Clinical trial NCT02152956
Conditions: AML
Keywords: AML leukemia myelogenous myeloid refractory
Sponsor: MacroGenics
Start date: 2014-06-09; Completion date: 2022-07-05
Enrollment: 244 participants; Allocation: NON_RANDOMIZED; Intervention model: SINGLE_GROUP

Brief summary:
Open-label, multi-dose, single-arm, multi-center, Phase 1/2 study conducted in three segments: the Single Patient Dose Escalation Segment (complete), followed by the Multi-Patient Dose Escalation Segment (complete) and the Maximum Tolerated Dose and Schedule (MTDS) Expansion Cohort Segment (closed). Having characterized safety and determined the maximum tolerated dose and schedule, the primary objective of this study now is to assess the anti-neoplastic activity of flotetuzumab in patients with PIF/ER AML, as determined by the proportion of patients who achieve CR or CRh. Starting with Cycle 2, patients who are benefiting from flotetuzumab may receive up to a maximum of 8 cycles of treatment.

Patients will receive daily increasing doses of flotetuzumab for the first week of Cycle 1 (Lead-In Dosing) followed by 3 weeks of continuous intravenous infusion at a the assigned dose. Subsequent cycles are each 4 weeks of continuous infusion at the assigned dose. Dosing may continue for up to 8 cycles. Follow up visits may continue for 6 months after treatment is discontinued.

Detailed description:

Arms: arm 1: None arm 2: None arm 3: None arm 4: None arm 5: None arm 6: None arm 7: None arm 8: None arm 9: None arm 10: None arm 11: None arm 12: None arm 13: None
Interventions: intervention 1: Flotetuzumab 3 ng/kg/day, 4 days on and 3 days off intervention 2: Flotetuzumab 10 ng/kg/day, 4 days on and 3 days off intervention 3: Flotetuzumab 30 ng/kg/day, 4 days on and 3 days off intervention 4: Flotetuzumab 100 ng/kg/day, 4 days on and 3 days off intervention 5: Flotetuzumab 300 ng/kg/day, 4 days on 3 days off, after one-step lead-in dose intervention 6: Flotetuzumab 500 ng/kg/day, 4 days on 3 days off, after one-step lead-in dose intervention 7: Flotetuzumab 500 ng/kg/day, continuous infusion, after multi-step lead-in dose intervention 8: Flotetuzumab 700 ng/kg/day, 4 days on 3 days off, after multi-step lead-in dose intervention 9: Flotetuzumab 700 ng/kg/day, continuous infusion, after multi-step lead-in dose intervention 10: Ruxolitinib intervention 11: Flotetuzumab 300 ng/kg/day, continuous infusion, after multi-step lead-in dose
Intervention descriptions: intervention 1: Flotetuzumab is a CD123 x CD3 bispecific antibody-based molecular construct referred to as a DART® molecule. intervention 2: Flotetuzumab is a CD123 x CD3 bispecific antibody-based molecular construct referred to as a DART molecule. intervention 3: Flotetuzumab is a CD123 x CD3 bispecific antibody-based molecular construct referred to as a DART molecule. intervention 4: Flotetuzumab is a CD123 x CD3 bispecific antibody-based molecular construct referred to as a DART molecule. intervention 5: Flotetuzumab is a CD123 x CD3 bispecific antibody-based molecular construct referred to as a DART molecule. intervention 6: Flotetuzumab is a CD123 x CD3 bispecific antibody-based molecular construct referred to as a DART® molecule. intervention 7: Flotetuzumab is a CD123 x CD3 bispecific antibody-based molecular construct referred to as a DART molecule. intervention 8: Flotetuzumab is a CD123 x CD3 bispecific antibody-based molecular construct referred to as a DART molecule. intervention 9: Flotetuzumab is a CD123 x CD3 bispecific antibody-based molecular construct referred to as a DART molecule. intervention 10: Oral inhibitor of JAK kinase intervention 11: Flotetuzumab is a CD123 x CD3 bispecific antibody-based molecular construct referred to as a DART molecule.

Protocol documents:
Prot_000.pdf: 
Flotetuzumab 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGD006-01 
Amendment 13, 26 April 2021 
CLINICAL TRIAL PROTOCOL: CP-MGD006-01
PROTOCOL AMENDMENT 13 
Study Title:
A Phase 1/2, First-in-Human, Dose Escalation Study of MGD006, a CD123 x 
CD3 Dual Affinity Re-Targeting (DART) Bi-Specific Antibody-Based 
Molecule, in Patients with Relapsed or Refractory Acute Myeloid Leukemia or 
Intermediate-2/High Risk Myelodysplastic Syndrome 
Study Number:
CP-MGD006-01 
Development Phase:
1/2 
Product Name:
Flotetuzumab 
Product Number:
MGD006 (S80880) 
IND Number:
 
EudraCT Number: 
 
Indication:
Primary induction failure (PIF)/early relapse (ER) Acute Myeloid Leukemia 
(AML) 
Coordinating Principal 
Investigator:
 
Chief, Division of Oncology 
Deputy Director, Siteman Cancer Center 
Washington University School of Medicine 
660 S Euclid Ave 
St Louis, MO 63110 
USA 
European Coordinator:
 
Département d’Hématologie
Institut Paoli-Calmettes 
13002 Marseille 
France 
Sponsor:
MacroGenics, Inc. 
9704 Medical Center Drive 
Rockville, MD 20850 
USA 
301-251-5172
Sponsor’s Medical 
Monitor:
 
SVP Clinical Development 
Chief Medical Officer 
MacroGenics, Inc. 
9704 Medical Center Drive 
Rockville, MD 20850 
USA 
301-251-5172
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Flotetuzumab 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGD006-01 
Amendment 13, 26 April 2021 
 
 
 
 
 
Confidentiality Statement 
The information contained in this document is the property of MacroGenics, Inc. It is provided in confidence by 
MacroGenics to the Investigator, potential investigator, or consultant for review. This document and its contents 
may only be shared with the investigator’s team and the appropriate Institutional Review Board and/or 
Independent Ethics Committee. 
 
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Clinical Trial Protocol: CP-MGD006-01 
Amendment 13, 26 April 2021 
 
 
 
 
TABLE OF CONTENTS 
SPONSOR SIGNATURES ........................................................................................................ 8 
 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ........................................... 12 
1 
SYNOPSIS ................................................................................................................... 16 
2 
BACKGROUND INFORMATION ............................................................................. 25 
2.1 
Disease Background............................................................................................ 25 
2.1.1 
Acute Myeloid Leukemia ......................................................................... 25 
2.1.2 
Myelodysplastic Syndromes ..................................................................... 26 
2.2 
Flotetuzumab Background .................................................................................. 27 
2.3 
Rationale for Study ............................................................................................. 32 
2.3.1 
First-in-Human Dose Selection ................................................................. 32 
2.3.2 
Rationale for Overall Study Design and Summary of Prior Study 
Development ............................................................................................. 36 
2.3.2.1 
Single Patient Dose Escalation Segment (Completed) ................... 36 
2.3.2.2 
Multi-Patient Dose Escalation Segment and Determination 
of MTDS (Completed) .................................................................... 37 
2.3.2.3 
Cohort Expansion Segment (Ongoing) ........................................... 39 
2.4 
Clinical Experience with Flotetuzumab .............................................................. 40 
2.5 
Risk and Benefit Assessment .............................................................................. 40 
3 
STUDY PURPOSE AND OBJECTIVES .................................................................... 42 
3.1 
Primary Objective ............................................................................................... 42 
3.2 
Secondary Objectives.......................................................................................... 42 
3.3 
Exploratory Objectives ....................................................................................... 42 
4 
TRIAL DESIGN .......................................................................................................... 44 
4.1 
Overall Study Design and Plan ........................................................................... 44 
4.1.1 
Cohort Expansion Dosing ......................................................................... 46 
4.1.2 
Concurrent Ruxolitinib Cohort within Cohort Expansion ........................ 47 
4.2 
Dose Limiting Toxicity Definitions .................................................................... 49 
4.3 
Study Duration and Dates ................................................................................... 49 
4.4 
Definition of End of Trial ................................................................................... 50 
5 
SELECTION AND WITHDRAWAL OF PATIENTS ................................................. 51 
5.1 
Inclusion Criteria ................................................................................................ 51 
5.2 
Exclusion Criteria ............................................................................................... 53 
5.3 
Rationale for Exclusion of Certain Study Candidates ........................................ 55 
5.4 
Withdrawal of Patient from the Trial or Study Drug .......................................... 55 
6 
STUDY TREATMENTS ............................................................................................. 57 
6.1 
Description of Treatment(s) ................................................................................ 57 
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Amendment 13, 26 April 2021 
 
 
 
 
6.2 
Treatments Administered .................................................................................... 57 
6.2.1 
Flotetuzumab ............................................................................................. 57 
6.2.1.1 
Drug Supply .................................................................................... 57 
6.2.1.2 
Drug Dose Solution Preparation and Administration ...................... 58 
6.3 
Modification (Including Discontinuation) of Flotetuzumab Dose or 
Schedule .............................................................................................................. 59 
6.4 
Special Situations and Supportive Care Measures .............................................. 61 
6.4.1 
Infusion-related Reactions including CRS ................................................ 61 
6.4.1.1 
Premedications and Prophylaxis ..................................................... 62 
6.4.1.2 
Management of Observed Flotetuzumab Infusion Reactions 
and Infusion-related Adverse Events............................................... 63 
6.4.2 
Tumor Lysis Syndrome ............................................................................. 67 
6.4.3 
Neutropenic Sepsis/Fungemia .................................................................. 68 
6.4.4 
Immune-related Adverse Experiences ...................................................... 68 
6.4.5 
Neurotoxicity ............................................................................................ 68 
6.4.6 
Capillary Leak Syndrome ......................................................................... 69 
6.4.7 
Epstein-Barr Virus Reactivation ............................................................... 69 
6.5 
Blinding............................................................................................................... 69 
6.6 
Concomitant Therapy .......................................................................................... 69 
6.7 
Restrictions ......................................................................................................... 71 
6.7.1 
Prior Therapy ............................................................................................ 71 
6.7.2 
Fluid and Food Intake ............................................................................... 71 
6.7.3 
Patient Activity Restrictions ..................................................................... 71 
6.8 
Treatment Compliance ........................................................................................ 71 
6.9 
Packaging and Labeling ...................................................................................... 71 
6.10 
Storage and Accountability ................................................................................. 71 
6.10.1 
Flotetuzumab and IV Solution Stabilizer Storage ..................................... 71 
6.10.2 
Accounting for the Materials .................................................................... 72 
6.10.3 
Return or Destruction of Investigational Product ..................................... 72 
7 
STUDY PROCEDURES ............................................................................................. 73 
7.1 
Informed Consent................................................................................................ 73 
7.2 
Medical History .................................................................................................. 73 
7.3 
Prior and Concomitant Medications ................................................................... 73 
7.4 
Physical Examination.......................................................................................... 73 
7.5 
Vital Signs ........................................................................................................... 74 
7.6 
Clinical Laboratory Tests .................................................................................... 74 
7.7 
Electrocardiography and Continuous Telemetry Monitoring ............................. 76 
7.8 
Left Ventricular Ejection Fraction....................................................................... 76 
7.9 
Pulmonary Function Testing ............................................................................... 76 
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7.10 
Efficacy Assessments .......................................................................................... 76 
7.11 
Safety Assessments ............................................................................................. 78 
7.11.1 
Adverse Event: Definitions ....................................................................... 78 
7.11.2 
Performing Adverse Event Assessments ................................................... 80 
7.11.3 
Adverse Events of Special Interest ........................................................... 82 
7.11.4 
Reporting of Adverse Events to the Sponsor ............................................ 82 
7.12 
Notification to the Sponsor of Events Requiring Immediate Reporting ............. 83 
7.13 
Emergency Unblinding ....................................................................................... 84 
7.14 
Other Study Procedures ...................................................................................... 84 
7.14.1 
Pharmacokinetics, Biomarkers, and ADA ................................................ 84 
7.14.1.1 
Pharmacokinetics ............................................................................ 84 
7.14.1.2 
ADA (Anti-flotetuzumab Antibodies) ............................................. 84 
7.14.2 
Flow Cytometric Analyses on Bone Marrow and Peripheral Blood 
Samples ..................................................................................................... 84 
7.14.3 
Other Assessments .................................................................................... 85 
7.14.4 
Bone Marrow Assessments ....................................................................... 85 
7.14.5 
Cytokine Analyses .................................................................................... 85 
7.14.6 
Minimal Residual Disease ........................................................................ 85 
7.14.7 
T Lymphocyte Repertoire ......................................................................... 86 
7.14.8 
Sample Collection, Storage, and Shipping ............................................... 86 
7.14.9 
Sample Retention and Further Testing ...................................................... 86 
7.15 
Appropriateness of Measurements ...................................................................... 86 
8 
STUDY ACTIVITIES .................................................................................................. 88 
8.1 
Pre-treatment Evaluations ................................................................................... 88 
8.1.1 
Within 14 Days Before Treatment ............................................................ 88 
8.1.2 
Within 5 Days Before Treatment .............................................................. 89 
8.1.2.1 
Patient Registration ......................................................................... 89 
8.1.3 
Within 1 Day Before Treatment ................................................................ 90 
8.2 
Study Evaluations Applicable During Cohort Expansion ................................... 90 
8.3 
End of Treatment Visit/Follow-up ...................................................................... 90 
8.3.1 
End of Treatment Visit: 28-Days (4 Weeks) After Last Dose of 
Study Drug or at the Time of Treatment Failure ....................................... 90 
8.3.2 
Follow-up Period ...................................................................................... 90 
9 
PLANNED STATISTICAL METHODS ..................................................................... 93 
9.1 
Determination of Sample Size for Primary Efficacy Analysis ........................... 93 
9.2 
Analysis Populations ........................................................................................... 94 
9.3 
Demographics and Baseline Characteristics ....................................................... 94 
9.4 
Study Drug Exposures and Concomitant Medications ....................................... 95 
9.5 
Safety Endpoint(s) and Analyses ........................................................................ 95 
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9.5.1 
Adverse Events ......................................................................................... 95 
9.5.2 
Laboratory Values ..................................................................................... 96 
9.5.3 
Other Safety Endpoints ............................................................................. 96 
9.6 
Efficacy Endpoints and Analyses ........................................................................ 96 
9.6.1 
Primary Efficacy Analysis ........................................................................ 97 
9.6.2 
Secondary Efficacy Analyses .................................................................... 97 
9.6.2.1 
Key Secondary Efficacy Analyses .................................................. 97 
9.6.2.2 
Additional Secondary Efficacy Analyses ........................................ 98 
9.7 
Other Assessments or Analyses .......................................................................... 99 
9.7.1 
Immunogenicity ........................................................................................ 99 
9.7.2 
Pharmacokinetics ...................................................................................... 99 
9.7.3 
Safety and Efficacy of Tocilizumab in Treatment of IRR/CRS ................ 99 
9.7.4 
Other Studies ............................................................................................. 99 
9.8 
Final Analysis at End of Trial ........................................................................... 100 
10 
QUALITY CONTROL AND ASSURANCE ............................................................ 101 
10.1 
Investigational Site Training ............................................................................. 101 
10.2 
Monitoring, Auditing and Inspections .............................................................. 101 
10.3 
Data Entry and Computerized Systems ............................................................ 102 
11 
ADMINISTRATIVE CONSIDERATIONS............................................................... 103 
11.1 
Institutional Review Board (IRB/IEC) or Independent Ethics 
Committee (IEC) Approval ............................................................................... 103 
11.2 
Data Safety Monitor and Independent Data Monitoring Committee................ 104 
11.3 
Ethical Conduct of the Study ............................................................................ 104 
11.4 
Patient Information and Consent ...................................................................... 104 
11.5 
Patient Confidentiality ...................................................................................... 105 
11.6 
Case Report Forms and Study Records ............................................................ 105 
11.7 
Access to Source Documentation ..................................................................... 105 
11.8 
Retention of Data .............................................................................................. 106 
11.9 
Financial Disclosure.......................................................................................... 106 
11.10 
Publication and Disclosure Policy .................................................................... 106 
11.11 
Discontinuation of the Study or Study Sites ..................................................... 107 
11.11.1 
Discontinuation of Study Sites ................................................................ 107 
11.11.2 
Discontinuation of the Study .................................................................. 107 
11.12 
Identification of the Coordinating Principal Investigator ................................. 107 
12 
REFERENCES .......................................................................................................... 108 
 
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Clinical Trial Protocol: CP-MGD006-01 
Amendment 13, 26 April 2021 
 
 
 
 
LIST OF TABLES  
Table 1 
Planned Total Dose Administered in Cycle 1 ................................................ 38 
Table 2 
Cohort Expansion: Induction and Consolidation Dosing Schedule 
(Beginning with Amendment 11) .................................................................. 47 
Table 3 
Flotetuzumab Drug Product Composition ..................................................... 57 
Table 4 
Premedication and Prophylaxis for Infusion-related Reactions .................... 63 
Table 5 
CRS Grading and Recommended Management Guidance ........................... 65 
Table 6 
Definition of High Dose Vasopressor ............................................................ 67 
Table 7 
Local Routine Laboratory Tests .................................................................... 75 
 
LIST OF FIGURES  
Figure 1 
Flotetuzumab Activity in AML Patient PBMCs ............................................ 28 
Figure 2 
Inhibition of Tumor Growth by Flotetuzumab in NOD/SCID Mice 
Implanted with Human AML Tumor Cells (RS4:11 and MOLM-13) ........... 29 
Figure 3 
Flotetuzumab-Mediated Cytokine Induction in Normal Human 
Donor PBMCs Co-cultured with Kasumi-3 Cells ......................................... 34 
Figure 4 
Projected Serum Concentration-time Profile of Flotetuzumab in 
Humans at a Dose of 3 ng/kg/day for 4 days Scaled from Monkey 
PK Parameters Obtained in Studies 4605 and Study 2158 ............................ 35 
Figure 5 
Induction and Consolidation Treatment in the Expansion Cohort ................ 46 
 
LIST OF APPENDICES  
APPENDIX 1 
SCHEDULE OF EVENTS APPLICABLE TO COHORT 
EXPANSION (ALL CYCLES) 
APPENDIX 2 
PHARMACOKINETIC, IMMUNOGENICITY, AND 
PHARMACODYNAMIC BIOMARKERS BLOOD SAMPLING 
SCHEDULE 
APPENDIX 3 
INTERNATIONAL WORKING GROUP (IWG) RESPONSE 
CRITERIA FOR ACUTE MYELOID LEUKEMIA (AML) MODIFIED FOR 
ASSESSMENT OF AML IN THIS STUDY 
APPENDIX 4 
EASTERN COOPERATIVE ONCOLOGY GROUP (ECOG) 
PERFORMANCE STATUS 
APPENDIX 5 
PRINCIPAL INVESTIGATOR’S AGREEMENT 
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Clinical Trial Protocol: CP-MGD006-01 
Amendment 13, 26 April 2021 
 
 
 
 
                 SPONSOR SIGNATURES  
Study Title: 
A Phase 1/2, First-in-Human, Dose Escalation Study of MGD006, 
a CD123 x CD3 Dual Affinity Re-Targeting (DART) Bi-Specific 
Antibody-Based Molecule, in Patients with Relapsed or Refractory 
Acute Myeloid Leukemia or Intermediate-2/High Risk 
Myelodysplastic Syndrome 
Study Number: 
CP-MGD006-01 
 
This clinical study protocol has been approved by the Sponsor: 
 
Signed: 
[See appended electronic signature page] 
Date: 
 
 
 
SVP Clinical Development 
Chief Medical Officer 
MacroGenics, Inc. 
 
 
Signed: 
[See appended electronic signature page] 
Date: 
 
 
 
Executive Director, Biostatistics 
MacroGenics, Inc. 
 
 
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Clinical Trial Protocol: CP-MGD006-01 
Amendment 13, 26 April 2021 
 
 
 
 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS  
21CFR 
United States Code of Federal Regulations, Title 21 
ADA 
anti-drug antibody 
ADR 
adverse drug reaction 
AE 
adverse event 
AESI 
adverse event of special interest 
ALB 
albumin 
ALK-P 
alkaline phosphatase 
ALL 
acute lymphoblastic leukemia 
ALT 
alanine aminotransferase 
AML 
acute myeloid leukemia 
ANC 
absolute neutrophil count 
APTT 
activated partial thromboplastin time 
AST 
aspartate aminotransferase  
BID 
twice daily 
BP 
blood pressure 
bpm 
beats per minute 
BUN 
blood urea nitrogen 
Ca 
calcium 
CAR 
chimeric antigen receptor 
CBC 
complete blood count 
CDR 
complementary-determining region 
CFR 
Code of Federal Regulations 
CI 
confidence interval 
CK 
creatine kinase 
Cl 
chloride 
Cmax 
maximum concentration 
CNS 
central nervous system 
COVID-19 
coronavirus disease-2019 
CR 
complete remission (mCR, CRc, or CRm) 
CR1 
initial CR 
CRc 
cytogenetic complete remission 
CRh 
complete remission with partial hematologic recovery 
CRi 
complete remission with incomplete blood cell recovery 
CRm 
molecular complete remission 
CRn 
CR with incomplete neutrophil recovery 
CRp 
CR with incomplete platelet recovery 
CRS 
cytokine release syndrome 
CTCAE 
common terminology criteria for adverse events 
DLCO 
carbon monoxide diffusion capacity in the lung 
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DLT 
dose-limiting toxicity 
DP 
drug product 
DSM 
Data Safety Monitor 
EBV 
Epstein-Barr virus 
EC 
effective concentration 
EC10 
concentration at 10% of the maximum effect 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 
EFS 
event-free survival 
ELISA 
enzyme-linked immunosorbent assay 
EMD 
extramedullary disease 
EOTV 
End of Treatment Visit 
ER 
early relapse 
E:T 
effector to target ratio 
FDA 
Food and Drug Administration 
FEV1 
forced expiratory volume in 1 second 
FIH 
first-in-human 
FISH 
fluorescence in situ hybridization 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practice 
GM-CSF 
granulocyte macrophage–colony-stimulating factor 
GvHD 
graft versus host disease 
Hct 
hematocrit 
HSCT 
hematopoietic stem cell transplantation 
Hgb 
hemoglobin 
HIPAA 
United States Health Insurance Portability and Accountability Act 
HIV 
human immunodeficiency virus 
IB 
Investigator’s Brochure 
ICH 
International Conference on Harmonisation 
IDMC 
Independent Data Monitoring Committee 
IFN-γ 
interferon gamma 
IHC 
immunohistochemistry 
IL-3R 
interleukin-3 receptor alpha chain 
IND 
Investigational New Drug 
IPSS 
International Prognostic Scoring System 
IRB/IEC 
Institutional Review Board/Independent Ethics Committee 
IRE 
immediately reportable event 
IRR 
infusion-related reaction 
IUD 
intrauterine device 
IV 
intravenous 
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IWG 
International Working Group 
K 
potassium 
LSC 
leukemic stem cells 
LVEF 
left ventricular ejection fraction 
mAb 
monoclonal antibody 
MABEL 
minimum anticipated biological effect level 
mCR 
morphologic CR 
MDS 
myelodysplastic syndrome 
MLFS 
morphologic leukemia-free state 
MRD 
minimal residual disease 
MTD 
maximum tolerated dose 
MTDS 
maximum tolerated dose and schedule 
MUGA 
multiple-gated acquisition scan 
Na 
sodium 
NCI 
National Cancer Institute 
NK 
natural killer 
NOAEL 
no observed adverse effect level 
NOD/SCID 
non-obese diabetic/severe combined immunodeficient 
OB 
other benefit 
OCRR 
overall complete response rate 
OS 
overall survival 
PBMC 
peripheral blood mononuclear cell 
PD 
progressive disease 
pDC 
plasmacytoid dendritic cell 
PFT 
pulmonary function test 
PIF 
primary induction failure 
PK 
pharmacokinetics 
PO 
by mouth 
PR 
partial remission 
PS 
performance status 
PT 
prothrombin time, preferred term 
qw 
once weekly 
SAE 
serious adverse event 
SARS-CoV-2 
severe acute respiratory syndrome coronavirus 2 
SC 
subcutaneous 
SD 
stable disease 
TCR 
T-cell receptor 
TEAE 
treatment-emergent adverse event 
TLS 
tumor lysis syndrome 
ULN 
upper limit of normal 
US 
United States 
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USP 
United States Pharmacopeia 
WBC 
white blood cell (count) 
WHO 
World Health Organization 
 
