A Phase 2 Study of Cusatuzumab Plus Azacitidine in Patients With Newly Diagnosed Acute Myeloid Leukemia Who Are Not Candidates for Intensive Chemotherapy
Phase: PHASE2
Conditions: Leukemia, Myeloid, Acute
Sponsor: OncoVerity, Inc.

 
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Status: Approved, Date: 13 Jun 2023 
OncoVerity, Inc 
 
Clinical Protocol 
 
Protocol Title 
A Phase 2 Study of Cusatuzumab Plus Azacitidine in Patients With Newly Diagnosed 
Acute Myeloid Leukemia who are not Candidates for Intensive Chemotherapy 
 
Protocol CULM20236; Phase 2 
AMENDMENT 4 
 
 OV-1001* (Cusatuzumab) 
 
*Previously JNJ-74494550 (Protocol 74494550AML2001)  
 
US sites of this study will be conducted under US Food & Drug Administration IND regulations 
(21 CFR Part 312). 
 
EudraCT NUMBER: 2019-000473-23 
 
 
 
 
 
Status: 
Approved   
Date: 
13 Jun 2023 
Prepared by: OncoVerity, Inc 
 
 
GCP Compliance:  This study will be conducted in compliance with Good Clinical Practice, and applicable regulatory 
requirements.  
Confidentiality Statement 
The information provided herein contains Company trade secrets, commercial or financial information that the Company 
customarily holds close and treats as confidential. The information is being provided under the assurance that the recipient will 
maintain the confidentiality of the information under the Trade Secrets Act, Procurement Integrity Act, other applicable statutes, 
regulations, rules, protective orders or otherwise and as such, the information provided herein is exempt from disclosure under 
Exemption 4 of the Freedom of Information Act (“FOIA”). 
 

OV-1001 (Cusatuzumab) 
 
Clinical Protocol CULM20236 Amendment 3 
 
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Status: Approved, Date: 13 Jun 2023 
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE 
Document 
Date 
Amendment 4
13 Jun 2023
Amendment 3
30 September 2021
Amendment 2
19 August 2020
Amendment 1
22 October 2019
Original Protocol
18 March 2019
 
Amendment 4 (19 May 2023) 
Overall Rationale for the Amendment: After 22 Oct 2021 (after the primary endpoint analysis had been 
completed), subjects who are still benefiting from study treatment can continue to receive study treatments 
and will have a reduced schedule of assessments. 
Section Number 
and Name 
Description of Change 
Brief Rationale 
 
 
 
 
 
 
 
Throughout the 
protocol 
Updates to the program number (from JNJ-74494550 to 
OV-1001), 
study 
number 
(from 
AML2001 
to 
CULM20236), and study sponsor (from Janssen Research 
and Development to OncoVerity Inc.).  
Updating for a new sponsor, 
namely OncoVerity, Inc.. 
 
 

OV-1001 (Cusatuzumab) 
 
Clinical Protocol CULM20236 Amendment 3 
 
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Status: Approved, Date: 13 Jun 2023 
TABLE OF CONTENTS 
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE ............................................................... 2 
TABLE OF CONTENTS ............................................................................................................................... 3 
LIST OF IN-TEXT TABLES AND FIGURES ................................................................................................ 6 
1. 
PROTOCOL SUMMARY ..................................................................................................................... 7 
1.1. 
Synopsis ........................................................................................................................................... 7 
1.2. 
Schema ............................................................................................................................................ 9 
1.3. 
Schedule of Activities (SoA) ........................................................................................................... 10 
2. 
INTRODUCTION................................................................................................................................ 18 
2.1. 
Study Rationale .............................................................................................................................. 18 
2.1.1. 
Study Design Rationale .............................................................................................................. 18 
2.1.2. 
Rationale for the Selected Patient Population ............................................................................ 19 
2.1.3. 
Rationale for Combination Treatment With Cusatuzumab Plus Azacitidine .............................. 19 
2.1.4. 
Rationale for Dose Selection ...................................................................................................... 20 
2.1.5. 
Rationale for Administration Schedule ....................................................................................... 21 
2.2. 
Background .................................................................................................................................... 21 
2.2.1. 
Acute myeloid leukemia .............................................................................................................. 21 
2.2.2. 
Cusatuzumab .............................................................................................................................. 22 
2.2.2.1. 
Clinical Data............................................................................................................................. 22 
2.2.3. 
Azacitidine .................................................................................................................................. 25 
2.3. 
Benefit/Risk Assessment ............................................................................................................... 25 
3. 
OBJECTIVES AND ENDPOINTS ..................................................................................................... 26 
4. 
STUDY DESIGN ................................................................................................................................ 27 
4.1. 
Overall Design ................................................................................................................................ 27 
4.2. 
Scientific Rationale for Study Design ............................................................................................. 29 
4.2.1. 
Study-Specific Ethical Design Considerations ........................................................................... 30 
4.3. 
Justification of Dose ....................................................................................................................... 30 
4.4. 
End of Study Definition................................................................................................................... 31 
5. 
STUDY POPULATION ...................................................................................................................... 31 
5.1. 
Inclusion Criteria ............................................................................................................................ 31 
5.2. 
Exclusion Criteria ........................................................................................................................... 33 
5.3. 
Lifestyle Considerations ................................................................................................................. 35 
5.4. 
Screen Failures .............................................................................................................................. 35 
6. 
STUDY INTERVENTION ................................................................................................................... 36 
6.1. 
Study Interventions Administered .................................................................................................. 36 
6.1.1. 
Premedications ........................................................................................................................... 37 
6.1.2. 
Anti-infective Prophylaxis............................................................................................................ 37 
6.2. 
Preparation/Handling/Storage/Accountability ................................................................................ 37 
6.3. 
Measures to Minimize Bias: Randomization and Blinding ............................................................. 38 
6.4. 
Study Intervention Compliance ...................................................................................................... 38 
6.5. 
Concomitant Therapy ..................................................................................................................... 38 
6.5.1. 
Permitted Therapies ................................................................................................................... 38 
6.5.2. 
Prohibited Therapies and Procedures ........................................................................................ 39 
6.5.3. 
Subsequent Anticancer Therapy ................................................................................................ 39 
6.6. 
Dose Modification ........................................................................................................................... 39 
6.6.1. 
Management Guidelines for Potential Toxicities During Cusatuzumab Infusion ........................ 39 
6.6.2. 
Management Guidelines for Toxicities Attributed to Cusatuzumab ........................................... 40 
6.6.3. 
Management Guidelines for Toxicities Attributed to Azacitidine ................................................ 40 
6.7. 
Intervention After the End of Treatment ......................................................................................... 42 

OV-1001 (Cusatuzumab) 
 
Clinical Protocol CULM20236 Amendment 3 
 
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7. 
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ............................................................................................... 42 
7.1. 
Discontinuation of Study Intervention ............................................................................................ 42 
7.2. 
Participant Discontinuation/Withdrawal From the Study ................................................................ 42 
7.2.1. 
Withdrawal From the Use of Research Samples ....................................................................... 43 
7.3. 
Lost to Follow-up ............................................................................................................................ 43 
8. 
STUDY ASSESSMENTS AND PROCEDURES ............................................................................... 44 
8.1. 
Efficacy Assessments .................................................................................................................... 44 
8.2. 
Safety Assessments ....................................................................................................................... 47 
8.2.1. 
Physical Examination .................................................................................................................. 47 
8.2.2. 
Vital Signs ................................................................................................................................... 48 
8.2.3. 
Electrocardiogram ....................................................................................................................... 48 
8.2.4. 
Spirometry Test .......................................................................................................................... 48 
8.2.5. 
ECOG Performance Status ........................................................................................................ 48 
8.2.6. 
Clinical Safety Laboratory Assessments .................................................................................... 48 
8.3. 
Adverse Events and Serious Adverse Events ............................................................................... 49 
8.3.1. 
Time Period and Frequency for Collecting Adverse Event and Serious Adverse Event 
Information .................................................................................................................................. 49 
8.3.2. 
Method of Detecting Adverse Events and Serious Adverse Events .......................................... 49 
8.3.3. 
Follow-up of Adverse Events and Serious Adverse Events ....................................................... 50 
8.3.4. 
Regulatory Reporting Requirements for Serious Adverse Events ............................................. 50 
8.3.5. 
Adverse Events of Special Interest ............................................................................................. 50 
8.3.6. 
Pregnancy ................................................................................................................................... 50 
8.4. 
Treatment of Overdose .................................................................................................................. 50 
8.5. 
Pharmacokinetics ........................................................................................................................... 51 
8.5.1. 
Evaluations ................................................................................................................................. 51 
8.5.2. 
Analytical Procedures ................................................................................................................. 51 
8.5.3. 
Pharmacokinetic Parameters and Evaluations ........................................................................... 52 
8.6. 
Genetics ......................................................................................................................................... 52 
8.6.1. 
Cytogenetics/ Mutational Analysis .............................................................................................. 52 
8.7. 
Pharmacodynamics ........................................................................................................................ 53 
8.8. 
Biomarkers ..................................................................................................................................... 53 
8.9. 
Patient-Reported Outcomes .......................................................................................................... 54 
8.10. 
Medical Resource Utilization .......................................................................................................... 55 
9. 
STATISTICAL CONSIDERATIONS .................................................................................................. 55 
9.1. 
Statistical Hypotheses .................................................................................................................... 55 
9.2. 
Sample Size Determination ........................................................................................................... 56 
9.3. 
Populations for Analyses................................................................................................................ 56 
9.4. 
Statistical Analyses ........................................................................................................................ 56 
9.4.1. 
Efficacy Analyses ........................................................................................................................ 56 
9.4.2. 
Safety Analyses .......................................................................................................................... 56 
9.4.3. 
Other Analyses ........................................................................................................................... 57 
9.5. 
Interim Analyses ............................................................................................................................. 60 
9.6. 
Data Review Committee ................................................................................................................ 62 
10. 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS ............................ 63 
10.1. 
Appendix 1: Abbreviations and Trademarks .................................................................................. 63 
10.2. 
Appendix 2: Clinical Laboratory Tests ........................................................................................... 65 
10.3. 
Appendix 3: Regulatory, Ethical, and Study Oversight Considerations ......................................... 66 
10.4. 
Appendix 4: Adverse Events: Definitions and Procedures for Recording, Evaluating, 
Follow-up, and Reporting ............................................................................................................... 77 
10.5. 
Appendix 5: Contraceptive and Barrier Guidance and Collection of Pregnancy Information ........ 83 
10.6. 
Appendix 6: ECOG Performance Status Score ............................................................................. 86 
10.7. 
Appendix 7: New York Heart Failure Criteria ................................................................................. 87 
10.8. 
Appendix 8: Patient-reported Outcomes FACT-Leu Questionnaire .............................................. 88 
10.9. 
Appendix 9: Patient-reported Outcomes EQ-5D-5L Questionnaire ............................................... 91 

OV-1001 (Cusatuzumab) 
 
Clinical Protocol CULM20236 Amendment 3 
 
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10.10. Appendix 10: Risk Stratification by Genetics ................................................................................. 93 
10.11. Appendix 11: Protocol Amendment History ................................................................................... 94 
11. 
REFERENCES................................................................................................................................. 102 
INVESTIGATOR AGREEMENT ............................................................................................................... 104 
 
 
 

OV-1001 (Cusatuzumab) 
 
Clinical Protocol CULM20236 Amendment 3 
 
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LIST OF IN-TEXT TABLES AND FIGURES 
TABLES 
Table 1: 
Schedule of Activities Up to 22 Oct 2021 ................................................................................. 10 
Table 1A: Schedule of Activities After 22 Oct 2021 .................................................................................. 13 
Table 2: 
Schedule of Pharmacodynamic and Biomarker Evaluations .................................................... 15 
Table 3: 
Schedule of Pharmacokinetic Evaluations for the First 50 Participants (approximately 
25 for each dose; intensive PK sampling) ................................................................................ 16 
Table 4: 
Schedule of Pharmacokinetic Evaluations for Azacitidinea ...................................................... 17 
Table 5:  
Schedule of Pharmacokinetic Evaluations for Participants Randomized after the 50th 
Participant (sparse PK sampling) ............................................................................................. 17 
Table 6:  
Response Assessments based on ELN 2017 (Dohner 2017)6 ................................................. 46 
Table 7:  
Statistical Decision Parameters for Study Part 1: Observed CR, 1-Sided Confidence 
Interval (CI), and Statistical Decision ........................................................................................ 61 
Table 8: 
Operating Characteristics of Particular Interest ........................................................................ 62 
Table 9: 
ELN Risk Stratification by Genetics6 ......................................................................................... 93 
 
FIGURES 
Figure 1: 
Schema for Study CULM20236 .................................................................................................. 9 
 

OV-1001 (Cusatuzumab) 
 
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1. 
PROTOCOL SUMMARY  
1.1. 
Synopsis 
A Phase 2 Study of Cusatuzumab Plus Azacitidine in Patients With Newly Diagnosed Acute Myeloid 
Leukemia who are not Candidates for Intensive Chemotherapy. 
CD70 is a cell surface antigen normally expressed in a small subset of activated B- and T- lymphocytes and 
is involved in lymphocyte differentiation and survival signaling upon binding to its receptor, CD27. CD70 
is over-expressed in several tumor types, often together with CD27 in hematological malignancies 
suggesting its involvement in proliferation and survival of the malignant cells. Over 95% of acute myeloid 
leukemia (AML) blasts harvested from newly diagnosed AML patients expressed CD70 on the cell surface.  
Cusatuzumab (OV-1001) is a humanized monoclonal antibody of camelid origin, binding with high affinity 
to human CD70. Cusatuzumab has been modified to induce enhanced antibody-dependent cell-mediated 
cytotoxicity (ADCC) for therapeutic use in patients with cancer. 
Primary Objective 
The primary objective of this study is to determine the complete response (CR) rate of 2 dose levels of 
cusatuzumab in combination with azacitidine in participants with previously untreated AML who are not 
eligible for intensive chemotherapy.  
Hypothesis 
The primary hypothesis of this study is that the combination of cusatuzumab at doses of 10 mg/kg or 
20 mg/kg with azacitidine has a CR rate of no less than 35% in patients with previously untreated AML 
who are not eligible for intensive chemotherapy.  
OVERALL DESIGN 
Up to approximately 150 participants will be treated in this randomized study of 2 dose levels of 
cusatuzumab in combination with azacitidine in patients with previously untreated AML who are not 
eligible for intensive chemotherapy. The study will consist of 2 parts: the purpose of Part 1 is to select a 
dose based on the totality of the data; the purpose of Part 2 is to evaluate and confirm the efficacy and safety 
of the selected dose level. NOTE: Part 2 of the study will not be conducted because further development of 
this regimen (cusatuzumab in combination with azacitidine) in patients with unfit AML will not be pursued 
due to the evolving treatment landscape in AML. 
After 22 Oct 2021, ongoing subjects (on treatment or in follow-up) will be treated and assessed according 
to a reduced schedule of assessment (Table 1A).  
TREATMENT GROUPS AND DURATION 
In Part 1 of the study, participants will be randomized in a 1:1 ratio to receive cusatuzumab and azacitidine 
in 1 of the following 2 dosing regimen groups:  
 
Group A: Azacitidine 75 mg/m2 SC or IV on Day 1 through Day 7, cusatuzumab 10 mg/kg IV on Day 
3 and Day 17 of each 28-day cycle 
 
Group B: Azacitidine 75 mg/m2 SC or IV on Day 1 through Day 7, cusatuzumab 20 mg/kg IV on Day 
3 and Day 17 of each 28-day cycle 
Participants will be treated until disease progression, relapse, unacceptable toxicity, or withdrawal due to 
investigator discretion or withdrawal of consent. The Follow-up Phase will begin once a participant 
discontinues study intervention, and will continue until death, loss to follow up, consent withdrawal for 

OV-1001 (Cusatuzumab) 
 
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study participation, or study end, whichever occurs first. The end of study will be reached when all subjects 
have completed or discontinued study treatment. The final data from the study site will be sent to the 
Sponsor (or designee) after completion of the final participant visit at the study site, in the time frame 
specified in the Clinical Trial Agreement. 
EFFICACY EVALUATIONS  
Disease evaluations will include peripheral blood and bone marrow assessments and will be conducted per 
local laboratory as indicated in the Schedule of Activities. Disease status will be evaluated according to 
European Leukemia Network (ELN) Response Criteria in AML (2017). Survival status and subsequent 
anticancer therapy will also be collected. 
PHARMACOKINETIC EVALUATIONS 
Plasma and serum samples will be analyzed to determine concentrations of azacitidine and cusatuzumab, 
respectively. Cusatuzumab concentrations in bone marrow may also be determined.  
PHARMACODYNAMIC AND BIOMARKER EVALUATIONS 
Pharmacodynamic biomarker tests will include evaluation of the change in soluble CD27 (sCD27) level, 
change of CD70 and CD27 expression levels, decrease of blasts and leukemia stem cells in whole blood 
and bone marrow by flow cytometry, and expression of CD70-CD27 signaling and leukemic stem 
cell-related genes by transcriptome analysis. Biomarker tests will also evaluate the mechanism of action of 
cusatuzumab by flow cytometric or time of flight mass cytometry (CyTOF) assessment of natural killer 
(NK), T- and B-cells. Minimal/measurable residual disease will be evaluated by flow cytometry and 
molecular approaches according to ELN guidance 2018.  
SAFETY EVALUATIONS 
The safety of cusatuzumab will be assessed by physical examinations, Eastern Cooperative Oncology 
Group (ECOG) performance status, clinical laboratory tests, vital signs, and adverse event monitoring.  
STATISTICAL METHODS 
Part 1 of the study will utilize a 3-stage monitoring approach to determine, at each stage and for each dose 
group, if the observed CR rate warrants the respective dose to be continued into the next stage or into Part 
2 of the study. Only 1 dose will be selected to continue to Part 2. Participants will be enrolled into Part 2 at 
the selected cusatuzumab dose until a cumulative total of 100 participants have been treated with the 
selected dose from Part 1 and Part 2. The study has a >90% power to reject the null hypothesis of a CR rate 
of 20% under the alternative hypothesis of 35% for a total of 100 participants (from Part 1 and Part 2) at 
the selected dose level. This sample size is based on the single-arm Wilson Score test without continuity 
correction at an overall 1-sided type 1 error rate <2.5%.   
 
 

OV-1001 (Cusatuzumab) 
 
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1.2. 
Schema 
A diagram of the study design is provided in Figure 1. 
NOTE: Part 2 of the study will not be conducted because further development of this regimen 
(cusatuzumab in combination with azacitidine) in patients with unfit AML will not be pursued due 
to the evolving treatment landscape in AML.  
Figure 1: 
Schema for Study CULM20236 
 

OV-1001 (Cusatuzumab) 
 
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1.3. 
Schedule of Activities (SoA)  
Table 1: 
Schedule of Activities Up to 22 Oct 2021 
NOTE: As of Amendment 3: After 22 Oct 2021, subjects will no longer follow this SoA. Subjects will be treated and assessed according to Table 1A. 
 
Screening 
Randomization 
Treatment 
Follow-up 
Study Procedure 
Within 28 days of 
randomization 
Within 72 hours of 
first dose 
Azacitidine/ cusatuzumab combination therapy 
(28-day cycle) 
EOTa 
30 days (±3 days) 
after last dose of 
study treatment and 
then every 3 months 
thereafter (±7 days)b
Cycle 1 – EOT 
Screening/ Administrative
Informed consentc
X
Demographics/ medical 
history
X 
 
 
 
 
Cytogenetic testing/ 
Mutational analysis
Xd 
 
 
 
 
Inclusion/exclusion criteriae 
X 
X 
 
 
 
Study Intervention Administration
Randomization 
 
X 
 
 
 
Pre-medicationsf
X
Azacitidine 75 mg/m2 SC or 
IVe 
 
 
Day 1 to Day 7 of each 28-day cycle  
 
 
 
Cusatuzumab IV infusion at 
selected dosef 
 
 
Day 3 and Day 17 of each 28-day cycle  
(+2 days) 
 
 
Efficacy Assessments
Disease evaluationg 
 
Xh 
 
Every other cycle, starting at Cycle 1, (between Day 21 up to and 
including Day 1 of the next cycle) until CR or progressive disease. 
Once CR is achieved, disease evaluation can be performed every 4th 
cycle until relapse. Once CR without MRD is achieved, a repeat bone 
marrow examination to confirm should be performed at least 4 weeks 
later. In cases of cycle delays, timing of disease evaluations should be 
performed per protocol at the end of the specified odd cycle.
X 
 
Bone marrow aspiratei 
Within 7 days of Cycle 1/ 
Day 1
 
At every disease evaluation 
X 
 
Evaluation of extramedullary 
diseasej 
X 
 
At every disease evaluation as needed 
X 
 
Transfusion status 
X 
 
At every disease evaluation 
X 
 

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Screening 
Randomization 
Treatment 
Follow-up 
Study Procedure 
Within 28 days of 
randomization 
Within 72 hours of 
first dose 
Azacitidine/ cusatuzumab combination therapy 
(28-day cycle) 
EOTa 
30 days (±3 days) 
after last dose of 
study treatment and 
then every 3 months 
thereafter (±7 days)b
Cycle 1 – EOT 
Survival status/subsequent 
therapy/ other malignancies
 
 
 
X 
Xk 
Safety Assessments (See Section 8)
Adverse events and 
concomitant therapy
X 
 
X 
X 
X 
Physical Examination height 
and weight
X 
 
Day 1 of each cycle 
(height is measured at screening only)
X 
 
Vital signsl 
X 
 
Days 1, 3, and 17 of each cycle 
X 
 
ECOG assessment 
X 
 
Day 1 of each cycle 
X 
 
12-lead ECGl 
X 
 
For participants with baseline cardiac disease, perform additional ECG every other cycle  
(at same time as disease evaluation). For other participants, only if clinically indicated   
Spirometry 
X 
(only for participants with 
baseline pulmonary disease) 
 
For participants with baseline pulmonary disease, perform spirometry every 4th cycle at same time as 
disease evaluation. For other participants, only if clinically indicated 
Medical resource utilizationm
Continuous from the time of signing of the ICF until 30 days after the last dose of study intervention
Clinical Laboratory tests (See Appendix 2, Section 10.2)
Hematology, including 
peripheral blood blast counts 
X 
 
During Cycle 1: hematology should be checked weekly. For all other 
cycles, check on Day 1 and Day 17 of each cycle and with each disease 
evaluation.n If clinically indicated, monitoring should be more 
frequent.
X 
 
Chemistry 
X 
 
During Cycle 1: chemistry should be checked weekly. For all other 
cycles, check on Day 1 and Day 17 of each cycle and with each disease 
evaluation.n If clinically indicated, monitoring should be more frequent. 
X 
 
Pregnancy test for women of 
childbearing potential
X 
 
X 
Xo 
 
Hepatitis and HIVp
X
Pharmacodynamics and Biomarkers (whole blood/ PBMC/ serum/ bone marrow sample collection)   
PD/ Biomarker testing  
(See Table 2) 
Within 7 days of Cycle 1/  
Day 1 
 
See Table 2 for Sampling Schedule  
Pharmacokinetics (Bone marrow and Peripheral blood)  
PK testing (See Table 3 and 
Table 5) 
Within 7 days of Cycle 1/ Day 
1 
 
See Table 3 for Sampling Schedule for first 50 participants (25 per group) and Table 5 for participants 
randomized after the 50th 

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Screening 
Randomization 
Treatment 
Follow-up 
Study Procedure 
Within 28 days of 
randomization 
Within 72 hours of 
first dose 
Azacitidine/ cusatuzumab combination therapy 
(28-day cycle) 
EOTa 
30 days (±3 days) 
after last dose of 
study treatment and 
then every 3 months 
thereafter (±7 days)b
Cycle 1 – EOT 
Patient-reported outcomes (PRO)q
Fact-Leu 
 
 
Day 1 of each cycle  
X 
Only at first visitk 
EQ-5D-5L 
 
 
Day 1 of each cycle  
X 
Only at first visitk 
AML= acute myeloid leukemia; CR= complete response; CRh= <5% blasts in the bone marrow, no evidence of disease and partial recovery of platelets to >50,000/μL and absolute neutrophil count 
>500/μL;  CRi= complete response with incomplete blood count recovery; ECG= electrocardiogram; ECOG= Eastern Cooperative Oncology Group status score; EOT= end of treatment; HIV= 
human immunodeficiency virus;  ICF= informed consent form; IV= intravenous; MRD= minimal residual disease; PK= pharmacokinetics; PRO= patient-reported outcomes; SC= subcutaneous   
a. 
The End of Treatment Visit must occur in person within approximately 7 days of treatment discontinuation. 
b. 
As per Section 8.3.1, all adverse events will be reported until 30 days after the last dose of study intervention or until the start of subsequent anti-AML therapy, if earlier. 
c. 
ICF must be signed before first study-related activity is performed. 
d. 
Assessment of mutational status must be performed and must include testing for all mutations listed in Appendix 10. Mutational analyses should be performed on bone marrow collected 
at screening. Central and/or local testing is acceptable. Local, standard-of-care assessment of mutational status obtained prior to the ICF signing will be accepted in lieu of a repeat 
assessment on screening marrow, provided that it includes testing for all mutations outlined in Appendix 10. Left over fresh or frozen bone marrow samples may be requested for central 
mutational analysis if all tests are not performed by the local study site.  
e. 
Minimum criteria for the availability of documentation supporting the eligibility criteria are described in Source Documents in Appendix 3.  
f. 
See Section 6.1 and Section 6.1.1 for dosing schedule and premedications. When cusatuzumab and azacitidine are scheduled to be administered together, azacitidine should be 
administered first. It is recommended that there is at least 30 minutes waiting time between the end of azacitidine administration and the start of the cusatuzumab infusion. 
g. 
Evaluation includes bone marrow evaluation (bone marrow aspirate preferred for assessment of blast %), hematology with differential, transfusion assessment, and assessment for 
extramedullary disease per local standard of care. Results of MRD testing will be provided by the Sponsor when appropriate. For participants who discontinue study treatment without 
disease progression, disease evaluations should continue with the same frequency as during study treatment until disease progression. 
h. 
Obtain 2 to 3 peripheral blood blast counts during screening     
i. 
A bone marrow aspirate should be performed for the disease assessment (for bone marrow blasts) within 7 days of first dose (or Cycle 1 Day 1). Once a bone marrow aspirate is 
performed, the sample must be sent to central laboratory within 48 hours for biomarker and PK testing. In case of a dry tap, a biopsy may also be utilized for disease assessment. See 
Table 2 for bone marrow biomarker sampling and Table 3 for bone marrow PK sampling. Any unscheduled bone marrow assessments must be reported. 
j. 
Evaluation for extramedullary disease required only for participants with suspicion of or known extramedullary AML disease 
k. 
Assessments may occur via telephone contact. 
l. 
Vital Signs: heart rate, blood pressure (monitor with same method and position [sitting or supine] throughout study), respiratory rate, and temperature to be performed prior to 
administration of any study intervention. If blood sampling or vital sign measurement is scheduled for the same timepoint as ECG recording, the procedures should be performed in the 
following order: ECG(s), vital signs, blood draw.  See Section 8.2.2 
m. 
Information on health care needs during treatment (eg, physiotherapist) to be collected by study staff. 
n. 
Samples may be obtained within 24 hours of the Day 1 and Day 17 visits. 
o. 
Pregnancy testing to also be performed for women of childbearing potential 1 month after last dose of study treatment. 
p. 
Laboratory testing for hepatitis and HIV at screening is to be performed for all participants. 
q. 
PROs should be performed before dosing and before any study tests or procedures or consultations are conducted when possible.
 
