Conditions: Breast Cancer Non Small Cell Lung Cancer GastroEsophageal Cancer Bladder Cancer
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 21
Healthy volunteers: no

Brief summary:
This study evaluated ADCT-502 in participants with Advanced Solid Tumors with HER2 Expression. Participants participated in a dose-escalation phase (Part 1) and were due to participate in the dose expansion phase (Part 2). In Part 2, patients were due to receive the dose level identified in Part 1, but the study was terminated prior to the beginning of Part 2.

Detailed description:
Study ADCT-502-101 was the first clinical study with ADCT-502 in participants with Advanced Solid Tumors with HER2 Expression.

ADCT-502 is an antibody drug conjugate (ADC) composed of an engineered version of the humanized monoclonal antibody trastuzumab, directed against the human HER2 receptor, conjugated to a pyrrolobenzodiazepine (PBD) dimer cytotoxin. ADCT-502 specifically binds to HER2, and once internalized, releases the PBD dimer to allow cross-linking of DNA and eventually trigger cell death.

The study had 2 parts. In Part 1 (dose escalation) participants received an infusion of ADCT-502, at escalating doses. Part 1 continued until the maximum tolerated dose or the recommended dose(s) and schedule(s) for expansion were determined. In Part 2 (expansion), participants were due to be assigned to the recommended dose level of ADCT-502 identified in Part 1 by the Dose Escalation Steering Committee, but the study was terminated prior to the beginning of Part 2.

For each participant, the study included a screening period (up to 28 days), a treatment period, and a follow-up period to assess disease progression and survival for up to 12 weeks after the last dose of study drug. The total study duration was dependent on overall participant tolerability to the study drug and response to treatment as participants were able to continue treatment until disease progression or unacceptable toxicity.

Arms:
arm 1: Part 1 (dose escalation): Participants received an infusion of ADCT-502, at escalating doses. Part 1 continued until the maximum tolerated dose or the recommended dose(s) and schedule(s) for expansion were determined.

Part 2 (expansion): Participants were due to be assigned to the recommended dose level of ADCT-502 as identified in Part 1 by the Dose Escalation Steering Committee.

Interventions: intervention 1: ADCT-502
Intervention descriptions: intervention 1: Intravenous Infusion

Protocol document:
Prot_000.pdf: 
Protocol Number:   ADCT-502-101  
 
Official Title:    A Phase 1, Open-Label, Dose-Escalation Study to Evaluate the Safety, Tolerability, 
Pharmacokinetics, and Antitumor Activity of ADCT-502 in Patients With Advanced Solid Tumors With 
HER2 Expression 
 
NCT Number:  NCT03125200 
 
Document Date:  August 17, 2017   


ADC Therapeutics 
ADCT-502 
ADCT-502-101
Protocol Amendment 2
Date of Protocol Amendment 2: 17 August 2017 
Page 1 
CLINICAL STUDY PROTOCOL 
IND: 132540 
EudraCT Number: 2017-001787-38 
A Phase 1, Open-Label, Dose-Escalation Study to Evaluate the Safety, 
Tolerability, Pharmacokinetics, and Antitumor Activity of ADCT-502 in 
Patients with Advanced Solid Tumors with HER2 Expression 
PROTOCOL NO.:  ADCT-502-101 
Sponsor:
ADC Therapeutics SA
 
 
 
Sponsor Contact: 
 
 
 
Medical Monitor:  
 
 
 
 
Date of Original Protocol:  
18 January 2017 
Date of Protocol Amendment 1: 
20 March 2017 
Date of Protocol Amendment 2: 
17 August 2017 
Confidentiality Statement 
All financial and nonfinancial support for this study will be provided by ADC Therapeutics 
SA.  The concepts and information contained in this document or generated during the study 
are considered proprietary and may not be disclosed in whole or in part without the expressed, 
written consent of ADC Therapeutics SA.  The study will be conducted according to the 
current version of the International Council for Harmonisation harmonised tripartite 
guideline E6, Good Clinical Practice.
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Declaration of Investigator
I have read and understood all sections of the protocol entitled: “A Phase 1, Open-Label, 
Dose-Escalation Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Antitumor 
Activity of ADCT-502 in Patients with Advanced Solid Tumors with HER2 Expression “ and 
the accompanying Investigator Brochure (IB).
I agree to supervise all aspects of the protocol and to conduct the clinical investigation in 
accordance with the Protocol Amendment 2, dated 17 August 2017, the current version of the
International Council for Harmonisation (ICH) harmonised tripartite guideline E6: Good 
Clinical Practice and all applicable governmental regulations. I will not make changes to the 
protocol before consulting with ADC Therapeutics or implement protocol changes without 
independent ethics committee approval except to eliminate an immediate risk to patients. I 
agree to administer study treatment only to patients under my personal supervision or the 
supervision of a sub-Investigator.
I will not supply the investigational drug to any person not authorized to receive it. 
Confidentiality will be protected.  Patient identity will not be disclosed to third parties or 
appear in any study reports or publications.
I will not disclose information regarding this clinical investigation or publish results of the 
investigation without authorization from ADC Therapeutics SA.
Signature of Principal Investigator
Date
Printed Name of Principal Investigator
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Table of Contents
Table of Contents ...................................................................................................................... 4
List of Tables............................................................................................................................. 8
List of Figures........................................................................................................................... 8
Protocol Synopsis...................................................................................................................... 9
Schedule of Events.................................................................................................................. 20
List of Abbreviations............................................................................................................... 25
1
Introduction and Background......................................................................................... 27
1.1
HER2 and HER2 Targeting Therapies...................................................................27
1.2
Description of ADCT-502......................................................................................29
1.3
Nonclinical Efficacy and Toxicology of ADCT-502..............................................29
2
Rationale......................................................................................................................... 30
2.1
Study Rationale and Purpose .................................................................................30
2.2
Rationale for Study Design....................................................................................30
2.3
Starting Dose Justification .....................................................................................31
2.4
Plans and Justification for Provisional Dose Levels..............................................31
3
Study Objectives and Endpoints..................................................................................... 32
3.1
Objectives ..............................................................................................................32
3.1.1
Primary Objectives ...................................................................................32
3.1.2
Secondary Objectives ...............................................................................32
3.2
Endpoints ...............................................................................................................32
3.2.1
Primary Endpoints ....................................................................................32
3.2.2
Secondary Endpoints ................................................................................33
4
Study Design................................................................................................................... 33
4.1
Overview................................................................................................................33
4.2
Patient Selection and Evaluation of HER2 Expression/Amplification/Mutation..34
4.3
Number of Patients ................................................................................................36
4.4
Duration of Patient Participation ...........................................................................36
4.5
Duration of Study...................................................................................................37
4.6
Description of Dose Escalation Process ................................................................37
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4.6.1
Safety Oversight by the Dose Escalation Steering Committee.................38
4.6.2
Definition of Dose-Limiting Toxicities ....................................................38
5
Management of Toxicity Including Dose Delays and Modifications............................. 39
5.1
ADCT-502 General Dose Modification Guidelines...............................................40
5.2
Guidelines for Dose Modification: Hematologic Toxicities..................................40
5.3
Guidelines for Dose Modification: Non-hematologic Toxicities...........................44
5.4
Guidelines for Dose Modifications: Left Ventricular Dysfunction........................46
6
Patient Population........................................................................................................... 47
6.1
Inclusion Criteria ...................................................................................................47
6.2
Exclusion Criteria ..................................................................................................49
6.3
Definition of HER2 Expression Levels .................................................................51
7
Reasons for Withdrawal/Discontinuation....................................................................... 51
7.1
Handling of Withdrawals.......................................................................................52
7.1.1
Patient Replacements................................................................................52
8
Study Drug...................................................................................................................... 52
8.1
ADCT-502 Drug Product.......................................................................................52
8.2
Packaging and Storage...........................................................................................52
8.3
Preparation and Administration .............................................................................53
8.4
Study Drug Accountability ....................................................................................53
8.5
Treatment Compliance...........................................................................................53
9
Concomitant Treatment .................................................................................................. 53
9.1
Prophylaxis Mandated During the Study...............................................................53
9.2
Prohibited During Study ........................................................................................54
9.3
Permitted Treatment During Study........................................................................54
9.3.1
Palliative Radiotherapy.............................................................................54
9.3.2
Oral Contraception....................................................................................54
9.3.3
Anti-emetics..............................................................................................54
9.3.4
Anti-diarrheal Treatment ..........................................................................54
9.3.5
Growth Factors .........................................................................................55
9.3.6
Steroids .....................................................................................................55
9.3.7
Skin Toxicity Therapy...............................................................................55
9.3.8
Bisphosphonates or Denosumab...............................................................55
9.3.9
Androgen Deprivation Therapy................................................................55
9.4
Prophylaxis for Hypersensitivity ...........................................................................55
9.5
Treatment of Edema and/or Pleural Effusion.........................................................56
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9.6
Other Supportive Care ...........................................................................................56
10
Description of Procedures .............................................................................................. 56
10.1 Triplicate 12-Lead ECGs .......................................................................................57
10.2 Laboratory Analyses (Safety) ................................................................................57
10.2.1
Complete Blood Count with Differential..................................................57
10.2.2
Coagulation...............................................................................................57
10.2.3
Chemistry 58
10.2.4
Urinalysis 58
10.3 Efficacy Assessments.............................................................................................58
10.4 Pharmacokinetic, Pharmacodynamic, and Exploratory Analyses..........................59
10.4.1
Pharmacokinetics......................................................................................59
10.4.2
Pharmacodynamic and Other Exploratory Assessments ..........................59
10.5 Sample Handling, Storage and Shipment ..............................................................59
11
Adverse Events............................................................................................................... 60
11.1 Definitions of Adverse Events ...............................................................................60
11.2 Eliciting and Documenting Adverse Events ..........................................................60
11.3 Reporting Adverse Events......................................................................................61
11.4 Assessment of Severity..........................................................................................62
11.5 Assessment of Causality ........................................................................................62
11.6 Follow-Up of Patients Reporting Adverse Events.................................................62
11.7 Overdose ................................................................................................................62
11.8 Pregnancy...............................................................................................................63
12
Statistical Methods ......................................................................................................... 63
12.1 Sample Size Calculations.......................................................................................63
12.2 Interim Analysis (Part 2)........................................................................................63
12.3 Analysis Populations..............................................................................................64
12.4 Safety Analyses......................................................................................................64
12.4.1 Adverse Events .........................................................................................64
12.4.2
Clinical Laboratory Results......................................................................65
12.4.3
Additional Safety Assessments.................................................................65
12.5 Efficacy Analyses...................................................................................................65
12.5.1
Overall Response Rate..............................................................................65
12.5.2
Disease Control Rate ................................................................................66
12.5.3
Duration of Response ...............................................................................66
12.5.4
Progression-Free Survival ........................................................................66
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12.5.5 Overall Survival........................................................................................66
12.6 Pharmacokinetic and Pharmacodynamic Analyses................................................66
12.7 Study Drug Exposure.............................................................................................67
13
Data Quality Assurance .................................................................................................. 67
13.1 Data Management ..................................................................................................67
14
Study Conduct and Administration................................................................................. 67
14.1 Ethical Conduct of the Study.................................................................................67
14.2 Independent Ethics Committee or Institutional Review Board .............................68
14.3 Patient Information and Consent ...........................................................................68
14.4 Investigator’s Obligations......................................................................................69
14.4.1
Confidentiality..........................................................................................69
14.4.2
Financial Disclosure and Obligations.......................................................69
14.4.3
Adverse Events and Study Report Requirements.....................................69
14.4.4
Investigator Documentation......................................................................70
14.4.5
Study Conduct ..........................................................................................70
14.4.6
Adherence to Protocol ..............................................................................70
14.4.7
Investigator’s Final Report .......................................................................70
14.4.8
Records Retention.....................................................................................71
15
Study Management......................................................................................................... 71
15.1 Monitoring .............................................................................................................71
15.1.1
Monitoring of the Study............................................................................71
15.1.2
Inspection of Records ...............................................................................71
15.2 Management of Protocol Amendments and Deviations.........................................71
15.2.1
Modification of the Protocol.....................................................................71
15.2.2
Protocol Deviations ..................................................................................72
15.3 Study Termination..................................................................................................72
15.4 Final Report ...........................................................................................................72
16
Publications .................................................................................................................... 73
17
Reference List................................................................................................................. 74
18
Appendices ..................................................................................................................... 77
18.1 CTCAE Immune System Hypersensitivity Grades................................................77
18.2 Eastern Cooperative Oncology Group Performance Status...................................79
18.3 Somatic Mutations Observed via Next Generation Sequencing............................79
18.4 Appendix: Modified Continual Reassessment Method of Dose Escalation..........81
18.4.1
Overview....................................................................................................81
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18.4.2 Model and Priors.......................................................................................81
18.4.3
Dose Escalation Rule and Choice of Cohort Size ....................................82
18.4.3.1
Stopping Rules....................................................................... 83
18.4.4
Interim Monitoring ...................................................................................83
18.4.4.1
Safety Monitoring.................................................................. 83
18.4.5
Operating Characteristics..........................................................................83
18.4.5.1
Scenarios................................................................................ 83
List of Tables
Table 1: Schedule of Events.................................................................................................... 20
Table 2: Timing for ECG, Vital Signs and Sample Collection Schedule for Exploratory 
Assessments......................................................................................................... 24
Table 3: Dose Modification Guidelines for Left Ventricular Dysfunction ............................. 47
Table 4: Definition of Severity Grades for Common Terminology Criteria for Adverse Events 
(CTCAE).............................................................................................................. 62
Table 5: List of Somatic ERBB2/HER2 Mutations Obtained from the Cbioportal Database. 79
Table 6: List of ERBB2/HER2 Mutations Known to be Oncogenic ....................................... 80
Table 7: Insertional HER2 Mutations Predominantly Identified in Lung Cancer .................. 80
Table 8: List of Mutations from Cbioportal............................................................................ 81
Table 9: Planned Dose Levels for ADCT-502......................................................................... 81
List of Figures
Figure 1: ADCT-502-101 Study Schematic............................................................................ 19
Figure 2: Preferred sequence for triplicate ECG, vital signs, and PK sample assessments at 
end of infusion (EOI)........................................................................................... 57
Figure 3: Probability of a DLT Under 5 Simulated Scenarios................................................ 84
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Protocol Synopsis
Protocol Number:
ADCT-502-101
Title:
A Phase 1, Open-Label, Dose-Escalation Study to Evaluate the Safety, 
Tolerability, Pharmacokinetics, and Antitumor Activity of ADCT-502 in 
Patients with Advanced Solid Tumors with HER2 Expression
Sponsor:
ADC Therapeutics SA
Study Phase:
Phase 1
Indication:
Five (5) types of patients, based on HER2 expression levels and mutations, 
are selected in this FIH study of ADCT-502:
1.Patients with indications and HER2 expression levels that qualified 
them for (prior) treatment with trastuzumab and/or ado-
trastuzumab emtansine, e.g., HER2 positive BC and HER2 
positive G/GE cancer.
2.Patients with BC or G/GE cancer with HER2 expression that is 
present, but at a level that is below the threshold qualifying them 
for Item Number 1.
3.Patients with HER2 expression levels equivalent to Item Number 1, 
but who have a tumor type other than BC or G/GE cancer 
(NSCLC, small cell lung cancer (SCLC), CRC, bladder, 
pancreatic, biliary tract, prostate, ovarian, endometrial, and 
salivary gland cancer).
4.Patients from the same indication list as in Item Number 3, except 
with HER2 expression levels present but lower than that, i.e. 
equivalent to expression levels in Item Number 2.
5.Patients with 1 of the 12 indications mentioned in Items 1–4 who 
have been shown to possess a HER2 hotspot mutation; they are 
either classified as HER2-high if a concomitant amplification was 
demonstrated, otherwise they are classified as HER2-low.  
Patients with such HER2 genetic alteration pre-defined prior to 
study enrollment and not belonging to 1 of the 12 indications may 
be included in the dose escalation part after sponsor agreement.
Rationale:
The mechanism of action and preclinical data of ADCT-502 supports its use 
in patients with relapsed or refractory metastatic breast and gastric cancer 
who have been previously treated with trastuzumab/T-DM1.  Given the 
substantial prevalence of HER2 expression in a range of other advanced 
cancers, including NSCLC, bladder, biliary tract, and ovarian cancer, for 
which HER2 targeted therapies are not licensed, ADCT-502 will also be 
evaluated as an anticancer treatment in patients with such tumor types for 
which there is published clinical evidence of HER2 expression.  Also, there 
is high unmet medical need in breast and gastric/GE junction cancers in 
which HER2 expression is observed but below the defined thresholds for 
HER2 targeted therapy.
Results of preclinical studies in PDX suggest that ADCT-502 may have 
potent clinical activity in both groups of patients, those with HER2-
positive/high tumors as well as those 
 
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Objectives:
Primary Objectives

Evaluate safety, tolerability, and determine the MTD and/or RDE of 
single agent ADCT-502 in patients with advanced solid tumors with 
known HER2 status (IHC ≥1+ or HER2 amplified/mutated) (Part 1).

Further evaluate safety and tolerability at the dose level determined in 
Part 1 in patients with advanced solid tumors including breast cancer, 
lung, gastroesophageal, and bladder cancer or a basket of other solid 
tumors known to express HER2
(HER2-high or HER2-low status confirmed prospectively for study 
entry) (Part 2).
Secondary Objectives

Evaluate the preliminary antitumor activity of ADCT-502.

Characterize the PK profile of ADCT-502.

Determine the immunogenicity of ADCT-502.
 
 
 
Patient Selection:
Inclusion Criteria
1. Male or female age 18 years or older. 
2. Refractory to or intolerant of existing therapy(ies) known to provide 
clinical benefit for their condition.
3. Eastern Cooperative Oncology Group (ECOG) performance status:
a. Part 1: 0-2
b. Part 2: 0-1
4. Availability of formalin-fixed paraffin-embedded (FFPE) tumor tissue 
block (or unstained slides (minimum 7; 10 preferred) if block is not 
available) to demonstrate HER2 expression.
Note: any biopsy since initial diagnosis is acceptable, but if several are 
available, the most recent sample is preferred. 
5. Pathologic diagnosis of solid tumor malignancy that is locally advanced 
or metastatic at time of Screening: 
Part 1 (Dose Escalation):
Advanced solid tumors with documented HER2 status of IHC ≥1+ or 
HER2 amplified/mutated by FISH or NGS.
Note: Clinical pathology report of HER2 status must be available for 
review to confirm eligibility in Part 1.
Part 2 (Dose Expansion): 
HER2-high* or HER2-low** advanced solid tumor belonging to one of 
the pre-specified indications for groups A – E (breast cancer, gastric & 
gastroesophageal cancer, bladder cancer, non-small cell lung cancer) or 
one of the eight pre-specified indications for the basket group 
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(SCLC, CRC, pancreatic, biliary tract, prostate, ovarian, endometrial, or 
salivary gland) according to assigned treatment group for which HER2 
status has been confirmed prospectively (HER2-high or HER2-low) for 
study entry.
* A HER2-high patient is defined as IHC 3+, or IHC 2+ with FISH 
amplification.  
** A HER2-low patient is defined as IHC 1+, or IHC 2+ without FISH 
amplification.
Note: A patient with IHC 0 / IHC 1+ with amplification is HER2-high for 
study purposes; a patient with IHC 3+ with negative amplification results 
is HER2-low for study purposes.
6. Part 2/Dose Expansion Only: Measurable disease as defined by Response 
Evaluation Criteria in Solid Tumors (RECIST) version 1.1.
Note: Lytic bone lesions or mixed lytic-blastic lesions, with identifiable 
soft tissue components, that can be evaluated by cross sectional imaging 
techniques such as CT or MRI can be considered as measurable lesions if 
the soft tissue component meets the definition of measurability per 
RECIST.
7. Screening laboratory values within the following parameters:
a.
Absolute neutrophil count (ANC) ≥ 1500/mm3 (≥1.5 x 109/L).
b.
Platelet count ≥100,000 /mm3 (≥100 x 109/L).
c.
Hemoglobin ≥ 9 g/L (≥5.6 mmol/L).
d.
Aspartate transaminase (AST) and alanine aminotransferase (ALT)
≤ 2.5x upper limit of normal (ULN); or ≤ 5.0x ULN if liver 
metastases are present.
e.
Total bilirubin ≤ 1.5x ULN (or ≤ 3x ULN, with direct bilirubin
≤1.5x ULN, in patients with known Gilbert syndrome).
f.
Serum/plasma creatinine ≤ 1.5x ULN; or, if creatinine > 1.5x ULN, 
a measured creatinine clearance must be >60mL/min as calculated 
by the Cockcroft and Gault equation for patient to be eligible.
8.
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-502.  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-502.  
  *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.  
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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.
Known history of ≥ Grade 3 hypersensitivity to a therapeutic antibody.
2.
Known history of positive serum human ADA to trastuzumab.
3.
History of Stevens-Johnson syndrome or toxic epidermal necrolysis 
syndrome.
4.
Major surgical procedure or significant traumatic injury, radiotherapy, 
chemotherapy, targeted therapy, hormone therapy (except for luteinizing 
hormone-releasing hormone (LHRH) agonists or denosumab) or other 
anticancer therapy within 21 days OR within 5 half-lives of the product, 
whichever is shorter, prior to the Cycle 1, Day 1 visit.
Note: cumulative dose of anthracycline >450 mg/m2 is prohibited.
5.
Failure to recover to Grade 0 or Grade 1 from acute non-hematologic
toxicity due to previous therapy, prior to screening (with the exception 
of alopecia).
6.
Central Nervous System (CNS) disease only.
7.
Symptomatic CNS metastases or evidence of leptomeningeal disease 
(brain MRI or previously documented cerebrospinal fluid (CSF) 
cytology).  
Previously treated asymptomatic CNS metastases are permitted provided 
that the last treatment (systemic anticancer therapy and/or local 
radiotherapy) was completed ≥ 8 weeks prior to Day 1 except usage of 
low dose of steroids on a taper (i.e. up to 10 mg on Day 1 and 
consecutive days is permissible if being tapered down).  Patients with 
discrete dural metastases are eligible.
8.
Active cardiac disease including any of the following:
Angina pectoris that requires the use of anti-anginal medication.
Ventricular arrhythmias except for benign premature ventricular 
contractions.
Supraventricular and nodal arrhythmias requiring a pacemaker or not 
controlled with medication.
Clinically significant valvular disease with documented compromise in 
cardiac function.
Symptomatic pericarditis.
Congenital long QT syndrome or a corrected QTc [QTcF] interval 
≥450 ms at Screening. 
LVEF < 50% at Screening or a history of decrease in LVEF to < 40% 
during previous treatment with HER2 targeted therapy.
9.
History of clinically significant cardiovascular dysfunction including 
any one of the following:
History of myocardial infarction (MI) or recent MI documented by 
elevated cardiac enzymes or persistent regional wall abnormalities on 
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assessment of left ventricular function within 6 months prior to Day 1.
History of documented congestive heart failure (New York Heart 
Association functional classification III-IV). 
Documented cardiomyopathy.
Uncontrolled hypertension (systolic blood pressure >180 mm Hg or 
diastolic blood pressure >100 mm Hg).
10. Active ulceration of the upper gastrointestinal tract or gastrointestinal 
bleeding.
11. Active autoimmune disease, motor neuropathy considered of 
autoimmune origin, and other CNS autoimmune disease.
12. Patients receiving concomitant immunosuppressive agents or chronic 
corticosteroids use, at study entry except in cases outlined below: 