 
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1 
SYNOPSIS  
Sponsor: MacroGenics, Inc. 
IND Number: 116832 
EudraCT Number: 2015-003813-11 
Name of Finished Product: Flotetuzumab, MGD006 (CD123 x CD3 DART protein) 
Study Title: A Phase 1/2, First-in-Human, Dose Escalation Study of MGD006, a CD123 x 
CD3 Dual Affinity Re-Targeting (DART) Bi-Specific Antibody-Based Molecule, in 
Patients with Relapsed or Refractory Acute Myeloid Leukemia or Intermediate-2/High 
Risk Myelodysplastic Syndrome 
Study Number: CP-MGD006-01 
Investigator(s)/Centers: 
The study will be carried out at approximately 50 institutions globally, preferably with 
experience in the conduct of studies in patients with acute myeloid leukemia (AML) or 
myelodysplastic syndrome (MDS). 
Study Phase: 1/2 
Primary Objective: 
To assess the anti-neoplastic activity of flotetuzumab in patients with PIF/ER AML, as 
determined by the proportion of patients who achieve CR/CRh. 
Secondary Objectives: 
• Assessment of CR rate, CRh rate, overall complete response rate (OCRR; 
CR, CRh, CRi [CRn, CRp], or MLFS), objective response rate (CR, CRh, 
CRi [CRn, CRp], MLFS, or PR), time to response and duration of response 
(DOR). 
• To measure early mortality rates, overall survival (OS) and event-free 
survival (EFS). 
• To determine the rate of eligible patients, per institution criteria, that 
transition to successful stem cell transplant after achieving overall complete 
response (CR, CRh, CRi [CRn, CRp], or MLFS). 
• To assess rate of conversion to and maintenance of transfusion independence. 
• To evaluate duration of initial hospitalization for flotetuzumab 
administration. 
• To evaluate incidence and duration of hospitalizations subsequent to initial 
discharge. 
• To monitor the safety and tolerability of flotetuzumab. 
• To characterize the PK and immunogenicity of flotetuzumab. 
• To determine safety and efficacy of tocilizumab in the treatment of 
IRR/CRS. 
Exploratory Objectives: Refer to Section 3.3 for complete list of exploratory objectives. 
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Study Design: 
This is an open-label, multi-dose, single-arm, multi-center, Phase 1/2, dose-escalation and 
expansion study to define an MTDS; describe preliminarily safety; and assess the PK, 
immunogenicity, immunomodulatory activity, and potential anti-neoplastic activity of 
flotetuzumab in patients with AML and MDS whose disease is not expected to benefit from 
cytotoxic chemotherapy. 
This study is designed in three segments: the Single Patient Dose Escalation Segment 
(completed), followed by the Multi-patient Dose Escalation Segment (completed), and the 
MTDS Expansion Cohort Segment (ongoing). Two expansion cohorts were planned, one in 
AML and one in MDS. As of Amendment 7, the Sponsor stopped enrolling patients with 
MDS into this study. The primary objective of the study going forward is to assess anti-
neoplastic activity of flotetuzumab in AML, as determined by the proportion of patients 
who achieve CR/CRh. Trial design aspects relating to continuation of the ongoing Cohort 
Expansion Segment, as of Amendment 11, are presented in this synopsis. For a summary of 
prior study development see Section 2.3.2. 
During Cohort Expansion, flotetuzumab is dosed as a continuous infusion following a 
multi-step lead-in dose in Cycle 1 Week 1. With Amendment 11 all cycles of flotetuzumab, 
whether induction or consolidation, will be administered as a continuous infusion in 28 day 
cycles (see Figure 5).  
Starting with Cycle 2, patients who are benefiting from flotetuzumab treatment may 
continue to receive additional cycles of treatment with flotetuzumab, up to a maximum of 8 
cycles in total. Benefit will be defined as a response of CR, CRh, CRi (CRn, CRp), 
morphologic leukemia-free state (MLFS), and partial response (PR). Patients with evidence 
of PD at the end of Cycle 1 may receive one further cycle to establish evidence of response 
(treat one cycle beyond PD), if tolerated and at the discretion of the investigator, prior to 
determining treatment failure. 
Flotetuzumab dosing during the Cohort Expansion Segment consists of 2 treatment phases, 
“Induction” and “Consolidation” (see Figure 5). 
Induction is comprised of Week 1 multi-step lead-in dosing of 30, 60, 100, 200, 300, 400, 
and 500 ng/kg/day flotetuzumab for 24 hours each for Days 1 through 7, followed by 500 
ng/kg/day continuous IV infusion from Days 8 to 28 (Cycle 1). Patients who do not 
achieve a CR or CRh after the initial induction cycle (Cycle 1) may receive additional 
cycles (Cycles 2 – 6) of induction therapy. Further induction therapy consists of 
flotetuzumab at a dose of 500 ng/kg/day as a 7-day continuous IV infusion each week in 
each 28-day cycle, which does not include the lead-in dosing as in Cycle 1. Treatment may 
continue in 4-week cycles until: 
• attainment of a CR or CRh, 
• no evidence of anti-leukemic activity (PR or better, defined as 50% decrease in 
BM blasts or a decrease to between 5 and 25% blasts in the BM) after at least 2 
successive cycles, 
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• evidence of progressive disease after one subsequent cycle of flotetuzumab 
following disease progression at the end of Cycle 1 (one cycle beyond 
progression), 
• evidence of disease progression after achieving a response of PR, 
• transition to stem cell transplant, 
• the occurrence of DLT, 
• death, 
• exercise of Investigator discretion, or 
• withdrawal of consent by the patient. 
Consolidation: Patients who achieve a complete remission with complete or partial 
hematologic recovery (CR or CRh) after the induction cycle(s) may then receive up to 2 
cycles of consolidation treatment consisting of flotetuzumab at 500 ng/kg/day dosed as a 
7-day continuous IV infusion each week of a 28-day cycle. 
Based on the judgment of the investigator, patients who achieve a CRi may receive one 
additional cycle of induction (not to exceed a total of 6 induction cycles), and then be 
considered for transition to consolidation. 
At any point during induction or consolidation therapy a patient may transition to receive a 
stem cell transplant, if eligible per individual institution criteria. Patients who have 
completed treatment and are scheduled for a stem cell transplant may continue to receive 
flotetuzumab treatment until the time of the transplant. 
Treatment after Cycle 1 Day 8 (and after a minimum of 24 hours at the 500 ng/kg/day 
maximum dose) may take place in the outpatient setting based on the patient’s tolerance of 
therapy. 
Safety evaluations will also be conducted on an ongoing basis during the Cohort Expansion 
Segment of the study. Review by an Independent Data Monitoring Committee (IDMC, 
replacing the DSM previously involved in safety reviews), consisting of two physicians 
and one biostatistician, will be conducted in regular intervals. The interval analysis will 
utilize data from all cycles of treatment. If during the conduct of the interval cohort 
analysis, the Bayesian posterior probability is greater than 80% that the DLT event rate is 
more than 20%, enrollment will be paused and an ad hoc meeting of the IDMC will be held 
to consider dose reduction or study termination. The IDMC will also review aggregate 
efficacy data for two planned interim analyses to determine enrollment continuation 
according to futility and efficacy boundaries. 
DLT will be defined employing the National Cancer Institute Common Terminology 
Criteria for Adverse Events, Version 4.0 (CTCAE v4.0), except CRS which will be defined 
by the modified criteria proposed by Lee et al. (26) as described in Section 6.4.1.2. 
DLT is defined as: 
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• Grade 4 neutropenia lasting ≥ 42 days from start of cycle in absence of evidence 
of active AML (< 5% blasts). 
• Grade 3−5 nonhematologic toxicity not clearly resulting from the underlying 
disease and at least possibly related to protocol indicated treatment EXCEPT: 
o Grade 3 fatigue, asthenia, fever, anorexia, or constipation 
o Grade 3 nausea, vomiting or diarrhea not requiring tube feeding, total 
parenteral nutrition, or requiring or prolonging hospitalization, and 
resolve, with or without intervention, to  Grade 2 levels in < 7 days 
will not be considered DLT 
o Infection, bleeding, or other expected direct complication of cytopenias 
due to active underlying disease 
o Grade 3 or 4 tumor lysis syndrome (TLS) if it is successfully managed 
clinically and resolves within 7 days without end-organ damage 
o Grade 3 or 4 isolated biochemical laboratory abnormalities (i.e., those 
occurring without clinical consequence) that resolve, with or without 
intervention, to  Grade 2 levels in < 72 hours will not be considered 
DLT 
o Grade 3 rashes, myalgias or arthralgias that resolve within 96 hours and 
respond to medical intervention 
o Grade 3 infusion-related reaction or CRS that lasts < 72 hours and 
responds to medical intervention 
• For patients in the ruxolitinib cohort, an increase of ≥ 2 CTCAE v4.0 grades in 
either hemoglobin or platelet count in patients while on ruxolitinib will also be 
considered a DLT 
• Any treatment-related death 
Study Population: 
A total of 47 patients were enrolled in the completed Dose Escalation segments of the 
study. 
A total of approximately 283 patients will ultimately be enrolled in the Cohort Expansion 
segment, including: 
• approximately 271 patients treated with flotetuzumab at 500 ng/kg/day 
• up to 12 patients in an exploratory mini-cohort treated with flotetuzumab at 
500 ng/kg/day plus ruxolitinib 
Patient Population/Key Entry Criteria: 
The patient population to be enrolled will consist of adult patients with a confirmed 
diagnosis of primary or secondary AML that meet criteria for primary induction failure 
(PIF) or early relapse (ER) AML (see Inclusion Criterion 2). Patients must have an 
ECOG performance status  2, adequate hepatic and renal function, adequate organ reserve 
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sufficient to undergo therapy, recovery from toxicities of clinical consequence attributed to 
previous chemotherapy to CTCAE v4.0 Grade  1, and no serious concurrent illnesses that 
would increase the risk to the patient or confound the results of the study. 
Test Product, Dose, and Mode of Administration: 
Patients in Cohort Expansion will receive flotetuzumab as a multi-step-up lead-in dose in 
Week 1 Cycle 1. This comprises an initial dose of 30 ng/kg/day on Day 1, followed by 
doses of 60, 100, 200, 300, and 400 ng/kg/day on Days 2, 3, 4, 5, and 6, respectively. On 
Day 7, the final step up occurs to 500 ng/kg/day (defined as the MTD), given as a 
continuous infusion through Day 28 of Cycle 1. Throughout subsequent induction and 
consolidation cycles, dosing continues at 500 ng/kg/day as a 7-day continuous IV infusion 
each week of a 28-day cycle. Patients that have a dosing interruption > 72 hours will 
reinitiate dosing with a modified multi-step lead-in dose starting at 30 ng/kg/day (followed 
by steps up to 60, 100, 200, 300, 400, and 500 ng/kg/day) with dose changes every 4-6 
hours as tolerated. 
Duration of Treatment and Study Duration: 
Patients who benefit as described above in the Study Design Section may continue to 
receive treatment with flotetuzumab following Cycle 1 for a maximum of up to 8 cycles in 
total. 
The Single Patient Dose Escalation Segment of the study occurred over an 18-month 
period, and the Multi-patient Dose Escalation Segment of the study occurred over a 20-
month period. The Cohort Expansion Segment of the study is expected to occur over an 
approximately 5-year period. End of study will occur after the last patient has received the 
last dose of study drug and has been followed until disease progression, stem cell 
transplant, withdrawal of consent, or until death, whichever occurs first, and the data 
collection process is complete (time of study database lock). 
Total time for conduct of the trial is expected to be approximately 8 years. These estimates 
of timing for study conduct may vary from that observed in the actual conduct of the trial. 
Criteria for Evaluation 
Safety Assessments: 
• Safety is based on evaluation of AEs and serious adverse events (SAEs) from 
the time of study drug administration until either 28 days after last 
administration of study drug or until the start of a subsequent systemic 
anticancer therapy, if earlier. SAEs considered related to study drug may be 
reported at any time, even after the patient’s final visit. Additionally, protocol-
related AEs and SAEs are collected from the time the patient has consented to 
study participation. Progression of the underlying neoplasm resulting in 
hospitalization or death (e.g., patient hospitalized for or dies from disease 
progression only, without any other SAE) will be documented as an efficacy 
outcome of the study and not as an SAE. If an SAE occurs in a patient and it is 
unclear if the event is due to progressive disease, the SAE should be reported. 
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PK and Immunogenicity Assessments: 
• Pharmacokinetics: Serum concentrations of flotetuzumab will be monitored 
with frequent sampling during Cycle 1 and less frequent sampling thereafter for 
flotetuzumab using an electrochemiluminescence-based sandwich assay, and 
PK analyses will be performed using industry standard software. Population PK 
modeling will be performed, and an appropriate model and model parameters 
will be described. 
• Immunogenicity: Anti-drug antibody (ADA) production will be monitored 
using a bridging enzyme-linked immunosorbent assay (ELISA). The proportion 
of patients who become positive in this assay will be reported. 
Efficacy Assessments: 
• Response Assessments: Disease activity will be assessed by the study 
investigators, by using CBC and peripheral blood cell morphological 
examination, examination of bone marrow aspiration (or biopsy if required), 
and physical exam. Modifications to the Revised Recommendations of the 
International Working Group (IWG) for Diagnosis, Standardization of 
Response Criteria, Treatment Outcomes, and Reporting Standards for 
Therapeutic Trials in Acute Myeloid Leukemia will be used (Appendix 3). 
Response assessment will be based on bone marrow aspirate/biopsy and the 
best CBC up to 14 days post bone marrow aspirate/biopsy. Responses will be 
categorized as: 
o CR (mCR [morphologic CR], CRc [cytogenetic CR], or CRm 
[molecular CR]); 
o CRh (CR with partial hematologic recovery); 
o CRi (CR with incomplete blood count recovery): CRn (CR with 
incomplete neutrophil recovery) or CRp (CR with incomplete platelet 
recovery); 
o MLFS; 
o PR; 
o OB; 
o SD; 
o PD. 
Other Assessments: 
The following exploratory studies may be performed in all or a subset of patients: 
• CD123 expression on leukemic blasts in bone marrow and peripheral blood at 
baseline and over time 
• Flow cytometric analysis of bone marrow and peripheral blood cells to describe 
the status of the leukemia and monocytes, natural killer (NK) cells, 
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plasmacytoid dendritic cells (pDC), lymphocytes, and lymphocyte subsets and 
activation markers at baseline and over time 
• Minimal residual disease (MRD) 
• T-cell immune function (TCR repertoire, in vitro immune assessments) 
• Transcriptomic bone marrow tumor microenvironment immune contexture 
• Cytokine production at baseline and over time 
Analysis Populations: 
Three populations will be used for analysis, as defined below: 
• Efficacy population – All patients that have been enrolled under Protocol 
Amendment 11 or later and treated with flotetuzumab at the MTD of 500 
ng/kg/day as a continuous 7-day per week IV infusion during Cycle 1, have 
received any portion of one dose of flotetuzumab, and met the definition of 
PIF/ER AML based on inclusion criteria as revised in Amendment 11 (see 
Section 5.1). This population will be used for the primary analysis of efficacy 
endpoints. 
• Safety population – All patients who received any portion of any dose of 
flotetuzumab. AML and MDS will be analyzed as pooled and separate 
populations for safety and PK. The analysis of all safety endpoints will be based 
on the safety population. 
• Response evaluable population – All patients in the efficacy population that 
have a baseline bone marrow assessment, have at least one post-infusion 
assessment of their disease status or were removed from the study for reason of 
documented evidence of disease progression, death or treatment-related adverse 
event. This population will be used in the summary of response rate as a 
secondary analysis. 
Statistical Methods: 
Summary statistics will consist of absolute and relative frequencies of each category of 
discrete variables as well as of means, standard deviations, medians, minimum and 
maximum values of continuous variables. 
A three-stage design with two interim analyses will be employed to test the null hypothesis 
(H0) of CR/CRh rate = 14.7% against the alternative hypothesis (H1) of CR/CRh rate = 
23%. Demonstration of CR/CRh rate improvement (H1) by rejecting H0 at a 1-sided type I 
error of 0.025 with adequate power (80%) in a sequential design requires 170 patients. 
Specifically, the planned number of patients and the futility and efficacy boundaries at each 
stage are as follows: 
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a. First Interim analysis: The first interim analysis will be performed after 40 
patients have been enrolled and either have had their responses evaluated or were 
discontinued for any reason from study treatment prior to their first response 
assessments. This interim analysis is for futility only, that is, the study enrollment 
will continue if at least 5 (12.5%) out of 40 patients have response of CR/CRh. 
b. Second Interim analysis: If the enrollment continues after the first interim 
analysis, a second interim analysis will be performed after additional 60 patients 
have been enrolled (100 patients in total) and either have had their response 
evaluated or were discontinued for any reason from study treatment prior to their 
first response assessment. This interim analysis is for both futility and efficacy. 
Specifically, 
i. If the number of CR/CRh is less than 15 (15%) out of 100 patients, then 
the study is considered futile and enrollment will be stopped. 
ii. If the number of CR/CRh is 15 (15%) or greater out of 100 patients, then 
enrollment will continue. 
iii. If the number of CR/CRh is 25 (25%) or greater out of 100 patients, then 
H0 is rejected and the study is considered positive. The enrollment will still 
continue. 
c. Final Analysis: If enrollment continues after the second interim, then the final 
analysis will be performed after additional 70 patients have been enrolled (170 
patients in total) and either have had their response evaluated or were discontinued 
for any reason from study treatment prior to their first response assessments. If the 
number of CR/CRh is at least 35 (20.6%) out of the total of 170 patients, then H0 is 
rejected and the study is considered positive. 
The above design yields a 1-sided alpha of 0.005 for the efficacy boundary at the second 
interim analysis and an overall 1-sided alpha of 0.024 with approximately 80% power at 
the final analysis. The probability of early termination under H0 (futility) in the first two 
stages is 55%. 
The primary efficacy endpoint for the AML expansion cohort is the CR/CRh rate, 
calculated as the proportion of patients in the efficacy population that has achieved a best 
response of CR (mCR, CRc, or CRm) or CRh at any point during treatment by 
investigator’s assessment, according to IWG AML response criteria (Appendix 3). 
CR/CRh rate will be summarized for the total combined PIF/ER patients as the primary 
analysis, as well as for PIF and ER patients separately, and for PIF/ER patients in the 
response-evaluable population as a sensitivity analyses. A two-sided exact 95% confidence 
interval will be calculated around response rates. 
For the second interim analysis of 100 patients, as well as for the final analysis of 170 
patients, all treated patients will be followed for at least 6 months or until death from any 
cause, whichever occurs first, prior to data cutoff for the analysis. If the trial passes the pre-
specified efficacy boundary (25% observed CR/CRh rate) at the second interim analysis, a 
two-sided exact 95% confidence interval as described by Jennison and Turnbull (21) will 
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be produced to account for the bias in the conventional exact confidence interval for fixed 
sample test. 
The key secondary efficacy endpoints include CR rate, CRh rate, duration of response, 
post-baseline transfusion independence rate, hematopoietic stem cell transplantation 
(HSCT) rate, and incidence and duration of hospitalization. Additional secondary efficacy 
endpoints include overall complete response rate, objective response rate, subgroup 
analyses of CR/CRh, CR, CRh and overall complete response rates, overall survival, event-
free survival, time to response, mortality rate at 30, 60, 90, and 180 days, six-month and 
one-year survival. Counts, percentages, and two-sided exact 95% confidence intervals will 
be used to describe categorical secondary variables. Kaplan-Meier (KM) methods will be 
used to estimate time-to-event endpoints, unless otherwise specified. All secondary 
efficacy endpoints will be summarized in both efficacy and response evaluable population 
by PIF, ER, and total. 
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2 
BACKGROUND INFORMATION  
2.1 
Disease Background  
2.1.1 
Acute Myeloid Leukemia  
Acute myeloid leukemia (AML) is a heterogeneous group of diseases characterized by 
infiltration of the blood, bone marrow, and other tissues by neoplastic cells of hematopoietic 
origin (47). The disease occurs at a rate of 3.5 per 100,000 people per year in the United 
States (US). Incidence increases with age and the median age at onset is 67 years. Heredity, 
radiation, chemical and occupational exposures, and drugs (particularly chemotherapeutic 
agents) have been implicated in the etiology of AML. A number of chromosomal and 
molecular genetic abnormalities have been described in this disease and subclassification 
based on these abnormalities is now commonplace. Patients often present with nonspecific 
symptoms, particularly fatigue and/or unexplained fevers resulting from anemia, 
leukocytosis, leukopenia or leukocyte dysfunction, and/or thrombocytopenia. Initial physical 
findings may include splenomegaly, hepatomegaly, lymphadenopathy, sternal tenderness, 
bleeding or hemorrhage, and/or soft tissue infiltration. Diagnosis depends upon examination 
of peripheral blood elements or, more importantly, characterization of bone marrow 
cellularity and composition. Therapy for AML has changed little in the last 30 years. 
Standard induction therapy usually consists of the “7 + 3” regimen of cytarabine and 
daunorubicin. This is followed by consolidation therapy that may include hematopoietic stem 
cell transplantation (HSCT) in high-risk patients. However, outcomes from standard therapy 
are disappointing. Age limits aggressive treatment for many patients and older patients 
subjected to aggressive therapy have more resistant disease and a greater likelihood of early 
demise (1), and even in patients younger than 60 years, remission rates to standard induction 
therapy are only 65-75%. Half of those who do not reach complete remission experience a 
fatal complication related to bone marrow aplasia or impaired recovery of normal 
hematopoiesis and half have chemotherapy resistant disease. Even when patients enter 
complete remission, the occurrence of relapse is high. Salvage therapies, including stem cell 
transplantation, have limited impact, and most patients succumb to this disease in short order 
(5,25,46). New therapies are clearly needed. 
Acute myeloid leukemia is thought to arise in and be perpetuated by a small population of 
leukemic stem cells (LSCs) (4). These cells are generally dormant, resist apoptosis, and are 
relatively resistant to conventional chemotherapeutic agents (45). They are characterized 
phenotypically as CD34+, CD38-. The CD34+, CD38- population of AML cells has been 
examined for other cellular characteristics. These cells were found to express high levels of 
CD123, the alpha chain of the interleukin 3 receptor (IL-3R), while the CD34+, CD38- 
fraction of cells from normal bone marrow demonstrated no detectable expression of CD123 
(24). Based on these observations, it was suggested that targeting CD123 could be a 
promising strategy in the preferential ablation of AML cells. A monoclonal antibody (mAb) 
(7G3) targeting CD123 was shown to impair homing of AML-LSCs to bone marrow, reduce 
AML-LSC engraftment, and improve survival in a non-obese diabetic/severe combined 
immunodeficient (NOD/SCID) mouse model of human AML (22). However, in a Phase 1 
study in high-risk AML patients sponsored by CSL Limited in Australia, the anti-CD123 
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mAb, CSL360, exhibited little anti-leukemic activity (38). The antibody was administered 
with an acceptable safety profile, i.e., little on-target toxicity, at doses from 0.1 to 10 mg/kg. 
CD123 saturation and down-regulation were accomplished and ex-vivo proliferative 
responses to IL-3 were eliminated at doses of 3 mg/kg. The investigators in the Phase 1 study 
suggested that re-engineering the mAb to improve its ability to mediate antibody dependent 
cellular cytotoxicity (ADCC) could result in an efficacious anti-leukemic agent. Such an 
agent is in Phase 1 testing. Other investigators have described the development and use, in 
preclinical models, of CD123 chimeric antigen receptor (CAR) containing T cells. These 
CAR T cells exhibited leukemic blast cell killing in vitro and anti-leukemic activity in a 
xenogeneic model of disseminated AML (29). While CAR T cells have shown promise in the 
treatment of patients with advanced chemotherapy resistant chronic lymphocytic leukemia 
(34,41), acute lymphocytic leukemia (18,25), and mantle cell lymphoma (41), these 
approaches are labor intensive, require transfection of autologous lymphocytes, and have 
proven to have a difficult-to-manage safety profile. MacroGenics believes that DART® 
molecules like flotetuzumab, described below may provide the benefits of CAR T cell 
therapy without many of the problems associated with the CARs. 
2.1.2 
Myelodysplastic Syndromes  
Myelodysplastic syndromes (MDS) are a group of heterogeneous myeloid neoplasms 
characterized by ineffective hematopoiesis in one or more bone marrow lineages leading to 
abnormal proliferation and differentiation, with high risk of evolving into acute myeloid 
leukemia (39). The median age of diagnosis is 70 years old and there are an estimated 15,000 
new cases a year in the US and 25,000 new cases a year in Europe (28). 
Myelodysplastic syndromes are classified according to either the French-American-British 
(FAB) or newer World Health Organization (WHO) schemes with respect to morphological 
characteristics. Risk stratification is done using histopathological, chromosomal and clinical 
criteria. Using the International Prognostic Scoring System (IPSS) (16,17), one of three 
commonly used methods of risk stratification, patients are assigned either Low, Intermediate-
1, Intermediate-2 or High Risk, with markedly different median OS. Patients with 
Intermediate-2 or High risk have median survivals of 1.2 and 0.4 years, respectively. In 
addition, the likelihood of evolution to frank AML increases with higher risk categorization. 
National Comprehensive Cancer Network guidelines (32) for patients with Intermediate-2 or 
High risk MDS stratify patients by the suitability for stem cell transplant, this being the only 
available curative therapy. Patients who are not eligible for transplant are usually treated with 
a demethylating agent, but will relapse and overall have a poor outcome with a median OS of 
less than 6 months (35). The need for additional therapies is acute. 
Expression of CD123 on stem cells in MDS has not been as extensively studied as in AML. 
Preliminary data with small patient numbers suggest that about 50% of samples assayed 
express CD123 on CD34+CD38- cells (48) and the proportion of CD123+ cells may increase 
with worsening disease (50). Together, these data suggest that CD123 is a reasonable target 
for a T-cell based targeted immunotherapy such as flotetuzumab. 
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2.2 
Flotetuzumab Background  
The DART technology is a novel, bispecific antibody platform designed to eradicate AML (or 
other tumor) cells through co-engagement of a leukemia- or tumor-specific cell surface 
marker (e.g., CD123) and the T-cell receptor (TCR)/CD3 complex on T cells as effector cells 
(23,31). Cell-association studies indicated that the DART protein architecture is well suited 
for maintaining cell-to-cell contact, apparently contributing to the high level of target cell 
killing. CD19 x TCR and CD19 x CD3 DART proteins have demonstrated in vitro killing of 
B-cell lymphomas by human T cells or peripheral blood mononuclear cells (PBMCs) (23) 
that exceeds the killing associated with a similar bispecific antibody construct, BiTE (2,31). 
The CD19 x TCR DART protein has also been used in in vivo tumor models and has 
demonstrated inhibition of B-cell lymphoma in NOD/SCID mice when co-administered with 
human PBMCs (31). 
Flotetuzumab, also known as MGD006 and S80880, is a novel CD123 x CD3 DART protein 
developed by MacroGenics, Inc. Flotetuzumab is designed to target CD123-positive cells 
(including AML cells) for recognition and elimination by CD3-expressing T lymphocytes as 
effector cells (7,23,31). 
In nonclinical studies, the ability of flotetuzumab to mediate redirected T cell killing was 
demonstrated across multiple CD123-expressing target tumor cell lines in vitro with efficacy 
generally correlating with the level of CD123 cell surface expression. Data from multiple 
experiments with T cells from different human donors have indicated that flotetuzumab-
mediated redirected cell killing is potent. Flotetuzumab-mediated redirected killing was 
associated with a concomitant dose-dependent activation of T cells evidenced by 
upregulation of the activation markers CD25 and CD69 on CD4 and CD8 T cells. Dose-
dependent upregulation of granzyme B and perforin levels in both CD8 and CD4 T cells also 
was observed. Upregulation of granzyme B and perforin was almost two-fold higher in CD8 
T cells compared with CD4 T cells, suggesting that flotetuzumab-mediated target cell killing 
may be preferentially mediated through the granzyme B and perforin pathway by CD8+ T 
cells. Similarly, treatment of normal PBMC from healthy donors in vitro with flotetuzumab 
resulted in depletion of the CD123 expressing cells [i.e., plasmacytoid dendritic cells (pDCs) 
and monocytes in healthy PBMC] that was accompanied by a concomitant T cell activation 
markers (CD25 and CD69), upregulation of granzyme B and perforin, and secretion of 
cytokines. 
In AML patient primary PBMC samples with very low E:T ratio (~1:300), flotetuzumab 
treatment resulted in near complete depletion of blast cells with concomitant expansion of 
residual CD8+ and CD4+ T cells. Expanded T cells exhibited greater Ki67 and CD25 
expression suggesting T cell activation and proliferation. Additional evaluations performed to 
elucidate mechanism showed that expression of granzyme B and perforin was elevated in 
CD8+ T cells following flotetuzumab treatment, while a more modest elevation was observed 
on CD4+ T cells. Secretion of cytokines, predominantly interferon gamma (IFN-γ) and IL-6, 
were also observed following treatment with flotetuzumab (Figure 1). Additional in vitro 
data demonstrated productive T cell activation and re-directed killing by flotetuzumab is 
dependent upon co-engagement of both the T cell and the CD123-expressing target cell. 
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Figure 1 
Flotetuzumab Activity in AML Patient PBMCs  
CD25
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PBS
4420 hXR32 0.01ng/mL
4420 hXR32 0.1ng/mL
MGD006 0.01ng/mL
MGD006 0.1ng/mL
0
1000
2000
3000
CD4+
CD8+
MFI
CD45+CD33+
PBS
4420 hXR32 0.01ng/mL
4420 hXR32 0.1ng/mL
MGD006 0.01ng/mL
MGD006 0.1ng/mL
0
10000
20000
30000
Absolute Cell  Number
CD4+
PBS
4420 hXR32 0.01ng/mL
4420 hXR32 0.1ng/mL
MGD006 0.01ng/mL
MGD006 0.1ng/mL
0
5000
10000
15000
Absolute Cell  Number
CD8+
PBS
4420 hXR32 0.01ng/mL
4420 hXR32 0.1ng/mL
MGD006 0.01ng/mL
MGD006 0.1ng/mL
0
5000
10000
15000
20000
25000
Absolute Cell  Number
Cytokines at 144 h
PBS
4420 hXR32 0.01ng/mL
4420 hXR32 0.1ng/mL
MGD006 0.01ng/mL
MGD006 0.1ng/mL
0
20
40
60
80
200
400
600
800
1000
TNF-a
IFN-g
IL-10
IL-6
IL-4
IL-2
pg/mL
 
AML patient primary PBMCs were treated with flotetuzumab (MGD006), phosphate-buffered saline, or 
a control DART protein with an irrelevant anti-fluorescein arm and the same anti-CD3 arm as in 
flotetuzumab (4420-hXR32) for 144 hours. Absolute numbers of leukemic blast cells (CD45+/CD33+) and 
T cells (top panel) and mean fluorescence intensity of granzyme B, perforin, Ki67 (middle row), and 
CD25 (bottom left), cytokines measured in the culture supernatants after indicated treatments (bottom 
right) are shown. 
Flotetuzumab also showed potent anti-tumor activity against human tumor cell lines 
implanted in mice. Flotetuzumab administered intravenously (IV) to NOD/SCID mice 
implanted with RS4:11 acute lymphoblastic leukemia (ALL) or MOLM-13 AML leukemia 
cells in the presence of human T lymphocytes resulted in dose-dependent inhibition of tumor 
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growth. The different dose sensitivity correlated with the relative level of CD123 expression, 
which was low on RS4:11 cells and intermediate on MOLM-13 cells (see Figure 2). 
Figure 2 
Inhibition of Tumor Growth by Flotetuzumab in NOD/SCID Mice 
Implanted with Human AML Tumor Cells (RS4:11 and 
MOLM-13)  
 
0
5
10
15
20
0
500
1000
1500
2000
Vehicle (MOLM-13)
MGD006 (0.020 mg/kg)
MGD006 (0.004 mg/kg)
MGD006 (0.0008 mg/kg)
Study Day
Tumor Volume (mm3)
 
Female NOD/SCID mice (n = 8/group) were implanted subcutaneous (SC) with 1 x 106 human T cells + 5 
x 106 RS4:11 tumor cells on Day 0 followed by treatment with vehicle control, negative control DART 
protein or flotetuzumab (MGD006) on Days 0-3 (indicated by arrows on the x-axis) for a total of 4 doses 
administered IV. The negative control DART protein (4420-hXR32) has an irrelevant anti-fluorescein 
binding arm and the same anti-CD3 arm as in flotetuzumab. RS4:11 tumor volume was measured daily 
through Day 12 and MOLM-13 tumor volume was measured on Days 8, 11, 15, and 18 (mean ± SEM is 
shown). Results of the two-way ANOVA test showed that treatment with flotetuzumab significantly 
inhibited tumor growth (p < 0.0001). 
Production of cytokines from T cells stimulated through their CD3 receptor is an anticipated 
side effect of this molecule. In the toxicology studies, cytokine release was predominantly a 
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first-dose effect that was mitigated by using a within-subject dose escalation strategy such 
that flotetuzumab was administered at an initial low dose and escalated stepwise on a weekly 
basis. A series of pilot toxicology studies were performed in which small groups of 
1-4 animals were treated with doses of flotetuzumab ranging from 0.1 ng/kg/day to 5 
µg/kg/day as either continuous 4-day on/3-day off infusions, or back-to-back, continuous 7-
day infusions. In these studies, a starting dose of 5 µg/kg/day, the highest starting dose tested, 
was associated with severe acute cytokine release causing pallor, weakness, and depressed 
body temperature eventually leading to the death or unscheduled termination of the animals. 
A dose of 5 µg/kg/day, however, could be reached without cytokine storm through stepwise 
within-subject dose escalation. The pilot toxicology studies established the highest safe 
starting dose (100 ng/kg/day) and weekly escalation intervals (up to 1000 ng/kg/day in 
3 steps) with manageable cytokine release. 
The information gained from these studies led to the design of a Good Laboratory Practice 
(GLP) toxicology study, in which groups of 8 animals (4 male/4 female monkeys) were 
treated for 4 weeks with vehicle or flotetuzumab at doses of 100, 300, 600, or 1000 ng/kg/day 
using within group dose-escalation such that all flotetuzumab-treated groups received an 
initial dose of 100 ng/kg/day but the maximum dose in a group was escalated stepwise to 
300, 600 or 1000 ng/kg/day. The GLP toxicology study included evaluation of both the 4-day 
on, 3-day off infusion schedule as well as the continuous 7-day infusion. At the dose regimen 
implemented in the GLP toxicology study, production of measured cytokines IFN-γ, TNF-α, 
IL-2, IL-4, IL-5 or IL-6 was generally not seen or minimal; most often IL-6, most commonly 
on the first dose, and rarely exceeding 100 pg/mL, returning to baseline levels prior to the 
subsequent dose (by 72 hours post start of infusion in the GLP toxicology study). 
Anemia and thrombocytopenia appeared to be proportional to total exposure and was 
observed later during the dosing cycle. At the highest flotetuzumab exposure achieved in the 
GLP toxicology study (continuous 7-day infusion starting at 100 ng/kg/day and escalated 
weekly stepwise to 300, 600 or 1000 ng/kg/day without interruption), the degree of 
hematological toxicity observed was tolerable in this species without supporting measures 
(e.g., blood or platelet transfusions). The observed toxicity appeared reversible during the 
4-week recovery period allowed in the study. 
A dose-dependent, decrease in red cell mass parameters [mean hemoglobin (Hgb), hematocrit 
(Hct), and red blood cells (RBC)] was observed following administration of flotetuzumab at 
the 100 ng/kg/day or higher dose levels. As shown in the GLP study, the decrease persisted 
throughout the dosing phase and its magnitude increased with each escalating dose, except 
where the uniform presence of ADA in a group of animals may have mitigated the effect of 
flotetuzumab. The effect was generally modest, with the mean hemoglobin at nadir across the 
flotetuzumab-treated groups ranging from 9.6 to 11.6 g/dL. Two animals in had adverse drops 
in hemoglobin (below 7 g/dL) at dose levels ≥ 600 ng/kg/day. The effect on red cell mass was 
reversible, with parameters recovering in affected animals following cessation of dosing. The 
erythropoietic reticulocyte response appeared to function at all dose levels of flotetuzumab 
evaluated as a 4-day-on/3-day-off infusion, as reticulocytes increased with respect to both 
vehicle-treated control animals or compared to prestudy values. The reticulocyte response in 
animals with the greatest exposure to flotetuzumab (e.g., 7-day continuous infusion in Group 
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6 in the GLP study) was lower and not commensurate with the observed drops in red cell 
parameters. 
Substantive platelet count variations were observed across all studies; generally, however, 
platelet levels remained higher than baseline levels and within the expected ranges for 
cynomolgus monkeys throughout the treatment period in animals that received flotetuzumab 
on a 4-day-on/3-day-off schedule (doses up to 1000 ng/kg/day). Some animals in the GLP 
study that received flotetuzumab as 7-day, escalating-dose infusions to up to 1000 ng/kg/day 
showed mild reversible, dose-dependent thrombocytopenia (lowest individual value 
69,000/mm3), although the group average never dropped below 200,000/mm3. There was no 
evidence of petechiae or suffusions for any treated monkeys at any time during the course of 
the studies. 
CD123 is not expressed (or expressed at very low level) by normal hematopoietic stem cells 
(HSCs); however, expression, albeit at low levels, occurs on committed hematopoietic 
precursors, such as common myeloid precursors (CMPs). The anemia observed following 
treatment with flotetuzumab at the doses and regimen employed in the GLP study is best 
explained by the cumulative effects of blood sampling and the flotetuzumab-mediated 
cytotoxic activity against hematopoietic precursors. Flow cytometric analysis of bone marrow 
samples from flotetuzumab-treated animals demonstrated a decrease in the frequency of 
CD123+ cells among the Lineage-negative immature bone marrow cells (~ 20% reduction to 
a near complete depletion in individual flotetuzumab-treated animals and mean group 
reductions of 64-80% in Groups 2-6), an effect that was reversible following cessation of 
treatment. This effect did not translate into morphological or myeloid/erythroid (M/E) ratio 
changes in bone marrow smears during the time frame of these studies, probably because the 
population of CD123-positive precursors is small. The blunted reticulocyte response 
observed in animals subjected to the greatest flotetuzumab exposure suggests a cytotoxic 
activity on a precursor (e.g., CMP) from which reticulocytes originate. 
In all these studies, there was consistent evidence of the pharmacodynamic activity of 
flotetuzumab demonstrated by the full depletion of CD123-expressing pDCs at doses as low 
as 10 ng/kg/d; importantly, this effect was also reversible as pDCs were observed in 
peripheral blood a few weeks following cessation of dosing. 
In active treatment groups (Groups 2-6), 28 out of 40 monkeys treated with flotetuzumab 
(Groups 2-6) developed anti-drug antibodies (ADA) against flotetuzumab by Day 22 (n = 16) 
or Day 29 (n = 12). The range of ADA titers was broad and the impact on flotetuzumab 
variable across individual animals. All animals were exposed to flotetuzumab through at least 
Study Day 19 (i.e., through at least 2 infusion cycles) and 24 of 40 animals were exposed to 
flotetuzumab during all four infusion cycles (including 12 ADA-positive animals). Moreover, 
pharmacodynamic activity was detectable even in the presence of ADA in some animals. The 
presence of ADA can also interfere with the detection of flotetuzumab in the PK assay, 
resulting in falsely low or undetectable flotetuzumab levels. Assessment of the specificity of 
the ADA in these animals indicated that ADA reactivity is predominantly directed to the 
humanized Fv sequences of flotetuzumab as opposed to other sequences (i.e., the linker 
sequence) in the DART molecule. Most ADA-positive animals (19/24, 79%) showed no or 
minimal reactivity to the linker sequences; of the 5 remaining animals, the reactivity to the 
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linker sequences was several-fold lower than the reactivity to the humanized Fv sequences. 
Consistent with its reactivity against the antibody paratopes, presence of ADA was not 
associated with exaggerated pharmacology, adverse clinical observations, increased cytokine 
release, or other safety signal. Immunogenic responses to human therapeutic proteins in 
cynomolgus monkeys do not predict immunogenicity in humans; in whom the antibody 
sequences would not be foreign. Therefore, these data suggest immunogenicity may be 
anticipated to be much less prevalent in humans. 
In conclusion, flotetuzumab shows potent activity to redirect T cell killing against CD123-
expressing cell lines and primary AML blasts in vitro. Flotetuzumab also demonstrated 
inhibition of growth of leukemic cell lines in mice and depletion of the CD123-positive pDC 
cells in the repeat-dose toxicology studies. The data from the nonclinical studies provide 
strong scientific rationale that an evaluation of the safety and potential activity of the CD123 
x CD3 DART protein, flotetuzumab, in patients with AML whose disease is not expected to 
benefit from additional cytotoxic chemotherapy (as specified below), is warranted. 
The trial will be conducted in accordance with this protocol, International Conference on 
Harmonization Guideline on Good Clinical Practice (ICH E6), and applicable regulatory 
requirements. 
2.3 
Rationale for Study  
2.3.1 
First-in-Human Dose Selection  
Because the target of one arm of the flotetuzumab CD123 x CD3 DART protein is a 
component of the T cell antigen receptor/CD3 complex with the potential to promote T cell 
activation and potentially clinically significant cytokine production, careful consideration 
was given to the determination of the first-in-human (FIH) dose for this molecule. 
In an exploratory, non-GLP repeat-dose toxicology study in cynomolgus monkeys, significant 
cytokine production was observed only at the highest studied dose (5 µg/kg/day). This dose 
produced cytokine-related moribundity and mortality in the small number of animals 
employed in the study. Although the cynomolgus monkey is considered a relevant 
toxicological species on the basis of similar CD3 and CD123 antigen expression to which 
flotetuzumab binds with similar high affinities as it does the human antigens, it was 
considered prudent to also perform in vitro studies with human PBMCs, to ensure the 
potential of flotetuzumab to induce cytokine production from human cells was thoroughly 
evaluated prior to dosing in humans. 
The determination of the starting dose for this study was based not only on the selection of a 
dose that is at least 10-fold less than the no observable adverse effect level (NOAEL) (which 
was determined to be 300 ng/kg/day in cynomolgus monkeys) from the toxicology studies, 
but also based on consideration of the minimal anticipated biological effect level (MABEL) 
of flotetuzumab. 
The ability of normal human PBMCs to produce cytokines when placed in culture alone or 
with target cells expressing high density of CD123 in the presence of flotetuzumab was 
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examined experimentally. In vitro cytokine release assays were performed under two 
conditions: the initial set of experiments examined flotetuzumab-mediated cytokine release 
from human PBMCs from healthy donors. The number of PBMCs utilized in these 
experiments (200,000 cells/200 µL) was selected to represent the approximate density of 
cells in peripheral blood (about 1 x 106/mL), and the range of concentrations of flotetuzumab 
was selected to be representative of the steady state concentration level that would be 
predicted to exist in human serum after treatment with flotetuzumab at the planned dose 
range. A second set of experiments, shown in Figure 3 below, was then performed using 
normal human PBMCs mixed with an equal number of Kasumi-3 target cells, an AML cell 
line with high CD123 surface expression. The PBMC + Kasumi-3 experiments utilized an 
excess of leukemic blasts (represented by Kasumi-3 cells) in combination with a physiologic 
number of normal T cells. This scenario simulates the situation that could be encountered in 
the AML patient in whom the presence of frequent target cells expressing a high antigen 
density is combined with a normal number of fully functional circulating T cells – 
presumably a “worst-case scenario” for cytokine production (highest likelihood of cytokine 
induction). In these experiments, IFN-γ, IL-2, TNF-α, and IL-6 were the most prominent 
cytokines produced (maximum plateau level of cytokine released, Emax) upon treatment of 
normal human donor PBMCs alone with flotetuzumab. Production of IL-10 and IL-4 was 
more modest. The addition of Kasumi-3 target cells to the PBMCs enhanced the production 
(Emax) of all cytokines tested, except for IL-4. Under these conditions, the enhancement of IL-
2 and IFN-γ production was more pronounced compared to that of TNF-α, IL-6, and IL-10. 
Flotetuzumab EC50 and EC10 values were generally similar under both conditions tested for 
all cytokines evaluated. 
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Figure 3 
Flotetuzumab-Mediated Cytokine Induction in Normal Human 
Donor PBMCs Co-cultured with Kasumi-3 Cells  
 