 

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Table 1A: 
Schedule of Activities After 22 Oct 2021 
 
Treatment 
Follow-up 
Study Procedure 
Azacitidine/ cusatuzumab combination therapy 
(28-day cycle) 
EOTa 
30 days (±3 days) 
after last dose of study 
treatment and then 
every 3 months 
thereafter (±7 days)b
Cycle 1 – EOT 
Study Intervention Administration
Pre-medicationsc
X
Azacitidine 75 mg/m2 SC or IVd 
Day 1 to Day 7 of each 28-day cycle  
 
 
Cusatuzumab IV infusion at selected dosec 
Day 3 and Day 17 of each 28-day cycle  
(+2 days) 
 
 
Efficacy Assessments
Disease evaluationd 
 
Every other cycle, starting at Cycle 1, (between Day 21 up to and including Day 1 of the next cycle) 
until CR or progressive disease. Once CR is achieved, disease evaluation can be performed every 4th 
cycle until relapse. Once CR without MRD is achieved, a repeat bone marrow examination to confirm 
should be performed at least 4 weeks later. In cases of cycle delays, timing of disease evaluations 
should be performed per protocol at the end of the specified odd cycle.
X 
 
Bone marrow aspiratee 
At every disease evaluation 
X 
 
MRDe 
Bone marrow: Every 4 cycles following CR and every 2 cycles following CRi/CRh  
(collected between Day 21 up to and including Day 1 of the next cycle)  
Whole Blood: Every 2 cycles following CR/CRi/CRh on Day 1
X 
 
Evaluation of extramedullary diseasef 
At every disease evaluation as needed 
X 
 
Transfusion status
At every disease evaluation
X
Survival status/subsequent therapy/ other malignancies
X
Xg
Safety Assessments (See Section 8)
Adverse events and concomitant therapy
X
X
X
Weight
Day 1 of each cycle 
X
Clinical Laboratory tests (See Appendix 2, Section 10.2)
Hematology, including peripheral blood blast counts 
Beyond cycle 1, check on Day 1 and Day 17 of each cycle, with each disease evaluation and as 
clinically indicated. 
X 
 
Chemistry
With each disease evaluation and as clinically indicated
X
Pregnancy test for women of childbearing potential
X
Xh
AML= acute myeloid leukemia; CR= complete response; CRh= CR with partial hematological recovery (<5% blasts in the bone marrow, no evidence of disease and partial recovery of platelets to 
>50,000/μL and absolute neutrophil count >500/μL);  CRi= complete response with incomplete blood count recovery; IV= intravenous; MRD= minimal residual disease; SC= subcutaneous 
a. 
The End of Treatment Visit must occur in person within approximately 7 days of treatment discontinuation. 
b. 
As per Section 8.3.1, all adverse events will be reported until 30 days after the last dose of study intervention or until the start of subsequent anti-AML therapy, if earlier. 
c. 
See Section 6.1 and Section 6.1.1 for dosing schedule and premedications. When cusatuzumab and azacitidine are scheduled to be administered together, azacitidine should be 
administered first. It is recommended that there is at least 30 minutes waiting time between the end of azacitidine administration and the start of the cusatuzumab infusion. 
d. 
Evaluation includes bone marrow evaluation (bone marrow aspirate preferred for assessment of blast %), hematology with differential, transfusion assessment, and assessment for 
extramedullary disease per local standard of care. In case of a dry tap, a biopsy may be utilized for disease assessment. For participants who discontinue study treatment without disease 
progression, disease evaluations should continue with the same frequency as during study treatment until disease progression or start of subsequent therapy, whichever occurs first. Any 
unscheduled bone marrow assessments must be reported. 

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Treatment 
Follow-up 
Study Procedure 
Azacitidine/ cusatuzumab combination therapy 
(28-day cycle) 
EOTa 
30 days (±3 days) 
after last dose of study 
treatment and then 
every 3 months 
thereafter (±7 days)b
Cycle 1 – EOT 
e. 
Once a bone marrow aspirate is performed, the sample must be sent to central laboratory within 48 hours for MRD analysis by flow cytometry. Results of MRD testing will be provided 
by the Sponsor when appropriate. 
f. 
Evaluation for extramedullary disease required only for participants with suspicion of or known extramedullary AML disease 
g. 
Assessments may occur via telephone contact. 
h. 
Pregnancy testing to also be performed for women of childbearing potential 1 month after last dose of study treatment. 
 

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Table 2: 
Schedule of Pharmacodynamic and Biomarker Evaluations 
 
Note: After 22 Oct 2021, the assessments below will not be performed except for MRD, which is included in Table 1A. 
 
Study Day 
Dose 
Time  
(window) 
Flow cytometry/ 
CyTOF 
Flow 
cytometry/CyTO
F/MRDa 
Cytokines 
Protein 
Quantification 
Gene expression 
MRDa 
DNA 
sequencing 
Sample 
Whole blood 
Bone marrow 
aspirate 
Serumb 
Serum 
Whole blood 
Whole 
blood 
Bone marrow 
aspirate 
Screeningc 
 
 
X 
 
 
 
X 
X 
Cycle 1 /  
Day 1
Azacitidine 
Predose 
X 
 
X 
X 
X 
 
 
Cycle 1/  
Day 2
Azacitidine 
Postdose 
X 
 
 
X 
X 
 
 
Cycle 1 /  
Day 3 
Azacitidine/ 
cusatuzumab
Predose 
 
  
X 
 
 
 
 
Cusatuzumab 
EOI 
(+10 min)
 
 
X 
 
 
 
 
Cycle 1 /  
Day 3
Cusatuzumab 
6 hr after EOI 
(± 30 min)
 
 
X 
 
 
 
 
Cycle 1 /  
Day 4
Cusatuzumab 
24 hr after EOI  
(± 2 hrs)
 
 
X 
 
 
 
 
Cycle 1 /  
Day 7
Cusatuzumab 
96 hr after EOI 
(± 2 hrs)
X 
 
 
X 
X 
 
 
Cycle 1 / 
Day 17
Cusatuzumab 
Predose 
X 
 
 
X 
X 
 
 
Every 2 cycles following CR/CRi/CRh  
on Day 1
 
 
 
 
 
X 
 
At every disease evaluation 
X 
X 
 
X 
X 
 
 
EOT 
 
 
X 
X 
 
X 
X 
X 
 
CyTOF= time of flight mass cytometry; EOI= end of infusion; MRD= minimal/measurable residual disease; PBMC= peripheral blood mononuclear cells 
a. Bone marrow aspirate samples will be analyzed by flow cytometry; bone marrow aspirate and blood samples will be stored for analysis in the future by molecular methods. 
b. Cytokine testing for the first 30 participants only. Additional serum samples will be collected from a participant when a Grade 3 or higher infusion-related reaction event is 
observed. If the infusion-related reaction event coincides with the serum samples that are already being collected, then additional samples do not need to be collected. 
c. Screening samples will be taken within 7 days of Cycle 1/ Day 1. 
 

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Table 3: 
Schedule of Pharmacokinetic Evaluations for the First 50 Participants (approximately 25 for 
each dose; intensive PK sampling) 
 
Note: After 22 Oct 2021, no pharmacokinetic samples will be collected. 
Study Cycle 
and Day 
Time (Window) 
Serum 
Cusatuzumab PK 
Whole Blood 
ROa 
Serum ADA 
Bone Marrow 
Cusatuzumab 
PKb
Screening
X
Cycle 1 
Day 3 
Predosec
X
X
X
EOI postdose 
(+10 min)
X 
X 
 
 
Cycle 1 
Day 4 
24 hours 
postdose 
(±2 hours)
X 
X 
 
 
Cycle 1 
Day 7 
96 hours 
postdose 
(±6 hours)
X 
X 
 
 
Cycle 1 
Day 10 
168 hours 
postdose 
(±12 hours)
X 
X 
 
 
Cycle 1 
Day 17 
Predosec
X
X
X
EOI postdose 
(+10 min)
X 
X 
 
 
Cycle 2 
Day 3 
Predosec
X
X
X
EOI postdose 
(+10 min)
X 
X 
 
 
Cycle 2 
Day 17 
Predosec
X
X
X
EOI postdose 
(+10 min)
X 
X 
 
 
Cycle 3 Day 3 
and Cycle 4 
Day 3 
Predosec
X
X
X
EOI postdose 
(+10 min)
X 
X 
 
 
Cycle 3 Day 17 
and Cycle 4 
Day 17 
Predosec 
X 
X 
 
 
EOI postdose 
(+10 min)
X 
X 
 
 
Cycle 3 Day 21 
to Cycle 4  
Day 1
At disease 
evaluation 
X 
 
 
X 
Cycle 5 
Day 3 
Predosec
X
X
EOI postdose 
(+10 min)
X 
 
 
 
Cycle 5 Day 21 
to Cycle 6  
Day 1
At disease 
evaluation 
X 
 
 
X 
Odd cycles ≥ 
Cycle 7 
Day 3 
Predosec
X
X
EOI postdose 
(+10 min)
X 
 
X 
 
EOT
(±7 days)
X
X
ADA=anti-drug antibody; EOI=end-of-infusion; EOT=end-of-treatment; PK=pharmacokinetics; RO=receptor 
occupancy 
i. 
Whole blood RO: For first 4 cycles only, dependent on assay availability. 
j. 
Bone marrow concentration will only be evaluated in approximately 8 participants in each cohort. Bone 
marrow aspirates should be collected at disease evaluation. A blood sample for serum PK should also be 
collected at the same time. 
Predose samples may be collected within 2 hours before dosing unless otherwise indicated.  

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Table 4: 
Schedule of Pharmacokinetic Evaluations for Azacitidinea 
 
Note: After 22 Oct 2021 no pharmacokinetic samples will be collected. 
Study Cycle and Daya 
Time (Window) 
Cycle 1 
Day 1 
Predoseb
EOI postdose (+10 min) 
30 min postdose (±5 min) 
Cycle 1  
Day 3 
Predoseb
EOI postdose (+10 min) 
30 min postdose (±5 min) 
Cycle 3 
Day 3 
Predoseb
EOI postdose (+10 min)
30 min postdose (±5 min)
EOT
(±7 days)
EOI= end of infusion; EOT= end of treatment 
a. 
Azacitidine PK samples are to be collected from at least 20 participants from each azacitidine administration group (IV 
or SC). Whichever route of administration (IV or SC) is given for the first dose should be continued for all subsequent 
doses whenever possible in participants selected to have samples collected for azacitidine PK. 
b. 
Cusatuzumab pre-dose samples may be collected within 2 hours before dosing unless otherwise indicated. 
 
Table 5:  
Schedule of Pharmacokinetic Evaluations for Participants Randomized after the 50th 
Participant (sparse PK sampling) 
 
Note: After 22 Oct 2021, no pharmacokinetic samples will be collected.  
 
 
a. 
For first 4 cycles only 
b. 
Cusatuzumab pre-dose samples may be collected within 2 hours before dosing unless otherwise indicated.  
 
 
 
Study Cycle and 
Day 
Time (Window) 
Serum Cusatuzumab 
PK 
Whole Blood 
ROa 
Serum ADA 
Screening
Cycle 1, 2, 3 and 4 
Day 3 
Predoseb
X
X
X
EOI postdose 
(+10 min)
X 
X 
 
Cycle 1, 2, 3 and 4 
Day 17 
Predoseb
X
X
X
EOI postdose 
(+10 min)
X 
X 
 
Odd cycles ≥Cycle 
5 
Day 3 
Predoseb
X
X
EOI postdose 
(+10 min)
X 
 
 
EOT 
(±7 days) 
X 
 
X 

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2. 
INTRODUCTION 
2.1. 
Study Rationale 
This study is intended to evaluate cusatuzumab plus azacitidine in patients with previously 
untreated AML who are not candidates for intensive chemotherapy and are generally older or with 
medical comorbidities. As of January 24, 2019, cusatuzumab has been studied in the same patient 
population in 29 patients with AML in study ARGX-110-1601. In the Phase 1 portion of the Phase 
1/2 dose escalation study of 1 to 20 mg/kg cusatuzumab plus azacitidine a maximum tolerated 
dose was not reached and combination therapy resulted in a CR rate of 67% (n=12). Higher doses 
of cusatuzumab (10 and 20 mg/kg) achieved target drug levels in the peripheral blood and bone 
marrow and lower rates of anti-drug antibodies (ADA) than at lower dose levels (Section 2.2.2).  
This two-part Phase 2 study, CULM20236, will evaluate the safety and efficacy of 2 dose levels 
of cusatuzumab, 10 mg/kg and 20 mg/kg, in combination with azacitidine, in participants with 
previously untreated AML who are not candidates for intensive chemotherapy. Part 1 of the study 
is to select a dose and Part 2 will further characterize the efficacy and safety of cusatuzumab at the 
selected dose in combination with azacitidine.   
2.1.1. 
Study Design Rationale 
Safety and tolerability of cusatuzumab monotherapy initially were described in the first-in-human 
(FIH) Phase 1 dose escalation study ARGX-110-1201 of up to a dose of 10 mg/kg once every 
3 weeks in adult subjects with advanced (solid tumor and hematological) malignancies. In a 
subsequent open-label non-randomized study in AML or high-risk myelodysplastic syndrome 
(MDS) patients who are not candidates for intensive chemotherapy, study ARGX-110-1601 
investigated the safety and tolerability of escalating doses of cusatuzumab at 1, 3, 10, and 20 mg/kg 
given once as monotherapy followed by every 2 weeks in combination with standard doses of 
azacitidine. As of 24 January 2019, 12 adult subjects with AML have received the combination of 
cusatuzumab and a standard dose of azacitidine in the Phase 1 portion of the study and 
17 additional AML subjects have been enrolled in an expansion cohort of cusatuzumab 10 mg/kg 
in combination with azacitidine in the Phase 2 portion of the study. No patients with MDS have 
been enrolled.  
Data from the Phase 1 portion of Study ARGX-110-1601 (n=12) demonstrated that cusatuzumab 
up to 20 mg/kg every 2 weeks in combination with azacitidine has a safety profile consistent with 
azacitidine toxicity with the addition of infusion-related reactions (IRRs). Combination therapy 
demonstrated a CR rate of 67%, a promising result in this patient population (Section 2.2.2). 
This study, CULM20236, will evaluate 2 doses of cusatuzumab, 10 mg/kg and 20 mg/kg, in 
combination with standard dose azacitidine in participants with AML who are not candidates for 
intensive chemotherapy to determine a dose level (Part 1) at which to further evaluate and confirm 
the response rate, other efficacy endpoints, tolerability, and PK/PD (Part 2). NOTE: Part 2 of the 
study will not be conducted because further development of this regimen (cusatuzumab in 
combination with azacitidine) in patients with unfit AML will not be pursued due to the evolving 
treatment landscape in AML. Up to approximately 150 participants will be enrolled for the entire 

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study. Randomization will be implemented for Part 1 of the study and will be stratified by type of 
AML (de novo versus secondary AML) and ECOG score (0-1 versus 2). A 3-stage monitoring 
approach will be utilized in Part 1 so that a dose may be selected early (see Schema in Figure 1). 
The term "Sponsor" used throughout this document refers to the entities listed in the Contact 
Information page(s), which will be provided as a separate document. The term "participant" 
throughout the protocol refers to the common term "subject" enrolled in this study. The term “study 
intervention” throughout the protocol refers to either study drug.  
2.1.2. 
Rationale for the Selected Patient Population 
Five-year survival in older patients with AML is less than 5% and has not improved significantly 
in the last few decades, especially in those over 75 years of age.25 More effective therapies are 
clearly needed. Multiple clinical studies are underway combining novel therapy with azacitidine 
in the hope of achieving better clinical outcomes than with azacitidine alone. 
The study population of this study as outlined in the inclusion/exclusion criteria (Section 5) are 
consistent with published guidelines8,18 and other recent clinical studies that define this unfit 
population. Although choice of therapy in patients with AML is dependent on the patient’s age, 
comorbidities, and patient/ physician preference,13,27 low intensity therapy with hypomethylating 
agents such as azacitidine is an accepted standard of care option in the patient population included 
in this study.  
2.1.3. 
Rationale for Combination Treatment With Cusatuzumab Plus 
Azacitidine 
Riether (2017)23 demonstrated that >95% of AML blasts harvested from newly diagnosed AML 
patients expressed CD70 on the cell surface. In 70% to 95% of these samples, expression of CD70 
and CD27, its ligand, was observed. Additionally, significantly elevated soluble CD27 levels 
(sCD27), resulting from ligation of CD70 to its receptor and subsequent cleavage by a cell surface 
protease were observed. More extensive transcriptome studies revealed a role for CD70-CD27 
signaling in proliferation and stem cell maintenance of AML blast populations. Ex vivo and in 
vivo models demonstrated a pathological role for CD70-CD27 signaling in maintaining the 
stemness character of the AML blast population.  
Transient treatment (2 weeks) with an anti-human CD70 blocking antibody significantly reduced 
colony formation in primary and secondary replating experiments and in secondary transplantation 
in AML patient xenografts, indicating that treatment affected the leukemic stem cells (LSC).23 
This is particularly relevant as LSCs are responsible for minimal residual disease (MRD) and AML 
relapse.9,21,22 Notably, normal hematopoietic stem cells lack CD70 expression.10 Therefore, 
effective targeting of CD70 should result in the ablation of leukemic blasts and LSC while sparing 
normal hematopoiesis. 
Cusatuzumab is an anti CD70 antibody that binds with high affinity to CD70, thereby blocking 
interaction with CD27 (see Section 2.2.2). This blockade interferes with anti-apoptotic 
CD70-CD27 signaling, likely hampering tumor growth. CD70 targeting by cusatuzumab 
demonstrated efficacy in patients with AML possibly by blocking proliferation of AML blasts, 

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depleting CD70-positive AML blasts via enhanced ADCC (Potelligent® technology), reducing 
the stemness of AML blasts and targeting leukemic stem cells and driving them towards myeloid 
differentiation.   
Azacitidine and decitabine are inhibitors of DNA methyltransferases known to upregulate gene 
expression by promoter hypomethylation. Hypomethylating agents (HMA) are the standard of care 
for first line treatment in patients with AML who are not candidates for intensive chemotherapy.  
CD70 expression has also been shown to be increased on AML stem/progenitor cells from patients 
treated with HMAs suggesting hypomethylating agents upregulate CD70 by inducing CD70 
promoter hypomethylation.10,23  
We hypothesize that targeting both the proliferative and the stem cell compartment of the pool of 
AML blasts with cusatuzumab, in combination with the upregulation of CD70 with azacitidine, 
may result in better clinical outcomes for patients with AML. It is anticipated that azacitidine’s 
effectiveness will be enhanced by the antiproliferative and stemness-reducing activity of 
cusatuzumab and that combination therapy will have a complimentary effect on AML. The 
preliminary efficacy of cusatuzumab and azacitidine combination therapy was demonstrated in 
study ARGX-110-1601. Additionally, the safety profiles of the agents indicate that toxicities are 
not overlapping and adverse events will be managed with monitoring and supportive care 
(Section 2.2.2). 
2.1.4. 
Rationale for Dose Selection 
Preclinical and clinical data analyzed to date suggest that a target steady-state trough concentration 
(Ctrough) of cusatuzumab >100 µg/mL (bone marrow concentration >20 µg/mL) is required for both 
bone marrow penetration and to elicit strong clinical responses in the heterogenous AML 
population. Based on preliminary clinical pharmacokinetic modeling and simulation, the median 
serum cusatuzumab Ctrough >100 µg/mL at steady-state should be achieved after 5 to 6 doses (ie, 
2-3 cycles) at dose levels of 10 mg/kg (median predicted Ctrough ~103 µg/mL) or by the second 
dose (ie, 1 cycle) at 20 mg/kg (median predicted Ctrough ~208 µg/mL) given every 2 weeks. 
Analysis from Study ARGX-110-1601 suggests that these dosages are advantageous because the 
negative impact of anti-drug antibodies (ADAs) on serum cusatuzumab exposure was more 
apparent at lower doses (ie, 1 and 3 mg/kg) compared with higher doses (ie, 10 and 20 mg/kg). 
Specifically, ADA-positive subjects treated at the lower doses showed lower serum cusatuzumab 
exposure compared with ADA-negative subjects. Doses of cusatuzumab below 10 mg/kg were 
subtherapeutic with a higher incidence of ADAs; thus, they were not considered for further 
exploration. 
Additionally, efficacy results from Study ARGX-110-1601 support further exploration of doses of 
cusatuzumab ≥10 mg/kg administered every 2 weeks. The dose-escalation Phase 1 portion of the 
study had a CR rate of 67% overall (n=8/12) and in each of the studied dose levels (2 of 3 subjects 
in each of the following doses: 1, 3, 10, and 20 mg/kg). Notably, both subjects in the 20 mg/kg 
dose who achieved CR had adverse-risk AML by cytogenetics and molecular profiling; moreover, 
neither had disease progression after at least 60 weeks of therapy. Contrary to this observation, 

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none of the subjects at 10 mg/kg dose level had adverse cytogenetics in Part 1; however, all have 
progressed with longer follow-up.  
The safety profile of cusatuzumab at all dose levels remains favorable, with only IRRs being 
reported above the expected azacitidine toxicities. There appears to be no relevant differences in 
safety profiles across the dose levels tested or among subjects.  
Based on the safety, efficacy, and PK assessments of cusatuzumab in ARGX-110-1601 study 
(Section 2.2.2.1), doses of cusatuzumab ≥10 mg/kg given Q2W may be required to achieve 
optimal therapeutic levels in the bone marrow and may also provide target exposure across a larger 
spectrum of patients due to observed high inter-subject variability and heterogeneity of AML 
population and disease burden. 
The dose of azacitidine used in this study (75 mg/m2 BSA) is as indicated in the azacitidine 
Summary of Product Characteristics (SPC) and the United States Package Insert (USPI).  
2.1.5. 
Rationale for Administration Schedule 
Preliminary Cycle 1 data from study ARGX-110-1201 showed dose proportionality over the dose 
range studied, and a half-life (t1/2) of approximately 11 days. Therefore, a 2-week dosing schedule 
was chosen for this study. In study ARGX-110-1601 a monotherapy dose of cusatuzumab was 
given 2 weeks prior to initiation of cusatuzumab plus azacitidine combination therapy in order to 
collect safety, PK, PD, and efficacy data regarding cusatuzumab monotherapy in this patient 
population. For this study, the monotherapy dose has been removed in order to provide standard 
of care therapy with azacitidine from the onset of study treatment given that sufficient safety, PK, 
PD, and efficacy data has been collected in ARGX-110-1601. All participants in this study will 
receive azacitidine on Days 1 through 7 and cusatuzumab on Day 3 and Day 17 of each 28-day 
cycle. 
2.2. 
Background 
2.2.1. 
Acute myeloid leukemia 
Acute myeloid leukemia (AML) is a heterogeneous disease characterized by uncontrolled clonal 
expansion of hematopoietic progenitor cells. As the most common form of acute leukemia, AML 
accounts for the largest number of annual deaths from leukemia. This poor prognosis is in part due 
to the fact that AML affects patients at a more advanced median age of 67 years with a third of 
patients diagnosed at an age of over 75 years.17,18 Advanced age associated with comorbidities, 
end-organ dysfunction, and poor performance status severely limits tolerance to intensive 
chemotherapy.  
In addition, the biology of AML in the elderly contributes to the poor therapeutic outcome. In older 
patients, AML arises more frequently from an overt or unrecognized myelodysplastic syndrome 
(MDS), and appears to be associated with complex, monosomal, or combination karyotypes, 
adverse cytogenetics, as well as a multidrug resistant phenotype.15 In recent years, 
hypomethylating agents such as azacitidine and decitabine have emerged as one of the preferred 
therapies for AML patients who cannot tolerate intense induction and consolidation 

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chemotherapy.4,15  Azacitidine or decitabine monotherapy results in low response rates (10%-50%, 
including hematologic improvement), requires 3.5 to 4.3 months to achieve best response, and is 
not curative, with a median overall survival (OS) of less than 1 year.7,12 Thus, there is a critical 
need to develop targeted therapies capable of rapidly inducing a high rate of clinical response, with 
better tolerability and durable responses for elderly patients with AML.            
2.2.2. 
Cusatuzumab 
Cusatuzumab is a humanized monoclonal antibody of camelid origin, binding with high affinity 
to human CD70. Cusatuzumab has been modified using Potelligent® technology to induce 
enhanced antibody-dependent cell-mediated cytotoxicity (ADCC)16 for therapeutic use in patients 
with advanced cancer. 
Cusatuzumab is targeted to CD70, a cell surface antigen normally expressed in a small subset of 
activated B- and T- lymphocytes as well as mature dendritic cells,2  and is involved in lymphocyte 
differentiation and survival signaling upon binding to its cell surface receptor, CD27.1 
CD70-induced signaling of CD27 results in increased production and activation of regulatory T 
cells.5 Cusatuzumab is a potent and dose-dependent inhibitor of CD27 signaling. 
CD70 expression is low or absent from normal tissues of all vital organs. CD70 is over-expressed 
in several tumor types, including AML, often together with CD27 in hematological malignancies 
suggesting its involvement in proliferation and survival of the malignant cells.2,19 Soluble CD27 
(sCD27) level, which results from ligation of CD70 to its receptor and subsequent cleavage by a 
cell surface protease, is elevated in acute lymphoblastic leukemia19 and other B cell lymphomas 
and leukemias.2,26 
CD70 also appears to play a role in evasion of immune surveillance by inducing T cells with 
regulatory potential thus promoting tumor growth.5,11,28 
Inhibition of the CD70-CD27 signaling pathway in regulatory T cells is also believed to impede 
regulatory T cell recruitment or activation thereby potentially restoring a participant’s 
immune-surveillance 
in 
the 
tumor 
microenvironment.5 
Cusatuzumab 
also 
exerts 
antibody-dependent cellular phagocytosis (ADCP) and complement-dependent cytotoxicity 
(CDC) of CD70 positive tumor cells. 
It is therefore expected that cusatuzumab, by virtue of its pleiotropic mechanisms of action, has 
increased cell killing properties compared to other CD70 targeting agents, ie, by induction of 
cytotoxicity against CD70-positive tumor cells via enhanced antibody effector mechanisms, and 
by blocking proliferation and survival signals of malignant cells and induction of an anti-tumor 
immune response following interruption of CD70-CD27 signaling.24  
2.2.2.1. 
Clinical Data 
Cusatuzumab currently is being investigated in 3 studies:  
 
Study ARGX-110-1201 is a completed Phase 1 study in adult subjects with advanced 
malignancies expressing CD70. Subjects received cusatuzumab monotherapy by intravenous 

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(IV) infusions, once every 3 weeks. In the dose escalation part, a total of 26 subjects with solid 
tumors or hematological malignancies expressing CD70 were treated with cusatuzumab at a 
dose of 0.1 mg/kg (n=6), 1 mg/kg (n=5), 2 mg/kg (n=7), 5 mg/kg (n=3), or 10 mg/kg (n=5). 
In the dose expansion part, a total of 73 subjects were treated with cusatuzumab at a dose of 
1 mg/kg (n=2) or 5 mg/kg (n= 71). 
 