Topical applications (e.g. rash), inhaled sprays (e.g. obstructive 
airways diseases), eye drops or local injections (e.g. intra-articular), 
or as physiologic replacement, are permitted.
13. Known human immunodeficiency virus (HIV) infection; known 
seropositive for hepatitis B surface antigen (HBsAg), or antibody to 
hepatitis C virus (anti-HCV) with confirmatory testing and requiring 
anti-viral therapy.
Note: Testing is not mandatory to be eligible.  Testing for HCV should 
be considered if the patient is at risk for having undiagnosed HCV 
(e.g., history of injection drug use).
14. Any other malignancy within 3 years prior to Day 1, with the exception 
of adequately treated in-situ carcinoma of the cervix uteri, basal or 
squamous cell carcinoma or other non-melanomatous skin cancer.
15. Active bleeding diathesis or significant anticoagulation (such as with an 
oral anti-vitamin K medication. Low-dose warfarin, aspirin, or 
equivalent, are permitted as long as the INR ≤2.0. 
16. History of thromboembolic or cerebrovascular events within the last 
6 months, including transient ischemic attack, cerebrovascular accident, 
deep vein thrombosis or pulmonary embolism.
17. Clinically significant third space fluid accumulation (i.e., ascites 
requiring tap or pleural effusion that is either requiring tap or associated 
with shortness of breath).
18. Breastfeeding or pregnant. 
19. Other concurrent severe and/or uncontrolled medical conditions 
(e.g., uncontrolled diabetes mellitus, active untreated or uncontrolled 
infection including viral and systemic fungal infections, chronic 
obstructive or chronic restrictive pulmonary disease including dyspnea at 
rest from any cause) that could cause unacceptable safety risks or 
compromise compliance with the protocol.
Study Design:
This is a first-in-human (FIH) Phase 1, multicenter, open-label study to 
evaluate the safety, tolerability, PK, pharmacodynamics (PD), 
immunogenicity, and preliminary antitumor activity of ADCT-502 used as a 
single agent in patients with advanced solid tumors with documented HER2 
expression.  The study consists of two parts.   
During Part 1 (Dose Escalation), patients will receive escalating doses of 
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ADCT-502 according to a modified continual reassessment method 
(mCRM) to determine the MTD and/or RDE.  
Patients participating in Part 2 (Dose Expansion) will have their HER2 status 
prospectively measured to be classified as either HER2-high or HER2-low 
as defined for the study and assigned to 1 of 9 groups as follows:
Group A: HER2-high breast cancer
Group B: HER2-low breast cancer
Group C: HER2-high gastric/GE cancer (and staggered HER2-low)
Group D: HER2-high bladder cancer (and staggered HER2-low)
Group E: HER2-high NSCLC (and staggered HER2-low)
Group F: Basket of 8 HER2-high solid tumor indications (SCLC, CRC, 
pancreatic, biliary tract, prostate, ovarian, endometrial, or salivary 
gland)
The proposed indication for Group C (HER2-high gastric/GE cancer) may 
be exchanged with the indication of Group D or E (HER2-high bladder 
cancer or NSCLC), or one of the indications from the basket group, 
depending on emerging data from Part 1.
Simon’s 2-Stage design will be used during Part 2.  Enrollment will be 
paused and a futility analysis performed after Stage 1.  If futility is not 
triggered, enrollment for that group will continue to Stage 2. 
Groups A, B, and C will be opened for enrollment simultaneously.  If for one 
or more of Groups A, B, or C futility is not triggered, Groups D, E, and F 
will be opened. 
If futility for the HER2-high patients enrolled in Stage 1 of Groups C, D, or 
E is not triggered, enrollment of HER2-low expressing patients in the 
respective group will be opened. 
This recruitment of HER2-low patients in indications of Groups C, D and E 
is also subject to a Simon 2-stage design.
Estimated Duration 
of Patient 
Participation and 
Study Duration:
The duration of each patient’s participation will be dependent on individual 
response to treatment and will include a Screening Period (of up to 28 days), 
Treatment Period, and Follow-up Period.  Patients may continue treatment 
until disease progression or unacceptable toxicity.
All patients will have an end of treatment (EOT) visit as soon as possible
after decision to discontinue ADCT-502 and prior to initiation of new 
anticancer treatment.  If possible, patients will have an additional follow-up 
visit 12 weeks after the last dose of ADCT-502 for collection of PK, soluble 
HER2, and ADA samples, unless a new anticancer treatment has been 
initiated.  
All patients will be followed approximately every 12 weeks after the last 
dose of study drug to collect survival information.  Follow-up for survival 
may continue for up to 2 years after treatment discontinuation.
Any patients who discontinue treatment for any reason other than disease 
progression will continue to be followed by radiographic examination every 
12 weeks until disease progression or initiation of new anticancer treatment. 
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. 
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Study duration will be dependent on overall patient tolerability and response 
to treatment.  It is anticipated that the entire study (Part 1 and Part 2) could 
be approximately 3 years from first patient treated to last patient completed.
Efficacy 
Assessments:
Computerized tomography (CT) or magnetic resonance imaging (MRI) 
scans with contrast of the chest, abdominal and pelvic area or brain scans 
(CT or MRI with contrast), and bone scans or X-ray exam if clinically 
indicated, will be performed.  For image acquisition specifications, including 
instruction in the event of allergy to contrast dye, refer to Appendix II of 
RECIST version 1.1 (Specifications for Standard Anatomical Radiological 
Imaging).
The same methods used at Baseline which identify sites of disease should be 
used uniformly for all subsequent assessments.  Response to treatment will 
be determined by the Investigator as complete response (CR), partial 
response (PR), stable disease (SD), or progressive disease (PD) according to 
RECIST version 1.1.
Pharmacokinetic, 
Pharmacodynamic, 
and Other 
Exploratory 
Assessments:
Pharmacokinetics
The PK profile of ADCT-502 (total antibody), pyrrolobenzodiazepine
(PBD)-conjugated antibody, and free warhead SG3199 will be assessed 
centrally.  The PK profile will include determination of standard PK 
parameters
(e.g., maximum concentration [Cmax], time to Cmax [Tmax], area under the 
curve [AUC]).
 
  
Safety Assessments:
The safety objective will be evaluated by summarization of AEs, SAEs, and 
changes in laboratory parameters, vital signs, ECGs, and 
MUGA/echocardiograms.  Dose interruptions, reductions, and relative dose 
intensity will also be summarized.  Adverse events will be graded according 
to CTCAE version 4.0.
Definition of DLT
A DLT is defined as any of the following events that occur during the
21-day DLT evaluation period, except those that are clearly due to 
underlying disease or extraneous causes. 
A hematologic DLT is defined as:
Event
Severity
Febrile neutropenia or neutropenic 
infection
Grade 3 or 4
Neutropenia lasting > 7 days
Grade 4
Thrombocytopenia
Grade 4 
Thrombocytopenia with clinically 
significant bleeding
Grade 3
Thrombocytopenia requiring a platelet 
transfusion
Grade 3
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Anemia
Grade 4
Anemia requiring transfusion
Grade 3
A non-hematologic DLT is defined as:
Event
Severity
Hy’s law case 
AST and/or ALT > 3x ULN and bilirubin
> 2x ULN, and without initial findings of 
cholestasis (serum alkaline phosphatase 
(ALP) activity < 2x ULN) and no other 
reason that could explain the combination 
of increased transaminases and serum total 
bilirubin, such as viral hepatitis A, B, or C, 
preexisting or acute liver disease, or another 
drug capable of causing the observed 
injury.
Hypersensitivity/infusion-related 
reaction (regardless of 
premedication)
Grade 3 or higher.  A Grade 3 
hypersensitivity / infusion-related reaction 
that resolves within 24 hours after onset 
with appropriate clinical management does 
not qualify as a DLT.
All other non-hematologic 
toxicity  
Grade 3 & 4.
The following conditions are not considered non-hematologic DLTs:
Event
Severity
Fatigue
Grade 3 for ≤ 7 days.
Diarrhea, nausea, or vomiting
Grade 3 in the absence of premedication 
that responds to therapy and improves by 
at least 1 grade within 3 days for Grade 3 
events or to ≤ Grade 1 within 7 days.
Serum lipase or serum amylase
Grade 3 for ≤ 7 days if without clinical 
signs or symptoms of pancreatitis.
Electrolyte abnormalities
≤ Grade 3 which normalize within 48 hrs 
(with or without medical intervention) and 
which do not manifest themselves 
clinically; in such instance, a follow-up 
sample MUST be taken within 48 hrs to 
check whether such normalization has 
occurred.
Investigational 
ADCT-502 is a sterile formulation containing PBD-conjugated humanized 
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Product, Dosage, 
and Mode of 
Administration:
monoclonal IgG1 antibody (DAR 1.8 ±0.3) and engineered trastuzumab 
(DAR = 0).  ADCT-502 is formulated as a sterile liquid at 5 mg/mL in a 
10 mL glass vial (2.0 mL nominal fill).  The drug product is designed to 
deliver 10 mg ADCT-502 per vial and is intended for intravenous infusion 
following dilution in 0.9% sodium chloride
Patients will receive a 1-hour IV infusion of ADCT-502 on Day 1 of each
3-week (21-day) cycle.  If ADCT-502 is well tolerated after the first cycle, 
the infusion duration may be shortened to 30 minutes for subsequent cycles 
for that patient at the discretion of the Investigator.
Part 1
(Dose-Escalation 
Design):
Each cohort will consist of 2 patients.  There will be a 24-hour observation 
before enrolling the second patient at Dose Level 1.  The DLT observation 
period at each dose level is 1 cycle (3 weeks), after which it will be 
determined whether to escalate to the next dose level, stay at the current dose 
level, or de-escalate to the previous dose level for the next cohort.  
There will be no de-escalation from Dose Level 1.  Intrapatient dose 
escalation is not permitted.
Dose escalation is not permitted unless two or more patients have complete 
DLT information through the first cycle in any given dose level.  
Dose escalation will be determined by using a mCRM with a target DLT rate 
of 30% and an equivalence interval of 20% to 35%, and with dose
escalation-with-overdose-control (EWOC) and no dose skipping. 
The mCRM will be implemented in Part 1 under the oversight of a Dose 
Escalation Steering Committee (DESC).  The DESC will confirm each 
escalating dose level after reviewing all available safety data.  The PK data 
from patients in that dose level and prior dose levels may also inform DESC 
decision making.  The DESC may halt dose escalation prior to determining 
the MTD based on emerging PK, PD, toxicity, or response data. 
Additional patients may be included at any dose level to further assess the 
safety and tolerability if at least 1 patient in the study has achieved a partial 
response or better, or if further evaluation of PK or PD data is deemed 
necessary by the DESC to determine the RDE.
Furthermore, to better understand the potential efficacy of ADCT-502 in an 
indication approved for treatment with HER2 targeted antibodies, up to 3 
additional breast cancer patients who have previously been treated with an 
approved HER2 targeted therapy may be enrolled per cohort at given dose 
levels ≥60 µg/kg determined by the mCRM model to be safe.
Dose escalation will be stopped after the mCRM has assigned 3 cohorts 
consecutively to the same dose level. 
If the MTD is not reached, the recommended dose for expansion (RDE) will 
be determined.
Sample Size:
Part 1: The number of patients will depend upon the toxicities observed, 
the number of dose-level cohorts evaluated, and the number of dose-level 
cohorts expanded as the study progresses; approximately 30 patients are 
estimated. Overall sample size will be guided by the mCRM design.
Part 2: During the dose expansion phase of the study, up to 28 patients 
per each dose expansion cohort will be enrolled.  Simon's two-stage design 
will be used.  The null hypothesis that the true response rate is 7.5% will be 
tested against a one-sided alternative.  In the first stage, 13 patients will be 
enrolled.  If there are one (1) or fewer responses in these 13 patients, the 
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cohort will be closed. Otherwise, 15 additional patients will be enrolled for 
a total of 28 patients.  The null hypothesis will be rejected if five (5) or more 
responses are observed in these 28 patients. This design yields a type I error 
rate of 0.05 (one-sided) and power of 80% when the true response rate is 
25%. 
In the basket group, up to 24 patients will be enrolled, with no more than 
3 patients from each indication.  If responses are observed, plans are 
described in the Interim Analysis [Part 2]).
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Group C:
Gastric and GE-Junction
(HER2-high)
n=13
Group A:
mBC HER2-high
n=13
Group B:
mBC HER2-low
n=13
Group D:
Bladder (HER2-high)
n=13
2/13
2/13
2/13
Same n=15
Same
n=15
Same
n=15
DE
n=30
RDE
HER2-low, n=13
Same, 
n=15
Same, n=15
2/13
Same, 
n=15
2/13
HER2-low, n=13
2/13
Same, n=15
Same, 
n=15
HER2-low, n=13
2/13
Group F:
Basket (HER2-high)
n=24
Group E:
NSCLC (HER2-high) n=13
2/13
Figure 1: ADCT-502-101 Study Schematic
Decision intra-trial
Decision based on one 
condition true
Decision based on one of 
several options being true
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Schedule of Events
Table 1: Schedule of Events
Screening
Cycle 1
Cycle 2
Cycles
3, 4, 5, etc.
EOT
12-Week 
Follow-up1
Long-term 
Follow-up
Days
–28 to –1
Day
1
Day
2
Days
3 and 5
Day
8
Day
15
Day
1
Day
2
Days
3 and 5
Day
8
Day
15
Day
1
Day
82
Informed consent3
X
Demography4
X
Medical/Cancer 
history5
X
Available tumor 
tissue collection6
X
Physical 
examination7
X
X8
X
X
X8
X
X
X8
X
ECOG PS9
X
X
X
X
X
Height
X
Weight
X
X
X
X
X
Vital signs10
X
X
X
X
X
X
X
X
X
X
X
X
X
X
12-lead ECG
(triplicate) 11
X
X
X
X
X
X
X
ECHO or MUGA12
X
X
X
X
Disease 
assessments13
X
X14
X15
X16
β-HCG17
X
X
X18
X
CBC with 
differential19
X
X
X
X
X
X
X
X
X
X
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Screening
Cycle 1
Cycle 2
Cycles
3, 4, 5, etc.
EOT
12-Week 
Follow-up1
Long-term 
Follow-up
Days
–28 to –1
Day
1
Day
2
Days
3 and 5
Day
8
Day
15
Day
1
Day
2
Days
3 and 5
Day
8
Day
15
Day
1
Day
82
Coagulation19
X
X
X
X
X
Chemistry19
X
X
X
X
X
X
X
X
X
X
Urinalysis19
X
X
X
X
X
PK sample20
X
X
X
X
X
X
X
X
X
X
X
X
X
ADA sample20
X
X
X
X
X
X
sHER2 sample20
X
X
X
X
X
 