Dose-response curves for IFN-γ (top left), IL-2 (top middle), TNF-α (top right), IL-6 (bottom left), IL-10 
(bottom middle), and IL-4 (bottom right) measured in the culture supernatants of normal human donor 
PBMCs mixed with Kasumi-3 cells (n=6) following incubation with flotetuzumab (MGD006) for 24 hours. 
Pooled data from 6 independent donors were curve fitted to a sigmoidal, 4-parameter dose response 
function, except for IL-6 that was fitted to a 3-parameter sigmoidal dose-response function (GraphPad 
Prism 5 software). Solid red lines represent the fitted curve; dotted red lines show the 95% confidence 
interval. For each cytokine, Emax, EC50, and EC10 are reported as means and 95% confidence intervals 
(insets). Note different y-axis scales. 
Both estimates place the dose resulting in 10% of the maximum effect (EC10) for the most 
robust production of any cytokine at 14-18 pg/mL. Using a very conservative approach, 
taking the lower 95% confidence bound of the EC10, a projected MABEL was estimated at 
3 to 4 pg/mL. Allometric scaling from the non-GLP and GLP toxicology studies led to 
estimates of Cmax in humans of 0.9-1.8 pg/mL for a 3 ng/kg/day dose of flotetuzumab (see 
Figure 4). Thus, with respect to cytokine production, the use of a dose of 3 ng/kg/day in 
humans would represent an approximate 2- to 3-fold safety factor from the MABEL. 
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Figure 4 
Projected Serum Concentration-time Profile of Flotetuzumab in 
Humans at a Dose of 3 ng/kg/day for 4 days Scaled from Monkey 
PK Parameters Obtained in Studies 4605 and Study 2158  
 
Two other estimates of the MABEL derived from in vitro redirected target cell killing assays 
and in vivo observations in cynomolgus monkeys treated with flotetuzumab yielded results 
similar to the MABEL estimate for cytokine production. First, in vitro redirected target cell 
killing assays yielded an estimate of an EC10 of 1 pg/mL, but this estimate of the MABEL 
resulted only with target cells expressing high density of CD123 (Kasumi-3) and T cells with 
a highly artificial, non-physiologic, effector target ratio of 10:1. Use of targets with lower 
CD123 density or more physiologic E:T ratios of 5:1 or 1:1 (which still represent high E:T 
ratios relative to the situation in the disease target) yielded EC10 values approximately 10 to 
100 times greater than obtained with the 10:1 E:T ratio. Thus, the 1 pg/mL MABEL estimate 
based on redirected killing assays with a 10:1 E:T ratio is considered unrealistically 
conservative. Second, treatment of cynomolgus monkeys with flotetuzumab, resulted in 
depletion of peripheral CD123+ cells at a dose of 3 ng/kg/day (at an estimated, not measured, 
Cmax of 0.43 – 0.84 pg/mL). However, in these in vivo experiments, CD123+ cell depletion 
would have been accomplished at an E:T ratio of 100:1 (assuming 6 CD123+ cells/L and 
600 T cells/L). Reduction of CD123+ cells is a surrogate for a positive, rather than negative, 
effect in the patient. 
Therefore, given the severity and lethality of the underlying disease being studied in the FIH 
trial and wishing to treat a minimal number of patients with potentially ineffective doses of 
flotetuzumab, we conservatively propose to use a starting dose of 3 ng/kg/day in the Single 
Patient Dose Escalation Segment of the study. The dose of 3 ng/kg/day in humans has a 
predicted serum Cmax of 0.9-1.8 pg/mL based on allometric scaling (see again Figure 4) 
which is 2 to 4-fold less that the estimated MABEL concentration of 3 to 4 pg/mL based on 
flotetuzumab-mediated cytokine release in PBMCs, the major anticipated safety concern in 
humans. 
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2.3.2 
Rationale for Overall Study Design and Summary of Prior 
Study Development  
This study is designed in three segments: the Single Patient Dose Escalation Segment 
(completed), followed by the Multi-patient Dose Escalation Segment (completed) and the 
Maximum Tolerated Dose and Schedule (MTDS) Expansion Cohort segment (ongoing). In 
all segments of the study, flotetuzumab is administered using a series of continuous IV 
infusions administered on a weekly basis. Continuous infusion was chosen as the mode of 
administration for flotetuzumab because of its short half-life and the relative safety provided 
by the ability to reduce, interrupt or terminate the infusion with rapid elimination of serum 
concentrations in the event that cytokine-related adverse events (AEs) are encountered in the 
clinic, and experience of other experimental drugs in the class (2). A 4 days on/3 days off 
schedule was initially chosen over the 7-day-on schedule because it is the schedule with 
which the Sponsor has the most nonclinical experience, the schedule with the more limited 
apparent acute phase reaction, and the schedule which produced less severe and less 
prolonged anemia in the GLP toxicology study. Both the 4 days on/3 days off and the 
continuous 7-day infusion schedule are supported by pre-clinical toxicology data. 
The primary objective of the dose escalation segments was: 
• To characterize the dose-limiting toxicities (DLTs), and determine the 
maximum tolerated dose and schedule (MTDS) for the administration of 
flotetuzumab when given by continuous intravenous (IV) infusion for seven 
days in the first week, followed by infusion either for 4 days on/3 days off or 7 
days continuously during the first of sequential 4-week cycles in patients with 
relapsed or refractory AML or intermediate-2/high risk MDS. 
Secondary objectives of the dose escalation segments were: 
• To describe, in preliminary fashion, the safety profile of flotetuzumab when 
administered by continuous IV infusion in 4-week cycles over a broad dose 
range. 
• To characterize the pharmacokinetics (PK) and immunogenicity of 
flotetuzumab when given by continuous IV infusion over a broad dose range. 
• To describe any evidence of anti-neoplastic activity in AML and MDS. 
• To evaluate early mortality rates from any cause and overall survival. 
The primary objective of the study going forward is to assess anti-neoplastic activity of 
flotetuzumab in AML, as determined by the proportion of patients who achieve CR/CRh (see 
Section 3 for a full list of current objectives). 
A summary of prior study development is provided in Sections 2.3.2.1 to 2.3.2.3 below. 
2.3.2.1 
Single Patient Dose Escalation Segment (Completed)  
In the initial Single Patient Dose Escalation Segment, four 1-patient mini-cohorts 
(constituting, in aggregate, Cohort 0) were used to examine the effects of one 4-week cycle of 
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very low doses of flotetuzumab, at doses of 3, 10, 30 and 100 ng/kg/day, administered on a 4 
days on/3 days off schedule. This initial phase of the study was implemented to cautiously 
establish an acceptable starting dose for the second segment of the study, in view of the 
potential for systemic cytokine production with this T-cell activating molecule. 
Each mini-cohort consisted of one patient unless that patient experienced a  Grade 2 AE not 
clearly related to the underlying disease or  Grade 3 infusion-related reaction (IRR, 
including cytokine release syndrome [CRS]) in the first 28 days of treatment. The appearance 
and severity of IRRs has been greatly reduced with the introduction of steroid medication 
prior to flotetuzumab administration (Section 6.4.1.1); Grade 2 IRRs should be considered an 
acceptable toxicity in the context of flotetuzumab administration in this patient population. 
Any other AE  Grade 2, or  Grade 3 IRR or CRS necessitated expansion of the dose level 
with enrollment of an additional 3 patients at the same dose level. Use of the next dosing 
level occurred only if < 2 patients in the resulting 4-patient cohort experienced a DLT and all 
patients on that dosing sequence had completed the first 21 days of treatment (i.e., received at 
least 75% of planned dosing). Transition to the Multi-patient Dose Escalation Segment of the 
study was based on review of the aggregate safety data on all patients participating in 
Cohort 0. 
2.3.2.2 
Multi-Patient Dose Escalation Segment and Determination of 
MTDS (Completed)  
The Multi-patient Dose Escalation Segment employed a classical 3 + 3 dose escalation study 
design including cohorts of patients with either AML or MDS. Prior to Amendment 5, all 
patients in this segment were to be treated with 100 ng/kg/day for 4 days on/3 days off in 
Week 1, followed by a step-up dose (to 300, 500, 700, 900, or 1000 ng/kg/day in Cohorts 1, 
2, 3, 4, and 5, respectively) for 4 days on/3 days off in Week 2 and beyond. This step-up 
dosing followed the GLP toxicology study in which intra-monkey dose escalation appeared to 
enhance tolerability of flotetuzumab, apparently through reduction in cytokine release. 
Starting with Amendment 5, two modifications to the dosing scheme were made. The first 
was to include an additional step-up dose (two-step lead-in dose: 30 ng/kg/day for 3 days 
followed by 100 ng/kg/day for 4 days) during the first week of dosing to minimize the extent 
of IRR/CRS (cytokine release syndrome). The second was to evaluate, in parallel, a 7-day 
continuous infusion schedule in Weeks 2-4 during Cycle 1, to ameliorate IRR/CRS and AML 
circulating blast rebound noted with intermittent (4 days on/3 days off) dosing. The patients 
on the continuous infusion schedule were to receive the two-step lead-dose in Week 1, 
followed by 300, 500, 700, 900, and 1000 ng/kg/day in Cohorts 6, 7, 8, 9, and 10, 
respectively, in Week 2 and beyond. 
The introduction of the two-step lead-in dose during Week 1 of Cycle 1 was justified by both 
the pre-clinical toxicology studies and the data observed during the evaluation of Cohort 0 
and Cohorts 1 and 2 in the Multi-patient Dose Escalation segment. Nine of 10 of these 
patients treated with 100 ng/kg/day in the first week had Grade 1-3 IRR/CRS. Patients who 
went on to receive higher doses (300 ng/kg/day in Cohort 1 and 500 ng/kg/day in Cohort 2) 
still experienced IRR/CRS upon reintroduction of flotetuzumab in Week 2, but the severity 
was consistently the same or less than in week one despite the increase in dose. To fully 
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evaluate the effect of the two-step lead-in dose on the incidence and severity of IRR/CRS in 
Weeks 1 and 2, the Cohort 2 dose level (500 ng/kg/day in Weeks 2 and beyond) was re-
evaluated using the two-step lead-in approach. 
Evaluation of treatment by 7-day continuous infusion commenced at the 300 ng/kg/day dose 
level as this dose level was determined to be safe during dose escalation under Amendment 4 
and was predicted to have approximately the same exposure and total dose administered as in 
Cohort 2 (500 ng/kg/day 4 days on/3 days off starting in Week 2), which had demonstrated 
acceptable tolerability. This was done in parallel with determination of the maximum 
tolerated dose (MTD) in the 4 days on/3 days off schedule. Dose escalation in the two 
schedules proceeded independently, although data from all treated patients was used for dose 
escalation decision making. With continuous 7-day infusion, the total dose administered was 
higher at any given dose level (Table 1). This correlates with the observed toxicity to date, 
IRR/CRS, which had been related to Cmax (initially occurring within the first 24 hours) and 
not to total exposure. 
Table 1 
Planned Total Dose Administered in Cycle 1  
Schedule 
Dose Levels: Weeks 1/Weeks 2-4 
Cohort 1 or 6 
30 1-100/300 
Cohort 2 or 7 
30 1-100/500 
Cohort 3 or 8 
30-100/700 
Cohort 4 or 9 
30-100/900 
Cohort 5 or 10 
30-100/1000 
Cohorts 1-10  
(total dose Week 1) 
Cohort 1: 400 ng 1 
Cohort 6: 490 ng 
Cohort 2: 400 
and 490 ng 1 
Cohort 7: 490 ng 
490 ng 
490 ng 
490 ng 
Cohorts 1-5  
(total dose Weeks 2-4):  
4 days on/3 days off  
3600 ng 
6000 ng 
8400 ng 
10800 ng 
12000 ng 
Cohorts 6-10  
(total dose Weeks 2-4): 
7-Day infusion 
6300 ng 
10500 ng 
14700 ng 
18900 ng 
21000 ng 
At the 300 ng/kg/day level (Cohort 1), no 30 ng/kg/day lead-in dose was studied for the 4 days on/ 3 days off 
schedule; at the 500 ng/kg/day level for the 4 days on/3 days off schedule (Cohort 2), Week 1 was studied ± 
the 30 ng/kg/day lead-in dose. 
 
As of 28 July 2017, by agreement of the Sponsor’s Medical Monitor, the Sponsor’s 
Pharmacovigilance Physician, the independent Data Safety Monitor (DSM), and participating 
Investigators, the MTD in this study has been established as 500 ng/kg/day across both 
dosing schedules. The 7-day on schedule was selected to open the Cohort Expansion phase of 
the study, because it was tolerated and potentially offers better anti-leukemic activity. The 
recommended MTDS was therefore defined as initial two-step lead-in dose on Week 1 
followed by 500 ng/kg/day administered by continuous intravenous infusion. 
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2.3.2.3 
Cohort Expansion Segment (Ongoing)  
Dosing Modifications 
Implementation of the two-step lead-in dose with Amendment 5 decreased IRR/CRS severity 
compared to the single-step lead-in dose (20). However, data from a cynomolgus monkey 
toxicology study revealed that large step-up dose intervals were less well-tolerated than 
smaller increments (data presented in the flotetuzumab Investigator’s Brochure). Hence, as 
of Amendment 8, the lead-in dose was modified from a two-step lead-in dose to a multi-step 
lead-in dose, comprised of sequential smaller and more frequent dose increments (30 to 60 to 
100 to 200 to 300 to 400 to 500 every 24 hours) until reaching the MTD of 500 ng/kg/day. 
Although more involved, it was anticipated that this more conservative approach to 
intrapatient dose escalation may further attenuate IRR/CRS. 
Prior to Amendment 9, all patients eligible to receive flotetuzumab beyond Cycle 1 received 
drug on a 4 days on/3 days off schedule in Cycle 2 and beyond. With Amendment 9, dosing 
was modified to specify 2 treatment phases, “Induction” (up to six 28-day cycles of 
continuous IV infusion [with multi-step lead-in dosing during Week 1 of Cycle 1] until 
response criteria were met), followed by “Consolidation” (up to two 28-day cycles of 4 days 
on/3 days off each week). With Amendment 11 all cycles of flotetuzumab, whether induction 
or consolidation, will be administered as a continuous infusion in 28 day cycles (see Figure 5 
and Section 4.1). 
In summary, flotetuzumab is dosed as a continuous infusion based on data from the current 
trial, and centered around two basic premises. Firstly, in some patients that have not achieved 
full remission and are treated on intermittent dosing, rebound of peripheral blood AML blasts 
during the period off flotetuzumab has been observed; secondly, elimination of on-off 
interruptions in treatment with flotetuzumab may help further limit IRR/CRS. 
Selection of Target Patient Population 
Both relapsed or refractory AML and Intermediate-2/High Risk MDS patients in whom 
methylating agents have failed were evaluated in the initial phases of the study. CD123 is 
expressed on stem cells in both diseases, and both are treated similarly in clinical practice. As 
such, there is rationale for also evaluating treatment of MDS with flotetuzumab. Allowing 
both MDS and AML during dose escalation hastened identification of a safe dose to be 
evaluated in expansion. Given the similarity between MDS and AML in both clinical 
presentation and pathologic progression, it was expected that the two would behave similarly 
in response to flotetuzumab. As of Amendment 7, the Sponsor stopped enrolling patients with 
MDS into this study. 
Published translational data (44) suggested that AML patients resistant to chemotherapy 
displayed an immune infiltrated bone marrow tumor microenvironment, leading to the 
hypothesis that immunotherapy could be effective in this population. The protocol therefore 
aimed to enrich the expansion cohort for patients with primary refractory disease (defined as, 
prior to Amendment 9, leukemia refractory to ≥ 2 induction attempts (primary induction 
failure; PIF), leukemia in first relapse with initial CR (CR1) duration < 6 months (early 
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relapse; ER), or prior treatment failure with at least four cycles of a hypomethylating agent). 
The initial 24 patients enrolled under Amendment 7 were restricted to 75% (i.e., 18/24) with 
primary refractory AML. Guided by response data from the first 24 patients, the Sponsor 
further restricted enrollment to PIF and ER (CR1 < 6 months) patients. Under Amendment 9, 
enrollment was restricted to patients with PIF AML (defined as leukemia refractory to ≥ 2 [or 
≥ 1 for patients > 65 years of age] induction attempts, or leukemia in first relapse with initial 
CR1 duration < 6 months). Under Amendment 10, PIF AML was further defined as leukemia 
refractory to induction attempts, including but not limited to (1) leukemia refractory to ≥ 1 
intensive induction attempt(s), per institution, or (2) for adults who are age 75 years or older, 
or who have comorbidities that preclude use of intensive induction chemotherapy, leukemia 
refractory to ≥ 2 lower intensity induction attempts; a maximum of up to 2 prior salvage 
attempts was allowed. With Amendment 11, primary refractory AML was redefined as 
patients with PIF or ER (see Inclusion Criterion 2). Patients treated solely with 
hypomethylating agents (HMA) have been excluded from the trial. Greater than 4 cycles of 
HMA are required to define HMA failure. Previously published data show that HMA 
treatment leads to upregulation of checkpoint molecules, including PD-L1 (49), and our 
clinical data suggest that PD-L1 expression decreases flotetuzumab activity (37). 
Primary Efficacy Analysis 
Based on study design and conduct, the MTD was defined at 500 ng/kg/day after noting DLT 
at 700 ng/kg/day. The MTD was also defined as the effective dose, as no complete responses 
(CR, CRh, CRi [CRn, CRp], or MLFS) were noted at doses below 500 ng/kg/day. The lead-in 
dose or ‘priming’ dose is designed to safely reach the MTD. While it is best achieved with a 
multi-step lead-in dose, patients treated with the two-step lead-in dose had still been able to 
achieve the dose of 500 ng/kg/day safely. Hence, patients treated at 500 ng/kg/day as a 
continuous infusion, preceded by either a two-step or multi-step lead-dose, may be included 
in the primary efficacy population as described below. 
The sample size for the primary efficacy analysis is 170 patients, and will include all patients, 
irrespective of when they were enrolled in the study, that 1) were treated with flotetuzumab at 
the MTD of 500 ng/kg/day as a continuous IV infusion during Cycle 1, irrespective of two-
step or multi-step lead-in dose; and 2) meet the definition of PIF/ER AML based on inclusion 
criteria as revised in Amendment 11 (see Inclusion Criterion 2). 
2.4 
Clinical Experience with Flotetuzumab  
Details of the clinical experience with flotetuzumab may be found in the current version of 
the Investigator’s Brochure. 
2.5 
Risk and Benefit Assessment  
The patients expected to enroll in the CP-MGD006-01 study have primary induction failure 
or early relapsed AML. The administration of study drugs to patients with AML in the CP-
MGD006-01 trial could potentially result in clinical benefit such as prevention of disease 
progression and longer survival. 
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In reference to safety concerns for severe acute respiratory syndrome coronavirus 2 
(SARS-CoV-2), there is currently no known evidence of increased risk for SARS-CoV-2 
infection or its exacerbation during treatment with flotetuzumab. No increased risk to patients 
is anticipated as a result of receiving SARS-CoV-2 vaccines, which are permitted during the 
study. MacroGenics’ medical team will continue to review and monitor patient data and 
ensure patient safety at all times.
The Sponsor and the principal investigators will provide updates on the impact of prior or 
concurrent SARS-CoV-2 and the impact, if any, on patient safety as new information 
becomes available, and implement strategies to ensure patient safety and the validity of the 
trial.
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3 
STUDY PURPOSE AND OBJECTIVES  
3.1 
Primary Objective  
To assess the anti-neoplastic activity of flotetuzumab in patients with PIF/ER AML, as 
determined by the proportion of patients who achieve CR/CRh. 
3.2 
Secondary Objectives  
• Assessment of CR rate, CRh rate, overall complete response rate (OCRR; CR, 
CRh, CRi [CRn, CRp], or MLFS), objective response rate (CR, CRh, CRi 
[CRn, CRp], MLFS, or PR), time to response and duration of response (DOR). 
• To measure early mortality rates, overall survival (OS) and event-free survival 
(EFS). 
• To determine the rate of eligible patients, per institution criteria, that transition 
to successful stem cell transplant after achieving overall complete response 
(CR, CRh, CRi [CRn, CRp], or MLFS). 
• To assess rate of conversion to and maintenance of transfusion independence. 
• To evaluate duration of initial hospitalization for flotetuzumab administration. 
• To evaluate incidence and duration of hospitalizations subsequent to initial 
discharge. 
• To monitor the safety and tolerability of flotetuzumab. 
• To characterize the PK and immunogenicity of flotetuzumab. 
• To determine safety and efficacy of tocilizumab in the treatment of IRR/CRS. 
3.3 
Exploratory Objectives  
• To evaluate CD123 expression on blast cells 
• To evaluate circulating cytokine levels at baseline and over time 
• To evaluate circulating leukemic and normal cells at baseline and over time 
• To evaluate circulating T lymphocyte populations and activation markers at 
baseline and over time  
• To evaluate leukemic cells, leukemic stem cells, normal progenitor cells and T 
lymphocytes at baseline and over time in the bone marrow 
• To evaluate molecular markers of minimal residual disease (MRD) 
• To examine changes in T lymphocyte repertoire 
• To evaluate the correlation between cytogenetic abnormalities with responses 
to flotetuzumab immunotherapy. 
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• To study adaptive immune changes during flotetuzumab treatment. 
• To study the tumor microenvironment (TME) immune contexture. 
• Ruxolitinib Cohort Objectives: 
o To characterize the onset, duration, and severity of IRR/CRS on an 
exploratory, pilot basis in flotetuzumab-treated patients receiving 
ruxolitinib and compare that to historical experience in patients not 
receiving ruxolitinib. 
o To measure and compare cytokine profile and T-lymphocyte populations in 
patients receiving the combination of ruxolitinib and flotetuzumab vs 
flotetuzumab alone. 
o To determine the safety and tolerability of the combination of ruxolitinib 
and flotetuzumab. 
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4 
TRIAL DESIGN  
4.1 
Overall Study Design and Plan  
This is an open-label, multi-dose, single-arm, multi-center, Phase 1/2, dose-escalation and 
expansion study to define an MTDS, describe preliminarily safety, and to assess PK, 
immunogenicity, immunomodulatory activity, and potential anti-neoplastic activity of 
flotetuzumab in patients with AML and MDS whose disease is not expected to benefit from 
cytotoxic chemotherapy. 
This study is designed in three segments: The Single Patient Dose Escalation Segment 
(completed), followed by the Multi-patient Dose Escalation Segment (completed), and the 
MTDS Expansion Cohort Segment (ongoing). Two expansion cohorts were planned, one in 
AML and one in MDS. As of Amendment 7, the Sponsor stopped enrolling patients with 
MDS into this study. The primary objective of the study going forward is to assess anti-
neoplastic activity of flotetuzumab in AML, as determined by the proportion of patients who 
achieve CR/CRh. Trial design aspects relating to continuation of the ongoing Cohort 
Expansion Segment, as of Amendment 11, are presented in this section. For a summary of 
prior study development see Section 2.3.2. 
A total of approximately 283 patients will ultimately be enrolled in the Cohort Expansion 
segment, including: 
• approximately 271 patients treated with flotetuzumab at 500 ng/kg/day; 
• up to 12 patients in an exploratory mini-cohort treated with flotetuzumab at 500 
ng/kg/day plus ruxolitinib. 
As previously stated (Section 2.3.2.3), during Cohort Expansion, flotetuzumab is dosed as a 
continuous infusion following a multi-step lead-in dose in Cycle 1 Week 1. With Amendment 
11 all cycles of flotetuzumab, whether induction or consolidation, will be administered as a 
continuous infusion in 28 day cycles (see Figure 5). 
Starting with Cycle 2, patients who are benefiting from flotetuzumab treatment may continue 
to receive additional cycles of treatment with flotetuzumab, up to a maximum of 8 cycles in 
total. Benefit will be defined as a response of CR, CRh, CRi (CRn, CRp), morphologic 
leukemia-free state (MLFS), and PR. Patients with evidence of PD at the end of Cycle 1 may 
receive one further cycle to establish evidence of response (treat one cycle beyond PD), if 
tolerated and at the discretion of the investigator, prior to determining treatment failure. 
Continuation beyond Cycle 1 in these patients is justified given the mechanism of action of 
flotetuzumab. As is known with other immunotherapies, responses may be delayed compared 
to those seen with cytotoxic chemotherapy. In this study, 3/21 (14%) patients who achieved a 
CR did so after an initial increase (PD) in BM blast counts following Cycle 1. 
Flotetuzumab dosing during the Cohort Expansion Segment consists of 2 treatment phases, 
“Induction” and “Consolidation” (see Figure 5). 
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Induction is comprised of Week 1 multi-step lead-in dosing of 30, 60, 100, 200, 300, 400, 
and 500 ng/kg/day flotetuzumab for 24 hours each for Days 1 through 7, followed by 
500 ng/kg/day continuous IV infusion from Days 8 to 28 (Cycle 1). Patients who do not 
achieve a CR or CRh after the initial induction cycle (Cycle 1) may receive additional cycles 
(Cycles 2 – 6) of induction therapy. Further induction therapy consists of flotetuzumab at a 
dose of 500 ng/kg/day as a 7-day continuous IV infusion each week in each 28-day cycle, 
which does not include the lead-in dosing as in Cycle 1. Treatment may continue in 4-week 
cycles until: 
• attainment of a CR or CRh, 
• no evidence of anti-leukemic activity (PR or better, defined as 50% decrease in 
BM blasts or a decrease to between 5 and 25% blasts in the BM) after at least 2 
successive cycles, 
• evidence of progressive disease after one subsequent cycle of flotetuzumab 
following disease progression at the end of Cycle 1 (one cycle beyond 
progression), 
• evidence of disease progression after achieving a response of PR, 
• transition to stem cell transplant, 
• the occurrence of DLT, 
• death, 
• exercise of Investigator discretion, or 
• withdrawal of consent by the patient. 
Consolidation: Patients who achieve a complete remission with complete or partial 
hematologic recovery (CR or CRh) after the induction cycle(s) may then receive up to 2 
cycles of consolidation treatment consisting of flotetuzumab at 500 ng/kg/day dosed as a 
7-day continuous IV infusion each week of a 28-day cycle. 
Based on the judgment of the investigator, patients who achieve a CRi may receive one 
additional cycle of induction (not to exceed a total of 6 induction cycles), and then be 
considered for transition to consolidation. 
At any point during induction or consolidation therapy a patient may transition to receive a 
stem cell transplant, if eligible per individual institution criteria. Patients who have completed 
treatment and are scheduled for a stem cell transplant may continue to receive flotetuzumab 
treatment until the time of the transplant. 
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Figure 5 
Induction and Consolidation Treatment in the Expansion Cohort  
 