Study ARGX-110-1401 is an ongoing Phase 1 safety and feasibility study in subjects with 
nasopharyngeal carcinoma, who receive treatment with cusatuzumab by IV infusions, once 
every 3 weeks. As of 30 September 2018, 11 subjects have been treated with 5 mg/kg 
cusatuzumab.  
 
Study ARGX-110-1601 is an ongoing Phase 1/2, dose-escalation, safety, and efficacy study 
in subjects with previously untreated AML or  high-risk myelodysplastic syndrome (MDS) 
who receive treatment with cusatuzumab monotherapy on Day 1 of a 14 day first cycle 
followed by cusatuzumab  IV every 2 weeks on Days 3 and 17 of each 28-day cycle and 
azacitidine on Days 1 to 7 of each cycle, at the standard dose of 75 mg/m2 subcutaneous 
injection. As of 30 September 2018, 20 subjects have been treated with cusatuzumab; 
3 subjects each at doses of 1, 3, 10, and 20 mg/kg in the dose escalation portion of the study 
and 8 additional subjects were treated at 10 mg/kg following selection of this dose for further 
evaluation.  
At the cut-off date of 30 September 2018, cusatuzumab has been administered to 130 subjects. 
Please see the Investigator’s Brochure for further details.  
Safety 
The most commonly reported drug-related treatment-emergent adverse events (TEAEs) were 
fatigue, infusion-related reactions (IRRs), pyrexia, dyspnea, decreased appetite, abdominal pain, 
nausea, and anemia. The majority of these events were National Cancer Institute Common 
Terminology Criteria for Adverse Events (NCI-CTCAE) Grade 1 or Grade 2 with no significant 
differences between dose levels, including 10mg/kg and 20mg/kg. 
Apart from IRRs, which were manageable with concomitant medication, the frequency and profile 
of reported adverse events in all cusatuzumab studies is consistent with the symptomology of the 
underlying disease.  
As of 15 October 2018, in the Phase 1 portion (n=12) of the ARGX-110-1601 study of 
cusatuzumab in combination with azacitidine in AML patients, other than expected IRRs, there 
were no safety signals identified other than known azacitidine toxicities. Infusion-related reactions 
were generally low grade; 1 subject (7.1%) was reported with a Grade 3 IRR leading to 
cusatuzumab discontinuation. Fifty percent of subjects (6 of 12) were reported with Grade 3 or 4 
hematologic toxicities including anemia, thrombocytopenia, neutropenia, leukopenia and febrile 
neutropenia.   

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Efficacy  
As of 15 October 2018, in the Phase 1 portion of the ARGX-110-1601 study (n=12), 50% of 
subjects had adverse risk AML and the median age was 75 years. Eight subjects (67%) achieved 
CR and 11 subjects (92%) demonstrated a response including CR, CRi, and partial response (PR) 
and 1 subject (8.3%) had stable disease. The median time to first response was 14 weeks and 
3 subjects (25%) reached a first response after a single dose of cusatuzumab (prior to initiation of 
azacitidine therapy). The median duration of response was 5.5 months. The median event free 
survival was 8.1 months (range: 2 months - 17.4 months). 
Pharmacokinetics 
In the Phase 1 portion of study ARGX-110-1601, four dose levels (1, 3, 10 and 20 mg/kg every 
2 weeks) of cusatuzumab in combination with azacitidine were administered to AML patients. 
Based on preliminary PK analysis, for dosing regimens of 1 and 3 mg/kg every 2 weeks, the serum 
drug exposures were lower after the 2nd dose compared to that of the 1st dose due to the presence 
of ADA. Doses of 1 or 3 mg/kg every 2 weeks resulted in peripheral Ctrough of <50 µg/mL in AML 
patients. A linear PK was observed in the dose range of 10 to 20 mg/kg administered every 2 weeks 
with an estimated mean half-life of 200 to 262 hr (8.3-11 days). A peripheral Ctrough >100 µg/mL 
was achieved with dosing regimens of 10 mg/kg and 20 mg/kg every 2 weeks for subjects with 
adverse risk AML.   
In study ARGX-110-1201, cusatuzumab demonstrated dose proportionality over the dose range of 
1 to 10 mg/kg, but not at 0.1 mg/kg. The median maximum concentration (Cmax) in Cycle 1 was 
1.6 μg/mL, 21.6 μg/mL, 39.4 μg/mL, 109.0 μg/mL and 287.0 μg/mL, and the median area under 
the curve (AUC) was 4072.2, 9036.6, 35845.1 and 72437.8 μg×h/mL for the 1, 2, 5, and 10 mg/kg 
cohorts, respectively. The median t1/2 of cusatuzumab ranged from 263.1 hours for the 1 mg/kg 
cohort to 315.3 hours for the 10 mg/kg cohort (11 to 13.1 days). The data should be carefully 
interpreted because of the limited number of subjects and short observation window. There were 
no apparent correlations between PK parameters and either clinical treatment response or adverse 
events (AEs). 
Immunogenicity 
In the Phase 1 portion of ARGX-110-1601 study of cusatuzumab in combination with azacitidine 
in AML patients, based on preliminary analysis, no ADA was observed in 3 of 3 subjects treated 
with 20 mg/kg cusatuzumab every 2 weeks and 1 of 3 subjects were ADA positive who were 
treated with 10 mg/kg cusatuzumab every 2 weeks. However, the presence of ADA has minimum 
impact on the drug exposure achieved at high doses (≥10 mg/kg).  At the dose level of 1 mg/kg 
every 2 weeks, 3 of 3 subjects were ADA positive and at the dose level of 3 mg/kg every 2 weeks, 
2 of 3 subjects were ADA positive and presence of ADA resulted in faster clearance and relatively 
lower exposure.    
In the dose escalation of the Phase I study ARGX-110-1201, anti-drug antibodies (ADAs) 
appeared to be inversely related to the administered dose. Following administration of the first 
dose of cusatuzumab, ADA responses were observed in all subjects in the 0.1 mg/kg cohort, 60.0% 

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of subjects treated in the 1 mg/kg cohort, 42.9% of subjects treated in the 2 mg/kg cohort and 
33.3% of subjects treated in the 5 mg/kg cohort. No subjects in the 10 mg/kg cohort had positive 
ADA results following administration of the first dose of cusatuzumab.  
For the subjects at the lowest dose group (0.1 mg/kg), PK data suggest that ADAs are associated 
with an accelerated clearance of cusatuzumab. At doses of 1 mg/kg and above where only low 
ADA titers were observed, significantly accelerated clearance of cusatuzumab has not been 
observed. 
In the safety extension phase, in which subjects received 5 mg/kg cusatuzumab, ADAs were 
observed in 1 of 15 subjects with hematological malignancies; no subjects with solid tumors had 
ADAs. For the most comprehensive nonclinical and clinical information regarding cusatuzumab, 
refer to the latest version of the cusatuzumab Investigator’s Brochure. 
2.2.3. 
Azacitidine 
Azacitidine (5-azacytidine) is a pyrimidine nucleoside analogue of cytidine with antineoplastic 
activity. Azacitidine is indicated for the treatment of adult patients with AML or intermediate 2 
and high-risk MDS with >20% marrow blasts who are not eligible for hematopoietic stem cell 
transplantation. The most common side effects with azacitidine in patients with MDS, chronic 
myelomonocytic leukemia (CMML) or AML, which were seen in more than 60% of patients, are 
thrombocytopenia, neutropenia, leucopenia, nausea and vomiting, and injection site reactions. For 
the most up to date information refer to the azacitidine Summary of Product Characteristics (SPC) 
and USPI. 
2.3. 
Benefit/Risk Assessment 
Cusatuzumab is a first-in-class anti CD70 ADCC-enhanced antibody that selectively targets LSCs 
and blast cells of AML patients while sparing normal hematopoietic stem cells that lack CD70 
expression. Additionally, preclinical data demonstrated that treatment with azacitidine upregulates 
CD70 on AML LSCs, suggesting that treatment with combination therapy of cusatuzumab and 
azacitidine may have a synergistic inhibitory effect on AML growth.  
Patients with AML who are generally older and are not candidates for intensive chemotherapy are 
known to have poor outcomes. The proposed combination of cusatuzumab with azacitidine, a 
hypomethylating agent (HMA), ensures standard-of-care for patients who cannot benefit from 
other currently available intensive chemotherapy options, and may lead to a potent, synergistic 
therapeutic effect, resulting from the different underlying mechanisms of action by the 2 agents. 
Results from the ongoing clinical studies show that the risks with cusatuzumab appear to be mainly 
limited to infusion-related reactions (IRRs), a recognized adverse reaction associated with the 
administration of antibodies.14 In the current study, that risk will be managed with the use of a 
prophylactic premedication regimen consisting of anti-pyretics, anti-histamines, and 
corticosteroids (see Section 6.1.1).  
Additionally, study ARGX-110-1601 demonstrated a safety profile similar to that of azacitidine 
with the addition of IRRs in an untreated AML patient population and demonstrated efficacy with 

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an overall response rate of 92% and CR rate of 67%. Taken together, the administration of 
cusatuzumab in combination with standard doses of azacitidine in patients with newly diagnosed 
AML who are not fit for intensive chemotherapy (ie, generally older or with comorbidities) is 
considered to have a manageable safety profile. The safety profiles of the 2 agents indicate that 
toxicities are non-overlapping and adverse events can be managed with monitoring and supportive 
care. More detailed information about the known and expected benefits and risks of cusatuzumab 
is provided in the IB. 
3. 
OBJECTIVES AND ENDPOINTS 
Objectives 
Endpoints 
Primary 
To determine the efficacy of 
cusatuzumab in combination with 
azacitidine in patients with previously 
untreated AML who are not eligible 
for intensive chemotherapy 
Complete response (CR) rate per ELN 2017 (Dohner 2017)6 
Secondary 
To determine other response 
measures (see definitions in Table 6)  
 
 
Rate of CRh 
 
Rate of CR + CRh 
 
Rate of CRi  
 
Overall response rate (ORR) = Rate of CR+ CRh+ 
CRi 
 
Rate of CR without MRD  
 
Rate of MRD negativity among participants achieving 
CR, CRh, CRi, or MLFS; defined as less than 1 blast 
or leukemic stem cell in 1,000 leukocytes (MRD level 
<10-3) 
To assess time to response and 
duration of response  
 
 
 
To determine transfusion 
independence 
Time to response, defined as time from randomization in Part 1 
or enrollment in Part 2 to achieving the first response of CR, 
CRh, or CRi; duration of response, defined as time from 
achieving the first response of CR, CRh, or CRi to disease 
relapse or death from any cause. 
 
Transfusion independence (RBC or platelets) is defined as a 
period of at least 56 consecutive days with no transfusion 
between first dose of study drug and the last dose of study drug 
+ 30 days. 
To assess the safety profile of 
cusatuzumab in combination with 
azacitidine 
Safety profile of Adverse Events (AE) and Serious Adverse 
Events (SAE) 
To assess the pharmacokinetics of 
cusatuzumab alone and in 
combination with azacitidine   
Pharmacokinetics 

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Objectives 
Endpoints 
To assess the immunogenicity of 
cusatuzumab alone and in 
combination with azacitidine 
Immunogenicity / anti-drug antibody testing 
 
 
Exploratory 
To assess progression-free survival 
(PFS) 
 
PFS is defined as the time from randomization in Part 1 or 
enrollment in Part 2 to progressive disease, relapse from 
CR/CRh/CRi, or death from any cause, whichever occurs first. 
To assess overall survival (OS) 
OS is defined as the time from randomization in Part 1 or 
enrollment in Part 2 to death 
To assess pharmacodynamics and to 
explore biomarkers predictive of 
clinical response 
Exploratory biomarkers including baseline level of CD70+ 
blasts, CD70+LSC, sCD27, NK cells 
To assess patient-reported symptom 
severity and health-related quality of 
life 
PROs using the FACT-Leu and EQ 5D 5L (See Section 10.8 
Appendix 8 and Section 10.9 Appendix 9) 
To collect medical resource 
utilization (MRU) data that may be 
used in future economic modeling 
(the construction and reporting of the 
economic model will be conducted 
separately from this study). 
Duration of hospitalization (total days length of stay, including 
duration by wards; eg, intensive care unit) 
Outpatient medical encounters and treatments (including 
physician or emergency room visits, selected tests and 
procedures, and medications) 
 
HYPOTHESIS 
The primary hypothesis of this study is that the combination of cusatuzumab at doses of 10 mg/kg 
or 20 mg/kg with azacitidine has a CR rate of no less than 35% in patients with previously untreated 
AML who are not eligible for intensive chemotherapy.  
4. 
STUDY DESIGN 
4.1. 
Overall Design 
This is an open-label study. The study will consist of 2 sequential parts, Part 1 and Part 2, as 
described below. The purpose of Part 1 is to select a dose schedule based on the totality of the data, 
including CR rate and other efficacy endpoints, PK, biomarkers, and safety. The purpose of Part 2 
is to further evaluate and confirm the efficacy and safety of the combination therapy at the selected 
dose of cusatuzumab.   
NOTE: Part 2 of the study will not be conducted because further development of this regimen 
(cusatuzumab in combination with azacitidine) in patients with unfit AML will not be pursued due 
to the evolving treatment landscape in AML. 
NOTE: After 22 Oct 2021, ongoing subjects (on treatment or in follow-up) will be treated and 
assessed according to a reduced schedule of assessment (Table 1A).  

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Part 1 of the study is a randomized study of 2 doses of cusatuzumab in combination with 
azacitidine in patients with previously untreated AML who are not eligible for intensive 
chemotherapy. Part 2 of the study is an expansion of the selected dose. The study will include a 
Screening Phase, a Treatment Phase, and a Follow-up Phase. The Screening Phase will be up to 
28 days prior to randomization. The Treatment Phase will extend from Cycle 1/ Day 1 until study 
intervention discontinuation. Participants will be treated with their assigned dosing regimen until 
disease progression, relapse, unacceptable toxicity, or withdrawal due to investigator discretion or 
withdrawal of consent. The Follow-up Phase will begin once a participant discontinues study 
intervention, and will continue until death, loss to follow up, consent withdrawal for study 
participation, or study end, whichever occurs first. Safety and efficacy data will be closely 
monitored on an ongoing basis by the Sponsor’s central clinical team. 
Part 1:  
During Part 1, participants will be stratified by type of AML (de novo versus secondary AML) and 
ECOG score (0-1 versus 2) and then assigned randomly in a 1:1 ratio to receive cusatuzumab and 
azacitidine according to 1 of the following 2 dosing regimen groups:  
 
Group A: Azacitidine 75 mg/m2 SC or IV on Day 1 through Day 7, cusatuzumab 10 mg/kg IV 
on Day 3 and Day 17 of each 28-day cycle 
 
Group B: Azacitidine 75 mg/m2 SC or IV on Day 1 through Day 7, cusatuzumab 20 mg/kg 
IV on Day 3 and Day 17 of each 28-day cycle 
Part 1 of the study utilizes a 3-stage monitoring approach as the statistical guidance to select a dose 
schedule (see Section 9.5, Interim Analysis). The cumulative number of participants for each dose 
group at each of the 3 stages are 15, 30, and 50, respectively. Response will be based on all 
evaluations up to the time point when the last participant is treated for a minimum of 3 cycles with 
combination therapy (cusatuzumab + azacitidine). At each stage, available data of efficacy, safety, 
pharmacodynamics, and biomarkers will be evaluated by a Data Review Committee (DRC) to 
determine if either or both of these treatment groups should continue into the next stage of Part 1, 
and by the end of Part 1 (n=50/group), to select 1 dose schedule to be continued into study Part 2. 
The DRC will be formed prior to the first participant being enrolled in the trial and will remain in 
place until the conclusion of the trial. Enrollment does not pause at each stage. Refer to Committees 
Structure in Appendix 3 (Section 10.3), Regulatory, Ethical, and Study Oversight Considerations 
for details. 
If, based upon the totality of the data, 1 treatment group is considered to be less effective at any 
stage of Part 1, then that treatment group will be closed to enrollment.  Upon 1 dose level being 
selected to continue, the DRC may determine to switch ongoing participants to treatment with the 
dose level selected. If 1 dose group is determined at Stage 1 or Stage 2 not to continue, the other 
dose group will be continued into study Part 2 directly without further evaluations in Part 1. 
Enrollment will continue at each of the above 3 stages while efficacy and safety data are 
accumulated and evaluated. 

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Additionally, after 5, 15, 30, and 50 participants have enrolled on each arm, respectively, and been 
treated for 3 cycles, cumulative safety data will be evaluated by the DRC to ensure continued study 
treatment is safe.  
Part 2:  
For Part 2, the treatment group to be studied will be dependent upon the results from Part 1. At the 
end of Part 1, all available data will be evaluated by the DRC to select 1 of the cusatuzumab 
treatment groups for further evaluation in Part 2. 
The sample size for Part 2 will result in approximately 100 participants for the selected treatment 
group from Parts 1 and 2 combined. A formal interim analysis of the primary endpoint, CR rate, 
is planned during Part 2 to include 80 participants from the selected dose group, at the time when 
the last participant of the 80 has been treated for a minimum of 4 cycles of combination therapy. 
The final analysis will be based on 100 participants. A diagram of the study design is provided in 
Section 1.2, Figure 1. 
NOTE: Part 2 of the study will not be conducted because further development of this regimen 
(cusatuzumab in combination with azacitidine) in patients with unfit AML will not be pursued due 
to the evolving treatment landscape in AML. 
4.2. 
Scientific Rationale for Study Design 
Blinding, Control, Study Phase/Periods, Intervention Groups 
Randomization will be used to allocate participants to the 2 dose schedule groups in study Part 1. 
Although there is no formal statistical comparison between the 2 groups, randomization can 
minimize bias and imbalance in baseline characteristics between the 2 dose groups to facilitate the 
decision making of selecting a dose schedule. 
This is an open-label study. 
DNA and Biomarker Collection 
It is recognized that genetic variation can be an important contributory factor to interindividual 
differences in intervention distribution and response and can also serve as a marker for disease 
susceptibility and prognosis. Pharmacogenomic research may help to explain interindividual 
variability in clinical outcomes and may help to identify population subgroups that respond 
differently to an intervention. The goal of the pharmacogenomic component is to collect DNA to 
allow the identification of genetic factors that may influence the pharmacokinetics (PK), 
pharmacodynamics (PD), efficacy, safety, or tolerability of cusatuzumab and azacitidine and to 
identify genetic factors associated with AML. 
Biomarker samples will be collected to evaluate the mechanism of action of cusatuzumab and 
azacitidine or help to explain interindividual variability in clinical outcomes or may help to identify 
population subgroups that respond differently to an intervention. The goal of the biomarker 

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analyses is to evaluate the PD of cusatuzumab and azacitidine and aid in evaluating the 
intervention-clinical response relationship.  
DNA and Biomarker samples may be used to help address emerging issues and to enable the 
development of safer, more effective, and ultimately individualized therapies. 
Patient-Reported Outcomes 
Patient-reported outcomes will be collected to monitor participants’ symptoms and health-related 
quality of life.  PRO data will be used to describe any changes in symptoms and/or HRQoL over 
the course of treatment.  Direct patient reports may also provide supplemental information about 
dose tolerability.  
Medical Resource Utilization  
Medical resource utilization (MRU) data will be collected to determine the medical cost impact of 
the treatment regimen. The data collected will be used to conduct exploratory analyses that may 
be used to support the value and cost-effectiveness modeling for market access. 
4.2.1. 
Study-Specific Ethical Design Considerations 
Potential participants will be fully informed of the risks and requirements of the study and, during 
the study, participants will be given any new information that may affect their decision to continue 
participation. They will be told that their consent to participate in the study is voluntary and may 
be withdrawn at any time with no reason given and without penalty or loss of benefits to which 
they would otherwise be entitled. Only participants who are fully able to understand the risks, 
benefits, and potential adverse events of the study, and provide their consent voluntarily will be 
enrolled.  
Study ARGX-110-1601 demonstrated similar safety and efficacy in subjects with AML treated 
with cusatuzumab at 10 mg/kg and 20 mg/kg every two weeks in combination with azacitidine. 
Participants on this study, CULM20236, will be treated with 1 of these 2 dose levels that have 
already shown promising preliminary response results. Additionally, all participants on this study 
receive standard of care treatment for their disease with azacitidine which has shown to be effective 
in this patient population and has a manageable safety profile. The clinical equipoise between the 
two dose levels and receipt of standard of care, along with the risk benefit considerations discussed 
earlier, attest to an ethical study design. Safety and efficacy data for all participants will be closely 
and frequently monitored to ensure the risk benefit ratio favors continued treatment.    
The total blood volume to be collected is considered to be an acceptable amount of blood to be 
collected over this time period from the population in this study based upon the standard of the 
American Red Cross (see Section 8.1). 
4.3. 
Justification of Dose 
The selection of doses for cusatuzumab and azacitidine are discussed in Section 2.1.4 Rationale 
for Dose Selection.  

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4.4. 
End of Study Definition 
The end of study will be reached when all subjects have completed or discontinued study treatment. 
The final data from the study site will be sent to the Sponsor (or designee) after completion of the 
final participant visit at the study site, in the time frame specified in the Clinical Trial Agreement. 
5. 
STUDY POPULATION 
Screening for eligible participants will be performed within 28 days of randomization unless 
otherwise noted in the Schedule of Activities. Refer to Section 5.4, Screen Failures for conditions 
under which the repeat of any screening procedures are allowed. 
The inclusion and exclusion criteria for enrolling participants in this study are described below. If 
there is a question about these criteria, the investigator must consult with the appropriate Sponsor 
representative and resolve any issues before enrolling a participant in the study. The Sponsor will 
review patient eligibility before participants are enrolled. Waivers are not allowed. 
5.1. 
Inclusion Criteria 
Each potential participant must satisfy all of the following criteria to be enrolled in the study: 
1. ≥18  years of age 
2. Criterion modified per Amendment 1 
      2.1 AML according to WHO 2016 criteria and fulfilling all of the following criteria that defines 
those who are “not candidates for intensive chemotherapy”: 
 
≥75 years of age or 
 
<75 years of age with of at least one of the following comorbidities: 
o ECOG Performance Status of 2 
o Severe cardiac comorbidity defined as congestive heart failure or ejection fraction 
≤50% 
o Severe pulmonary comorbidity defined as documented pulmonary disease with 
lung diffusing capacity for carbon monoxide (DLCO) ≤65% of expected, or forced 
expiratory volume in 1 second (FEV1) ≤65% of expected or dyspnea at rest 
requiring oxygen 
o Moderate hepatic impairment defined according to NCI organ dysfunction 
classification criteria (total bilirubin ≥1.5 up to 3 times upper limit of normal 
[ULN])  
o Creatinine clearance <45 mL/ min/1.73 m² (by MDRD formula)   
o Comorbidity that, in the Investigator’s opinion, makes the patient unsuitable for 
intensive chemotherapy and must be documented and approved by the Sponsor 
before randomization 
3.   Criterion numbering modified per Amendment 1 

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3.1   De novo or secondary AML. 
4.   Criterion modified per Amendment 1 
4.1  Previously untreated AML (except: emergency leukapheresis, hydroxyurea, and/or 1 dose 
of cytarabine [eg, 1-2g/m2] during the Screening Phase to control hyperleukocytosis. 
These treatments must be discontinued ≥24 hours prior to start of study drug). Empiric 
all trans retinoic acid (ATRA) treatment for presumed acute promyelocytic leukemia 
(APL) is permitted but APL must be ruled out and ATRA must be discontinued ≥24 
hours prior to the start of study drug; 
5.   Criterion numbering modified per Amendment 1 
5.1    Not eligible for an allogeneic hematopoietic stem cell transplantation. 
6.   Criterion numbering modified per Amendment 1 
6.1    ECOG Performance Status score of 0, 1 or 2. 
7.   Criterion numbering modified per Amendment 1 
7.1    The following clinical laboratory values at screening: 
 
Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) <3 times ULN; 
for participants with leukemic infiltration of the liver (documented by biopsy or 
imaging), AST and ALT <5 times ULN is permitted 
 
Total bilirubin ≤ 3 times ULN unless bilirubin rise is due to Gilbert’s syndrome or of 
non-hepatic origin or in case of liver infiltration by AML (documented by biopsy or 
imaging) serum total bilirubin <5 times ULN 
 
Creatinine Clearance >30 mL/min (by MDRD formula) 
8.   Criterion modified per Amendment 1 
8.1    A woman must be either: 
 
Not of childbearing potential: postmenopausal (amenorrhea for at least 12 months); 
 
Of childbearing potential and practicing a highly effective method of birth control 
consistent with local regulations regarding the use of birth control methods for 
participants in the clinical study while receiving study treatment and for at least 3 
months after the last dose of study treatment: Examples of highly effective methods of 
contraception are located in Appendix 5, Contraceptive and Barrier Guidance and 
Collection of Pregnancy Information. 
A woman of childbearing potential must have a negative highly-sensitive serum 
(-human chorionic gonadotropin [-hCG]) or urine pregnancy test at screening. 
A woman of childbearing potential must agree to not donate eggs (ova, oocytes) for 
the purposes of assisted reproduction during the study treatment and for 3 months after 
the last dose of study treatment. 
Note: If the childbearing potential changes after start of the study (eg, woman who is not 
heterosexually active becomes active, premenarchal woman experiences menarche) a 
woman must begin a highly effective method of birth control, as described above. 