Concomitant 
medications21
X
Adverse events22
X
ADCT-502 
administration23
X
X
X
1st New anticancer 
treatment24
X
X
Survival 
X25
Visit Scheduling Windows: For scheduling purposes, the following allowances will be made for Visits:
Day 1: Cycles 2, 3, 4, etc. (excluding Cycle 1, Day 1): ± 3 days
Days 8 and 15: ± 1 day
EOT: As soon as possible after decision to discontinue the study drug AND prior to initiation of new anticancer treatment
12-Week Follow-up: ± 7 days after last dose of study drug
Long Term Follow-Up (approx. every 12 weeks after last dose): ± 4 weeks
Refer to Section 10.2 for details of CBC, coagulation, chemistry, and urinalysis panels. 
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1
If possible, collection of pharmacokinetic (PK), soluble HER2, and anti-drug antibodies (ADA) samples will take place at the follow-up visit 12 weeks after 
the last dose of ADCT-502, unless a new anticancer treatment has been initiated.  
2
After completion of 6 treatment cycles, the Day 8 visit is not required unless clinically indicated.
3
A signed and dated Institutional Review Board (IRB) /Independent Ethics Committee (IEC) approved informed consent form (ICF) obtained prior to 
performing any study evaluations.  Results (e.g., from laboratory tests or radiographic evaluations, etc.) obtained prior to the date of informed consent, 
but within the allowed timeframe for Screening may be used for determination of patient eligibility only if obtained as part of the patient’s standard of care. 
Patients must meet entry criteria at Screening, and should continue to meet entry criteria at Cycle 1 Day 1 pre-dose.  However, clinically acceptable 
variations, if they are in the opinion of the Investigator not compromising patient safety, may be allowed on that day.
4
Demography includes collection of date of birth, sex, and race.
5
Medical/Cancer history to include a complete history of all surgeries, significant diagnoses, and all cancer treatments. Results of testing for genetic 
abnormalities associated with the patient’s tumor type (such as BRCA1, for example) will be recorded.
6
During Part 1, ship tissue sample to the central laboratory for retrospective analysis of HER2.  An FFPE block (or slides) from any biopsy since initial 
diagnosis is acceptable, but if several are available, the most recent sample is preferred.  Either tumor tissue block or freshly cut unstained slides (minimum 
7; 10 preferred) is acceptable. During Part 2, ship tissue sample to the central laboratory for prospective analysis of HER2 to confirm eligibility.
7
Physical examinations will include a complete review of body systems.  Investigators should be cognizant of potential toxicities for ADCT-502 and similar 
compounds as described in the Investigator’s Brochure (IB) and refer unexplained findings or abnormalities to a specialist accordingly (e.g., ocular toxicity 
to an ophthalmologist, etc.).
8
A physical examination does not need to be repeated if performed within 72 hours prior to Day 1 of any cycle.
9
Refer to Appendix 18.2 for definitions of Eastern Cooperative Oncology Group (ECOG) Performance Status grades.
10
Refer to Table 2 for timing of vital sign measurements. Vital sign measurements include arterial blood pressure, heart rate, respiratory rate, and body 
temperature.  
11
The Fridericia formula for rate correction of QT intervals should be used for all patients throughout the study.  Refer to Table 2 for timing of 
electrocardiogram (ECG) in relation to PK sample collection.  
12
Perform multiple-gated acquisition (MUGA) scan or echocardiogram (ECHO) at Screening, after Cycle 1, every 3 cycles (i.e., every 9 weeks), and at 
End of Treatment (EOT). All patients will have measurements of left ventricular ejection fraction (LVEF) via a consistent method (MUGA scan or ECHO), 
regardless of symptoms.  If the LVEF is reported as a range, the average should be taken.  
13
Screening (Baseline) imaging (computerized tomography [CT] or magnetic resonance imaging [MRI]) must be performed within 4 weeks prior to Day 1,
Cycle 1.  See Section 10.3 for details.
14
Disease assessments will be conducted every 2 cycles ± 1 week for the first 2 time points (e.g., after Cycles 2 and 4), and every 4 cycles thereafter 
(i.e., approximately every 12 weeks).  Patients with metastatic breast cancer (MBC) enrolled in Groups A and B will have disease assessments every 
4 cycles.
……………………………………………………………………………………Footnotes continue on next page
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15
Disease assessments do not need to be repeated at EOT if last assessment was performed within 6 weeks prior to the EOT visit, or if patient already has 
documented progression of disease (PD).   
16
Any patients who discontinue treatment for any reason other than disease progression will continue to be followed by radiographic examination every 12 
weeks until disease progression or initiation of new anticancer treatment.  Once the final efficacy analysis for progression-free survival (PFS) is performed 
(Part 2), the frequency of tumor response assessment for patients remaining under treatment may be further decreased and/or performed according to 
standard of care.
17
Blood or urine pregnancy test for women of childbearing potential.  For eligibility confirmation, a negative blood pregnancy test is required; the test does 
not need to be repeated if it was obtained within 7 days prior to Cycle 1, Day 1.
18
A pregnancy test will be repeated at Day 1 of every other cycle (every 6 weeks) and at EOT.
19   
Does not need to be repeated if performed within 72 hours prior to Day 1 of any cycle.
20
Refer to Table 2 for timing of collection for PK and PD samples.  PK and/or ADA samples may be collected at other time points if clinically indicated, e.g., 
at the time of other significant AE that are at least possibly related to ADCT-502.
21
Concomitant medications will include prescription and/or over-the-counter medication, herbal or naturopathic products within 14 days prior to Cycle 1, 
Day 1, during the treatment period, and within 30 days after the last dose of study drug, and will be recorded in the electronic case report form (eCRF).
22
For all patients, collection of adverse events (AEs) and serious adverse events (SAEs) will continue for 30 days after the last dose of study drug or initiation 
of new anticancer treatment.
23  
Volume of study drug administration should be recalculated if there is a weight increase or decrease ≥10% compared to the weight used to calculate 
administration at Cycle 1, Day 1.  
24
The first new anticancer treatment should be documented for all patients.
25
After documentation of disease progression or start of new treatment, all patients will be followed approximately every 12 weeks after the last dose of study 
drug to collect survival information.  Follow-up for survival may continue for up to 2 years after treatment discontinuation. 
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List of Abbreviations
Abbreviation
Definition
ADA
anti-drug antibodies
ADC
antibody drug conjugate
ADL
activities of daily living
anti-HCV
antibody to hepatitis C virus 
ASCO
American Society of Clinical Oncology
AUC
area under the concentration versus time curve  
β-HCG
beta human chorionic gonadotropin
BID
twice a day (bis in die)
BSA
body surface area  
CAT or CT
computerized tomography 
CBC
complete blood count 
cfDNA
circulating free DNA 
CLIA
Clinical Laboratory Improvement Amendments
Cmax
maximum serum concentration
CNS
central nervous system 
CR
complete response
CRC
colorectal cancer
CSF
cerebrospinal fluid 
DAR
drug to-antibody ratio 
DCR
disease control rate   
DESC
dose escalation steering committee  
DLT
dose limiting toxicities 
DOR
duration of response  
DSMB
data safety monitoring board 
ECHO
echocardiogram 
ECOG
Eastern Cooperative Oncology Group 
ECOG PS
Eastern Cooperative Oncology Group Performance Status
eCRF
electronic case report form
EGFR
epidermal growth factor receptor
EOI
end of infusion
EOT
end of treatment
EWOC
escalation with overdose control 
FDA
Food and Drug Administration
FIH
first–in-human 
FISH
fluorescence in situ hybridization
FFPE
formalin-fixed paraffin-embedded 
HBsAg
hepatitis B surface antigen 
HER2/neu receptor
human epidermal growth factor receptor-2
HED
human equivalent dose  
HIV
human immunodeficiency virus
HNSTD
highest non-severely toxic dose 
HR
hazard ratio
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G/GE
gastric/gastroesophageal 
GLP
good laboratory practices  
IB
Investigator’s Brochure 
IHC 
immunohistochemistry
ISH
in situ hybridization
IV
intravenous  
LHRH
luteinizing hormone-releasing hormone
LVEF
left ventricular ejection fraction 
mAb
monoclonal antibody 
MBC
metastatic breast cancer 
mCRM
modified continual reassessment method
MedDRA
Medical Dictionary for Regulatory Activities
MI
myocardial infarction 
mPFS
median progression-free survival 
MRI
magnetic resonance imaging
MTD
maximum tolerated dose  
MUGA
multigated acquisition 
mOS
median overall survival
NCI CTCAE
National Cancer Institute Common Terminology Criteria for 
Adverse Events
NGS
next generation sequencing
NSCLC
non-small cell lung cancer 
ORR
overall response rate  
OS
overall survival 
PBD
pyrrolobenzodiazepine 
PD
pharmacodynamics 
PDX
patient derived xenograft 
PFS
progression-free survival
PK
pharmacokinetic 
PO
per os
PS
performance status
RDE
recommended dose for expansion
RECIST
Response Evaluation Criteria in Solid Tumors
SAE
serious adverse event
SCLC
small cell lung cancer 
sHER2
soluble HER2 
SUSARs
Suspected Unexpected Serious Adverse Reactions
TEAE
treatment-emergent adverse event
Tmax
time to Cmax
U 
United States
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1
Introduction and Background
1.1 HER2 and HER2 Targeting Therapies
The human epidermal growth factor receptor-2 (HER2/neu receptor), a member of the 
epidermal growth factor family of receptor tyrosine kinases (including EGFR/ErbB1/HER1, 
ErbB3/HER3, and HerbB4/HER4), is a 185 kDa transmembrane glycoprotein, which 
provides signal transduction for cell proliferation and differentiation. The HER2 monomeric 
protein has three main regions: the extracellular amino-terminal region comprising four 
subdomains (I-IV), the hydrophobic transmembrane domain and the carboxy-terminal kinase 
domain comprising the juxtamembrane domain, tyrosine kinase and C-terminal tail with 
autophosphorilation sites.  HER2 has no known ligand, and it is activated by 
homodimerization or heterodimerization with other member of the ERBB family 
(Omar, 2015).
HER2 is over-expressed/amplified in several solid tumor types (Yan, 2015).  Targeted HER2 
therapies are approved for the treatment of breast and gastric/esophageal cancers that over-
express or are gene-amplified for HER2. 
Trastuzumab (Herceptin®), a humanized monoclonal antibody (mAb), binds to the HER2 
receptor and downregulates its expression on the cell surface. Trastuzumab is approved in 
the United States (US) and in Europe for the treatment of HER2-positive breast cancer in the 
adjuvant and metastatic settings, defined as HER2 IHC (immunohistochemistry) 3+ or 
IHC 2+/ fluorescence in-situ hybridization (FISH)-amplification (Herceptin® [trastuzumab]
US Prescribing Information, 2016). In the metastatic setting, trastuzumab is used in 
combination with chemotherapy regimens and/or in combination with pertuzumab in the 
first-line setting (CLEOPATRA study) (Swain, 2015) followed by ado-trastuzumab 
emtansine (T-DM1) after relapse or disease progression. Despite improved patient outcomes, 
acquired resistance affects the majority of patients previously exposed to trastuzumab, and 
the molecular mechanisms conferring trastuzumab resistance are likely to be multifactorial.
In addition, trastuzumab is indicated in combination with cisplatin and capecitabine or
5-fluorouracil for the treatment of patients with HER2 overexpressing metastatic gastric or 
gastroesophageal junction adenocarcinoma, who have not received prior treatment for 
metastatic disease (ToGA trial) (Bang, 2010). Trastuzumab-based therapy significantly 
improved median overall survival (mOS) compared with the chemotherapy alone 
(hazard ratio [HR] 0.74; p=0.0046 and mOS: 13.8 months versus 11.1 months). 
However, acquired resistance to trastuzumab usually limits the duration of response to this 
treatment despite its improvement over the chemotherapy alone (duration of response
[DOR]) 6.9 months versus 4.8 months). 
Ado-trastuzumab emtansine (Kadcyla®), also known as T-DM1, is an antibody-drug 
conjugate of trastuzumab containing a potent microtubule inhibitor, DM1 (a derivative of 
maytansine) approved in the US in 2013 for the treatment of HER2-positive metastatic breast 
cancer for patients who had previously been treated with trastuzumab and a taxane 
chemotherapy (EMILIA study) (Verma, 2012). Median progression-free survival (mPFS) 
was 9.6 months with T-DM1 versus 6.4 months with lapatinib plus capecitabine (HR for 
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progression or death from any cause, 0.65; P<0.001), and mOS at the second interim analysis 
crossed the stopping boundary for efficacy (30.9 months versus 25.1 months; HR for death 
from any cause, 0.68; P<0.001). Ado-trastuzumab emtansine (T-DM1) has also demonstrated 
the potential to prolong PFS in the third-line setting based on results from the Phase 3 
TH3RESA study (Krop, 2014) (mPFS 6.2 months for T-DM1 versus 3.3 months for 
physician’s choice). However, results from the Phase 3 MARIANNE study (Perez, 2016) 
indicate that median PFS in the frontline setting for patients with advanced breast cancer 
treated with T-DM1 was non-inferior, but not superior, compared to those treated with 
trastuzumab plus a taxane-based chemotherapy.  Ado-trastuzumab emtansine is often 
accompanied by unacceptable thrombocytopenia and hepatotoxicity at doses higher than the 
approved regimen (3.6 mg/kg every 3 weeks), as well as reductions in left ventricular 
ejection fraction (LVEF), and peripheral sensory neuropathy. In preclinical gastric cancer 
models, T-DM1 has shown more potent antitumor activity than trastuzumab (Barok, 2011). 
However, the multicenter adaptive phase 2/3 of T-DM1 in HER2-positive patients with 
unresectable locally advanced or metastatic gastric or gastroesophageal (GE) junction cancer
who progressed during or after first-line fluoropyrimidine plus platinum therapy with or 
without HER2–targeted therapy did not show a benefit of T-DM1 vs. taxane based 
chemotherapy (Kang, 2016).
The third HER2 targeting mAb based therapeutic modality currently approved in the 
oncology setting, is pertuzumab (PERJETA®). Pertuzumab is a HER2/neu receptor 
antagonist indicated for use in combination with trastuzumab and docetaxel for treatment of 
patients with HER2-positive metastatic breast cancer (MBC) who have not received prior 
anti-HER2 therapy or chemotherapy for metastatic disease. It is also approved in 
combination with trastuzumab and docetaxel as neoadjuvant treatment of patients with 
HER2-positive, locally advanced, inflammatory, or early stage breast cancer as part of a 
complete treatment regimen for early breast cancer (PERJETA ® US Prescribing Information, 
2012).
In the Phase 3 randomized trial (CLEOPATRA study) (Swain, 2015) of pertuzumab plus 
trastuzumab and docetaxel vs. placebo plus trastuzumab and docetaxel, independent review 
indicated that the pertuzumab-treated group demonstrated an increase in mPFS of 6.3 months 
(18.7 months in the pertuzumab -treated group vs. 12.4 months in the placebo-treated group). 
Approximately 20% of all cases of breast cancer have HER2 gene amplification and high 
levels of HER2 protein expression that predict the response to trastuzumab.  Gastric cancer is 
the fourth most commonly diagnosed cancer and the second most common cause of
cancer-related deaths worldwide.  HER2 over-expression/amplification occurs in 7–34% of 
gastric cancer and is associated with poor prognosis. While trastuzumab based therapy is the 
standard of care in both metastatic breast and gastroesophageal cancer, the known prevalence 
of HER2 over-expression/amplification across tumor types in general suggests that other 
patient populations may benefit from treatment with HER2 targeted agents. A number of 
smaller studies or case reports have demonstrated this, for example in patients with colorectal 
cancer (CRC) (Sartore-Bianchi, 2016; Harder, 2012; Javle, 2015; de Bono, 2007; Bookman, 
2003; Fleming, 2010; Oudard, 2015; Limaye, 2013).
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In one of the largest studies to date, (Yan, 2015) HER2 expression status in diverse cancers 
was examined in approximately 38,000 patients. Indications planned for inclusion in this 
protocol were found to be positive in the range of 0.6% (prostate) to 12.4% (bladder 
carcinoma). Since these percentages of HER2 positive patients refer to what is termed 
HER2-high in this protocol, the percentage of patients anticipated to ultimately benefit from 
ADCT-502 may be higher, as patients with HER2-low expressing tumors were not evaluated 
but will be included in this protocol in a staggered fashion, depending on efficacy results in 
HER2-high expressing patients.
In certain malignancies, principally non-small cell lung cancer (NSCLC), the HER2 protein 
can be constitutively activated through genetic mutations; initial efficacy data suggest that 
HER2 targeting modalities can also be of therapeutic benefit for such patients 
(Mazieres, 2013).
1.2 Description of ADCT-502
ADCT-502 is an antibody drug conjugate (ADC) composed of an engineered version of the 
humanized monoclonal antibody trastuzumab, directed against the human HER2 receptor, 
site-specifically conjugated to SG3199, a pyrrolobenzodiazepine (PBD) dimer cytotoxin, 
through a protease-cleavable valine-alanine linker. 
 
ADCT-502 specifically binds to HER2, and once internalized, releases the PBD dimer to 
allow cross-linking of DNA and eventually trigger cell death. ADCT-502 has demonstrated
potent and specific in vitro and in vivo antitumor activity in 
 with differing levels of HER2 expression. 
1.3 Nonclinical Efficacy and Toxicology of ADCT-502
In vitro studies support a mechanism of action whereby ADCT-502 binds to HER2, 
internalizes, and releases its cytotoxic payload. In preclinical in vivo xenograft experiments
(including patient derived xenograft [PDX] models), ADCT-502 
 
The efficacy of ADCT-502 in these models is due 
to HER2-mediated delivery of the PBD cytotoxin SG3199. 
ADCT-502
 
 
 
 
.
Additional details may be found in the current ADCT-502 Investigator’s Brochure (IB).
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2
Rationale
2.1
Study Rationale and Purpose
Three mAb-based therapies targeting HER2 are currently licensed across 2 indications, 
namely breast cancer and/or gastric/GE junction cancers. Use of any of these agents is 
limited to patients whose tumors are defined as HER2 positive, which in this protocol is 
specified as HER2-high. Until HER2 targeted therapies became available, HER2 expression 
was associated with worse prognosis compared to patients whose tumors did not
over-express HER2.
Consequently, there is unmet medical need in those indications where HER2 is expressed at 
high levels, but for which the current treatments are not licensed.  Also, there is high unmet 
medical need in breast and gastric/GE junction cancers in which HER2 expression is 
observed but below the defined thresholds for HER2 targeted therapy.
In addition, high unmet medical need exists in the licensed indications once current HER2 
targeted therapy is no longer effective and patients relapse, or which are primary resistant to 
this therapeutic approach. For example, a substantial number of patients develop resistance 
to trastuzumab or T-DM1 (Chung, 2013; Barok, 2011).   
Finally, trastuzumab-based regimens are associated with significant side effects, largely 
because of the cytotoxic chemotherapy component (Hernández-Blanquisett, 2016; 
Chung, 2013; Arteaga, 2011). The effects of many of these drugs are short-lived, and a 
significant proportion of these patients still relapse and die of breast cancer.  Thus, promising 
new approaches are being developed, such as antibodies linked to cytotoxic moieties, to 
enhance the risk-benefit ratio of drugs.
The mechanism of action and preclinical data of ADCT-502 supports its use in patients with 
relapsed or refractory metastatic breast and gastric cancer who have been previously treated 
with trastuzumab/T-DM1. Given the substantial prevalence of HER2 expression in a range 
of other advanced cancers, including NSCLC, bladder, biliary tract and ovarian cancer,
ADCT-502 will be evaluated as an anticancer treatment in patients with such tumor types for 
which there is published clinical evidence of HER2 expression.
Results of preclinical studies in PDX models suggest that ADCT-502 may have potent 
clinical activity in both groups of patients, those with HER2-positive/high tumors as well as 
those with HER2 low-expressing and/or heterogeneous tumors, the latter being a patient 
population currently not served by approved HER2 targeting agents at all.
2.2
Rationale for Study Design
The dose escalation portion of this Phase 1, open-label, dose finding study is designed to 
establish a safe and tolerated dose of ADCT-502 for further testing in patients with solid 
tumors expressing HER2 (high and low expressers). Up to nine (9) groups are planned in the 
expansion portion to further characterize the safety and evaluate preliminary efficacy.  
As indicated in Section 4.1, the enrollment of the groups is staggered in order to allow for an
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evaluation of the therapeutic potential in a limited number of patients with breast and 
GE cancer prior to exposing patients with other tumor types to ADCT-502.    
Part 1 will utilize a modified continual reassessment method (mCRM) to guide dose 
escalation and estimate the maximum tolerated dose (MTD) and/or determine the 
recommended dose for expansion (RDE) for ADCT-502. The mCRM and escalation with 
overdose control (EWOC) enables incorporation of available prior information and updates 
the model parameters based upon new information about observed dose limiting toxicities 
(DLT) seen in the clinical study. The dose recommended by the model at any stage of the 
trial is based on the entire history of all available DLT information from previous cohorts as 
opposed to only the number of DLTs observed in the last group of patients.  Part 2 will utilize 
the Simon two-stage optimal design with a futility stop and staggered enrollment to minimize 
exposure of patients when evidence for efficacy is weak.  
2.3
Starting Dose Justification
The starting dose of ADCT-502 in this study is based on the intravenous (IV) 
Good Laboratory Practice (GLP) toxicology study with once every 3 weeks dosing.
Based on the ADCT-502-related effects observed in this GLP study, 
 
 
The starting dose for an ADC is based on the conversion of the HNSTD (
to a 
Human Equivalent Dose (HED) based on body surface area (BSA) through multiplication 
with a species specific factor (
), which is followed by division 
with a standard safety factor of
 
 
2.4
Plans and Justification for Provisional Dose Levels
Overall, approximately 10 dose levels are planned. An initial increase of 100% for lower 
dose levels is foreseen, resulting in provisional dose levels of 30, 60 and 120 µg/kg. 
Midstage escalation is somewhat more conservative to account for potential low-grade 
toxicity to become apparent, with dose level increases of 50%, 33% and 25%, resulting in 
doses of 180, 240 and 300 µg/kg. Subsequent levels are determined by a fixed dose increase 
of 50 µg/kg (i.e., 300, 350, 400, 450 and 500 µg/kg) as the highest dose level to be tested, 
if allowed by the mCRM with EWOC. The default dosing regimen is once every 3-week 
dosing.  Clinical and pharmacokinetic (PK) data will be reviewed on an ongoing basis and 
may provide evidence to support interim dose levels. In addition, or as an alternative to
decreasing doses to interim dose levels, the dosing interval may be extended (but not 
shortened), for example, to dosing every 4, 5 or 6 weeks instead of every 3 weeks. Once the 
dose interval is changed or an intermediate dose not predefined in the mCRM model is used, 
3+3 design may be used for future dose escalation. One situation in which such approach 
may be advantageous is drug accumulation; implementation will need DESC approval 
(DESC, see Section 4.6.1) and may affect both ongoing patients as well as new cohorts.
Similarly, it is at the discretion of the DESC to modify the dosing regimen that mandates 
omitting dosing of every n-th cycle, e.g. every 3rd cycle. Note: Scheduled visits will be kept, 
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except when C2 dosing is skipped; in that case C2D2-D5 would be omitted (respective 
assessment will not be done). This approach may be beneficial in balancing efficacy and 
adverse events. The cumulative dose of ADCT-502 in such a revised regimen can only be less 
than or equal to the cumulative dose of a dose-level that has been tested and found to be safe 
per mCRM.
3
Study Objectives and Endpoints
3.1
Objectives
3.1.1 Primary Objectives
Evaluate safety, tolerability, and determine the MTD and/or RDE of single agent 
ADCT-502 in patients with advanced solid tumors with known HER2 status (IHC ≥1+ 
or HER2 amplified/mutated) (Part 1).
Further evaluate safety and tolerability at the dose level determined in Part 1 in patients 
with advanced solid tumors including breast cancer, lung, gastroesophageal, and 
bladder cancer or a basket of other solid tumors known to express HER2
(HER2-high or HER2-low status confirmed prospectively for study entry) (Part 2).
3.1.2 Secondary Objectives
Evaluate the preliminary antitumor activity of ADCT-502.
Characterize the PK profile of ADCT-502.
Determine the immunogenicity of ADCT-502.
 
3.2
Endpoints
3.2.1 Primary Endpoints
Frequency and severity of DLTs (Part 1 only), adverse events (AEs), serious adverse 
events (SAEs), laboratory abnormalities, physical examinations, ECOG performance 
status, vital signs, and 12-lead ECGs.
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3.2.2 Secondary Endpoints
Overall Response Rate (ORR), Disease Control Rate (DCR), Duration of Response 
(DOR), PFS, and OS.
Determination of PK parameters for ADCT-502 (area under the concentration versus 
time curve (AUC) of total antibody, (drug to-antibody ratio [DAR] ≥0),
PBD-conjugated antibody (DAR ≥1), and free warhead SG3199).
Anti-drug antibody (ADA) titers to ADCT-502 before, during, and after treatment with 
ADCT-502.
 