Treatment after Cycle 1 Day 8 (and after a minimum of 24 hours at the 500 ng/kg/day 
maximum dose) may take place in the outpatient setting based on the patient’s tolerance of 
therapy. 
Safety evaluations will be conducted on an ongoing basis during the Cohort Expansion 
Segment of the study. Review by an Independent Data Monitoring Committee (IDMC, 
replacing the DSM previously involved in safety reviews), consisting of two physicians and 
one biostatistician, will be conducted in regular intervals. The interval analysis will utilize 
data from all cycles of treatment. If during the conduct of the interval cohort analysis, the 
Bayesian posterior probability is greater than 80% that the DLT (see Section 4.2) event rate is 
more than 20%, enrollment will be paused and an ad hoc meeting of the IDMC will be held 
to consider dose reduction or study termination. The IDMC will also review aggregate 
efficacy data for two planned interim analyses to determine enrollment continuation 
according to futility and efficacy boundaries described in Section 9.1. 
4.1.1 
Cohort Expansion Dosing  
The highest incidence and severity of IRR/CRS is usually noted in the first week of dosing, 
with peak incidence around 48 to 72 hours post start of dosing; IRR/CRS was not typically 
observed beyond the first week of administration. In view of this, patients who experienced 
Grade 1 or 2 IRR/CRS that required minimal intervention, i.e., only anti-pyretics or 
antihistamines and after consultation between the treating Investigator and the Sponsor, may 
receive flotetuzumab as outpatients after Cycle 1 Day 8 (and after a minimum of 24 hours at 
the 500 ng/kg/day maximum dose). Following a dosing interruption for > 24 hours for any 
reason, patients are required to be hospitalized for the first 24-48 hours of dose re-initiation 
for observation and management of IRR/CRS. Once no IRR/CRS ≥ Grade 2 is observed in a 
given patient, and they have otherwise demonstrated acceptable tolerability of the 
flotetuzumab regimen in the judgment of the Investigator, they may be considered for 
outpatient treatment without hospitalization for observation. 
Flotetuzumab will be dosed using a multi-step lead-in dose approach for intrapatient dose 
escalation using multiple-step increments in dosing as follows: 30, 60, 100, 200, 300, 400 
ng/kg/day each for 24 hours (± 2 hours). On Day 7, the dose will be increased to 500 
ng/kg/day and administered as a continuous infusion for the remainder of Cycle 1 (Table 2). 
Cycle 1 Week 2 and beyond will follow the Table 2 dosing schedule.  
Re-INDUCTION
LID
Flotetuzumab lead-in dose
Flotetuzumab
1
22
8
15
29
LID
CR/ CRh (CRi)
NOTE: One cycle Only
NOTE: Up to 2 cycles Only
CONSOLIDATION
INDUCTION
NOTE: Continue induction therapy up to 5 
additional cycles, until meet criteria for CR/CRh or 
criteria for discontinuation
1
22
8
15
29
1
22
8
15
29
HSCT
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Patients that have a dosing interruption > 72 hours will reinitiate dosing with a modified 
multi-step lead-in dose starting at 30 ng/kg/day (followed by steps up to 60, 100, 200, 300, 
400, and 500 ng/kg/day) with dose changes every 4-6 hours as tolerated. 
Table 2 
Cohort Expansion: Induction and Consolidation Dosing 
Schedule (Beginning with Amendment 11)         
Cycle 
Week 
Days 
ng/kg/day 
Induction 
1 
1 
Day 1 
30 
Day 2 
60 
Day 3 
100 
Day 4 
200 
Day 5 
300 
Day 6 
400 
Day 7 
500 
2 
Days 8-14 
500 
3 
Days 15-21 
500 
4 
Days 22-28 
500 
Additional Induction Cycles, if appropriate 
up to 5 
cycles 
1 
Days 1 – 7 
500 
2 
Days 8 – 14 
500 
3 
Days 15 – 21 
500 
4 
Days 22 – 28 
500 
Additional Consolidation Cycles, if appropriate 
up to 2 
cycles 
1 
Days 1 – 7 
500 
2 
Days 8 – 14 
500 
3 
Days 15 – 21 
500 
4 
Days 22 – 28 
500 
 
4.1.2 
Concurrent Ruxolitinib Cohort within Cohort Expansion  
Cytokine release syndrome (CRS) is a potentially life-threatening toxicity that has been 
observed following administration of natural and bispecific antibodies and adoptive T-cell 
therapies for cancer. CRS is believed to be the direct result of excess of inflammatory 
cytokines and is associated with elevated IFN-γ, IL-6, and TNFα levels with increases in 
IL-2, granulocyte macrophage–colony-stimulating factor (GM-CSF), IL-10, IL-8, IL-5, and 
fracktalkine/CX3CL1. Antibodies directed against IL-6, such as tocilizumab, have reduced 
the severity of CRS in patients receiving bispecific antibodies and CAR-T cell therapy, 
including patients treated on the current trial, where incorporation of two-step lead-in dosing 
and early intervention with tocilizumab has helped to ameliorate CRS in patients treated with 
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flotetuzumab. However, CRS may still occur despite the use of corticosteroids and anti-IL-6 
therapy, which may limit the therapeutic window of novel immunotherapeutic agents. 
Disruption of cytokine signaling via Janus Kinase (JAK) pathway may represent a 
complementary approach to blocking CRS. JAK signaling involves recruitment of signal 
transducers and activators of transcription (STATs) to cytokine receptors, activation, and 
subsequent localization of STATs to the nucleus, leading to modulation of gene expression. 
Dysregulation of the JAK/STAT pathway is observed in patients with myeloproliferative 
neoplasms (51,40,8,10). 
Ruxolitinib (INCB018424 phosphate, INC424, ruxolitinib phosphate) is a potent and 
selective inhibitor of JAK1 (inhibition concentration 50% [IC50] = 3.3 ± 1.2 nM) and JAK2 
(IC50 = 2.8 ± 1.2 nM) with modest to marked selectivity against TYK2 (tyrosine kinase 2) 
(IC50 = 19 ± 3.2 nM) and JAK3 (IC50 = 428 ± 243 nM), respectively, and is approved for the 
treatment of myelofibrosis and polycythemia vera. Ruxolitinib interferes with the signaling of 
a number of cytokines and growth factors that are important for hematopoiesis and immune 
function. Data from preclinical murine models suggests that JAK inhibition blocks IFN-γ and 
IL-6 signaling, thus blocking the development of graft versus host disease while preserving 
the graft versus leukemia effect (8,9,10). 
We hypothesize that disruption of IFN-γ and IL-6 signaling via the JAK/STAT pathway with 
ruxolitinib may reduce the frequency and severity of cytokine release syndrome in patients 
undergoing treatment with flotetuzumab. We propose to test this hypothesis by investigating a 
regimen consisting of prophylactic oral ruxolitinib in an exploratory cohort of patients with 
relapsed or refractory AML treated with flotetuzumab, to assess whether this can further 
ameliorate the occurrence and/or severity of CRS. 
Overall, this cohort will enroll up to 12 patients at a single site (Washington University, St. 
Louis, MO) to test if the use of ruxolitinib mitigates IRR/CRS. Patients treated with strong 
CYP3A4 inhibitors or fluconazole will be excluded. An interim assessment by the medical 
monitor and investigators after 6 patients will be conducted to determine safety as well as 
effect on severity and incidence of IRR/CRS. Based on the toxicity profile, the dose of 
ruxolitinib may be increased to 20 mg twice daily (max recommended dose) (FDA package 
insert). The most common toxicities encountered with ruxolitinib include anemia and 
thrombocytopenia; hence, an increase of ≥ 2 CTCAE v4.0 grades in either hemoglobin or 
platelet count while on ruxolitinib will be considered a DLT in addition to the DLTs defined 
in Section 4.2. Initially, 6 patients will be treated with ruxolitinib at a dose of 10 mg twice 
daily on days 0-14 of Cycle 1. The dose of ruxolitinib used in the initial 6 patients will be 
50% of the maximum recommended dose of ruxolitinib (package insert), as a precautionary 
measure. If < 2 out of 6 patients experience a DLT, as defined above, the dose will be 
escalated to 20 mg twice daily upon interim assessment and discussion between medical 
monitor and principal investigator. Six more patients will be treated at 20 mg twice daily on 
days 0-14 of Cycle 1. The cohort will be stopped and dose deescalated to 10 mg if 2 or more 
patients experience a DLT, as defined above, at 20 mg twice daily. If at any point during the 
ruxolitinib cohort, 4 or more patients experience a DLT, as defined above, the cohort will be 
stopped. Based on the mechanism of action of ruxolitinib and flotetuzumab and the observed 
and reported toxicities, it is not anticipated that the side effects will be additive. Most 
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toxicities observed with ruxolitinib are a consequence of chronic usage. Patients on the 
ruxolitinib cohort will only be treated for 15 days of Cycle 1. 
4.2 
Dose Limiting Toxicity Definitions  
DLT will be defined employing the National Cancer Institute Common Terminology Criteria 
for Adverse Events, Version 4.0 (CTCAE v4.0), except IRR/CRS which will be defined by 
the modified criteria proposed by Lee et al. (26) and described in Section 6.4.1.2 and in 
Table 5. Note: IRR/CRS will be assessed by the grading of the overall IRR/CRS event, and 
not the grade of component signs or symptoms. 
DLT is defined as: 
• Grade 4 neutropenia lasting ≥ 42 days from start of cycle in absence of evidence 
of active AML (< 5% blasts). 
• Grade 3−5 nonhematologic toxicity not clearly resulting from the underlying 
disease and at least possibly related to protocol indicated treatment, EXCEPT: 
o Grade 3 fatigue, asthenia, fever, anorexia, or constipation; 
o Grade 3 nausea, vomiting or diarrhea not requiring tube feeding, total 
parenteral nutrition, or requiring or prolonging hospitalization, and 
resolve, with or without intervention, to  Grade 2 levels in < 7 days will 
not be considered DLT; 
o Infection, bleeding, or other expected direct complication of cytopenias 
due to active underlying disease; 
o Grade 3 or 4 tumor lysis syndrome (TLS) if it is successfully managed 
clinically and resolves within 7 days without end-organ damage; 
o Grade 3 or 4 isolated biochemical laboratory abnormalities (i.e., those 
occurring without clinical consequence) that resolve, with or without 
intervention, to  Grade 2 levels in < 72 hours will not be considered DLT. 
o Grade 3 rashes, myalgias or arthralgias that resolve within 96 hours and 
respond to medical intervention. 
o Grade 3 infusion-related reaction or CRS that lasts < 72 hours and 
responds to medical intervention. 
• For patients in the ruxolitinib cohort, an increase of ≥ 2 CTCAE v4.0 grades in 
either hemoglobin or platelet count in patients while on ruxolitinib will also be 
considered a DLT. 
• Any treatment-related death. 
4.3 
Study Duration and Dates  
The Single Patient Dose Escalation Segment of the study occurred over an 18-month period 
and the Multi-patient Dose Escalation Segment of the study occurred over a 20-month period. 
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The Cohort Expansion Segment of the study is expected to occur over an approximately 5-
year period. 
Total time for conduct of the trial is expected to be approximately 8 years. These estimates of 
timing for study conduct may vary from that observed in the actual conduct of the trial. 
4.4 
Definition of End of Trial  
End of trial will occur after the last patient has received the last dose of study drug and has 
been followed until disease progression, stem cell transplant, withdrawal of consent, or until 
death, whichever occurs first, and the data collection process is complete (time of study 
database lock). 
 
 
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5 
SELECTION AND WITHDRAWAL OF PATIENTS  
5.1 
Inclusion Criteria  
Each patient must meet all the following criteria to be enrolled in this study. No exceptions to 
these criteria can be granted by the Sponsor. 
1. Patients must have a confirmed diagnosis of primary or secondary AML (any 
subtype except acute promyelocytic leukemia [APL]) according to World Health 
Organization (WHO) classification. 
2. Patients with AML must meet one of the following criteria, a or b: 
a. Primary Induction Failure (PIF) AML, defined as disease refractory to 
one of the following, i or ii: 
i. An intensive induction attempt, per institution. 
Induction attempts include high-dose and/or standard-dose cytarabine 
± an anthracyclines/anthracenedione ± an anti-metabolite, with or 
without growth factor or targeted therapy containing regimens. 
Examples include but are not limited to: 
1. One cycle of high dose cytarabine (HiDAC) containing 
regimen 
2. One cycle of liposomal cytarabine and daunorubicin 
3. Two cycles of standard dose cytarabine containing regimen  
ii. For adults who are age 75 years or older, or who have comorbidities 
that preclude use of intensive induction chemotherapy; PIF is defined 
as AML refractory to one of the following less intensive regimens, 1 or 
2: 
1. ≥ 2 but ≤ 4 cycles of Bcl-2 inhibitors in combination with 
azacitidine, decitabine, or low dose cytarabine 
2. ≥ 2 but ≤ 4 cycles of gemtuzumab ozogamicin monotherapy 
b. Early relapse (ER) AML, defined as AML in first relapse with initial CR1 
duration < 6 months 
3. Limit of 3 prior lines of therapy (excluding focal radiation therapy for palliative 
purposes): up to 2 induction (induction, re-induction) or 1 induction plus/minus 1 
consolidation attempt, followed by a maximum of 1 salvage/re-induction attempt. 
4. Eastern Cooperative Oncology Group (ECOG) performance status  2. 
5. Life expectancy of at least 4 weeks. 
6. Peripheral blast count  20,000/mm3 at the time of first dose of study treatment 
(see related Exclusion Criterion 3). 
7. Adequate hepatic and renal function: 
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a. hepatic transaminase (both alanine aminotransferase (ALT) and aspartate 
aminotransferase (AST) levels  2.5 times the institutional upper limit of 
normal (ULN), 
b. total bilirubin level  1.5 times the ULN (unless the patient has a history of 
Gilbert’s Syndrome, in which case, total bilirubin must be  2.5 times the 
ULN), 
c. serum creatinine level  1.5 times the ULN or a calculated or measured 
creatinine clearance of  50 ml/min. 
8. Adequate organ reserve including cardiovascular (left ventricular ejection fraction 
[LVEF] within institutional normal limits, if patient has a history or signs and 
symptoms of cardiac disease), pulmonary (baseline pulmonary function test 
[PFT]: carbon monoxide diffusion capacity in the lung [DLCO] > 50%, forced 
expiratory volume in 1 second [FEV1] > 70%), renal, and hepatic functioning 
sufficient, in the judgment of the Investigator, to undergo therapy. 
• During the coronavirus disease-2019 (COVID-19) pandemic, except in 
Germany, if PFT equipment is not available, a correlative stair-climbing 
test may be conducted instead, together with lung CT and echocardiogram 
irrespective of cardiac history. The patient must pass the stair-climbing 
test, with O2 saturation ≥ 95%, lung CT with normal appearing lung 
parenchyma, and normal echocardiogram [see Section 8.1.1]. 
9. Normal thyroid function or stable thyroid tests on supplementation, except 
euthyroid sick syndrome. 
10. Recovery from toxicities of clinical consequence attributed to previous 
chemotherapy to CTCAE v4.0 Grade  1 (i.e., certain toxicities such as alopecia 
will not be considered in this category). 
11. Female patients of childbearing potential must test negative for pregnancy at 
enrollment and during the study. Sexually active women of child-bearing 
potential, unless surgically sterile, must be willing to use a highly effective 
method of birth control defined as those which result in a low failure rate (i.e., less 
than 1% per year) such as implants, injectables, combined oral contraceptives, 
intra-uterine devices (IUDs) or vasectomized partner. Male patients with partners 
of childbearing potential must be either vasectomized or agree to use a condom in 
addition to having their partners use another method of contraception resulting in 
a highly effective method of birth control defined as those which result in a low 
failure rate (i.e., less than 1% per year) such as implants, injectables, combined 
oral contraceptives, or IUDs. Patients should not have sexual intercourse with 
females who are either pregnant or lactating without a condom. Contraception 
should be employed from the time of consent through 12 weeks after 
flotetuzumab administration. Patients should also abstain from sperm/egg 
donation during the course of the study. 
12. Eighteen (18) years of age or older. 
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13. Ability to comply with study procedures, including hospitalization and protocol-
specified acquisition of blood and/or bone marrow specimens. 
14. Provide informed consent as documented by signing an IRB/IEC-approved 
informed consent document prior to execution of any study procedures not 
considered to be standard of care. 
5.2 
Exclusion Criteria  
Patients who meet any of the following criteria will be excluded from the study. No 
exceptions to these criteria can be granted by the Sponsor. 
1. Prior history of allogeneic stem cell transplantation. 
2. Prior treatment with an anti-CD123-directed agent. 
3. Need for concurrent other cytoreductive chemotherapy (use of hydroxyurea or 
other cytoreductive agents should have ceased by the time the study medication is 
begun (Cycle 1 Day 1) – however, hydroxyurea may be reinstituted at the 
discretion of the Investigator for the prevention or treatment of signs or symptoms 
of leukostasis, see Section 6.6), i.e., the target peripheral blast count for inclusion 
in the study should be  20,000/mm3 at the time of first dose of study treatment. 
4. Any active untreated autoimmune disorders (with the exception of vitiligo, 
resolved childhood atopic dermatitis, prior Grave’s disease now euthyroid 
clinically and with stable supplementation). 
5. Second primary malignancy that requires active therapy. Adjuvant hormonal 
therapy is allowed. 
6. Antitumor therapy (chemotherapy, radiotherapy, antibody therapy, molecular-
targeted therapy, retinoid therapy, or investigational agent) within 14 days or 5 
half-lives of Cycle 1 Day 1, whichever is longer. Ruxolitinib is permitted for 
patients in the ruxolitinib mini-cohort. 
7. Requirement, at the time of study entry, for concurrent steroids > 10 mg/day of 
oral prednisone or the equivalent, except steroid inhaler, otic preparations, nasal 
spray or ophthalmic solution. 
8. Use of immunosuppressant medications (other than steroids as noted) in the 2 
weeks prior to study drug administration (Cycle 1 Day 1). 
9. Use of granulocyte colony stimulating or granulocyte-macrophage colony 
stimulating factor in the 2 weeks prior to study drug administration (Cycle 1 Day 
1). 
10. Known central nervous system (CNS) leukemia. Patients with suspected CNS 
leukemia must be evaluated by lumbar puncture and be free of CNS disease prior 
to study entry. Previously treated CNS leukemia is allowed provided adequate 
treatment has been provided and the patient is free of CNS disease. 
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11. Any medical or psychiatric condition limiting full compliance or increasing the 
safety risk, such as: 
a. active uncontrolled infection (including, but not limited to viral, bacterial, 
fungal, or mycobacterial infection), 
b. known human immunodeficiency virus infection, unless all of the 
following criteria are met: 
i. 
CD4+ count ≥ 350 cells/μL, 
ii. 
undetectable viral load, and 
iii. 
receiving highly active antiretroviral therapy. 
c. known history of or current acute or chronic hepatitis B virus (HBV) 
infection (as evidenced by detectable HBV surface antigen and HBV DNA 
≥ 500 IU/mL), 
d. history of hepatitis C virus (HCV) infection, unless the infection has been 
treated and cured, 
e. active SARS-CoV-2 infection. While SARS-CoV-2 testing is not 
mandatory for study entry, testing for ongoing infection should follow 
local clinical practice guidelines/standards. Participants with a positive test 
result for ongoing SARS-CoV-2 infection, known ongoing asymptomatic 
infection, or suspected ongoing infection are excluded from enrolling in 
the study. Such patients who are asymptomatic, or become asymptomatic, 
and who have a subsequent negative SARS-CoV-2 laboratory test may be 
enrolled.  
f. Grade 3 or 4 bleeding, 
g. significant pulmonary compromise including the requirement for 
supplemental oxygen, history of non-infectious pneumonitis (including 
radiation pneumonitis), pulmonary fibrosis, or severe chronic obstructive 
pulmonary disease (COPD), 
h. uncontrolled (persistent) hypertension (systolic pressure > 180 mm Hg or 
diastolic pressure > 100 mm Hg), 
i. clinically significant arrhythmia, or QTcF > 480 msec (ECG to be obtained 
in triplicate, patient to be excluded if average of 3 readings is > 480 msec), 
j. unstable angina, 
k. recent myocardial infarction within 6 months prior to study drug 
administration (Cycle 1 Day 1), 
l. clinically significant heart disease, such as, congestive heart failure, 
history of pericarditis, myocarditis, 
m. history of stroke or transient ischemic event within 3 months prior to study 
drug administration (Cycle 1 Day 1), 
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n. untreated pulmonary embolism, or non-catheter-related deep-vein 
thrombosis in the 3 months prior to study drug administration (Cycle 1 
Day 1), 
o. known adrenal insufficiency, 
p. pregnancy, or breast feeding, 
q. major surgery or trauma within 4 weeks before enrollment. 
12. Known hypersensitivity to murine, yeast, or recombinant proteins; 
 
recombinant human serum albumin; benzyl alcohol; or any excipient contained in 
the flotetuzumab drug formulation. 
13. Dementia or altered mental status that would preclude sufficient understanding to 
provide informed consent. 
14. Currently abuses drugs or alcohol that, in the Investigator’s opinion, would cause 
the individual to be noncompliant. 
15. Any investigative site personnel directly affiliated with this study. 
16. Employees of MacroGenics, Inc. 
17. Prisoners or others who are compulsorily detained. 
18. Any reason that, in the opinion of the Investigator, would contraindicate the 
patient’s participation in the trial or confound the results of the study. 
19. Treatment with strong CYP3A4 inhibitors or fluconazole (ruxolitinib exploratory 
mini-cohort only). 
5.3 
Rationale for Exclusion of Certain Study Candidates  
The Exclusion Criteria above include clinical situations that may prevent patients from 
completing the protocol, have an influence or effect on tolerance of study drug thus 
confounding the data analysis, or are serious conditions that pose an increased risk for 
morbidity and mortality while the patient would be participating in the study. 
5.4 
Withdrawal of Patient from the Trial or Study Drug  
The Investigator may withdraw a patient from the study and/or from dosing for any of the 
following reasons. The Sponsor or its designee must be notified within 24 hours using the 
procedures outlined in Section 7.12: 
• A violation of enrollment criteria or other significant protocol violation is 
discovered after a patient has enrolled and been treated, 
• A serious, intolerable, or dose-limiting AE (as described in the DLT definitions 
above, Section 4.2) occurs, 
• Patients who are symptomatic from, or require treatment for, SARS-CoV-2 active 
infection should be withdrawn from study drug. The Sponsor, in consultation with 
the investigator, may grant exceptions to this rule if the benefit:risk ratio of 
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continuing therapy with study drug outweighs the benefit:risk ratio of withdrawal 
from study drug (see Section 6.3), 
• The Sponsor, Investigator, or regulatory agency terminates the study, 
• The patient requests to be discontinued from the study, 
• The Investigator, in his/her best medical judgment, decides that the patient should 
be withdrawn from the study or from dosing, 
• If the patient becomes pregnant during the study, the patient must discontinue the 
study drug immediately. The health status of mother and child should be followed 
and reported after delivery, 
• Patient has not achieved at least a PR (defined as decrease of bone marrow blast 
percentage to 5% to 25%, or decrease of pretreatment bone marrow blast 
percentage by at least 50%) following 2 cycles of flotetuzumab therapy, 
• Patient with evidence of disease progression after achieving at least PR, 
• Patient transitions to stem cell transplant. 
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6 
STUDY TREATMENTS  
6.1 
Description of Treatment(s)  
Flotetuzumab is the only study-specific investigational drug product to be administered in 
this study. Flotetuzumab will be administered as described in Section 4.1.1. 
6.2 
Treatments Administered  
6.2.1 
Flotetuzumab  
Flotetuzumab is a CD123 x CD3 bi-specific antibody-based molecular construct referred to 
as a DART molecule. Its purpose is to bring into close proximity immune effector cells 
bearing the CD3 antigen, which is a component of the T cell antigen receptor complex, and 
target cells bearing the CD123 antigen, which is a component of the interleukin-3 receptor. 
As a result of opposing the two cells and activating the T cell, it is hypothesized that the 
neoplastic cells will be killed. 
6.2.1.1 
Drug Supply  
6.2.1.1.1 
Flotetuzumab  
Flotetuzumab drug product (DP) is provided as a sterile aqueous solution 
 
 
 