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9.   Criterion modified per Amendment 1 
9.1 
A man who is sexually active with a woman of childbearing potential and has not had a      
vasectomy must agree to use a barrier method of birth control eg, either condom with 
spermicidal foam/gel/film/cream/suppository or partner with occlusive cap (diaphragm 
or cervical/vault caps) with spermicidal foam/gel/film/cream/suppository for at least 
3 months after last study treatment. 
 
Must agree to not donate sperm during the study treatment and for 3 months 
after the last dose of study treatment. 
 
Not plan to father a child during the study treatment and for 3 months after the 
last dose of study treatment. 
10. Criterion modified per Amendment 1 
10.1.  Must sign an informed consent form (ICF) indicating that he or she (or their legally 
acceptable representative) understands the purpose of, and procedures required for, the 
study and is willing to participate in the study. 
5.2. 
Exclusion Criteria 
Any potential participant who meets any of the following criteria will be excluded from 
participating in the study: 
1. 
1.1 
Criterion modified per Amendment 1 
Acute promyelocytic leukemia. 
2. 
Leukemic involvement or clinical symptoms of leukemic involvement of the central 
nervous system. 
3. 
3.1 
Criterion modified per Amendment 1 
Use of immune suppressive agents for the past 4 weeks before the first administration of 
cusatuzumab on Cycle 1 Day 3. For regular use of systemic corticosteroids, participants 
may only be included if free of systemic corticosteroids for a minimum of 5 days before 
the first administration of cusatuzumab. Treatment of adrenal insufficiency with 
physiologic replacement doses of corticosteroids are allowed. 
4. 
Prior treatment with a hypomethylating agent for treatment of AML or MDS 
5. 
5.1 
Criterion modified per Amendment 1 
Active malignancies (ie, progressing or requiring treatment in the last 24 months) other 
than the disease being treated under study. The only allowed exceptions are:  
 
Non-melanoma skin cancer treated within the last 24 months that is considered 
completely cured 

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 
Adequately treated breast lobular carcinoma in situ and breast ductal carcinoma 
in situ 
 
Adequately treated cervical carcinoma in situ without evidence of disease 
 
History of localized breast cancer and receiving antihormonal agents, or history 
of localized prostate cancer (N0M0) and receiving androgen deprivation therapy 
 
Malignancy that is considered cured with minimal risk of recurrence 
6. 
6.1 
Criterion modified per Amendment 1 
Any active systemic infection  
7. 
7.1 
Criterion modified per Amendment 1 
A history of human immunodeficiency virus (HIV) antibody positive or tests positive for 
HIV at screening 
8. 
8.1 
Criterion modified per Amendment 1 
Active hepatitis B or C infection or other clinically active liver disease  
Seropositive for hepatitis B: defined by a positive test for hepatitis B surface antigen 
[HBsAg]. Participants with resolved infection (ie, participants who are HBsAg negative 
with antibodies to total hepatitis B core antigen [anti-HBc] with or without the presence of 
hepatitis B surface antibody [anti-HBs]) must be screened using real-time polymerase 
chain reaction (RT-PCR) measurement of hepatitis B virus (HBV) DNA levels. Those who 
are RT-PCR positive will be excluded. Participants with serologic findings suggestive of 
HBV vaccination (anti-HBs positivity as the only serologic marker) AND a known history 
of prior HBV vaccination, do not need to be tested for HBV DNA by RT-PCR. 
Known Hepatitis C infection or positive serologic testing for Hepatitis C (anti-HCV 
antibody) 
9. 
New York Heart Association Class IV heart failure or ongoing unstable angina (See 
Section 10.7 Appendix 7) 
10. 
Known allergies, hypersensitivity, or intolerance to cusatuzumab or azacitidine or its 
excipients (ie, mannitol, an excipient of azacitidine). 
11. 
Any condition for which, in the opinion of the investigator, participation would not be in 
the best interest of the participant (eg, compromise the well-being) or physical limitations 
that could prevent, limit, or confound the protocol-specified assessments. 

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12. 
12.1 
Criterion modified per Amendment 1 
 
Major surgery (eg, requiring general anesthesia) within 4 weeks prior to initiation of the 
study. 
13. 
Criterion added per Amendment 1 
Women who are breastfeeding 
14. 
Criterion added per Amendment 1 
Received a live, attenuated vaccine within 4 weeks prior to initiation of study treatment. 
NOTE: Investigators should ensure that all study enrollment (inclusion/exclusion) criteria have 
been met at screening and prior to the first dose of study intervention. If a participant's clinical 
status changes (including any available laboratory results or receipt of additional medical records) 
after screening but before the first dose of study intervention is given such that he or she no longer 
meets all eligibility criteria, then the participant should be excluded from participation in the study. 
Section 5.4, Screen Failures, describes options for retesting. The required source documentation 
to support meeting the enrollment criteria are noted in Appendix 3 (Section 10.3) Regulatory, 
Ethical, and Study Oversight Considerations. 
5.3. 
Lifestyle Considerations 
Potential participants must be willing and able to adhere to the following lifestyle restrictions 
during the course of the study to be eligible for participation: 
 
Agree to follow all requirements that must be met during the study as noted in the inclusion 
and exclusion criteria (eg, contraceptive requirements). 
 
Refer to Section 6.5, Concomitant Therapy for details regarding prohibited and restricted 
therapy during the study. 
 
In addition to contraceptive precautions discussed for male participants in Inclusion Criterion 
9 and Appendix 5, male participants should inform fertile female partners to use effective 
methods of birth control. 
5.4. 
Screen Failures 
Participant Identification, Enrollment, and Screening Logs 
The investigator agrees to complete a participant identification and enrollment log to permit easy 
identification of each participant during and after the study. This document will be reviewed by 
the Sponsor study-site contact for completeness. 
The participant identification and randomization log will be treated as confidential and will be 
filed by the investigator in the study file. To ensure participant confidentiality, no copy will be 
made. All reports and communications relating to the study will identify participants by participant 
identification and age at initial informed consent. In cases where the participant is not randomized 
into the study, the date seen and age at initial informed consent will be used. 

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Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened once after prior discussion with the Sponsor clinical team.  
6. 
STUDY INTERVENTION 
6.1. 
Study Interventions Administered 
In this protocol, “study intervention” refers to treatment with cusatuzumab or azacitidine. Detailed 
information on the composition of the study interventions can be found in the Investigator’s 
Brochure for cusatuzumab, and in the azacitidine label.   
Study intervention administration must be captured in the source documents and the eCRF.  Study 
interventions may be dispensed only by the investigator or by a member of study staff specifically 
authorized by the investigator, as appropriate. 
Dosing schedule 
After randomization, participants will receive combination therapy in 28-day cycles beginning 
with Cycle 1 Day 1, with azacitidine administered SC or IV (per local standard of care) at the 
standard dose of 75 mg/m² BSA on Days 1 through 7 of each cycle and cusatuzumab administered 
IV on Days 3 and 17 of each cycle. If Day 1 of azacitidine must be administered before Day 28 of 
the prior cycle due to scheduling or logistical reasons, a +/- 2 day window is allowed for the start 
of a cycle. The dose of the cusatuzumab will be based on the treatment group to which the 
participant is randomized, as follows: 
 
Treatment Group A: Azacitidine 75 mg/m2 SC or IV on Day 1 through Day 7; cusatuzumab 
10 mg/kg IV on Day 3 and Day 17 of each 28-day cycle 
 
Treatment Group B: Azacitidine 75 mg/m2 SC or IV on Day 1 through Day 7; cusatuzumab 
20 mg/kg IV on Day 3 and Day 17 of each 28-day cycle 
Body surface area and dose should only be recalculated if there is >10% weight change from the 
weight used in the previous dose calculation.  
The infusion of cusatuzumab will be started at a rate of 10 mL/hour. In the absence of IRRs, the 
infusion rate may be doubled every 30 minutes, to a maximum of 160 mL/hour. Cusatuzumab 
administration is according to the schedule given in the Pharmacy Manual and according to the 
tolerability of the intervention by the participant. In the absence of IRRs, subsequent infusions 
may be administered at the highest rate that was well tolerated in the preceding infusion. Refer to 
IRR guidelines in Section 6.6.1.  
When cusatuzumab and azacitidine are scheduled to be administered on the same day, azacitidine 
should be administered first. It is recommended that there is at least a 30-minute waiting time 
between the end of azacitidine administration and the start of the cusatuzumab infusion. 

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6.1.1. 
Premedications 
Pre-medication will be administered prior to each cusatuzumab infusion as follows. Variance 
based on institutional practice is acceptable once discussed with the Sponsor. 
 
Acetaminophen (eg, 650-1000 mg PO) approximately 30 minutes prior to the planned infusion 
time  
 
Antihistamine (eg, diphenhydramine 25-50 mg or equivalent antihistamine) PO or IV; 
approximately 30 minutes prior to the planned infusion time  
 
Corticosteroids (eg, methylprednisolone 125 mg or dexamethasone 20 mg); IV approximately 
1-3 hours prior to the planned infusion time 
For participants who do not experience IRRs for the first three cusatuzumab infusions, subsequent 
doses of cusatuzumab may be administered with only acetaminophen and antihistamine as 
pre-medication with no corticosteroids, or lower doses of corticosteroids if deemed necessary.  
Participants should be premedicated with anti-emetics for nausea and vomiting according to 
standard practice and as indicated in the azacitidine SPC and USPI.  
6.1.2. 
Anti-infective Prophylaxis 
Anti-infective prophylaxis (antibacterial, antifungal, or antiviral) on study should primarily be 
guided by institutional drug-resistance patterns and prevalent organisms. For participants in this 
study prophylaxis with a quinolone should be given at the start of therapy per ELN 
recommmendations.6  During periods of severe neutropenia (defined as ANC<500), prophylaxis 
with an antiviral agent such as acyclovir or valacyclovir and antifungal agent such as posaconazole, 
voriconazole, fluconazole must be initiated. Pneumocystis prophylaxis should also be considered. 
6.2. 
Preparation/Handling/Storage/Accountability 
Study Intervention Information - Cusatuzumab 
Cusatuzumab must be stored according to the label. 
Body weight used for cusatuzumab dose calculation is capped at a maximum of 100 kg (please 
refer to the Pharmacy manual for more details). Refer to the pharmacy manual/study site 
investigational product and procedures manual for additional guidance on study intervention 
preparation, handling, and storage.  
Study Intervention Information – Azacitidine 
Azacitidine must be stored as indicated on the clinical label.  
Refer to the pharmacy manual and SPC or USPI for additional guidance on study intervention 
preparation, handling, and storage.  

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6.3. 
Measures to Minimize Bias: Randomization and Blinding 
Participants will be randomized to 1 of the 2 dosing groups. Randomization will be stratified by 
type of AML (de novo versus secondary) and ECOG score (0-1 versus 2).  
Blinding 
As this is an open-label study, blinding procedures are not applicable. 
6.4. 
Study Intervention Compliance 
Cusatuzumab will be administered as an IV infusion by qualified staff; azacitidine will be 
administered by subcutaneous injection or IV infusion by qualified staff. The details of each 
administration will be recorded in the eCRF and the participant’s medical records.  
6.5. 
Concomitant Therapy 
Prestudy therapies administered up to 28 days before first dose of study intervention must be 
recorded at screening. Prior systemic therapies for MDS or myeloproliferative neoplasms (MPN) 
administered before signing of the informed consent should be collected at screening. 
Concomitant therapies must also be recorded through the study beginning with the start of the first 
dose of azacitidine to 30 days after the last dose of study intervention. All therapies (prescription 
or over-the-counter medications, including vaccines, vitamins, herbal supplements) different from 
the study intervention must be recorded in the eCRF.  Recorded information will include 
description of the type of therapy, start and stop date, duration of use, dosing regimen, route of 
administration, and indication.   
6.5.1. 
Permitted Therapies 
All concomitant medications for medical conditions other than AML are permitted, as clinically 
indicated. Localized or hormonal treatment for non-AML malignancies and localized radiotherapy 
for conditions other than AML may be considered with approval of the Sponsor. All supportive 
therapies, needed for the management of participants enrolled in this study, are permitted, except 
for those listed as prohibited therapies. 
The following medications and supportive therapies are examples of supportive care therapies that 
are recommended during the study: 
 
Short-term (≤7 days) treatment with low doses of systemic corticosteroids when medically 
necessary for the control of acute symptoms or as premedication for cusatuzumab; topical 
corticosteroids are permitted 
 
Prophylactic antibacterial, antifungal, or antiviral agents per ELN guidelines (see 
Section 6.1.2); 
 
Growth factors should be used for the treatment of febrile neutropenia (temperature ≥38.5°C 
and absolute neutrophil count < 1,000/µL) or an active bacterial or fungal infection (ie, 
requiring intravenous anti-infectives or extensive supportive care) in neutropenic participants. 
Growth factors need to also be used to prevent treatment delay due to neutropenia. 

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 
Red blood cell and platelet transfusions per institutional guidelines. 
6.5.2. 
Prohibited Therapies and Procedures 
The following medications are prohibited during the study treatment: 
 
Leukapheresis or other concurrent non-study anticancer therapy; 
 
Any additional monoclonal antibody;  
 
Investigational agents; and 
 
Live attenuated vaccination. 
The Sponsor must be notified in advance (or as soon as possible thereafter) of any instances in 
which prohibited therapies are administered. 
6.5.3. 
Subsequent Anticancer Therapy 
Data on subsequent anticancer therapy (AML directed therapy, radiotherapy, surgery, or 
hematopoietic stem cell transplant) administered after the last dose of study intervention should be 
documented in the eCRF (including start and end date and best response, if available) until the 
clinical cutoff for the primary CSR analysis. 
6.6. 
Dose Modification 
Participants will be treated with their assigned dosing regimen until disease progression, relapse, 
unacceptable toxicity, or withdrawal due to investigator discretion or withdrawal of consent. 
6.6.1. 
Management Guidelines for Potential Toxicities During Cusatuzumab 
Infusion 
Trained study staff at the study site should be prepared to intervene in case any IRRs occur. 
Resuscitation equipment and other agents necessary to treat anaphylaxis must be readily available 
(eg, epinephrine, corticosteroids, IV anti-histamines, bronchodilators, and oxygen). Attention to 
staffing should be considered when multiple participants will be dosed at the same time. 
Participants should be monitored for IRRs for 1 hour after completion of the cusatuzumab infusion. 
If after 3 cycles no IRRs are seen, monitoring after the infusion can be discontinued. 
For IRRs and hypersensitivity reactions of any grade/severity during the time of cusatuzumab 
infusion, immediately interrupt the infusion and manage symptoms. Management of IRRs and 
hypersensitivity reactions may require reduction in the rate of infusion for future treatment cycles. 
The following guidance is provided for investigators. 
 
Grade 1-2 (mild to moderate) IRRs or hypersensitivity reactions: Once reaction symptoms 
resolve, resume the infusion at no more than half the rate at which the reaction occurred. If 
the participant does not experience any further reaction symptoms, infusion rate escalation 
may resume incrementally. 
 
Grade 3 (severe) IRR or hypersensitivity reaction: Once reaction symptoms resolve, consider 
restarting the infusion at no more than half the rate at which the reaction occurred. If the 
participant does not experience additional symptoms the infusion rate may be increased at the 

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investigator’s discretion. Permanently discontinue cusatuzumab upon the third occurrence of 
a Grade 3 IRR or hypersensitivity reaction. 
 
Grade 4 (life threatening) IRR or hypersensitivity reactions: permanently discontinue 
cusatuzumab treatment 
Best supportive care should be administered, as applicable. Dose modifications due to toxicity are 
further described in Section 6.6.2. 
Participants should be managed for potential toxicities to azacitidine as indicated in the azacitidine 
SPC and USPI and Section 6.6.3.  
6.6.2. 
Management Guidelines for Toxicities Attributed to Cusatuzumab 
Toxicities attributed to cusatuzumab should be managed by modifying the infusion rate in the case 
of infusion-related reactions, temporarily stopping cusatuzumab, or discontinuing cusatuzumab 
altogether. Doses may be postponed based on the severity of and recovery from a previous toxicity. 
Dose reductions or escalations are not allowed except as recommended by the DRC at the time of 
dose selection.  
The following rules apply with respect to dose delays.  
 
There should be a time interval of at least 14 days and no more than 35 days between 
2 consecutive cusatuzumab doses. If greater than 35 days, investigators should contact the 
Sponsor’s clinical team to determine if the participant can continue to receive cusatuzumab. 
 
In case the start of a planned treatment cycle is delayed, for example due to recovery from 
hematological toxicities or logistical/organizational reasons, the subsequent treatment cycle 
will be the first day of azacitidine administration (Day 1). The administration of cusatuzumab 
will be shifted according to the shift in azacitidine dosing and will occur on Day 3 and Day 
17 of the 28-day azacitidine cycle.  
 
For participants who develop Grade 4 hematological or Grade 3 to 4 non-hematological 
toxicities that may be attributed to cusatuzumab alone, cusatuzumab treatment should be 
postponed until resolution of the adverse event to baseline or ≤ Grade 2. Azacitidine treatment 
may be maintained during the cusatuzumab interruption within the same cycle. Upon toxicity 
resolution, cusatuzumab administration should be again aligned with the azacitidine dosing 
cycle (ie, Day 3 and Day 17 of the 28-day azacitidine cycle).  
 
A cycle may be delayed (ie, cessation of both study interventions) for up to 21 days from the 
expected start date of the scheduled cycle; a hold >21 days must be reviewed and approved 
by the Sponsor’s clinical team prior to implementation.  
6.6.3. 
Management Guidelines for Toxicities Attributed to Azacitidine 
For participants who develop hematological or non-hematological toxicities that may be attributed 
to azacitidine alone, azacitidine treatment should be delayed/modified as per azacitidine SPC, 
USPI, or local standard of care. Cusatuzumab treatment may be maintained on a bi-weekly dosing 
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The following excerpts describe azacitidine (VIDAZA®) dose reduction guidelines from the 
VIDAZA SPC. 
 
Patients without reduced baseline blood counts (ie, White Blood Cells (WBC) ≥3.0 x 109 /L 
and ANC ≥ 1.5 x 109 /L, and platelets ≥ 75.0 x 109 /L) prior to the first treatment 
 
 If hematological toxicity is observed following Vidaza treatment, the next cycle of the 
therapy should be delayed until the platelet count and the ANC have recovered. If recovery is 
achieved within 14 days, no dose adjustment is necessary. However, if recovery has not been 
achieved within 14 days, the dose should be reduced according to the following table. 
Following dose modifications, the cycle duration should return to 28 days. 
Nadir Counts
% Dose in the next cycle, if recovery* is not 
achieved within 14 days 
ANC (x 109/L)
Platelets (x 109/L)
≤ 1.0
≤ 50.0
50%
> 1.0
> 50.0
100%
*Recovery = counts ≥ nadir count + (0.5 x [baseline count – nadir count]) 
 
 
Patients with reduced baseline blood counts (i.e. WBC < 3.0 x 109/L or ANC < 1.5 x 109/L or 
platelets< 75.0 x 109/L) prior to the first treatment 
 
Following Vidaza treatment, if the decrease in WBC or ANC or platelets from that prior to 
treatment is ≤ 50%, or greater than 50% but with an improvement in any cell line 
differentiation, the next cycle should not be delayed and no dose adjustment made. 
 If the decrease in WBC or ANC or platelets is greater than 50% from that prior to 
treatment, with no improvement in cell line differentiation, the next cycle of Vidaza therapy 
should be delayed until the platelet count and the ANC have recovered. If recovery is 
achieved within 14 days, no dose adjustment is necessary. However, if recovery has not 
been achieved within 14 days, bone marrow cellularity should be determined. If the bone 
marrow cellularity is > 50%, no dose adjustments should be made. If bone marrow 
cellularity is ≤ 50%, treatment should be delayed and the dose reduced according to the 
following table: 
 
Bone marrow cellularity
% Dose in the next cycle if recovery is not achieved within 14 days
Recovery * ≤ 21 days
Recovery * > 21 days
15-50 %
100%
50%
< 15%
100%
33%
         *Recovery = counts ≥ nadir count + (0.5 x [baseline count – nadir count]) 
 
 
Azacitidine can be administered to participants with renal impairment without initial dose 
adjustment. If unexplained reductions in serum bicarbonate levels to <20 mmol/L occur, the 
dose should be reduced by 50% on the next cycle. If unexplained elevations in serum 
creatinine or blood urea nitrogen (BUN) to ≥2-fold above baseline values and above ULN 
occur, the next cycle should be delayed until values return to normal or baseline and the dose 
should be reduced by 50% on the next treatment cycle. 
Following dose modifications, the cycle duration should return to 28 days. 

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6.7. 
Intervention After the End of Treatment  
Participants will be contacted to determine survival and subsequent therapy every 3 months 
(±7 days) after the last dose of study intervention, unless the participant has died, is lost to 
follow-up, or has withdrawn consent. If the information on survival, subsequent therapy and other 
malignancies is obtained via telephone contact, written documentation of the communication must 
be available for review in the source documents. If the participant has died, the date and cause of 
death will be collected and documented on the eCRF. 
Investigators may recontact the participant to obtain long-term follow-up information regarding 
the participant's safety or survival status as noted in the ICF (refer to Informed Consent in 
Appendix 3 Section 10.3, Regulatory, Ethical, and Study Oversight Considerations). 
Participants who are continuing to derive benefit from treatment with cusatuzumab, azacitidine or 
both agents as assessed by their investigator at the end of the study may continue to receive these 
medications. 
7. 
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL 
7.1. 
Discontinuation of Study Intervention 
A participant's study intervention must be permanently discontinued if: 
 
The participant (or the participant’s legally acceptable representative) withdraws consent to 
receive study intervention 
 
The participant experiences unacceptable toxicity (participants may discontinue 
1 intervention while continuing treatment with the other intervention); 
 
The investigator believes that for safety reasons or tolerability reasons (eg, adverse event) it 
is in the best interest of the participant to discontinue study intervention 
 
The participant experiences disease progression or relapse (see Table 6). 
If the participant becomes pregnant Refer to Appendix 5 Section 10.5, Contraceptive Guidance 
and Collection of Pregnancy Information. Treatment should be suspended and the Sponsor’s 
clinical team should be contacted as soon as possible to discuss study treatment options. 
If a participant discontinues study intervention for any reason before the end of the study then the 
end of treatment assessments should be obtained.  
7.2. 
Participant Discontinuation/Withdrawal From the Study 
A participant will be withdrawn from the study for any of the following reasons: 
 
Lost to follow-up 
 
Withdrawal of consent  
 
Death 

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 
The study investigator or Sponsor, for any reason, stops the study or stops the participant’s 
participation in the study 
When a participant withdraws before study completion, the reason for withdrawal is to be 
documented in the eCRF and in the source document. If the reason for withdrawal from the study 
is withdrawal of consent then no additional assessments are allowed. 
Withdrawal of Consent 
A participant declining to return for scheduled visits does not necessarily constitute withdrawal of 
consent. Alternate follow-up mechanisms that the participant agreed to when signing the consent 
form apply as local regulations permit. 
7.2.1. 
Withdrawal From the Use of Research Samples 
A participant who withdraws from the study will have the following options regarding the optional 
research samples: 
 
The collected samples will be retained and used in accordance with the participant's original 
separate informed consent for optional research samples. 
 
The participant may withdraw consent for research samples, in which case the samples will 
be destroyed and no further testing will take place. To initiate the sample destruction process, 
the investigator must notify the Sponsor study site contact of withdrawal of consent for the 
research samples and to request sample destruction. The Sponsor study site contact will, in 
turn, contact the biomarker representative to execute sample destruction. If requested, the 
investigator will receive written confirmation from the Sponsor that the samples have been 
destroyed. 
Withdrawal From the Use of Samples in Future Research 
The participant may withdraw consent for use of samples for research (refer to Long-Term 
Retention of Samples for Additional Future Research in Appendix 3 Section 10.3 Regulatory, 
Ethical, and Study Oversight Considerations). In such a case, samples will be destroyed after they 
are no longer needed for the clinical study. Details of the sample retention for research are 
presented in the main ICF. 
7.3. 
Lost to Follow-up 
To reduce the chances of a participant being deemed lost to follow-up, prior to randomization 
attempts should be made to obtain contact information from each participant, eg, home, work, and 
mobile telephone numbers and email addresses for both the participant as well as appropriate 
family members. 
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site. A participant cannot be deemed 
lost to follow-up until all reasonable efforts made by the study-site personnel to contact the 
participant are deemed futile. The following actions must be taken if a participant fails to return to 
the study site for a required study visit: 

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 
The study-site personnel must attempt to contact the participant to reschedule the missed visit 
as soon as possible, to counsel the participant on the importance of maintaining the assigned 
visit schedule, to ascertain whether the participant wishes to or should continue in the study. 
 
