of infusion for all subsequent infusions.  For Cycles 1 and 2, patients 
will be monitored for 4 hours post-infusion with vital signs being 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.   
• Disease assessments: 
o 
To be performed within 6 days prior to Day 1 of Cycles 3 and 5 and thereafter 
every third cycle (i.e., Cycles 8, 11, 14, etc.), until disease progression or more 
frequently, if clinically indicated.  
o 
The same methods used at Screening which identify sites of disease should be 
used uniformly for all subsequent assessments. 
Note:  The results of the disease assessment are to be available to the Investigator 
prior to administration of study drug. 
Note: if PET-CT examination is negative at Screening, subsequent PET-CT is not 
required.  For CTCL patients with disease limited to the skin, disease assessments 
after screening will be performed using mSWAT; radiological imaging after 
screening for CTCL patients with disease limited to the skin is not required unless 
clinically indicated.   


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• 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.  
• Urinalysis and sample collection for additional renal function studies will be done 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 (see Section 7.3.5 for timing of serial ECG measurements).  
• Sample collection for central laboratory assessment of PK, 
, ADA, 
(for additional sample collections following dosing, see Appendix 13.1.2).  
• Sample collection and shipment for PBMC subset analysis (Cycles 1 and 2, 
for additional sample collections following dosing see Appendix 13.1.2; only in 
Study Part 2).  
• Sample collection for 
, Cycles 1 and 2. 
• Sample collection for 
, Cycles 1 and 3. 
• AEs.  
• Concomitant medication use.  
• Premedication administration, if applicable (Section 6.2).  
• ADCT-301 administration. 
5.1.3 Day 8 (± 1 day) of Each Cycle 
• 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 will be referred to a dermatologist for 
further evaluation and skin biopsy, if clinically warranted (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  
• Vital signs.  


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• Hematology.  
• Biochemistry.  
• Urinalysis. 
• Additional renal function studies. 
• PK blood sample collection (Cycles 1 and 2). 
• Sample collection and shipment for PBMC subset analysis (Cycles 1 and 2, for 
additional sample collections following dosing see Appendix 13.1.2; only in 
Study Part 2).  
• AEs.  
• Concomitant medication use.  
5.1.4 Day 15 (± 1 day)  
• 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 will be referred to a dermatologist for 
further evaluation and skin biopsy, if clinically warranted (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  
• Vital signs (Cycles 1 and 2). 
• Hematology.  
• Biochemistry.  
• Urinalysis. 
• Additional renal function studies. 
• Sample collection for analysis of PK. 
• Sample collection and shipment for PBMC subset analysis (Cycles 1 and 2, for 
additional sample collections following dosing see Appendix 13.1.2; only in 
Study Part 2).  
• AEs.  
• Concomitant medication use.  


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5.1.5 End of Treatment Visit  
The following procedures will be performed as soon as possible after decision to discontinue 
the study drug and prior to initiation of anticancer treatment: 
• Serum or urine pregnancy test. 
• 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 will 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. 
• Vital sign measurements.  
• ECOG performance status.  
• Weight 
• Disease assessments: 
o Patients who already have documented objective disease progression do not need to 
have assessments repeated. 
o Patients who do not already have documented objective disease progression will have 
assessments performed at the end of treatment visit if the most recent disease 
assessment was > 9 weeks prior to the end of treatment visit.  
• Hematology.  
• Coagulation panel. 
• Biochemistry.  
• Urinalysis. 
• Additional renal function studies. 
• 12-lead ECG. 
• Sample collection for central laboratory assessment of PK, 
, ADA, and 
 
• Sample collection and shipment for PBMC subset analysis (only in Study Part 2). 
• AE collection (collected until 84 days [12 weeks] after last dose of study drug). 
• Concomitant medication use.  


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5.1.6 Long-term Follow-up 
Patients who discontinue treatment for any reason other than objective disease progression 
will continue to be followed with scans approximately every 12 weeks from the last tumor 
assessment until disease progression, or initiation of new anticancer treatment.  If a patient 
discontinues treatment for a hematopoietic stem cell transplant, the frequency of imaging will 
be as per the transplant center standard of care. 
After documentation of disease progression or start of new anticancer treatment, patients will 
be contacted by telephone approximately every 12 weeks for up to 12 months after the last 
dose of study drug to collect survival information. 
Blood Sample Collection and Adverse Event Monitoring During Long-Term Follow-up 
For all patients, PK and ADA blood sample collection will be performed 12 weeks 
(± 1 week) following the last dose of ADCT-301, unless a new anticancer treatment has been 
initiated. 
Patients who test positive for ADAs may be requested to supply additional ADA samples. 
For all patients, collection of AEs and SAEs will continue for 12 weeks after the last dose of 
study drug or initiation of new anticancer treatment (see Section 7.3.2.2). 
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 by the Investigator or others at the study site.  A patient may be 
withdrawn from treatment for any of the following reasons: 
• Objective disease progression. 
• Clinical 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 


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• Other (e.g., development of contraindications with use of the study drug). 
• The Investigator determines if 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. 
 
5.2.2 Handling of Withdrawals 
Upon occurrence of a serious or intolerable AE, the Investigator will confer with the Sponsor.  
If a patient discontinues because of an AE, then the event will be followed until it is resolved.  
When a patient withdraws from the study, the reason(s) for withdrawal shall be recorded by 
the Investigator on the relevant page of the electronic case report form (eCRF).  
Whenever possible, all patients who discontinue study treatment or withdraw from the study 
prematurely will undergo all end of treatment assessments.  Patients who fail to return for 
final assessments will be contacted by the site.  Following a minimum of two documented 
unsuccessful telephone calls, a registered letter will be sent to the patient in a final attempt to 
ensure protocol compliance. 
5.2.3 Patient Replacements 
Patients in Part 1 who discontinue treatment for any reason without a DLT AE before 
completion of the first treatment cycle will be replaced.  No other patients will be replaced. 


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6 Study Treatments 
6.1 Method of Assigning Patients to Treatment Groups 
This is an open-label study that will be conducted in 2 parts.  In both parts, ADCT-301 will 
be administered on Day 1 of each cycle.  The duration of each cycle will be 21 days 
(3 weeks).  
In Part 1, dose escalation will begin with the 3 µg/kg dose starting dose (Dose Level 1).  
The maximum dose will be 300 µg/kg.  Patients will be assigned to the appropriate dose level 
according to the CRM design (Section 13.5) and judgment of the DESC. 
In expansion (Part 2), all patients will be assigned to the dose level of ADCT-301 as 
identified in Part 1 by the DESC.  
6.2 Prophylactic Treatments for Hypersensitivity 
If Grade 2 or higher infusion-related hypersensitivity reactions are observed in a patient at 
any time during the study, this patient must receive prophylactic treatment with all 
subsequent dosing, as described below or as per the institution’s standard of care, to reduce 
the risk of hypersensitivity reactions: 
• Patient will be instructed to take 20 mg of dexamethasone orally at 12 hours and 
6 hours before the start of ADCT-301 infusion on Day 1 of each cycle.  When necessary, 
12 and 6 hours before the first infusion may be defined as “immediately before 
sleeping” and “immediately after waking up.” 
• Patient will be given 50 mg of diphenhydramine hydrochloride intravenously 
30 minutes before the start of the ADCT-301 infusion on Day 1 of each cycle. 
• Patient will be given 50 mg of ranitidine intravenously 30 minutes before the start of 
ADCT-301 infusion on Day 1 of each cycle. 
• For 2 days after administration of ADCT-301, dexamethasone 4 mg (twice per day) will 
be taken orally by the patient. 
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 Grade 1 or Grade 2 hypersensitivity occurs in a patient, the following medications should 
be administered for 48 hours after ADCT-301 infusion: 
• Ranitidine 150 mg orally given 2 times per day 
• Diphenhydramine hydrochloride 50 mg orally given 3 times per day 
If a Grade 3 or higher hypersensitivity occurs, the patient should be discontinued from the 
study and must be treated immediately with hydrocortisone 20 mg administered 
intravenously and/or other appropriate medications.  In case of life-threatening symptoms 
(e.g., arrhythmia, hypotension, respiratory distress, seizures, shock, stridor, unconsciousness, 
wheezing), epinephrine 0.2 to 0.5 mL of 1:1000 dilution should be administered 
subcutaneously or intramuscularly, repeating every 5 minutes to a total dose of 1 mg.  
In these cases, patients must be carefully observed after the treatment.  Additional therapy 
per institution standard of care should also be followed. 
6.3 Treatments Administered 
Part 1 of the study will investigate ADCT-301 administration every 3 weeks.  In Part 2, 
all patients will be assigned to the dose level identified in Part 1 by the DESC.  ADCT-301 
will be administered on Day 1 of each cycle as a 1-hour IV infusion.  If ADCT-301 is well 
tolerated after the first cycle, the infusion duration may be shortened as a 30 minutes IV 
infusion for subsequent cycles, at the Investigator’s discretion. 
Variation 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 deviations.  
Prophylactic antiemetic medications, electrolyte supplementation, and other standard 
supportive care measures may be administered according to standard treatment center 
protocols.  
Although the study patient population has a low risk for development of tumor lysis 
syndrome (TLS) compared to patients with acute disease,1 patients should be observed for 
development of TLS and treated according to standard treatment center protocols. 
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 study indicating no specific 
accumulation to melanin containing tissues, skin or eyes. 


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However, skin rash has been reported in the ADCT-301 program, as well as with another 
investigational agent containing the same pyrollobenzodiazepine warhead.3  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. 
6.4 Dose Delays and Modifications 
The Investigator may 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 
other toxicity of any grade.   
Resumption of dosing with ADCT-301 after any suspension, even when longer than 21 days, 
is at the discretion of the Investigator, in consultation with the Sponsor, based on assessment 
of the patient’s clinical condition and whether or not the patient is deriving potential clinical 
benefit from treatment with ADCT-301. Following recovery to Grade 1 or baseline, 
treatment 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 in either part of the study.  If toxicity 
reoccurs at a severity that would mandate a dose delay, then the dose may be further reduced 
1 dose level.  If toxicity reoccurs 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. 
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 experiencing the following significant toxicities will be immediately and 
permanently withdrawn from treatment with ADCT-301: 
• Any patient who experiences a Grade 3 or higher hypersensitivity reaction, regardless 
of premedication, during any cycle of treatment per CTCAE definitions 
(Appendix 13.4).  
• Any patient who experiences a recurrent Grade 3 or 4 toxicity excluding hematological 
toxicity. 
• Any patient who requires a dosing delay > 21 consecutive days from the planned Day 1 
dosing at any time during treatment (except in case of potential patient benefit, which 
must be approved by the Sponsor). 


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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 13.6), treatment with ADCT-301 must be stopped and patient must be 
permanently discontinued. 
Patients with Grade ≥ 3 neurologic toxicities defined as peripheral sensory and peripheral 
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 paused if any of the following circumstances occur: 
• ≥ 30% of patients experience a specific Grade 4 or higher non-hematologic 
treatment-emergent AE.  
• if any patient in Part 1 or Part 2 experiences a CTCAE Grade 5 AE, or 2 non-hematologic 
CTCAE Grade 4 AEs that 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. 
Furthermore, the Sponsor will notify regulatory agencies within 48 hours of being made 
aware of any new confirmed cases of GBS/polyradiculopathy to discuss, if appropriate, and 
determine whether or not the benefit-risk ratio has changed and dosing of additional patients 
and/or dosing of ongoing patients must be stopped. IRBs/IECs will be informed about the 
outcome of the assessment as appropriate. 


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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:  
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.  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 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. 


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6.7.2 
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. 
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 Day 1 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 anticancer therapy, with the exception of hormonal therapy for maintenance 
treatment of breast and prostate cancer. 
• Radiation therapy is prohibited during the first cycle of therapy.  After the first cycle, 
radiation is permitted for palliative use only if documented radiographic disease 
progression is ruled out first. 
• Other investigational agents. 
• Chronic treatment with prednisone ≥40 mg/day or equivalent. 
• Live vaccines. 


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6.10.2 Permitted During Study 
After confirmation and documentation of eligibility, supportive care treatments 
(transfusions, etc.) can be prescribed as medically appropriate.  Note: hematopoietic growth 
factors are permitted per American Society of Clinical Oncology guidelines; however, 
prophylactic use of growth factors is not allowed during the first treatment cycle.  
If Grade 2 or higher infusion-related hypersensitivity reactions are observed in a patient at 
any time during the study, this patient must receive prophylactic treatment with all 
subsequent dosing as per 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) 
Patients scheduled to receive ADCT-301 are to be administered prophylactic steroid 
treatment as follows, unless contraindicated:  
Dexamethasone 4 mg PO BID  
• Day -1 (day prior to dosing – if possible) 
• Day 1 (day of dosing; give at least 2 hours prior to administration when not given the 
day before; otherwise any time prior to administration) 
• Day 2 (day after dosing) 
Note: prophylaxis for hypersensitivity will supersede stipulations on dexamethasone 
prophylaxis. 
In addition, spironolactone, at standard doses, may be instituted at any time for patients with 
weight gain greater than 1 kg (2.2 pounds) from Cycle 1 Day 1, new or worsening edema, 
and/or new or worsening pleural effusion.  The dose of spironolactone should be titrated as 
clinically indicated.  Additional diuretic support may be added if there is further increase in 
weight, edema or pleural effusion.  
Any concomitant medication deemed necessary for the welfare of the patient during the 
study may be given at the discretion of the Investigator. 