 
Drug product is supplied as a sterile aqueous solution packaged in a United States 
Pharmacopeia (USP) and Ph. Eur. conforming Type I borosilicate, 5 cc clear glass vial with a 
20 mm FluroTec® and B2-40-coated 4432/50 gray butyl rubber serum stopper. The vial is 
sealed with a 20 mm TruEdge® aluminum closure with a plastic overseal. 
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6.2.1.1.2 
IV Solution Stabilizer  
Intravenous (IV) Solution Stabilizer is provided with flotetuzumab and used during dose 
solution preparation to coat the IV bag prior to the addition of flotetuzumab. This step helps 
ensure that the active drug product does not adhere to the IV bag and IV tubing. There are 
two custom IV Solution Stabilizers; which one of MGV002 or MGV004 IV Solution 
Stabilizer will be used for dose solution preparation and continuous infusion depends on 
country-specific Regulatory Authority requirements and approvals. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6.2.1.2 
Drug Dose Solution Preparation and Administration  
Flotetuzumab DP, and MGV002 IV Solution Stabilizer or MGV004 IV Solution Stabilizer 
will be supplied by the Sponsor for use in this study as appropriate to accommodate the 
method of study drug dose preparation and duration of continuous IV administration. 
Parenteral drug products should be inspected visually prior to use. If discoloration or foreign 
particulates are observed, drug should not be administered. Some proteinaceous particles may 
be present; thus, a low protein binding 0.2 µm in-line filter must be used for administration of 
flotetuzumab. 
Recommended safety measures for handling and preparation include masks, protective 
clothing, gloves, and vertical laminar airflow safety cabinet. 
Flotetuzumab is administered to patients at exceedingly low doses. 
All doses employed in this study are described in units of ng/kg/day. 
Nanogram measurement is infrequently used in clinical practice. 
[A nanogram (ng) is  
1 billionth (1/109) of a gram (g), 
1 millionth (1/106) of a milligram (mg); and 
1 thousandth (1/103) of a microgram (g)] 
Errors in dilution could result in fatal Cytokine Release Syndrome (CRS). 
Every reasonable precaution should be exercised 
in the preparation, verification, and administration of the flotetuzumab dose. 
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Independent verification of patient weight and of the calculated dose must be carried 
out and documented by a second individual. 
Similarly, the administration pump settings should be independently reviewed and 
documented by a second individual 
before study drug administration commences. 
Due to the low concentration of flotetuzumab in prepared doses, MGV002 IV Solution 
Stabilizer or MGV004 IV Solution Stabilizer is used during dose solution preparation to coat 
the IV bag and reduce adsorption and minimize losses of active drug during administration. 
Flotetuzumab is administered by IV infusion using a single ambulatory pump, or standard IV 
infusion pump. Instructions for the dose solution preparation and administration of 
flotetuzumab are detailed in the Pharmacy Manual. 
General Administration Information: 
Flotetuzumab must not be administered as an IV push or bolus. During the Cohort 
Expansion Phase, at least for the first 8 days of Cycle 1 (and after a minimum of 24 hours at 
the 500 ng/kg/day maximum dose), the drug will be administered in an inpatient hospital 
setting; but afterwards may be administered in an outpatient setting as described in 
Section 4.1.1. The type of pump used for administration of flotetuzumab may differ by 
country or region. It is important that at any point, THE INFUSION BAG CONTAINING 
FLOTETUZUMAB MUST NOT BE SHAKEN; excessive agitation may cause aggregate 
formation. Subsequent to Cycle 1 Day 8 (and after a minimum of 24 hours at the 
500 ng/kg/day maximum dose), patients may, as appropriate (see Section 6.3), receive 
flotetuzumab as a continuous infusion in an outpatient setting using an ambulatory pump 
configuration. Specific instructions for dose preparation and administration in both the 
inpatient and outpatient settings are provided in the Pharmacy Manual. 
Sites must ensure patients who receive flotetuzumab in the outpatient setting will be provided 
instructions and trained appropriately and monitored for compliance and safety. 
Flotetuzumab should not be admixed or diluted with other drugs. Any partially used vials or 
diluted dosing solutions should be discarded using appropriate drug disposal procedures. 
6.3 
Modification (Including Discontinuation) of Flotetuzumab Dose 
or Schedule  
Interruption or discontinuation of dose or schedule may be necessitated by the observation of 
suspected drug-associated or drug-related adverse events (AEs). The Investigator should use 
his/her best medical judgment to intervene in order to safeguard the patient’s welfare. The 
following guidelines should be observed: 
In general, observation of any  Grade 3 AE (by CTCAE v4.0), except IRR/CRS which will 
be by the modified criteria proposed by Lee et al. (26) considered related to flotetuzumab 
should result in suspension of flotetuzumab study drug administration; for patients in the 
mini-cohort, ruxolitinib administration should also be suspended. Reinstitution of assigned 
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flotetuzumab study drug administration, and ruxolitinib administration for patients in the 
mini-cohort, should occur if the AE meets one of the exceptions to the definition of DLT (see 
Section 4.2). Otherwise, the patient should be withdrawn from further study drug 
administration unless there are extenuating circumstances, and the Investigator concludes that 
the patient is continuing to derive clinical benefit. 
If after reinstituting flotetuzumab for a first occurrence of a  Grade 3 AE (as exempted by 
the DLT definition), the patient experiences a second (either similar or different)  Grade 3 
AE, study drug administration should once again be suspended. As before, reinstitution of 
any study drug administration should be delayed to see if the AE meets one of the exceptions 
to the DLT definitions. If so, the Investigator may elect to reinstitute flotetuzumab; patients 
that have a dosing interruption > 72 hours will reinitiate dosing with a modified multi-step 
lead-in dose starting at 30 ng/kg/day (followed by steps up to 60, 100, 200, 300, 400, and 500 
ng/kg/day) with dose changes every 4-6 hours as tolerated. If the observed AE is associated 
with autoimmunity, the study drug should be discontinued. 
If the second  Grade 3 AE meets the definition of DLT, or a third instance of a  Grade 3 AE 
occurs, the Investigator should consider the patient to have experienced DLT and the patient 
should be withdrawn from further study drug administration (see Section 5.4). 
Signs and symptoms of active viral infections may overlap with the signs and symptoms of 
CRS (e.g., fever, hypoxemia). The management of CRS in the setting of active coronavirus 
infections could theoretically potentially confound the course of the viral infection. The 
following guidelines apply to participants with confirmed (by a laboratory test) or presumed 
(test pending/clinical suspicion) SARS-CoV-2 infection: 
• Study drug should be stopped in patients who are symptomatic from, or require 
treatment for, SARS-CoV-2 active infection. The Sponsor, in consultation with 
the investigator, may permit study drug to be restarted, on a case-by-case basis, 
if the benefit:risk ratio of continuing therapy with study drug outweighs the 
benefit:risk ratio of withdrawal from study drug. 
• Prior to restarting study drug, when stopped for SARS-CoV-2 infection, 
participants should be afebrile for at least 72 hours, and SARS-CoV-2–related 
symptoms should have recovered to ≤ Grade 1 or baseline for a minimum of 48 
hours. 
• The Sponsor should be informed when restarting flotetuzumab. 
When dosing is delayed for ≥ 24 hours, continue to follow the Schedule of Events in 
Appendix 1 and Blood Sampling Schedule in Appendix 2, including on days when no 
study drug is administered (with the exception of samples for PK, which should not be 
collected on days when no study drug is administered) or when lead-in dosing escalation 
is needed to restart flotetuzumab. If a delay of ≥ 24 hours during any dosing period 
occurs, or if less than 75% of the intended dose will be administered if the original 
schedule is followed, the MacroGenics Medical Monitor should be consulted as to 
whether the total infusion time should be extended to allow sufficient study drug to be 
administered. 
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6.4 
Special Situations and Supportive Care Measures  
6.4.1 
Infusion-related Reactions including CRS  
The predicted mechanism of action of flotetuzumab is the creation of an immunological 
synapse between the leukemic blast target cell bearing CD123 and immune effectors bearing 
the T cell specific CD3 complex, leading to T cell activation and killing of the leukemic cell. 
Activation of T cells is associated with the elaboration of various cytokines. In vitro 
preclinical testing using human PBMCs has suggested that the most vigorous cytokine 
production is that of IFN-, but increases in production of TNF-, IL-2, IL-6, IL-4, and IL-10 
were documented. Cytokine production, primarily of IL-6, was also documented in normal 
cynomolgus monkeys receiving flotetuzumab - a circumstance in which relatively few target 
cells (mostly CD123-bearing pDCs) were present in the animal’s peripheral blood but 
elimination of those cells was observed. In the cynomolgus monkey, very high doses of 
flotetuzumab (i.e., 5 µg/kg/day) were associated with severe cytokine release of multiple 
cytokines including IL-6, IFN-γ, IL-2, TNF-α and to a lesser extent IL-8 and IL-4, resulting 
in moribundity or death. 
Infusion-related reactions or Cytokine Release Syndrome (CRS) may occur. 
Anaphylactic or anaphylactoid-type reactions are possible.  
Precautions for the management of these reactions should be observed  
during flotetuzumab administration. 
Infusion-related reactions (including CRS) associated with flotetuzumab administration 
should be managed according to the standard practice of medicine. General guidelines for the 
management of such reactions are provided in this section. However, severe reactions may 
require extraordinary interventions like those that have been required to extinguish the 
syndrome of cytokine storm which may have anaphylactoid features. 
Patients should be monitored closely for the development of IRRs during flotetuzumab 
infusion. Medications and supportive measures for the treatment of such reactions should be 
available for immediate use for an infusion reaction during study drug administration and 
may include, but are not limited to: subcutaneous (SC) epinephrine (0.3 to 0.5 mL of a 
1:1000 solution), antihistamines (e.g., diphenhydramine 25 to 50 mg IV), corticosteroids 
(e.g., dexamethasone 10 mg IV push or equivalent), IV fluids, vasopressors, oxygen, 
bronchodilators, and antipyretics. Resuscitation equipment and other supplies for the 
emergency management of an allergic/toxic reaction must be available. The patient should be 
treated according to the best available local practices and procedures. All supportive 
measures consistent with optimal patient care will be provided throughout the study 
according to institutional standards. 
Should symptoms of fever or chills develop it may be difficult or impossible to distinguish 
among potential causes of the symptoms including underlying leukemia, neutropenic fever, 
emerging infection (including SARS-CoV-2), or infusion reaction. Temporarily halting the 
flotetuzumab infusion to collect cultures, institute antimicrobials, etc., may provide 
information regarding etiology. If the fever and chills are considered not related (as described 
in Section 7.11.2) to the infusion of study drug, the study drug may be reinstituted at the 
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same rate of administration after administration of ibuprofen or acetaminophen and 
diphenhydramine hydrochloride if not administered previously for premedication. More 
complex symptom composites may require additional intervention. Please refer to 
Section 6.4.1.2 for management of infusion reactions if the event is considered related to 
flotetuzumab. If during assessment of IRR/CRS a patient undergoes imaging study and/or 
sample collection, e.g., pleural fluid, intra-articular joint aspiration, or ascitic fluid, a sample 
may be provided to the Sponsor to help elucidate etiology. 
6.4.1.1 
Premedications and Prophylaxis  
Based on the clinical experience to date (Section 2.4), similar findings from other bispecific 
molecules, such as blinatumomab, reported clinical experience with CAR-T therapies, and 
after consultation with the study investigators and the prior independent DSM (now replaced 
by the IDMC), all patients treated in clinical protocol CP-MGD006-01 will receive 
premedication to prevent or mitigate potential infusion-related reactions. Specific pre-
treatment regimens are described below. Table 4 presents the premedication and prophylaxis 
regimens. 
Prior to the first dose and during Cycle 1 Week 1, all patients are to be treated as described in 
Table 4 below. Patients should receive adequate hydration during study therapy, 
preferentially oral if tolerated. The addition of IV fluids to maintain intravascular volume 
(e.g., 50-100 mL/hr of normal saline) is recommended for at least 48 hours after the start of 
therapy. 
For infusion-related reactions during the course of treatment, supportive care measures 
should be implemented as outlined in Section 6.4.1. 
Dose interruption: 
If dosing is interrupted for > 24 hours, the premedication schedule for Week 1 Day 1 should 
be followed (Table 4). If dosing is interrupted twice for > 24 hours, and the patient has no 
IRR/CRS upon each resumption of dosing, then no premedication is required after the third 
and subsequent interruptions. Patients that have a dosing interruption > 72 hours will 
reinitiate dosing with a modified multi-step lead-in dose starting at 30 ng/kg/day (followed by 
steps up to 60, 100, 200, 300, 400, and 500 ng/kg/day) with dose changes every 4-6 hours as 
tolerated. 
Ruxolitinib Cohort (Single Site [Washington University, St. Louis, MO]; up to 12 
patients) 
Treatment Plan: 
Up to 12 patients will be treated with prophylactic ruxolitinib and flotetuzumab as follows: 
1. Ruxolitinib 10 mg PO BID will be administered on Days 0-14 of Cycle 1 of 
flotetuzumab beginning the day prior to initiation of flotetuzumab. 
a. Patients in the ruxolitinib cohort should receive all other prophylaxis as 
indicated in Table 4. 
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b. Based on cohort interim safety assessment, outlined above, ruxolitinib may 
be increased to 20 mg twice daily (max recommended dose) (8). 
2. Flotetuzumab will be administered per the Cycle 1 schedule provided in Table 2. 
Dose modifications: 
Ruxolitinib may be interrupted or reduced to 5 mg BID for suspected ruxolitinib-related 
adverse events (AEs), i.e., anemia or thrombocytopenia decrease of > 2 Grade decrease while 
on ruxolitinib. 
Table 4 
Premedication and Prophylaxis for Infusion-related Reactions     
Medication 
7-day Continuous Infusion Schedule, Cycle 1 Week 1 1 
Day 1 
Day 7 
Acetaminophen 
(1000 mg PO) 
Or 
Paracetamol 
(1000 mg PO) 
Or 
Ibuprofen 
(400 mg PO) 
30 minutes prior to dosing 
 
Then q 8 hours for 48 hours 
30 minutes prior to dose change  
 
Then q 8 hours for 48 hours 
Diphenhydramine 
(25-50 mg IV or PO) 
or equivalent  
30 minutes prior to dosing 
 
Then q 8 hours for 48 hours 
30 minutes prior to dose change 
 
Then q 8 hours for 48 hours 
Famotidine 
(20 mg IV or PO)  
or equivalent 
30 minutes prior to dosing 
 
Then q 8 hours for 48 hours 
30 minutes prior to dose change 
 
Then q 8 hours for 48 hours 
Dexamethasone 
(or equivalent) 
10-20 mg IV 
up to 30 minutes prior to dosing 
 
Then 4 mg IV at 12 hours after dosing 
 
Then 4–10 mg up to every 8 hours 2 
10 mg IV  
up to 30 minutes prior to dose change 
 
Then 4 mg 12 hours later 
 
Then 4–10 mg up to every 8 hours 2 
1 
If dosing is interrupted for > 24 hours during continuous infusion, the premedication schedule for Week 1 
should be followed. 
2 
Low dose steroids may be administered every 8 hours as clinically indicated to facilitate achievement of 
the target dose 500 mg/kg. 
 
6.4.1.2 
Management of Observed Flotetuzumab Infusion Reactions 
and Infusion-related Adverse Events  
The following are treatment guidelines (which may be modified as needed by the responsible 
Investigator according to the best practices of medicine) for flotetuzumab IRRs including 
CRS. Early intervention at the first signs of IRR/CRS, including pyrexia, tachycardia, 
tachypnea and/or hypotension in the absence of alternative etiologies and in consistent 
temporal relationship to administration of flotetuzumab, should be undertaken. 
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Through Amendment 4, IRR/CRS has been graded using CTCAE v4.0. Based on current 
understanding gained with patients treated with CAR-T cells (which have a T-cell activating 
mechanism of action in common with flotetuzumab), CRS is likely to be a common toxicity 
that can be managed through supportive care and anti-cytokine interventions to allow for full 
activity of T cells during therapy. An alternative grading scale for CRS proposed by Lee et al. 
(26) allows for more intensive supportive care and treatment of the underlying cause of the 
CRS (excessive cytokine production) before the event must be considered Grade 3 or Grade 4 
severity. Adopting this definition of CRS as described in Table 5, and concomitantly 
modifying the guidelines for management of IRR/CRS (below) as implemented in 
Amendment 5 and further modified in Amendment 13, will allow for more flexible 
management of patients who develop CRS and who may nonetheless experience clinical 
benefit despite the need to manage through mild or moderate infusion reactions while not 
jeopardizing overall safety. 
Infusion related reaction including CRS is a common toxicity with flotetuzumab, especially 
when the drug is initiated and dose escalated during lead-in dosing. Evaluate for and treat 
other causes of fever, hypoxia, and hypotension according to institutional best practices or 
guidelines. Initial IRR/CRS management with fluids and antipyretics is allowed as clinically 
indicated, per local institutional practices. Celecoxib (14), if platelet counts allow, may be 
considered for myalgia and arthralgia. If celecoxib is contraindicated consider the use of 
corticosteroids per Table 5, Grade 1 CRS. If CRS is suspected, refer to Table 5 for 
management guidelines or treat according to local institutional guidance. Every attempt 
should be made to continue the infusion during management of the reaction. The definitions 
for high-dose vasopressors are shown in Table 6. 
 
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Table 5 
CRS Grading and Recommended Management Guidance          
CRS Grade (26) 
Dose Modification 
Tocilizumab 
Corticosteroids 
Grade 1 
Symptoms are not life threatening and require 
symptomatic treatment only, e.g., fever, 
nausea, fatigue, headache, myalgias, malaise 
Slow infusion rate by 10-20%. 
 
After stabilization/resolution 
increase infusion rate as 
clinically indicated every 4-6 
hours. 
Administer tocilizumab (14) 8 mg/kg IV 
over 1 hour (not to exceed 800 
mg/dose). If no clinical improvement in 
the signs and symptoms of CRS after the 
first dose, repeat tocilizumab every 8 
hours as needed. Limit to a maximum of 
3 doses in a 24-hour period; maximum 
total of 4 doses. 
Administer dexamethasone 
(e.g., 4 to 6 mg IV or oral 
every 8 hours) for 24-48 
hours. 
Grade 2 
Symptoms require and respond to moderate 
intervention 
Oxygen requirement < 40% or 
Hypotension responsive to fluids or low-dose 
of one vasopressor (Table 6) or 
Grade 2 organ toxicity 
Slow infusion rate by 25-50%. 
 
After stabilization/resolution 
increase infusion rate as 
clinically indicated every 4-6 
hours. 
Per Grade 1 
Manage per Grade 3 if no 
improvement or worsening 
within 24 hours after starting 
tocilizumab. 
Grade 3 
Symptoms require and respond to aggressive 
intervention 
Oxygen requirement ≥ 40% or 
Hypotension requiring high-dose vasopressors 
or multiple vasopressors (Table 6) or 
Grade 3 organ toxicity (except transaminitis) or 
Grade 4 transaminitis 
Interrupt infusion, DO NOT 
FLUSH line. Aspirate residual 
drug from line. 
 
After resolution or stabilization 
to Grade 1 resume infusion at 
previous tolerated dose, and 
increase rate as clinically 
indicated every 4-6 hours. 
Per Grade 1 
Administer dexamethasone 
(e.g., 8 to 10 mg intravenously 
every 8 hours) or equivalent. 
Continue corticosteroid use 
until the event is Grade 1 or 
less, then taper over 3 days. 
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Table 5 
CRS Grading and Recommended Management Guidance          
CRS Grade (26) 
Dose Modification 
Tocilizumab 
Corticosteroids 
Grade 4 
Life-threatening symptoms 
Requirement for ventilator support or 
Grade 4 organ toxicity (excluding 
transaminitis) 
Discontinue flotetuzumab 
permanently. 
Per Grade 1 
Per Grade 3 
Grade 5 
• 
Notify the Sponsor’s Medical Monitor or designee immediately. 
• 
Report the event as an SAE. 
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Table 6 
Definition of High Dose Vasopressor          
Pressor 
High Dose 
(doses less than these would be considered Low Dose) 
Norepinephrine monotherapy 
≥ 20 µg/min 
Dopamine monotherapy 
≥ 10 µg/kg/min 
Phenylephrine monotherapy 
≥ 200 µg/min 
Epinephrine monotherapy 
≥ 10 µg/min 
If on vasopressin  
Vasopressin + norepinephrine 
equivalent of ≥ 10 µg/min* 
If on combination vasopressors 
(not vasopressin) 
Norepinephrine equivalent of 
≥ 20 µg/min* 
* 
VASST Trial vasopressor equivalent equation: norepinephrine equivalent dose = [norepinephrine 
(µg/min)] + [dopamine (µg/kg/min) ÷ 2] + [epinephrine (µg/min)] + [phenylephrine (µg/min) ÷10]. 
Source: Lee, et al. (26) 
 
The above grading scale should be used to grade all infusion reactions in this study, 
irrespective of the underlying mechanism of the reaction. Certain AEs may occur in temporal 
proximity to infusion of study drug and therefore, be considered “infusion-related” while not 
being considered an “infusion reaction;” such events may be graded separately according to 
CTCAE specific criteria. If these events are considered part of an IRR/CRS, however, they 
should be captured within the Adverse Event of Special Interest (AESI) reporting criteria as 
described in Section 7.11.3 and graded according to the criteria in Table 5. The Sponsor’s 
Medical Monitor or designee should be contacted if questions arise concerning the grade of 
the reaction. 
Other types of adverse reactions may be observed during infusion that are not interpreted as 
related to cytokine release, but may be related to flotetuzumab. Such reactions should be 
diagnosed, graded and managed according to best practices. Consultation with the study 
Medical Monitor is encouraged. 
6.4.2 
Tumor Lysis Syndrome  
Tumor lysis syndrome (TLS) is the most common disease-related emergency encountered by 
physicians caring for children or adults with hematologic cancers (19). Characteristic 
findings are hyperuricemia, hyperkalemia, hyperphosphatemia, and hypocalcemia. These 
electrolyte and metabolic disturbances can progress to clinical toxic effects, including renal 
insufficiency, cardiac arrhythmias, seizures, and death due to multi-organ failure. 
Prophylaxis for TLS should be administered for patients with AML. Aggressive hydration, 
allopurinol, and oral phosphate binders should be implemented starting preferably 24 hours 
before flotetuzumab administration. Serum chemistries should be closely monitored during 
flotetuzumab administration in accordance with institutional standards for the treatment of 
acute leukemia. If TLS is observed, rasburicase should be considered for management as per 
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institutional standards. Patients who develop TLS should be monitored closely for abnormal 
serum chemistries or signs of end organ damage and treated appropriately. 
6.4.3 
Neutropenic Sepsis/Fungemia  
While there is no evidence that flotetuzumab targets and depletes neutrophils in vitro in 
human samples or decreases circulating neutrophils in monkeys receiving the drug, caution 
should be exercised in assessing the possibility of infections in these patients. Early initiation 
of empirical broad-spectrum antibacterial antibiotics is recommended in the event of fever. 
Several monotherapy or multicomponent regimens have been employed. Investigators should 
employ these agents in compliance with best medical practices and institutional guidelines 
and standards. If fever persists for 4 to 7 days, an echinocandin or liposomal amphotericin B 
should be considered. Again, the Investigator should employ best medical judgment and 
institutional guidelines. The use of recombinant hematopoietic growth factors in AML is 
controversial. Their use is specifically prohibited in Cycle 1. However, beyond Cycle 1, while 
discouraged, their use is not specifically prohibited by this protocol and they may be 
employed at the discretion of the Investigator. 
6.4.4 
Immune-related Adverse Experiences  
Immune checkpoint blockade has been associated with several syndromes resulting from the 
breaking of immunological tolerance (42). Although not observed in non-clinical studies to 
date, similar immunomodulation might be expected with flotetuzumab. These syndromes 
include: pneumonitis, colitis, autoimmune hepatitis, arthritis, glomerulonephritis, myocarditis 
and cardiomyopathy, hypophysitis, or thyroiditis. Immune related adverse experiences will be 
considered AESIs (Section 7.11.3). Their occurrence dictates interruption, and potentially 
discontinuation, of study drug administration pending further evaluation. 
6.4.5 
Neurotoxicity  
Neurotoxicity, including changes in mental status, has been reported with other T-cell 
directed therapies including chimeric-antigen receptor (CAR)-T cells and CD3xCD19 based 
bispecific antibodies such as blinatumomab. The exact mechanism of the toxicity is 
unknown. As a result, additional monitoring of patients receiving flotetuzumab is indicated. 
An alteration in mental status refers to general changes in brain function, such as confusion, 
amnesia, loss of alertness, disorientation, defects in judgment or thought, and disruption in 
perception and psychomotor skills. Patients should be monitored for changes in mental status 
or other potential neurotoxic events and should be evaluated for orientation to time, place and 
person at baseline prior to treatment with flotetuzumab and at regular intervals during 
therapy. Any suspected neurotoxic event should prompt full evaluation including imaging 
studies, lumbar puncture and neurological consultation as indicated to rule out other causes. 
The incidence of CNS involvement by AML is low and routine lumbar puncture is not 
generally considered indicated. Patients with known, active CNS leukemia are excluded from 
the study and those with suspected disease must be evaluated by lumbar puncture prior to 
enrollment. 
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6.4.6 
Capillary Leak Syndrome  
Risk of capillary leak syndrome (CLS) has been associated with T-cell redirecting therapy, 
including chimeric antigen receptor (CAR-T)-cell and CD3-engaging bispecific antibody-
based molecules, and reported for the CD123-directed cytotoxin, tagraxofusp-erzs 
(Elzonris®). While CLS has not been observed with frequency in patients treated with 
flotetuzumab, a detailed review of recent clinical data across all flotetuzumab studies 
identified 3 patients who received flotetuzumab monotherapy that, concomitant with cytokine 
release syndrome during multi-step lead-in dosing, exhibited rapid weight gain, decreased 
albumin, and systemic edema suggestive of CLS. Please be aware that CLS may or may not 
be associated with hemoconcentration in this patient population. 
Healthcare professionals should monitor for weight gain of greater than 2.0 kg compared to 
previous day's weight, fluid status, new onset or worsening edema, and decreased albumin. 
Patient’s fluid status should be managed as clinically indicated with intravenous fluids and 
vasopressors if hypotensive, and with diuretics if normotensive or hypertensive until the 
patient’s body weight normalizes. Flotetuzumab dose interruption should be considered. 
Further recommendations include administration of 10 mg dexamethasone or equivalent for 
patients with weight gain of greater than 2.0 kg, fluid overload, and edema, non-responsive to 
diuretics and/or fluid management. 
6.4.7 
Epstein-Barr Virus Reactivation  
Epstein-Barr virus (EBV) belongs to the herpes virus family. After primary EBV infection, 
the virus quickly enters the latent phase and is characterized by a lifelong presence in B-cells. 
EBV-reactivation may occur in immune-compromised patients, and patients may experience 
signs or symptoms of mononucleosis, such as fatigue, weakness, fever, sore throat, and 
swollen lymph nodes. In immunosuppressed patients, including those who have received 
flotetuzumab, viral reactivation, specifically, EBV reactivation, has been reported. To date, on 
the CP-MGD006-01 study, four patients have experienced EBV reactivation. Reported 
symptoms included non-CRS related fever and fatigue. Rituximab (anti-CD20 antibody) is an 
effective treatment option in patients with EBV-reactivation and should be considered per 
institutional guidelines. 
6.5 
Blinding  
No blinding will be employed. 
6.6 
Concomitant Therapy  
All concomitant medications and blood products administered during the patient’s 
participation in the study must be recorded in the source document and on the electronic Case 
Report Form (eCRF). Patients’ blood product administered up to 28 days before enrollment 
should also be specified in the eCRF. Specifically, concomitant medications must be recorded 
through 7 days after the last administration of study drug or until the End-of-Treatment visit, 
whichever is later. Any concomitant medication associated with an AE or SAE that is 
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considered related to study drug must be recorded through 28 days after the last 
administration of study drug or End-of-Treatment visit, whichever is later. 
Patients may not receive the following concurrent therapy: 
• Any other therapies for leukemia. Use of hydroxyurea or other cytoreductive 
agents for the purposes of achieving an initial peripheral blast count  
20,000/mm3 should have ceased by the time of first dose of study treatment 
(Cycle 1 Day 1). However, hydroxyurea may be reinstituted at the discretion of 
the Investigator for the prevention or treatment of signs or symptoms of 
leukostasis during the time of study participation. 
• Previous treatment with any other investigational agent within 14 days or 5 half-
lives, whichever is longer, prior to study drug administration (Cycle 1 Day 1) is 
prohibited. Ruxolitinib is permitted for patients in the ruxolitinib mini-cohort. 
• Patients may not receive other investigational drugs during the period of study 
participation. 
• Because flotetuzumab employs a mechanism of action dependent upon the 
engagement of T lymphocytes, the use of corticosteroids other than those 
employed for premedication should be limited to the extent possible. Chronic 
doses of corticosteroids in excess of 10 mg daily of prednisone or equivalent are 
prohibited other than for the management of drug-related adverse experiences. 
Corticosteroid pretreatment should follow the recommended dose and schedule. 
Steroids may be employed in the treatment of suspected flotetuzumab-associated 
immunoinflammatory or autoimmune AEs or leukemia-associated AEs in 
consultation with the Sponsor. 
• Use of granulocyte colony stimulating factor or granulocyte-macrophage colony 
stimulating factor is prohibited during Cycle 1. 
• Vaccinations (with the exception of the annual inactivated influenza vaccine and 
SARS-CoV-2 vaccines) are prohibited during the study. SARS-CoV-2 vaccine 
may be administered during screening and up to 3 days prior to the first dose or 
after reaching the MTD of 500 ng/kg/day flotetuzumab. 
Patients may receive the following concurrent therapy: 
• Antiemetics, antidiarrheals, anticholinergics, antispasmodics, antipyretics, 
antihistamines, analgesics, antibiotics and other antimicrobials, histamine receptor 
(H2) antagonists or proton pump inhibitors, and other medications intended to 
treat symptoms or signs of disease. 
• Transfusions such as red blood cells and platelets are permitted to treat symptoms 
or signs of anemia or thrombocytopenia and should be documented on the 
transfusions eCRF. 
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• The use of hematopoietic growth factors is discouraged. However, granulocyte 
colony stimulating factor or Granulocyte-macrophage colony stimulating factor 
may be used in accordance with the practice of medicine and institutional norms 
or guidelines outside of Cycle 1. 
6.7 
Restrictions  
6.7.1 
Prior Therapy  
Prior therapy restrictions are described in the inclusion/exclusion criteria specified in 
Sections 5.1 and 5.2. 
6.7.2 
Fluid and Food Intake  
There are no requirements for fasting and no restrictions for fluid and food intake by the 
patients during the study, although it is recommended that, to the extent possible, patients 
have a fluid intake of  2 liters on days associated with PK sampling, and that 
electrocardiograms (ECGs) be obtained pre-meal. Potassium and phosphorus intake should 
be limited during the risk period for TLS according to institutional practices and guidelines. 
6.7.3 
Patient Activity Restrictions  
Patients who have received flotetuzumab must refrain from driving a motor vehicle or 
operating heavy machinery while receiving flotetuzumab, and for 30 days from the date of 
last study drug administration. 
6.8 
Treatment Compliance  
Flotetuzumab will be administered by healthcare professionals under the supervision of the 
Investigators. Records of flotetuzumab dose calculation, administration, and dosing regimen 
will be accurately maintained by site staff. The monitor will review medication accountability 
during investigational site visits and at the completion of the study. 
6.9 
Packaging and Labeling  
All investigational product will be labeled, at a minimum, according to local regulatory 
requirements. Please see the Pharmacy Manual for detailed information about the packaging 
and labeling of the flotetuzumab study drug, MGV002 IV Solution Stabilizer, and MGV004 
IV Solution Stabilizer. 
6.10 
Storage and Accountability  
6.10.1 
Flotetuzumab and IV Solution Stabilizer Storage  
Vials containing flotetuzumab, MGV002 IV Solution Stabilizer, or MGV004 IV Solution 
Stabilizer should be stored upright under refrigeration at 2°–8°C (36°–46°F) in an 
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appropriate, locked room accessible only to pharmacy personnel, the Investigator, or a duly 
designated person. Flotetuzumab, MGV002 IV Solution Stabilizer, and MGV004 IV Solution 
Stabilizer must not be frozen. Monitor temperature and document and report any excursions 
as instructed in the Pharmacy Manual. Protect from light during storage as described in the 
Pharmacy Manual. DO NOT SHAKE. Use standard laboratory practices for avoidance of 
contact. Recommended safety measures for handling of the drug product and preparation of 
the dose solution include masks, protective clothing, gloves, and vertical laminar airflow 
safety cabinet. Follow standard hygiene practices, such as hand washing after handling. If 
material is released or spilled, soak up material with absorbent material and wash spill area 
thoroughly with soap and water. Dispose of collected material in accordance with applicable 
waste disposal regulations. 
6.10.2 
Accounting for the Materials  
Accurate accounting of all study medication must be maintained. The Investigator agrees to 
keep an inventory of study drugs using the institution’s drug accountability logs or logs 
provided by MacroGenics. Drug disposition records must be kept in compliance with 
applicable guidelines and regulations. 
A Pharmacy Manual will be provided to the Investigator or designee. When the study is 
completed, copies of all study drug accountability records must be provided to the Sponsor. 
Original drug accountability records must be maintained with the rest of the documentation in 
accordance with Sections 10 and 11 for inspection by the study monitors. 
6.10.3 
Return or Destruction of Investigational Product  
All vials of flotetuzumab study medication and all vials of, MGV002 IV Solution Stabilizer 
and MGV004 IV Solution Stabilizer must be returned to MacroGenics or its representative, 
unless the site has received written authorization from MacroGenics to destroy vials at the 
site. All drug or stabilizer solution returns to MacroGenics must be accompanied by the 
appropriate documentation and be clearly identified by protocol number and study site 
number on the outermost shipping container. If MacroGenics approves the destruction of 
drug and/or stabilizer solution at the site, the Investigator must ensure arrangements are made 
for proper disposal and that appropriate records of disposal are documented and maintained 
and copies provided to the Sponsor. 
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7 
STUDY PROCEDURES  
This section provides a detailed description of the procedures and assessments associated 
with the study. A tabular schedule of events is shown in Appendix 1 for Cohort Expansion 
patients. 
7.1 
Informed Consent  
The Investigator is responsible for ensuring that the patient or his/her legal representative 
provides informed consent prior to performing any study related assessments, evaluations, or 
procedures. This event should be documented in the patient’s medical records. Informed 
consent for this study may be provided by signing an IRB/IEC-approved informed consent 
document (Consent for Study Participation). A copy of the relevant signed informed consent 
document must be provided to the patient, another copy kept with the study records, and the 
original maintained according to institutional procedures. In addition, the medical record will 
include documentation of the informed consent process (see Section 11.4). 
7.2 
Medical History  
A complete medical history should be obtained during the screening visit. All concurrent 
medical conditions in the last 60 days and any significant medical conditions (e.g., 
hospitalizations, surgeries, prior cancer history) should be collected. During the screening 
period (prior to first dose of flotetuzumab), any untoward event that occurs should be 
collected as a concurrent medical history and not as an adverse event, unless it is due to a 
protocol-related procedure. Thereafter (i.e., after the time of drug administration), any 
untoward event should be collected as an AE. Details of the disease (sub-classification for 
AML and risk stratification (e.g., cytogenetics) for AML) will be collected on the eCRF. 
7.3 
Prior and Concomitant Medications  
All concomitant medications, including blood products, administered during the patient’s 
participation in the study must be recorded in the source document and on the eCRF. 
Historical data regarding blood products administered up to 28 days prior to enrollment will 
also be collected in the eCRF. Specifically, concomitant medications must be recorded 
through 7 days after the last administration of study drug or End-of-Treatment visit, 
whichever is later. Any concomitant medication associated with an AE or SAE that is 
considered related to study drug must be recorded through 28 days after the last 
administration of study drug or End-of-Treatment visit, whichever is later. 
Prior courses of chemotherapy will be documented on the eCRF. 
7.4 
Physical Examination  
The Investigator will perform physical examination of all patients. Physical examination will 
include height (screening only), weight, and examination of skin, HEENT (head, eyes, ears, 
nose, and throat), lymph nodes, heart, chest, lungs, abdomen, extremities, and 
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neurologic system as specified in the Schedule of Events for Cohort Expansion (Appendix 
1). 
7.5 
Vital Signs  
Vital signs including blood pressure, heart rate, respirations, pulse oximetry, and temperature 
will be taken immediately prior to the start of flotetuzumab infusion, and repeated as outlined 
in Appendix 1. Vital signs may also be captured as necessary to elucidate the course of any 
untoward event or AE. 
7.6 
Clinical Laboratory Tests  
Blood and urine specimens will be collected at the times specified in Appendix 1. 
Hematology, chemistry, coagulation, pregnancy, and urinalysis testing will be performed 
locally. Table 7 below lists the specific tests that will be performed locally for this study. 
Investigators must document their review of each laboratory result. 
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Table 7 
Local Routine Laboratory Tests                                                        
Hematology: 
• 
Hematocrit (Hct) 
• 
Hemoglobin (Hgb) 
• 
Mean corpuscular volume (MCV) 
• 
Mean corpuscular hemoglobin (MCH) 
• 
Mean corpuscular Hgb concentration (MCHC) 
• 
Erythrocytes distribution width (RDW) 
• 
Red blood cell count (RBC) 
• 
White blood cell (WBC) count with differential 
including blast count 
• 
Platelet count 
• 
Mean platelet volume (MPV) 
• 
Reticulocytes 
Urinalysis: 
• 
glucose (by standard dipstick) 
• 
bilirubin (by standard dipstick) 
• 
ketones (by standard dipstick) 
• 
specific gravity (by standard dipstick) 
• 
blood (by standard dipstick) 
• 
pH (by standard dipstick) 
• 
protein (by standard dipstick) 
• 
urobilinogen (by standard dipstick) 
• 
nitrite (by standard dipstick) 
• 
leukocytes (by standard dipstick) 
• 
microscopic evaluation of urinary sediment 
 