Before a participant is deemed lost to follow up, the investigator or designee must make every 
reasonable effort to regain contact with the participant (where possible, 3 telephone calls, 
e-mails, fax, and, if necessary, a certified letter to the participant’s last known mailing address, 
or local equivalent methods. Locator agencies may also be used as local regulations permit. 
These contact attempts should be documented in the participant’s medical records. 
 
Should the participant continue to be unreachable, they will be considered to have withdrawn 
from the study. 
Should a study site close, eg, for operational, financial, or other reasons, and the investigator cannot 
reach the participant to inform them, their contact information will be transferred to another study 
site. 
8. 
STUDY ASSESSMENTS AND PROCEDURES 
Overview 
The Schedules of Activities summarizes the frequency and timing of efficacy, PK, 
immunogenicity, PD, biomarker, and safety measurements applicable to this study. 
If standard of care tests are performed within the allowable screening period but prior to signing 
of the ICF the results for these tests may be used for determination of participant eligibility. In this 
case, after the participant signs the ICF, samples for the local laboratory may not be required, 
however samples for the central laboratory may still be required as referenced in Schedule of 
Events. 
All PRO assessments should be conducted/completed before any tests, procedures (including bone 
marrow examination), or other consultations to prevent influencing participant perceptions. 
Sample collections for PK and PD assessments should be kept as close to the specified time as 
possible. Other measurements may be done earlier than specified timepoints if needed. Actual 
dates and times of assessments will be recorded in the source documentation and the eCRF or lab 
requisition form. 
8.1. 
Efficacy Assessments 
Disease assessments are based on bone marrow evaluations, peripheral blood counts, and the 
presence of extramedullary disease and will be conducted per the Schedule of Activities at the 
local laboratory (Table 1/Table 1A). Bone marrow aspirates should be performed for the disease 
assessment (for bone marrow blasts), for biomarker testing, and for PK. In case of a dry tap, the 
biopsy may also be utilized for disease assessment. Extramedullary disease evaluations may 
include computed tomography (CT) scans, magnetic resonance imaging (MRI), positron emission 
tomography (PET) scans, ultrasound, and physical examinations. See Table 2 for bone marrow 
biomarker sampling and Table 3 for bone marrow PK sampling. All treatment decisions will be 
based on local assessments. De-identified copies of the bone marrow aspirate (or biopsy) 

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pathology report will be sent in to the Sponsor. Transfusion status should also be collected per 
Schedule of Activities at the time of disease evaluations. 
Participants will be assessed for disease status based on the ELN 2017 Response Criteria in AML 
(Table 6) at the timepoints indicated in Schedule of Activities through CR, CRi, CRh, and at the 
time of progressive disease. If progressive disease is suspected due to clinical indications or 
increased peripheral blast counts, then a bone marrow sample must be obtained to confirm 
progressive disease as defined in Table 6. In the case of overt leukostasis, uncontrollable 
coagulopathy, or new extramedullary leukemia requiring immediate action and a bone marrow 
sample cannot be obtained, the Sponsor must be consulted to confirm progressive disease for the 
participant.  
Before participants discontinue the Treatment Phase due to progressive disease or relapse from 
CR/CRi/CRh, sites will document progressive disease or relapse as soon as possible and within 
48 hours. The primary reason for discontinuation of study treatment is to be recorded in the eCRF. 
For all participants, the Sponsor should be informed as soon as progressive disease or relapse from 
CR/CRi/CRh is confirmed. Discontinuation criteria for all participants must be reviewed and 
confirmed by the Sponsor prior to discontinuation. 
Investigator’s disease assessments will be used for response in Part 1 . Overall best response across 
all cycles of treatment will be used to assess response rate. For an overall best response of stable 
disease, disease stabilization must have lasted for at least 3 months. 

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Table 6:  
Response Assessments based on ELN 2017 (Dohner 2017)6   
Category 
Definition 
Complete response (CR) 
Bone marrow blasts <5%; absence of circulating blastsa and blasts with Auer 
rods; absence of extramedullary disease; absolute neutrophil count ≥1.0 × 109/L 
(1000/μL); platelet count ≥100 × 109/L (100 000/μL) 
CR with incomplete recovery 
(CRi)
All CR criteria except for residual neutropenia (absolute neutrophil count <1.0 
× 109/L [1000/μL]) or thrombocytopenia (platelets <100 × 109/L [100 000/μL]) 
CR with partial hematological 
recovery (CRh)* 
Bone marrow blasts <5%; absence of circulating blasts and blasts with Auer 
rods; absence of extramedullary disease; absolute neutrophil count >0.5 × 109/L 
[500/μL] and platelet count >50 × 109/L [50, 000/μL]
CR without MRD (CRMRD-) 
CR without MRD; defined as less than 1 blast or leukemic stem cell in 1,000 
leukocytes (MRD level <10-3; determined by central lab) 
Morphologic leukemia-free 
state (MLFS)
Bone marrow blasts <5%; absence of blasts with Auer rods; absence of 
extramedullary disease; no hematologic recovery required 
Partial response (PR) 
All hematologic criteria of CR; decrease of bone marrow blast percentage to 5% 
to 25%; and decrease of pretreatment bone marrow blast percentage by at least 
50% 
Stable disease 
Absence of CR, CRi, CRh, PR, MLFS and criteria for progressive disease not 
met
Relapse after CR, CRi, CRh 
Bone marrow blasts ≥5%; or reappearance of blasts in the blood; or development 
of extramedullary disease 
Progressive Disease 
Evidence for an increase in bone marrow blast percentage and/or increase of 
absolute blast counts in the blood: 
 
>50% increase in bone marrow blasts over baseline (a minimum 15% point 
increase is required in cases with <30% blasts at baseline or; 
 
Persistent marrow blast percentage of >70% over at least 3 months; without 
at least a 100% improvement in ANC to an absolute level (>0.5 × 109/L 
[500/µL], and/or platelet count to >50 × 109/L [50 000/µL] nontransfused) 
or;  
 
 >50% increase in peripheral blasts (WBC x % blasts) to >25 × 109/L 
(>25000/uL) (in the absence of differentiation syndrome) or;  
 
New extramedullary disease
* If both CRi and CRh criteria are met, CRh  should be reported. 
a Unless circulating blasts can be attributed to recent GCSF administration 
The total blood volume to be collected from each participant will be between 700 to 770 mL, 
depending upon what samples are taken and assuming 8 cycles of treatment. Repeat or 
unscheduled samples may be taken for safety reasons or for technical issues with the samples. 
Sample Collection and Handling 
The actual dates and times of sample collection must be recorded in the eCRF or laboratory 
requisition form. If blood samples are collected via an indwelling cannula, an appropriate amount 
(1 mL) of serosanguineous fluid slightly greater than the dead space volume of the lock will be 
removed from the cannula and discarded before each blood sample is taken. After blood sample 
collection, the cannula will be flushed with 0.9% sodium chloride, United States Pharmacopeia 
(USP) (or equivalent) and charged with a volume equal to the dead space volume of the lock. If a 
mandarin (obturator) is used, blood loss due to discard is not expected. 
Refer to the Schedule of Activities for the timing and frequency of all sample collections. 

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Instructions for the collection, handling, storage, and shipment of samples are found in the 
laboratory manual that will be provided. Collection, handling, storage, and shipment of samples 
must be under the specified, and where applicable, controlled temperature conditions as indicated 
in the laboratory manual. 
Study-Specific Materials 
The investigator will be provided with the following supplies: 
 
Investigator's Brochure (cusatuzumab); SPC or United States Package Insert for azacitidine  
 
Pharmacy manual/study site investigational product and procedures manual 
 
Laboratory manual 
 
NCI-CTCAE Version 5.0 
 
PRO questionnaires  
 
EQ-5D-5L v 2 and FACT-Leu V 4  
 
IVRS/IWRS Manual  
 
eDC Manual 
 
Sample ICF 
8.2. 
Safety Assessments 
Adverse events will be reported and followed by the investigator as specified in Adverse Events 
and Serious Adverse Events Section 8.3 and Appendix 4 Section 10.4, Adverse Events: Definitions 
and Procedures for Recording, Evaluating, Follow-Up, and Reporting. 
Any clinically relevant changes occurring during the study must be recorded on the Adverse Event 
section of the eCRF. 
Any clinically significant abnormalities persisting at the end of the study/early withdrawal will be 
followed by the investigator until resolution or until a clinically stable condition is reached.  
The study will include the following evaluations of safety and tolerability according to the time 
points provided in the Schedule of Activities:Table 1/Table 1A 
8.2.1. 
Physical Examination 
A full physical examination will be performed at screening. Subsequently, a directed physical 
examination (including all organ systems that were previously abnormal or involved with disease 
and documentation of any clinically relevant abnormalities in any organ) will be performed at the 
timepoints specified in the Schedule of Activities. Any changes that are clinically significant will 
be recorded on the AE eCRF. Height will be measured at Screening only; weight will be measured 
prior to the start of each cycle and at the EOT. 

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8.2.2. 
Vital Signs 
Temperature, heart rate, respiratory rate, blood pressure will be recorded according to the Schedule 
of Activities (Table 1/Table 1A). Blood pressure and heart rate measurements should be preceded 
by at least 5 minutes of rest in a quiet setting without distractions (eg, television, cell phones) and 
be monitored with the same method and position (sitting or supine) throughout the study.  
8.2.3. 
Electrocardiogram 
During the collection of ECGs, participants should be in a quiet setting without distractions (eg, 
television, cell phones). Participants should rest in a supine position for at least 5 minutes before 
ECG collection and should refrain from talking or moving arms or legs. If blood sampling or vital 
sign measurement is scheduled for the same time point as ECG recording, the procedures should 
be performed in the following order: ECG(s), vital signs, blood draw. 
8.2.4. 
Spirometry Test 
Participant’s baseline pulmonary disease must have a spirometry test during the Screening Phase 
and then repeat evaluation per the Schedule of Activities Table 1/Table 1A. 
8.2.5. 
ECOG Performance Status 
The ECOG Performance Status scale will be used to grade changes in the participant’s daily living 
activities. The ECOG Performance Status scale is provided in Appendix 6 Section 10.6. The 
frequency of ECOG Performance Status assessment is provided in the Schedule of Activities Table 
1/Table 1A. 
8.2.6. 
Clinical Safety Laboratory Assessments 
Blood samples for serum chemistry and hematology will be collected as noted in Appendix 2 
Section 10.2, Clinical Laboratory Tests. The investigator must review the laboratory results, 
document this review, and record any clinically relevant changes occurring during the study in the 
adverse event section of the eCRF. The laboratory reports must be filed with the source documents. 
The following laboratory elevations may indicate severe liver injury (possible Hy’s law) and 
further workup and testing should be strongly considered. See Section 6.6 for study treatment dose 
modification guidelines. 
 
For participants with normal baseline AST, ALT and bilirubin, all events of AST or ALT 3 
× upper limit of normal (ULN) and bilirubin 2 × ULN  
 
For participants with baseline ALT or AST 3 × ULN, all events with ALT or AST 3 times 
baseline values in the absence of concurrent bilirubin elevations or new symptoms  
 
For participants with baseline ALT or AST 3 × ULN, all events with ALT or AST 2 × 
baseline values if concurrent bilirubin elevations or symptoms occur or no alternative causes 
are found.  
 
For participants with baseline bilirubin 2 × ULN, all events with bilirubin  2x baseline 

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8.3. 
Adverse Events and Serious Adverse Events 
Timely, accurate, and complete reporting and analysis of safety information from clinical studies 
are crucial for the protection of participants, investigators, and the Sponsor, and are mandated by 
regulatory agencies worldwide. The Sponsor has established Standard Operating Procedures in 
conformity with regulatory requirements worldwide to ensure appropriate reporting of safety 
information; all clinical studies conducted by the Sponsor or its affiliates will be conducted in 
accordance with those procedures. Adverse events will be reported by the participant (or, when 
appropriate, by a caregiver, surrogate, or the participant's legally acceptable representative).  
For further details on adverse events and serious adverse events (Definitions and Classifications; 
Attribution Definitions; Severity Criteria; Special Reporting Situations; Procedures) as well as 
product quality complaints, refer to Appendix 4 Section 10.4, Adverse Events: Definitions and 
Procedures for Recording, Evaluating, Follow-Up, and Reporting. 
8.3.1. 
Time Period and Frequency for Collecting Adverse Event and Serious 
Adverse Event Information 
All Adverse Events 
All adverse events and special reporting situations, whether serious or non-serious, will be reported 
from the time a signed and dated ICF is obtained until 30 days after the last dose of study 
intervention or until the start of subsequent anti-AML therapy, if earlier. Serious adverse events, 
including those spontaneously reported to the investigator within 30 days after the last dose of 
study intervention, must be reported using the Serious Adverse Event Form. The Sponsor will 
evaluate any safety information that is spontaneously reported by an investigator beyond the time 
frame specified in the protocol. 
Serious Adverse Events 
All serious adverse events occurring during the study must be reported to the appropriate Sponsor 
contact person by study-site personnel within 24 hours of their knowledge of the event. 
Information regarding serious adverse events will be transmitted to the Sponsor using the Serious 
Adverse Event Form, which must be completed and signed by a physician from the study site and 
transmitted to the Sponsor within 24 hours. The initial and follow-up reports of a serious adverse 
event should be made by facsimile (fax). 
8.3.2. 
Method of Detecting Adverse Events and Serious Adverse Events  
Care will be taken not to introduce bias when detecting adverse events or serious adverse events. 
Open-ended and nonleading verbal questioning of the participant is the preferred method to inquire 
about adverse event occurrence.  
Solicited Adverse Events 
Solicited adverse events are predefined local at the injection site and systemic events for which the 
participant is specifically questioned. 

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Unsolicited Adverse Events 
Unsolicited adverse events are all adverse events for which the participant is not specifically 
questioned. Care will be taken not to introduce bias when detecting adverse events or serious 
adverse events. Open-ended and nonleading verbal questioning of the participant is the preferred 
method to inquire about adverse event occurrence.  
8.3.3. 
Follow-up of Adverse Events and Serious Adverse Events 
Adverse events, including pregnancy, will be followed by the investigator as specified in 
Appendix 10.4, Adverse Events: Definitions and Procedures for Recording, Evaluating, 
Follow-up, and Reporting. 
8.3.4. 
Regulatory Reporting Requirements for Serious Adverse Events 
The Sponsor assumes responsibility for appropriate reporting of adverse events to the regulatory 
authorities. The Sponsor will also report to the investigator (and the head of the investigational 
institute where required) all suspected unexpected serious adverse reactions (SUSARs). The 
investigator (or Sponsor where required) must report SUSARs to the appropriate Independent 
Ethics Committee/ Institutional Review Board (IEC/IRB) that approved the protocol unless 
otherwise required and documented by the IEC/IRB. 
8.3.5. 
Adverse Events of Special Interest 
Grade ≥3 IRR will be followed as part of standard safety monitoring activities by the Sponsor. 
These events will be reported to the Sponsor within 24 hours of awareness irrespective of 
seriousness (ie, serious and nonserious adverse events) following the procedure described above 
for serious adverse events and will require enhanced data collection.  
8.3.6. 
Pregnancy 
All initial reports of pregnancy in female participants or partners of male participants must be 
reported to the Sponsor by the study-site personnel within 24 hours of their knowledge of the event 
using the appropriate pregnancy notification form. Abnormal pregnancy outcomes 
(eg, spontaneous abortion, fetal death, stillbirth, congenital anomalies, ectopic pregnancy) are 
considered serious adverse events and must be reported using the Serious Adverse Event Form. 
Any participant who becomes pregnant during the study must withhold treatment of the study 
intervention and notify the Sponsor’s clinical team. Follow-up information regarding the outcome 
of the pregnancy and any postnatal sequelae in the infant will be required. 
8.4. 
Treatment of Overdose 
For this study, any dose of cusatuzumab greater than 20 mg/kg, within a 24-hour time period will 
be considered an overdose.  
In the event of an overdose, the investigator or treating physician should: 
 
Contact the Sponsor immediately. The Sponsor’s clinical team will evaluate the extent of an 
overdose and will determine if the measures outlined below should be followed. 

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 
Closely monitor the participant for AE/SAE and laboratory abnormalities for a minimum of 
90 days. 
 
Obtain a serum sample for PK analysis within 3 days from the date of the last dose of study 
intervention if requested by the Medical Monitor (determined on a case-by-case basis). 
 
Document the quantity of the excess dose as well as the duration of the overdosing in the 
eCRF. 
Decisions regarding dose interruptions or modifications will be made by the investigator in 
consultation with the Medical Monitor based on the clinical evaluation of the participant. 
8.5. 
Pharmacokinetics 
Serum samples will be used to evaluate the PK of cusatuzumab. In addition, limited bone marrow 
aspirates may be used to evaluate cusatuzumab concentration in bone marrow. Limited plasma 
samples will be used to evaluate PK of azacitidine. Serum collected for PK may additionally be 
used to evaluate safety or efficacy aspects that address concerns arising during or after the study 
period. Genetic analyses will not be performed on these serum samples. Participant confidentiality 
will be maintained. 
8.5.1. 
Evaluations 
Venous blood samples of approximately 7 mL will be collected for measurement of serum 
concentrations of cusatuzumab and anti-cusatuzumab antibodies as suggested in the Schedule of 
Activities (Table 1/Table 1A). In addition to serum samples, plasma samples will be analyzed for 
measurement of azacitidine concentrations.  
Venous blood samples will be collected and each serum sample will be divided into 4 aliquots. 
Samples collected for analyses of cusatuzumab serum concentration and antibodies to 
cusatuzumab may additionally be used to evaluate safety or efficacy aspects that address concerns 
arising during or after the study period, for further characterization of immunogenicity or for the 
evaluation of relevant biomarkers. Genetic analyses will not be performed on these serum samples. 
Participant confidentiality will be maintained. Additional information about the collection, 
handling, and shipment of biological samples can be found in the Laboratory Manual. 
8.5.2. 
Analytical Procedures 
Pharmacokinetics 
Plasma and serum samples will be analyzed to determine concentrations of azacitidine and 
cusatuzumab, respectively, using validated, specific, and sensitive (eg, immunoassay and 
LC-MS/MS) methods by or under the supervision of the Sponsor. Additionally, concentrations of 
cusatuzumab in bone marrow will be determined for a small number of participants.  
Immunogenicity  
The detection and characterization of anti-cusatuzumab antibodies will be performed using a 
validated assay method by or under the supervision of the Sponsor. All samples collected for 

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detection of anti-cusatuzumab antibodies will also be evaluated for cusatuzumab serum 
concentration to enable interpretation of the antibody data. 
Anti-cusatuzumab antibodies will be evaluated in serum samples collected from all participants 
according to the Schedule of Activities. Additionally, serum samples should also be collected at 
the final visit from participants who are discontinued from intervention or withdrawn from the 
study. These samples will be tested by the Sponsor or Sponsor's designee. 
Serum samples will be screened for antibodies binding to cusatuzumab and the titer of confirmed 
positive samples will be reported. Other analyses may be performed to further characterize the 
immunogenicity of cusatuzumab. 
Serum samples will be used to evaluate the immunogenicity of anti-cusatuzumab antibodies. 
Samples collected for immunogenicity analyses may additionally be used to evaluate safety or 
efficacy aspects that address concerns arising during or after the study period. Genetic analyses 
will not be performed on these serum samples. Participant confidentiality will be maintained. 
Receptor Occupancy 
Whole blood samples will be analyzed for RO via flow cytometry. 
8.5.3. 
Pharmacokinetic Parameters and Evaluations 
Parameters 
Based on the individual serum concentration-time data, using the actual dose taken and the actual 
sampling times, PK parameters and exposure information of cusatuzumab will be derived using 
population PK modelling. Baseline covariates (eg, body weight, age, sex, CrCL, race) may be 
included in the model, if relevant. 
Pharmacokinetic/Pharmacodynamic Evaluations 
If sufficient data are available, pharmacokinetic/pharmacodynamic modeling may be performed, 
including exploring the relationship between serum concentrations of cusatuzumab and 
biomarkers, PD markers, or endpoints of clinical efficacy. If these analyses are performed, the 
details and results will be presented in a separate report. 
8.6. 
Genetics 
Genetics are not evaluated in this study, however, somatic mutations are evaluated in the tumor 
cells as described in Section 8.8. 
8.6.1. 
Cytogenetics/ Mutational Analysis 
Assessment of mutational status must be performed per schedule of activities (Table 1/Table 1A) 
and must include testing for all mutations listed in Appendix 10. Central and/or local testing is 
acceptable. Bone marrow collected at screening is preferred for mutational analyses. However, 
standard-of-care assessment of mutational status obtained prior to the ICF signing will be accepted 
in lieu of screening marrow, provided that it includes testing for all mutations listed in Appendix 

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10. Left over fresh or frozen bone marrow samples may be requested for central mutational 
analysis if all tests are not performed by the local study site. 
8.7. 
Pharmacodynamics 
Samples of bone marrow aspirates or whole blood for pharmacodynamics evaluations will be 
collected as specified in the Schedule of Activities Table 2. Biomarker tests will include, but not 
limited to: evaluation of CD70 and CD27 expression level and decrease numbers of blasts and 
leukemia stem cells (LSC) in whole blood and bone marrow by flow cytometry, mRNA levels for 
CD70, CD27 and other CD70-CD27 signaling-related genes, and LSC gene signature by 
transcriptome analysis. Serum samples will be collected and used for protein quantification for 
evaluation of soluble CD27 and may be for inflammatory cytokines. The changes in 
pharmacodynamic parameters from baseline to timepoints specified in the Schedule of Activities 
(Table 2) will be analyzed.   
8.8. 
Biomarkers 
Samples for biomarker evaluations will be collected as specified in The Schedule of Activities 
Table 2. The baseline levels and changes from baseline in biomarkers will be analyzed.  Additional 
information about the collection, handling, and shipment of biological samples can be found in the 
Laboratory Manual.   
The biomarkers to be tested in this study are based on the cusatuzumab mechanism of action, 
treatment with cusatuzumab results in induction of cytotoxicity against CD70-positive tumor cells 
by antibody effector mechanisms (enhanced ADCC, ADCP, CDC), by blocking proliferation and 
survival signals of malignant cells, and by induction of an anti-tumor immune response following 
interruption of CD70-CD27 signaling. The approaches of biomarker tests include, but not limited 
to, the following: 
Flow cytometry/ CyTOF: The main mechanism of action of cusatuzumab is ADCC through NK 
cell activation, therefore, bone marrow aspirates or whole blood will be analyzed for 
immunophenotyping by flow cytometry for NK cell counts and biomarker of NK cell activation. 
In addition, B cells, T cell subsets, and other immune cell subpopulations, such as activated T cells, 
Treg, may be evaluated by flow cytometry and/or CyTOF. An additional mechanism of action may 
be through the induction of myeloid differentiation. Bone marrow aspirates will be evaluated for 
markers of differentiation by flow cytometry. These assessments will be evaluated for the 
association with clinical outcome. 
Genomic analysis: DNA sequencing from tumor cells will be performed to identify mutations for 
characterization of disease subtype and potential predictive biomarkers of response and resistance. 
DNA methylation analysis may be performed. 
Gene expression/transcriptome profile: RT-PCR or RNAseq analysis for evaluating the effect 
of cusatuzumab plus azacitidine on mRNA levels of CD70, CD27, genes involved in CD70/CD27 
signaling pathways, and leukemic stem cell (LSC) signature. Baseline transcriptome profile will 
be correlated to clinical response to identify gene signatures potential predict response to 

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cusatuzumab plus azacitidine. 
Minimal/measurable residual disease (MRD) assessment: MRD assessments will be performed 
on bone marrow aspirates and whole blood samples collected from all participants at baseline by 
flow cytometry and molecular methods such as next generation of sequence (NGS) or droplet PCR 
to establish the clone for MRD monitoring. Additional bone marrow aspirate and whole blood 
sample will be taken for participants at suspected CR, then follow up until relapse or EOT to assess 
duration of MRD negativity. For flow cytometry MRD assay, the cutoff for MRD negativity is 
defined as less than 1 blast in 1,000 leukocytes (MRD level <10-3 as recommended by the ELN.6 
In addition, other lower cutoff values will be evaluated for MRD negativity. 
Additional Collections 
Additional blood samples will be collected if a participant experiences Grade 3 or greater infusion-
related reactions for cytokine analysis. If it is determined at any time before study completion that 
additional material is needed for the successful completion of the protocol-specified analyses, the 
Sponsor may request that additional material be retrieved from existing samples. Also, based on 
emerging scientific evidence, the Sponsor may request additional material from previously 
collected tumor samples during or after study completion for a retrospective analysis. In this case, 
such analyses would be specific to research related to the study intervention(s) or diseases being 
investigated. 
Stopping Analysis 
Biomarker analyses are dependent upon the availability of appropriate biomarker assays and 
clinical response rates. Biomarker analysis may be deferred or not performed, if during or at the 
end of the study, it becomes clear that the analysis will not have sufficient scientific value for 
biomarker evaluation, or if there are not enough samples or responders to allow for adequate 
biomarker evaluation. In the event the study is terminated early or shows poor clinical efficacy, 
completion of biomarker assessments is based on justification and intended utility of the data. 
8.9. 
Patient-Reported Outcomes 
Patient-reported outcome assessments will be conducted as described in the Schedule of Activities 
(Table 1/Table 1A). Patient-reported outcome assessments should be completed at the beginning 
of the corresponding assessment, before any other assessments, examinations, or treatments 
following the PRO completion guidelines. 
Patient-reported outcome instruments will be administered on paper forms to be filled out directly 
by the participant, except in the cases of follow-up assessments that may be conducted by 
telephone or under special circumstances as described in the PRO completion guidelines (eg, 
assisted administration for participants with visual impairment). In the event that PRO assessments 
cannot be completed as scheduled during a site visit it should be entered in the eCRF. 
Patient-reported outcome instruments included in this study are the Functional Assessment of 
Cancer Therapy – Leukemia (FACT-Leu) and EuroQoL 5 Dimension 5 Level questionnaire 
(EQ-5D-5L).  