 
4
Study Design
4.1
Overview 
This is a first-in-human (FIH) Phase 1, multicenter, open-label study to evaluate the safety, 
tolerability, PK, pharmacodynamics (PD), immunogenicity, and preliminary antitumor 
activity of ADCT-502 used as a single agent in patients with advanced solid tumors with 
documented HER2 expression.  The study consists of two parts (see Figure 1).   
During Part 1 (Dose Escalation), patients will receive escalating doses of ADCT-502 
according to a mCRM to determine the MTD and/or RDE.  
Patients participating in Part 2 (Dose Expansion) will have their HER2 status prospectively 
measured to be classified as either HER2-high or HER2-low as defined for the study and 
assigned to 1 of 9 groups as follows:
Group A: HER2-high breast cancer
Group B: HER2-low breast cancer
Group C: HER2-high gastric/GE cancer (and staggered HER2-low)
Group D: HER2-high bladder cancer (and staggered HER2-low)
Group E: HER2-high NSCLC (and staggered HER2-low)
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Group F: Basket of 8 HER2-high solid tumor indications (SCLC, CRC, pancreatic, 
biliary tract, prostate, ovarian, endometrial, or salivary gland)
The proposed indication for Group C (HER2-high gastric/GE cancer) may be exchanged with 
the indication of Group D or E (HER2-high bladder cancer or NSCLC), or one of the 
indications from the basket group, depending on emerging data from Part 1.
Simon’s 2-Stage design will be used during Part 2.  Enrollment will be paused and a futility 
analysis performed after Stage 1 (see Section 12.2, Interim Analysis [Part 2]). If futility is 
not triggered, enrollment for that group will continue to Stage 2. 
Groups A, B, and C will be opened for enrollment simultaneously. If for one or more of 
Groups A, B, or C futility is not triggered, Groups D, E, and F will be opened. 
If futility for the HER2-high patients enrolled in Stage 1 of Groups C, D, or E is not triggered, 
enrollment of HER2-low expressing patients in the respective group will be opened.
This recruitment of HER2-low patients in indications of Groups C, D and E is also subject to 
a Simon 2-stage design.
4.2
Patient Selection and Evaluation of HER2 
Expression/Amplification/Mutation
Five (5) types of patients, based on HER2 expression levels and mutations, are selected in 
this FIH study of ADCT-502:
1. Patients with indications and HER2 expression levels that qualified them for (prior) 
treatment with trastuzumab and/or ado-trastuzumab emtansine, e.g., HER2 positive BC 
and HER2 positive G/GE cancer.
2. Patients with BC or G/GE cancer with HER2 expression that is present, but at a level 
that is below the threshold qualifying them for Item Number 1.
3. Patients with HER2 expression levels equivalent to Item Number 1, but who have a 
tumor type other than BC or G/GE cancer (NSCLC, small cell lung cancer [SCLC], 
CRC, bladder, pancreatic, biliary tract, prostate, ovarian, endometrial, and salivary gland 
cancer).
4. Patients from the same indication list as in Item Number 3, except with HER2 
expression levels present but lower than that, i.e. equivalent to expression levels in Item 
Number 2.
5. Patients with 1 of the 12 indications mentioned in Items 1–4 who have been shown to 
possess a HER2 hotspot mutation; they are either classified as HER2-high if a 
concomitant amplification was demonstrated (or if they fulfill HER2-high criteria as per 
below definition), otherwise they are classified as HER2-low. Patients with such HER2
genetic alteration pre-defined prior to study enrollment and not belonging to 1 of the 12 
indications may be included in the dose escalation part after sponsor agreement.
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HER2 status will be tested by IHC (HercepTest, Dako, Denmark) and scored as 0, 1+, 2+, or 
3+, and/or FISH (HER2 FISH pharmDx, Dako).  HER2 amplification testing may be 
performed according to applicable in situ hybridization (ISH) methods as described in the 
ASCO guidelines (e.g., amplification testing is not limited to FISH). Amplification testing 
can also be done via NGS (see below).
A HER2-high patient is defined as IHC 3+, or IHC 2+ with FISH amplification.  
This definition is consistent with the approved indications for trastuzumab and
ado-trastuzumab emtansine [T-DM1] (Kadcyla) based therapy. 
A HER2-low patient is defined as IHC 1+, or IHC 2+ without FISH amplification.
Note: patients with IHC 0 / IHC 1+ with amplification is HER2-high for study purposes; a 
patient with IHC 3+ with negative amplification results is HER2-low for study purposes.
Mutational hotspots indicate selective pressure across a population of tumor samples
(Chang, 2016). Therefore, even if not formally demonstrated for each instance, it is plausible 
to assume that such mutational hotspots in HER2 signify expression of the protein, at least at 
HER2-low levels, and thus ADCT-502 should be beneficial as per pre-clinical data in low-
expressing HER2 models. Indeed, it was formally demonstrated that HER2 somatic 
mutations are being expressed, at the RNA level for a subset of mutations listed in the 
appendix (Bose, 2013).
Furthermore, Mazieres, 2013, has published supporting evidence with other HER2 targeting 
agents in a population with HER2 mutations; hence, such patients are allowed into the study.
More recently, also HER2 amplification status was shown to be reliably determined by 
hybridization capture-based NGS methods; e.g., NGS fold change > 1.8 was equivalent to 
FISH > 2.0 (Ross, 2017).
Therefore, patients with results available from next generation sequencing (NGS) from a 
Clinical Laboratory Improvement Amendment (CLIA) certified laboratory will be assigned 
to these groups as follows:
For Part 1:
HER2 gene amplification irrespective of mutational status: HER2-high.
HER2 mutated in the absence of amplification: HER2-low.  Refer to Appendix 18.3 for 
genetic changes that constitute a mutation for purposes of this study.
Irrespective of NGS results, HER2 expression status will be confirmed retrospectively in a 
central laboratory.
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For Part 2:
Assignment of HER2-high or –low status via NGS (as described above) must be 
prospectively confirmed centrally by IHC and FISH (if applicable).
Patients in Part 2 must have their HER2 status measured prospectively for study entry and be 
classified as either HER2-high or HER2-low as defined for the study.
The different level of scrutiny applied to HER2 testing (historic local vs. prospective central, 
allowing defined HER2 mutations as a proxy for HER2 expression during dose escalation) 
corresponds to the different goals of the two phases of the study: Part 1 being primarily 
driven to establish a safe dose for expansion, and Part 2 assessing both tolerability as well as 
initial signs of efficacy.
4.3
Number of Patients
During Part 1, approximately 30 patients may be treated, depending on safety observations 
and number of dose levels tested.  
In Part 2, the total number of patients will be determined by the number of responses for each 
tumor type stratified by the level of HER2 expression. Initially, 3 groups (Groups A, B, and 
C) with 13 patients in each group will be enrolled (39 patients).  Depending on efficacy 
signals, up to approximately 248 patients across 9 different groups could be enrolled
(i.e., between approximately 39 and 248 patients will be enrolled in Part 2). 
The total number of patients will be between approximately 69 and 278.
4.4
Duration of Patient Participation
The duration of each patient’s participation will be dependent on individual response to 
treatment and will include a Screening Period of up to 28 days, Treatment Period, and 
Follow-up Period.  Patients may continue treatment until disease progression or unacceptable 
toxicity.
All patients will have an EOT visit as soon as possible after decision to discontinue ADCT-
502 and prior to initiation of new anticancer treatment.  If possible, collection of PK, soluble 
HER2, and ADA samples will take place at the follow-up visit 12 weeks after the last dose of 
ADCT-502, unless a new anticancer treatment has been initiated.  
All patients will be followed approximately every 12 weeks after the last dose of study drug 
to collect survival information.  Follow-up for survival may continue for up to 2 years after 
treatment discontinuation.
Any patients who discontinue treatment for any reason other than disease progression will 
continue to be followed by radiographic examination every 12 weeks until disease 
progression or initiation of new anticancer treatment.
The duration of the study participation for each patient is defined as the time from the date of 
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signed written informed consent through the completion of the follow-up period, or 
withdrawal of consent.
4.5
Duration of Study
Study duration will be dependent on overall patient tolerability and response to treatment. It
is anticipated that the entire study (Part 1 and Part 2) could be approximately 3 years from 
first patient treated to last patient completed.
4.6
Description of Dose Escalation Process
Each cohort will consist of 2 patients.  There will be a 24-hour observation before enrolling 
the second patient at Dose Level 1.  The DLT observation period at each dose level is 1 cycle 
(3 weeks), after which it will be determined whether to escalate to the next dose level, stay at 
the current dose level, or de-escalate to the previous dose level for the next cohort.  
There will be no de-escalation from Dose Level 1.  Intrapatient dose escalation is not 
permitted.
Dose escalation is not permitted unless two or more patients have complete DLT information 
through the first cycle in any given dose level. Dose escalation will be determined by using a 
mCRM with a target DLT rate of 30% and an equivalence interval of 20% to 35%, and with 
dose escalation-with-overdose-control (EWOC) and no dose skipping. 
The mCRM will be implemented in Part 1 under the oversight of a Dose Escalation Steering 
Committee (DESC). The DESC will confirm each escalating dose level after reviewing all 
available safety data.  PK data from patients in that dose level and prior dose levels may also 
inform decision making. The DESC may halt dose escalation prior to determining the MTD 
based on emerging PK, PD, toxicity, or response data. 
Additional patients may be included at any dose level to further assess the safety and 
tolerability if at least 1 patient in the study has achieved a partial response or better, or if 
further evaluation of PK or PD data is deemed necessary by the DESC to determine the RDE.
Furthermore, to better understand the potential efficacy of ADCT-502 in an indication 
approved for treatment with HER2 targeted antibodies, up to 3 additional breast cancer 
patients who have previously been treated with an approved HER2 targeted therapy may be 
enrolled per cohort at given dose levels ≥ 60 µg/kg determined by the mCRM model to be 
safe.
Dose escalation will be stopped after the mCRM has assigned 3 cohorts consecutively to the 
same dose level.  
If the MTD is not reached, the recommended dose(s) and schedule(s) for expansion (RDE) 
will be determined.
Once the Part 2 RDE(s) is/are determined, patients receiving lower or higher dose levels of 
ADCT-502 enrolled in part 1 may be offered continued treatment at the RDE(s).
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4.6.1 Safety Oversight by the Dose Escalation Steering Committee
A DESC comprised of ADC Therapeutics and the investigators will review patient safety on 
an ongoing basis during Part 1 to determine if the dose escalation schedule prescribed by the 
mCRM warrants modification. In addition to safety observations, PK and/or PD data may 
also inform DESC decision making.  Intermediate doses or extended dosing intervals may be 
assigned after agreement between ADC Therapeutics and the investigators.  The DESC will 
continue to provide oversight during Part 2.  No formal Data Safety Monitoring Board 
(DSMB) will be used.
4.6.2 Definition of Dose-Limiting Toxicities
A DLT is defined as any of the following events that occur during the 21-day DLT
evaluation period, except those that are clearly due to underlying disease or extraneous 
causes.
A hematologic DLT is defined as:
Event
Severity
Febrile neutropenia or neutropenic infection
Grade 3 or 4
Neutropenia lasting > 7 days
Grade 4
Thrombocytopenia
Grade 4 
Thrombocytopenia with clinically significant bleeding
Grade 3
Thrombocytopenia requiring a platelet transfusion
Grade 3
Anemia
Grade 4
Anemia requiring transfusion
Grade 3
A non-hematologic DLT is defined as:
Event
Severity
Hy’s law case 
AST and/or ALT > 3x ULN and bilirubin > 2x ULN, 
and without initial findings of cholestasis (serum 
alkaline phosphatase (ALP) activity < 2x ULN) and 
no other reason that could explain the combination 
of increased transaminases and serum total bilirubin, 
such as viral hepatitis A, B, or C, preexisting or 
acute liver disease, or another drug capable of 
causing the observed injury.
Hypersensitivity/infusion-related 
Grade 3 or higher. A Grade 3 hypersensitivity / 
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reaction (regardless of 
premedication)
infusion-related reaction that resolves within 
24 hours after onset with appropriate clinical 
management does not qualify as a DLT.
All other non-hematologic toxicity  
Grade 3 & 4
The following conditions are not considered non-hematologic DLTs:
Event
Severity
Fatigue
Grade 3 for ≤ 7 days.
Diarrhea, nausea, or vomiting
Grade 3 in the absence of premedication that 
responds to therapy and improves by at least 1 grade 
within 3 days for Grade 3 events or to ≤ Grade 1 
within 7 days.
Serum lipase or serum amylase
Grade 3 for ≤ 7 days if without clinical signs or 
symptoms of pancreatitis.
Electrolyte abnormalities
≤Grade 3 which normalize within 48 hrs (with or 
without medical intervention) and which do not 
manifest themselves clinically; in such instance, a 
follow-up sample MUST be taken within 48 hrs to 
check whether such normalization has occurred.
Patients who experience a DLT that resolves or stabilizes with appropriate medical 
management may continue treatment at the discretion of the Investigator in consultation with 
the Sponsor. 
5
Management of Toxicity Including Dose Delays and Modifications
The Investigator may suspend ADCT-502 dosing for up to 1 cycle (i.e., 21 days of the 
default dosing schedule) for any patient who experiences a protocol-defined DLT. 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-502 after any suspension, even when longer than 21 days,
is at the discretion of the Investigator, in consultation with the Sponsor, on assessment of the 
patient’s clinical condition and whether or not the patient is deriving potential clinical benefit 
from treatment with ADCT-502. 
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5.1
ADCT-502 General Dose Modification Guidelines 
Guidelines for management of specific toxicities are detailed in Sections 5.2, 5.3, and 5.4.  
For management of events not specified in these sections, the following may serve as a 
guidance to investigators:
AE Grade
ADCT-502 Management Guideline
1
No dose adjustment is required.
2
First Occurrence:
Consider holding ADCT-502 until improvement to ≤ Grade 1 or Baseline. Up to 1 dose of 
ADCT-502 may be skipped to permit improvement.  If improvement to ≤Grade 1 or 
Baseline occurs within 21 days from the last scheduled (but missed) ADCT-502 dose, 
continue ADCT-502 at the original assigned dose level in subsequent treatment cycles.
If improvement to ≤ Grade 1 or Baseline does not occur within 21 days from the last 
scheduled (but missed) ADCT-502 dose, permanently discontinue ADCT-502.
Second Occurrence:
Hold ADCT-502 until improvement to ≤ Grade 1 or Baseline. Up to 1 dose of ADCT-502 
may be skipped to permit resolution.  If improvement to ≤ Grade 1 or Baseline occurs within 
21 days from the last scheduled (but missed) ADCT-502 dose, continue ADCT-502 at 1 dose 
level below the original assigned dose in subsequent treatment cycles.  If improvement to
≤ Grade 1 or Baseline does not occur within 21 days from the last scheduled (but missed) 
ADCT-502 dose, permanently discontinue ADCT-502.
Third Occurrence:
Permanently discontinue ADCT-502.
3
First Occurrence:
Hold ADCT-502 until improvement to ≤ Grade 1 or Baseline. Up to 1 dose of ADCT-502 
may be skipped to permit improvement, then continue ADCT-502 at 1 dose level below the 
original assigned dose in subsequent treatment cycles.
Second Occurrence:
Permanently discontinue ADCT-502.
4
Permanently discontinue ADCT-502.
5.2
Guidelines for Dose Modification: Hematologic Toxicities
Adverse Event
Grade
ADCT-502 Management Guideline
Febrile neutropenia
3
Hold ADCT-502 until the patient recovers. Up to 1 dose of
ADCT-502 may be skipped to permit improvement. Consider use of 
granulocyte colony stimulating factor (G-CSF) as per institutional 
guidelines or as per ASCO guidelines. G-CSF prior to ADCT-502 is not 
allowed unless approved by sponsor.
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Adverse Event
Grade
ADCT-502 Management Guideline
First Occurrence:
If patient recovers from febrile neutropenia prior to next scheduled dose 
or within 21 days from last scheduled (but missed)
ADCT-502 dose, then continue ADCT-502 at 1 dose level below the 
original assigned dose in subsequent treatment cycles. If the patient does 
not recover within 21 days from the last scheduled
(but missed) ADCT-502 dose, permanently discontinue ADCT-502.
Second Occurrence:
Permanently discontinue ADCT-502 if febrile neutropenia recurs despite 
ADCT-502 dose reduction.
Febrile neutropenia
4
Permanently discontinue ADCT-502.
Thrombocytopenia 
with significant 
bleeding or platelet 
transfusion required 
as per PI assessment
3
Hold ADCT-502 until bleeding has stopped and improvement has 
occurred to ≤ Grade 1. Up to 1 dose of ADCT-502 may be skipped to 
permit improvement.
First Occurrence:
Upon improvement to ≤ Grade 1 within 21 days from last scheduled 
(but missed) ADCT-502 dose, continue ADCT-502 at 1 dose level below 
the original assigned dose in subsequent treatment cycles.  
If improvement to CTCAE ≤ Grade 1 does not occur within 21 days from 
the last scheduled (but missed) ADCT-502 dose, permanently discontinue 
ADCT-502.
Second Occurrence:
Upon improvement to ≤ Grade 1 within 21 days from last scheduled 
(but missed) ADCT-502 dose, continue ADCT-502 at 2 dose levels 
below the original assigned dose in subsequent treatment cycles. 
If improvement to ≤ Grade 1 does not occur within 21 days from the last 
scheduled (but missed) ADCT-502 dose, permanently discontinue 
ADCT-502.
Third Occurrence:
Permanently discontinue ADCT-502.
Thrombocytopenia 
(regardless of 
whether significant 
bleeding is present 
or not)
4
Hold ADCT-502 until bleeding has stopped and improvement has 
occurred to ≤ Grade 1. Up to 1 dose of ADCT-502 may be skipped to 
permit improvement.
First Occurrence:
Upon improvement to ≤ Grade 1 within 21 days from last scheduled 
(but missed) ADCT-502 dose, continue ADCT-502 at 1 dose level below 
the original assigned dose in subsequent treatment cycles.
If improvement to CTCAE ≤ Grade 1 does not occur within 21 days from 
the last scheduled (but missed) ADCT-502 dose, permanently discontinue 
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ADCT-502.
Second Occurrence:
Upon improvement to ≤ Grade 1 within 21 days from last scheduled 
(but missed) ADCT-502 dose, continue ADCT-502 at 2 dose levels
below the original assigned dose in subsequent treatment cycles. 
If improvement to ≤ Grade 1 does not occur within 21 days from the last 
scheduled (but missed) ADCT-502 dose, permanently discontinue 
ADCT-502.
Third Occurrence:
Permanently discontinue ADCT-502.
Neutropenia or 
thrombocytopenia 
(in the absence of 
bleeding)
3
Hold ADCT-502 until improvement to ≤ Grade 1. Up to 1 dose of 
ADCT-502 may be skipped to permit improvement. Consider use of
G-CSF as per institutional guidelines or as per ASCO guidelines. G-CSF 
prior to ADCT-502 is not allowed unless approved by sponsor.
First Occurrence:
If improvement to ≤ Grade 1 within 21 days from last scheduled 
(but missed) ADCT-502 dose, then continue ADCT-502 at original 
assigned dose in subsequent treatment cycles. 
If improvement to ≤ Grade 1 does not occur within 21 days from the last 
scheduled (but missed) ADCT-502 dose, permanently discontinue 
ADCT-502.
Second Occurrence:
If improvement to ≤ Grade 1 within 21 days from last scheduled 
(but missed) ADCT-502 dose, then continue ADCT-502 at 1 dose level 
below the original assigned dose in subsequent treatment cycles. 
If improvement to ≤ Grade 1 does not occur within 21 days from the last 
scheduled (but missed) ADCT-502 dose, permanently discontinue 
ADCT-502.
Third Occurrence:
Permanently discontinue ADCT-502
Neutropenia
4
Hold ADCT-502 until improvement to ≤ Grade 1. Up to 1 dose of 
ADCT-502 may be skipped to permit improvement.  Consider use of
G-CSF as per institutional guidelines or as per ASCO guidelines. G-CSF 
prior to ADCT-502 is not allowed unless approved by sponsor.
First Occurrence:
If improvement to ≤ Grade 1 within 21 days from last scheduled 
(but missed) ADCT-502 dose, then continue ADCT-502 at original 
assigned dose in subsequent treatment cycles. If improvement to ≤ Grade 
1 does not occur within 21 days from the last scheduled (but missed) 
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ADCT-502 dose, permanently discontinue ADCT-502.
Second Occurrence:
If improvement to ≤ Grade 1 within 21 days from last scheduled 
(but missed) ADCT-502 dose, then continue ADCT-502 at 1 dose level 
below the original assigned dose in subsequent treatment cycles. 
If improvement to ≤ Grade 1 does not occur within 21 days from the last 
scheduled (but missed) ADCT-502 dose, permanently discontinue 
ADCT-502.
Third Occurrence:
Permanently discontinue ADCT-502.
Anemia 
3
Hold ADCT-502 until improvement to ≤ Grade 1 or Baseline.
Up to 1 dose of ADCT-502 may be skipped to permit improvement. 
Consider use of erythropoietin (EPO) as per institutional guidelines.
First Occurrence:
If improvement to ≤ Grade 1 or Baseline prior to next scheduled dose, 
continue ADCT-502 at the original assigned dose at the next scheduled 
treatment cycle. If improvement to ≤ Grade 1 or Baseline within 21 days 
from last scheduled (but missed) ADCT-502 dose, then continue
ADCT-502 at 1 dose level below the original assigned dose in subsequent 
treatment cycles. If improvement to ≤ Grade 1 or Baseline does not 
occur within 21 days from the last scheduled (but missed) ADCT-502 
dose, permanently discontinue ADCT-502.
Second Occurrence:
If improvement to ≤ Grade 1 or Baseline within 21 days from last 
scheduled (but missed) ADCT-502 dose, then continue ADCT-502 at 
2 dose level below the original assigned dose in subsequent treatment 
cycles.  If improvement to ≤ Grade 1 or Baseline does not occur within 
21 days from the last scheduled (but missed) ADCT-502 dose, 
permanently discontinue ADCT-502.
Third Occurrence:
Permanently discontinue ADCT-502.
Anemia
4
Hold ADCT-502 until improvement to ≤ Grade 1 or Baseline.
Up to 1 dose of ADCT-502 may be skipped to permit improvement.  
Consider use of EPO as per institutional guidelines.
First Occurrence:
If improvement to ≤ Grade 1 or Baseline within 21 days from last 
scheduled (but missed) ADCT-502 dose, then continue ADCT-502 at 
1 dose level below the original assigned dose in subsequent treatment 
cycles.  If improvement to ≤ Grade 1 or Baseline does not occur within 
21 days from the last scheduled (but missed) ADCT-502 dose, 
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permanently discontinue ADCT-502.
Second Occurrence:
If improvement to ≤ Grade 1 or Baseline within 21 days from last 
scheduled (but missed) ADCT-502 dose, then continue ADCT-502 at 
2 dose level below the original assigned dose in subsequent treatment 
cycles.  If improvement to ≤ Grade 1 or Baseline does not occur within 
21 days from the last scheduled (but missed) ADCT-502 dose, 
permanently discontinue ADCT-502.  
Third Occurrence:
Permanently discontinue ADCT-502.
5.3
Guidelines for Dose Modification: Non-hematologic Toxicities
Adverse Event
Grade
ADCT-502 Management Guideline
Infusion-related 
reactions
1
The infusion rate may be decreased by 50% or temporarily interrupted for 
up to 6 hours to permit resolution of the event.
Acetaminophen (paracetamol) and/or H1- and H2-receptor antagonists 
(e.g., diphenhydramine, ranitidine) may be administered for symptomatic 
treatment per institutional standard at the discretion of the Investigator.
Consider premedication (e.g., secondary prophylaxis) with acetaminophen 
(paracetamol) and/or H1- and H2-receptor antagonists at least 30 minutes 
prior to start of subsequent doses.
2
Interrupt ADCT-502 infusion for up to 6 hours to permit resolution of the 
event. If the event resolves within 6 hours, resume
ADCT-502 infusion at 50% of the prior infusion rate.  Acetaminophen 
(paracetamol) and H1- and H2-receptor antagonists (diphenhydramine and 
ranitidine) should be administered for symptomatic treatment. If the 
patient experiences chest tightness, dyspnea, or shortness of breath, IV 
methylprednisolone 100 mg
(or the equivalent) should be administered.
If the event resolves within 6 hours and requires IV steroid treatment, pre-
medicate (e.g., secondary prophylaxis) with acetaminophen (paracetamol), 
H1- and H2-receptor antagonists
(e.g., IV diphenhydramine, and IV ranitidine), and IV methylprednisolone 
100 mg (or the equivalent) at least 30 minutes prior to start of subsequent 
doses.
If the event resolves within 6 hours and did not require IV steroid 
treatment, pre-medication (e.g., secondary prophylaxis), at least 
30 minutes prior to start of subsequent doses may be considered.
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Hypersensitivity 
and infusion-related 
reactions
3
Permanently discontinue ADCT-502 unless AE resolves within 24 hours 
after onset (with or without clinical management). Manage severe 
infusion-related reactions per institutional guidelines (i.e., treatment with 
IV diphenhydramine, IV ranitidine, and IV glucocorticoids).  
Intramuscular epinephrine should be used after failure of other therapeutic 
options.
Hypersensitivity 
and infusion-related 
reactions
4
Permanently discontinue ADCT-502.
Transaminase 
(AST/ALT) 
Abnormalities
2
No dose modification is required.
3
Hold ADCT-502 until improvement to ≤ Grade 1 or Baseline. Up to 1 
dose of ADCT-502 may be skipped to permit improvement.  
First Occurrence:
If improvement to ≤ Grade 1 or Baseline occurs prior to next scheduled 
dose, continue ADCT-502 at the original assigned dose at the next 
scheduled treatment cycle. 
If improvement to ≤ Grade 1 or Baseline within 21 days from last 
scheduled (but missed) ADCT-502 dose, continue ADCT-502 at 1 dose 
level below the original assigned dose in subsequent treatment cycles.  If
improvement to ≤ Grade 1 or Baseline does not occur within 21 days from 
the last scheduled (but missed)
ADCT-502 dose, permanently discontinue ADCT-502.
Second Occurrence:
If improvement to ≤ Grade 1 or Baseline within 21 days from last 
scheduled (but missed) ADCT-502 dose, then continue ADCT-502 at 2 
dose level below the original assigned dose in subsequent treatment cycles.  
If improvement to ≤ Grade 1 or Baseline does not occur within 21 days 
from the last scheduled (but missed)
ADCT-502 dose, permanently discontinue ADCT-502.  
Third Occurrence: 
Permanently discontinue ADCT-502.
Hyperbilirubin-
emia
2
Hold ADCT-502 until improvement to ≤ Grade 1 or Baseline. 
If improvement to ≤ Grade 1 or Baseline occurs prior to next scheduled 
dose, continue ADCT-502 at the original assigned dose at the next 
scheduled treatment cycle. 
First Occurrence:
If improvement to ≤ Grade 1 or Baseline within 21 days from last 
scheduled (but missed) ADCT-502 dose, continue ADCT-502 at 1 dose 
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level below the original assigned dose in subsequent treatment cycles.  If 
improvement to ≤ Grade 1 or Baseline does not occur within 21 days from 
the last scheduled (but missed)
ADCT-502 dose, permanently discontinue ADCT-502.
Consider close monitoring as needed.
Second occurrence:
Permanently discontinue ADCT-502
Permanently discontinue ADCT-502 for any case meeting
Hy’s Law criteria.
3
Hold ADCT-502 until improvement to ≤ Grade 1 or Baseline.  Up to 1 
dose of ADCT-502 may be skipped to permit improvement.
First occurrence:
If improvement to ≤ Grade 1 or Baseline occurs prior to next scheduled 
dose, continue ADCT-502 at the original assigned dose at the next 
treatment cycle.  If improvement to ≤ Grade 1 or Baseline occurs within 
21 days from the last scheduled (but missed) ADCT-502 dose, continue 
ADCT-502 at 1 dose level below the original assigned dose in subsequent 
treatment cycles. If improvement to ≤ Grade 1 or Baseline does not occur 
within 21 days from last scheduled (but missed) ADCT-502 dose, 
permanently discontinue ADCT-502.
Second occurrence:
Permanently discontinue ADCT-502.
Changes in LVEF
1-4
See Table 3
5.4
Guidelines for Dose Modifications: Left Ventricular Dysfunction
ADCT-502 should be discontinued in any patient who develops confirmed congestive heart 
failure (CHF) (i.e., Grade ≥ 3 left ventricular systolic dysfunction as defined by NCI CTCAE
version 4.0). CHF should be treated and monitored according to standard medical practice. 
If ADCT-502 is withheld due to clinically significant (e.g., ≥ Grade 3 or per investigator 
judgement) left ventricular cardiac dysfunction and treatment is then resumed, left ventricular 
ejection fraction (LVEF) measurement must be repeated after every cycle for the next 
2 cycles and then every 3 cycles and at End of Treatment (EOT). 
ADCT-502 must be discontinued in all patients for whom a drop of LVEF to below 40% is 
documented (unless it is not confirmed with a repeat assessment within 21 days). 
For patients whose LVEF drops to values between 40% and 45%, the decision to stop or 
continue ADCT-502 should be based on Table 3. Additional evaluations to evaluate safety 
may be performed as clinically indicated.
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Table 3: Dose Modification Guidelines for Left Ventricular Dysfunction
Symptomatic 
CHF
LVEF < 40%
(Grade 3 or 4)
LVEF 40% to ≤ 45% 
and Decrease is 
≥10% Points from 
Baseline (Grade 2)
LVEF 40% to ≤ 45% 
and Decrease is
< 10% Points from 
Baseline (Grade 2)
LVEF > 45%
(≤Grade 2)
Discontinue
ADCT-502
Do not administer 
ADCT-502.
Repeat LVEF 
assessment within 
3 weeks.  If LVEF 
<40% is confirmed, 
permanently 
discontinue
ADCT-502.
Do not administer 
ADCT-502.  
Repeat LVEF 
assessment within 
3 weeks.  
If the LVEF has not 
recovered to within 
10% points from 
Baseline, discontinue
ADCT-502.
Continue treatment 
with ADCT-502. 
Repeat LVEF 
assessment within 
3 weeks.
Continue 
treatment with 
ADCT-502.
CHF = congestive heart failure; LVEF = Left ventricular ejection fraction
6
Patient Population
6.1
Inclusion Criteria
1. Male or female age 18 years or older.
2. Refractory to or intolerant of existing therapy(ies) known to provide clinical benefit 
for their condition.
3. Eastern Cooperative Oncology Group (ECOG) performance status:
a.
Part 1: 0-2
b.
Part 2: 0-1
4. Availability of formalin-fixed paraffin-embedded (FFPE) tumor tissue block (or 
unstained slides (minimum 7; 10 preferred) if block is not available) to demonstrate 
HER2 expression.
Note: any biopsy since initial diagnosis is acceptable, but if several are available, the 
most recent sample is preferred. 
5. Pathologic diagnosis of solid tumor malignancy that is locally advanced or metastatic 
at time of Screening: 
Part 1 (Dose Escalation):
Advanced solid tumors with documented HER2 status of IHC ≥1+ or HER2 
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amplified/mutated by FISH or NGS (refer to Section 4.2 and Appendix 18.3).
Note: Clinical pathology report of HER2 status must be available for review to 
confirm eligibility in Part 1.
Part 2 (Dose Expansion): 
HER2-high* or HER2-low** advanced solid tumor belonging to one of the pre-
specified indications for groups A – E (breast cancer, gastric & gastroesophageal 
cancer, bladder cancer, non-small cell lung cancer) or one of the eight pre-specified 
indications for the basket group (SCLC, CRC, pancreatic, biliary tract, prostate,
ovarian, endometrial, or salivary gland) according to assigned treatment group for 
which HER2 status has been confirmed prospectively (HER2-high or HER2-low) for 
study entry.
* A HER2-high patient is defined as IHC 3+, or IHC 2+ with FISH amplification.  
** A HER2-low patient is defined as IHC 1+, or IHC 2+ without FISH amplification.
Note: A patient with IHC 0 / IHC 1+ with amplification is HER2-high for study 
purposes; a patient with IHC 3+ with negative amplification results is HER2-low for 
study purposes.
6. Part 2/Dose Expansion Only: Measurable disease as defined by Response Evaluation 
Criteria in Solid Tumors (RECIST) version 1.1.
Note: Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue 
components, that can be evaluated by cross sectional imaging techniques such as 
CT or MRI can be considered as measurable lesions if the soft tissue component meets 
the definition of measurability per RECIST.
7. Screening laboratory values within the following parameters:
a. Absolute neutrophil count (ANC) ≥ 1500/mm3 (≥1.5x 109/L).
b. Platelet count ≥100,000 /mm3 (≥100 x 109/L).
c. Hemoglobin ≥ 9 g/L (≥5.6 mmol/L).
d. Aspartate transaminase (AST) and alanine aminotransferase (ALT) ≤ 2.5x upper 
limit of normal (ULN); or ≤ 5.0x ULN if liver metastases are present.
e. Total bilirubin ≤ 1.5× ULN (or ≤ 3x ULN, with direct bilirubin ≤1.5x ULN, in 
patients with known Gilbert syndrome).
f. Serum/plasma creatinine ≤ 1.5x ULN; or, if creatinine > 1.5x ULN, a measured 
creatinine clearance must be >60mL/min as calculated by the Cockcroft and Gault 
equation for patient to be eligible.
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8. 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-502.  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-502.  
*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.
6.2
Exclusion Criteria
1. Known history of ≥ Grade 3 hypersensitivity to a therapeutic antibody.
2. Known history of positive serum human ADA to trastuzumab.
3. History of Stevens-Johnson syndrome or toxic epidermal necrolysis syndrome.
4. Major surgical procedure or significant traumatic injury, radiotherapy, chemotherapy, 
targeted therapy, hormone therapy (except for luteinizing hormone-releasing hormone 
(LHRH) agonists or denosumab) or other anticancer therapy within 21 days OR within 
5 half-lives of the product, whichever is shorter, prior to the Cycle 1, Day 1 visit.
Note: cumulative dose of anthracycline >450 mg/m2 is prohibited.
5. Failure to recover to Grade 0 or Grade 1 from acute non-hematologic toxicity due to 
previous therapy, prior to screening (with the exception of alopecia).
6. Central Nervous System (CNS) disease only.
7. Symptomatic CNS metastases or evidence of leptomeningeal disease (brain MRI or 
previously documented cerebrospinal fluid (CSF) cytology).  
Previously treated asymptomatic CNS metastases are permitted provided that the last 
treatment (systemic anticancer therapy and/or local radiotherapy) was completed
≥ 8 weeks prior to Day 1 except usage of low dose of steroids on a taper (i.e. up to 10 mg 
on Day 1 and consecutive days is permissible if being tapered down). Patients with 
discrete dural metastases are eligible.
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8. Active cardiac disease including any of the following:

Angina pectoris that requires the use of anti-anginal medication.

Ventricular arrhythmias except for benign premature ventricular contractions.

Supraventricular and nodal arrhythmias requiring a pacemaker or not controlled with 
medication.

Clinically significant valvular disease with documented compromise in cardiac 
function.

Symptomatic pericarditis.

Congenital long QT syndrome or a corrected QTc interval ≥450 ms at Screening.

LVEF < 50% at Screening or a history of decrease in LVEF to < 40% during previous 
treatment with HER2 targeted therapy.
9. History of clinically significant cardiovascular dysfunction including any one of the 
following:

History of myocardial infarction (MI) or recent MI documented by elevated cardiac 
enzymes or persistent regional wall abnormalities on assessment of left ventricular 
function within 6 months prior to Day 1.

History of documented congestive heart failure (New York Heart Association 
functional classification III-IV).

Documented cardiomyopathy.

Uncontrolled hypertension (systolic blood pressure >180 mm Hg or diastolic blood 
pressure >100 mm Hg).
10. Active ulceration of the upper gastrointestinal tract or gastrointestinal bleeding.
11. Active autoimmune disease, motor neuropathy considered of autoimmune origin, and 
other CNS autoimmune disease.
12. Patients receiving concomitant immunosuppressive agents or chronic corticosteroids use, 
at study entry except in cases outlined below:
a. Topical applications (e.g. rash), inhaled sprays (e.g. obstructive airways diseases), 
eye drops or local injections (e.g. intra-articular), or as physiologic replacement are 
permitted.
13. Known human immunodeficiency virus (HIV) infection; known seropositive for hepatitis 
B surface antigen (HBsAg), or antibody to hepatitis C virus (anti-HCV) with 
confirmatory testing and requiring anti-viral therapy.
Note: Testing is not mandatory to be eligible. Testing for HCV should be considered if 
the patient is at risk for having undiagnosed HCV (e.g., history of injection drug use).
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14. Any other malignancy within 3 years prior to Day 1, with the exception of adequately 
treated in-situ carcinoma of the cervix uteri, basal or squamous cell carcinoma or other 
non-melanomatous skin cancer.
15. Active bleeding diathesis or significant anticoagulation (such as with oral anti-vitamin K 
medication. Low-dose warfarin, aspirin, or equivalent, are permitted as long as the INR 
≤2.0.
16. History of thromboembolic or cerebrovascular events within the last 6 months, including 
transient ischemic attack, cerebrovascular accident, deep vein thrombosis or pulmonary 
embolism.
17. Clinically significant third space fluid accumulation (i.e., ascites requiring tap or pleural 
effusion that is either requiring tap or associated with shortness of breath).
18. Breastfeeding or pregnant.
19. Other concurrent severe and/or uncontrolled medical conditions (e.g., uncontrolled 
diabetes mellitus, active untreated or uncontrolled infection including viral and systemic 
fungal infections, chronic obstructive or chronic restrictive pulmonary disease including 
dyspnea at rest from any cause) that could cause unacceptable safety risks or compromise 
compliance with the protocol.
6.3
Definition of HER2 Expression Levels 
Expression levels for HER2 are classified as HER2-high or HER2-low for the purposes of 
this protocol. Please see Section 4.2 for details.
7
Reasons for Withdrawal/Discontinuation
Patients may withdraw from the study at any time and for any reason without prejudice to 
their future medical care by the Investigator or others at the study site.
A patient may be withdrawn from treatment with ADCT-502 for any of the following 
reasons:
Disease progression.
AE.
Withdrawal of consent.
Major protocol deviation.
Required treatment delay >21 days (except in case of potential patient benefit, which 
must be approved by the Sponsor).
Non-compliance, including lost to follow-up.
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Pregnancy.
Other (e.g., development of contraindications with use of the study drug).
The Investigator determines that it is in the best interest of the patient to discontinue the 
patient’s participation in the study.
Discontinuation of the study by the Sponsor.
Death.
7.1
Handling of Withdrawals
The Investigator will confer with the Sponsor if a patient experiences a serious or intolerable 
AE. If a patient discontinues from the study because of an AE, the patient will be followed 
to satisfactory resolution, until the Investigator deems the event to be chronic or not clinically 
significant, or until the patient is considered to be stable.
For each patient who discontinues study treatment and withdraws from the study, the 
Investigator will record the reason(s) for discontinuation on the relevant page of the 
electronic case report form (eCRF). Whenever possible, each patient who discontinues study 
treatment will undergo an EOT visit and all EOT assessments.  Patients who fail to return for 
final assessments are to be contacted by the investigative site. Following a minimum of two,
documented unsuccessful telephone calls, the investigative site will send a registered letter to 
the patient in a final attempt to ensure protocol compliance.
Note: Once discontinued from the study for any reason, patients are not permitted to be 
re-enrolled into the study.
7.1.1 Patient Replacements
Any patient in Part 1 who discontinues before completion of the first treatment cycle, for any 
reason other than a DLT, will be replaced.
8
Study Drug 
8.1
ADCT-502 Drug Product
ADCT-502 is a sterile formulation containing PBD-conjugated humanized monoclonal IgG1 
antibody 
and engineered trastuzumab
  Refer to the current IB for 
additional information regarding formulation.
8.2
Packaging and Storage
ADCT-502 is formulated as a sterile liquid at 5 mg/mL in a 10 mL glass vial (2.0 mL nominal 
fill). The drug product is designed to deliver 10 mg ADCT-502 per vial and is intended for 
intravenous infusion following dilution in 0.9% sodium chloride.
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The drug product storage temperature is ≤ -60°C.
8.3
Preparation and Administration
The study drug will be supplied by ADC Therapeutics through the designated packaging, 
labeling, and distribution center.  After the vials have been completely thawed, the study drug 
may be prepared per the instructions provided in the ADCT-502 Pharmacy Manual.
ADCT-502 must be diluted in 0.9% sodium chloride due to compatibility reasons and
administered via a metered IV pump.
Patients will receive a 1-hour IV infusion of ADCT-502 on Day 1 of each 3-week (21-day) 
cycle. If ADCT-502 is well tolerated after the first cycle, the infusion duration may be 
shortened to 30 minutes for subsequent cycles for that patient at the discretion of the 
Investigator. Variations in infusion times due to minor differences in IV bag overfill/underfill 
and the institution’s procedure for flushing chemotherapy lines will not result in protocol 
deviation.
Additional instructions regarding study drug shipment, handling, storage, and preparation are 
included in the pharmacy manual.
8.4
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.
8.5
Treatment Compliance
Administration of ADCT-502 will be performed by the Investigator or a qualified designee.  
Compliance will be verified based on the source documentation of study drug administration 
information. 
9
Concomitant Treatment
All medications used within 14 days prior to Cycle 1, Day 1, during the treatment period, and 
within 30 days after the last dose of study drug are recorded in the eCRF. 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.
9.1
Prophylaxis Mandated During the Study
Unless contraindicated, administer dexamethasone 4 mg PO BID the day before ADCT-502
administration (if possible/feasible), the day of ADCT-502 administration (give at least 2 
hours prior to administration when not given the day before; otherwise any time prior to 
administration), and the day after ADCT-502 administration.
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9.2
Prohibited During Study

Other anticancer therapy.

Other investigational agents.

Chronic treatment with corticosteroids (prednisone ≥12.5 mg/day or dexamethasone
≥2 mg/day).  Inhaled steroids, intraocular, joint injections, and nasal steroids, or as 
physiologic replacement, are permitted.