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6.10.3 Diagnostic, Work-up, and Management of 
Polyradiculopathy/Guillain-Barré Syndrome 
It is recommended starting management of polyradiculopathy/GBS with either intravenous 
immunoglobulin (IVIg) 0.4 g/kg/day for 5 days or plasma exchange (PLEX) once the 
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 13.7).  
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 
Management includes: 
• IVIg or PLEX as above  
• If IVIg and/or PLEX do not result in improvement, consider using steroids14 
• 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 
Disease assessments will occur every other cycle for the first 2 evaluations (6 weeks [end of 
Cycle 2 ±1 week] and 12 weeks [end of Cycle 4 ±1 week]), and every third cycle 
(every 9 weeks [e.g., end of Cycles 7, 10, 13, etc., ±1 week]) thereafter until progression or 
more frequently, if clinically indicated.  Assessments may be performed within ± 1 week of 
the required timepoint and response assessment must be available prior to initiation of dosing 
at the subsequent cycle.  
In case of dose delays, disease assessment should be maintained at the frequencies defined 
above and response assessment is required prior to resumption of ADCT-301 dosing 
(only if the interval from last scan is ≥ 6/9 weeks, as applicable) to rule out disease 
progression. 
Tumor response will be determined by the Investigator, based on the 2014 Lugano 
Classification Criteria (Appendix 13.2) and Global Response Score Grading Scales for CTCL 
(Appendix 13.3).  Images will be obtained according to local site imaging requirements.  
Images will be required to be submitted for a central/independent review for Part 2.  
Submission instructions for the central/independent review will be provided in a separate 
manual. 
7.2 Pharmacokinetic and Pharmacodynamic Assessments 
Blood samples (5 mL draw) will be collected for PK assessment processed according to the 
instructions provided by the bioanalytical laboratory to the clinical sites.  The concentration 
versus time profile of total antibody HuMax-TAC, PBD-conjugated HuMax-TAC and free 
warhead SG3199 in serum will be determined centrally in Cycles 1 and 2.  
In Cycles 1 and 2, whole blood samples for analysis of PK parameters will be collected at the 
following times: before the start of the ADCT-301 infusion, end of the infusion, and at 1, 3, 6, 
24, 48, 96, 168 (Day 8), and 336 hours (Day 15) after the end of the ADCT-301 infusion 
(Appendix 13.1.2).  In all subsequent cycles, PK blood samples will be collected before the 
start of the ADCT-301 infusion, at end of the infusion, at End of Treatment (EOT), and 
12 weeks following the last ADCT-301 infusion. Additional PK/biomarker blood samples 
will be collected, at the discretion of the Investigator, during any visit where toxicity is 
observed.  All PK samples will be evaluable as long as the actual collection times are 
recorded. 
Please see Appendix 13.1.2 for details on timing windows for blood sample collection for all 
PK and pharmacodynamic assessments.  


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Antidrug (ADCT-301) antibodies will be measured centrally at the following times in serum: 
before the start of each ADCT-301 infusion, at EOT, at 12 weeks following the last 
ADCT-301 infusion, and optionally in PK samples if needed. 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
7.3 Safety and Tolerability Assessments 
Safety will be assessed based on AEs, SAEs, treatment discontinuations due to AEs, DLTs, 
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.  Additional safety assessments include periodic 12-lead ECG recordings, 
physical examination, vital sign measurements, and ECOG performance status.  A schedule 
of all assessments, including safety, is provided in Appendix 13.1.1. 


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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 (not applicable for ATLL patients): 
o Grade 3 or 4 febrile neutropenia or neutropenic infection. 
o Grade 4 neutropenia lasting > 7 days. 
o Grade 4 thrombocytopenia. 
o Grade 3 thrombocytopenia with clinically significant bleeding, or Grade 3 
thrombocytopenia requiring a platelet transfusion. 
o Grade 4 anemia. 
• For ATLL patients, a hematologic DLT is defined as: 
o Any Grade 4 neutropenia lasting ≥ 42 days from the start of the cycle in the absence 
of evidence of residual leukemia. 
o Grade 3 or higher event of thrombocytopenia or a Grade 4 anemia, with a 
hypocellular bone marrow lasting for ≥ 42 days from the start of the cycle, in the 
absence of evidence of residual leukemia (i.e., with <5% malignant cells).  
• 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 (including nausea, vomiting, diarrhea, and electrolyte imbalances 
lasting ≥ 48 hours despite optimal therapy [excluding all grades of alopecia]).  
o Grade 3 or higher hypersensitivity reaction (regardless of premedication) 
(Appendix 13.4). 
o Skin ulceration ≥ Grade 2. 
o Peripheral sensory or motor neuropathy ≥ Grade 2. 
Note: The DLT period for dose escalation will be 1 cycle; however, the adaptive 
dose-escalation algorithm will incorporate cumulative DLTs occurring through Cycle 3.  


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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.  
• In accordance with the CRM (Appendix 13.5), determine dose levels to be administered 
and the MTD based on assessment of safety findings and determination of DLTs.  
• While the DESC cannot dictate dose level(s) higher than those prescribed by the CRM, 
the medical judgment of the DESC will supersede the statistical parameters of the CRM. 
• Approve any amendments or administrative changes to the protocol, when required. 
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.  
Dose escalation will be conducted according to a CRM, as described in Appendix 13.5.   
The first patient at each new dose will be monitored for any AEs for 7 days before 
proceeding with dosing for second patient.  
During dose escalation, the DESC may expand enrollment at doses below the current dose 
level being evaluated as part of the dose escalation process.  Patients may only be added to 
the lower doses provided there is at least 1 patient with an efficacy evaluation showing stable 
disease.  No more than 10 patients in total can be treated at any dose level unless at least 3 of 
the 10 patients have documented partial response or better using the 2014 Lugano 
Classification criteria2 or other appropriate measures of response (Appendix 13.3). 
The DESC will be maintained during Part 2 (expansion) of the study to continue to monitor 
and evaluate patient safety.  


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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 the patient signs the ICF if any symptoms develop. 
A treatment-emergent AE (TEAE) is defined as any event not present before exposure to 
study drug or any event already present that worsens in either intensity or frequency after 
exposure to study drug. 
A serious adverse event (SAE) is defined as any event that results in death, is immediately 
life threatening, requires inpatient hospitalization or prolongation of existing hospitalization, 
results in persistent or significant disability/incapacity, or is a congenital anomaly/birth 
defect.  Hospitalization for elective procedures or for protocol compliance is not considered 
an SAE.  
Important medical events that may not result in death, 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 
All AEs will be assessed from the time the patient signs the ICF until 84 days (12 weeks) 
after the last dose of study drug, or initiation of new anticancer treatment. 
Any SAEs that occur > 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). 


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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 and relationship to study drug, date of resolution 
of the event, seriousness, any required treatment or evaluations, and outcome.  With the 
exception of disease progression, AEs resulting from concurrent illnesses, reactions to 
concurrent illnesses, and reactions to concurrent medications also must be reported.  All AEs 
will be followed to adequate resolution.  CTCAE Version 4.0 will be used to grade all AEs.  
The CTCAE includes 5 grades (1 to 5), with Grade 5 being death. 
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: 
 
  
 
 
 
 
 
 


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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 adverse events, regardless of assessment of causality, are reported in the eCRF.   
All SAEs considered at least possibly related to the study drug will be considered 
unexpected; and therefore, reported as Suspected Unexpected Serious Adverse Reactions 
(SUSARs). 
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. 


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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 
Complete blood count (CBC) includes WBC with a 5-part differential, platelet count, 
hemoglobin, hematocrit, and ANC. Coagulation panel includes prothrombin time (PT) 
expressed in seconds, 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 
Biochemistry 
includes 
alanine 
aminotransferase, 
aspartate 
aminotransferase, 
gamma-glutamyl transferase, alkaline phosphatase, amylase, lipase, total bilirubin, sodium, 
potassium, calcium, magnesium, blood urea nitrogen or urea, carbon dioxide/bicarbonate, 
chloride, creatinine, creatine phosphokinase, total protein, albumin, glucose, triglycerides, 
total cholesterol, phosphorus, and lactate dehydrogenase.  At Day 1 of each cycle, 
biochemistry will include creatinine clearance (calculated using the Cockcroft and Gault 
1976 formula). 
7.3.4.3 
Urinalysis 
Urinalysis analytes will include pH, protein, specific gravity, glucose, ketones, bilirubin, 
nitrites, and occult blood.  The urinalysis may be performed using a urine dipstick. 


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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 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. 
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 will be performed before the start of the 
ADCT-301 infusion, at completion of infusion and at 3 hours and 24 hours (Day 2) after the 
end of infusion.  ECGs should occur within 10% of nominal time (e.g., 3 hours ± 18 minutes).  
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.5  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 will 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 patients are advised to monitor their weight on a 
daily basis because new or worsening edema and / or new or worsening pleural effusion have 
been observed.  Patients should inform their Investigator if their weight increases by more 
than 1 kg (2.2 pounds) after Cycle 1 Day 1.   


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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 sign measurements will include arterial blood pressure, heart rate, respiratory rate, and 
temperature.  Any clinically significant abnormalities, including those that worsen from 
baseline, are to be recorded as AEs or SAEs. 
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 grades9 below: 
0: 
Fully active, able to carry on all pre-disease performance without restriction 
1: 
Restricted in physically strenuous activity but ambulatory and able to carry out work of a light 
or sedentary nature, e.g., light house work, office work 
2: 
Ambulatory and capable of all self-care but unable to carry out any work activities.  Up and 
about more than 50% of waking hours 
3: 
Capable of only limited self-care, confined to bed or chair more than 50% of waking hours 
4: 
Completely disabled.  Cannot carry on any self-care.  Totally confined to bed or chair 
5: 
Dead 
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 central Laboratory Manual.   
During the study, whole blood samples will be collected for PK, ADA, pharmacodynamics 
PBMC subset analysis), and safety analyses (clinical chemistry,
 
, and hematology). 
For PK, ADA,
 blood samples are to be collected and 
processed on site according to the Laboratory Manual. The resulting serum samples should 
be aliquoted and stored frozen at ≤ -70°C until shipment.  Each sample tube 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.  
Serum and urine samples are to be packed in sufficient dry ice and shipped from the study 
center to the central laboratory.  Once labeled, samples should be stored at ≤ -70°C until 
shipment.  Samples should be shipped according to the sample shipment schedule provided 


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in Laboratory Manual. 
 
 
 
 
The clinical chemistry and hematology samples, which should not be frozen, are transferred 
at ambient temperature to local laboratories.  
For the PBMC subset analysis, whole blood is to be collected and shipped as per the central 
Laboratory Manual directly to the testing laboratory for immediate processing. 


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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 (graded using CTCAE v4.0), treatment 
discontinuations due to AEs, DLTs, hematology, coagulation panel, biochemistry, pregnancy 
testing (for women of child-bearing potential) and urinalysis test results.  Additional safety 
assessments include periodic 12-lead ECG recordings, physical examinations, vital sign 
measurements, and ECOG performance status.  A schedule of the safety assessments is 
provided in Appendix 13.1.1. 
8.2 Study Endpoints 
8.2.1 Primary Endpoints 
The primary objectives for Part 1 (dose escalation) and Part 2 (expansion) of the study are: 
• Determine the safety of ADCT-301 by assessing DLTs and determining the MTD in 
Part 1 (dose-escalation). 
• Determine the recommended dose of ADCT-301 for Part 2 (expansion). 
• Evaluate the safety and tolerability of ADCT-301 in patients with relapsed/refractory 
lymphoma in Part 2 (expansion). 
8.2.2 Secondary Endpoints 
The following secondary endpoints will be determined in Part 1 and Part 2: 
• Evaluate response to ADCT-301 using the Lugano Classification Criteria (2014) 
(Appendix 13.2) and Global Response Score Grading Scales for CTCL (Appendix13.3) 
through the evaluation of complete response (CR), partial response (PR), progressive 
disease (PD), and stable disease (SD). 
• Characterize PK profile of HuMax-TAC (total antibody; drug-to-antibody ratio [DAR] 
≥ 0), PBD-conjugated HuMax-TAC (DAR ≥1), and free warhead SG3199 
(see Section 8.6.3). 
• Determine anti-drug antibodies ADAs in blood before, during, and after treatment with 
ADCT-301. 


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8.3 Sample Size Calculations 
This is a Phase 1 study with a total sample size of approximately 140 patients.  It is expected 
that Part 1 will enroll approximately 80 patients, and Part 2 will enroll approximately 
60 patients (Section 4.1.1 and Section 4.1.2).  
Simulations were performed assuming scenarios with different dose-toxicity relationships to 
evaluate the sample size for Part 1.  
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 
Five analysis sets will be used in this study: 
• The Safety analysis set consists of all patients who receive study drug 
• The DLT-evaluable analysis set consists of all patients in Part 1 who receive study 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.  Patients who do not have a post baseline 
assessment due to early clinical progression, toxicity, or death will also be included. 
• The PK analysis set consists of all patients who receive study drug and have sufficient 
concentration data for PK analysis. 