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The FACT-Leu is a 44-item instrument measuring health-related quality of life concepts.  It is 
comprised of 4 subscales that make up the FACT-G: physical well-being (PWB, 7 items), 
social/family well-being (SWB, 7 items), emotional well-being (EWB, 6 items), and functional 
well-being (FWB, 7 items) and a fifth subscale for leukemia-specific concerns (LeuS, 17 items).  
Items are rated on a response scale from 0 (not at all) to 4 (very much).  Subscale and total scores 
may be calculated according to instrument administration and scoring guidelines; higher scores 
indicated better health-related quality of life.  
The EQ-5D consists of 5 items describing health state and the EuroQoL visual analog scale (VAS) 
of self-rated overall health.  Responses for the 5 descriptive items are converted into a single index 
value or utility score according to EQ-5D scoring algorithm ranging from -1 to 1 where lower 
scores indicate worse health status. EQ-5D-VAS responses range from 0 (the worst health you can 
imagine) to 100 (the best health you can imagine). 
Minimum important difference (MID) thresholds for improvement/worsening will be specified in 
the statistical analysis plan for any PRO score analyses requiring a threshold.  All PRO scale scores 
will be calculated according to published instrument manuals (ie, administration and scoring 
guidelines) for scoring and handling of missing data unless otherwise specified. 
8.10. 
Medical Resource Utilization 
Medical resource utilization data, associated with medical encounters, will be collected in the 
eCRF by the investigator and study-site personnel for all participants throughout the study. 
Protocol-mandated procedures, tests, and encounters are excluded. The data collected may be used 
to conduct exploratory economic analyses and will include: 
 
Number and duration and reasons for medical care encounters, including surgeries, and other 
selected procedures (inpatient and outpatient) 
 
Duration of hospitalization (total days length of stay, including duration by wards; 
eg, intensive care unit) 
 
Number and character of diagnostic and therapeutic tests and procedures 
 
Outpatient medical encounters and treatments (including physician or emergency room visits, 
tests and procedures, and medications) and reasons 
9. 
STATISTICAL CONSIDERATIONS 
Detailed statistical methods used in the study design are described in this section. Statistical 
analysis will be done by the Sponsor or under the authority of the Sponsor. A general description 
of the statistical methods to be used to analyze the efficacy and safety data is outlined below. 
Specific details will be provided in the Statistical Analysis Plan.  
9.1. 
Statistical Hypotheses 
The primary hypothesis is that participants treated with the combination of cusatuzumab (at a dose 
level of 10 mg/kg or 20 mg/kg) and azacitidine can achieve a CR rate of 35% or greater against 
the null hypothesis of 20%. 

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9.2. 
Sample Size Determination 
Up to 50 participants will be enrolled for each dose group in Part 1 of the study. Part 1 will utilize 
a 3-stage monitoring approach to determine, at each stage and for each dose group, if the observed 
CR rate warrants the respective dose to be continued into the next stage or into Part 2 of the study 
(see details in Section 9.5, Interim Analysis). Participants will be enrolled into Part 2 at the selected 
cusatuzumab dose until a cumulative total of 100 participants have been treated with the selected 
dose from Part 1 and Part 2. The study has a >90% power to reject the null hypothesis of a CR rate 
of 20% under the alternative hypothesis of 35% for a total of 100 participants (from Part 1 and 
Part 2) at the selected dose level. This sample size is based on the single-arm Wilson Score test 
without continuity correction at an overall 1-sided type 1 error rate <2.5%.   
9.3. 
Populations for Analyses 
The primary analysis of efficacy will be based on the intent-to-treat (ITT) population that includes 
all randomized (Part 1) and all enrolled (Part 2) participants. Selected efficacy endpoints will also 
be performed on the efficacy-evaluable population that includes all ITT participants who have 
baseline and at least one post-baseline disease evaluation. Safety will be evaluated on the safety 
population that includes all participants who have received at least 1 dose of study intervention. 
The pharmacokinetic analyses will be performed on the pharmacokinetic evaluable population. 
9.4. 
Statistical Analyses 
9.4.1. 
Efficacy Analyses 
Binary endpoints will be summarized with number and percentage of participants achieving the 
endpoint along with the corresponding 2-sided 95% exact confidence interval. These endpoints 
include CR, CR + CRh, CR+CRh+CRi, CR without MRD, MRD negativity, and transfusion 
independence. Hypothesis testing for the primary endpoint of CR rate will be performed using the 
Wilson Score test without continuity correction against the null hypothesis of 20% at the planned 
interim and final analyses (see Section 9.5, Interim Analysis).  
The Kaplan-Meier method will be used to summarize time-to-events endpoints, including time to 
CR, time to CR + CRh + CRi, duration of CR, duration of CR+ CRh + CRi, PFS, and OS. Time 
to and duration of response are defined only for participants who achieved such responses; PFS 
and OS are defined for all participants. Duration of transfusion independence will also be 
summarized for participants who achieved such status. 
No formal hypothesis testing or formal statistical comparison between the 2 dose groups is planned 
for study Part 1. 
9.4.2. 
Safety Analyses 
Adverse Events 
The verbatim terms used in the eCRF by investigators to identify adverse events will be coded 
using the Medical Dictionary for Regulatory Activities (MedDRA). Toxicities will be graded for 
severity according to NCI-CTCAE, version 5.0. Intervention-emergent adverse events are adverse 

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events with onset during the intervention phase or that are a consequence of a pre-existing 
condition that has worsened since baseline. All reported adverse events will be included in the 
analysis. For each adverse event, the percentage of participants who experience at least 
1 occurrence of the given event will be summarized by intervention group. In addition, 
comparisons between intervention groups will be provided if appropriate. 
Specifically, the following will be summarized: 
 
All adverse events; 
 
Grade 3 or higher adverse events; 
 
Serious adverse events; 
 
Adverse events leading to discontinuation of treatment; 
 
Adverse events leading to death; and 
 
Adverse events of special interest.  
Summaries, listings, datasets, or participant narratives may be provided, as appropriate, for those 
participants who die, who discontinue intervention due to an adverse event, or who experience a 
severe or a serious adverse event. 
Parameters with predefined National Cancer Institute Common Terminology Criteria for Adverse 
Events (NCI-CTCAE) toxicity grades will be summarized. Change from baseline to the worst 
adverse event grade experienced by the participant during the study will be provided as shift tables. 
Clinical Laboratory Tests 
Laboratory data will be summarized by type of laboratory test. Reference ranges and markedly 
abnormal results (specified in the Statistical Analysis Plan) will be used in the summary of 
laboratory data. Descriptive statistics will be calculated for each laboratory analyte at baseline. 
Parameters with predefined NCI-CTCAE toxicity grades will be summarized. Change from 
baseline to the worst adverse event grade experienced by the participants during the study will be 
provided as shift tables. 
Electrocardiogram (ECG) 
Electrocardiogram data will be presented by descriptive analysis only.  
Physical Examination 
Clinically significant abnormal physical examination changes will be recorded and summarized 
as adverse events. 
9.4.3. 
Other Analyses 
A Data Review Committee (DRC) will be established as noted in Committees Structure in 
Appendix 3 Section 10.3 Regulatory, Ethical, and Study Oversight Considerations. 
Pharmacokinetic Analyses  

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A snapshot date for PK samples to be analyzed will be defined, if required. Samples collected 
before this date will be analyzed for cusatuzumab and included in the population PK analysis. 
Samples collected after the snapshot date will be analyzed at a later date and may be included in a 
population PK re-analysis when they become available after database lock. 
Data will be listed for all participants with available serum concentrations per intervention group. 
Participants will be excluded from the PK analysis if their data do not allow for accurate 
assessment of the PK (eg, incomplete administration of the study intervention; missing information 
of dosing and sampling times; concentration data not sufficient for PK parameter calculation). 
All concentrations below the lowest quantifiable concentration or missing data will be labeled as 
such in the concentration database. All participants and samples excluded from the analysis will 
be clearly documented in the study report. 
For each intervention group, descriptive statistics, including arithmetic mean, SD, coefficient of 
variation, median, minimum, and maximum will be calculated for all individual derived PK 
parameters including exposure information of cusatuzumab. 
All serum concentrations below the lowest quantifiable concentration or missing data will be 
labeled as such in the concentration data presentations or SAS dataset. Concentrations below the 
lower quantifiable concentration will be treated as zero in the summary statistics. All participants 
and samples excluded from the analysis will be clearly documented in the Clinical Study Report. 
Descriptive statistics will be used to summarize cusatuzumab serum concentrations at each 
sampling time point and PK parameters of cusatuzumab: Cmin and Cmax. Other PK parameters, 
including but not limited to AUC(t1-t2), t1/2, CL, and V, when available, will also be summarized. 
Mean and or median serum cusatuzumab concentration time profiles will be plotted after the first 
dose of study intervention, and individual serum concentration time profiles may also be plotted. 
If sufficient data are available, population PK analysis of serum concentration-time data of 
cusatuzumab will be performed using nonlinear mixed effects modeling. Data may be combined 
with those of other selected studies to support a relevant structural model. Available baseline 
participant characteristics (demographics, laboratory variables, genotypes, race, etc.) will be tested 
as potential covariates affecting PK parameters. Details will be given in a population PK analysis 
plan and the results of the population PK analysis will be presented in a separate report. 
Exposure-response analyses may also be performed; if performed, details will be provided in a 
separate analysis plan and report. 
Biomarker Analyses  
The biomarker measures will be listed, tabulated, and where appropriate, plotted. Participants may 
be grouped by dose, or clinical endpoints. Analyses may be stratified by clinical covariates or 
molecular subgroups using the appropriate statistical methods (eg, parametric or non-parametric, 
univariate or multivariate, analysis of variance [ANOVA], or survival analysis, depending on the 

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endpoint). Correlation to clinical response may be explored to identify markers predictive of 
response (or resistance) to cusatuzumab and azacitidine combination treatment.  
Results of biomarker analyses may be presented in a separate report. Planned analyses are based 
on the availability of clinically valid assays and may be deferred if emerging study data show no 
likelihood of providing useful scientific information. 
Immunogenicity Analyses  
The incidence of anti-cusatuzumab antibodies will be summarized for all participants who receive 
at least 1 dose of cusatuzumab and have appropriate samples for detection of antibodies to 
cusatuzumab (ie, participants with at least 1 sample obtained after their first dose of cusatuzumab). 
A listing of participants who are positive for antibodies to cusatuzumab will be provided. The 
maximum titers of antibodies to cusatuzumab will be summarized for participants who are positive 
for antibodies to cusatuzumab. 
The incidence of neutralizing antibodies (NAbs) to cusatuzumab will be summarized for 
participants who are positive for antibodies to cusatuzumab and have samples evaluable for NAbs 
to cusatuzumab. 
Other immunogenicity analyses may be performed to further characterize the immune responses 
that are generated. 
Pharmacodynamic Analyses  
The pharmacodynamic biomarker measures will be listed, tabulated, and where appropriate, 
plotted. Changes in sCD27, blasts, LSCs, or gene expression over time from baseline will be 
summarized for groups by dose, or clinical endpoints. 
Patient-Reported Outcomes 
Total and subscale scores from the PRO instruments listed in Section 8.1 will be analyzed: 
EQ-5D-5L utility score, EQ-5D-VAS score, FACT-Leu Total, PWB, SWB, EWB, FWB, 
FACT-G, FACT-LeuS, FACT-Leu TOI.  
For each scale score descriptive statistics (mean, standard deviation, median, and range) will be 
calculated for each assessment time point, for change from baseline at each time point, and for 
change from previous time point.   
Mixed-model repeated measures will be used for longitudinal analyses of PRO score change over 
time for each subscale. Time-to-event analyses will also be conducted using the Kaplan-Meier 
method using specified MID thresholds to define time-to-worsening and time-to-improvement for 
each PRO scale score. 
Medical Resource Utilization Analyses  
Medical resource utilization will be descriptively summarized by intervention group. 

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9.5. 
Interim Analyses 
For each analysis (3 stages in Part 1 and the formal interim and final analysis in Part 2), the data 
cutoff will be the time point when the last participant in the respective analysis has been treated 
for a minimum of 3 cycles (Part 1) or 4 cycles (Part 2) of the combination therapy. 
NOTE: Part 2 of the study will not be conducted because further development of this regimen 
(cusatuzumab in combination with azacitidine) in patients with unfit AML will not be pursued due 
to the evolving treatment landscape in AML.  
Study Part 1 
Part 1 of the study consists of 3 stages of monitoring to select a dose schedule. The cumulative 
number of participants for each dose group at each of the 3 stages are 15, 30, and 50, respectively. 
At each stage, each dose group’s response rate will determine independently (without formal 
statistical comparison to the other group) if that dose group will be stopped or continued into the 
next stage or into study Part 2. Only 1 dose group will be selected for Part 2. The statistical criteria 
for such a determination will be based on the number (and percentage) of participants in each dose 
group achieving CR. 
The purpose of the 3-stage monitoring in Part 1 is to select, or to eliminate a dose, which will be 
based on the Pocock beta-spending function with an overall beta level of 10% allocated to the 
3 stages with respective and cumulative sample sizes of 15 (30%), 30 (60%), and 50 (100%) 
participants per group. Per this approach, the statistical decision criteria and corresponding 
inferences are summarized in Table 7, where 2 possible outcomes resulting in a stop or 
continuation decision, respectively, are presented for each stage. 
The statistical criteria shown in Table 7 ensure that the false negative error rate (ie, the probability 
of a stopping decision, when the true CR rate is ≥35%) is ≤6% at any stage; or equivalently, the 
upper limit of the 1-sided >94% confidence interval (CI) of the observed CR rate is <35% (which 
means that a CR rate of 35% or greater has been statistically ruled out). It’s important to control 
the false negative error rate at a low level when the number of participants is small to ensure that 
a stopping decision will not be made unless it is statistically convincing that a CR rate of ≥35% 
has been ruled out. The false positive error rate (ie, the probability of a continuation decision, when 
the true CR rate is ≤20%) is also assessed, but controlling the false positive error rate at a low level  
is not of a concern, hence is not applied in this circumstance (Table 8). 

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Table 7:  
Statistical Decision Parameters for Study Part 1: Observed CR, 1-Sided Confidence Interval 
(CI), and Statistical Decision 
 
 
 
Number (%) of 
Observed CR  
1-Sided 
CI Upper Bound1 
(%) 
 
 
Decision 
False Negative 
Error2 
False Positive 
Error3 
Stage 1, n=15 
 1 ( 6.7)
26.7
Stop 
≤4% 
NA 
  2 (13.3)
34.9
 3 (20.0)
42.3
Continue 
to Stage 2 
NA 
≤50% 
 4 (26.7)
49.3
Stage 2, n=30 
 5 (16.7)
30.5
Stop 
≤5% 
NA 
 6 (20.0)
34.3
 7 (23.3)
37.9
Continue 
to Stage 3 
NA 
≤32% 
 8 (26.7)
41.5
Stage 3, n=50 
11 (22.0)
32.3
Stop 
≤6% 
NA 
12 (24.0)
34.4
13 (26.0)
36.6
Continue 
to Part 2 
NA 
≤14% 
14 (28.0)
38.7
1 96%, 95%, and 94% for Stage 1, 2, and 3, respectively. 
2 False negative error: probability of a “stop” decision, when the true CR rate is ≥35%. 
3 False positive error: probability of a “continue” decision, when the true CR rate is ≤20%. 
Note: All statistical inferences are based on Wilson Score statistics without continuity correction.
 
If the number of participants at each stage is not exactly as specified in Table 7 the Pocock 
beta-spending function with an overall beta level of 10% will be adjusted based on the actual 
number participants. 
Per statistical criteria specified in Table 7, certain operating characteristics of particular interest 
are presented in Table 8, showing the probability of making a correct decision. 
The above statistical criteria for Part 1 will be served as guidance; the totality of the data including 
other efficacy outcomes (eg, duration of CR), available safety, and PK/PD data will be considered 
in making a decision at each stage. If both dose schedules warrant proceeding into study Part 2 per 
the above statistical criteria, only one dose schedule will be extended into Part 2 based on the 
observed CR rate as well as available data of other efficacy, safety, and PK/PD. 

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Table 8: 
Operating Characteristics of Particular Interest 
True CR Rate of Dose (20 mg/kg, 10mg/kg) 
Study Part 1, probability that: 
(35%, 35%) 
(35%, 20%) 
(20%, 20%) 
 At least one dose schedule continues into Part 2
98.4%
--
--
 20 mg/kg continues into Part 2, 10 mg/kg does not
--
74.3%
--
  Neither dose schedule continues into Part 2 
-- 
-- 
72.1% 
Study Part 2 
For study Part 2, one interim analysis of CR rate is planned to include 80 participants. The null 
hypothesis of a CR rate of 20% will be rejected if the 1-sided nominal p-value is ≤0.01221. If the 
null hypothesis is not rejected at this interim analysis, the final analysis will be performed with 
100 participants, and the null hypothesis will be rejected if the 1-sided nominal p-value is 
≤0.02144. The O’Brien-Fleming alpha-spending, and the Wilson Score test without continuity 
correction are to be implemented for the interim and final analyses. 
9.6. 
Data Review Committee  
A Data Review Committee (DRC) will be established as noted in Committees Structure in 
Appendix 3 Section 10.3, Regulatory, Ethical, and Study Oversight Considerations.  
 
 

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10. 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS 
10.1. 
Appendix 1: Abbreviations and Trademarks 
Abbreviations  
ADA
anti-drug antibody
ADCC
antibody-dependent cellular cytotoxicity
ADCP
antibody-dependent cellular phagocytosis
AE
adverse event
ALT
alanine aminotransferase
AML
acute myeloid leukemia
ANC
absolute neutrophil count
ATRA
all-trans retinoic acid
AUC
area under the concentration x time curve
BSA
body surface area
CDC
complement-dependent cytotoxicity
Cl
clearance
Cmax
maximum concentration
CR
complete response
CRh
complete response with incomplete hematological recovery
CRi
complete response with incomplete blood count recovery
CyTOF
time of flight mass cytometry
DRC
data review committee
DNMT
DNA methyltransferase
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic Case report form
ELN
European Leukemia Network
EOT
end-of-treatment
FACT-Leu
Functional Assessment of Cancer Therapy-Leukemia
FSH
follicle stimulating hormone
HIV
human immunodeficiency virus
HMA
hypomethylating agent
HRQoL
health-related quality of life
HRT
hormonal replacement therapy
ICF
informed consent form
IRR
infusion-related reaction
ITT
intent-to-treat population
IV
intravenous
LSC
leukemic stem cell
MDS
myelodysplastic syndrome
MedDRA
Medical Dictionary for Regulatory Activities
MLFS
morphologic leukemia-free state
MRD
minimal residual disease
MRU
medical resource utilization
NCI-CTCAE
National Cancer Institute Common Terminology Criteria for Adverse Events
NK
natural killer (cells)
ORR
overall response rate (CR + CRi + CRh)
OS
overall survival
PCR
polymerase chain reaction

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PD
pharmacodynamics
PFS
progression-free survival
PK
pharmacokinetics
PR
partial response
PRO
patient-reported outcome
RO
receptor occupancy
SAE
serious adverse event
SC
subcutaneous
SPC
Summary of Products Characteristics
SUSAR
suspected unexpected serious adverse reaction
ULN
upper limit of normal
USPI
United States Package Insert
WBC
white blood cells
 
 
 

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10.2. 
Appendix 2: Clinical Laboratory Tests 
 
The following tests will be performed according to the Schedule of Activities by the local 
laboratory: 
Protocol-Required Safety Laboratory Assessments  
Laboratory 
Assessments 
Parameters 
Hematology 
Platelet count 
Hemoglobin 
Absolute white blood cell (WBC) count 
Absolute eosinophils 
Absolute basophils 
Absolute monocytes 
Absolute neutrophil count 
Absolute lymphocyte count 
Peripheral blast count
Clinical 
Chemistry 
Sodium 
Bicarbonate 
Potassium 
Blood urea nitrogen (BUN) 
Urea (if BUN is not performed) 
Creatinine  
Aspartate aminotransferase (AST)/Serum glutamic-oxaloacetic 
Alanine aminotransferase (ALT)/Serum glutamic-oxaloacetic 
Total bilirubin 
Alkaline phosphatase 
Lactic acid dehydrogenase (LDH) 
Uric acid 
Calcium 
Phosphate 
Magnesium
Other 
Screening Tests 
Serum -hCG or urine pregnancy testing for women of childbearing potential only or 
if clinically indicated or required by local regulations. 
Serology (eg, HIV antibody, hepatitis B surface antigen [HBsAg], hepatitis B virus 
antibody, and hepatitis C virus antibody); screening is to be performed for all 
participants.  
 
 

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10.3. 
Appendix 3: Regulatory, Ethical, and Study Oversight Considerations 
REGULATORY AND ETHICAL CONSIDERATIONS 
Investigator Responsibilities 
The investigator is responsible for ensuring that the study is performed in accordance with the 
protocol, current International Counsel on Harmonization (ICH) guidelines on Good Clinical 
Practice (GCP), and applicable regulatory and country-specific requirements. 
Good Clinical Practice is an international ethical and scientific quality standard for designing, 
conducting, recording, and reporting studies that involve the participation of human participants. 
Compliance with this standard provides public assurance that the rights, safety, and well-being of 
study participants are protected, consistent with the principles that originated in the Declaration of 
Helsinki, and that the study data are credible. 
Protocol Amendments 
Neither the investigator nor the Sponsor will modify this protocol without a formal amendment by 
the Sponsor. All protocol amendments must be issued by the Sponsor, and signed and dated by the 
investigator. Protocol amendments must not be implemented without prior IEC/IRB approval, or 
when the relevant competent authority has raised any grounds for non-acceptance, except when 
necessary to eliminate immediate hazards to the participants, in which case the amendment must 
be promptly submitted to the IEC/IRB and relevant competent authority. Documentation of 
amendment approval by the investigator and IEC/IRB must be provided to the Sponsor. When the 
change(s) involve only logistic or administrative aspects of the study, the IEC/IRB (where 
required) only needs to be notified. 
During the course of the study, in situations where a departure from the protocol is unavoidable, 
the investigator or other physician in attendance will contact the appropriate Sponsor 
representative listed in the Contact Information page(s), which will be provided as a separate 
document. Except in emergency situations, this contact should be made before implementing any 
departure from the protocol. In all cases, contact with the Sponsor must be made as soon as possible 
to discuss the situation and agree on an appropriate course of action. The data recorded in the eCRF 
and source documents will reflect any departure from the protocol, and the source documents will 
describe this departure and the circumstances requiring it. 
Regulatory Approval/Notification 
This protocol and any amendment(s) must be submitted to the appropriate regulatory authorities 
in each respective country, if applicable. A study may not be initiated until all local regulatory 
requirements are met. 
Required Prestudy Documentation 
The following documents must be provided to the Sponsor before shipment of study intervention 
to the study site: 

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 
Protocol and amendment(s), if any, signed and dated by the principal investigator 
 
A copy of the dated and signed (or sealed, where appropriate per local regulations), written 
IEC/IRB approval of the protocol, amendments, ICF, any recruiting materials, and if 
applicable, participant compensation programs. This approval must clearly identify the 
specific protocol by title and number and must be signed (or sealed, where appropriate per 
local regulations) by the chairman or authorized designee. 
 
Name and address of the IEC/IRB, including a current list of the IEC/IRB members and their 
function, with a statement that it is organized and operates according to GCP and the 
applicable laws and regulations. If accompanied by a letter of explanation, or equivalent, from 
the IEC/IRB, a general statement may be substituted for this list. If an investigator or a 
member of the study-site personnel is a member of the IEC/IRB, documentation must be 
obtained to state that this person did not participate in the deliberations or in the vote/opinion 
of the study. 
 
Regulatory authority approval or notification, if applicable 
 
Signed and dated statement of investigator (eg, Form FDA 1572), if applicable 
 
Documentation of investigator qualifications (eg, curriculum vitae) 
 
Completed investigator financial disclosure form from the principal investigator, where 
required 
 
Signed and dated clinical trial agreement, which includes the financial agreement 
 
Any other documentation required by local regulations 
The following documents must be provided to the Sponsor before enrollment of the first 
participant: 
 
Completed investigator financial disclosure forms from all subinvestigators 
 
Documentation of subinvestigator qualifications (eg, curriculum vitae) 
 
Name and address of any local laboratory conducting tests for the study, and a dated copy of 
current laboratory normal ranges for these tests, if applicable 
 
Local 
laboratory 
documentation 
demonstrating 
competence 
and 
test 
reliability 
(eg, accreditation/license), if applicable 
Independent Ethics Committee or Institutional Review Board 
Before the start of the study, the investigator (or Sponsor where required) will provide the IEC/IRB 
with current and complete copies of the following documents (as required by local regulations): 
 
Final protocol and, if applicable, amendments 
 
Sponsor-approved ICF (and any other written materials to be provided to the participants) 
 
IB (or equivalent information) and amendments/addenda 
 
Sponsor-approved participant recruiting materials 
 
Information on compensation for study-related injuries or payment to participants for 
participation in the study, if applicable 

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 
Investigator's curriculum vitae or equivalent information (unless not required, as documented 
by the IEC/IRB) 
 
Information regarding funding, name of the Sponsor, institutional affiliations, other potential 
conflicts of interest, and incentives for participants 
 
Any other documents that the IEC/IRB requests to fulfill its obligation 
This study will be undertaken only after the IEC/IRB has given full approval of the final protocol, 
amendments (if any, excluding the ones that are purely administrative, with no consequences for 
participants, data or study conduct, unless required locally), the ICF, applicable recruiting 
materials, and participant compensation programs, and the Sponsor has received a copy of this 
approval. This approval letter must be dated and must clearly identify the IEC/IRB and the 
documents being approved. 
During the study the investigator (or Sponsor where required) will send the following documents 
and updates to the IEC/IRB for their review and approval, where appropriate: 
 
Protocol amendments (excluding the ones that are purely administrative, with no 
consequences for participants, data or study conduct) 
 
Revision(s) to ICF and any other written materials to be provided to participants 
 
If applicable, new or revised participant recruiting materials approved by the Sponsor 
 
Revisions to compensation for study-related injuries or payment to participants for 
participation in the study, if applicable 
 
New edition(s) of the IB and amendments/addenda 
 
Summaries of the status of the study at intervals stipulated in guidelines of the IEC/IRB (at 
least annually) 
 
Reports of adverse events that are serious, unlisted/unexpected, and associated with the study 
intervention 
 
New information that may adversely affect the safety of the participants or the conduct of the 
study 
 
Deviations from or changes to the protocol to eliminate immediate hazards to the participants 
 
Report of deaths of participants under the investigator's care 
 
Notification if a new investigator is responsible for the study at the site 
 
Development Safety Update Report and Line Listings, where applicable 
 
Any other requirements of the IEC/IRB 
For all protocol amendments (excluding the ones that are purely administrative, with no 
consequences for participants, data or study conduct), the amendment and applicable ICF revisions 
must be submitted promptly to the IEC/IRB for review and approval before implementation of the 
change(s). 
At least once a year, the IEC/IRB will be asked to review and reapprove this study, where required. 