Urine or serum human chorionic gonadotropin (hCG) 
(only for females who are not postmenopausal or sterile 
as the result of surgical procedure) 
Serum Chemistry: 
• 
Albumin (ALB) 
• 
Alkaline phosphatase (ALK-P) 
• 
Alanine aminotransferase (ALT) 
• 
Aspartate aminotransferase (AST) 
• 
Blood urea nitrogen (BUN) 
• 
Bicarbonate (HCO3) 
• 
C-reactive protein (CRP) 
• 
Calcium (Ca) 
• 
Chloride (Cl) 
• 
Creatinine 
• 
Glucose 
• 
Potassium (K) 
• 
Sodium (Na) 
• 
Total bilirubin 
• 
Total protein 
Special Chemistry: 
• 
Uric Acid 
• 
Phosphorus 
• 
Creatine kinase (CK) 
Coagulation: 
• 
Prothrombin time (PT) 
• 
Activated partial thromboplastin time 
(APTT) 
 
Bone marrow aspiration and biopsy specimens will be processed and evaluated locally at the 
investigational institution. Material may be requested for central review during or following 
completion of the study. A portion of the bone marrow aspirate and biopsy specimen will be 
collected for research purposes at specific time points (see Appendix 1). 
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Certain other testing of blood samples and bone marrow aspirate and biopsy specimens (PK, 
ADA, PBMC subsets and activation markers) will be carried out at Sponsor-specified central 
laboratories (refer to the Laboratory Manual). 
7.7 
Electrocardiography and Continuous Telemetry Monitoring  
Twelve-lead ECGs will be obtained according to Appendix 1 to evaluate the potential 
cardiac effect, including QTc interval prolongation. There are no requirements for fasting and 
no restrictions for fluid and food intake by the patients during the study, although it is 
recommended that, to the extent possible, ECGs be obtained pre-meal. 
To account for intrinsic variability, screening and Cycle 1 Day 15 (or when patient has 
reached 500 ng/kg/day dose level, if later than Cycle 1 Day 15) ECGs should be obtained in 
triplicate (3 ECGs per time point at approximately 1-minute intervals). Subsequent ECGs will 
be performed when clinically indicated, and will be single tracing unless clinical 
circumstances, and at the discretion of the investigator, indicate otherwise. Central 
interpretation of ECGs will be used for data analysis purposes. 
7.8 
Left Ventricular Ejection Fraction  
In the Cohort Expansion Segment, if the patient has a history or signs and symptoms of 
cardiac disease, an echocardiogram (or, except in Germany, multiple-gated acquisition scan 
[MUGA] if indicated) will be obtained during the screening period, if one was not performed 
within 30 days before the start of treatment (Cycle 1 Day 1). An echocardiogram (or, except 
in Germany, MUGA if indicated) may also be conducted during the study if clinically 
indicated. 
7.9 
Pulmonary Function Testing  
In the Cohort Expansion Segment, PFT, including DLCO and FEV1, will be conducted 
during the screening period if testing was not performed within 30 days before the start of 
treatment (Cycle 1 Day 1). PFT may also be conducted during the study if clinically 
indicated. 
• During the COVID-19 pandemic, except in Germany, if PFT equipment is not 
available, a correlative stair-climbing test may be conducted instead, together 
with lung CT and echocardiogram irrespective of cardiac history. The patient 
must pass the stair-climbing test, with O2 saturation ≥ 95%, lung CT with 
normal appearing lung parenchyma, and normal echocardiogram (see Section 
8.1.1). 
7.10 
Efficacy Assessments  
Response Assessments: evidence of clinical activity in these patients will be assessed by the 
study investigators by using CBC and peripheral blood cell morphological examination, 
examination of bone marrow aspiration (or biopsy if required), and physical exam according 
to the rules modified from the Revised Recommendations of the International Working Group 
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(IWG) for Diagnosis Standardization of Response Criteria, Treatment Outcomes, and 
Reporting Standards for Therapeutic Trials in Acute Myeloid Leukemia (Appendix 3), with 
modifications as described below. Response assessment will be based on bone marrow 
aspirate/biopsy and the best CBC up to 14 days post bone marrow aspirate/biopsy. Responses 
will be categorized as: 
• CR: mCR (morphologic CR), CRc (cytogenic CR), or CRm (molecular CR); 
• CRh (CR with partial hematologic recovery);  
• CRi (CR with incomplete blood count recovery): CRn (CR with incomplete 
neutrophil recovery) or CRp (CR with incomplete platelet recovery);  
• MLFS (morphologic leukemia free state); 
• PR (partial response); 
• OB (other benefit); 
• SD (stable disease); 
• PD (progressive disease). 
Bone marrow assessment should be performed at the end of each cycle whenever possible. 
However, at the end of Cycle 2, and at the end of each subsequent even cycle, in consultation 
with the Medical Monitor, the bone marrow assessment may be missed if the patient has 
clearly not achieved CR or CRh using the following criteria: 
• The patient has not achieved CR/CRh because the peripheral blood neutrophils 
are < 500/μL or platelets are < 50,000/μL, based on Study Day 22 CBC results 
for the cycle in question, and 
• The results of the bone marrow assessment will not influence the decision to 
continue study treatment (i.e., assessment of risks and benefits). 
The overall complete response rate (BM blasts < 5%) will be the proportion of patients with 
AML achieving any CR, CRh, CRi, [CRn, CRp], or MLFS when such responses are 
documented at any point of any cycle of treatment. The objective response rate will be the 
proportion of patients with AML achieving CR, CRh, CRi, [CRn, CRp], MLFS, or PR when 
such responses are documented at any point of any cycle of treatment. To support the 
composite endpoint CR/CRh, the duration of initial hospitalization for flotetuzumab 
administration, the incidence and duration of subsequent hospitalizations, and transfusion 
independence rate, as well as rate of conversion to transfusion independence and rate of 
maintenance of transfusion independence, will be assessed. The timing of the AML response 
evaluation, i.e., the allowance for response at a time later than Day 25 from the start of 
treatment, differs from those modified from the IWG guidelines for AML (which are based 
on responses to cytotoxic chemotherapy) to allow sufficient time for an immune-mediated 
response to be observed. Patients who do not demonstrate an objective response at early 
evaluations, may be subsequently categorized as responders at later evaluations. Response 
duration will be calculated from the time of initial response to the time of relapse or death, 
whichever occurs first. Patients who complete the study while still in response will be 
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censored at their last disease assessment. Time to response will be calculated from the time of 
first dose of study drug to the time of initial response. 
Event-free survival (EFS) will be calculated as the time from the first dose of study drug until 
date of relapse from CR, CRh, or CRi (CRn, CRp), or death from any cause, whichever 
occurs first. 
Overall survival (OS) will be calculated as the time from the first dose of study drug until the 
occurrence of death from any cause. Mortality rates from any cause within 30, 60, 90, and 
180 days from the first dose of study drug will be calculated. Six-month and one-year 
survival rates will be calculated. 
7.11 
Safety Assessments  
7.11.1 
Adverse Event: Definitions  
Adverse Event 
An adverse event (AE) is any untoward medical occurrence in a clinical investigation patient 
to whom a pharmaceutical product is administered. The event may or may not have a causal 
relationship with this treatment. An AE can, therefore, be any unfavorable and unintended 
sign (e.g., an abnormal laboratory finding), symptom, or disease temporally associated with 
the use of a medicinal product, whether or not considered related to the medicinal product. 
An AE will also be considered to be any untoward effect of a study-related procedure, which 
may be conducted after signed informed consent and prior to study drug administration. 
Adverse Drug Reaction 
An adverse drug reaction (ADR) is any noxious and unintended response to the medicinal 
product related to any dose. As used herein, the phrase "responses to a medicinal product" 
means that a causal relationship between a medicinal product and an AE is at least a 
reasonable possibility, (i.e., the relationship cannot be ruled out). 
Adverse Event of Special Interest 
An AESI is an event of scientific and medical interest or concern to the Sponsor’s product or 
program, for which ongoing monitoring and rapid communication to the Sponsor could be 
appropriate. It may be a serious or non-serious AE, which may require further investigation in 
order to characterize and understand it. 
Treatment-Emergent Adverse Event 
An event that is temporally associated with administration of study drug is defined as a 
treatment-emergent adverse event (TEAE). Events meeting this definition will be those 
occurring during study drug administration and up to and including at least terminal 
elimination of the drug (roughly 5 half-lives; for flotetuzumab the estimated elimination half-
life is a few hours). Events that existed before the first administration of study drug and then 
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increased in severity during or after the first administration of study drug will also be 
considered treatment emergent. Such events will be captured on the eCRF as new events, 
with the onset date as the date of the increase in severity. 
Serious Adverse Events 
A serious adverse event (SAE) is any AE that results in any of the following outcomes: 
• Death 
• Life-threatening (immediate risk of death) 
• Inpatient hospitalization or prolongation of existing hospitalization (even if the 
event is Grade 1) 
• Persistent or significant disability or incapacity 
• Congenital anomaly/birth defect 
• Important medical events that may not result in death, be life-threatening, or 
require hospitalization may be considered a SAE when, based upon appropriate 
medical judgment, they may jeopardize the patient and may require medical or 
surgical intervention to prevent one of the outcomes listed in this definition. 
Examples of such medical events include allergic bronchospasm requiring 
intensive treatment in an emergency room or at home; blood dyscrasias or 
convulsions that do not result in inpatient hospitalization or the development of 
drug dependency or drug abuse. 
Immediately Reportable Event 
Immediately reportable events (IREs) are events that must be reported immediately to 
MacroGenics Product Safety or designee within 24 hours of being identified (see  
Section 7.12). IREs include but are not limited to: 
• SAEs 
• AEs leading to permanent discontinuation of study drug in an individual patient 
• Pregnancy in a study patient or partner (Note: If the female partner of a male 
patient becomes pregnant, the partner must be requested to complete a Pregnant 
Partner Consent Form so that pregnant partner, fetal and/or newborn information 
can be collected.) Upon confirmation of serum pregnancy testing, the patient will 
be followed for the outcome of pregnancy. All live newborns will be followed six 
months after the birth, and all necessary information will be collected to assess the 
effects of study drug on the newborn. If necessary, the follow-up period will be 
extended for the newborn. 
• Grade 2 or higher infusion-related reactions including CRS 
• TLS as defined in Section 6.4.2 
• Neutropenic sepsis or fungemia as defined in Section 6.4.3 
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• Immune related adverse events as defined in Section 6.4.4 
• Grade 2 or higher neurological events as described in Section 6.4.5 
• Capillary leak syndrome as described in Section 6.4.6 
• EBV reactivation as described in Section 6.4.7 
• Confirmed or presumed (test pending/clinical suspicion) SARS-CoV-2 infection. 
Withdrawal of patient from study drug administration due to toxicity (e.g., AE, SAE, AESI) 
or pregnancy. 
In those cases in which the IRE is considered related to study drug and the event is of 
sufficient clinical concern, the study drug may be discontinued and the patient will continue 
participation in the study for observational safety and analysis (except for cases where the 
patient is withdrawn from the study by the Investigator). At any time after completion of the 
study, if an Investigator becomes aware of a SAE that s/he suspects is related to study drug, 
the Investigator should report the event to MacroGenics Product Safety or designee. 
7.11.2 
Performing Adverse Event Assessments  
Medical evaluation and classification of the AE must be performed by the Investigator who is 
qualified to review AE information. The determination of seriousness, severity and causality 
must be made according to the following criteria: 
Assessment of Seriousness: Event seriousness will be determined according to the definition 
of an SAE in Section 7.11.1. Seriousness serves as a guide for defining regulatory reporting 
obligations for AEs. 
Assessment of Severity: Event severity will be assigned according to the Investigator’s 
assessment using the following: 
CTCAE v4.0 (for described events and syndromes), except IRR/CRS which will be defined 
by the modified criteria proposed by Lee et al. (26) as described in Section 6.4.1.2, or for 
events not specifically defined in the CTCAE, using the following scale: 
Grade 1= Mild AE; 
Grade 2 = Moderate AE; 
Grade 3 = Severe AE; 
Grade 4 = Life-threatening or disabling AE; and 
Grade 5 = Death related to AE 
Any event or laboratory value judged as Grade 4 severity should be separately evaluated to 
determine whether it also meets the serious criterion of "immediately life threatening." 
Note: Severity is not synonymous with seriousness. The term "severe" is often used to 
describe the intensity (severity) of a specific event. The event itself, however, may be of 
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relatively minor medical significance (such as severe headache). This is not the same as 
"serious," which is based on patient/event outcome or action criteria usually associated with 
events that pose a threat to a patient's life or functioning. 
Assessment of Causality: The Investigator is required to provide an assessment of causality 
or relationship of AEs to the study drug based on: 1) temporal relationship of the event to the 
administration of study drug, 2) whether an alternative etiology has been identified, and 
3) biological plausibility. The causality assessment categories that will be used for this study 
are described below. 
Causality assessments that are considered Not Related to study drug: 
None: The event is related to an etiology other than the study drug (the alternative 
etiology must be documented in the patient’s medical record). 
Unlikely: The event is unlikely to be related to the study drug and likely to be related to 
factors other than study drug. 
If an SAE is considered "unlikely" or "unrelated" to study drug, the Investigator should offer 
his/her clinical opinion as to what factor(s), agent(s), or process(es) were the likely causative 
mechanism for the event. 
Causality assessments that are considered Related to study drug: 
Possible: There is an association between the event and the administration of the study 
drug and there is a plausible mechanism for the event to be related to study drug; but 
there may also be alternative etiology, such as characteristics of the patient’s clinical 
status or underlying disease. 
Probable: There is an association between the event and the administration of study 
drug, a plausible mechanism for the event to be related to the study drug and the event 
could not be reasonably explained by known characteristics of the patient’s clinical status 
or an alternative etiology is not apparent. 
Definite: There is an association between the event and the administration of study 
drug; a plausible mechanism for the event to be related to the study drug and causes other 
than the study drug have been ruled out and/or the event re-appeared on re-exposure to 
the study drug. 
Assessment of Expectedness: As part of the regulatory reporting requirements, the Sponsor 
must perform an assessment of expectedness (expected/unexpected from the perspective of 
previously observed, not on the basis of what might be anticipated from the pharmacological 
properties of a medicinal product) for AEs. Adverse reactions will be considered unexpected 
if the nature, seriousness, severity or outcome of the reaction(s) is not consistent with the 
reference information (e.g., the Adverse Drug Reaction section of the Investigator’s 
Brochure) for the study product. 
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7.11.3 
Adverse Events of Special Interest  
In this study, TLS (as defined in Section 6.4.2), neutropenic sepsis/fungemia  
(Section 6.4.3), immune-related events (Section 6.4.4), treatment-related ≥ Grade 2 
neurological events (Section 6.4.5), capillary leak syndrome (Section 6.4.6), and EBV 
reactivation (Section 6.4.7) are considered AESIs and should be reported as IREs and 
documented on the appropriate eCRF irrespective of attribution to flotetuzumab. 
All infusion related reactions including CRS are considered AESIs and should be 
documented on the appropriate eCRF; only ≥ Grade 2 events need to be reported to the 
Sponsor as IREs. 
7.11.4 
Reporting of Adverse Events to the Sponsor  
Adverse events and SAEs will be collected and followed from the time the patient provides 
informed consent for the study (see Section 8.1) through 28 days after the last administration 
of study drug or until the start of a subsequent systemic anticancer therapy, if earlier. If a 
patient experiences an AE after the informed consent document is signed and prior to 
treatment with study drug, it should be captured as medical history; however, if the 
Investigator believes the AE may have been caused by a protocol procedure, or related to 
ruxolitinib, it will be reported to the Sponsor or its designee and/or entered on the eCRF. 
Adverse events occurring after the patient undergoes early termination or completes the trial 
(attains 28 days after last administration of study drug or starts a subsequent systemic 
anticancer therapy, if earlier) need not be reported unless the event is serious and the 
Investigator believes that the event may have been caused by the study drug or a protocol 
procedure. 
To identify the occurrence of any new medical complaints or worsening of previous 
complaints, non-leading questioning should be posed to the patient. 
Events related to leukemia progression/worsening of underlying disease (including those with 
a fatal outcome) will be collected as efficacy endpoints, and not documented as AEs/SAEs. 
However, if an SAE occurs in a patient and it is unclear if the event is due to progressive 
disease, the SAE should be reported. 
If a patient reports signs and symptoms that represent a single medical syndrome, diagnosis, 
or concept, the syndrome/diagnosis/concept should be documented as an AE (e.g., cough, 
runny nose, fever = Upper Respiratory Tract Infection) in the eCRF. One exception is for 
IRR/CRS, for which the Sponsor would like to collect specific information on signs and 
symptoms. For IRR/CRS, report just the IRR/CRS event as an AE; signs and symptoms 
associated with IRR/CRS should only be reported on the IRR/CRS eCRF page and not as 
independent AEs. 
The Investigator must follow all SAEs until resolution. Resolution of an event is defined as 
the return to pre-treatment status or stabilization of the condition with the expectation that it 
will remain chronic. 
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Clinical Laboratory Changes: Safety laboratory assessments will be carried out locally and 
evaluated by the Investigator to ensure patient safety. The Investigator is responsible for 
reviewing the results of all laboratory tests as they become available. Laboratory tests will be 
graded according to CTCAE v4.0. Laboratory values that fall outside of a clinically accepted 
reference range or values that differ significantly from previous values must be evaluated by 
the Investigator for clinical significance. The Investigator may repeat the laboratory test or 
request additional tests to verify the results of the original laboratory tests, in which case the 
repeat assessment will be considered the true value. If the Investigator determines the 
laboratory value is an abnormal change from baseline and is of clinical significance for that 
patient, it is considered an AE. Generally, Grade 1 laboratory findings need not be reported as 
AEs unless clinically significant. The Investigator will evaluate laboratory findings of 
≥ Grade 2 classification to determine their clinical significance and if an AE has occurred. 
Consistent with the CTCAE designation of Grade 3 events as severe or medically significant 
and Grade 4 events as life-threatening, all such events should be reported as AEs or SAEs, as 
appropriate, unless these are considered an expected consequence of the underlying disease. 
Grade 2 events may be reported as AEs if, in the opinion of the Investigator, the event 
exhibits clinical significance. If clinically relevant abnormal laboratory values are associated 
with clinical symptom(s), or consistent with a diagnosis, the diagnosis should be reported as 
the AE (e.g., hemoglobin 9 g/dl in an adult female = anemia). If these clinically relevant 
abnormal laboratory values do not result in a diagnosis, the test result or finding should be 
reported as the AE assuming that it does not represent a laboratory error. Repeat testing may 
be indicated. Such laboratory values should generally be recorded as “increased” or 
“decreased” (e.g., change from baseline hemoglobin of 13 g/dl to 11 g/dl = hemoglobin 
decreased). 
7.12 
Notification to the Sponsor of Events Requiring Immediate 
Reporting  
Throughout the study, the Investigator must document all AEs on the eCRF in a timely 
manner. IREs, as defined in Section 7.11.1, are events that must be reported immediately to 
MacroGenics Product Safety within 24 hours of being identified. The Investigator must 
immediately complete and email or fax the Immediately Reportable Event (IRE) Report Form 
within 24 hours of identifying the event to MacroGenics Product Safety/designee (see the 
IRE Report Form and IRE Report Form Completion Guidelines for details). 
For pregnancy, the MacroGenics Pregnancy Exposure Form must also be completed and 
faxed/emailed to MacroGenics Product Safety. The Investigator must attempt to follow the 
pregnancy to term or termination in order to report on outcome and health status of mother 
and child. 
Contact information for MacroGenics Product Safety is shown below. 
• Email: SAEReports@macrogenics.com (preferred transmission) or 
• Fax: (301) 354-3800 
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7.13 
Emergency Unblinding  
Not applicable. 
7.14 
Other Study Procedures  
7.14.1 
Pharmacokinetics, Biomarkers, and ADA  
MacroGenics or its designee will provide the following blood sampling supplies: 
polypropylene transport tubes, labels, and log sheets. Serum tubes should be labeled with the 
patient’s unique study number, date, and time of sampling. The Investigator will maintain a 
log with the same data. 
Specimens must be appropriately prepared, divided if appropriate, frozen, and shipped (while 
often retaining certain replicate samples at the site) according to the instructions in the 
Laboratory Manual. 
7.14.1.1 
Pharmacokinetics  
It is expected that the sensitivity of the PK assay will be sufficient to detect concentrations of 
study drug in samples taken from patients receiving doses  100 ng/mg/day. Serum 
concentrations of flotetuzumab will be monitored using an electrochemiluminescence-based 
sandwich assay. PK analyses will be performed using industry standard software. Population 
PK modeling will be performed and an appropriate model will be selected to describe the 
data. 
Venous blood samples for PK analyses for flotetuzumab will be processed as instructed in the 
Laboratory Manual. 
7.14.1.2 
ADA (Anti-flotetuzumab Antibodies)  
Venous blood samples for ADA will be processed as instructed in the Laboratory Manual. 
Serum samples from all patients may be retained as described in Section 7.14.9 for detection 
of ADA and evaluation of neutralizing antibodies if there are any ADA- positive samples. 
7.14.2 
Flow Cytometric Analyses on Bone Marrow and Peripheral 
Blood Samples  
Multiparameter flow cytometric determination of the absolute number and phenotype of 
monocytes, NK cells, pDCs, and B and T lymphocyte subsets (including Treg, naïve/central 
memory/effector memory and Th1/Th2/Th17 subsets) will be performed based on the flow 
cytometry panels recently described by the Human Immunophenotyping Consortium (27). 
Other cell types based on the Human Immunophenotyping Consortium (27) flow cytometry 
panels may also be evaluated. Quantification of the number and phenotype of AML blast 
cells in the peripheral blood and bone marrow will be determined on fresh samples at each 
time point as described previously (43). Since AML is a heterogeneous and molecularly 
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complex group of diseases with variable hematologic phenotypes (14,33) selection of 
antigens for the identification and immunophenotypic characterization of AML blast cells 
will be determined from each patient’s prior flow cytometric testing. Antigenic expression 
patterns of CD123 on all normal peripheral blood cell subsets as well as malignant blasts will 
be evaluated. The activation state of CD3+CD4+ and CD3+CD8+ T cells could be assessed 
using monoclonal antibodies to Lag-3, PD-1, CD25 and CD69. The percentage of positive 
cells and median fluorescence intensity of each antigen will be determined. 
7.14.3 
Other Assessments  
Transcriptome in bone marrow aspirate samples will be analyzed for expression patterns 
reflective of immune cell infiltration to determine the effect of flotetuzumab on the tumor 
microenvironment. 
Generation of adaptive immune responses during flotetuzumab treatment will be evaluated in 
vitro cytotoxicity assays. T-cells will be interrogated for activation patterns, subgroup 
phenotyping, T cell receptor rearrangements, and complementarity determining region 3 
(CDR3) sequencing (see Section 7.14.7). 
7.14.4 
Bone Marrow Assessments  
Bone marrow aspirate and trephine biopsy will be obtained and analyzed locally per 
institutional guidelines during screening and upon completion of every treatment cycle. 
Marrow smears will be morphologically examined using a May-Grünwald-Giemsa or a 
Wright-Giemsa stain with a nucleated differential count from at least 200 cells performed. 
Percent marrow blasts should be recorded at both baseline and on study. Conventional 
cytogenetic analysis with a minimum of 20 metaphase cells analyzed from bone marrow 
should be performed at each assessment. For patients with pretreatment cytogenetic 
abnormalities, additional fluorescence in situ hybridization (FISH) may be performed at the 
time of baseline evaluation and again at the time of response evaluation. 
7.14.5 
Cytokine Analyses  
Cytokines will be centrally evaluated in serum using an immunoassay. 
7.14.6 
Minimal Residual Disease  
Change in tumor burden as measured by next generation sequencing with digital sequencing 
read counts of commonly recurring mutations in AML may predict clinical benefit in patients 
treated with flotetuzumab. Targeted resequencing of DNA obtained from serial bone marrow 
samples will be performed. 
In selected patients in the United States (only Washington University site in St. Louis, MO), 
sequencing of DNA obtained from buccal mucosa swab or saliva samples will be compared 
to baseline tumor samples to help define which nucleotide variants in these genes that are 
acquired in the malignant sample. 
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The change in mutation burden will be then tracked over the course of the patient’s treatment 
on the clinical trial. This analysis will also help identify and characterize individual subclones 
of tumor cells, which may demonstrate differential sensitivity to treatment. In addition, 
tracking the change of tumor burden may serve as a more sensitive early indicator or 
biomarker of response to treatment. 
7.14.7 
T Lymphocyte Repertoire  
To assess changes in T cell clonality and diversity in response to flotetuzumab, IgH and TCR 
from genomic DNA will be amplified using universal primer sets and quantify the frequency 
of clones using next-generation sequencing. CDR3 sequences will also be analyzed for 
clonotype across patients. 
7.14.8 
Sample Collection, Storage, and Shipping  
For samples to be analyzed at a central laboratory, sample collection, handling, labeling, and 
shipping procedures are described in the Laboratory Manual. 
7.14.9 
Sample Retention and Further Testing  
Samples acquired for protocol specified assays will be retained for study purposes 
(analysis/re-analysis) and may be retained up to 2 years after 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 formal 
discontinuation of clinical development of the investigational product. If patients consent to 
the use of their study samples for non-study research purposes, these samples may also be 
used for exploratory testing (including assay development/optimization) and may be retained 
up to 15 years from the end of study. 
7.15 
Appropriateness of Measurements  
Routine laboratory evaluations including hematology, chemistry, special chemistry, 
coagulation, and urinalysis will be carried out in local institutional laboratories. Additional 
local safety laboratory assessments may be used to supplement the protocol-prescribed 
assessments and may be used to elucidate certain AEs. If during assessment of AEs a patient 
undergoes imaging study and/or sample collection, e.g., pleural fluid, intra-articular joint 
aspiration, or ascitic fluid, a sample may be provided to the Sponsor to help elucidate 
etiology. 
Serum concentrations of flotetuzumab will be monitored. Standard bridging enzyme-linked 
immunosorbent assays (ELISAs) will be carried out in the Sponsor’s designated central 
laboratory to characterize the immunogenicity of flotetuzumab. Analysis of PK data will be 
carried out using industry standard software. The impact of AML on PK parameters will be 
evaluated. 
Baseline, on-treatment, and follow-up bone marrow aspiration and/or biopsy specimens will 
be used for the assessment of disease status and effects of flotetuzumab treatment. These 
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assessments will be carried out in routine fashion in the investigational institutions’ facilities. 
Material may be requested for central review during or following completion of the study. 
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8 
STUDY ACTIVITIES  
A table of study activities by study day is presented in the Schedule of Events for Cohort 
Expansion (Appendix 1). 
8.1 
Pre-treatment Evaluations  
Patients will be evaluated before registration. At this screening visit, patients will enter the 
study upon signing the study-specific informed consent document. Only those patients who 
meet all inclusion/exclusion criteria specified in Sections 5.1 and 5.2 will be enrolled. 
Informed consent must be obtained prior to performing any screening procedures and 
may be obtained prior to the start of the 14 day screening period. 
8.1.1 
Within 14 Days Before Treatment  
The screening window will start with the conduct of the first pre-treatment evaluation. 
Pre-treatment evaluations and activities include: 
• Obtain bone marrow aspirate and/or biopsy specimen, if not performed within 
30 days before the start of treatment (Cycle 1 Day 1), for local 
histopathological and immunohistochemical evaluation, central flow 
cytometric evaluation, and minimal residual disease analysis. 
• Obtain buccal mucosal sample (only Washington University Site in St. Louis, 
MO). 
• If patient has a history or signs and symptoms of cardiac disease, obtain 
echocardiogram (or, except in Germany, MUGA if indicated) if one was not 
performed within 30 days before the start of treatment (Cycle 1 Day 1). An 
echocardiogram (or, except in Germany, MUGA if indicated) may also be 
conducted during the study if clinically indicated. 
• Conduct PFT, including DLCO and FEV1, if testing was not performed within 
30 days before the start of treatment (Cycle 1 Day 1). PFT may also be 
conducted during the study if clinically indicated. 
o During the COVID-19 pandemic, except in Germany, if PFT equipment is 
not available to perform the required screening procedure, the 
recommended alternative is to perform a correlative stair-climbing test of 
5 flights (127 steps), per Bolton (3). The patient is to walk up several 
flights of stairs at his/her own moderate pace (timed with a stopwatch) 
and encouraged to proceed as far as possible without stopping. The 
patient is considered passing the stair climb screening test if the patient 
can complete all 5 flights (127 steps) without complications, such as 
prolonged recovery time, severe air hunger, or stopping the climb due to 
non-pulmonary complaints. The site will be expected to provide baseline 
data (including pulse rate, blood pressure, and respiratory rate) obtained 
prior to the stair climb, documentation of the number of stairs the patient 
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was able to climb, time in seconds, reason for stopping, and the O2 
saturation the patient achieved as described in Bolton et al. In addition, 
the pulse rate, blood pressure and respiratory rate should be recorded 
immediately post climb, at 2 minutes after stopping, at 5 minutes after 
stopping and at 10 minutes after stopping if the patient did not fully 
recover within 5 minutes. If the patient passes the stair climbing test, CT 
of the lung and echocardiogram, irrespective of cardiac history, must be 
performed. 
8.1.2 
Within 5 Days Before Treatment  
• Conduct medical history (including collection of AE reporting) and review of 
concomitant medications (including all transfusion requirements up to 28 days 
prior to dosing) 
• Report human leukocyte antigen (HLA) typing if available 
• Evaluate ECOG performance status 
• Conduct physical examination (examination of skin, HEENT [head, eyes, ears, 
nose, throat], lymph nodes, heart, chest, lungs, abdomen, extremities, and 
neurologic system), including height, weight, and disease assessment 
• Obtain ECG, standard 12-lead 
• Take vital signs (including blood pressure, heart rate, respirations, pulse 
oximetry, and temperature) 
• Obtain specimen for CBC with differential and platelet count 
• Obtain specimen for chemistry panel (ALB, ALK-P, ALT, AST, BUN, HCO3, 
Ca, Cl, creatinine, glucose, K, Na, total bilirubin, total protein) and CRP 
• Obtain specimen for Special Chemistry (phosphorus, uric acid, CK) 
• Obtain specimen for coagulation studies (PT, aPTT) 
• Obtain specimen for urinalysis and examination of urinary sediment 
• Perform urine or serum -hCG pregnancy test for women of childbearing 
potential 
• Obtain peripheral blood for flow cytometric evaluation 
8.1.2.1 
Patient Registration  
Each patient must be registered with MacroGenics before study entry. The following 
information should be provided during registration: 
• AML diagnosis, including disease risk classification and cytogenetics 
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• Prior AML treatment history, including dates of treatment, outcome of 
treatment, best response, and treatment failure, as well as number of treatment 
cycles received and duration of prior treatment outcome. 
• Date of signed informed consent 
• Planned date of first drug administration 
• Confirmation of conformity to the entry criteria 
8.1.3 
Within 1 Day Before Treatment  
Initiate TLS prophylaxis for patients with AML employing hydration, allopurinol, and oral 
phosphate binders as defined by institutional practices and standard of care. 
8.2 
Study Evaluations Applicable During Cohort Expansion  
Patients may be treated on an outpatient basis after Cycle 1 Day 8 (and after a minimum of 
24 hours at the 500 ng/kg/day maximum dose) of study treatment guided by tolerability of the 
regimen during the first 8 days of dosing, and at the discretion of the Investigator. Cycles 2 
and greater may be administered as an outpatient if the previous cycle was well-tolerated. 
During Cycle 1, laboratory assessment samples are to be drawn around the same time each 
day, and prior to start of infusion or dose change as applicable and after end of infusion on 
days when infusions end unless otherwise indicated. 
8.3 
End of Treatment Visit/Follow-up  
8.3.1 
End of Treatment Visit: 28-Days (4 Weeks) After Last Dose of 
Study Drug or at the Time of Treatment Failure  
It is recognized that certain patients (such as those experiencing progression of disease) may 
be cared for in facilities other than the participating investigational site, may proceed to 
receive other anti-leukemic therapy, and/or may elect not to return to the investigational site. 
Therefore, this visit is considered optional, but should be carried out whenever possible. 
8.3.2 
Follow-up Period  
Follow-up information will be requested by the Sponsor after end of treatment until death or 
withdrawal of consent, but not beyond 2 years after the last patient is enrolled. All patients 
will have clinical information including safety, transfusion requirements, disease and vital 
status information collected during the follow-up period. Depending on treatment response, 
patients may be required to continue follow-up at the study site for the first 6 months post 
treatment. After these first 6 months, follow-up can be conducted outside of study site, but 
follow-up information must still be provided to Sponsor as outlined. 
 