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• The pharmacodynamic analysis set consists of all patients who receive study drug and 
have sufficient concentration data for pharmacodynamic analysis. 
8.5 Description of Subgroups to be Analyzed 
Subgroup analyses, if planned, will be described in the SAP. 
8.6 Statistical Analysis Methodology 
8.6.1 
Efficacy Analysis 
8.6.1.1 
Overall Response Rate 
Overall response rate is defined as the proportion of patients with best overall response of PR 
or CR at the time each patient discontinues treatment with ADCT-301 (Appendix 13.2, 
Appendix 13.3). 
8.6.1.2 
Duration of Response 
Duration of response will be defined among responders (CR or PR) as the time from the 
earliest date of first response until the first date of either disease progression or death due to 
any cause.  The date of disease progression will be defined as the earliest date of disease 
progression as assessed by the Investigator using the 2014 Lugano Classification for response 
for Hodgkin and Non-Hodgkin Lymphoma2 (Appendix 13.2) or Global Response Score 
criteria for disease progression for CTCL (Appendix 13.3).  For patients who have not 
progressed or who have died at the time of the analysis, censoring will be performed using 
the date of the last adequate disease assessment.  In addition, patients with disease 
progression or death after an extended loss to follow-up will be censored at the date of the 
last adequate disease assessment prior to the extended loss to follow-up.  Further details on 
censoring rules will be outlined in the SAP. 
8.6.1.3 
Overall Survival 
Overall survival will be defined as the time from the beginning of ADCT-301 treatment until 
death due to any cause.  For patients who have not died at the time of the analysis, censoring 
will be performed using the date the patient was last known to be alive.  Further details on 
censoring rules will be outlined in the SAP. 
8.6.1.4 
Progression-Free Survival 
Progression-free survival will be defined as the time from first dose of study drug until the 
first date of either disease progression or death due to any cause.  The date of disease 
progression will be defined as the earliest date of radiological disease progression as assessed 
by the Investigator using the 2014 Lugano Classification for response for Hodgkin and 
Non-Hodgkin Lymphoma2 (Appendix 13.2) or Global Response Score criteria for disease 


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progression for CTCL (Appendix 13.3).  Patients with stable disease / without disease 
progression, or patients with death 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. 
8.6.2 
Safety Analyses 
8.6.2.1 
Analyses of Adverse Events 
An AE will be considered to be a TEAE if it begins or worsens on or after first dose date and 
before last dose date until 84 days (12 weeks).  Planned summaries of TEAEs are detailed in 
the statistical analysis plan and will include: 
• All TEAEs. 
• All serious TEAEs. 
• All treatment-related TEAEs. 
• All treatment-related serious TEAEs. 
• All TEAEs resulting in study drug discontinuation. 
• All DLTs. 
• Other AE analyses of interest will be specified in the SAP.  
The incidence of deaths and the primary cause of death will be summarized. 
8.6.2.2 
Clinical Laboratory Results 
Clinical hematology, biochemistry, and urinalysis data will be summarized at each scheduled 
assessment.  Numeric hematology and biochemistry results will be summarized using change 
from baseline.  All results will be summarized using shift from baseline.  Shifts for clinical 
laboratory results that can be graded according to CTCAE Version 4.0 will be summarized 
by CTCAE grade.  Shifts for other numeric laboratory results will be by high/normal/low 
flag.  Shifts for all other laboratory results will be by normal/abnormal flag. 
Summaries by visit will include data from scheduled assessments, and all data will be 
reported according to the nominal visit date for which it was recorded.  Unscheduled data 
will be included in “worst case post baseline” summaries, which will capture a worst case 
across all scheduled and unscheduled visits after the first dose of study treatment.  
Further details will be provided in the SAP. 


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8.6.2.3 
Additional Safety Assessments 
The 
results 
of 
scheduled 
assessments 
of 
vital 
signs, 
physical 
examinations, 
ECOG performance status, and 12-lead ECGs will be summarized.  All data will be reported 
according to the nominal visit date for which it was recorded (i.e., no visit windows will be 
applied).  Unscheduled data will be included in “worst case” summaries, which will capture a 
worst case across all scheduled and unscheduled visits after the first dose of study treatment.  
All data will be listed.  Further details will be provided in the SAP. 
8.6.3 
Pharmacokinetic and Pharmacodynamic Analyses 
In Cycles 1 and 2, whole blood for PK samples will be collected at the following times: 
before the start of the ADCT-301 infusion, at the end of infusion and at 1, 3, 6, 24, 48, 96, 
168 (Day 8) and 336 hours (Day 15) after the end of the ADCT-301 infusion. 
In all subsequent cycles PK blood samples will be collected before the start of the 
ADCT-301 infusion, at end of infusion, at EOT, and finally 12 weeks following the last 
ADCT-301 infusion. 
PK endpoints for HuMax-TAC, PBD-conjugated HuMax-TAC, and free warhead SG3199 
will be evaluated for all patients using noncompartmental analysis and may include: 
maximum concentration (Cmax), time to maximum concentration (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 (AUC0-∞), 
accumulation index (AI), volume of distribution at steady-state (Vss), mean residence time 
(MRT), terminal elimination phase rate constant (λz), apparent terminal half-life, CL, and Vz.  
Data for PK parameters will be summarized in tables and individual data will be listed. 
In addition, pharmacodynamic and ADA analyses will be performed to include:  
• PBMC subset analysis in Part 2 of the study by flow cytometry in whole blood  
 
 
  
 
  
 
 
 
  


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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; 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 16.0.  Concomitant medications will be coded using 
WHO Drug Dictionary 01 June 2013. 
After database lock, each study site will receive information about all of their site-specific 
eCRF data as entered into electronic data capture system for the study, including full 
discrepancy and audit history.  Additionally, a copy of all of the study site’s data from the 
study will be created and sent to the Sponsor for storage.  The CRO will maintain a duplicate 
copy for its records.  In all cases, patient initials will not be collected or transmitted to the 
Sponsor. 


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


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Before recruitment and enrollment, each prospective patient or his or her legal guardian will 
be given a full explanation of the study and be allowed to read the approved ICF.  Once the 
Investigator is assured that the patient/legal guardian understands the implications of 
participating in the study, the patient/legal guardian will be asked to give consent to 
participate in the study and that additional 
 
 


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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, the FDA, or the IRB/IEC. 
The Investigator and all employees and coworkers involved with this study may not disclose 
or use for any purpose other than performance of the study any data, record, or other 
unpublished, confidential information disclosed to those individuals for the purpose of the 
study.  Prior written agreement from the Sponsor or its designee must be obtained for the 
disclosure of any said confidential information to other parties. 
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 and local regulations.  In addition, the Investigator must provide to the Sponsor a 
commitment to promptly update this information if any relevant changes occur during the 
course of the investigation and for 1 year following the completion of the study. 
Neither the Sponsor nor the CRO is financially responsible for further testing or treatment of 
any medical condition that may be detected during the screening process.  In addition, in the 
absence of specific arrangements, neither the Sponsor nor the CRO is financially responsible 
for further treatment of the patient’s disease. 


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10.3 Investigator Documentation 
Prior to beginning the study, the Investigator will be asked to comply with the current version 
of ICH E6 8.2, Title 21 of the CFR, and local regulations by providing the following 
essential documents, including but not limited to: 
• IRB/IEC approval  
• Original Investigator-signed Investigator agreement page of the protocol  
• Form FDA 1572, fully executed, and all updates on a new fully executed 
Form FDA 1572 (where applicable)  
• Curriculum vitae for the Investigator and each sub-Investigator listed on 
Form FDA 1572 (where applicable)  
• Financial disclosure information to allow the Sponsor to submit complete and accurate 
certification or disclosure statements.  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 the 
current version of ICH E6.  The Investigator will conduct all aspects of this study in 
accordance with all national, state, and local laws or regulations.  Study information from 
this protocol will be posted on publicly available clinical study registers before enrollment of 
patients begins. 
10.5 Adherence to Protocol 
The Investigator agrees to conduct the study as outlined in this protocol in accordance with 
the current version of ICH E6 and all applicable guidelines and regulations. 


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10.6 Adverse Events and Study Report Requirements 
By participating in this study, the Investigator agrees to submit reports of SAEs to the 
Sponsor according to the timeline 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. 
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 investigational product.  These documents 
should be retained for a longer period, however, if required by the applicable regulatory 
requirements or by an agreement with the Sponsor.  It is the responsibility of the Sponsor to 
inform the Investigator/institution as to when these documents no longer need to be retained. 
10.9 Publications 
Data may be considered for reporting at a scientific meeting or for publication in a scientific 
journal.  In these cases, the Sponsor will be responsible for coordination of these activities 
and will work with the Investigators to determine how the manuscript is written and edited, 
the number and order of authors, the publication to which it will be submitted, and other 
related issues.  The Sponsor has final approval authority over all such issues. 
Data are the property of the Sponsor and cannot be published without prior authorization 
from the Sponsor, but data and publication thereof will not be unduly withheld. 


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11 Study Management 
11.1 Monitoring 
11.1.1 Monitoring of the Study 
The clinical monitor, as a representative of the Sponsor, has the obligation to follow the 
study closely.  In doing so, the monitor will visit the Investigator and study site at periodic 
intervals, in addition to maintaining necessary telephone and written contact.  The monitor 
will maintain current personal knowledge of the study through observation, review of study 
records and source documentation, and discussion of the conduct of the study with the 
Investigator and personnel. 
All aspects of the study will be carefully monitored by the Sponsor or its designee for 
compliance with applicable government regulation with respect to current GCP and current 
standard operating procedures. 
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 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 visit to 
the study site (includes any end of treatment visit to the site and any visit to the site to obtain 
confirmatory scan of response). 
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 reasonable 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. Cairo MS. Coiffier B, Reiter A, and Younes A, on behalf of the TLS Expert Panel.  
Recommendations for the evaluation of risk and prophylaxis of tumour lysis syndrome 
(TLS) in adults and children with malignant diseases: an expert TLS panel consensus. 
Br J Haem 2010, 149: 578–586. 
2. Cheson BD, Fisher RI, Barrington SF, et al. Recommendations for initial evaluation, 
staging, and response assessment of Hodgkin and Non-Hodgkin lymphoma:  The Lugano 
classification. J Clin Onc 2014, 32(27):3059-3068 
3. Rudin CM, Pietanza MC, Bauer TM, Spigel DR, Ready N, Morgansztern D, Glisson BS, 
Byers LA, Johnson ML, Burris HA, Robert F, Strickland DK, Zayed H, Govindan R, 
Dylla S, Pend SL. 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). 
4. Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. 
Nephron. 1976;16(1):31-41. 
5. Fridericia LS. The duration of systole in the electrocardiogram of normal subjects and of 
patients with heart disease. Act Med Scand 1920, 53:469–486.  Translation published in 
2003 in Annals Noninvasive Electrocardiology 8(4):343-351. 
6. Karube K, Aoki R, Nomura Y, et al. Usefulness of flow cytometry for differential 
diagnosis of precursor and peripheral T-cell and NK-cell lymphomas: analysis of 
490 cases. Pathol Int. 2008;58(2):89-97.  
7. LeMaistre CF, Saleh MN, Kuzel TM, et al. Phase I trial of a ligand fusion-protein 
(DAB389IL-2) 
in 
lymphomas 
expressing 
the 
receptor 
for 
interleukin-2. 
Blood. 1998;91(2):399-405. 
8. Novartis, New Jersey, USA. Prescribing information for Simulect., 2005, accessed at 
https://www.pharma.us.novartis.com/product/pi/pdf/simulect.pdf.  
9. Oken MM, Creech RH, Tormey DC, et al. Toxicity and response criteria of the 
Eastern Cooperative Oncology Group. Am J Clin Oncol. 1982;5(6):649-55. 
10. O'Malley DP, Chizhevsky V, Grimm KE, et al. Utility of BCL2, PD1, and CD25 
immunohistochemical 
expression 
in 
the 
diagnosis 
of 
T-cell 
lymphomas. 
Appl Immunohistochem Mol Morphol. 2014;22(2):99-104. 
11. Roche Pharmaceuticals, New Jersey, USA. Prescribing Information for Zenapax., 2005, 
accessed at http://www.gene.com/download/pdf/zenxapax_prescribing.pdf. 
12. Strauchen JA, Breakstone BA. IL-2 receptor expression in human lymphoid lesions. 
Immunohistochemical study of 166 cases. Am J Pathol. 1987;126(3):506-12. 


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13. 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. 
14. 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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13 Appendices 
13.1 Appendix: Schedule of Events  
The Schedule of Events for study procedures is shown in Section 13.1.1 of this Appendix.  
Timings for sample collections for assessments of PK, ADA, 
, and 
 
are shown in Section 13.1.2. 
 