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At the end of the study, the investigator (or Sponsor where required) will notify the IEC/IRB about 
the study completion (if applicable, the notification will be submitted through the head of 
investigational institution). 
Country Selection 
This study will only be conducted in those countries where the intent is to launch or otherwise help 
ensure access to the developed product if the need for the product persists, unless explicitly 
addressed as a specific ethical consideration in Section 4.2.1, Study-Specific Ethical Design 
Considerations. 
Other Ethical Considerations 
For study-specific ethical design considerations, refer to Section 4.2.1. 
FINANCIAL DISCLOSURE 
Investigators and subinvestigators will provide the Sponsor with sufficient, accurate financial 
information in accordance with local regulations to allow the Sponsor to submit complete and 
accurate financial certification or disclosure statements to the appropriate regulatory authorities. 
Investigators are responsible for providing information on financial interests during the course of 
the study and for 1 year after completion of the study. 
Refer to Required Prestudy Documentation (above) for details on financial disclosure. 
INFORMED CONSENT PROCESS  
Each participant (or a legally acceptable representative) must give written consent according to 
local requirements after the nature of the study has been fully explained. The ICF(s) must be signed 
before performance of any study-related activity. The ICF(s) that is/are used must be approved by 
both the Sponsor and by the reviewing IEC/IRB and be in a language that the participant can read 
and understand. The informed consent should be in accordance with principles that originated in 
the Declaration of Helsinki, current ICH and GCP guidelines, applicable regulatory requirements, 
and Sponsor policy. 
Before enrollment in the study, the investigator or an authorized member of the study-site 
personnel must explain to potential participants or their legally acceptable representatives the aims, 
methods, reasonably anticipated benefits, and potential hazards of the study, and any discomfort 
participation in the study may entail. Participants will be informed that their participation is 
voluntary and that they may withdraw consent to participate at any time. They will be informed 
that choosing not to participate will not affect the care the participant will receive for the treatment 
of his or her disease. Participants will be told that alternative treatments are available if they refuse 
to take part and that such refusal will not prejudice future treatment. Finally, they will be told that 
the investigator will maintain a participant identification register for the purposes of long-term 
follow up if needed and that their records may be accessed by health authorities and authorized 
Sponsor personnel without violating the confidentiality of the participant, to the extent permitted 
by the applicable law(s) or regulations. By signing the ICF the participant or legally acceptable 

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representative is authorizing such access, which includes permission to obtain information about 
his or her survival status. It also denotes that the participant agrees to allow his or her study 
physician to recontact the participant for the purpose of obtaining consent for additional safety 
evaluations, and subsequent disease-related treatments, if needed. 
The participant or legally acceptable representative will be given sufficient time to read the ICF 
and the opportunity to ask questions. After this explanation and before entry into the study, consent 
should be appropriately recorded by means of either the participant's or his or her legally 
acceptable representative's personally dated signature. After having obtained the consent, a copy 
of the ICF must be given to the participant. 
Participants who are rescreened are required to sign a new ICF.  
If the participant or legally acceptable representative is unable to read or write, an impartial witness 
should be present for the entire informed consent process (which includes reading and explaining 
all written information) and should personally date and sign the ICF after the oral consent of the 
participant or legally acceptable representative is obtained. 
When prior consent of the participant is not possible and the participant's legally acceptable 
representative is not available, enrollment procedures should be described in the protocol with 
documented approval/favorable opinion by the IEC/IRB to protect the rights, safety, and well-
being of the participant and to ensure compliance with applicable regulatory requirements. The 
participant or legally acceptable representative must be informed about the study as soon as 
possible and give consent to continue.  
DATA PROTECTION 
Privacy of Personal Data 
The collection and processing of personal data from participants enrolled in this study will be 
limited to those data that are necessary to fulfill the objectives of the study. 
These data must be collected and processed with adequate precautions to ensure confidentiality 
and compliance with applicable data privacy protection laws and regulations. Appropriate 
technical and organizational measures to protect the personal data against unauthorized disclosures 
or access, accidental or unlawful destruction, or accidental loss or alteration must be put in place. 
Sponsor personnel whose responsibilities require access to personal data agree to keep the identity 
of participants confidential. 
The informed consent obtained from the participant (or his or her legally acceptable representative) 
includes explicit consent for the processing of personal data and for the investigator/institution to 
allow direct access to his or her original medical records (source data/documents) for study-related 
monitoring, audit, IEC/IRB review, and regulatory inspection. This consent also addresses the 
transfer of the data to other entities and to other countries. 

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The participant has the right to request through the investigator access to his or her personal data 
and the right to request rectification of any data that are not correct or complete. Reasonable steps 
will be taken to respond to such a request, taking into consideration the nature of the request, the 
conditions of the study, and the applicable laws and regulations. 
Exploratory PD, biomarker, PK, and immunogenicity research is not conducted under standards 
appropriate for the return of data to participants. In addition, the Sponsor cannot make decisions 
as to the significance of any findings resulting from exploratory research. Therefore, exploratory 
research data will not be returned to participants or investigators, unless required by law or local 
regulations. Privacy and confidentiality of data generated in the future on stored samples will be 
protected by the same standards applicable to all other clinical data. 
LONG-TERM RETENTION OF SAMPLES FOR ADDITIONAL FUTURE RESEARCH  
Samples collected in this study may be stored for up to 15 years (or according to local regulations) 
for additional research. Samples will only be used to understand cusatuzumab, to understand AML, 
to understand differential intervention responders, and to develop tests/assays related to 
cusatuzumab and AML. The research may begin at any time during the study or the post-study 
storage period.  
Stored samples will be coded throughout the sample storage and analysis process and will not be 
labeled with personal identifiers. Participants may withdraw their consent for their samples to be 
stored for research (refer to Section 7.2.1, Withdrawal From the Use of Research Samples). 
COMMITTEES STRUCTURE 
Data Review Committee 
A DRC will be established to monitor data on an ongoing basis and to review interim data to ensure 
the continuing safety of the participants enrolled in this study and to meet efficacy objectives. This 
committee will consist of at least one medical expert in the relevant therapeutic area, at least one 
statistician, and a minimum of 2 investigators that will participate in the CULM20236 study; 
committee membership responsibilities, authorities, and procedures will be documented in its 
charter. The committee will meet periodically to review interim data. After the review, the DRC 
will make recommendations regarding the continuation of the study. 
PUBLICATION POLICY/DISSEMINATION OF CLINICAL STUDY DATA 
All information, including but not limited to information regarding cusatuzumab or the Sponsor's 
operations (eg, patent application, formulas, manufacturing processes, basic scientific data, prior 
clinical data, formulation information) supplied by the Sponsor to the investigator and not 
previously published, and any data, including biomarker research data, generated as a result of this 
study, are considered confidential and remain the sole property of the Sponsor. The investigator 
agrees to maintain this information in confidence and use this information only to accomplish this 
study and will not use it for other purposes without the Sponsor's prior written consent. 

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The investigator understands that the information developed in the study will be used by the 
Sponsor in connection with the continued development of cusatuzumab, and thus may be disclosed 
as required to other clinical investigators or regulatory agencies. To permit the information derived 
from the clinical studies to be used, the investigator is obligated to provide the Sponsor with all 
data obtained in the study. 
The results of the study will be reported in a Clinical Study Report generated by the Sponsor and 
will contain data from all study sites that participated in the study as per protocol. Recruitment 
performance or specific expertise related to the nature and the key assessment parameters of the 
study will be used to determine a coordinating investigator for the study. Results of biomarker 
analyses performed after the Clinical Study Report has been issued will be reported in a separate 
report and will not require a revision of the Clinical Study Report.  
Study participant identifiers will not be used in publication of results. Any work created in 
connection with performance of the study and contained in the data that can benefit from copyright 
protection (except any publication by the investigator as provided for below) shall be the property 
of the Sponsor as author and owner of copyright in such work. 
Consistent with Good Publication Practices and International Committee of Medical Journal 
Editors (ICMJE) guidelines, the Sponsor shall have the right to publish such primary (multicenter) 
data and information without approval from the investigator. The investigator has the right to 
publish study site-specific data after the primary data are published. If an investigator wishes to 
publish information from the study, a copy of the manuscript must be provided to the Sponsor for 
review at least 60 days before submission for publication or presentation. Expedited reviews will 
be arranged for abstracts, poster presentations, or other materials. If requested by the Sponsor in 
writing, the investigator will withhold such publication for up to an additional 60 days to allow for 
filing of a patent application. In the event that issues arise regarding scientific integrity or 
regulatory compliance, the Sponsor will review these issues with the investigator. The Sponsor 
will not mandate modifications to scientific content and does not have the right to suppress 
information. For multicenter study designs and sub-study approaches, secondary results generally 
should not be published before the primary endpoints of a study have been published. Similarly, 
investigators will recognize the integrity of a multicenter study by not submitting for publication 
data derived from the individual study site until the combined results from the completed study 
have been submitted for publication, within 18 months after the study end date, or the Sponsor 
confirms there will be no multicenter study publication. Authorship of publications resulting from 
this study will be based on the guidelines on authorship, such as those described in the ICMJE 
Recommendations for the Conduct, Reporting, Editing and Publication of Scholarly Work in 
Medical Journals, which state that the named authors must have made a significant contribution to 
the conception or design of the work; or the acquisition, analysis, or interpretation of the data for 
the work; and drafted the work or revised it critically for important intellectual content; and given 
final approval of the version to be published; and agreed to be accountable for all aspects of the 
work in ensuring that questions related to the accuracy or integrity of any part of the work are 
appropriately investigated and resolved. 

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Registration of Clinical Studies and Disclosure of Results 
The Sponsor will register and disclose the existence of and the results of clinical studies as required 
by law. The disclosure of the final study results will be performed after the end of study in order 
to ensure the statistical analyses are relevant. 
DATA QUALITY ASSURANCE 
Data Quality Assurance/Quality Control 
Steps to be taken to ensure the accuracy and reliability of data include the selection of qualified 
investigators and appropriate study sites, review of protocol procedures with the investigator and 
study-site personnel before the study, and periodic monitoring visits by the Sponsor Written 
instructions will be provided for collection, handling, storage, and shipment of samples.  
Guidelines for eCRF completion will be provided and reviewed with study-site personnel before 
the start of the study. The Sponsor will review eCRF for accuracy and completeness during on-
site monitoring visits and after transmission to the Sponsor; any discrepancies will be resolved 
with the investigator or designee, as appropriate. After upload of the data into the study database 
they will be verified for accuracy and consistency with the data sources.  
CASE REPORT FORM COMPLETION 
Case report forms are prepared and provided by the Sponsor for each participant in electronic 
format. All data relating to the study must be recorded in eCRF. All eCRF entries, corrections, and 
alterations must be made by the investigator or authorized study-site personnel. The investigator 
must verify that all data entries in the eCRF are accurate and correct. 
The study data will be transcribed by study-site personnel from the source documents onto an 
electronic eCRF, if applicable. Study-specific data will be transmitted in a secure manner to the 
Sponsor. 
Worksheets may be used for the capture of some data to facilitate completion of the eCRF. Any 
such worksheets will become part of the participant's source documents. Data must be entered into 
eCRF in English. The eCRF must be completed as soon as possible after a participant visit and the 
forms should be available for review at the next scheduled monitoring visit. 
All participative measurements (eg, pain scale information or other questionnaires) will be 
completed by the same individual who made the initial baseline determinations whenever possible. 
If necessary, queries will be generated in the eDC tool. If corrections to an eCRF are needed after 
the initial entry into the eCRF, this can be done in either of the following ways: 
 Investigator and study-site personnel can make corrections in the eDC tool at their own 
initiative or as a response to an auto query (generated by the eDC tool). 
 Sponsor or Sponsor delegate can generate a query for resolution by the investigator and 
study-site personnel. 

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SOURCE DOCUMENTS 
At a minimum, source documents consistent in the type and level of detail with that commonly 
recorded at the study site as a basis for standard medical care must be available for the following: 
participant identification, eligibility, and study identification; study discussion and date of signed 
informed consent; dates of visits; results of safety and efficacy parameters as required by the 
protocol; record of all adverse events and follow-up of adverse events; concomitant medication; 
intervention receipt/dispensing/return records; study intervention administration information; and 
date of study completion and reason for early discontinuation of study intervention or withdrawal 
from the study, if applicable.  
The author of an entry in the source documents should be identifiable. 
Specific details required as source data for the study and source data collection methods will be 
reviewed with the investigator before the study and will be described in the monitoring guidelines 
(or other equivalent document). 
The minimum source documentation requirements for Section 5.1, Inclusion Criteria and Section 
5.2, Exclusion Criteria that specify a need for documented medical history are as follows: 
 Referral letter from treating physician or 
 Complete history of medical notes at the site 
 Discharge summaries 
Inclusion and exclusion criteria not requiring documented medical history must be verified at a 
minimum by participant interview or other protocol required assessment (eg, physical 
examination, laboratory assessment) and documented in the source documents. 
An eSource system may be utilized, which contains data traditionally maintained in a hospital or 
clinic record to document medical care (eg, electronic source documents) as well as the clinical 
study-specific data fields as determined by the protocol. This data is electronically extracted for 
use by the Sponsor. If eSource is utilized, references made to the eCRF in the protocol include the 
eSource system but information collected through eSource may not be limited to that found in the 
eCRF. 
MONITORING 
The Sponsor will use a combination of monitoring techniques: central, remote, or on-site 
monitoring to monitor this study. 
The Sponsor will perform on-site monitoring visits as frequently as necessary. The monitor will 
record dates of the visits in a study site visit log that will be kept at the study site. The first 
post-initiation visit will be made as soon as possible after enrollment has begun. At these visits, 
the monitor will compare the data entered into the eCRF with the source documents 
(eg, hospital/clinic/physician’s office medical records). The nature and location of all source 
documents will be identified to ensure that all sources of original data required to complete the 

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eCRF are known to the Sponsor and study-site personnel and are accessible for verification by the 
Sponsor study-site contact. If electronic records are maintained at the study site, the method of 
verification must be discussed with the study-site personnel.  
Direct access to source documents (medical records) must be allowed for the purpose of verifying 
that the recorded data are consistent with the original source data. Findings from this review will 
be discussed with the study-site personnel. The Sponsor expects that, during monitoring visits, the 
relevant study-site personnel will be available, the source documents will be accessible, and a 
suitable environment will be provided for review of study-related documents. The monitor will 
meet with the investigator on a regular basis during the study to provide feedback on the study 
conduct. 
In addition to on-site monitoring visits, remote contacts can occur. It is expected that during these 
remote contacts, study-site personnel will be available to provide an update on the progress of the 
study at the site.  
Central monitoring will take place for data identified by the Sponsor as requiring central review. 
ON-SITE AUDITS 
Representatives of the Sponsor's clinical quality assurance department may visit the study site at 
any time during or after completion of the study to conduct an audit of the study in compliance 
with regulatory guidelines and company policy. These audits will require access to all study 
records, including source documents, for inspection. Participant privacy must, however, be 
respected. The investigator and study-site personnel are responsible for being present and available 
for consultation during routinely scheduled study-site audit visits conducted by the Sponsor or its 
designees.  
Similar auditing procedures may also be conducted by agents of any regulatory body, either as part 
of a national GCP compliance program or to review the results of this study in support of a 
regulatory submission. The investigator should immediately notify the Sponsor if he or she has 
been contacted by a regulatory agency concerning an upcoming inspection. 
RECORD RETENTION 
In compliance with the ICH/GCP guidelines, the investigator/institution will maintain all eCRF 
and all source documents that support the data collected from each participant, as well as all study 
documents as specified in ICH/GCP Section 8, Essential Documents for the Conduct of a Clinical 
Trial, and all study documents as specified by the applicable regulatory requirement(s). The 
investigator/institution will take measures to prevent accidental or premature destruction of these 
documents. 
Essential documents must 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 until at least 2 years have elapsed since the formal discontinuation of clinical 
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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. 
If the responsible investigator retires, relocates, or for other reasons withdraws from the 
responsibility of keeping the study records, custody must be transferred to a person who will accept 
the responsibility. The Sponsor must be notified in writing of the name and address of the new 
custodian. Under no circumstance shall the investigator relocate or dispose of any study documents 
before having obtained written approval from the Sponsor. 
If it becomes necessary for the Sponsor or the appropriate regulatory authority to review any 
documentation relating to this study, the investigator/institution must permit access to such reports. 
STUDY AND SITE START AND CLOSURE 
First Act of Recruitment 
The first site open is considered the first act of recruitment and it becomes the study start date. 
Study Termination 
The Sponsor reserves the right to close the study site or terminate the study at any time for any 
reason at the sole discretion of the Sponsor. Study sites will be closed upon study completion. A 
study site is considered closed when all required documents and study supplies have been collected 
and a study-site closure visit has been performed. 
The investigator may initiate study-site closure at any time, provided there is reasonable cause and 
sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by the Sponsor or investigator may include but are not 
limited to: 
 Failure of the investigator to comply with the protocol, the requirements of the IEC/IRB or 
local health authorities, the Sponsor's procedures, or GCP guidelines 
 Inadequate recruitment of participants by the investigator 
 Discontinuation of further study intervention development 
 
 

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10.4. 
Appendix 4: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting 
ADVERSE EVENT DEFINITIONS AND CLASSIFICATIONS 
Adverse Event 
An adverse event is any untoward medical occurrence in a clinical study participant administered 
a medicinal (investigational or non-investigational) product. An adverse event does not necessarily 
have a causal relationship with the intervention. An adverse event can therefore be any unfavorable 
and unintended sign (including an abnormal finding), symptom, or disease temporally associated 
with the use of a medicinal (investigational or non-investigational) product, whether or not related 
to that medicinal (investigational or non-investigational) product. (Definition per International 
Conference on Harmonisation [ICH]). 
This includes any occurrence that is new in onset or aggravated in severity or frequency from the 
baseline condition, or abnormal results of diagnostic procedures, including laboratory test 
abnormalities. 
Note: The Sponsor collects adverse events starting with the signing of the ICF (refer to All Adverse 
Events under Section 8.3.1, Time Period and Frequency for Collecting Adverse Events and Serious 
Adverse Events Information, for time of last adverse event recording). 
Serious Adverse Event 
A serious adverse event based on ICH and EU Guidelines on Pharmacovigilance for Medicinal 
Products for Human Use is any untoward medical occurrence that at any dose: 
 
Results in death 
 
Is life-threatening 
(The participant was at risk of death at the time of the event. It does not refer to an event that 
hypothetically might have caused death if it were more severe.) 
 
Requires inpatient hospitalization or prolongation of existing hospitalization 
 
Results in persistent or significant disability/incapacity 
 
Is a congenital anomaly/birth defect 
 
Is a suspected transmission of any infectious agent via a medicinal product 
 
Is Medically Important* 
*Medical and scientific judgment should be exercised in deciding whether expedited reporting is 
also appropriate in other situations, such as important medical events that may not be immediately 
life threatening or result in death or hospitalization but may jeopardize the participant or may 
require intervention to prevent one of the other outcomes listed in the definition above. These 
should usually be considered serious. 
If a serious and unexpected adverse event occurs for which there is evidence suggesting a causal 
relationship between the study intervention and the event (eg, death from anaphylaxis), the event 

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must be reported as a serious and unexpected suspected adverse reaction even if it is a component 
of the study endpoint (eg, all-cause mortality).  
Unlisted (Unexpected) Adverse Event/Reference Safety Information 
An adverse event is considered unlisted if the nature or severity is not consistent with the applicable 
product reference safety information. For cusatuzumab, the expectedness of an adverse event will 
be determined by whether or not it is listed in the IB. For azacitidine with a marketing 
authorization, the expectedness of an adverse event will be determined by whether or not it is listed 
in the SPC or USPI. 
Adverse Event Associated With the Use of the Intervention 
An adverse event is considered associated with the use of the intervention if the attribution is 
possible, probable, or very likely by the definitions listed below (see Attribution Definitions). 
ATTRIBUTION DEFINITIONS 
Not Related 
An adverse event that is not related to the use of the intervention. 
Doubtful 
An adverse event for which an alternative explanation is more likely, eg, concomitant treatment(s), 
concomitant disease(s), or the relationship in time suggests that a causal relationship is unlikely. 
Possible 
An adverse event that might be due to the use of the intervention. An alternative explanation, 
eg, concomitant treatment(s), concomitant disease(s), is inconclusive. The relationship in time is 
reasonable; therefore, the causal relationship cannot be excluded. 
Probable 
An adverse event that might be due to the use of the intervention. The relationship in time is 
suggestive (eg, confirmed by dechallenge). An alternative explanation is less likely, 
eg, concomitant treatment(s), concomitant disease(s). 
Very Likely 
An adverse event that is listed as a possible adverse reaction and cannot be reasonably explained 
by an alternative explanation, eg, concomitant treatment(s), concomitant disease(s). The 
relationship in time is very suggestive (eg, it is confirmed by dechallenge and rechallenge). 

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SEVERITY CRITERIA 
Adverse events will be graded by the investigator according to NCI-CTCAE, Version 5.0. 
Grade 1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention 
not indicated. 
Grade 2 
Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate 
instrumental activities of daily living (ADL)* 
Grade 3 
Severe or medically significant but not immediately life-threatening; hospitalization or 
prolongation of hospitalization indicated; disabling; limiting self-care activities of daily 
living** 
Grade 4 
Life-threatening consequences; urgent intervention indicated. 
Grade 5 
Death related to adverse event. 
Activities of Daily Living: 
 *Instrumental ADL refer to preparing meals, shopping for groceries or clothes, using the telephone, managing 
money, etc. 
**Self-care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking medications, and 
not bedridden.
 
The investigator should use clinical judgment in assessing the severity of events not directly 
experienced by the participant (eg, laboratory abnormalities). 
SPECIAL REPORTING SITUATIONS 
Safety events of interest on a Sponsor study intervention in an interventional study that may require 
expedited reporting or safety evaluation include, but are not limited to: 
 
Overdose of a Sponsor study intervention 
 
Suspected abuse/misuse of a Sponsor study intervention 
 
Accidental or occupational exposure to a Sponsor study intervention 
 
Medication error involving a Sponsor product (with or without participant/patient exposure to 
the Sponsor study intervention, eg, name confusion) 
 
Exposure to a Sponsor study intervention from breastfeeding 
Special reporting situations should be recorded in the eCRF. Any special reporting situation that 
meets the criteria of a serious adverse event should be recorded on the serious adverse event page 
of the eCRF. 

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PROCEDURES 
All Adverse Events 
All adverse events, regardless of seriousness, severity, or presumed relationship to study 
intervention, must be recorded using medical terminology in the source document and the eCRF. 
Whenever possible, diagnoses should be given when signs and symptoms are due to a common 
etiology (eg, cough, runny nose, sneezing, sore throat, and head congestion should be reported as 
"upper respiratory infection"). Investigators must record in the eCRF their opinion concerning the 
relationship of the adverse event to study therapy. All measures required for adverse event 
management must be recorded in the source document and reported according to Sponsor 
instructions. 
For all studies with an outpatient phase, including open-label studies, the participant must be 
provided with a "wallet (study) card" and instructed to carry this card with them for the duration 
of the study indicating the following:  
 
Study number 
 
Statement, in the local language(s), that the participant is participating in a clinical study 
 
Investigator's name and 24-hour contact telephone number 
 
Local Sponsor's name and 24-hour contact telephone number (for medical personnel only) 
 
Site number 
 
Participant number 
 
Any other information that is required to do an emergency breaking of the blind 
Serious Adverse Events 
All serious adverse events that have not resolved by the end of the study, or that have not resolved 
upon discontinuation of the participant's participation in the study, must be followed until any of 
the following occurs: 
 
The event resolves 
 
The event stabilizes 
 
The event returns to baseline, if a baseline value/status is available 
 
The event can be attributed to agents other than the study intervention or to factors unrelated 
to study conduct 
 
It becomes unlikely that any additional information can be obtained (participant or health care 
practitioner refusal to provide additional information, lost to follow-up after demonstration of 
due diligence with follow-up efforts) 
Suspected transmission of an infectious agent by a medicinal product will be reported as a serious 
adverse event. Any event requiring hospitalization (or prolongation of hospitalization) that occurs 
during the course of a participant's participation in a study must be reported as a serious adverse 
event, except hospitalizations for the following: 

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 
If the participant has not experienced a significant medical event but is hospitalized overnight 
only for observation following injection of study intervention, then the hospitalization should 
not be reported as an SAE 
 
Hospitalizations not intended to treat an acute illness or adverse event (eg, social reasons such 
as pending placement in long-term care facility) 
 
Surgery or procedure planned before entry into the study (must be documented in the eCRF). 
Note: Hospitalizations that were planned before the signing of the ICF, and where the 
underlying condition for which the hospitalization was planned has not worsened, will not be 
considered serious adverse events. Any adverse event that results in a prolongation of the 
originally planned hospitalization is to be reported as a new serious adverse event. 
 