Live vaccines.
9.3
Permitted Treatment During Study
After confirmation and documentation of eligibility, supportive care treatments 
(transfusions, etc.) can be prescribed as medically appropriate.  Prophylactic treatment for 
hypersensitivity has not been prospectively mandated, but may become required as specified 
in Section 9.4.
9.3.1
Palliative Radiotherapy
Local radiotherapy for analgesic/palliative purposes or for lytic lesions at risk of fracture may 
be carried out if required after completion of the DLT evaluation period. Whenever possible, 
these patients should have a tumor assessment of the lesion(s) before they receive 
radiotherapy to rule out progression of disease. No dose modification of study medication is 
needed during radiotherapy.
9.3.2
Oral Contraception
Oral contraception is allowed during the study. Refer to Section 6.1 for contraception
requirements.
9.3.3
Anti-emetics
Prophylactic anti-emetics will be withheld during the DLT observation period (i.e., Cycle 1).
Subsequently, patients may receive (prophylactic) anti-emetics at the discretion of the 
treating physician.
9.3.4
Anti-diarrheal Treatment
Anti-diarrheal treatment is recommended at the first sign of diarrhea.  As a recommendation, 
initial management of diarrhea should include dietary modifications, extra fluid, and 
loperamide.
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9.3.5
Growth Factors
Hematopoietic growth factors are permitted as per American Society of Clinical Oncology 
guidelines (Smith, 2006); however, prophylactic use of growth factors is not allowed during 
the DLT observation period (first treatment cycle).
9.3.6
Steroids
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)
9.3.7
Skin Toxicity Therapy
Appropriate skin toxicity therapy includes e.g. antihistamines, topical or systemic 
corticosteroids, , and should be used according to institutional guidelines (see also Section 
9.6 Other supportive care).
9.3.8
Bisphosphonates or Denosumab
Concomitant use of bisphosphonates or denosumab is allowed if started 12 weeks or more 
prior to first dose.
9.3.9
Androgen Deprivation Therapy 
Androgen deprivation therapy (ADT) is permitted if its continuation is in the best interest in 
the patient as per investigator assessment unless prohibited above.
Any other concomitant medication deemed necessary for the welfare of the patient during the
study may be given at the discretion of the Investigator.
9.4
Prophylaxis for Hypersensitivity
If one patient experiences a Grade 2 or higher infusion-related hypersensitivity reaction 
(Appendix 18.1) at any time during Part 1 (Dose Escalation), all subsequent patients must
receive prophylactic treatment per institutional standard of care or according to the guidelines 
below, to reduce the risk of hypersensitivity reactions:
On Day 1 of each cycle, patients will be instructed to take 20 mg orally of 
dexamethasone at 12 and 6 hours before the start of ADCT-502 infusion.  
When necessary, 12 and 6 hours before the first infusion may be defined as 
“immediately before sleeping” and “immediately after waking up.”
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On Day 1 of each cycle, patients will be given 50 mg IV of diphenhydramine 
hydrochloride at 30 minutes before the start of ADCT-502 infusion.
On Day 1 of each cycle, patients will be given 50 mg of ranitidine (or equivalent) IV at 
30 minutes before the start of ADCT-502 infusion.
For 2 days following administration of ADCT-502 on Day 1, all patients are to take 
dexamethasone 4 mg orally, twice per day.
Furthermore, prophylaxis for hypersensitivity will supersede prior stipulations on
dexamethasone prophylaxis as mandated in Section 9.1.
Treatment of hypersensitivity or infusion reactions may be administered according to 
standard treatment center protocols.  Additional guidance is provided in Section 5.3.
Medications for the treatment of severe hypersensitivity reactions, including anaphylaxis, 
should be available for immediate use.
9.5 Treatment of Edema and/or Pleural Effusion
Spironolactone, at standard doses, should be considered for patients with weight gain greater 
than 1 kg (2.2 pounds) from C1D1, new or worsening edema, and/or new or worsening 
pleural effusion. The dose of spironolactone may be titrated as clinically indicated. 
Additional diuretic support may be added if there is further increase in weight, edema, or 
pleural effusion. Additionally, patients are advised to monitor their weight on a daily basis, at 
around the same time (preferably in the morning), and to notify the study site if they gain 
>1 kg (2.2 pounds) over C1D1.
9.6 Other Supportive Care
The following supportive care needs to be considered:
Because of non-clinical observations related to nephropathy, adequate patient hydration 
(e.g., 8 to 10 glasses of water or equivalent per day) is recommended for patients 
receiving ADCT-502.
Skin rash has been reported with other investigational agents containing the same PBD
warhead (Rudin, 2016). Although there have not been signals of photosensitivity in the 
rat and monkey toxicology studies with ADCT-502, it is recommended that precautions 
are taken to avoid prolonged exposure of skin to direct sunlight.
10 Description of Procedures
Patients will undergo the procedures at the time points specified in schedule of events
(Table 1 and Table 2).  Any clinically significant abnormalities (including clinically 
significant laboratory abnormalities) that worsen from Baseline are to be recorded as AEs or 
SAEs and graded according to National Cancer Institute Common Terminology Criteria for 
Adverse Events (NCI CTCAE) version 4.0.  
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10.1
Triplicate 12-Lead ECGs
Three consecutive (also called triplicate) ECGs will be performed at defined timepoints 
throughout the study as per schedule of events (Table 1 and Table 2).
ECG will be performed after patient is resting for at least 5-min.
At timepoints coinciding with ECG measurements, PK blood collection should occur 
immediately after the end of the ECG recording and, when applicable, after vital signs
measurements (example in Figure 2).
If a patient experiences Torsade de Pointes, concomitant PK samples (e.g., unscheduled) 
should be collected.
Figure 2: Preferred sequence for triplicate ECG, vital signs, and PK sample 
assessments at end of infusion (EOI)
10.2
Laboratory Analyses (Safety)
10.2.1
Complete Blood Count with Differential
Complete blood count (CBC) includes white blood cells (WBC) with 5-part differential, 
platelet count, hemoglobin, hematocrit, and absolute neutrophil count. 
10.2.2
Coagulation
Coagulation panel must include partial thromboplastin time (PTT) and International 
Normalized Ratio (INR) (prothrombin time (PT) expressed in seconds is optional).  
Patients taking coumarin-derivative anticoagulants should be monitored closely and their 
anticoagulant dose adjusted as needed.
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10.2.3
Chemistry
Chemistry 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. 
10.2.4
Urinalysis
Urinalysis includespH, specific gravity, protein, white blood cells, hemoglobin, ketones,
glucose and bilirubin. Urinalysis may be performed by dipstick.
Abnormal findings will be followed up with a microscopic evaluation and/or additional 
assessments as clinically indicated. A microscopic evaluation consists at a minimum of 
WBC and RBC quantitation per high power field, as well as semi-quantitative assessment of 
other cells and substances, if present, such as epithelial cells, bacteria, and crystals 
(“few,” “moderate,” “many”). Other evaluations depending on microscopic findings may be 
added.
10.3
Efficacy Assessments
Computerized tomography (CT) or magnetic resonance imaging (MRI) scans with contrast of 
the chest, abdominal and pelvic area or brain scans (CT or MRI with contrast), and bone 
scans or X-ray exam if clinically indicated, will be performed. For image acquisition 
specifications, including instruction in the event of allergy to contrast dye, refer to
Appendix II of RECIST version 1.1 (Specifications for Standard Anatomical Radiological
Imaging).
The same methods used at baseline that identify sites of disease should be used uniformly for 
all subsequent assessments. Response to treatment will be determined by the Investigator as 
complete response (CR), partial response (PR), stable disease (SD), or progressive disease 
(PD) according to RECIST version 1.1.
Images will be obtained according to local site imaging requirements and may be required to 
be submitted for a central/independent review. Submission instructions for the 
central/independent review will be provided in a separate manual.
Once the final efficacy analysis for progression-free survival (PFS) is performed (Part 2), the 
frequency of tumor response assessment for patients remaining under treatment may be 
further decreased and/or performed according to standard of care.
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10.4.1
Pharmacokinetics
The PK profile of ADCT-502 (total antibody; DAR ≥0), PBD-conjugated antibody 
(DAR ≥1), and free warhead SG3199 will be assessed centrally. The PK profile will include 
determination of standard PK parameters (e.g., maximum concentration [Cmax], time to Cmax
[Tmax], area under the curve [AUC]). PK samples may be collected at other time points if 
clinically indicated.
At timepoints coinciding with ECG measurements, PK blood collection should occur 
immediately after the end of the ECG recording and, when applicable, after vital signs 
measurements (example in Figure 2). 
 
 
 
 
 
 
10.5
Sample Handling, Storage and Shipment
During this study, serum, whole blood and tissue samples will be collected and shipped to the 
central laboratory for analysis. Refer to Table 2 for the sample collection schedule. 
Serum isolated from whole blood will be collected for PK, ADA and sHER2 analysis.  
Serum samples should be clearly labeled with site number, patient ID and the sample 
collection time point prior to being stored.  Once labeled, serum samples should be stored at 
≤-70C until shipment.  Serum samples should be shipped according to the sample shipment 
schedule provided in the laboratory manual. 
Whole blood will be collected and shipped to the central laboratory for cfDNA and gDNA 
extraction. The extracted cfDNA and gDNA will be stored for future analysis.
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Instruction related to the collection and shipment of tumor tissue sample will be provided in 
separate laboratory manual(s). When sending tissue samples the patient ID and block ID 
(where appropriate) should be clearly indicated.
For detailed instructions related to central laboratory sample collection, labeling, processing, 
storage, or shipment refer to the appropriate laboratory manual(s). 
Please note samples collected for local analysis (CBC, Coagulation, Chemistry, UA, etc.) 
should not be frozen. Local samples should be transferred ambient to the appropriate local 
laboratories.
Biological samples may retained for up to 10 years to further address scientific questions as 
new information in regards to the disease or the study drug becomes available.
11 Adverse Events
11.1
Definitions of Adverse Events
The Investigator is responsible for reporting all AEs that are observed or reported during the 
study, regardless of their relationship to study drug or their clinical significance.
An AE is defined as any untoward medical occurrence in a patient enrolled into this study 
regardless of its causal relationship to study drug. Patients will be instructed to contact the 
Investigator at any time after ICF signature if any symptoms develop.
A treatment-emergent AE (TEAE) is defined as any event not present before exposure to 
study drug or any event already present that worsens in either intensity or frequency after 
exposure to study drug.
An SAE is defined as any event that results in death, is immediately life threatening, requires 
inpatient hospitalization or prolongation of existing hospitalization, results in persistent or 
significant disability/incapacity, or is a congenital anomaly/birth defect. Hospitalization for 
elective procedures or for protocol compliance is not considered an SAE.
Important medical events that may not result in death, are life threatening, or require 
hospitalization may be considered SAEs when, based upon appropriate medical judgment, 
the event may jeopardize the patient or may require medical or surgical intervention to 
prevent any of the outcomes listed in this definition. Examples of such medical events 
include allergic bronchospasm requiring intensive treatment in an emergency room or at 
home, blood dyscrasias or convulsions that do not result in inpatient hospitalization, or the 
development of drug dependency or drug abuse.
11.2
Eliciting and Documenting Adverse Events
All AEs will be assessed from the time the patient signs the ICF until 30 days after the last 
dose of study drug or initiation of new anticancer treatment.
Any SAEs that occur more than 30 days after the last dose of study drug do not need to be 
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reported unless the Investigator considers them related to study drug.
At every study visit, patients will be asked a standard non leading question to elicit any 
medically related changes in their well-being. They will also be asked if they have been 
hospitalized, had any accidents, used any new medications, or changed concomitant 
medication regimens (both prescription and over-the-counter medications).
In addition to patient observations, AEs will be documented from any data collected on the 
AE page of the eCRF (e.g., clinically significant changes in laboratory values, physical 
examination, ECG changes, etc.) or identified from review of other documents that are 
relevant to patient safety.
11.3
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 will include event terminology, date of onset, CTCAE version 4.0 
assessment of severity, relationship to and action taken with the study drug, date of resolution 
of the event, seriousness, any required treatment or evaluations, and outcome.  With the 
exception of disease progression, AEs resulting from concurrent illnesses, reactions to 
concurrent illnesses, and reactions to concurrent medications also must be reported. All AEs 
will be followed to adequate resolution.
Any AE that meets SAE criteria (Section 11.1) 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) through the EDC system. In case the EDC system is down or for SAE 
reporting questions, the following contact information may be used:
Pharmacovigilance Department
SAE Hotline: +1 (800) 772-2215
SAE Fax line: +1 (888) 772-6919
SAE Email Mailbox: CHOsafety@PRAHS.com
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11.4
Assessment of Severity
Adverse events will be graded according to CTCAE version 4.0. For events not included in 
the CTCAE criteria, the severity of the AE is graded on a scale of 1 to 5 as shown in Table 4. 
Table 4: Definition of Severity Grades for Common Terminology Criteria for
Adverse Events (CTCAE)
Grade
Definition
1
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated.
2
Moderate; minimal, local or noninvasive intervention indicated; limiting 
age-appropriate instrumental activities of daily living (ADL).a
3
Severe or medically significant but not immediately life threatening; hospitalization or 
prolongation of hospitalization indicated; disabling; limiting self-care ADL.b
4
Life-threatening consequences; urgent intervention indicated.
5
Death related to adverse event.
aInstrumental ADL refer to preparing meals, shopping for groceries or clothes, using the telephone, managing 
money, etc.
bSelf-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.
11.5
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 on 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).
11.6
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.
11.7
Overdose 
An overdose is any dose of study treatment given to a patient that exceeds the dose described 
in the protocol. Any overdose, with or without associated AEs, must be promptly reported to 
the Sponsor. There are no data available to determine what the effects of overdose are and 
whether they can be reversed. Symptomatic treatment and standard supportive care measures 
for the management of any observed toxicity should be applied.
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11.8
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 SAEs in Section 11.3, 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 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 that is brought to the Investigator’s 
attention after the patient has completed the study and considered by the Investigator as 
possibly related to the study treatment must be promptly reported in the same manner.
12 Statistical Methods
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). Results for the 
exploratory/correlation analyses may be reported separately.
12.1
Sample Size Calculations
Part 1: The number of patients will depend upon the toxicities observed, the number of
dose-level cohorts evaluated, and the number of dose-level cohorts expanded as the study 
progresses; approximately 30 patients are estimated. Overall sample size will be guided by 
the mCRM design.
Part 2: During the dose expansion phase of the study, up to 28 patients per each dose 
expansion cohort will be enrolled. Simon's two-stage design (Simon, 1989) will be used.  
The null hypothesis that the true response rate is 7.5% will be tested against a one-sided 
alternative. In the first stage, 13 patients will be accrued. If there are one (1) or fewer 
responses in these 13 patients, the cohort will be closed. Otherwise, 15 additional patients 
will be accrued for a total of 28 patients. The null hypothesis will be rejected if five (5) or 
more responses are observed in 28 patients. This design yields a type I error rate of 
0.05 (one-sided) and power of 80% when the true response rate is 25%. 
In the basket group, up to 24 patients will be enrolled, with no more than 3 patients from 
each indication. If responses are observed, plans are described in Section 12.2
(Interim Analysis [Part 2]).
12.2
Interim Analysis (Part 2)
According to the Simon 2-Stage design, interim futility analyses will be performed separately 
for each expansion group. 
Patients will be enrolled in Groups A, B, and C first.
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When 13 evaluable patients have been accrued in any of these 3 groups, enrollment will be 
paused and the futility analysis will be performed after the 13th patient has completed two 
post-baseline assessments.  If futility is not triggered, the enrollment for that cohort will 
continue until the enrollment of 28 patients is complete and Groups D, E, and F will be open
for enrollment.
Similarly, if futility for the HER2-high patients enrolled in Stage 1 of Groups C, D, or E is 
not triggered, enrollment of HER2-low expressing patients in the same respective group will 
be started. This recruitment of HER2-low patients in Groups C, D and E is subject to a 
Simon 2-stage design, and enrolment of all approximate 28 patients per group is only opened 
if futility is not triggered in the respective group after 13 patients have been accrued and 
evaluated. Statistical parameters for any further evaluation of a tumor type(s) identified via 
the basket Group F will be proposed under protocol amendment or evaluation in a new 
protocol.  
12.3
Analysis Populations
Safety Population: All patients who receive at least 1 dose of ADCT-502 will be 
evaluable for safety.  
DLT Evaluable Population: All patients in Part 1 who receive study drug, except 
patients who discontinue study drug during Cycle 1 without experiencing a DLT.
Efficacy Population: All patients who:
receive at least 1 dose of ADCT-502, have valid baseline disease assessment(s), and
at least one valid post-baseline disease assessment, unless
disease progression and death is documented at any time after receiving ADCT-502 

PK, PD, and Exploratory Evaluable Population: All patients who receive at least 1 dose 
of ADCT-502 with valid samples collected. 
12.4
Safety Analyses
The safety objective will be evaluated by summarization of AEs, SAEs, and changes in 
laboratory parameters, vital signs, ECGs, and MUGA/echocardiograms.  Dose interruptions, 
reductions, and relative dose intensity will also be summarized. 
12.4.1
Adverse Events
The focus of adverse event summarization will be on treatment-emergent adverse events. A 
treatment-emergent adverse event is defined as an adverse event that occurs or worsens in the 
period extending from the first dose of study drug to 30 days after the last dose of study drug 
in this study.
Treatment-emergent adverse events will be summarized. Summary tables will be presented to 
show the number of patients reporting treatment-emergent adverse events by severity grade 
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and corresponding percentages. A patient who reports multiple treatment-emergent adverse 
events within the same Preferred Term (or System Organ Class) is counted only once for that 
Preferred Term (or System Organ Class) using the worst severity grade. 
Separate summaries will be prepared for treatment-emergent adverse events classified as 
severe or life-threatening (Grade 3 or higher); study-drug-related adverse events; adverse 
events leading to treatment interruption, modification, or discontinuation; serious adverse 
events and death. 
12.4.2
Clinical Laboratory Results
Clinical hematology, coagulation panel, biochemistry, and urinalysis data will be 
summarized at each scheduled assessment. All results will be summarized using shift from
baseline. Shifts for clinical laboratory results that can be graded according to CTCAE 
version 4.0 will be summarized by CTCAE grade. 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.
12.4.3
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.
12.5
Efficacy Analyses
Efficacy objectives to assess preliminary anti-tumor activity will be summarized in terms of 
ORR, DCR, DOR, PFS and OS.  Analyses will be based on response as determined by the 
investigator per RECIST version 1.1. The potential impact of level of HER2 expression and 
potentially other biomarkers on clinical efficacy will also be explored.
12.5.1
Overall Response Rate
ORR will be defined as the proportion of patients with a best overall response of CR or PR at 
the time each patient discontinues ADCT-502. The percentage of ORR with its 80% 
confidence interval (CI) will be presented.
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12.5.2
Disease Control Rate
DCR will be calculated to facilitate comparison and to help with future publications. DCR
will be defined as the proportion of patients with a best overall response of CR or PR, or SD. 
Percentage of DCR with its 80% CI will be presented.
12.5.3
Duration of Response
DOR will be defined among responders (CR or PR) as the time from the earliest date of first 
response until the first date of either disease progression or death due to any cause. The date 
of disease progression will be defined as the earliest date of disease progression as assessed 
by the Investigator using RECIST version 1.1 for response.  For patients who have not 
progressed or died at the time of the analysis, censoring will be performed using the date of 
the last valid disease assessment. The data will be analyzed by Kaplan-Meier method. 
The median duration of response and 80% CI will be presented. Further details will be 
outlined in the SAP.
12.5.4
Progression-Free Survival
PFS will be defined among the efficacy population 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 RECIST version 1.1, or death.  For patients whose disease 
has not progressed at the time of the analysis, censoring will be performed using the date of 
the last valid disease assessment. The data will be analyzed by Kaplan-Meier method. 
The median PFS time and 80% CI will be presented. Further details will be outlined in the 
SAP.
12.5.5
Overall Survival
Median OS will be defined as the time from the beginning of study drug treatment until death 
due to any cause. For patients who have not died at the time of the analysis, censoring will 
be performed using the date the patient was last known to be alive. The data will be analyzed 
by Kaplan-Meier method. The median OS and 80% CI will be presented. Further details 
will be outlined in the SAP.
12.6
Pharmacokinetic and Pharmacodynamic Analyses
PK parameters will be determined for all PK-evaluable patients using
non-compartmental method(s) using Phoenix (Cetara USA, Inc., Princeton, NJ, USA) or 
other appropriate software. All data will be summarized with respect to demographic, 
baseline characteristics and safety observations using descriptive statistics (quantitative data) 
and contingency tables (qualitative data).  In addition, the influence of ADCT-502 and free 
warhead SG3199 concentrations on the QTc interval or LVEF values will also be explored.
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12.7
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 minus date of first 
dose of study drug plus 1.
13 Data Quality Assurance
13.1
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 an electronic data capture system. 
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 (MedDRA). Concomitant medications will be coded using WHO Drug
Dictionary.
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.
14 Study Conduct and Administration
14.1
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.
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14.2
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 the 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.
14.3
Patient Information and Consent
A written informed consent in compliance with US Title 21 Code of Federal Regulations 
(CFR) Part 50 shall be obtained from each patient before entering the study or performing 
any unusual or non-routine procedure that involves risk to the patient. An informed consent 
template may be provided by the Sponsor to investigative sites. If any institution-specific 
modifications to study-related procedures are proposed or made by the site, the consent 
should be reviewed by the Sponsor or its designee or both before IRB/IEC submission. 
Once reviewed, the consent will be submitted by the Investigator to his or her IRB/IEC for 
review and approval before the start of the study. If the ICF is revised during the course of 
the study, all patients on-study must sign the revised form, unless otherwise indicated by the 
IRB/IEC (local or global, as applicable). In such case, the reason for not re-consenting the 
patient should be documented.
Before recruitment and enrollment, each prospective patient or his or her legal guardian will 
be given a full explanation of the study and be allowed to read the approved ICF. Once the 
Investigator is assured that the patient/legal guardian understands the implications of 
participating in the study, the patient/legal guardian will be asked to give consent to 
participate in the study, and that additional exploratory studies can be done with collected 
blood/serum, by signing the ICF.
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14.4
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.
14.4.1
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.
14.4.2
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.
14.4.3
Adverse Events and Study Report Requirements
By participating in this study, the Investigator agrees to submit reports of SAEs to the 
Sponsor according to the time line and method outlined in the protocol. In addition, the 
Investigator agrees to submit annual reports to the study site IRB/IEC as appropriate.
The Sponsor will ensure that all relevant safety information (SAEs and SUSARSs) is
reported to the FDA and competent authorities of EU Member States, and to the IEC, 
in accordance with current legislation (US 21CFR.316 and EU Directive 2001/20/EC).
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14.4.4
Investigator Documentation
Prior to beginning the study, the Investigator will be asked to comply with the current version 
of ICH E6 8.2, Title 21 of the CFR, and local regulations by providing the following 
essential documents, including but not limited to:

IRB/IEC approval.

Original Investigator-signed Investigator agreement page of the protocol.

Form FDA 1572, fully executed, and all updates on a new fully executed Form
FDA 1572 or equivalent (where applicable).

Curriculum vitae for the Investigator and each sub-Investigator listed on Form
FDA 1572 or equivalent (where applicable).

Financial disclosure information to allow the Sponsor to submit complete and accurate
certification or disclosure statements required under 21 CFR 54. In addition, the
Investigators must provide to the Sponsor a commitment to promptly update this
information if any relevant changes occur during the course of the investigation and for
1 year after the completion of the study.