 


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13.1.1 Schedule of Study Procedures 
Procedure 
Screening 
Cycle 1 
Cycle 2 
Cycles 3 until 
Progression/ 
Discontinuation 
End of 
Treatment1 
Long-term 
Follow-up 
(up to 12 mos)  
Day –28 
to –1 
Day 1 
(±3 days) 
Day 8 
(±1 day) 
Day 15 
(±1 day) 
Day 1 
(±3 days) 
 
Day 8 
(±1 day) 
Day 15 
(±1 day) 
Day 1 
(±3 days) 
 
Day 8 
(±1 day) 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
 
 
 
 
 
Medical and cancer history2 
X 
 
 
 
 
 
 
 
 
 
 
Pregnancy test 
(β-HCG, serum or urine) 
X 
X3 
 
 
 
 
 
 
 
X 
 
Tumor tissue collection4 
X 
 
 
 
 
 
 
 
 
 
 
Physical examination, including 
neurological examination and 
whole body skin assessment5 
X 
X6 
X 
X 
X6 
X 
X 
X6 
 
X 
 
Vital signs 
X 
X7 
X 
X 
X7 
X 
X 
X7 
X 
X 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
Weight 
X 
X6 
X 
X 
X6 
X 
X 
X6 
X 
X 
 
ECOG Performance status 
X 
X6 
 
 
X6 
 
 
X6 
 
X 
 
Disease assessment8 
X 
 
 
 
 
 
 
X9 
 
X10 
X11 
Hematology12 
X 
X13 
X 
X 
X13 
X 
X 
X13 
X 
X 
 
Coagulation Panel14 
X 
X13 
 
 
X13 
 
 
X13 
 
X 
 
Biochemistry15 
X 
X13 
X 
X 
X13 
X 
X 
X13 
X 
X 
 
Urinalysis 16 
X 
X13 
X 
X 
X13 
X 
X 
X13 
X 
X 
 
Additional renal function studies17 
 
X13 
X 
X 
X13 
X 
X 
X13 
X 
X 
 
12-lead ECG 
X 
X18 
 
 
X18 
 
 
X 
 
X 
 
Sample collection for 
Pharmacokinetic assessments19 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
X20 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Procedure 
Screening 
Cycle 1 
Cycle 2 
Cycles 3 until 
Progression/ 
Discontinuation 
End of 
Treatment1 
Long-term 
Follow-up 
(up to 12 mos)  
Day –28 
to –1 
Day 1 
(±3 days) 
Day 8 
(±1 day) 
Day 15 
(±1 day) 
Day 1 
(±3 days) 
 
Day 8 
(±1 day) 
Day 15 
(±1 day) 
Day 1 
(±3 days) 
 
Day 8 
(±1 day) 
Sample collection for anti-drug 
antibody assessment19 
 
X 
 
 
X 
 
 
X 
 
X 
X20 
Sample collection and shipment for 
PBMC analysis21 
 
X 
X 
X 
X 
X 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ADCT-301 administration22 
 
X 
 
 
X 
 
 
X 
 
 
 
Prophylactic administrations23 
 
X 
 
 
X 
 
 
X 
 
 
 
Adverse events  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X24 
Concomitant medications25 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Survival information 
 
 
 
 
 
 
 
 
 
 
X26 
New anti-cancer treatment 
information 
 
 
 
 
 
 
 
 
 
 
X27 
Abbreviations: ANC, absolute neutrophil count; b-HCG, beta human chorionic gonadotropin; CBC, complete blood count; CT, computed tomography; CTCL, cutaneous T-cell 
lymphoma; ECOG, Eastern Cooperative Oncology Group; ECG, electrocardiogram; FDG, 18F-fluorodeoxyglucose; 
; INR, International 
Normalized Ratio; mos, months; MRI, magnetic resonance imaging; mSWAT, modified Severity-Weighted Assessment Tool; NHL, non-Hodgkin lymphoma; PBMC, peripheral 
blood mononuclear cells; PET-CT, positron emission tomography- computed tomography; PT, prothrombin time; PTT, Partial prothrombin time; WBC, white blood cell 
 
 
1  As soon as possible after decision to discontinue the study drug AND prior to initiation of anticancer treatment. 
2  To include a complete history of all surgeries, significant diagnoses, all cancer treatments, and assessment of cardiac risk factors. 
3  For women of childbearing potential. Not required if negative screening serum beta-human chorionic gonadotropin pregnancy (β-HCG) test was obtained 
within 7 days prior to Day 1, Cycle 1. 
 


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4  Collection of tumor tissue (formalin-fixed paraffin embedded block) for retrospective testing of 
 protein expression by immunochemistry at a central 
laboratory. Tissue from a recent biopsy is preferred, if available, and/or if patient provides consent for biopsy during screening. Archival tissue taken at any 
prior relapse is acceptable.  
5  Physical examination, including neurological examination and whole body skin assessment. Whole body skin assessment does not have to be performed by a 
dermatologist. Any unexplained lesion 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. 
6 
Not to be repeated on Day 1, Cycle 1 if last performed within 3 days prior to dosing. 
7  On Day 1 of Cycle 1, vital signs (arterial blood pressure, heart rate, respiratory rate, temperature) are measured before the start of the infusion, every 
30 minutes during the infusion, and at the end of infusion (± 15 minutes). If no clinically significant changes occur during the first infusion, measurements 
are required prior to infusion start, hourly during infusion, and end of infusion for all subsequent infusions. 
 
For Cycles 1 and 2, patients will be monitored for 4 hours post-infusion with vital signs being measured 1 hour after the end of infusion and at discharge 
(± 15 minutes). 
8  Screening tumor assessments: PET-CT and diagnostic CT of the neck/chest/abdomen/pelvis and other areas of known disease or newly suspected disease 
with a clinical examination for lymphoma. Contrast should be used unless contraindicated. Magnetic resonance imaging (MRI) is permitted if diagnostic CT 
is contraindicated. The same assessment methods used at Screening should be used for all subsequent assessments. Note: PET-CT is only required at 
screening for FDG-avid, nodal lymphomas (defined as per the Lugano Classification criteria as essentially all eligible histologies except small lymphocytic 
lymphoma, lymphoplasmacytic lymphoma/Waldenstrom’s macroglobulinemia, mycosis fungoides, and marginal zone NHLs, unless there is a suspicion of 
aggressive transformation. If PET-CT examination is negative at Screening, subsequent PET-CT is not required. If PET-CT is positive, subsequent 
diagnostic CT and MRI are not needed, unless clinically indicated. In case of dose delays, response assessment is required prior to resumption of ADCT-301 
dosing 
(only 
if 
the 
interval 
from 
last 
scan 
is 
≥ 
6/9 
weeks, 
as 
applicable) 
to 
rule 
out 
disease 
progression.   
For CTCL patients with disease limited to the skin, disease assessments after screening will be performed using mSWAT; radiological imaging after 
screening for CTCL patients with disease limited to the skin is not required unless clinically indicated. 
9  Disease assessments will be performed within 6 days prior to Day 1 of Cycles 3 and 5 and thereafter every third cycle (i.e., Cycles 8, 11, 14, etc.) until 
disease progression or more frequently, if clinically indicated. The same assessment methods used at Screening which identify sites of disease should be 
used uniformly for all subsequent assessments 
10  Patients who already have documented objective disease progression do not need to have assessments repeated. Patients who do not already have 
documented objective disease progression will have assessments performed if the most recent disease assessment was greater than 9 weeks prior to the end 
of treatment visit. 
11  Patients who discontinue treatment for any reason other than objective disease progression will continue to be followed with scans approximately every 
12 weeks from the last tumor assessment until disease progression, or initiation of new anticancer treatment.  If patient discontinues treatment for a 
hematopoietic stem cell transplant, the frequency of imaging will be as per the transplant center standard of care. 
12  Hematology: complete blood count (CBC) to include WBC with 5-part differential, platelet count, hemoglobin, hematocrit, and ANC. 
13  Sample collection to occur prior to dosing on Day 1 unless the last sample was collected: <24 hours before the start of ADCT 301 infusion on Day 1 of 
Cycle 1, or <72 hours before the start of ADCT-301 infusion on Day 1 of Cycle 2 and subsequent cycles. 
 


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14  Coagulation panel includes prothrombin time (PT) expressed in seconds, International Normalized Ratio (INR), and partial thromboplastin time (PTT).  
15  Biochemistry: alanine aminotransferase, aspartate aminotransferase, gamma-glutamyl transferase, alkaline phosphatase, amylase, lipase, total bilirubin, 
sodium, potassium, calcium, magnesium, blood urea nitrogen or urea, carbon dioxide/bicarbonate, chloride, creatinine, creatine phosphokinase, total protein, 
albumin, glucose, triglycerides, total cholesterol, phosphorus, and lactate dehydrogenase. At Day 1 of each cycle, biochemistry will include creatinine 
clearance (calculated using the Cockcroft and Gault 1976 formula). 
16  Urinalysis will include pH, specific gravity, protein, occult blood, glucose, ketones, nitrites and bilirubin.  The urinalysis may be performed using a urine 
dipstick. 
17  Urine to be collected for testing of biomarkers suggestive of potential renal injury (aquaporin-2, calbindin D28, and clusterin). 
18  On Day 1 of Cycles 1 and 2, a 12-lead ECG is to be performed before the start of the ADCT-301 infusion, at completion of infusion, and at 3 hours and 
24 hours (Day 2) after the end of infusion.  ECGs should occur within 10% of nominal time (e.g., 3 hours ± 18 minutes). 
19  See Section 13.1.2 of this Appendix for timing.  
20  Sample for assessment to be obtained 12 weeks (± 1 week) after last dose of ADCT-301, unless a new anticancer treatment has been initiated. 
21  Sampling for peripheral blood mononuclear cell (PBMC) subset analysis by Flow Cytometry in Cycles 1 and 2, and at EOT; only in Part 2.  
See Section 13.1.2 of this Appendix for sample timing. 
22  Patients to receive ADCT-301 intravenously over 1 hours (± 15 minutes).  If ADCT-301 is well tolerated after the first cycle, the infusion duration may be 
shortened to a 30-minutes intravenous infusion for subsequent cycles at the Investigator’s discretion.  The IP administration window is ± 15 minutes. 
23  Dexamethasone prophylaxis (4 mg BID on Day -1, Day 1, and Day 2) should be administered, unless contraindicated. If Grade 2 or higher infusion-related 
hypersensitivity reactions are observed in a patient at any time during the study, this patient must receive prophylactic treatment with all subsequent dosing 
to reduce the risk of hypersensitivity reaction. Prophylaxis for hypersensitivity will supersede stipulations on dexamethasone prophylaxis 
24  For all patients, collection of AEs and SAEs will continue for 12 weeks (84 days) after the last dose of study drug or initiation of new anticancer treatment.  
Any SAEs that occur more than 84 days after the last dose of study drug do not need to be reported unless the Investigator considers the event to be related 
to study drug. 
25 To include prescription or over-the-counter medication, herbal or naturopathic products within the 14 days prior to Day 1, throughout the study, and for 
30 days after last dose of study drug. 
26  After documentation of disease progression or start of new anti-cancer treatment, patients will be contacted by telephone approximately every 12 weeks for 
up to 12 months after the last dose of study drug to collect survival information. 
27 Information on anti-cancer treatment initiated after discontinuation of ADCT-301 to be recorded in the eCRF. 
 


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13.1.2 
Timing of ECG and Sample Collection for PK, ADA, 
 and PBMCs 
Assessment 
Cycles 1 and 2 
Cycle 3 – 
Progression 
EOT 
 
Follow 
up  
3 mos 
after last 
infusion 
(±7 days) 
Day 1 
Day 2 
Day 3 
Day 5 
Day 8 
Day 15 
Day 1 
Before 
start 
infusion 
EOI 
(±10%)* 
1 hr 
after 
EOI 
(±10%) 
3 hrs 
after 
EOI 
(± 10%) 
6 hrs 
after 
EOI 
(± 10%) 
24 hrs 
after 
EOI 
(± 10%) 
48 hrs 
after EOI 
(± 10%) 
96 hrs 
after 
EOI 
(±1 day) 
168 hrs 
after 
EOI 
(±2 
days) 
336 hrs 
after 
EOI 
(±2 
days) 
Before 
start 
infusion 
(± 10%) 
EOI 
(±10%) 
PK 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X1 
ADA2 
X 
 
 
 
 
 
 
 
 
 
X 
 
X 
X1 
sCD25 
X 
 
 
 
 
 
 
 
 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PBMC 
subsets 
(Study 
Part 2 
only) 
X 
 
 
X 
 
 
X 
X 
X 
X 
 
 
X 
 
ECG 
X 
X 
 
X 
 
X 
 
 
 
 
X 
 
X 
 
 
Abbreviations:  ADA, anti-drug antibody; EOI, end of infusion; EOT, end of treatment; 
; hr, hour(s); mos, months; 
PK, pharmacokinetics;
 PBMC, peripheral blood mononuclear cells. 
Note:  No sample collections for PK, ADA, 
, links at the screening visit. 
* Samples to be collected within 10% of nominal time point (e.g., 1 hr ± 6 min, 48 hrs ± 4.8 hrs) for first 48 hours. 
 
1 Sample to be obtained at Follow-up, unless a new anticancer treatment has been initiated. 
2 Patients who test positive for ADAs may be requested to supply additional ADA samples. 
 