For convenience the investigator may choose to hospitalize the participant for the duration of 
the intervention period.  
Expected progression of disease should not be considered an adverse event (or serious adverse 
event). However, if determined by the investigator to be more likely related to the study 
intervention than the underlying disease, the clinical signs or symptoms of progression and the 
possibility that the study intervention is enhancing disease progression, should be reported per the 
usual reporting requirements. 
CONTACTING SPONSOR REGARDING SAFETY 
The names (and corresponding telephone numbers) of the individuals who should be contacted 
regarding safety issues or questions regarding the study are listed in the Contact Information 
page(s), which will be provided as a separate document. 
PRODUCT QUALITY COMPLAINT HANDLING 
A product quality complaint (PQC) is defined as any suspicion of a product defect related to 
manufacturing, labeling, or packaging, ie, any dissatisfaction relative to the identity, quality, 
durability, or reliability of a product, including its labeling or package integrity. A PQC may have 
an impact on the safety and efficacy of the product. Timely, accurate, and complete reporting and 
analysis of PQC information from studies are crucial for the protection of participants, 
investigators, and the Sponsor, and are mandated by regulatory agencies worldwide. The Sponsor 
has established procedures in conformity with regulatory requirements worldwide to ensure 
appropriate reporting of PQC information; all studies conducted by the Sponsor or its affiliates 
will be conducted in accordance with those procedures. 
Procedures 
All initial PQCs must be reported to the Sponsor by the study-site personnel within 24 hours after 
being made aware of the event. 
If the defect is combined with a serious adverse event, the study-site personnel must report the 
PQC to the Sponsor according to the serious adverse event reporting timelines (refer to 
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Event Information). A sample of the suspected product should be maintained for further 
investigation if requested by the Sponsor. 
Contacting Sponsor Regarding Product Quality 
The names (and corresponding telephone numbers) of the individuals who should be contacted 
regarding product quality issues are listed in the Contact Information page(s), which will be 
provided as a separate document. 
 
 

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10.5. 
Appendix 5: Contraceptive and Barrier Guidance and Collection of 
Pregnancy Information  
Participants must follow contraceptive measures as outlined in Section 5.1, Inclusion Criteria. 
Pregnancy information will be collected and reported as noted in Section 8.3.6, Pregnancy and 
Appendix 4 Section 10.4 Adverse Events: Definitions and Procedures for Recording, Evaluating, 
Follow-up, and Reporting. 
Definitions 
Woman of Childbearing Potential (WOCBP) 
A woman is considered fertile following menarche and until becoming postmenopausal unless 
permanently sterile (see below). 
Woman Not of Childbearing Potential 
 
premenarchal 
 
A premenarchal state is one in which menarche has not yet occurred. 
 
postmenopausal  
A postmenopausal state is defined as no menses for 12 months without an alternative medical 
cause. A high follicle stimulating hormone (FSH) level (>40 IU/L or mIU/mL) in the 
postmenopausal range may be used to confirm a postmenopausal state in women not using 
hormonal contraception or hormonal replacement therapy (HRT), however in the absence of 
12 months 
of 
amenorrhea, 
a 
single 
FSH 
measurement 
is 
insufficient. 
If there is a question about menopausal status in women on HRT, the woman will be required 
to use one of the non-estrogen-containing hormonal highly effective contraceptive methods if 
she wishes to continue HRT during the study. 
 
permanently sterile 
 
Permanent sterilization methods include hysterectomy, bilateral salpingectomy, bilateral tubal 
occlusion/ligation procedures, and bilateral oophorectomy. 
Note: If the childbearing potential changes after start of the study (eg, a premenarchal woman 
experiences menarche) or the risk of pregnancy changes (eg, a woman who is not heterosexually 
active becomes active), a woman must begin a highly effective method of contraception, as 
described throughout the inclusion criteria. 
If reproductive status is questionable, additional evaluation should be considered. 
Contraceptive (birth control) use by men or women should be consistent with local regulations 
regarding the acceptable methods of contraception for those participating in clinical studies. 
Typical use failure rates may differ from those when used consistently and correctly. Use should 
be consistent with local regulations regarding the use of contraceptive methods for participants in 
clinical studies. 
 

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Examples of Contraceptives  
EXAMPLES OF CONTRACEPTIVESa ALLOWED DURING THE STUDY INCLUDE: 
USER INDEPENDENT  
Highly Effective Methods That Are User Independent Failure rate of <1% per year when used 
consistently and correctly.
 Implantable progestogen-only hormone contraception associated with inhibition of ovulationb 
 Intrauterine device (IUD) 
 Intrauterine hormone-releasing system (IUS) 
 Bilateral tubal occlusion 
 Vasectomized partner 
(Vasectomized partner is a highly effective contraceptive method provided that the partner is the 
sole sexual partner of the woman of childbearing potential and the absence of sperm has been 
confirmed. If not, additional highly effective method of contraception should be used. 
Spermatogenesis cycle is approximately 74 days.) 
USER DEPENDENT 
Highly Effective Methods That Are User Dependent Failure rate of <1% per year when used 
consistently and correctly. 
 Combined (estrogen- and progestogen-containing) hormonal contraception associated with 
inhibition of ovulationb 
 oral 
 intravaginal 
 transdermal 
 injectable 
 Progestogen-only hormone contraception associated with inhibition of ovulationb 
 oral 
 injectable 
 Sexual abstinence 
(Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study intervention. 
The reliability of sexual abstinence needs to be evaluated in relation to the duration of the study 
and the preferred and usual lifestyle of the participant.) 
NOT ALLOWED AS SOLE METHOD OF CONTRACEPTION DURING THE STUDY (not 
considered to be highly effective - failure rate of 1% per year)
 Progestogen-only oral hormonal contraception where inhibition of ovulation is not the primary 
mode of action. 
 Male or female condom with or without spermicidec 
 Cap, diaphragm, or sponge with spermicide 
 A combination of male condom with either cap, diaphragm, or sponge with spermicide (double-
barrier methods)c 
 Periodic abstinence (calendar, symptothermal, post-ovulation methods) 
 Withdrawal (coitus-interruptus) 
 Spermicides alone 
 Lactational amenorrhea method (LAM) 

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a) Typical use failure rates may differ from those when used consistently and correctly. Use should be 
consistent with local regulations regarding the use of contraceptive methods for participants in 
clinical studies. 
b) Hormonal contraception may be susceptible to interaction with the study intervention, which may 
reduce the efficacy of the contraceptive method. In addition, consider if the hormonal contraception 
may interact with the study intervention. 
c) Male condom and female condom should not be used together (due to risk of failure with friction).
 
Pregnancy During the Study 
All initial reports of pregnancy must be reported to the Sponsor by the study-site personnel within 
24 hours of their knowledge of the event using the appropriate pregnancy notification form. 
Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, congenital 
anomalies, and ectopic pregnancy) are considered serious adverse events and must be reported 
using the Serious Adverse Event Form. Follow-up information regarding the outcome of the 
pregnancy and any postnatal sequelae in the infant will be required. 
Because the effect of the study intervention on sperm is unknown, pregnancies in partners of male 
participants included in the study will be reported as noted above. 
 
 

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10.6. 
Appendix 6: ECOG Performance Status Score 
Grade  
Eastern Cooperative Oncology Group Performance Status 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of a 
light or sedentary nature, eg, 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 
 
Source: Oken 198220  
 

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10.7. 
Appendix 7: New York Heart Failure Criteria 
 
The following table presents the New York Heart Association classification of cardiac disease: 
 
Class  
Functional Capacity 
Objective Assessment 
I 
Patients with cardiac disease but without resulting limitations 
of physical activity. Ordinary physical activity does not cause 
undue fatigue, palpitation, dyspnea, or anginal pain. 
No objective evidence of 
cardiovascular disease 
II 
Patients with cardiac disease resulting in slight limitation of 
physical activity. They are comfortable at rest. Ordinary 
physical activity results in fatigue, palpitation, dyspnea, or 
anginal pain. 
Objective evidence of minimal 
cardiovascular disease 
III 
Patients with cardiac disease resulting in marked limitation of 
physical activity. They are comfortable at rest. Less than 
ordinary activity causes fatigue, palpitation, dyspnea, or 
anginal pain.  
Objective evidence of 
moderately severe 
cardiovascular disease 
IV 
Patients with cardiac disease resulting in inability to carry on 
any physical activity without discomfort. Symptoms of heart 
failure or the anginal syndrome may be present even at rest. If 
any physical activity is undertaken, discomfort is increased. 
Objective evidence of severe 
cardiovascular disease 
 
 

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10.8. 
Appendix 8: Patient-reported Outcomes FACT-Leu Questionnaire 
 

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10.9. 
Appendix 9: Patient-reported Outcomes EQ-5D-5L Questionnaire 
 

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10.10. Appendix 10: Risk Stratification by Genetics 
Assessment of mutational status must be performed and must include testing for all mutations 
listed below (Table 9). Central and/or local testing is acceptable. Bone marrow collected at 
screening is preferred for mutational analyses. However, standard-of-care assessment of 
mutational status obtained prior to the ICF signing will be accepted in lieu of screening marrow, 
provided that it includes testing for all mutations outlined below. Left over fresh or frozen bone 
marrow samples may be requested for central mutational analysis if all tests are not performed by 
the local study site. 
Table 9: 
ELN Risk Stratification by Genetics6 
 
 
 

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10.11. Appendix 11: Protocol Amendment History 
The Protocol Amendment Summary of Changes Table for the current amendment is located 
directly before the Table of Contents (TOC). 
Amendment 3 (30 September 2021) 
Overall Rationale for the Amendment: After 22 Oct 2021 (after the primary endpoint analysis had been 
completed), subjects who are still benefiting from study treatment can continue to receive study treatments 
and will have a reduced schedule of assessments. 
Section Number 
and Name
Description of Change
Brief Rationale
1.3 Schedule of 
Activities (SoA) 
Table 1 
Note was added indicating that after 22 Oct 2021, subjects 
will no longer be treated and assessed per Table 1 but will 
follow reduced schedule of assessments per Table 1A. 
Modified timing of blood 
sample collection/analyses 
and assessments to reduce 
burden for ongoing study 
participants 
1.3 Schedule of 
Activities (SoA) 
Table 1A 
A new SoA table was added limiting the number of 
assessments. 
Minimal residual disease analysis is included in Table 1A. 
Bone marrow: every 4 cycles following CR and every 2 
cycles following complete response with incomplete blood 
count recovery (CRi)/ complete response with partial 
hematological recovery (CRh) (collected between Day 21 
up to and including Day 1 of the next cycle). Whole Blood: 
Every 2 cycles following CR/CRi/CRh on Day 1. 
A note was added that for participants who discontinue 
study treatment without disease progression, disease 
evaluations should continue with the same frequency as 
during study treatment until disease progression or start of 
subsequent therapy, whichever occurs first. 
Synopsis; 1.3 
Schedule of 
Activities (SoA); 
Table 2; Table 3; 
Table 4; Table 5; 
Section 4.1
Note was added that after 22 Oct 2021, blood samples for 
pharmacodynamic, biomarker, and pharmacokinetic 
analysis will not be collected. 
Throughout the 
protocol 
Minor grammatical, formatting, or spelling changes were 
made. 
To provide clarity.
 
 

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Amendment 2 (19 August 2020) 
Overall Rationale for the Amendment:  This amendment removes Part 2 of the study and addresses 
feedback from the investigators on the timing of disease assessments and use of anti-infective prophylaxis. 
Section Number 
and Name 
Description of Change 
Brief Rationale 
Synopsis: Overall 
Design, Treatment 
Groups and 
Administration, 
Statistical Methods; 
1.2 Schema; 2.1.1 
Study Design 
Rationale; 4.1 
Overall design; 4.2 
Scientific Rationale 
for Study Design; 
9.2 Sample Size 
Determination; 9.5 
Interim Analyses
Added language indicating Part 2 of the study has 
been removed; deleted language pertaining to 
Part 2 
Further development of 
cusatuzumab in combination with 
azacitidine alone will not be 
pursued 
Synopsis: Treatment 
Groups and 
Administration; 4.4. 
End of Study 
Definition
Changed end-of-study definition.  It will be 
reached when all subjects have completed or 
discontinued study treatment.  
Clarified study procedures 
Synopsis: Efficacy 
Evaluations; 4.1. 
Overall Design; 4.2. 
Scientific Rationale 
for Study Design; 
8.1 Efficacy 
Assessments; 9.4.1. 
Efficacy Analyses; 
10.1 Appendix 1 
Abbreviations and 
Trademarks
Deleted language referring to the IRC 
IRC is no longer needed as it was 
planned to only be established for 
Part 2 
1.3 Schedule of 
Activities Table 1
Clarified Cytogenetic testing also included 
Mutational analysis; added footnote d.
Clarified study procedures 
1.3 Schedule of 
Activities Table 1 
Modified disease evaluation to be performed until 
CR or progressive disease (deleted CRi and CRh); 
clarified in cases of cycle delays, timing of disease 
evaluations should be performed per protocol at the 
end of the specified odd cycle.
To provide clarity on the frequency 
of disease evaluations and study 
procedures  
 
2.1.5 Rationale for 
Administration 
Schedule
Modified language to describe azacitidine dosing 
in all cycles is on Day 1 through Day 7 
6.1 Study 
Interventions 
Administered 
Modified language to clarify that in the absence of 
IRRs, subsequent infusions with cusatuzumab are 
to be administered at the highest rate in the 
preceding infusion 
6.1.2 Anti-infective 
Prophylaxis; 6.5.1 
Permitted Therapies
Described anti-infective prophylaxis per ELN 
recommendations 

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Section Number 
and Name 
Description of Change 
Brief Rationale 
6.6.1 Management 
Guidelines for 
Potential Toxicities 
During 
Cusatuzumab 
Infusion 
Modified language regarding infusion rate for 
subjects that do not experience IRR symptoms after 
a Grade 3 IRR 
8.1 Efficacy 
Assessments 
Added footnote to Table 6 to clarify CR definition 
with the absence of circulating blasts unless they 
can be attributed to GCSF administration
8.3.1 Time Period 
and Frequency for 
Collecting Adverse 
Event and Serious 
Adverse Event 
Information
Stipulated that adverse event reporting is 
performed until 30 days after the last dose of study 
intervention or until the start of subsequent anti-
AML therapy, if earlier. 
8.6.1 Cytogenetics; 
10.10 Appendix 10: 
Risk Stratification 
by Genetics
Added section with description of cytogenetic 
testing for mutational status 
10.2 Appendix 2: 
Clinical Laboratory 
Tests
Added clinical laboratory assessment for Urea 
Throughout the 
protocol
Minor grammatical, formatting, or spelling changes 
were made.
Minor errors were noted 
 
 
 

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Amendment 1 (22 October 2019) 
Overall Rationale for the Amendment:   To address comments from health authorities and to provide 
additional clarity 
Section number 
and Name 
Description of Change 
Brief Rationale 
Synopsis; 9.2 Sample Size 
Determination
Modified description of numbers of 
participants
To provide clarity 
Schedule of Activities Table 1 
 
Added cytogenetic testing at screening; 
Increased the frequency of hematology and 
chemistry monitoring; deleted additional 
monitoring of chemistry for participants with 
baseline ALT/AST elevations because all 
participants will have increased monitoring; 
added footnote “m” to permit sampling 
within 24 hours of the Day 1 and Day 17 
visits; added language to column header to 
describe first follow-up visit at 30 days after 
last study treatment; added footnote “b” to 
reinforce that all adverse events are reported 
until 30 days after the last dose of study 
intervention; clarified that pregnancy testing 
should be done at each cycle visit, at the end-
of-treatment visit, and (footnote “n”) 1 
month after the last dose of study treatment; 
removed stipulation of disease evaluation 
within 7 days of Cycle 1 Day 1, added 
starting at Cycle 1 following phrase “every 
other cycle”; modified footnote “f” to clarify 
that disease evaluations should continue for 
participants who discontinue treatment 
without disease progression; added footnote 
“g” for disease assessments to include 2-3 
peripheral blood samples for blast counts at 
screening; modified footnote “h” to stipulate 
that bone marrow aspirates are to be sent to 
the central laboratory within 48 hours for 
biomarker and PK testing; relettered 
footnotes. 
To increase monitoring of 
participants and define first 
follow-up visit; added footnotes 
to provide clarity. 
Schedule of Activities Table 1; 
Appendix 2 Clinical Laboratory 
Tests 
 
 
 
 
Schedule of Activities Table 1; 
8.1 Efficacy Assessments 
Deleted coagulation testing; Modified 
footnote “o” to change testing for hepatitis 
and HIV at screening to make it mandatory 
for all participants 
 
 
Footnote “h”: removed the words “bone 
marrow biopsy” from associating with 
biomarkers and PK samples  
Removed unnecessary laboratory 
assessments to reduce burden on 
study participants.  
 
 
 
Clarified that bone marrow biopsy 
or aspirate can be used for 
morphology assessment; however, 
biomarker and PK testing require 
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Section number 
and Name 
Description of Change 
Brief Rationale 
Schedule of Activities Table 2 
 
 
 
 
 
 
 
 
 
 
 
8.8. Biomarkers 
Added MRD assessment to flow cytometry 
column; added column for DNA sequencing; 
added assessments for flow 
cytometry/CyTOF/MRD on bone marrow 
and blood samples, protein quantification, 
and gene expression at every disease 
evaluation; changed Cycle 1 Day 3 sampling 
to Day 2; Footnote “a”: added “samples 
stored for future analysis”; removed whole 
blood sample at screening for gene 
expression.  
 
Explained that the bone marrow aspirate 
sample will also be used for myeloid 
differentiation assay.
Aligned the schedule of 
biomarkers assessment with that 
of disease evaluations 
 
Clarified that MRD assessments 
will be done upon assay 
availability 
 
 
 
 
 
 
To inform regarding mechanism 
of action of cusatuzumab  
Schedule of Activities Table 3 
Cycle 1 Day 7 assessments were removed; 
defined assessments for Cycles 2 to 5 and for 
odd cycles beginning with Cycle 7. 
  
Footnote “a”: added “dependent upon assay 
availability” 
Removed unnecessary sampling 
to reduce burden on participants. 
 
 
Clarified that PK/RO assessments 
will be done depending on the 
validated assay availability  
Added Schedule of Activities 
Table 4 
Separated timing for samples for 
pharmacokinetic evaluations for azacitidine 
to a unique table
To provide clarity 
Schedule of Activities Table 5 
Table 4 of original protocol becomes Table 5 
To match sampling for 
participants after the 50th 
participant with participants 
randomized before the 50th 
participant
2.1.4 Rationale for Dose 
Selection 
Text added to describe target concentrations 
and the proportion of patients who achieve 
this at each dose level being studied. 
Provided additional clarity around 
available PK data and 
compartmental effect on PK to 
strengthen the dose selection 
rationale
2.2.2.1 Clinical Data 
Removed the word “RP2D” 
To provide further clarifications 
of the existing text
3. Objectives and Endpoints 
Clarified the definition of time to response 
and duration of response; added the 
secondary endpoint of transfusion 
independence and its definition  
To provide further clarification of 
the existing text 
 
Added relevant endpoint for AML 
studies
10.3 Appendix 3: Data Review 
Committee 
Added language regarding membership and 
activities of the Data Review Committee 
To further clarify membership 
and activities of the Data Review 
Committee
4.1 Overall Design; 9.5 Interim 
Analyses 
Changed timing of data for DRC review to 
minimum of 3 cycles for Part 1 and 4 cycles 
for Part 2 from 4 cycles per participant; 
added language regarding activities of the 
DRC 
To provide further clarification of 
the existing text 
 

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Section number 
and Name 
Description of Change 
Brief Rationale 
5.1. Inclusion Criteria 
Clarified co-morbidity inclusion criterion; 
added hydroxyurea and changed low dose 
cytarabine to dose of cytarabine (1-2g/m2) to 
exceptions for treatment; renumbered 
inclusion criteria with 3 bulleted items from 
criteria 2 in the original protocol placed as 
criteria 3 to 5; clarified contraceptive 
language; removed age restriction for 
definition of “postmenopausal”; added 
language to include legally acceptable 
representative in understanding the ICF; 
added criteria related to donation of eggs or 
sperm; added criteria related to fathering a 
child.      
To manage hyperleukocytosis; to 
clarify inclusion criteria 
5.2. Exclusion Criteria 
Removed language defining genetic marker 
for APL; clarified that the immune 
suppressive agent administration should be 
terminated before the Cycle 1 Day 3 
cusatuzumab dose; removed “untreated” 
from systemic infection exclusion criterion; 
removed “if tested” from HIV related 
exclusion criteria because all are tested; 
added instructions for treatment of adrenal 
insufficiency; added criterion to exclude 
women who are breastfeeding; modified 
criteria related to prior/current other 
malignancies; added criterion to exclude 
participants who received live attenuated 
vaccines; clarified criterion with regard to 
hepatitis B and C infection; clarified 
exclusion for major surgery 4 weeks prior to 
initiation of study. 
Corrected day to match 
cusatuzumab dosing; clarified 
exclusion criteria; added 
exclusion criteria  
5.3 Lifestyle Considerations 
Added statement that male participants 
should inform fertile female partners to use 
effective methods of birth control. 
To further clarify contraception 
instructions for male participants 
6.1 Study Interventions 
Administered 
Clarified that BSA and dose only be 
recalculated if there is a >10% change in 
body weight from previous calculation
To provide clarity 
6.1.1 Premedications 
Removed sentence stipulating that 
cusatuzumab premedications be given prior 
to azacitidine administration
To provide clarity 
6.5 Concomitant Therapy 
Removed need for non-pharmacologic 
therapies to be recorded in the eCRF
To eliminate unnecessary 
documentation
6.5.1. Permitted Therapies 
Added text allowing certain treatments for 
non-AML malignancies; changed time 
period defining short-term corticosteroid use 
to ≤7 days  
To add exemptions to prohibited 
medications 
6.5.2 Prohibited Therapies and 
Procedures 
Removed definition of short-term 
corticosteroid; added “treatment” after 
“study” to define period of time; added text 
allowing certain treatments for non-AML 
malignancies; removed language regarding 
ATRA treatment; removed cytoreduction 
language; added any other monoclonal 
antibody 
To reduce redundancy; to restrict 
treatment with other therapies or 
procedures only during the period 
when participants are receiving 
study treatment; to add 
exemptions to prohibited 
medications 

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Section number 
and Name 
Description of Change 
Brief Rationale 
6.5.3 Subsequent Anticancer 
Therapy
Removed stipulation that only the first 
anticancer therapy be documented
To provide clarity 
6.6. Dose Modification; 6.6.2. 
Management Guidelines for 
Toxicities Attributed to 
Cusatuzumab 
Divided section into 2 subsections (1 for 
cusatuzumab and 1 for azacitidine); removed 
the guidance allowing for cusatuzumab dose 
escalations or reductions; clarified that 
escalations and reductions are only allowed 
at the time of dose selection; changed 
wording from “must” to “should” in first 
bullet.
To provide clarity 
6.6.1 Management Guidelines 
for Potential Toxicities During 
Cusatuzumab Infusion 
Deleted Section 6.1.2 and moved to Section 
6.6.1; changed title to reflect guidelines for 
toxicity management during cusatuzumab 
infusion; modified guideline to stipulate 
IRRs or hypersensitivity reactions.
For participant safety 
6.6.3. Management Guidelines 
for Toxicities Attributed to 
Azacitidine
Added text for azacitidine dose reductions 
from the SPC 
To provide clarity 
6.7 Intervention After the End of 
Treatment
Changed title from end of the study to end of 
treatment 
To reflect correct description of 
section
7.1 Discontinuation of Study 
Intervention 
Removed bullet referring to discontinuation 
following initiation of treatment with a 
prohibited medication 
To align with Section 6.5.2: 
Prohibited Therapies and 
Procedures which requires 
notification to the Sponsor for 
administration of any prohibited 
medications
8 Study Assessments and 
Procedures 
Clarified that standard of care tests 
performed within the screening period but 
prior to signing the ICF can be used for 
eligibility
To provide clarity 
8.1. Efficacy Assessments 
Added methods of extramedullary disease 
evaluation. 
 
Changed total blood volume needed from 
participants 
To provide further clarifications 
of the existing text 
 
Changes to PK and biomarker 
sampling warranted changes to 
total blood volume needed 
8.4 Treatment of Overdose 
Clarified Sponsor’s clinical team will 
evaluate participants with suspected 
overdose 
To correct language 
8.6 Genetics 
Added phrase “in tumor cells” 
To stipulate that genetics is 
performed on tumor cell samples 
9.3. Populations for Analysis 
Differentiated between the Part 1 
randomized and Part 2 enrolled participants, 
all comprising the ITT population
To provide further clarifications 
of the existing text 
9.4.1 Efficacy Analyses 
Added transfusion independence as an 
endpoint; clarified presentation of response 
rate results 
To add relevant endpoint for 
AML studies 
9.4.2 Safety Analyses 
Removed paragraph on vital signs; modified 
text regarding physical examination to state 
that clinically significant abnormal 
examination findings would be reported as 
adverse events 
To provide correct description of 
activities 
10.2 Appendix 2: Clinical 
Laboratory Tests
Added hepatitis B virus antibody to 
examples of serology tests
To provide clarity 

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Section number 
and Name 
Description of Change 
Brief Rationale 
10.4 Appendix 4: Adverse 
Events: Definitions and 
Procedures for Recording, 
Evaluating, Follow-up, and 
Reporting
Added NCI-CTCAE v5.0 severity criteria 
To provide details for investigator 
assessment of adverse events 
Throughout the protocol 
Minor grammatical, formatting, or spelling 
changes were made.
To provide clarity 
 
 
 

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11. 
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