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Follow-up Frequency 
• Responders (CR, CRh, CRi [CRn, CRp], or MLFS): 
Patients who respond to treatment should have monthly visits at the study site for 
6 months post end of treatment. After 6 months post treatment, patients may be 
followed up at the study site or by a local physician, and follow-up data will be 
collected at 3-month intervals. 
• Non-Responders: 
Patients who do not respond to treatment may be followed up at the study site or 
by a local physician, and follow-up data will be collected at 3-month intervals 
post treatment. 
Bone Marrow Aspirate and Biopsy 
• Responders (CR, CRh, CRi [CRn, CRp], or MLFS): 
Patients who respond to treatment should have a bone marrow aspirate and biopsy 
collection at 3 and 6 months post treatment at the study site. After 6 months post 
treatment, bone marrow aspirate and/or biopsy will be performed per standard of 
care. 
• Non-Responders: 
Patients who do not respond to treatment will have bone marrow aspirate and/or 
biopsy performed per standard of care. 
• All patients: 
If patients have a bone marrow aspirate and/or biopsy done as part of their 
standard of care, they have the option to consent to donate aspirate or biopsy 
specimens for assessment of disease status and further research to help elucidate 
immune mechanisms involved in flotetuzumab function. As with all other biopsies 
collected for this study, these samples may be used for histopathological and 
immunohistochemical evaluation, flow cytometric evaluation, and minimal 
residual disease analysis. 
Disease and Vital Status 
The Sponsor will request the following clinical data that supports or gives context to the 
patient’s reported disease status. This information is to be collected at all follow-ups for all 
patients. 
• hematology data (i.e., CBC results per standard of care) 
• applicable concomitant medications 
• further treatments, including transplant status 
• transfusion information - date of transfusions, transfusion frequency, units, type 
(red blood cells, platelets), and reason for transfusion 
• date of disease progression (if applicable) 
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• death (if applicable) - appropriately redacted documentation should be collected 
for source document verification (i.e. a redacted death certificate) 
Safety Follow-up  
Ongoing AEs at the time of study drug discontinuation will be followed until either 28 days 
after last administration of study drug or until the start of a subsequent systemic anticancer 
therapy, if earlier. SAEs will be followed to resolution or stabilization (see Section 7.11.4). 
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9 
PLANNED STATISTICAL METHODS  
Summary statistics will consist of absolute and relative frequencies of each category of 
discrete variables as well as of means, standard deviations, medians, minimum and maximum 
values of continuous variables. These summaries will be applied by dose cohort and by dose 
schedule in each phase of the study. Statistical methods will be applied primarily to the 
expansion cohorts. AML and MDS patients will be summarized together for safety and the 
AML efficacy population separately for efficacy analysis. 
9.1 
Determination of Sample Size for Primary Efficacy Analysis  
The planned sample size for the pivotal portion of the study under Protocol Amendment 11 
onwards is 170 patients, based on a three-stage design. 
To determine the sample size under Amendment 11 inclusion criteria, historical reference 
response rates to standard treatments were ascertained through a meta-analysis based on 5 
published studies that included PIF/ER AML patients selected from 963 publications 
identified through database search (11,12,13,30,36). Based on this analysis, the estimated 
combined CR/CRh rate was 11.8%, with a 95% confidence interval of 9.4% to 14.7%. The 
upper 95% CI of 14.7% was chosen as the rate for the null hypothesis (H0) and a target of 
23% CR/CRh was established as a clinically meaningful endpoint in this patient population. 
A three-stage design with two interim analyses will be employed to test the null hypothesis 
(H0) of CR/CRh rate = 14.7% against the alternative hypothesis (H1) of CR/CRh rate = 23%. 
Demonstration of CR/CRh rate improvement (H1) by rejecting H0 at a 1-sided type I error of 
0.025 with adequate power (80%) in a sequential design requires 170 patients. Specifically, 
the planned number of patients and the futility and efficacy boundaries at each stage are as 
follows: 
a. First interim analysis: The first interim analysis will be performed after 40 patients 
have been enrolled and either have had their responses evaluated or were discontinued 
for any reason from study treatment prior to their first response assessments. This 
interim analysis is for futility only, that is, the study enrollment will continue if at 
least 5 (12.5%) out of 40 patients have response of CR/CRh. 
b. Second interim analysis: If the enrollment continues after the first interim analysis, a 
second interim analysis will be performed after additional 60 patients have been 
enrolled (100 patients in total) and either have had their response evaluated or were 
discontinued for any reason from study treatment prior to their first response 
assessment. This interim analysis is for both futility and efficacy. Specifically, 
i. If the number of CR/CRh is less than 15 (15%) out of 100 patients, then the 
study is considered futile and enrollment will be stopped. 
ii. If the number of CR/CRh is 15 (15%) or greater out of 100 patients, then 
enrollment will continue. 
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iii. If the number of CR/CRh is 25 (25%) or greater out of 100 patients, then H0 
is rejected and the study is considered positive. The enrollment will still 
continue. 
c. Final Analysis: If enrollment continues after the second interim, then the final 
analysis will be performed after additional 70 patients have been enrolled (170 
patients in total) and either have had their response evaluated or were discontinued for 
any reason from study treatment prior to their first response assessments. If the 
number of CR/CRh is at least 35 (20.6%) out of the total of 170 patients, then H0 is 
rejected and the study is considered positive. 
The above design yields a 1-sided alpha of 0.005 for the efficacy boundary at the second 
interim analysis and an overall 1-sided alpha of 0.024 with approximately 80% power at the 
final analysis. The probability of early termination under H0 (futility) in the first two stages is 
55%. 
9.2 
Analysis Populations  
Three populations will be used for analysis, as defined below: 
• Efficacy population – All patients that have been enrolled under Protocol 
Amendment 11 or later and treated with flotetuzumab at the MTD of 500 
ng/kg/day as a continuous 7-day per week IV infusion during Cycle 1, have 
received any portion of one dose of flotetuzumab, and met the definition of 
PIF/ER AML based on inclusion criteria as revised in Amendment 11 (see Section 
5.1). This population will be used for the primary analysis of efficacy endpoints. 
• Safety population – All patients who received any portion of any dose of 
flotetuzumab. AML and MDS will be analyzed as pooled and separate populations 
for safety and PK. The analysis of all safety endpoints will be based on the safety 
population. 
• Response evaluable population – All patients in the efficacy population that 
have a baseline bone marrow assessment, have at least one post-infusion 
assessment of their disease status or were removed from the study for reason of 
documented evidence of disease progression, death or treatment-related adverse 
event. This population will be used in the summary of response rate as a 
secondary analysis. 
9.3 
Demographics and Baseline Characteristics  
Patient disposition, demographics and baseline characteristics, AML status (PIF/ER) and 
prior therapy, AML subclassifications and cytogenetics, and medical history will be 
summarized. 
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9.4 
Study Drug Exposures and Concomitant Medications  
Study drug exposures and concomitant medications will be summarized by descriptive 
statistics. Dose intensity will be calculated as the percentage of dose actually administrated 
divided by the intended dose during the treatment period and up to the last dose on study 
drug. Dose intensity will be summarized by cycle. 
9.5 
Safety Endpoint(s) and Analyses  
9.5.1 
Adverse Events  
Adverse events will be coded to the Medical Dictionary for Regulatory Activities 
(MedDRA). Only TEAEs, as defined in Section 7.11.1 will be summarized in tables. Events 
prior to treatment (e.g., due to study-related procedure) will be listed in an appendix to the 
final study report. DLTs will be listed. 
The following tables of AE data will be created to summarize the number and percent of 
patients who experience at least one event of each of the following types: 
• All AEs 
• Drug-related AEs 
• AEs by CTCAE Grade 
• Drug related AEs by CTCAE Grade 
• AEs with CTCAE Grade severity ≥ Grade 3 
• Drug-related AEs with CTCAE Grade severity  Grade 3 
• SAEs (this may be a listing if there are few events) 
• Drug-related SAEs 
• Fatal AEs (this may be a listing if there are few events) 
• AEs that result in study discontinuation 
• AEs that lead to withdrawal of study drug 
• AEs categorized as AESI and/or IREs 
Tabulated data will display the number and percent of patients that experience individual 
events by System Organ Class (SOC) and Preferred Term (PT). Events will be displayed 
alphabetically for SOC and in descending order of overall PT incidence within each SOC. 
An overall summary of AEs will display the number and percent of patients who experience 
at least one event of each of the following types: 
• Any AE 
• Any drug-related AE 
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• Any AE with CTCAE Grade severity  Grade 3 
• Any drug-related AE with CTCAE Grade severity  Grade 3 
• Any SAE 
• Any drug-related SAE 
• Any AE that results in study or study drug discontinuation 
• Any fatal AE 
• Any AESI 
• Any IREs 
9.5.2 
Laboratory Values  
Summaries of laboratory values will display descriptive statistics for numerically quantified 
labs. Summaries will be grouped by lab panel (e.g., hematology, blood chemistry, and 
urinalysis) and will be displayed by visit for each lab parameter. Graphs of mean values over 
time or individual values at each time point may be used. 
Shift tables will be used to display the percent of patients who have a shift in their lab values 
from normal at baseline to each post-baseline visit by CTCAE v4.0 severity Grade. 
9.5.3 
Other Safety Endpoints  
Electrocardiograms will be collected and analyzed for evidence of cardiac toxicity, especially 
prolongation of QT interval. Vital signs will be summarized with descriptive statistics at each 
visit and time point where they are collected. 
9.6 
Efficacy Endpoints and Analyses  
Disease activity will be assessed by the study investigators, by using CBC and peripheral 
blood cell morphological examination, examination of bone marrow aspiration (or biopsy if 
required), and physical examination. Modifications to the Revised Recommendations of the 
International Working Group for Diagnosis (IWG), Standardization of Response Criteria, 
Treatment Outcomes, and Reporting Standards for Therapeutic Trials in Acute Myeloid 
Leukemia will be used (Appendix 3). Response assessment will be based on bone marrow 
aspirate/biopsy and the best CBC up to 14 days post bone marrow aspirate/biopsy. Responses 
will be categorized as: 
• CR (mCR [morphologic CR], CRc [cytogenic CR], or CRm [molecular CR]); 
• CRh; 
• CRi (CRn [CR with incomplete neutrophil recovery]; CRp [CR with 
incomplete platelet recovery]); 
• MLFS; 
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• PR; 
• OB; 
• SD; 
• PD. 
The number and percent of PIF/ER AML patients will be summarized by best overall 
response. Efficacy analyses will be based on the PIF/ER AML population (see Inclusion 
Criterion 2). All efficacy results will be summarized by PIF, ER and the total combined 
PIF/ER populations. 
9.6.1 
Primary Efficacy Analysis  
The primary efficacy endpoint for the AML expansion cohort is the CR/CRh rate, calculated 
as the proportion of patients in the efficacy population that has achieved a best response of 
CR (mCR, CRc, or CRm) or CRh at any point during treatment by investigator’s assessment, 
according to IWG AML response criteria (Appendix 3). CR/CRh rate will be summarized 
for the total combined PIF/ER patients as the primary analysis, as well as for PIF and ER 
patients separately, and for PIF/ER patients in the response-evaluable population as a 
sensitivity analyses. A two-sided exact 95% confidence interval will be calculated around 
response rates. 
For the second interim analysis of 100 patients, as well as for the final analysis of 170 
patients, all treated patients will be followed for at least 6 months or until death from any 
cause, whichever occurs first, prior to data cutoff for the analysis. If the trial passes the pre-
specified efficacy boundary (25% observed CR/CRh rate) at the second interim analysis, a 
two-sided exact 95% confidence interval as described by Jennison and Turnbull (21) will be 
produced to account for the bias in the conventional exact confidence interval for fixed 
sample test. 
9.6.2 
Secondary Efficacy Analyses  
Counts, percentages, and two-sided exact 95% confidence intervals will be used to describe 
categorical secondary variables. Kaplan-Meier (KM) methods will be used to estimate time-
to-event endpoints, unless otherwise specified. All secondary efficacy endpoints will be 
summarized in both efficacy and response evaluable population by PIF, ER, and total. 
9.6.2.1 
Key Secondary Efficacy Analyses  
The key secondary efficacy endpoints include CR rate, CRh rate, duration of response, post-
baseline transfusion independence rate, HSCT rate, and incidence and duration of 
hospitalization. 
Duration of response (DOR) will be calculated from the time of initial documentation of 
response to the time of disease relapse or death due to any cause, whichever occurs first. 
Patients who are still in response at study completion without alternative therapies will be 
censored at the time of their last disease assessment. Duration of response will be calculated 
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for patients who achieve the first evidence of CR or CRh as primary analysis. A separate 
exploratory analysis will be conducted for patients who achieve the first evidence of overall 
complete response (CR, CRh, CRi [CRn, CRp], or MLFS). 
Post-baseline transfusion independence is defined as no transfusion during any consecutive 
56-day period on-study. Post-baseline transfusion independence will be summarized for RBC 
and platelet transfusion separately and in total. Transfusion dependence at baseline is defined 
as any red blood cell or platelet transfusions during the 28 days prior to the first dose of study 
drug. The rate of conversion from transfusion dependence to transfusion independence will 
be calculated. The rate of patients who are transfusion independent at baseline and remain 
independent during any 56-day post-baseline period will also be calculated. 
HSCT rate is defined as rate of successful HSCT through study treatment. Patients who 
received other therapies (except for conditioning therapy) for AML after discontinuation of 
study drug and later undergo a subsequent HSCT will not be included. Number and 
percentage of patients with HSCT will be summarized. 
Incidence and Duration of Hospitalization, summaries will be provided for the efficacy 
population, as well as independently for patients who achieved CR or CRh. Summaries will 
include duration of initial hospitalization as well as incidence, number and duration of 
subsequent hospitalizations following the initial discharge, number of days hospitalized, and 
the reasons for hospitalization. 
9.6.2.2 
Additional Secondary Efficacy Analyses  
Additional secondary efficacy endpoints include overall complete response rate, objective 
response rate, subgroup analyses of CR/CRh, CR, CRh and overall complete response rates, 
overall survival, event-free survival, time to response, mortality rate at 30, 60, 90, and 180 
days, six-month and one-year survival. 
Overall complete response rate (OCRR) is defined as the rate of CR+CRh+CRi [CRn, 
CRp]+MLFS according to IWG AML response criteria (Appendix 3), and includes any 
response which achieves < 5% BM blasts by morphology. 
Objective response rate is defined as the rate of CR+CRh+CRi [CRn, CRp]+MLFS+PR 
according to IWG AML response criteria (Appendix 3). 
Subgroup analyses of CR/CRh, CR, CRh, and overall complete response rates will be 
performed by baseline disease characteristic (e.g., age group [< 70, ≥ 70], gender, cytogenetic 
risk status [high, intermediate, low], prior line of therapy [1, 2, 3], TP53 gene mutations). 
Overall survival is defined as the time between the date of the first dose of study drug and 
death from any cause. Patients who are alive or whose death status is unknown will be 
censored at the last date known to be alive on or before the data cutoff date. 
Event-free survival is defined as the time from the first dose of study drug until date of 
relapse from CR, CRh, or CRi (CRn, CRp), or death from any cause, whichever occurs first. 
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Patients who are not known to have any of these events at study completion will be censored 
at the date of the last disease assessment. 
Time to response (TTR) is defined as time from first dose of study drug to first CR, CRh, 
CRi (CRn, CRp), or MLFS, and will be summarized with descriptive statistics. Time to 
CR/CRh and time to best overall response will be calculated. 
Mortality rate is defined as rate of death from any cause within 30, 60, 90, or 180 days of 
first dose of study drug. 
Six-month survival rate is defined as the probability of survival at 6 months from first dose 
of study drug. 
One-year survival rate is defined as the probability of survival at 1 year from first dose of 
study drug. 
9.7 
Other Assessments or Analyses  
9.7.1 
Immunogenicity  
Anti-drug antibody production will be monitored using a bridging ELISA method. The 
proportion of patients who become positive in this assay will be reported. 
9.7.2 
Pharmacokinetics  
Serum concentrations of flotetuzumab will be monitored using an electrochemiluminescence-
based sandwich assay. PK analyses will be performed using industry standard software. 
Population PK modeling will be performed and an appropriate model and model parameters 
will be described. This analysis will be performed by an outside consultant. 
9.7.3 
Safety and Efficacy of Tocilizumab in Treatment of IRR/CRS  
IRR/CRS events are captured as AESIs (see Section 7.11.3). The incidence, severity and 
duration of IRR/CRS events will be summarized in tables. Furthermore, safety with the use 
of tocilizumab will also be assessed. 
9.7.4 
Other Studies  
The following exploratory studies may be performed in all or a subset of patients: 
• CD123 expression on leukemic blasts in bone marrow and peripheral blood at 
baseline and over time 
• Flow cytometric analysis of bone marrow and peripheral blood cells to describe 
the status of the leukemia and monocytes, natural killer (NK) cells, plasmacytoid 
dendritic cells (pDC), lymphocytes, and lymphocyte subsets and activation 
markers at baseline and over time 
• Minimal residual disease (MRD)  
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• T-cell immune function (TCR repertoire, in vitro immune assessments) 
• Transcriptomic bone marrow tumor microenvironment immune contexture 
• Cytokine production at baseline and over time. 
These data will be summarized by using descriptive statistics and, where appropriate, 
graphed over time. 
9.8 
Final Analysis at End of Trial  
If there are patients continuing on study at the time of the primary analysis, a final analysis of 
all data will be carried out at the End of the Trial (as defined in Section 4.4). 
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10 
QUALITY CONTROL AND ASSURANCE  
Quality review activities will be undertaken to ensure accurate, complete, and reliable data. 
MacroGenics, Inc. and/or its representatives will do the following: 
• Provide instructional material to the study sites, as appropriate. 
• Sponsor a start-up training session (Investigator Meeting or Study Initiation Visit) 
to instruct the Investigators and study coordinators. This session will give 
instruction on the protocol, the completion of the eCRFs, and study procedures. 
• Make periodic visits to the study site. 
• Be available for consultation and stay in contact with the study site personnel by 
mail, e-mail, telephone, and/or fax. 
• Review and evaluate eCRF data and use standard computer checks to detect and 
query errors in data collection. 
• Conduct a quality review of the database. 
10.1 
Investigational Site Training  
MacroGenics, Inc. will provide quality investigational staff training prior to study initiation. 
Training topics will include but are not limited to: GCP, AE reporting, study details and 
procedures, eCRFs, study documentation, informed consent, and enrollment of women of 
child-bearing potential. 
10.2 
Monitoring, Auditing and Inspections  
To ensure the safety of participants in the study, compliance with applicable regulations, and 
to ensure accurate, complete, and reliable data, the Investigator will keep records of 
laboratory tests, clinical notes, and patient medical records in the patient files as source 
documents for the study (refer to Section 11.7 for additional information on source 
documents). 
MacroGenics, Inc. or its designee will monitor the study on a regular basis throughout the 
study period according to the study monitoring plan. The Investigator will allocate adequate 
time for such monitoring activities. The study monitor periodically will conduct a cross-
check of a sample of the patient data recorded on eCRFs against source documents at the 
study site. The Investigator will also ensure that the monitor is given access to all the above 
noted study-related documents, source documents (regardless of media) and study-related 
facilities (e.g., pharmacy, diagnostic laboratory, etc.), and has adequate space to conduct the 
monitoring visit. Queries may be raised if any datum is unclear or contradictory. The 
Investigator must address all queries. 
Participation as an Investigator in this study implies acceptance of the potential for inspection 
by the study Sponsor/representatives, US or non-US government regulatory authorities, 
IRB/IEC and applicable compliance and quality assurance offices. The Investigator will 
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permit study-related audits and inspections and will provide access to all study-related 
documents (e.g., source documents, regulatory documents, data collection instruments, study 
data, etc.). The Investigator will ensure the capability for inspections of applicable study-
related facilities (e.g., pharmacy, diagnostic laboratory, etc.). 
10.3 
Data Entry and Computerized Systems  
An electronic data capture system will be used in this trial. Other data assessments, such as 
ECG data, will be managed by central vendors for transfer to MacroGenics, Inc. or 
representative for use in the study analysis database. 
 
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11 
ADMINISTRATIVE CONSIDERATIONS  
11.1 
Institutional Review Board (IRB/IEC) or Independent Ethics 
Committee (IEC) Approval  
The Investigator should provide the Sponsor with a statement of compliance from the 
IRB/IEC indicating compliance with the applicable regulations in the region and ICH. Any 
documents that the IRB/IEC may need to fulfill its responsibilities, such as the protocol and 
any amendments, Investigator’s Brochure, and information concerning patient recruitment, 
payment or compensation procedures, or information from the Sponsor will be submitted to 
the IRB/IEC. The IRB/IEC’s written unconditional approval of the study protocol and the 
informed consent forms will be in the possession of the Investigator and the Sponsor before 
shipment of study drug to the Investigator’s site. The Investigator will transmit the IRB/IEC’s 
unconditional approval statement to the Sponsor. This approval must include the date of 
review, and refer to the study by protocol title and/or study number and version number and 
refer to the informed consent forms by version number or date. If the IRB/IEC or institution 
uses its own unique number for the protocol instead of the Sponsor’s number, that unique 
number should be noted on the approval statement. If approval of the informed consent forms 
is stamped on the forms (instead of documented in the IRB/IEC approval statement) the date 
of approval and/or expiration must be included. 
Protocol modifications or changes may not be initiated without approval from the Sponsor 
and, when required, prior written IRB/IEC approval, except when necessary to eliminate 
immediate hazards to the patients. Such modifications will be submitted to the IRB/IEC; 
written verification that the modification was submitted should be obtained. 
The Investigator must submit to the IRB/IEC: 
• The protocol and the Investigator’s Brochure (IB) and any amendments or updates 
• The informed consent form and any amendments or changes 
• Any documents given to patients or potential patients (e.g., recruitment materials, 
diary cards) and the plan for distribution/use 
• Revisions of other documents originally submitted for review or for notification 
• Serious and/or unexpected AEs occurring during the study, according to local 
regulations/procedures 
• New information that may adversely affect the safety of patients or conduct of the 
study 
• At minimum, an annual update and/or request for re-approval of study, unless 
otherwise specified by IRB/IEC 
• Protocol violations or deviations, as required by local regulations 
• Notification when the study has been completed 
• Proof of indemnity/liability insurance 
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11.2 
Data Safety Monitor and Independent Data Monitoring 
Committee  
An independent DSM (with disease-specific and/or immunotherapy expertise) was involved 
in all decisions regarding transition from the Single Patient Dose Escalation Segment to the 
Multi-patient Dose Escalation Segment and regarding the definition of MTDS and transition 
to the MTDS Cohort Expansion Segment of the study. In the Single Patient Dose Escalation 
Segment, safety data from all patients followed through Study Day 28 (Cycle 2 Day 1) was 
reviewed. Safety data from each dose escalation cohort in the Multi-patient Dose Escalation 
Segment was made available to the DSM after each cohort of patients had been followed for 
a minimum of 28 Study Days. 
Safety evaluations will be conducted on an ongoing basis during the Cohort Expansion 
Segment of the study. Review by an IDMC (replacing the DSM previously involved in safety 
reviews), consisting of two physicians and one biostatistician, will be conducted in regular 
intervals. The interval analysis will utilize data from all cycles of treatment. If during the 
conduct of the interval cohort analysis, the Bayesian posterior probability is greater than 80% 
that the DLT (see Section 4.2) event rate is more than 20%, enrollment will be paused and an 
ad hoc meeting of the IDMC will be held to consider dose reduction or study termination (see 
Section 4.1). The IDMC will also review aggregate efficacy data for two planned interim 
analyses to determine enrollment continuation according to futility and efficacy boundaries 
described in Section 9.1. 
11.3 
Ethical Conduct of the Study  
The investigational study will be conducted according to the Protection of Human Subjects 
(21 CFR 50), IRBs (21 CFR 56), Obligations of Clinical Investigators (21 CFR 312.60 − 
312.69), the current ICH Guideline for Good Clinical Practice (ICH E6), and all other 
applicable regulations. 
The protocol and the informed consent document will be reviewed and approved by the 
IRB/IEC of each participating center before study initiation. SAEs regardless of causality will 
be reported to the Sponsor/designee and to the IRB/IEC, and the Investigator will keep the 
IRB/IEC informed regarding the progress of the study. 
11.4 
Patient Information and Consent  
It is the responsibility of the Investigator to obtain and document oral or written informed 
consent from the patient or legally authorized representative. Informed consent in compliance 
with the principles of informed consent in ICH E6 and all applicable local regulations should 
be obtained before any protocol-specified procedures or interventions are conducted. The 
Sponsor reserves the right to delay initiation of the study at a site where informed consent 
forms do not meet the standards of applicable local regulations or ICH E6. 
Information should be given to the patient in both oral and written form, and patients or their 
legally authorized representatives must be given ample opportunity to inquire about details of 
the study. 
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The consent form generated by the Investigator must be approved by the IRB/IEC. The 
Investigator will provide the Sponsor with a copy of the IRB/IEC-approved consent forms 
and a copy of the IRB/IEC’s written approval before the start of the study. 
Consent forms must be written so as to be understood by the prospective patient. Informed 
consent will be documented by the use of a written consent form approved by the IRB/IEC. 
Special attention will be given to the sections of the consent form relevant to genetic analyses 
(minimal residual disease and T lymphocyte repertoire). The form must be signed and dated 
by the patient or the patient's legally authorized representative, and by the person who 
conducted the discussion of the informed consent. 
All versions of each patient’s signed informed consent form must be kept on file by the 
Investigator for possible inspection by regulatory authorities and/or authorized MacroGenics’ 
professional and regulatory compliance persons. The patient or the patient’s legal 
representative should receive a copy of the signed and dated written informed consent form 
and any other written information provided to the patients. 
11.5 
Patient Confidentiality  
To maintain confidentiality of patients, all laboratory specimens, evaluation forms, reports, 
and other records will be identified by a coded number and initials only. Clinical information 
will not be released without written permission of the patient, except as necessary for 
monitoring by the relevant regulatory authorities, the Sponsor of the clinical trial, or the 
Sponsor’s representative. The Investigator must also comply with all local applicable privacy 
regulations [e.g., US Health Insurance Portability and Accountability Act of 1996 (HIPAA)], 
on protection of individuals with regard to personal data. 
11.6 
Case Report Forms and Study Records  
Source data in a clinical trial are the original records or certified copies where clinical 
observations are first recorded, which may include, but are not limited to, the patient’s 
medical file, original laboratory reports, histology, and pathology reports (as applicable). The 
Investigator is responsible for maintaining adequate and accurate medical records from which 
accurate information will be entered onto eCRFs designed to capture all observations and 
other data pertinent to the clinical investigation. Data should be recorded on source 
documents and entered onto eCRFs. Electronic CRFs should be filled out completely by the 
Investigator or his/her designee. Prior to eCRF database lock, the Investigator will verify the 
completeness and accuracy of the data and indicate that he/she has done so by providing a 
signature on the appropriate eCRF. The Investigator will retain a copy of all source 
documents. 
11.7 
Access to Source Documentation  
The Investigator and study center will permit the Sponsor, its representatives, IRB/IEC and 
all relevant regulatory agencies direct access to all original source data and documents 
regardless of media, for study monitoring audits and inspections. 
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The Investigator may be subjected to a field audit by MacroGenics (or designee) and/or 
regulatory inspectors in order to validate the participation of patients in the study and to 
verify the data reported on the eCRFs on file at MacroGenics, Inc. MacroGenics should be 
notified immediately of any audits scheduled by any regulatory authorities. Copies of audit 
reports, findings and/or correspondence from regulatory authorities for audits conducted on a 
MacroGenics-sponsored study should be promptly forwarded to MacroGenics. 
11.8 
Retention of Data  
Per ICH guidelines, all essential documents, including eCRFs, source documents (regardless 
of media), signed informed consent forms, and laboratory test results, should be retained by 
the Investigator for at least 2 years after 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 formal discontinuation of clinical 
development of the investigational product. There may be other circumstances for which 
MacroGenics, Inc. is required to maintain study records for longer periods (e.g., applicable 
local regulations); therefore, MacroGenics, Inc. should be contacted before study records are 
removed from the investigational site for any reason. The Investigator must obtain written 
permission from MacroGenics, Inc. prior to destruction of study documents. 
11.9 
Financial Disclosure  
The Investigator and Sub-Investigators will be required to disclose any financial arrangement 
whereby the value of the compensation for conducting the study could be influenced by the 
outcome of the study. The following information will be collected: any significant payments 
of other sorts from MacroGenics, Inc., such as a grant to fund ongoing research, 
compensation in the form of equipment, retainer for ongoing consultation or honoraria, any 
proprietary interest in flotetuzumab, and any significant equity interest in MacroGenics, as 
defined in 21 CFR 54. Investigators are obligated to update the Sponsor with any changes in 
reported information up to one year following the end of the study (as defined in 
Section 4.4). 
In consideration of participation in the study, MacroGenics, Inc., or its designee, will pay the 
Investigator or nominated payee the sums set out in the payment schedule attached to the 
Investigator agreement. 
Financial disclosure information will be documented in writing and signed and dated by the 
Investigator. This information will be collected at the beginning of the study. 
11.10 
Publication and Disclosure Policy  
Data collected in this clinical study belong to the study Sponsor, which will formulate a 
policy on the use of study data. This includes authorship issues, scheduling and prioritizing 
analyses for reports, publications, and presentations, and developing a review and approval 
process. 
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11.11 
Discontinuation of the Study or Study Sites  
11.11.1 
Discontinuation of Study Sites  
Participation may be discontinued if MacroGenics, the Investigator, a regulatory authority, or 
the IRB/IEC of the study sites deems it necessary for any reason. 
11.11.2 
Discontinuation of the Study  
The study may be discontinued by a regulatory authority or at the discretion of the Sponsor. 
The Investigator maintains the right to discontinue his/her participation in the study should 
his/her clinical judgment so dictate. The Investigator will notify the IRB/IEC of any study 
discontinuation. Study records must be retained as noted above. 
11.12 
Identification of the Coordinating Principal Investigator  
Dr. John DiPersio (Washington University School of Medicine, St. Louis, MO) has been 
appointed as the US Coordinating Principal Investigator. For Europe, Dr. Norbert Vey 
(Institute Paoli-Calmettes, Marseille, France) is the European Coordinator. 
As part of their responsibilities, the Coordinating Principal Investigator/European 
Coordinator will review the final Clinical Study Report. Agreement with the final Clinical 
Study Report will be documented by the dated signature of the Coordinating Principal 
Investigator/European Coordinator. 
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12 
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35. Prebet T, Gore SD, Esterni B, Gardin C, Itzykson R, Thepot S, et al. Outcome of 
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39. Seiter K. Myelodysplasia: new approaches. Curr Treat Options Oncol 2013 
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acute myeloid leukemia. Sci Transl Med. 2020;12:eaaz0463. 
45. Wang JC, Dick JE. Cancer stem cells: lessons from leukemia. Trends Cell Biol 2005 
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46. Weltermann A, Fonatsch C, Haas OA, Greinix HT, Kahls P, Mitterbauer G, et al. 
Impact of cytogenetics on the prognosis of adults with de novo AML in first relapse. 
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48. Xie W, Wang X, Du W, Liu W, Qin X, Huang S. Detection of molecular targets on the 
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49. Yang H, Bueso-Ramos C, DiNardo C, Estecio MR, Davanlou M, Geng Q, et al. 
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51. Zeiser R, Burchert A, Lengerke C, Verbeek M, Maas-Bauer K, Metzelder SK, et al. 
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Appendix 1 
Schedule of Events Applicable to Cohort Expansion (All Cycles)  
The study procedures outlined below also apply to patients with AML who participate in the ruxolitinib cohort. 
Informed consent must be obtained prior to performing any screening procedures, and may be obtained prior to the start of 
the 14 day screening period. 
 