 


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


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Response Assessment of Hodgkin and Non-Hodgkin Lymphoma (Lugano Classification) 
Response / Site 
PET-CT-Based Response 
CT-Based Response 
Nonmeasured lesion 
• Not applicable 
• Absent/normal, regressed, but no increase 
Organ enlargement 
• Not applicable 
• Spleen must have regressed by >50% in 
length beyond normal 
New lesions 
• None 
• None 
Bone marrow 
• Residual uptake higher than uptake in 
normal marrow but reduced compared with 
baseline (diffuse uptake compatible with 
reactive changes from chemotherapy 
allowed).  If there are persistent focal 
changes in the marrow in the context of a 
nodal response, consideration should be 
given to further evaluation with MRI or 
biopsy or an interval scan 
• No applicable 
No response or stable 
disease 
No metabolic response 
 
Stable disease 
Target nodes/nodal 
masses, extranodal 
lesions 
• Score 4 or 5 with no significant change in 
FDG update from baseline at interim or end 
of treatment 
• <50% decrease from baseline in SPD of up 
to 6 dominant, measurable nodes and 
extranodal sites; no criteria for progressive 
disease are met 
Nonmeasured lesions 
• Not applicable 
• No increase consistent with progression 
Organ enlargement 
• Not applicable 
• No increase consistent with progression 
New lesions 
• None 
• None 
Bone marrow 
• No change from baseline 
• Not applicable 
Progressive disease 
Progressive metabolic disease 
Progressive disease  
(requires at least 1 of the following) 
Individual target 
nodes/nodal masses 
• Score 4 or 5 with an increase in intensity of 
uptake from baseline and/or 
• PPD progression 


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Response Assessment of Hodgkin and Non-Hodgkin Lymphoma (Lugano Classification) 
Response / Site 
PET-CT-Based Response 
CT-Based Response 
Extranodal lesions 
• New FDG-avid foci consistent with 
lymphoma at interim or end of treatment 
assessment 
An individual node/lesion must be abnormal 
with: 
• LDi > 1.5 cm and 
• Increase by ≥50% from PPD nadir and  
• An increase in LDi or SDi from nadir 
0.5 cm for lesions ≤ 2 cm 
1.0 cm for lesions > 2 cm 
• In the setting of splenomegaly, the splenic 
length must increase by > 50% of the extent 
of its prior increase beyond baseline (e.g., a 
15-cm spleen must increase to > 16 cm).  If 
no prior splenomegaly, must increase by at 
least 2 cm from baseline 
• New or recurrent splenomegaly 
Nonmeasured lesions 
• None 
• New or clear progression of preexisting 
nonmeasured lesions 
New lesions 
• New FDG-avid foci consistent with 
lymphoma rather than another etiology (e.g., 
infection, inflammation).  If uncertain 
regarding etiology of new lesions, biopsy or 
interval scan may be considered 
• Regrowth of previously resolved lesions 
• A new node > 1.5 cm in any axis 
• A new extranodal site > 1.0 cm in any axis; 
if < 1.0 cm in any axis, its presence must be 
unequivocal and must be attributable to 
lymphoma 
• Assessable disease of any size 
unequivocally attributable to lymphoma 
Bone marrow 
• New or recurrent FDG-avid foci 
• New or recurrent involvement 
Abbreviations: 5PS, 5-point scale; CT, computed tomography; FDG, fluorodeoxyglucose; IHC, immunohistochemistry; 
LDi, longest transverse diameter of a lesion; MRI, magnetic resonance imaging; PET, positron emission tomography; PPD, 
cross product of the LDi and perpendicular diameter; SDi, shortest axis perpendicular to the LDi; SPD, sum of the product 
of the perpendicular diameters for multiple lesions. 
 
* A score of 3 in many patients indicates a good prognosis with standard treatment, especially if at the time of an interim 
scan.  However, in trials involving PET where de-escalation is investigated, it may be preferable to consider a score of 3 as 
inadequate response (to avoid undertreatment).  Measured dominant lesions: Up to six of the largest dominant nodes, nodal 
masses, and extranodal lesions selected to be clearly measurable in two diameters.  Nodes should preferably be from 
disparate regions of the body and should include, where applicable, mediastinal and retroperitoneal areas.  Non-nodal 
lesions include those in solid organs (e.g., liver, spleen, kidneys, lungs), GI involvement, cutaneous lesions, or those noted 
on palpation.  Nonmeasured lesions: Any disease not selected as measured, dominant disease and truly assessable disease 
should be considered not measured.  These sites include any nodes, nodal masses, and extranodal sites not selected as 


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Response Assessment of Hodgkin and Non-Hodgkin Lymphoma (Lugano Classification) 
Response / Site 
PET-CT-Based Response 
CT-Based Response 
dominant or measurable or that do not meet the requirements for measurability but are still considered abnormal, as well as 
truly assessable disease, which is any site of suspected disease that would be difficult to follow quantitatively with 
measurement, including pleural effusions, ascites, bone lesions, leptomeningeal disease, abdominal masses, and other 
lesions that cannot be confirmed and followed by imaging.  In Waldeyer’s ring or in extranodal sites (e.g., GI tract, liver, 
bone marrow), FDG uptake may be greater than in the mediastinum with complete metabolic response, but should be no 
higher than surrounding normal physiologic uptake (e.g., with marrow activation as a result of chemotherapy or myeloid 
growth factors). 
 
** PET 5PS: 1, no uptake above background; 2, uptake ≤ mediastinum; 3, uptake > mediastinum but ≤ liver; 4, uptake 
moderately > liver; 5, uptake markedly higher than liver and/or new lesions; X, new areas of uptake unlikely to be related to 
lymphoma. 
 
Reference:  Cheson BD, Fisher RI, Barrington SF, Cavalli F, Schwartz H, Lister TA.  Recommendations for initial 
evaluation, staging, and response assessment of Hodgkin and Non-Hodgkin lymphoma:  The Lugano classification.  J Clin 
Onc 2014, 32(27):3059-3068 


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13.3 Appendix: Global Response Score Grading Scales for Modified 
Severity-weighted Assessment Tool (mSWAT) for CTCL  
13.3.1 Skin Scoring 
13.3.1.1 
Total Body Surface Area (TBSA) Involvement by Skin 
Disease 
The body is divided into 12 regions with pre-assigned percentage (%) total body surface area 
(TBSA) based on the burn literature.  The extent of skin disease in each region is quantified 
by using the patient’s palm to measure the %TBSA involvement within region: patient’s 
palm with 4 fingers (excluding the thumb) is 1% of TBSA.  Patient’s palm without fingers is 
0.5% of TBSA.  The patient’s palm with 4 fingers is traced on a transparency sheet at the 
baseline visit, using a permanent marker that will not rub off or smear.  The transparency of 
the patient’s palm should be used in all mSWAT assessments during the course of the 
clinical study.  The transparency will be labeled with the patient’s study ID number kept in 
the patient’s study file on site.  Using the baseline visit transparency of the patient’s palm, the 
Investigator will measure and record the %TBSA for each lesion type within each of the 
12 regions. 
13.3.1.2 
Severity Weighting Factor 
The severity weighting factors will be the following: 
• 1= patch (flat erythema or erythema with mild infiltration) 
• 2=plaque (elevated erythema or erythema with moderate infiltration) 
• 4= tumor or ulceration (erythema with fissuring, ulceration or tumor) 
Patch is defined as abnormal skin not elevated from normal skin.  A plaque is defined as 
abnormal skin elevated from normal skin by < 5 mm.  A plaque elevated ≥ 5 mm is a tumor. 
13.3.1.3 
Calculating Skin Scores 
The sum of %TBSA by lesion is derived by summing the %TBSA from all regions affected 
by the lesion.  The sum of %TBSA across lesion types (patches, plaques and tumors) within 
each region cannot exceed the %TBSA for the region.  For example, the %TBSA for the 
head region is 7%.  The sum of %TBSA across lesion types from head can only range from 
0-7%.  The skin score subtotal by lesion type are derived by multiplying the sum of %TBSA 
for patches from all regions by 1, sum of %TBS of plaques from all regions by 2, and the 
sum of %TBSA of tumors or ulcers from all regions by 4.  The skin score total is derived 
from summing the skin score subtotals for patches, plaques and tumors or ulcers. 
The skin score total is dimensionless with a scale of 0 to 400. 


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%TBSA for Each Lesion Type Within Each of the 12 Regions 
Region 
Percentage TBSA 
for the region 
Percentage TBSA 
patch (or flat 
erythema) 
Percentage TBSA 
plaque (or 
elevated/indurated 
erythema) 
Percentage TBSA 
tumor/ulceration 
(or erythema 
w/fissuring, 
ulceration 
Head 
7 
 
 
 
Neck 
2 
 
 
 
Anterior Trunk 
13 
 
 
 
Posterior Trunk 
13 
 
 
 
Buttocks 
5 
 
 
 
Genitalia 
1 
 
 
 
Upper Arms 
8 
 
 
 
Forearms 
6 
 
 
 
Hands 
5 
 
 
 
Thighs 
19 
 
 
 
Lower Leg 
14 
 
 
 
Feet 
7 
 
 
 
%BSA by category 
100 
 
 
 
Severity Weighting 
factor 
 
×1 
×2 
×4 
Skin Score subtotal 
 
 
 
 
Abbreviations: TBSA, total body surface area; BSA, body surface area 


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13.3.1.4 
Response Definitions 
Responses will be determined by the criteria described in the table below.  Progression of 
disease while on treatment should be confirmed by a second assessment 1 to 4 weeks later so 
that patients who experience a temporary flare of disease due to skin infection or other 
intercurrent illnesses are not removed from the study prematurely. 
 
Response 
Description 
Skin 
 
Complete 
Response (CR) 
No evidence of disease; 100% clearance of skin lesions. 
Partial Response
(PR) 
≥50% decrease in skin scores compared to baseline and improvement is maintained for a 
minimum of 4 weeks 
Stable Disease 
(SD) 
< 50% decrease in skin scores compared to baseline 
Progressive 
Disease (PD) 
≥ 25% increase in skin scores compared to baseline while the patient is actively taking the 
study drug, 
or new tumor(s) ≥ 1 cm diameter in skin disease only patient, 
or ≥ 50% increase in the sum of the products of the greatest diameters of pathologically 
positive lymph nodes (should be documented by biopsy) compared to baseline while the 
patient is actively taking the study drug. 
Relapse 
Any disease recurrence in those with complete response. 
Lymph Nodes (peripheral and central) 
CR 
All lymph nodes are now ≤ 1.5 cm in greatest transverse (long axis) diameter by method 
used to assess lymph nodes at baseline or biopsy negative for lymphoma; in addition, lymph
nodes that were N3 classification and ≤ 1.5 cm in their long axis and > 1 cm in their short 
axis at baseline, must now be ≤ 1 cm in their short axis or biopsy negative for lymphoma  
PR 
Cumulative reduction > 50% of the SPD of each abnormal lymph node at baseline and no 
new lymph node > 1.5 cm in the diameter of the long axis or >1.0 cm in the diameter of the 
short axis if the long axis is 1-1.5 cm diameter  
SD 
Fails to attain criteria for CR, PR, or PD 
PD 
≥ 50% increase in SPD from baseline of lymph nodes  
or Any new node > 1.5 cm in the long axis or > 1 cm in the short axis if 1-1.5 cm in the 
long axis that is proven to be N3 histologically  
or Loss of response: > 50% increase from nadir in SPD of lymph nodes in those with PR 
Relapse 
Any new lymph node > 1.5 cm in the long axis in those with CR proven to be N3 
histologically. 
Viscera 
 
CR 
Liver or spleen or any organ considered involved at baseline should not be enlarged on 
physical exam and should be considered normal by imaging; no nodules should be present 
on imaging of liver or spleen; any post treatment mass must be determined by biopsy to be 
negative for lymphoma 
PR 
≥ 50% regression in any splenic or liver nodules, or in measurable disease (SPD) in any 
organs abnormal at baseline; no increase in size of liver or spleen and no new sites of 
involvement 
SD 
Fails to attain criteria for CR, PR, or PD 


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Response 
Description 
PD 
>50% increase in size (SPD) of any organs involved at baseline 
or New organ involvement  
or Loss of response: >50% increase from nadir in the size (SPD) of any previous organ 
involvement in those with PR 
Relapse 
New organ involvement in those with CR. 
Blood 
 
CR (a) 
B0: Absence of significant blood involvement, <5% of peripheral blood lymphocytes are 
atypical (Sézary) cells 
PR (b) 
>50% decrease in quantitative measurements of blood tumor burden from baseline in those 
with high tumor burden at baseline (B2) 
SD 
Fails to attain criteria for CR, PR, or PD 
PD 
B0 to B2 
or >50% increase from Baseline and at least 5,000 neoplastic cells/µL, 
or >50% increase from nadir and at least 5,000 neoplastic cells/µL for those with OR who 
were originally B2 at baseline. 
Relapse 
Increase of neoplastic blood lymphocytes to ≥ B1 in those with CR 
SPD = sum of the maximum linear dimension (major axis) x longest perpendicular dimension (minor axis) 
 
13.3.2 Global Response Score 
The individual component scores for skin, nodes, blood, and viscera are incorporated into the 
definition of the Global Response Score (see table below). 
Global Score 
Definition 
Skin 
Nodes 
Blood 
Viscera 
Complete 
Response (CR) 
Complete disappearance of all 
clinical evidence of disease 
CR 
All categories have CR/noninvolved (NI) 
Partial 
Response (PR) 
Regression of measurable 
disease 
CR 
All categories do not have a CR/NI and no 
category has a PD 
PR 
No category has a PD and if any category 
involved at baseline, at least one has a CR or 
PR 
Stable Disease 
(SD) 
Failure to attain CR, PR, or 
PD representative of all 
disease 
PR 
No category has a PD and if any category 
involved at baseline, no CR or PR in any 
SD 
CR/NI, PR, SD in any category and no 
category has a PD 
Progressive 
Disease (PD) 
Progressive disease 
 
PD in any category 
Relapse 
Recurrence disease in prior 
CR 
 
Relapse in any category 
References: 
Olsen EA, S Whittaker, Kim YH, Duvic M, Prince HM, Lessin SR, et al. Clinical end points and response 
criteria in mycosis fungoides and Sézary Syndrome:  a consensus statement of the International Society for 
Cutaneous Lymphomas, the United States Cutaneous Lymphoma Consortium, and the Cutaneous Lymphoma 
Task Force of the European Organisation for Research and Treatment of Cancer.  J Clin Onc 2011; 
29(18):2598-2607. 
Stevens SR, Ke MS, Parry EJ, Mark J, Cooper KD.  Quantifying skin disease burden in mycosis fungoides-type 
cutaneous T-cell lymphomas:  the severity-weighted assessment tool (SWAT).  Arch Dermatol 2002; 138:42-48. 
 