IRB/IEC-approved informed consent, samples of site advertisements for recruitment for
this study, and any other written information regarding this study that is to be provided
to the patient or legal guardian.
14.4.5
Study Conduct
The Investigator agrees that the study will be conducted according to the principles of the 
current version of ICH E6. The Investigator will conduct all aspects of this study in 
accordance with all national, state, and local laws or regulations. Study information from this 
protocol will be posted on publicly available clinical study registers before enrollment of 
patients begins.
14.4.6
Adherence to Protocol
The Investigator agrees to conduct the study as outlined in this protocol in accordance with
the current version of ICH E6 and all applicable guidelines and regulations.
14.4.7
Investigator’s Final Report
Upon completion of the study, where applicable, the Investigator should provide the IRB/IEC 
with a summary of the study outcome and the Sponsor and regulatory authority(ies) with any 
reports required.
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14.4.8
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.
15 Study Management
15.1
Monitoring
15.1.1
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.
15.1.2
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.
15.2
Management of Protocol Amendments and Deviations
15.2.1
Modification of the Protocol
Any change in the study plan requires a protocol amendment. 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.
Only protocol amendments intended to eliminate an apparent immediate hazard to patient(s) 
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may be implemented immediately, i.e., without IRB/IEC and Sponsor approval, but the 
circumstances of the change must be documented and submitted to the IRB/IEC and to the 
Sponsor for further evaluation.   
15.2.2
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.
15.3
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 EOT visit to the site and any visit to the site to obtain 
confirmatory scan of response).
15.4
Final Report
Whether the study is completed or prematurely terminated, the Sponsor will ensure that the 
clinical study reports are prepared and provided to regulatory agency(ies) as required by the 
applicable regulatory requirement(s). 
An Investigator will be identified to act as the signatory for the clinical study report. 
The Investigator will be provided access to statistical tables, figures, and relevant reports and 
will have the opportunity to review the complete study results.
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16 Publications
Following completion of the study, the results from the study may be reported publicly by 
making any oral public presentation and/or submitting or presenting a manuscript, abstract, 
or other materials relating to the Study at scientific meetings and/or to a publisher, reviewer, 
or other outside person in scientific journals (“Publication”), provided however that
Publication of the results of the Study conducted at a site shall not be made before the first 
multi-site Publication by Sponsor.  The Sponsor shall coordinate the drafting, editing, 
authorship, and other related activities of such Publication and shall mutually agree with the 
Investigator(s) on the number, medium, forum and timing for Publication. Sponsor shall 
solicit input regarding contents of the Publication from all Investigators and in consultation 
with all sites.  The Sponsor acknowledges the right of the Investigator(s) to publish the 
results of this study after the entire study has completed, but also reserves the right to a 
window to review the Publication for regulatory compliance as well as for protection of its 
intellectual property.  In particular, Sponsor may request to remove Sponsor’s confidential 
information and suspend Publication for a certain period of time to protect Sponsor’s 
intellectual property interest, as further set forth in the Clinical Trial Agreement with the 
clinical study site(s) and Investigator(s).
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17 Reference List
Arteaga CL, Sliwkowski MX, Osborne CK, Perez EA, Puglisi F, Gianni L. Treatment of 
HER2-positive breast cancer: current status and future perspectives.  Nat Rev Clin 
Oncol., 2011 Nov 29;9(1):16-32.
Bang Y, Cutsem EV, Feyereislova A, Chung HC, Shen L, Sawaki A, et al.  Trastuzumab in 
combination with chemotherapy versus chemotherapy alone for treatment of
HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): 
a phase 3, open-label, randomised controlled trial.  www.thelancet.com, Vol 376 
August 28, 2010.
Barok M, Tanner M, Köninki K, Isola J.  Trastuzumab-DM1 is highly effective in 
preclinical models.  Cancer Letters, 306 (2011) 171–179.
Bookman MA, Darcy KM, Clarke-Pearson D, Boothby RA, Horowitz IR.  Evaluation of 
Monoclonal Humanized Anti-HER2 Antibody, Trastuzumab, in Patients With Recurrent 
or Refractory Ovarian or Primary Peritoneal Carcinoma With Overexpression of HER2: 
A Phase II Trial of the Gynecologic Oncology Group.  Journal of Clinical Oncology, 
Vol 21, No 2 (January 15), 2003: pp 283-290.
Bose R, Kavuri SM, Searleman AC, Shen W, Shen D, Koboldt DC, et al.  HER2 mutations 
in HER2 gene amplification negative breast cancer.  Cancer Discov, 2013 
Feb;3(2):224-37.
Buttitta1 F, Barassi F, Fresu G, Felicioni L, Chella A, Paolizzi D, et al.  Mutational analysis 
of the HER2 gene in lung tumors from Caucasian patients: Mutations are mainly 
present in adenocarcinomas with bronchioloalveolar features.  Int. J. Cancer: 119, 
2586–2591 (2006).
Chang MT, Asthana S, Gao SP, Lee BH, Chapman JS, Kandoth C, et al.  Identifying 
recurrent mutations in cancer reveals widespread lineage diversity and mutational 
specificity.  Nat Biotechnol, 2016 Feb; 34(2):155-63.
Chung A, Cui X, Audeh W, Giuliano A.  Current status of anti-her2 therapies: predicting 
and overcoming herceptin resistance.  Clin Breast Cancer.,  2013 Aug; 13(4): 223-232.
de Bono JS, Bellmunt J, Attard G, Droz JP, Miller K, Flechon A, et al.  Open-Label Phase II 
Study Evaluating the Efficacy and Safety of Two Doses of Pertuzumab in Castrate 
Chemotherapy-Naïve Patients With Hormone-Refractory Prostate Cancer.  Journal of 
Clinical Oncology, Volume 25, Number 3, January 20, 2007.
Fleming GF, Sill MW, Darcy KM, McMeekin DS, Thigpen JT, Adler LM, et al.
Phase II trial of trastuzumab in women with advanced or recurrent, HER2-positive.  
Gynecologic Oncology 116 (2010) 15–20.
Gonzalvez F, Zhu X, Huang WS, Baker TE, Ning Y, Wardwell SD, et al.  Abstract 2644: 
AP32788, a potent, selective inhibitor of EGFR and HER2 oncogenic mutants, 
including exon 20 insertions, in preclinical models.  Cancer Res 2016; 76 
(14 Suppl):Abstract nr 2644.
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Harder J, Ihorst G, Heinemann V, Hofheinz R, Moehler M, Buechler P, et al.  Multicentre 
phase II trial of trastuzumab and capecitabine in patients with HER2 overexpressing 
metastatic pancreatic cancer.  British Journal of Cancer (2012) 106, 1033 – 1038.
HERCEPTIN® (trastuzumab) Prescribing Information, 2016.
Hernández-Blanquisett A, Touya D, Strasser-Weippl K, Ruiz R, St Louis J, Goss P. Current 
and emerging therapies of HER2-positive metastatic breast cancer.  Breast, 2016 
Oct;29:170-7.
Hyman DM, Piha-Paul SA, Rodón J, Saura C, Puzanov I, Shapiro GI, et al. 
Abstract PD5-05: Neratinib for ERBB2 mutant, HER2 non-amplified, metastatic breast 
cancer: Preliminary analysis from a multicenter, open-label, multi-histology phase II 
basket trial.  Cancer Res 2016; 76(4 Suppl):Abstract nr PD5-05.
Javle1M, Churi C , Kang HC, Shroff  R, Janku F, Surapaneni R, et al.  HER2/neu-directed 
therapy for biliary tract cancer.  Journal of Hematology & Oncology (2015) 8:58.
Kang YK, Shah MA, Ohtsu A, Van Cutsem E, Ajani JA, van der Horst T, et al.  
A randomized, open-label, multicenter, adaptive phase 2/3 study of trastuzumab 
emtansine (T-DM1) versus a taxane (TAX) in patients (pts) with previously treated 
HER2-positive locally advanced or metastatic gastric/gastroesophageal junction 
adenocarcinoma (LA/MGC/GEJC).  J Clin Oncol 34, 2016 (suppl 4S; abstr 5).
Krop IE, Kim SB, González-Martín A, LoRusso PM, Ferrero JM, Smitt M, et al. 
Trastuzumab emtansine versus treatment of physician's choice for pretreated
HER2-positive advanced breast cancer (TH3RESA): a randomised, open-label, phase 3 
trial.  The Lancet Oncology.  The Lancet Oncology, Volume 15, No. 7, p689–699, 
June 2014.
Limaye SA, Posner MR, Krane JF, Fonfria M, Lorch JA,  Dillon DA.  Trastuzumab for the 
Treatment of Salivary Duct Carcinoma.  The Oncologist, 2013;18:294–300.
Mazieres J, Peters S, Lepage B, Cortot AB, Barlesi F, Beau-Faller M, et al.  Lung Cancer 
That Harbors an HER2 Mutation: Epidemiologic Characteristics and Therapeutic 
Perspectives.  Journal of Clinical Oncology, Volume 31, Number 16, June 2013.
Neuenschwander B, Branson M, and Gsponer T.  Critical aspects of the Bayesian approach 
to phase I cancer trials. Stat Med. 2008 Jun 15;27(13):2420-39.
Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, et al.  Toxicity 
and response criteria of the Eastern Cooperative Oncology Group.  Am J Clin Oncol. 
1982 Dec;5(6):649-55.
Omar N, Yan B, Salto-Tellez M.  HER2: An emerging biomarker in non-breast and
non-gastric cancers.  Pathogenesis 2 (2015) 1–9.
Oudard S, Culine S, Vano Y, Goldwasser F, Theodore C, Nguyen T, et al.  Multicentre 
randomised phase II trial of gemcitabine + platinum, with or without trastuzumab,
in advanced or metastatic urothelial carcinoma overexpressing Her2.  
European Journal of Cancer (2015) 51, 45– 54.
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With or Without Pertuzumab Versus Trastuzumab Plus Taxane for Human Epidermal 
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Growth Factor Receptor 2–Positive, Advanced Breast Cancer: Primary Results From 
the Phase III MARIANNE Study.  J Clin Oncol 34, 2016.
PERJETA® (pertuzumab) Prescribing Information, 2012.  
Ross DS, Zehir A, Cheng DT, Benayed R, Nafa K, Hechtman JF, et al.  Next-Generation 
Assessment of Human Epidermal Growth Factor Receptor 2 (ERBB2) Amplification 
Status: Clinical Validation in the Context of a Hybrid Capture-Based, Comprehensive 
Solid Tumor Genomic Profiling Assay (2017).  J Mol Diagn 19(2):244-254
Rudin CM, Pietanza MC, Bauer TM, Spigel DR, Ready N, Morgansztern D, et al.  Safety 
and efficacy of single-agent rovolpituzumab tesirine (SC16LD6.5), a delta-like protein 
3 (DLL3)-targeted antibody-drug conjugate (ADC) in recurrent or refractory small cell 
lung cancer (SCLC).  J Clin Oncol 34 (2016) (suppl: abstr LBA8505).
Sartore-Bianchi A, Trusolino L, Martino C, Bencardino K, Lonardi S, Francesca Bergamo 
F, et al.  Dual-targeted therapy with trastuzumab and lapatinib in treatment-refractory, 
KRAS codon 12/13 wild-type, HER2-positive metastatic colorectal cancer 
(HERACLES): a proof-of-concept, multicentre, open-label, phase 2 trial.  
thelancet.com/oncology, Vol 17, June 2016.
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Somatic Mutations of the HER2 Kinase Domain in Lung Adenocarcinomas.  
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18 Appendices
18.1
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
Allergic reaction = A disorder characterized by an adverse local or general response from exposure to an 
allergen.
Anaphylaxis
-
-
Symptomatic 
bronchospasm, 
with or without 
urticaria; parenteral 
intervention 
indicated; allergy-
related 
edema/angioedema
; hypotension
Life-threatening 
consequences;
urgent 
intervention 
indicated
Death
Anaphylaxis = 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
Autoimmune disorder = 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.
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Adverse Event
Grade 1
Grade 2
Grade 3
Grade 4
Grade 5
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
Cytokine release syndrome = 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
Serum sickness = A disorder characterized by a delayed-type hypersensitivity reaction to foreign proteins 
derived from an animal serum. It occurs approximately 6 to 21 days following the administration of the 
foreign antigen. Symptoms include fever, arthralgias, myalgias, skin eruptions, lymphadenopathy, chest 
marked discomfort, and dyspnea.
Immune 
system 
disorders -
Other, 
specify
Asymptomatic or 
mild symptoms; 
clinical or 
diagnostic 
observations only; 
intervention not 
indicated
Moderate; 
minimal, local 
or noninvasive 
intervention 
indicated; 
limiting 
age-appropriate 
instrumental 
ADL
Severe or 
medically 
significant but not 
immediately 
life-threatening; 
hospitalization or 
prolongation of 
existing 
hospitalization 
indicated; 
disabling; limiting 
self-care ADL
Life-threatening 
consequences;
urgent 
intervention 
indicated
Death
ADL = Activities of daily living; NSAIDs = non-steroidal anti-inflammatory drugs.
Adapted from CTCAE version 4.0 – June 14, 2010, Immune system disorders.
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18.2
Eastern Cooperative Oncology Group Performance Status
Performance status will be assessed using the ECOG performance status grades as indicated 
below:
Grade
Definition
0
Fully active, able to carry on all predisease performance without restriction.
1
Restricted in physically strenuous activity but ambulatory and able to carry out work of a 
light or sedentary nature (e.g., light house work, office work).
2
Ambulatory and capable of all self-care but unable to carry out any work activities. 
Up and about more than 50% of waking hours.
3
Capable of only limited self-care, confined to bed or chair more than 50% of waking 
hours.
4
Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair.
5
Dead.
Oken, 1982
18.3
Somatic Mutations Observed via Next Generation Sequencing
Table 5 lists somatic ERBB2/HER2 mutations obtained from the cbioportal database 
(http://www.cbioportal.org, accessed 20 December 2016), which were identified as recurrent 
hotspots (statistically significant) in a population-scale cohort of tumor samples of various 
cancer types using methodology based on Chang, 2016.
Table 5: List of Somatic ERBB2/HER2 Mutations Obtained from the Cbioportal Database
Amino Acid Position
Mutation Type
L755M
Single Residue Change
L755P
Single Residue Change
L755S
Single Residue Change
L755W
Single Residue Change
S310F
Single Residue Change
S310Y
Single Residue Change
V777L
Single Residue Change
V777M
Single Residue Change
V842I
Single Residue Change
D769H
Single Residue Change
D769N
Single Residue Change
D769Y
Single Residue Change
R678Q
Single Residue Change
Additional ERBB2/HER2 mutations, which are known to be oncogenic based in part on Bose, 
2013; Hyman, 2016; and Gonzalvez, 2016, are listed below in Table 6.
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Table 6: List of ERBB2/HER2 Mutations Known to be Oncogenic
Amino Acid Position
Mutation Type
G309A
Single Residue Change
G309E
Single Residue Change
V842I
Single Residue Change
R896C
Single Residue Change
Y772_V773insRDGE
Insertion
Y772_A775dup
synonymous 772-775, in-frame indel
Duplication
G778_S779insLPS
In frame insertion 
P780-Y781insGSP
synonymous G778_p780dup
In frame Insertion
L869R
Single Residue Change
Most of the HER2 mutations observed in lung cancer to date have been insertions within a 
small stretch of exon 20 on the ERBB2/HER2 gene.  Such aberrations are likely oncogenic 
and are displayed in Table 7 (Mazieres, 2013; Buttitta, 2006; Shigematsu, 2005).
Table 7: Insertional HER2 Mutations Predominantly Identified in Lung Cancer
Amino Acid Position
Mutation Type
G776_777insVC
synonymous G776>VC
synonymous G776delinsVC
In frame insertion
A775 or G776
Any in frame insertion/duplication at this position, 
including but not limited to A775_G776insYVMA
e.g. 776–779 (YVMA) qualifies as well
GSP 781-783 ins
In frame insertion
G776V
In frame codon insertion
G776L
In frame codon insertion
It is plausible to assume that all listed mutations are likely to have a tumor promoting impact 
on the HER2 protein, and that tumor cells therefore express such altered protein in order to 
gain a growth and/or survival advantage over neighboring cells. 
Moreover, HER2 hotspot mutations are a good predictor for functional relevance 
(Bose, 2013), and hence all mutations listed in this section including the ones from cbioportal 
listed in Table 8 qualify for participation in Part 1 of the study. Additionally, patients with 
mutations that are reported with variation in terminology on the corresponding NGS report,
but that have the same meaning as those listed here, will be permitted into the study.
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Date of Protocol Amendment 2: 17 August 2017
Page 81
Table 8: List of Mutations from Cbioportal
Amino Acid Position
Mutation Type
G776S
Single Residue Change
G660D
Single Residue Change
G660R
Single Residue Change
T733I
Single Residue Change
T862A
Single Residue Change
T862S 
Single Residue Change
18.4 Appendix: Modified Continual Reassessment Method of Dose 
Escalation
18.4.1Overview
Planned dose levels for ADCT-502 are shown below in Table 9. Dose escalation will be
conducted according to a mCRM, with dose EWOC and no dose skipping. 
A recommendation to escalate, stay, or deescalate the dose level for the next 2 patient cohorts
will be made according to the planned dose scheme in Table 9. 
The study will be continuously monitored for safety and early stopping for successfully 
identifying the MTD. Dose escalation will be stopped when 3 cohorts are consecutively 
assigned to the same dose level, which will be identified as the MTD.
Table 9: Planned Dose Levels for ADCT-502
Dose Level
Dose of ADCT-502
Dose Level
Dose of ADCT-502
1
30 µg/kg
7
240 µg/kg
2
60 µg/kg
8
300 µg/kg
3
120 µg/kg
9
350 µg/kg
4
150 µg/kg
10
400 µg/kg
5
180 µg/kg
11
450 µg/kg
6
210 µg/kg
12
500 µg/kg
18.4.2Model and Priors
Dose escalation in this study will be conducted using the mCRM. 
For each dose, d = 1,…., n, we model the binary outcome of non-DLT, or a DLT. 
The log odds of a DLT are modeled as








DLT
DLT
d



1
log
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Date of Protocol Amendment 2: 17 August 2017
Page 82
with a 2-parameter model 
*)
/
log(
)
exp(
d
di
d





where d* is the reference dose, which is used to standardize the dose di and allows for the 
interpretation of α as the odds of a DLT at d*. Exp(β) is positive, ensuring a monotonically 
increasing dose-toxicity relationship. 
Neuenschwander, 2008 placed a bivariate lognormal prior on the two parameters and
proposed eliciting information on the risk of DLT at two (2) or more doses to obtain prior 
means and variances. Several articles have examined the specification of priors. When there 
are no previous historical clinical data available, it is possible to use uninformative prior. 
For this purpose, the above model can be re-parametrized in terms of (ρ0,γ), where ρ0 is the 
probability of a DLT at the starting dose d1 and γ is the MTD, the dose expected to produce 
DLT at 0.3 probability in this study, with
)
)
1
log(
)
(log(
*
)
exp(










d
d
and placing the following independent prior distributions on the parameters. 
ρ0 ~ Uniform(0, 0.30)
γ ~ Uniform(d1, dn).
18.4.3Dose Escalation Rule and Choice of Cohort Size
Dose escalation will begin with 2 patients enrolled at the initial starting dose. The cohort size 
is 2, which means that 2 patients will be assigned to escalate to the next dose level,
de-escalate to the prior dose level, or, stay at the current dose level. 
On the completion of each cohort (i.e., 2 patients treated and assessed for DLT after 1-cycle), 
the posterior distributions of θ(d) are summarized for each dose level by the probabilities of 
under-dosing, targeted toxicity, or excessive/unacceptable toxicity. These 3 probabilities are 
defined as:
Under-dosing:
)
20
.0,0
(

d

Targeted Toxicity:
]
35
.0,
20
.0
[

d

Excessive or Unacceptable Toxicity:
]1,
35
.0
(

d

The dose which maximizes the probability of targeted toxicity while controlling the 
probability of excessive or unacceptable toxicity to ≤25% will be recommended for the next 
cohort of 2 patients. The model has the flexibility for a larger cohort size if additional patient 
are available.
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18.4.3.1
Stopping Rules
Patients will continue to be recruited into the study until 3 cohorts of patients are 
consecutively assigned to the same dose level, which will be identified as the MTD.
18.4.4Interim Monitoring
The study will be 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. 
18.4.4.1
Safety Monitoring
The lowest dose (the initial starting dose) will be considered unsafe if the probability of 
excessive or unacceptable toxicity is > 25%. The trial will stop, and no MTD found, if the 
lowest dose is considered unsafe (hence all doses are considered unsafe).
18.4.5Operating Characteristics
Different dose-toxicity scenarios were simulated to evaluate how the dose escalation design 
will perform (Figure 1). The operating characteristics of the study are based on 1,000 
simulations per scenario. For each scenario, the mean probability of selecting the dose as 
MTD is plotted versus dose, number of patients at the target dose, lower dose, high dose, and 
number of DLTs. 
18.4.5.1
Scenarios 
 
 
 
 
 
 
 
 
 
 
 
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Figure 3: Probability of a DLT Under 5 Simulated Scenarios
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Date of Protocol Amendment 2: 17 August 2017
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Scenario 1: True Probability of a DLT (with 0.1, 0.17, 0.3, 0.38, 0.46, 0.51, 
0.57, 0.67, 0.75, 0.8, 0.84, 0.87)
0
0.5
Proability of selecting the dose as MTD with 3 dose 
escalation designs
3+3
0
5
10
15
20
25
30
Total # of Pts
# of Pts at
Targeted
dose
# of Pts at
low doses
# of Pts at
high doses
Total # of DLT
Expected number of patients
3+3
mCRM2
mCRM3
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Date of Protocol Amendment 2: 17 August 2017
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Scenario 2: True Probability of a DLT (with 0.05, 0.075, 0.1, 0.12, 0.13, 
0.15, 0.18, 0.3, 0.60, 0.75, 0.8, 0.85)
0
0.1
0.2
0.3
0.4
0.5
0.6
Proability of selecting the dose as MTD
3+3
mCRM2
mCRM3
0
5
10
15
20
25
30
35
Total # of
Pts
# of Pts at
Targeted
dose
# of Pts at
low doses
# of Pts at
high doses
Total # of
DLT
Expected number of patients
3+3
mCRM2
mCRM3
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Scenario 3: True Probability of a DLT (with 0.02, 0.04, 0.06, 0.07, 0.08, 0.09, 0.105, 
0.125, 0.165, 0.22, 0.3, 0.45)
0
0.1
0.2
0.3
0.4
0.5
Proability of selecting the dose as MTD
3+3
mCRM2
mCRM3
0
5
10
15
20
25
30
35
Total # of Pts
# of Pts at Targeted
dose
# of Pts at low
doses
# of Pts at high
doses
Total # of DLT
Expected number of patients
3+3
mCRM2
mCRM3
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Scenario 4: True Probability of a DLT (with 0.10, 0.125, 0.16, 0.19, 
0.22, 0.25, 0.30, 0.37, 0.5, 0.6, 0.7, 0.8)
0
0.1
0.2
0.3
0.4
Proability of selecting the dose as MTD
3+3
mCRM2
mCRM3
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Scenario 5: True Probability of a DLT (with 0.13, 0.15, 0.17, 0.18, 0.19, 0.20, 
0.21, 0.22, 0.24, 0.30, 0.36, 0.44)
0
0.05
0.1
0.15
0.2
0.25
0.3
Proability of selecting the dose as MTD
3+3
mCRM2
MCRM3
0
10
20
30
40
Total # of Pts
# of Pts at
Targeted dose
# of Pts at low
doses
# of Pts at high
doses
Total # of DLT
Expected number of patients
3+3
mCRM2
mCRM3
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Clinical Protocol Amendment 2 Summary of Changes
A Phase 1, Open-Label, Dose-Escalation Study to Evaluate the Safety, 
Tolerability, Pharmacokinetics, and Antitumor Activity of ADCT-502 in 
Patients with Advanced Solid Tumors with HER2 Expression
The primary reasons for Protocol Amendment 2 (17 August 2017) were to revise the modified 
continual Reassessment Method (mCRM) model and include additional flexibility around 
provisional dose levels and dosing regimen; as well as to incorporate revisions and clarifications 
throughout the document following increasing scientific knowledge, such as HER2 amplification 
status measured by next-generation sequencing (NGS).
Summary of Substantial Changes:

Since there is no mathematical model which could accurately correlate DLT rate when the 
dose interval is changed or intermediate doses not predefined in the mCRM model are used, 
the possibility to use a 3+3 design has been introduced in Section 2.4 to cover for these 
situations.