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13.4 Appendix: CTCAE Immune System Hypersensitivity Grades 
 
 
Adverse Event 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Grade 5 
Allergic reaction 
Transient 
flushing or rash, 
drug fever 
<38°C 
(<100.4°F); 
intervention not 
indicated 
Intervention or 
infusion 
interruption 
indicated; 
responds 
promptly to 
symptomatic 
treatment (e.g., 
antihistamines, 
NSAIDS, 
narcotics); 
prophylactic 
medications 
indicated for 
≤24 hours 
Prolonged (e.g., 
not rapidly 
responsive to 
symptomatic 
medication 
and/or brief 
interruption of 
infusion); 
recurrence of 
symptoms 
following initial 
improvement; 
hospitalization 
indicated for 
clinical sequelae 
(e.g., renal 
impairment, 
pulmonary 
infiltrates) 
Life-threatening 
consequences; 
urgent intervention 
indicated 
Death 
Definition: A disorder characterized by an adverse local or general response from exposure to an allergen. 
Anaphylaxis 
- 
- 
Symptomatic 
bronchospasm, 
with or without 
urticaria; 
parenteral 
intervention 
indicated; allergy-
related 
edema/angioedem
a; 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. 
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 


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Adverse Event 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Grade 5 
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 66 to 21 days following the administration of the foreign 
antigen.  Symptoms include fever, arthralgias, myalgias, skin eruptions, lymphadenopathy, chest marked 
discomfort, and dyspnea. 


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Adverse Event 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Grade 5 
Immune 
system 
disorders - 
Other, specify 
Asymptomatic or 
mild symptoms; 
clinical or 
diagnostic 
observations 
only; 
intervention not 
indicated 
Moderate; 
minimal, local 
or noninvasive 
intervention 
indicated; 
limiting 
age-appropriat
e instrumental 
ADL 
Severe or 
medically 
significant but 
not immediately 
life-threatening; 
hospitalization 
or prolongation 
of existing 
hospitalization 
indicated; 
disabling; 
limiting self-
care ADL 
Life-threatening 
consequences; 
urgent 
intervention 
indicated 
Death 
 
Abbreviations: ADL, Activities of daily living; NSAIDs, non-steroidal anti-inflammatory drugs. 
Adapted from CTCAE 4.0 – June 14, 2010, Immune system disorders. 
 


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13.5 Appendix: Dose Escalation Scheme Report 
13.5.1 Overview 
A primary objective of the dose escalation portion of the study is to estimate an MTD.  
The MTD will be the highest safe dose that has at least a 60% probability that the dose 
limiting toxicity (DLT) rate is < 30%.  The DLT observation period is 1 cycle.  
Dose escalation will begin with the 3 µg/kg starting dose (Dose Level 1).  There will be 
33 dose levels including all dose levels from: 
• 0.003 to 0.02 mg/kg in increments of 0.001 
• 0.02 to 0.05 mg/kg in increments of 0.005 
• 0.05 to 0.10 mg/kg in increments of 0.01 
• 0.10 to 0.30 mg/kg in increments of 0.05 
Dose escalation will be conducted according to a continual reassessment method (CRM).  
Non-DLT toxicity events (i.e. Grade 2 or higher toxicities) will inform the probability of 
DLT at each dose level.  Dose escalation is also conducted according to a set of rules that 
govern entry into the study and assignment of dose level.  These rules allow that untried dose 
levels may be skipped.  The trial is continuously monitored for safety and early stopping for 
successfully identifying the MTD. 


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13.5.2 Continual Reassessment Method  
Dose escalation in this study will be conducted using the CRM.  For each dose, d = 1,….,33, 
we model the ordinal outcome of no toxicity event, non-DLT (i.e. Grade 2) toxicity event, or 
a DLT.  
We model the log odds of a DLT, 
 
with a two-parameter model  
 
We model the log odd-odds of a non-DLT toxicity  
 
as related to DLTs by including an additive term, γ, which must be > 0,  
. 
We place the following independent prior distributions on the parameters.  
α ~ N(–3, 62) 
β ~ N(8, 202) 
γ ~ N+(3, 62) 
This parameterization imposes that Grade 2 or higher toxicities (which include DLTs) will 
occur more frequently than DLTs.  We use “pseudo-prior” weighting to impose a prior 
expectation of the rate of DLTs that helps shape the correlation of the parameters.  
We assume one observation each of three doses.  We place one observation with 0% DLT on 
the 0.003 mg/kg dose, with 30% DLT on the on the 0.10 mg/kg dose, and with 60% DLT on 
the 0.20 mg/kg dose.  
After each patient is treated and assessed for non-DLT toxicity or DLT, the distributions of 
all parameters are updated and the MTD is estimated based on the posterior probability of 
DLT at each dose.  
Additionally, we define a dose as safe if there is at least a 60% probability that the DLT rate 
is < 30%,  
Pr(πd < 30%) > 60%. 
 


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Patients cannot be assigned to a dose that is not safe by this definition.  
13.5.3 Dose Escalation Rules 
Dose escalation begins with enrollment of patients on the 0.003 mg/kg dose.  The queue 
refers to the number of patients that have been allocated to doses, but have not yet completed 
the observation period.  For safety purposes we want to keep the queue size moderate to 
prevent large numbers of patients being enrolled at any one time.  Until 4 patients have 
complete DLT information the queue maximum is 2.  After 4 patients have complete DLT 
information, the queue increases to 3.  Patients cannot be enrolled for dose escalation if the 
queue maximum has been reached.  
13.5.3.1 
Starting Dose and Entry into the Study 
Dose escalation begins with enrollment of patients on the 0.003 mg/kg dose (dose escalation 
will be conducted according to a CRM, as described in Appendix 13.5).   
The queue refers to the number of patients that have been allocated to doses, but have not yet 
completed the observation period.  For safety purposes we want to keep the queue size 
moderate to prevent large numbers of patients being enrolled at any one time. 
Until 4 patients have complete DLT information the queue maximum is 2.  After 4 patients 
have complete DLT information the queue increases to 3.  Patients cannot be enrolled for 
dose escalation if the queue maximum has been reached.  
13.5.3.2 
Assignment of Dose Level 
The dose-toxicity model will be used to assign patients to doses.  However, assignment of 
dose level is also governed by rules that govern the speed of dose escalation and rules that 
determine if untried dose levels may be skipped.  
There must be complete DLT information through the first cycle (3 weeks) on at least 
2 patients in order to escalate.  When the dose is escalated, the dose level may increase by 
100% as long as no toxicity events are observed.  Once a non-DLT toxicity is observed, the 
dose may only be increased by 67%; and once a DLT is observed, the dose may only increase 
by 50%.  In addition, the dose may never increase by more than 100% or by more than an 
absolute value of 1) 0.02 mg/kg at dose levels below 0.10 or 2) 0.10 mg/kg for dose levels 
between 0.10 and 0.30. 
The increase in dose level is always constrained by the dose-toxicity model.  The dose may 
never escalate to a dose that is considered unsafe.  
  


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13.5.4 Interim Monitoring 
The trial is continuously monitored for safety and for success in identifying the MTD.  
If dose escalation is not stopped for either safety or success in identifying the MTD it will 
continue to enroll to the maximum sample size.  
13.5.4.1 
Safety Monitoring 
The lowest dose (0.003 mg/kg) will be considered unsafe if it has a probability < 25% of a 
DLT rate < 30%.  The trial will stop, and no MTD found, if the lowest dose is considered 
unsafe (hence all doses are considered unsafe). 
13.5.4.2 
Success in Identifying the MTD 
Dose escalation may be stopped early when sufficient information around the MTD has been 
obtained.  We characterize this by having a sufficient number of patients at and around the 
MTD.  We require at least 3 patients with complete information at the MTD and at least 
6 patients with complete information within a certain interval around the MTD.  If the MTD 
is 0.010 mg/kg or lower, we require 6 patients at the MTD.  If the MTD is 0.011 mg/kg or 
greater, we require a total of 6 patients between the MTD and the dose level below.  
13.5.5 Operating Characteristics 
To evaluate how the dose escalation design performs, we simulated the study considering 
different dose-toxicity scenarios.  We show operating characteristics of the trial based on 
1,000 simulations per scenario.  For each scenario we plot the mean sample size and 
cumulative probability of MTD across the 33 dose levels including all dose levels from: 
• 0.003 to 0.02 mg/kg in increments of 0.001 
• 0.02 to 0.05 mg/kg in increments of 0.005 
• 0.05 to 0.10 mg/kg in increments of 0.01 
• 0.10 to 0.30 mg/kg in increments of 0.05   
The true DLT scenario is shown for reference along with a line indicating a 30% DLT rate.  
We further summarize the performance of the dose escalation design by showing the mean 
sample size and the 10%, 20%, 50%, 80%, and 90% quantiles of the cumulative MTD curve.  


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13.5.5.1 
All Doses Safe 
 
 
 
 
 
Quantile of Cumulative MTD Selection 
True 
MTD 
Mean 
N 
10% 
20% 
50% 
80% 
90% 
0.3 
38 
0.25 
0.30 
0.30 
0.30 
0.30 
 


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13.5.5.2 
MTD is the Highest Dose (0.30 mg/kg) 
 
 
 
 
 
Quantile of Cumulative MTD Selection 
True 
MTD 
Mean 
N 
10% 
20% 
50% 
80% 
90% 
0.30 
38.3 
0.10 
0.15 
0.20 
0.30 
0.30 


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13.5.5.3 
MTD is a Middle Dose (0.15 mg/kg) 
 
 
 
 
 
Quantile of Cumulative MTD Selection 
True 
MTD 
Mean 
N 
10% 
20% 
50% 
80% 
90% 
0.15 
35.6 
0.10 
0.10 
0.15 
0.15 
0.20 
 


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13.5.5.4 
MTD is a Middle Dose (0.10 mg/kg) 
 
 
 
 
 
Quantile of Cumulative MTD Selection 
True 
MTD 
Mean 
N 
10% 
20% 
50% 
80% 
90% 
0.1 
34.9 
0.07 
0.09 
0.10 
0.10 
0.15 
 


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13.5.5.5 
MTD is a Low Dose (0.05 mg/kg) 
 
 
 
 
 
Quantile of Cumulative MTD Selection 
True 
MTD 
Mean 
N 
10% 
20% 
50% 
80% 
90% 
0.05 
34.2 
0.04 
0.05 
0.06 
0.07 
0.08 
 


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13.5.5.6 
MTD is a Low Dose (0.02 mg/kg) 
 
 
 
 
 
Quantile of Cumulative MTD Selection 
True 
MTD 
Mean 
N 
10% 
20% 
50% 
80% 
90% 
0.02 
32.6 
0.013 
0.018 
0.020 
0.025 
0.03 
 


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13.5.5.7 
No Doses Safe 
In this scenario, there is a 61% probability of stopping early for safety.  The lowest dose is 
selected as the MTD with 37% probability. 
 


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13.6 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 201113 
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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13.7 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 201113 
 

SAP_001.pdf: 
Protocol Number:  ADCT-301-001 
 
Official Title:  A Phase 1 Adaptive Dose-Escalation Study to Evaluate the Tolerability, Safety, 
Pharmacokinetics, and Antitumor Activity of ADCT-301 in Patients with 
Relapsed or Refractory Hodgkin Lymphoma and Non-Hodgkin Lymphoma  
 
NCT Number: NCT02432235 
 
Document Date:  24-Mar-2020 


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Statistical Analysis Plan 
 
 
 
 
A Phase 1 Adaptive Dose-Escalation Study to Evaluate the Tolerability, 
Safety, Pharmacokinetics, and Antitumor Activity of ADCT-301 in subjects 
with Relapsed or Refractory Hodgkin Lymphoma and Non-Hodgkin 
Lymphoma 
 
PROTOCOL NO.:  ADCT-301-001  
 
 
 
SAP Version No./ Date: 1.0/ Dec 20, 2019 
SAP Version No./ Date: 2.0/ Mar 24, 2020 
 
Statistician: 
 
 
 
 
 
  
Confidentiality Statement 
All financial and nonfinancial support for this study will be provided by ADC Therapeutics 
SA. The concepts and information contained in this document or generated during the study 
are considered proprietary and may not be disclosed in whole or in part without the 
expressed, written consent of ADC Therapeutics SA. The study will be conducted according 
to the International Conference on Harmonisation harmonised tripartite guideline E6(R1), 
Good Clinical Practice. 
 




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Table of Contents 
Table of Contents ..................................................................................................................3 
1 Introduction ........................................................................................................................5 
2 Study Objectives ................................................................................................................6 
2.1 Primary Objectives .................................................................................................. 6 
2.2 Secondary Objectives .............................................................................................. 6 
 
3 Study Design ......................................................................................................................7 
3.1 Sample Size Consideration ...................................................................................... 7 
3.2 Randomization ........................................................................................................ 7 
3.3 Modifications to the statistical section of the protocol .............................................. 8 
4 Statistical methods ..............................................................................................................9 
4.1 Analysis Sets ........................................................................................................... 9 
4.1.1 Safety Analysis Set ...................................................................................... 9 
4.1.2 DLT-evaluable Analysis Set (Part 1) ............................................................ 9 
4.1.3 Efficacy Analysis Set ................................................................................... 9 
4.2 Patient Disposition .................................................................................................. 9 
4.3 Protocol Deviations ............................................................................................... 10 
4.4 Demographic and Baseline Characteristics ............................................................ 10 
4.5 Cancer History and Medications History ............................................................... 10 
4.6 Prior or Concomitant Medications (other than anticancer therapies) ....................... 12 
4.7 Exposure to Treatment ........................................................................................... 12 
4.7.1 Extent of ADCT-301 Exposure .................................................................. 12 
4.7.2 Prophylactic Medications for Hypersensitivity .......................................... 12 
4.7.3 Subsequent Anticancer Therapy or Procedure ............................................ 12 
4.8 Safety Analyses ..................................................................................................... 13 
4.8.1 Dose-limiting Toxicities (Part 1) ................................................................ 13 
4.8.2 Adverse Events, Serious Adverse Events, and Deaths ................................ 13 
4.8.2.1 Analyses of adverse events ......................................................... 13 
4.8.2.2 Deaths ....................................................................................... 15 
4.8.3 Laboratory Data ........................................................................................ 15 
4.8.4 Electrocardiogram ..................................................................................... 15 
4.8.5 Vital Signs ................................................................................................. 16 
4.8.6 ECOG Performance Status ........................................................................ 16 


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4.8.7 Physical Examinations and Body Weight ................................................... 16 
4.9 Efficacy Analyses .................................................................................................. 16 
4.9.1 Overall Response Rate .............................................................................. 17 
4.9.2 Duration of Response ................................................................................ 17 
4.9.3 Time to Response: ..................................................................................... 18 
4.9.4 Progression-free Survival .......................................................................... 18 
4.9.5 Overall Survival ........................................................................................ 18 
5 Interim Analyses ............................................................................................................... 18 
6 Data handling conventions ................................................................................................ 19 
6.1 General conventions .............................................................................................. 19 
6.1.1 Missing data .............................................................................................. 19 
6.1.2 Unscheduled visits..................................................................................... 20 
6.1.3 Duplicated visits ........................................................................................ 20 
Appendix 1 Glossary of Abbreviations ................................................................................ 21 
 


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1 Introduction 
This statistical analysis plan (SAP) describes the statistical methods to be used during the 
reporting and analyses of data collected under ADC Therapeutics Protocol ADCT-301-001. 
This SAP should be read in conjunction with the study protocol and case report form (CRF). 
This version of the plan has been developed using the protocol Amendment 9 dated 04 
January 2019 and CRF version PROD 10.0 dated 29 March 2018. 
 


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2  Study Objectives 
2.1 Primary Objectives  
 Evaluate the safety and tolerability and determine the maximum tolerated dose (MTD) 
of ADCT-301 in subjects with relapsed/refractory lymphoma (Part 1). 
 Determine the recommended dose of ADCT-301 for Part 2 (expansion). 
 Evaluate the safety and tolerability of ADCT-301 in Part 2 at the dose level 
recommended in Part 1. 
2.2 Secondary Objectives 
 Evaluate the activity of ADCT-301 measured by overall response rate (ORR), duration 
of response (DOR), progression-free survival (PFS), and overall survival (OS). 
 Characterize the pharmacokinetic (PK) profile of HuMax-TAC (total antibody; drug-
to-antibody ratio [DAR] ≥0), pyrrolobenzodiazepine (PBD)-conjugated HuMax-TAC 
(DAR ≥1), and free warhead SG3199. 
 Evaluate anti-drug antibodies (ADAs) in blood before, during, and after treatment with 
ADCT-301. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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3 Study Design 
This is a Phase 1, first in human (FIH), open-label, dose-escalation (Part 1) and expansion (Part 
2) study of ADCT-301 in patients with relapsed and refractory lymphoma. The study will 
evaluate the safety and tolerability of ADCT-301 as monotherapy, as well as the preliminary 
activity, PK, PD, and formation of ADAs of ADCT-301 in patients. The patient population 
includes those with relapsed or refractory histologically confirmed non-Hodgkin lymphoma 
(NHL; including Stage ≥Ib cutaneous T-cell lymphoma [CTCL]) or Hodgkin lymphoma (HL). 
In Part 1, patients will receive ADCT-301 administered as a 2-hour intravenous infusion on 
Day 1 of each 3-week cycle. The initial dose level for Part 1 will be 3 μg/kg. The highest 
possible dose will be 300 μg/kg. The MTD will be the highest safe dose that has at least a 
60% probability that the dose-limiting toxicity (DLT) rate is less than 30%.  
Dose escalation will be conducted according to a continual reassessment method (CRM). 
Dose levels from 3 to 300 μg/kg are possible, but the final dose level and number of doses 
will be dependent on the emergent toxicity profile and will be decided by a Dose Escalation 
Steering Committee (DESC). PK and PD evaluations may also inform decision making. See 
separate DESC Plan document. 
The DLT period for dose escalation is changed from 2 cycles to 1 cycle in protocol amendment 
4. However, the adaptive dose-escalation algorithm will incorporate cumulative DLTs 
occurring through Cycle 3. No intra-patient dose escalation will be allowed during the study. 
However, 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. 
During Part 1, the DESC may expand enrollment at doses below the current dose level being 
evaluated 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 with documented stable disease. Not more 
than 10 patients in total can be treated at any dose level unless at least 3 of the 10 patients 
have documented partial response or better using the 2014 Lugano Classification criteria or 
other appropriate measures of response. 
In Part 2 (expansion), patients will be assigned to receive the recommended dose(s) of ADCT-
301, as determined by the DESC during Part 1 of the study. The patient population (e.g., disease 
subtypes) to be enrolled in Part 2 (expansion) may be refined based on results and observations 
from Part 1. Different recommended dose(s) for expansion may be defined and carried forward 
into part 2 for different lymphoma subtypes. 
3.1 Sample Size Consideration 
This is a Phase 1 study with a maximum total sample size of 140 patients. Part 1 will enroll 
approximately 80 patients and Part 2 will enroll approximately 60 patients. 
3.2 Randomization 
This study is not randomized. 


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3.3 Modifications to the statistical section of the protocol  
The efficacy analysis set was defined in the protocol as all patients with valid baseline data 
who receive at least 2 doses of study drug or who have documented progression of disease at 
any time after the first dose of study drug. The efficacy analysis set is updated in the SAP to 
include all patients who have received at least one dose of ADCT-301 with a valid baseline 
and at least one valid post-baseline disease assessment or patients who have documented 
progression of disease or death at any time after the first dose of study drug. 


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4 Statistical methods  
All analyses use SAS® version 9.4 or higher. Summary tables will be organized by each dose 
level; if some dose levels have few patients, then dose levels could be combined into dose 
ranges. All available data will be used in the analyses, and important data will be included in 
data listings, sorted by dose level, patient, and by visit within patient. Missing data will not be 
imputed, except via censoring in survival analyses and as otherwise specified. 
Unless otherwise noted, categorical data will be presented using counts and percentages, with 
the number of patients in the analysis set by treatment group as the denominator for percentages. 
Percentages will be rounded to one decimal place, except 100% will be displayed without any 
decimal places and percentages will not be displayed for zero counts. Continuous data, unless 
otherwise noted, will be summarized using the number of observations (n), mean, standard 
deviation (std), median, minimum, and maximum. Minima and maxima will be rounded to the 
precision of the original value, and means, medians, and 95% confidence intervals (CIs) if 
presented will be rounded to 1 decimal place greater than the precision of the original value. 
The std will be rounded to 2 decimal places greater than the precision of the original value, up 
to a maximum of 3 decimal places.  
No hypothesis testing will be performed in this study. 
4.1 Analysis Sets  
4.1.1 Safety Analysis Set 
The safety analysis set consists of all patients who receive ADCT-301. 
4.1.2 DLT-evaluable Analysis Set (Part 1) 
The DLT-evaluable analysis set consists of patients who complete two cycle of ADCT-301 if 
enrolled prior to protocol amendment 4 and patients who complete one cycle of ADCT-301 if 
enrolled after protocol amendment 4. The patients with completed DLT information will be 
included even if they discontinue early before the end of cycle 2 or cycle 1 respectively. 
4.1.3 Efficacy Analysis Set 
The efficacy analysis set consists of patients who receive at least one dose of ADCT-301 with 
a valid baseline and at least one valid post-baseline disease assessment or patients who have 
documented progression of disease or death at any time after the first dose of study. 
4.2 Patient Disposition 
The number and percentage of patients enrolled and treated in the study will be presented along 
with the number and percentage of patients in each analysis set for each dose level. In addition, 
for the safety analysis set, the number and percentage of patients who withdrew from study 
treatment and who discontinued the study for each reason will be tabulated for each dose level. 
Patient disposition data will be listed.  


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4.3 Protocol Deviations 
The number and percentage of patients with any important clinical study report (CSR) 
reportable protocol deviation will be summarized overall and by type of deviation. The pre-
defined important CSR reportable protocol deviations are listed below; in addition, any other 
protocol deviations deemed by ADCT medical to be important CSR reportable deviations 
will be included in the summary.  
1. Patient entered the study even though they did not satisfy the entry criteria 
2. Patient received a prohibited concomitant treatment during the study 
3. Patients who met criteria for mandatory withdrawal of study drug during the study 
but did not have study drug withdrawn. The criteria for mandatory withdrawal of 
study drug included: 
- Any patient who experiences a Grade 3 or higher hypersensitivity (Appendix 13.4 in 
the protocol) reaction, regardless of premedication, during any cycle of treatment.  
- Any patient who experiences a recurrent Grade 3 or 4 toxicity, excluding 
hematological toxicity. 
- Any patient who requires a dosing delay >21 consecutive days from the planned Day 
1 dosing at any time during treatment (except in case of potential patient benefit, 
which must be approved by the Sponsor).  
4. Patient who received the wrong treatment or incorrect dose. For example, 
- Actual dose of study drug was more than 15% greater than protocol defined planned 
dose level.  
- Patient started next cycle less than 18 days later after Day 1 of the most recent 
treatment cycle.  
Important protocol deviations will be listed. 
4.4 Demographic and Baseline Characteristics 
Demographic and baseline characteristics will be tabulated for the safety analysis set by dose 
level. Variables include the following: 
 Sex (female, male) 
 Race (white, black or African American, Asian, American Indian or Alaska native, 
native Hawaiian or other Pacific Islander, other) 
 Ethnicity (Hispanic or Latino, not Hispanic or Latino) 
 Age (years) 
 Age group (<55, ≥55 - < 65, ≥ 65 - < 75, ≥ 75 years) 
 Height (cm) 
 Weight (kg) 
 Body mass index (kg/m2) 
 Eastern Cooperative Oncology Group (ECOG) performance status 
Demographic and baseline characteristics data will be listed. 
4.5 Cancer History and Medications History 
Cancer history will be presented for the safety analysis set by dose level. Cancer history will 
include the following variables: 


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 Duration since diagnosis 
 Disease diagnosis (non-Hodgkin lymphoma : T-cell lymphoma, B-lymphoma ; 
Hodgkin lymphoma)  
 Disease diagnosis subtype (for non-Hodgkin lymphoma: diffuse large B-cell 
lymphoma, follicular lymphoma, mucosa-associated lymphatic tissue lymphoma/ 
extranodal marginal zone B-cell lymphoma, small cell lymphocytic lymphoma/chronic 
lymphocytic leukemia, mantle cell lymphoma, mediastinal [thymic] large B-cell 
lymphoma, lymphoplasmacytic lymphoma and Waldenstrom macroglobulinemia, 
nodal marginal zone B-cell lymphoma, splenic marginal zone lymphoma, intravascular 
large B-cell lymphoma, primary effusion lymphoma, Burkitt lymphoma-Burkitt 
leukemia, lymphomatoid granulomatosis, peripheral T-cell lymphoma not otherwise 
specified, cutaneous T-cell lymphoma [Sézary], cutaneous T-cell lymphoma [mycosis 
fungoides], anaplastic large cell lymphoma, angioimmunoblastic T-cell lymphoma, 
lymphoblastic lymphoma [can sometimes be a B-cell subtype], NK-cell lymphoma, 
other; for Hodgkin lymphoma (classical Hodgkin lymphoma): nodular sclerosis 
classical Hodgkin lymphoma, lymphocyte-rich classical Hodgkin lymphoma, mixed 
cellularity classical Hodgkin lymphoma, lymphocyte-depleted classical Hodgkin 
lymphoma, other) 
 Stage of disease (NHL and HL, non-CTCL; Stage I, II, III, IV; constitutional symptoms 
A, B; Subtype E, X, S) 
 Stage of disease (CTCL,  IA, IB, IIA, IIB, IIIA, IIIB, IVA1, IVA2, IVB) 
 Cytogenetic analysis (results available yes, t [11;14], t [11q], +12, del [11q], del [13q], 
del [17p], t [14;18], t [8; 14], other) 
 Immunophenotypic analysis (results available yes; IgVH status mutated, unmutated, 
not applicable; CD5, CD10, CD19, CD20, CD21, CD23, CD43, BCL1, BCL2, BCL6, 
CYCLIN D1, ZAP70 negative, positive, not done) 
Prior anticancer procedure or therapy will include the following variables: 
 Number of lines of therapy/ regimens per patient 
 Any prior surgeries for the current malignancy (yes, no) 
 Any prior radiotherapy for the current malignancy (yes, no) 
 Any prior systemic therapy for the current malignancy (yes, no) 
 Type of systemic therapy (Brentuximab Vedotin, Checkpoint inhibitor, other) 
 Reason for stopping therapy (progression, toxicity, other) 
 Best response (complete response [CR], partial response [PR], stable disease [SD], 
progressive disease [PD], not evaluable [NE]) 
 Any prior stem cell transplant (yes, no) 
 Type of transplant (allogenic, autologous, both, other) 
Medical and cancer history data will be listed. Results of cytogenetic analysis and 
immunophenotypic analysis will be listed. CD25 expression level data will be listed if 
available. Tumor tissue biopsy collection will not be listed, but will be contained in datasets. 
Prior anticancer surgery, radiotherapy, systemic therapy, and stem cell transplant data will be 
listed. 