A new potential dosing schedule consisting in omitting dosing every n-th cycle (e.g. every 
3rd cycle) has been introduced in Section 2.4. This approach is being employed in a clinical 
trial with an antibody-drug conjugate (ADC) with the identical linker and warhead as 
ADCT-502 (NCT03033511) and may have the potential to optimize anti-tumor activity 
while limiting adverse events.

Section 4.2 has been revised to: 
o
clarify that any immunohistochemistry (IHC) result can be overruled by 
contemporaneous or subsequent amplification results for the purpose of this study. 
o
clarify that NGS (hybridization capture-based NGS) can also be used for 
determination of HER2 amplification.
o
clarify for Part 1 that a retrospective confirmation of HER2 expression is needed 
when NGS is used for HER2 classification, irrespective of NGS results.
o
update Inclusion criterion 5 and Appendix 18.3 accordingly.

Clarified and revised time windows for visits and assessments in Schedule of Events (SoE) 
Table 1 and Table 2, and Section 4.4.

It has been clarified in Section 4.4 and footnote 16 and 24 of the SoE that the Follow-up 
period is applicable for the whole study, i.e., both Part 1 and Part 2, including the follow-
up by radiographic examination for any patients who discontinue treatment for any reason 
other than disease progression.

The possibility to enroll additional breast cancer patients in cohorts of Part 1 to better 
understand the potential efficacy of ADCT-502 in an indication approved for treatment with 
HER2 targeted antibodies has been implemented in Section 4.6.
Page 279 of 280



Intra-patient escalation in Part 1 was made possible once the recommended dose(s) has
been identified in Part 2, Section 4.6.

Resuming dosing for drug delays longer than 21 days are also permitted for DLTs as long
as the patient can potentially benefit from ADCT-502. This is supported by the fact that
patients treated with different ADCs with the same warhead (e.g. ADCT-402) have
demonstrated long-lasting tumor suppression during prolonged (> 1 month) drug holidays,
Section 5.

The recommendation of G-CSF use in case of (febrile) neutropenia was revised for
clarification with additional reference to ASCO guidelines, Section 5.2.

Inclusion criterion 4 was further clarified to provide more accurate information on the
tumor tissue that is expected to be received for demonstrating HER2 expression. The
number of slides had to be increased in case retesting is needed. The SoE Table 1 was
revised accordingly.

The unit of creatinine clearance was corrected in Inclusion criterion 7.

Exclusion criterion 15 was revised for clarification.

Prophylaxis with dexamethasone (Section 9.1), recommendations for treatment of edema
and/or pleural effusion (Section 9.5), and other supportive care (Section 9.6) were added
based on emerging safety data of other investigational agents containing the same
pyrollobenzodiazepine warhead.

ECG will be recorded in triplicate in order to more robustly investigate the ECG-PK
relationship. Associated instructions, e.g., sequence of assessments, are provided in SoE
Table 1 and Table 2, Section 10.1, and 10.4.1.

Section 10.3 indicates that imaging central review will be used.

Sections 10.3, 10.4, and 10.4.2 were revised to include the instructions already present in
footnotes of the SoE Table 1.

PK, soluble HER2, and ADA samples will not be collected beyond starting new anticancer
treatment due to practicality issues, e.g., when patients would enter a new oncology clinical
study, SoE Table 1 and Section 10.4.2.

In order to prevent stability issues with PK samples, the storage temperature has been set
strictly to ≤ -70°C, Section 10.5.

Revised instruction for AE reporting in Section 11.1 to start from ICF signature for
consistency with Section 11.2.

Additional dose levels (150 and 210 mg) have been implemented in the mCRM, Table 9 of
Appendix 18.4. Therefore, the number of dose levels has not been limited to 10 in the
statistical model in 18.4.2, and Figure2 and the graphical representations of Scenarios 1 to
5 have been updated.
In addition, administrative and editorial changes have been performed and revisions to the
protocol text have also been applied to the synopsis section.
Page 280 of 280

SAP_001.pdf: 
Protocol Number:   ADCT-502-101  
 
Official Title:    A Phase 1, Open-Label, Dose-Escalation Study to Evaluate the Safety, Tolerability, 
Pharmacokinetics, and Antitumor Activity of ADCT-502 in Patients With Advanced Solid Tumors With 
HER2 Expression 
 
NCT Number:  NCT03125200 
 
Document Date:  July 5, 2018 


Abbreviated Clinical Study Report 
ADCT-502-101 
 
Confidential
ADCT-502 
 
 
 
 
16.1.9 
Documentation of Statistical Methods 
ADCT-502-101 Statistical Analysis Plan FINAL version 1.0 July 5, 2018 
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ADC Therapeutics 
ADCT-502 
ADCT-502-101 
SAP version 1.0 
 
 
 
 
 
Statistical Analysis Plan 
 
 
 
 
A Phase 1, Open-Label, Dose-Escalation Study to Evaluate the Safety, 
Tolerability, Pharmacokinetics, and Antitumor Activity of ADCT-502 in 
Patients with Advanced Solid Tumors with HER2 Expression 
 
PROTOCOL NO.:  ADCT-502-101  
 
 
 
SAP Version No./ Date: 1.0/ July 5, 2018 
 
 
 
 
 
 
  
Confidentiality Statement 
All financial and nonfinancial support for this study will be provided by ADC Therapeutics 
SA. The concepts and information contained in this document or generated during the study 
are considered proprietary and may not be disclosed in whole or in part without the 
expressed, written consent of ADC Therapeutics SA. The study will be conducted according 
to the International Conference on Harmonisation harmonised tripartite guideline E6(R1), 
Good Clinical Practice. 
 
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Page 3 of 15
ADC Therapeutics 
ADCT-502-101 
Study Title 
Protocol Number 
Original SAP Version 
Date: 
SAP Approval - Sponsor Signatory 
ADCT-502 
SAP version 1.0 
A Phase 1, Open-Label, Dose-Escalation Study to Evaluate 
the Safety, Tolerability, Pharmacokinetics, and Anti tumor 
Activity of ADCT-502 in Patients with Advanced Solid 
Tumors with HER2 Expression 
ADCT-502-101 
05JUL2018 
SAP accepted and approved by: 


ADC Therapeutics 
ADCT-502 
ADCT-502-101 
SAP version 1.0 
Table of Contents 
Table of Contents ...................................................................................................................... 3 
List of Tables ............................................................................................................................. 4 
List of Figures ........................................................................................................................... 4 
1 Introduction ............................................................................................................................ 5 
2 Study Objectives .................................................................................................................... 6 
2.1 Primary Objectives ......................................................................................................6 
2.2 Secondary Objectives ..................................................................................................6 
 
3 Study Design .......................................................................................................................... 7 
3.1 Sample Size Consideration ..........................................................................................7 
3.2 Randomization .............................................................................................................7 
3.3 Modifications to the statistical section of the protocol ................................................7 
4 Statistical methods ................................................................................................................. 8 
4.1 Analysis Sets ................................................................................................................8 
4.1.1 Safety Analysis Set .........................................................................................8 
4.2 Subject Disposition ......................................................................................................8 
4.3 Demographic and Baseline Characteristics .................................................................8 
4.4 Pre-treatment disease characteristics and medical history ..........................................9 
4.5 Prior anticancer therapy ...............................................................................................9 
4.6 Prior or Concomitant Medications (other than anticancer therapies) ..........................9 
4.7 Exposure to Treatment .................................................................................................9 
4.7.1 Extent of ADCT-502 Exposure .......................................................................9 
4.7.2 Subsequent Anticancer Therapy or Procedure ..............................................10 
4.8 Safety Analyses .........................................................................................................10 
4.8.1 Dose-limiting Toxicities ................................................................................10 
4.8.2 Adverse Events, Serious Adverse Events, and Deaths ..................................10 
4.8.2.1 Analyses of adverse events .......................................................... 10 
4.8.2.2 Deaths ...........................................................................................11 
4.8.3 Laboratory Data ............................................................................................ 11 
4.8.4 Electrocardiogram .........................................................................................12 
4.8.5 Vital Signs .....................................................................................................12 
4.8.6 ECOG Performance Status ...........................................................................12 
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4.9 Efficacy Analyses ......................................................................................................12 
4.10 Pharmacokinetic Analyses and Pharmacodynamic Analyses ..................................12 
5 Interim Analyses .................................................................................................................. 12 
6 Data handling conventions ................................................................................................... 13 
6.1 General conventions ..................................................................................................13 
6.1.1 Missing data ..................................................................................................13 
6.1.2 Unscheduled visits ........................................................................................13 
6.1.3 Duplicated visit .............................................................................................13 
 
List of Tables 
 
NA 
List of Figures 
 
NA 
 
 
 
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ADCT-502 
ADCT-502-101 
SAP version 1.0 
1 Introduction 
This statistical analysis plan (SAP) describes the statistical methods to be used during the 
reporting and analyses of data collected under ADC Therapeutics Protocol ADCT-502-101. 
This SAP should be read in conjunction with the study protocol and case report form (CRF).  
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2  Study Objectives 
2.1 Primary Objectives  
• Evaluate safety, tolerability, and determine the MTD and/or RDE of single agent 
ADCT-502 in patients with advanced solid tumors with known HER2 status (IHC ≥1+ 
or HER2 amplified/mutated) (Part 1).  
• Further evaluate safety and tolerability at the dose level determined in Part 1 in patients 
with advanced solid tumors including breast cancer, lung, gastroesophageal, and 
bladder cancer or a basket of other solid tumors known to express HER2 
(HER2-high or HER2-low status confirmed prospectively for study entry) (Part 2). 
2.2 Secondary Objectives 
• Evaluate the preliminary antitumor activity of ADCT-502.  
• Characterize the PK profile of ADCT-502.  
• Determine the immunogenicity of ADCT-502. 
 
 
 
 
 
 
  
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3 Study Design 
Refer to the corresponding section in the protocol.  
3.1 Sample Size Consideration 
Refer to the corresponding section in the protocol.  
3.2 Randomization 
This study is not randomized. 
3.3 Modifications to the statistical section of the protocol  
 Due to early termination of this trial, the dose-expansion portion (Part 2) of the study has not 
been performed. Therefore, only dose-escalation (Part 1) data has been analyzed and selected 
or modified analysis from the statistical section of the protocol will be performed.  Please see 
details in each section.  
 
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4 Statistical methods  
All analyses use SAS® version 9.4 or higher. Summary tables will be organized by each dose 
level for Part 1; if some dose levels have only a few subjects, then dose levels can be combined 
into dose ranges. All available data will be used in the analyses, and important data will be 
included in data listings, sorted by dose level for Part 1, subject, and by visit within subject. 
Missing data will not be imputed, except via censoring in survival analyses and otherwise 
specified. 
Unless otherwise noted, categorical data are presented using counts and percentages, with the 
number of subjects in the analysis set by treatment group as the denominator for percentages. 
Percentages are 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, are summarized using the number of observations (n), mean, standard 
deviation (std), median, minimum, and maximum. Minima and maxima are rounded to the 
precision of the original value, and means, medians, and confidence intervals (CIs) if presented 
are rounded to 1 decimal place greater than the precision of the original value. The std is 
rounded to 2 decimal places greater than the precision of the original value, up to a maximum 
of 3 decimal places.  
No hypothesis testing will be performed in this study. 
4.1 Analysis Sets  
4.1.1 Safety Analysis Set 
The safety analysis set consists of all subjects who receive ADCT-502. 
4.2 Subject Disposition 
For the Safety analysis set, the number and percentage of subjects who discontinued study 
treatment and discontinued the study for each reason will be tabulated for each dose level. 
Subject disposition data will be listed.  
4.3 Demographic and Baseline Characteristics 
Demographic and baseline characteristics will be tabulated for the Safety analysis set. 
Variables include the following: 
• Sex (female, male) 
• Race (white, black or African American, Asian, American Indian or Alaska native, 
native Hawaiian or other Pacific Islander, other) 
• Ethnicity (Hispanic or Latino, not Hispanic or Latino) 
• Age (years) 
• Age group (< 65, ≥ 65 - < 75, ≥ 75 years) 
• Height (cm) 
• Weight (kg) 
• Body mass index (kg/m2) 
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• ECOG PS 
Demographic and baseline characteristics data will be listed. 
4.4 Pre-treatment disease characteristics and medical history 
Cancer history will be listed for the Safety analysis set. Cancer history will include the 
following variables: 
• Primary tumor type (Breast, Gastric, Esophageal/GEJ, etc.) 
• Histology/ Genetics (where applicable) 
• Date of initial diagnosis 
• Initial staging (0, IA, IB, etc.) 
• Date of most recent occurrence 
• Stage at most recent occurrence 
HER2 testing results and medical history data will be listed. 
4.5 Prior anticancer therapy 
The number and percent of patients who had prior anticancer surgery and radiotherapy will 
be summarized.  
 
The number of lines of systemic therapies will be summarized. Number of lines is counted 
from the unique number of regimen number reported on the CRF.  
Prior anticancer surgery, radiotherapy and systemic therapy data will be listed. 
4.6 Prior or Concomitant Medications (other than anticancer therapies) 
All medications will be coded using the World Health Organization-Drug Dictionary (WHO-
DD). 
Patient listing of all prior and concomitant medications will be provided. Pre-medication for 
dosing (for example, prophylaxis for hypersensitivity) will listed separately.  
4.7 Exposure to Treatment 
4.7.1 Extent of ADCT-502 Exposure 
ADCT-502 exposure will be summarized for the Safety analysis set by dose level. The 
following items will be tabulated:  
• 
Duration of treatment (in weeks) = (date of last dose – date of first dose +1)/7 
• 
Number of infusions 
• 
Number of patients treated by cycle 
• 
Cumulative dose (in µg/kg) = sum of (dose administered at each infusion [µg] /last available 
weight[kg]), 
where dose administered at each infusion[µg]=Actual Volume [of IP, in mL]* 5 mg/mL 
*1000; if partial infusion, dose administered at each infusion[µg]= (1- volume of dosing 
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solution not administered [in mL]/ 50 mL) * ( Actual Volume [of IP, in mL]* 5 mg/mL 
*1000) 
Exposure data and infusion details will be listed together. 
4.7.2 Subsequent Anticancer Therapy or Procedure 
Subjects’ subsequent anticancer therapy or procedure including systemic therapy, radiation, 
or other, along with the start date of subsequent anticancer therapy or procedure will be 
collected and listed. 
4.8 Safety Analyses 
General common rules 
All safety analyses will be performed on the safety analysis set, unless otherwise specified, 
using the following common rules: 
• The baseline value is defined as the last non-missing value or measurement taken up to 
the first dose of the study drug 
• The analysis of the safety variables will be essentially descriptive and no systematic 
testing is planned. 
• If relevant, selected safety analyses may be summarized by age, sex, racial subgroups 
and any pertinent subgroups.  
• The toxicity grade will be taken into account in the summary. For subjects with multiple 
occurrences of the same event, the maximum grade is used. If a subject has both 
missing and non-missing severity grades for TEAEs within the same PT, the missing 
severity of the TEAE will be treated as the lower severity grade (ie, the subject will be 
counted under the non-missing severity grade). If there is non-missing severity grade, 
the subject will be counted under the non-missing severity grade. 
 
4.8.1 Dose-limiting Toxicities  
DLT data will be listed. 
4.8.2 Adverse Events, Serious Adverse Events, and Deaths 
4.8.2.1 Analyses of adverse events 
The primary focus of adverse event reporting will be on the treatment-emergent adverse 
events (TEAEs). A TEAE is defined as an adverse event that occurs or worsens in the period 
extending from the first dose of study drug to 30 days after the last dose of study drug in this 
study. 
If an AE date/time of onset (occurrence, worsening, or becoming serious) is incomplete, an 
imputation algorithm will be used to classify the AE as pre-treatment, TEAE, or post-treatment. 
For example, if only the day of the AE onset is missing, the year and month will be compared 
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with the first dose and 30 days after the last dose of study drug. And if the month and day of 
the AE onset are missing, the year will be compared with the first dose and 30 days after the 
last dose of study drug. The algorithm for imputing TEAE will be conservative and will classify 
an AE as a treatment emergent unless there is definitive information to determine it is non-
TEAEs (pre- or post-treatment).  
 
 
Analysis of all TEAE(s):  
The following TEAE summaries will be generated for the safety analysis set. 
• Overview of TEAEs, summarizing number of TEAE and number (%) of subjects with 
any 
- 
TEAE 
- 
Related TEAE (including possibly related, probably related, or related) 
- 
Any ≥ grade 3 TEAE 
- 
Serious TEAE  
- 
TEAE leading to death 
- 
TEAE leading to permanent treatment discontinuation 
- 
TEAE leading to ADCT-502 delay or reduction or interruption 
- 
TEAE with at least one infusion related reaction 
• All TEAEs by PT, showing number (%) of subjects with at least one TEAE, sorted by 
decreasing incidence of PTs 
• All TEAEs by SOC and PT, showing number (%) of subjects with at least one TEAE, 
sorted by SOC in alphabetic order and decreasing incidence of PTs within SOC. This 
sorting order will be applied to all other AE tables, unless otherwise specified 
• All TEAEs by SOC, PT and Maximum CTCAE grade 
• All ≥ grade 3 TEAEs by SOC, PT and Maximum CTCAE grade 
• All related TEAEs by SOC, PT and Maximum CTCAE grade (including possibly 
related, probably related, or related) 
• All Serious TEAEs by SOC and PT by SOC, PT and Maximum CTCAE grade 
All AEs (including non-TEAEs), all TEAEs leading to treatment withdrawal, all TEAEs 
leading to dose reduction, all TEAEs leading to dose delay, infusion related reaction and all 
TEAEs with fatal outcome will be listed.  
4.8.2.2 Deaths 
Reasons for deaths will be summarized separately for 1) all deaths, 2) death on therapy or 
within 30 days after last dose of study drug. 
4.8.3 Laboratory Data 
Laboratory data of hematology, chemistry, and coagulation will be reported in SI units.  
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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. 
Laboratory data, including urinalysis will be listed. Pregnancy test results will not be listed, 
but will be included in datasets. 
4.8.4 Electrocardiogram 
ECG parameters (e.g. corrected QT interval [QTc]) will not be converted or derived, but will 
be reported as provided by investigational sites. 
All ECG data will be listed, both for quantitative data and for overall interpretation. 
4.8.5 Vital Signs 
All vital signs data will be listed together with body weight. 
4.8.6 ECOG Performance Status 
All ECOG data will be listed. 
4.9 Efficacy Analyses 
Due to the early termination of the trial, efficacy data will be listed only. Lesion assessment 
data (target lesions, non-target lesions, and new lesions) will be listed.  
4.10 Pharmacokinetic Analyses and Pharmacodynamic Analyses 
Pharmacokinetic and biomarker data will be listed in the CSR Appendices. 
5 Interim Analyses  
Due to the early termination of the trial, interim analyses were not performed.  
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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 date of death, date of initial diagnosis 
for reporting, no imputation should be done at the data level. 
 
• If dates are completely missing, no imputation will be made.  
• For any partial date with missing year, no imputation will be made. 
• For missing initial diagnosis date and subsequent therapies, if only day is missing, then 
the 15th of the month will be used; if only year is present, then June 30th will be used. 
If such imputed date for initial diagnosis is on or after date of first dose, then date of 
first dose - 1 will be used. If such imputed date for subsequent therapies is before date 
of last dose, then date of last dose +1 will be used. 
• If the imputed date is for a date of death and is before the last date that the subject is 
known to be alive, the latter date will be used. 
 
Handling of missing relationship to investigational product of AEs 
If the assessment of the relationship to investigational product is missing, then the relationship 
to investigational product has to be assumed and the AE considered as such in the frequency 
tables of possibly related AEs, but no imputation should be done at the data level. 
 
Handling of missing severity/grades of AEs 
If the severity/grade is missing for one of the treatment emergent occurrences of an AE, the 
maximal severity on the remaining occurrences will be considered. If the severity is missing 
for all the occurrences a “missing” category will be added in summary table. 
 
No other imputation of values for missing data will be performed. 
 
6.1.2 Unscheduled visits 
Unscheduled visit measurements of laboratory data will be used for computation of baseline 
and worst values and/or grades. Re-windowing for unscheduled visits will not be performed  
 
6.1.3 Duplicated visit 
Depending on the statistical analysis method, single values may be required for each analysis 
window. For example, change from baseline by visit usually requires a single value per visit. 
Unless otherwise noted throughout the rest of this document, when a single value is needed, 
the following rule(s) will be used: 
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• 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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