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4.6 Prior or Concomitant Medications (other than anticancer therapies) 
All medications taken within 14 days before dosing and until the end of the study are to be 
reported in the CRF pages. 
All medications will be coded using the World Health Organization-Drug Dictionary (WHO-
DD) and presented by dose level for the safety analysis set. 
 Prior medications are those the patient used prior to first investigational product (IP) 
intake. Prior medications can be discontinued before first dosing or can be ongoing 
during the treatment phase.   
 Concomitant medications are any treatments received by the patient concomitantly to 
any IP(s), from first dose (or start of the observation period) to the last dose + 30 days. 
A given medication can be classified both as a prior medication and as a concomitant 
medication. Concomitant medications do not include medications started 30 days after 
the last dose.  
Any technical details related to computation, dates, and imputation for missing dates are 
described in Section 6.  
Prior medications will be listed together with concomitant medications. 
4.7 Exposure to Treatment 
4.7.1 Extent of ADCT-301 Exposure 
ADCT-301 exposure will be summarized for the safety analysis set by dose level. Duration 
of treatment, total number of cycles dosed, total dose received (in µg and µg/kg), and average 
dose per cycle (in µg and µg/kg) will be tabulated. When actual weight adjusted dose is 
needed, the last available weight before each infusion will be used. Dose administered at 
each infusion (µg) is calculated by concentrated IP volume (in mL)* 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). 
Dose delays and dose reductions could also be analyzed if relevant. A cycle is delayed if it 
starts more than 2 days post- scheduled date. 
Exposure data and infusion details will be listed together. 
4.7.2 Prophylactic Medications for Hypersensitivity  
Prophylactic medications for hypersensitivity will be listed only. 
4.7.3 Subsequent Anticancer Therapy or Procedure 
Patients’ subsequent anticancer therapies or procedures including systemic therapy, radiation, 
transplant, or other, along with the start date of new anticancer therapy or procedure will be 
collected and listed only. 


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4.8 Safety Analyses 
The summary of safety results will be presented by treatment group.  
General common rules 
All safety analyses will be performed on the safety analysis set, unless otherwise specified, 
using the following common rules: 
 The baseline value is defined as the last non-missing value or measurement taken up to 
the first dose in the study. 
 The analyses of the safety variables will be essentially descriptive and no systematic 
testing is planned. 
 If relevant, selected safety analyses will be summarized by age, sex, racial subgroups, 
and any pertinent subgroups.  
 The toxicity grade according to the Common Terminology Criteria for Adverse Events 
(CTCAE) version 4.0 will be taken into account in the summary. For patients with 
multiple occurrences of the same event, the maximum grade is used. If a patient has 
both missing and non-missing severity grades for treatment-emergent adverse events 
(TEAEs) within the same preferred term (PT), the patient will be counted under the 
non-missing severity grade. 
4.8.1 Dose-limiting Toxicities (Part 1) 
DLT data will be tabulated for the DLT-evaluable analysis set by dose group and type of 
DLT for Part 1 of the study. The patients enrolled prior to and post protocol amendment 4 
will be presented in separate tables. 
DLT data will be listed for Part 1 of the study. 
4.8.2 Adverse Events, Serious Adverse Events, and Deaths 
4.8.2.1 Analyses of adverse events 
The primary focus of adverse event reporting will be on TEAEs. An adverse event (AE) will 
be considered to be a TEAE if it begins or worsens on or after first dose date and until 84 days 
(12 weeks) after the last dose date, or start of a new anticancer therapy/procedure, whichever 
comes earlier. 
An AE occurring before the first dose or more than 84 days (12 weeks) after last dose date or 
after the start of a new anticancer therapy/procedure will not be included in TEAE displays, 
but will be listed as non-TEAEs. 
If an AE date/time of onset (occurrence, worsening, or becoming serious) is incomplete, an 
imputation algorithm will be used to classify the AE as pre-treatment, TEAE, or post-treatment. 
The algorithm for imputing date/time of onset will be conservative and will classify an AE as 
a treatment-emergent unless there is definitive information to determine it is a non-TEAE (pre- 
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Details on classification of AEs with missing or partial onset dates are provided in Section 6. 
Analysis of all TEAE(s):  
The following TEAE summaries will be generated for the safety analysis set in each dose level. 
 Overview of TEAEs, summarizing number of TEAE and number (%) of patients with 
any 
- 
TEAE 
- 
Related TEAE (including possibly related, probably related, or related) 
- 
Any TEAE ≥Grade 3  
- 
Serious TEAE  
- 
TEAE leading to death 
- 
TEAE leading to permanent treatment withdrawal 
- 
TEAE leading to ADCT-301 delay or reduction or interruption 
- 
TEAE with at least one infusion related reaction 
 All TEAEs by PT, showing number (%) of patients with at least one TEAE, sorted by 
decreasing incidence of PTs 
 All TEAEs ≥Grade 3 by PT, showing number (%) of patients with at least one TEAE, 
sorted by decreasing incidence of PTs 
 All TEAEs by primary System Organ Class (SOC) and PT, showing number (%) of 
patients with at least one TEAE, sorted by SOC in alphabetic agreed order and 
decreasing incidence of PTs within SOC. This sorting order will be applied to all other 
tables, unless otherwise specified. 
 All TEAEs by primary SOC, PT and Maximal CTCAE grade, showing number (%) of 
patients with at least one TEAE, sorted by SOC and PT in alphabetic order. This sorting 
order will be applied to all other tables, unless otherwise specified. 
 All TEAEs ≥Grade 3 by primary SOC, PT and Maximal CTCAE grade 
 All related TEAEs by primary SOC, PT and Maximal CTCAE grade (including 
possibly related, probably related, or related) 
 All TEAEs leading to treatment withdrawal by primary SOC, PT and Maximal CTCAE 
grade 
 All TEAEs leading to dose delay by primary SOC, PT and Maximal CTCAE grade 
 All TEAEs leading to dose reduction by primary SOC, PT and Maximal CTCAE grade 
 All TEAEs leading to infusion interruption by primary SOC, PT and Maximal CTCAE 
grade 
 All TEAEs with fatal outcome by primary SOC, PT and Maximal CTCAE grade 
 All Serious TEAEs by primary SOC, PT and Maximal CTCAE grade 


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


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Descriptive statistics (mean, standard deviation, median, and range) will be calculated for the 
raw data and for their changes from baseline at each scheduled assessment. 
The following abnormal QTc (including QTcF, QTcB and QTc with unspecified method) will 
be reported: 
 At any post-baseline with absolute value 
>450 - <=480 ms 
>480 - <=500 ms 
> 500 ms 
Change from Baseline 
 >30 – <=60 ms 
 >60 ms 
For patients with unspecified QTc method at either baseline or post-baseline, consistent 
correction method is assumed within a patient when calculating the change from baseline.  
Summary analyses will include data up to the start of subsequent anticancer therapy/procedure. 
All ECG data will be listed, both for quantitative data and for overall impression. 
4.8.5 Vital Signs 
Descriptive statistics (mean, standard deviation, median, and range) for vital signs data, 
including systolic and diastolic blood pressure, heart rate, respiration rate, and body 
temperature will be calculated for the raw data and for their changes from baseline at each 
scheduled assessment. 
Summary analyses will include data up to the start of subsequent anticancer therapy/procedure. 
All vital signs data will be listed together with body weight and ECOG performance score. 
4.8.6 ECOG Performance Status 
ECOG performance score data will be listed together with vital signs and body weight. 
4.8.7 Physical Examinations and Body Weight 
Physical examination will be performed according to protocol. Clinically significant findings 
from the physical examinations will be recorded as medical history (prior to first administration 
of ADCT-301) or AEs (subsequent to first administration of ADCT-301). 
Body weight will be listed together with vital signs and ECOG performance score. 
4.9 Efficacy Analyses 
Disease assessment will be performed according to protocol. The endpoints described in this 
section use the investigator’s evaluation according to the Lugano Classification criteria or 
Global Response Score Grading Scales for CTCL patients and clinical progression from End 
of Treatment (EOT)/Study disposition page.  


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Tumor assessment data (target lesions, non-target lesions, and new lesions, overall response, 
SUV max, Deauville score, etc.) for non-CTCL patients, and modified Severity-Weighted 
Assessment Tool (mSWAT) scores for CTCL patients will be listed. A separate listing will 
contain derived data for DOR, PFS, and OS. 
4.9.1 Overall Response Rate 
Overall response rate is defined as the proportion of patients who achieve either CR or PR as 
best overall response as assessed by investigators according to the Lugano Classification 
criteria or Global Response Score Grading Scales for CTCL patients before the start of 
subsequent anticancer therapy or procedure.  
The order of overall response category is: CR, PR, SD, NE, PD (including disease recurrence/ 
relapse). The overall response category will be derived based on response assessment 
performed on or before the start of subsequent anticancer therapy/procedure. Patients without 
documented subsequent anticancer therapy and/or with missing start date of anticancer therapy 
will be considered as not having received subsequent anticancer therapy. If a patient only has 
one valid disease assessment which is SD, and the assessment is within 35 days after the first 
dose, the overall response for this patient will be considered as NE. 
The overall response rate and the corresponding 95% two-sided exact confidence interval at 
each dose level will be presented. Subgroup analysis may be provided if relevant. 
Percent change from baseline in the sum of product of diameters (SPD) for target lesions for 
non-CTCL patients and mSWAT total score for CICL patients will be presented for available 
data in the efficacy analysis set by dose level. These data will also be displayed as a waterfall 
plot, with vertical bars representing the sorted values of best percent reduction for each patient.  
Tumor response and lesion measurement (or mSWAT) will be listed by assessment visit. 
4.9.2 Duration of Response 
Duration of response will be defined for patients with CR or PR only as the interval between 
the date of initial documentation of a response and the date of first documented evidence of 
progressive disease (based on radiographic or clinical progression at EOT/end of study [EOS]) 
or death. Patients who had the event after the start of subsequent anticancer therapy/procedure, 
or are progression-free and alive at the time of clinical cut-off, or have unknown status, will 
be censored at the last valid tumor assessment on or before the start of subsequent anticancer 
therapy/procedure or clinical cut-off time.  
Duration of response will be estimated and displayed by dose levels for the efficacy analysis 
set using Kaplan-Meier methods (SAS® PROC LIFETEST). A Kaplan-Meier plot will be 
presented. 
Subgroup analyses may be provided for disease subtype, disease stage, double/triple hit 
(yes/no), bulky disease (yes/no), age group, response to the first line and/or most recent line 
of prior systematic therapy (relapse: CR+PR vs. refractory: SD+PD vs. other: NE + missing), 
best response to ADCT-301 (CR/PR), and other relevant variables. 


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4.9.3 Time to Response:  
Time to response (TTR) for the subset of patients who achieve a CR or PR will be summarized 
using descriptive statistics. 
4.9.4 Progression-free Survival 
Progression-free survival is defined as the interval between the date of first dose and the date 
of disease progression (based on radiographic or clinical progression at EOT/EOS) or death, 
whichever occurs first. Patients who have the event after the start of subsequent anticancer 
therapy/procedure, or who are progression-free and alive at the time of clinical cutoff, or have 
unknown status, will be censored at the time of their last valid disease assessment on or before 
the start of subsequent anticancer therapy/procedure or clinical cut-off.  
Patients with no post-baseline disease assessment will be censored on Day 1. 
PFS will be estimated and displayed by dose levels for the efficacy analysis set using Kaplan-
Meier methods (SAS® PROC LIFETEST). Patients who do not have a PFS event during or 
after the study will be censored. A Kaplan-Meier plot will be presented. 
4.9.5 Overall Survival 
Overall survival is defined as the interval between the date of first dose and the date of death 
from any cause. Patients who are known to be alive as of their last known status will be 
censored at their date of last contact. Patients who are lost to follow-up will be censored at the 
date the patient is last known to have been alive. The last confirmed alive date is the latest of 
the following: study visit date, telephone contact date, end of study last confirmed alive date, 
follow-up systemic (anticancer) therapy end date or start date (if ongoing or end date is 
missing), local or central radiologist scan date, or other date in the clinical database. 
OS will be estimated and displayed by dose levels for the efficacy analysis set using Kaplan-
Meier methods (SAS® PROC LIFETEST). A Kaplan-Meier plot will be presented. 
5 Interim Analyses  
No formal interim analysis is planned. 


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


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


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Appendix 1 Glossary of Abbreviations 
Glossary of Abbreviations: 
ADA 
Anti-drug antibody 
AE 
Adverse event 
AI 
Accumulation index 
AUC 
Area under the concentration-time curve 
CD 
Cluster of differentiation  
CI 
Confidence interval 
CL 
Clearance 
Cmax 
Maximum concentration 
CR 
Complete response 
CRM 
Continual reassessment method 
CRF 
Case report form 
CSR 
Clinical study report 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTCL 
Cutaneous T-cell lymphoma 
DAR 
Drug-to-antibody ratio 
DESC 
Dose Escalation Steering Committee 
DLT 
Dose-limiting toxicity 
DOR 
Duration of response 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
EOS 
End of study 
EOT 
End of treatment 
HL 
Hodgkin lymphoma 
IP 
Investigational product 
MedDRA 
Medical Dictionary for Regulatory Activities 
mSWAT 
modified Severity-Weighted Assessment Tool 
MTD 
Maximum tolerated dose 
NE 
Not evaluable 
NHL 
Non-Hodgkin lymphoma 


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