Screening 
Cycle 1 
28 days 
Subsequent Cycles 
28 days 
End of 
Treatment 
Post-
treatment 
Follow-up 
 
Day 
Up to  
-14 
Days 
Up to 
-5 
Days 
Up to 
-1 
Days 
1 
8 
15 
22 
25 
and/or 
26 
1 
8 
15 
22 
25 
and/or 
26 
28-days 
Following Last 
Treatment or 
At Time of 
Treatment Failure 
Study Day 
Window 
 
 
 
+/- 1 
+/- 1 
+/- 1 
+/- 1 
+ 3 
+/- 1 
+/- 1 
+/- 1 
+/- 1 
+ 3 
+3 
 
Week 
 
 
 
1 
2 
3 
4 
 
5, 9, 13, 
etc. 
6, 10, 14, 
etc. 
7, 11, 15, 
etc. 
8, 12, 16, 
etc. 
 
 
 
EVALUATION OR PROCEDURE 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
STUDY DRUG 
ADMINISTRATION 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
TLS prophylaxis 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Flotetuzumab 3 
 
 
 
17 1 814 1 1521 1 2224 1 2528 1 
17 2 
814 2 
1521 2 
2224 2 2528 2 
 
 
1. 
Cycle 1 only: flotetuzumab administration will occur from Days 1 to 28 (7-day continuous IV infusion). Week 1 only: Patients will receive step-up dosing as detailed in Table 2. 
Weeks 2-4: Dosing will follow the scheme shown in Table 2. 
2. 
All other cycles: flotetuzumab administration will occur in a 7-Day continuous infusion schedule according to Table 2. 
3. 
All cycles: Scheduled dose/bag changes have a ± 2 hour window. 
ELIGIBILITY 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Diagnostic Bone Marrow 
Aspirate and core biopsy for 
local histopathological and 
immunohistochemical analysis, 
central flow cytometric 
evaluation, and next generation 
sequencing 
X 4 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
4. 
Obtain if not performed within 30 days before the start of treatment (Cycle 1, Day 1). 
Buccal mucosal sampling (Only 
Washington U., St. Louis, MO) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Screening 
Cycle 1 
28 days 
Subsequent Cycles 
28 days 
End of 
Treatment 
Post-
treatment 
Follow-up 
 
Day 
Up to  
-14 
Days 
Up to 
-5 
Days 
Up to 
-1 
Days 
1 
8 
15 
22 
25 
and/or 
26 
1 
8 
15 
22 
25 
and/or 
26 
28-days 
Following Last 
Treatment or 
At Time of 
Treatment Failure 
Study Day 
Window 
 
 
 
+/- 1 
+/- 1 
+/- 1 
+/- 1 
+ 3 
+/- 1 
+/- 1 
+/- 1 
+/- 1 
+ 3 
+3 
 
Week 
 
 
 
1 
2 
3 
4 
 
5, 9, 13, 
etc. 
6, 10, 14, 
etc. 
7, 11, 15, 
etc. 
8, 12, 16, 
etc. 
 
 
 
Medical history 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Report HLA typing (if available) 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Review of concomitant 
medications, including all 
transfusion requirements up to 
28 days prior to dosing 
 
X 
 
-- Continuous -- 
X 
X 5 
5. 
During follow-up, collect the following transfusion information: date of last transfusion; transfusion frequency, type (red blood cells, platelets), and units; and reason for transfusion. Also 
collect further treatment and transplant status. Applicable concomitant medications that support or give context to the patient’s reported disease status will also be collected. 
ECOG PS 
 
X 
 
 
 
 
 
 
X 6 
 
 
 
 
 
 
6. 
Cycle 2, Day 1 only 
ECG 7 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
 
Left ventricular ejection fraction 
X 8 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
7. 
ECG to be performed in triplicate (at approximately 1-minute intervals) at screening and Cycle 1 Day 15 (or when patient reaches 500 ng/kg/day, if this is later than Day 15). 
Subsequent ECGs to be performed when clinically indicated, and will be single tracing unless clinical circumstances, and at the discretion of the investigator, indicate 
otherwise. Treatment with flotetuzumab should be held or delayed for a clinically significant QTcF prolongation > 480 msec. 
8. 
If patient has a history or signs and symptoms of cardiac disease, obtain echocardiogram (or, except in Germany, MUGA if indicated) if one was not performed within 30 days 
before the start of treatment (Cycle 1, Day 1). An echocardiogram (or, except in Germany, MUGA if indicated) may also be conducted during the study if clinically indicated. 
PFT 
X 9 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
9. 
PFT to include DLCO and FEV1, if testing was not performed within 30 days before the start of treatment (Cycle 1 Day 1). PFT may also be conducted during the study if 
clinically indicated. During the COVID-19 pandemic, except in Germany, if PFT equipment is not available, a correlative stair-climbing test may be conducted instead, together 
with lung CT and echocardiogram irrespective of cardiac history (see Section 8.1.1). 
 
Serum or Urine -hCG 
pregnancy test 10 
 
X 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
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Screening 
Cycle 1 
28 days 
Subsequent Cycles 
28 days 
End of 
Treatment 
Post-
treatment 
Follow-up 
 
Day 
Up to  
-14 
Days 
Up to 
-5 
Days 
Up to 
-1 
Days 
1 
8 
15 
22 
25 
and/or 
26 
1 
8 
15 
22 
25 
and/or 
26 
28-days 
Following Last 
Treatment or 
At Time of 
Treatment Failure 
Study Day 
Window 
 
 
 
+/- 1 
+/- 1 
+/- 1 
+/- 1 
+ 3 
+/- 1 
+/- 1 
+/- 1 
+/- 1 
+ 3 
+3 
 
Week 
 
 
 
1 
2 
3 
4 
 
5, 9, 13, 
etc. 
6, 10, 14, 
etc. 
7, 11, 15, 
etc. 
8, 12, 16, 
etc. 
 
 
 
10. All Cycles: Day 1 only, predose or prior to bag change as applicable. Results of the pregnancy test must be negative prior to starting new cycle of flotetuzumab infusion. Women 
of childbearing potential only. 
 
Patient registration 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
SAFETY, PK, & 
MECHANISTIC EVALUATION 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination 11 
 
X 
 
 
 
 
 
X 12 
 
 
 
 
X 12 
X 
 
Weight 13 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
11. Includes height (screening only), and examination of skin, HEENT (head, eyes, ears, nose, and throat), lymph nodes, heart, chest, lungs, abdomen, extremities, and 
neurologic system 
12. Day 25-28 (to coincide with bone marrow aspiration and biopsy) 
13. All Cycles: Obtain weight daily during in hospital stay and at each clinic visit while an outpatient. 
CBC with differential, platelet 
count 
 
X 14 
 
X 15 
X 15 
X 15 
X 15 
X 15 
X 16 
X 16 
X 16 
X 16 
X 16 
X 
 
14. May be used as Study Day 1 baseline if within 24 hours of drug administration start 
15. Cycle 1 only, Days 1 -28: Study Day 1 - pre-infusion; Study Days 2 through 8 - sample may be drawn at any time relative to infusion. If inpatient, Study Days 9-28 (sample may 
be drawn any time relative to infusion). If outpatient, Study Days 15, 22 and 25 (sample may be drawn any time relative to infusion). 
16. All other cycles: Study Day 1, 8, 15 and 22 – prior to bag change as applicable; Study Days 5, 12, and 19 - sample may be drawn at any time relative to infusion (if patient 
returns to study site for end of infusion or bag change; collect prior to end of infusion/bag change); Study Day 26 - sample may be drawn at any time relative to infusion (when 
patient returns to study site for end of infusion or bag change; collect prior to end of infusion/bag change). A CBC must also be drawn on the same day of the bone marrow 
aspirate or biopsy. 
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Screening 
Cycle 1 
28 days 
Subsequent Cycles 
28 days 
End of 
Treatment 
Post-
treatment 
Follow-up 
 
Day 
Up to  
-14 
Days 
Up to 
-5 
Days 
Up to 
-1 
Days 
1 
8 
15 
22 
25 
and/or 
26 
1 
8 
15 
22 
25 
and/or 
26 
28-days 
Following Last 
Treatment or 
At Time of 
Treatment Failure 
Study Day 
Window 
 
 
 
+/- 1 
+/- 1 
+/- 1 
+/- 1 
+ 3 
+/- 1 
+/- 1 
+/- 1 
+/- 1 
+ 3 
+3 
 
Week 
 
 
 
1 
2 
3 
4 
 
5, 9, 13, 
etc. 
6, 10, 14, 
etc. 
7, 11, 15, 
etc. 
8, 12, 16, 
etc. 
 
 
 
Chemistry panel and CRP 
 
X 17 
 
X 18 
X 18 
X 18 
X 18 
X 18 
X 19 
X 19 
X 19 
X 19 
X 19 
X 
 
17. May be used as Study Day 1 baseline if within 24 hours of drug administration start 
18. Cycle 1: Study Day 1 (pre-infusion), Days 2 through 8 (sample may be drawn any time relative to infusion). If inpatient, Study Days 9-28 (sample may be drawn any time 
relative to infusion). If outpatient, Study Days 15, 22 and 25 (sample may be drawn any time relative to infusion). 
19. All other cycles: Study Day 1, 8, 15 and 22 – pre-infusion or prior to bag change as applicable; Study Days 5, 12, and 19 - if patient returns to study site for end of infusion or 
bag change; collect prior to end of infusion/bag change; Study Day 26 - when patient returns to study site for end of infusion or bag change; collect prior to end of infusion/bag 
change. 
Special Chemistry 
 
X 20 
 
X 21 
X 21 
X 21 
X 21 
 
X 21 
X 21 
X 21 
X 21 
 
X 
 
20. May be used as Study Day 1 baseline if within 24 hours of drug administration start 
21. Cycle 1 and all other cycles: Study Days 1, 8, 15, and 22. Samples to be obtained pre-infusion or prior to dose or bag change as applicable. 
 
Prothrombin time; Activated 
partial thromboplastin time 
 
X 22 
 
X 23 
 
 
 
 
X 23 
 
 
 
 
X 
 
22. May be used as Study Day 1 baseline if within 24 hours of drug administration start 
23. All cycles: Study Day 1. Samples to be obtained pre-infusion or prior to bag change, as applicable 
 
Urinalysis with microscopic 
evaluation of urinary sediment 
 
X 24 
 
X 25 
 
 
 
 
X 25 
 
 
 
 
X 
 
24. May be used as Study Day 1 baseline if within 24 hours of drug administration start 
25. All cycles: Study Day 1. Samples to be obtained pre-infusion or prior to bag change as applicable 
 
PK for flotetuzumab sampling 
---See Appendix 2 for all sample times and windows--- 
 
ADA blood sample (anti-
flotetuzumab) 
---See Appendix 2 for all sample times and windows--- 
 
Peripheral Blood Sample for 
Flow Cytometric Analysis 
---See Appendix 2 for all sample times and windows--- 
 
Peripheral Blood Sample for T 
cell Repertoire 
---See Appendix 2 for all sample times and windows--- 
 
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Screening 
Cycle 1 
28 days 
Subsequent Cycles 
28 days 
End of 
Treatment 
Post-
treatment 
Follow-up 
 
Day 
Up to  
-14 
Days 
Up to 
-5 
Days 
Up to 
-1 
Days 
1 
8 
15 
22 
25 
and/or 
26 
1 
8 
15 
22 
25 
and/or 
26 
28-days 
Following Last 
Treatment or 
At Time of 
Treatment Failure 
Study Day 
Window 
 
 
 
+/- 1 
+/- 1 
+/- 1 
+/- 1 
+ 3 
+/- 1 
+/- 1 
+/- 1 
+/- 1 
+ 3 
+3 
 
Week 
 
 
 
1 
2 
3 
4 
 
5, 9, 13, 
etc. 
6, 10, 14, 
etc. 
7, 11, 15, 
etc. 
8, 12, 16, 
etc. 
 
 
 
Vital signs (temperature, 
respiration, pulse oximetry, heart 
rate, blood pressure) 
 
X 
 
X 26 
X 26  
X 26 
X 26 
X 26 
X 27 
X 27 
X 27 
X 27 
X 27  
 
 
26. Cycle 1 only, Days 1 - 7: Study Day 1 – pre-infusion, at 1 hour, and 4 hours after infusion start; Study Days 2 - 7– prior to dose change and at 1 hour and 4 hours after dose 
change; except for pre-infusion or prior to dose change, vital signs can be taken within ± 10 minutes of indicated collection time. If inpatient: Study Day 11 – approximately 96 
hours after bag change; Study Days 15, 19, 22 and 26 – prior to bag changes as applicable. If outpatient: Study Days 15, 22, and 26 – prior to bag changes as applicable. 
27. All other cycles: Days 1, 8, 15, and 22 – prior to bag change as applicable; Days 5, 12, and 19 – if patient returns to study site for end of infusion or bag change; collect at end 
of infusion/before bag change; Study Day 26 – when patient returns to study site for end of infusion or bag change; collect at end of infusion/prior to bag change. 
 
Toxicity review and AE 
assessment 28 
 
 
 
--- Continuous --- 
X 
X 
28. Including orientation to person, place, and time. Ongoing AEs at the time of study drug discontinuation will be followed until either 28 days after last administration of study 
drug or until the start of a subsequent systemic anticancer therapy, whichever is earlier. 
 
THERAPEUTIC ACTIVITY 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Re-evaluation Bone Marrow 
Aspirate and core biopsy for local 
histopathological and 
immunohistochemical analysis, 
central flow cytometric analysis, 
and next generation sequencing 29 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
X 30 
X 31 
Survival 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 32 
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Flotetuzumab 
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Clinical Trial Protocol: CP-MGD006-01 
Amendment 13, 26 April 2021 
 
 
 
 
 
Screening 
Cycle 1 
28 days 
Subsequent Cycles 
28 days 
End of 
Treatment 
Post-
treatment 
Follow-up 
 
Day 
Up to  
-14 
Days 
Up to 
-5 
Days 
Up to 
-1 
Days 
1 
8 
15 
22 
25 
and/or 
26 
1 
8 
15 
22 
25 
and/or 
26 
28-days 
Following Last 
Treatment or 
At Time of 
Treatment Failure 
Study Day 
Window 
 
 
 
+/- 1 
+/- 1 
+/- 1 
+/- 1 
+ 3 
+/- 1 
+/- 1 
+/- 1 
+/- 1 
+ 3 
+3 
 
Week 
 
 
 
1 
2 
3 
4 
 
5, 9, 13, 
etc. 
6, 10, 14, 
etc. 
7, 11, 15, 
etc. 
8, 12, 16, 
etc. 
 
 
 
29. For Cycles > 1, bone marrow assessment should be performed at the end of every cycle whenever possible. A CBC must be drawn on the same day of the bone marrow aspirate. 
At the end of Cycle 2, and at the end of each subsequent even cycle, in consultation with the Medical Monitor, the bone marrow assessment may be missed if the patient has 
clearly not achieved CR or CRh using the following criteria: the patient has not achieved CR/CRh because the peripheral blood neutrophils are < 500/μL or platelets are 
< 50,000/μL), based on Study Day 22 CBC results for the cycle in question; and the results of the bone marrow assessment will not influence the decision to continue study 
treatment (i.e., assessment of risks and benefits). 
30. If indicated to establish treatment failure. 
31. Bone Marrow Collections: Responders (CR, CRh, CRi [CRn, CRp], or MLFS): bone marrow aspirate and biopsy collection at 3 and 6 months post treatment at the study site. 
After 6 months post treatment, bone marrow aspirate and/or biopsy will be performed per standard of care. Non-responders: bone marrow aspirate and/or biopsy performed 
per standard of care. All patients: During study follow-up, if patients have a bone marrow aspiration and/or biopsy done as part of their standard of care, they have the option 
to consent to donate aspirate or biopsy specimens for assessment of disease status and further research to help elucidate immune mechanisms involved in flotetuzumab function. 
As with all other biopsies collected for this study, these samples may be used for histopathological and immunohistochemical evaluation, flow cytometric evaluation, and 
minimal residual disease analysis. 
32. Follow-up Frequency: Responders (CR, CRh, CRi [CRn, CRp], or MLFS): monthly visits at the study site for 6 months post end of treatment. After 6 months post treatment, 
patients may be followed up at the study site or by a local physician, and follow-up data will be collected at 3-month intervals. Non-responders: follow up at the study site or by 
a local physician, and follow-up data will be collected at 3-month intervals post treatment. 
 
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Clinical Trial Protocol: CP-MGD006-01 
Amendment 13, 26 April 2021 
 
 
 
 
Appendix 2 
Pharmacokinetic, Immunogenicity, and Pharmacodynamic Biomarkers Blood Sampling 
Schedule  
Cycle 
Day 
PK 1 
ADA 
PBMC 
Flow Cytometry 
PBMC 
T Cell Repertoire 
Screening 
Screen 
 
 
Screening 2 
 
Cycle 1 
1 
Pre infusion 
Pre Infusion 
Pre Infusion 
Pre Infusion 
7-14 
Only done ONCE on Days 7-14, the first time the patient 
reaches 500 ng/kg/day dose level 
 
One sample at least 1 hour after 500 ng/kg/day dose level 
reached 
 
Only done on Day 8 
 
 
Sample may be 
drawn at any time 
relative to infusion 
 
15 
Patient reached 500 ng/kg/day dose level before Day 15: 
Sample may be drawn at any time relative to infusion 
 
Patient reaches 500 ng/kg/day dose level on Day 15: 
Sample at least 1 hour after 500 ng/kg/day dose level reached 
 
Sample may be 
drawn at any time 
relative to infusion 
 
22 
Patient reached 500 ng/kg/day dose level before Day 22: 
Sample may be drawn at any time relative to infusion 
 
Patient reaches 500 ng/kg/day dose level on Day 22: 
Sample at least 1 hour after 500 ng/kg/day dose level reached 
 
Sample may be 
drawn at any time 
relative to infusion 
 
25 
Patient reached 500 ng/kg/day dose level before Day 25: 
Sample may be drawn at any time relative to infusion 
 
Patient reaches 500 ng/kg/day dose level on Day 25: 
Sample at least 1 hour after 500 ng/kg/day dose level reached 
 
Sample may be 
drawn at any time 
relative to infusion 
Sample may be 
drawn at any time 
relative to infusion 
29 
Immediately prior to end of infusion 3 
 
 
 
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Flotetuzumab 
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Clinical Trial Protocol: CP-MGD006-01 
Amendment 13, 26 April 2021 
 
 
 
 
Cycle 
Day 
PK 1 
ADA 
PBMC 
Flow Cytometry 
PBMC 
T Cell Repertoire 
Cycles ≥ 2 
1 
Sample may be drawn at any time relative to infusion 
Sample may be 
drawn at any time 
relative to infusion 
Sample may be 
drawn at any time 
relative to infusion 
Sample may be 
drawn at any time 
relative to infusion 
End of 
Treatment 
n/a 
28-days following last treatment or 
at time of treatment failure 
28-days following 
last treatment or 
at time of treatment 
failure 
28-days following 
last treatment or 
at time of treatment 
failure 
28-days following 
last treatment or 
at time of treatment 
failure 
Abbreviations: ADA = anti-drug antibody; PBMC = peripheral blood mononuclear cell; PK = pharmacokinetics. 
1 
For patients who will discontinue therapy, a PK sample is to be collected at end of infusion. When dosing is delayed for ≥ 24 hours, PK samples should not 
be collected on days when no study drug is administered. After Cycle 1 Day 1, PK samples do not need to be collected if patient does not reach 
500 ng/kg/day dose level. 
2 
Sample may be drawn up to Day -5. 
3 
Cycle 1 Day 29 PK samples are only to be collected if there is a > 24 hour interruption in treatment between Cycles 1 and 2. 
 
 
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Clinical Trial Protocol: CP-MGD006-01 
Amendment 13, 26 April 2021 
 
 
 
 
Appendix 3 
International Working Group (IWG) Response Criteria for Acute Myeloid Leukemia 
(AML) Modified for Assessment of AML in this Study  
Response Criterion 
Time of 
Assessment 
Neutrophils* 
(µL) 
Platelets* 
(µL) 
Bone Marrow Blasts (%) 
Other 
Complete Remission (CR) 
Day 25 + 3 days 
(each cycle) 
≥ 1,000 
≥ 100,000 
< 5 
Transfusion# 
Extramedullary disease 
(EMD) 
• 
Morphologic CR (mCR) 
Day 25 + 3 days 
(each cycle) 
≥ 1,000 
≥ 100,000 
< 5 
Transfusion# EMD 
• 
Cytogenetic CR (CRc) 
Day 25 + 3 days 
(each cycle) 
≥ 1,000 
≥ 100,000 
< 5 
Cytogenetics – normal, 
EMD 
• 
Molecular CR (CRm) 
Day 25 + 3 days 
(each cycle) 
≥ 1,000 
≥ 100,000 
< 5 
Molecular – negative, 
EMD 
CR with partial hematologic 
recovery (CRh) 
Day 25 + 3 days 
(each cycle) 
≥ 500 
≥ 50,000 
< 5 
Transfusion$ EMD 
CR with incomplete blood 
count recovery (CRi) 
Day 25 + 3 days 
(each cycle) 
< 1,000 
< 100,000 
< 5 
Transfusion$ EMD 
• 
CR with incomplete 
neutrophil recovery 
(CRn) 
Day 25 + 3 days 
(each cycle) 
< 1,000 
≥ 100,000 
< 5 
Transfusion$ EMD 
• 
CR with incomplete 
platelet recovery (CRp) 
Day 25 + 3 days 
(each cycle) 
≥ 1,000 
< 100,000 
< 5 
Transfusion$ EMD 
Morphologic leukemia-free 
state (MLFS) 
Day 25 + 3 days 
(each cycle) 
NA 
NA 
< 5 
EMD 
Partial remission (PR) 
Day 25 + 3 days 
(each cycle) 
> 1,000 
> 100,000 
> 50% decrease or  
decrease to 5-25 
Blasts < 5% if Auer rod 
positive 
Other benefit (OB) 
Day 25 + 3 days 
(each cycle) 
NA 
NA 
> 30% decrease  
NA 
Stable disease (SD) 
Day 25 + 3 days 
(each cycle) 
NA 
NA 
Absence of CR, CRh, CRi, PR, MLFS, 
OB, and criteria for PD not met 
NA 
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Flotetuzumab 
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Clinical Trial Protocol: CP-MGD006-01 
Amendment 13, 26 April 2021 
 
 
 
 
Response Criterion 
Time of 
Assessment 
Neutrophils* 
(µL) 
Platelets* 
(µL) 
Bone Marrow Blasts (%) 
Other 
Progressive disease 
NA 
NA 
NA 
Evidence for an increase in bone 
marrow blast percentage and/or increase 
of absolute blast counts in the blood: 
• 
> 50% increase in 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 mo; 
without at least a 100% 
improvement in ANC to an 
absolute level (>0.5 x 109/L 
[500/mL], and/or platelet count to 
>50 x 109/L [50 000/mL] non-
transfused); or 
• 
> 50% increase in peripheral blasts 
(WBC x % blasts) to > 25 x 109/L 
(> 25 000/mL) (in the absence of 
differentiation syndrome)†; or 
• 
New extramedullary disease 
In general, at least 2 
cycles of flotetuzumab 
should be administered 
to determine 
“progressive disease”. 
“Progressive disease” is 
usually accompanied by a 
decline in ANC and 
platelets, increased 
transfusion requirement, 
and decline in 
performance status or 
increase in symptoms 
Recurrence/relapse 
Relapse after CR is defined as a reappearance of leukemic blasts in the peripheral blood and ≥ 5% blasts in the bone marrow 
not attributable to any other cause (e.g., bone marrow regeneration after consolidation therapy) 
CR = complete remission (includes mCR, CRc, CRm). 
CRi = includes neutrophil count ≥ 1000 or platelet count ≥ 100,000. 
*Assessment is quantitated by BM biopsy and best CBC (up to 14 days post BM biopsy). 
# No RBC and/or platelet transfusion within 5 days prior to response assessment. 
$ No platelet transfusion within 5 days prior to response assessment 
† Certain targeted therapies, for example, those inhibiting mutant IDH proteins, may cause a differentiation syndrome, that is, a transient increase in the percentage of bone marrow 
blasts and an absolute increase in blood blasts; in the setting of therapy with such compounds, an increase in blasts may not necessarily indicate PD. 
 
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Clinical Trial Protocol: CP-MGD006-01 
Amendment 13, 26 April 2021 
 
 
 
 
Appendix 4 
Eastern Cooperative Oncology Group (ECOG) 
Performance Status  
Grade 
Description 
0 
Fully active, able to carry on all pre-disease performance without restriction. 
1 
Restricted in physically strenuous activity, but ambulatory and able to carry out work of a 
light or sedentary nature (e.g., light house work or 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 
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Flotetuzumab 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGD006-01 
Amendment 13, 26 April 2021 
 
 
 
 
Appendix 5 
Principal Investigator’s Agreement  
Study Title: 
A Phase 1/2, First-in-Human, Dose Escalation Study of MGD006, a 
CD123 x CD3 Dual Affinity Re-Targeting (DART) Bi-Specific 
Antibody-Based Molecule, in Patients with Relapsed or Refractory 
Acute Myeloid Leukemia or Intermediate-2/High Risk 
Myelodysplastic Syndrome 
Study Number: 
CP-MGD006-01 
 
I have read the protocol described above. 
I have fully discussed the objectives of this trial and the contents of this protocol with the 
Sponsor’s representative. 
I understand that the information in this protocol is confidential and should not be disclosed, 
other than to those directly involved in the execution of the ethical review of the study, 
without written authorization from MacroGenics, Inc. It is, however, permissible to provide 
information to a subject in order to obtain consent. 
I agree to conduct this trial according to this protocol and to comply with its requirements, 
subject to ethical and safety considerations and guidelines, and to conduct the trial in 
accordance with ICH guidelines on GCP and with the applicable regulatory requirements. 
I understand that the Sponsor may decide to suspend or prematurely terminate the trial at any 
time for whatever reason; such a decision will be communicated to me in writing. 
Conversely, should I decide to withdraw from execution of the trial, I will communicate my 
intention immediately in writing to the Sponsor. 
Signed: 
 
Date: 
 
PI Name (printed): 
 
PI Affiliation: 
 
PI Address:  
 
PI Phone number: 
 
 
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CP-MGD006-01 Protocol Amendment 13 (26-Apr-2021)
This is the electronic signature page for the above referenced document.
User Task: eSignatories Approval
Data Management/Statistics Approval
(Intended or Designee)
04-May-2021 18:37:17 GMT+0000
User Task: eSignatories Approval
nt Approval (Intended or Designee)
04-May-2021 21:04:56 GMT+0000
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SAP_001.pdf: 
Flotetuzumab
MacroGenics, Inc.
CP-MGD006-01: Statistical Analysis Plan
Version 3.0, 19 April 2021
STATISTICAL ANALYSIS PLAN 
VERSION 3.0 
CLINICAL STUDY PROTOCOL CP-MGD006-01 
PROTOCOL AMENDMENT 12 (18 AUGUST 2020) 
A PHASE 1/2, FIRST-IN-HUMAN, DOSE ESCALATION STUDY OF 
MGD006, A CD123 X CD3 DUAL AFFINITY RE-TARGETING (DART) BI-
SPECIFIC ANTIBODY-BASED MOLECULE, IN PATIENTS WITH 
RELAPSED OR REFRACTORY ACUTE MYELOID LEUKEMIA OR 
INTERMEDIATE-2/HIGH RISK MYELODYSPLASTIC SYNDROME 
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NCT02152956


Flotetuzumab 
MacroGenics, Inc. 
CP-MGD006-01: Statistical Analysis Plan 
Version 3.0, 19 April 2021 
 
 
REVISION HISTORY  
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Flotetuzumab 
MacroGenics, Inc. 
CP-MGD006-01: Statistical Analysis Plan 
Version 3.0, 19 April 2021 
 
 
TABLE OF CONTENT 
1 
INTRODUCTION .............................................................................................................. 8 
 
 
3 
STUDY OBJECTIVES ..................................................................................................... 10 
3.1 
Primary Objectives................................................................................................... 10 
3.2 
Secondary Objective(s) ............................................................................................ 10 
3.3 
Exploratory Objectives ............................................................................................ 10 
4 
STUDY DESIGN AND PLAN ......................................................................................... 12 
4.1 
Overall Study Design and Plan ................................................................................ 12 
4.2 
Sample Size Determination...................................................................................... 12 
5 
STUDY POPULATIONS ................................................................................................. 16 
6 
STUDY ENDPOINTS ...................................................................................................... 17 
6.1 
Primary Efficacy Endpoint ...................................................................................... 17 
6.2 
Secondary Efficacy Endpoints ................................................................................. 17 
6.3 
Safety Endpoint ........................................................................................................ 18 
7 
STATISTICAL METHODOLOGY .................................................................................. 19 
7.1 
General Considerations ............................................................................................ 19 
7.2 
Missing Data ............................................................................................................ 20 
8 
PATIENT DISPOSITION AND BASELINE CHARACTERISTICS .............................. 21 
8.1 
Patient Disposition ................................................................................................... 21 
8.2 
Patient Demographics and Baseline Characteristics ................................................ 21 
8.2.1 
Demographics ................................................................................................ 21 
8.2.2 
Baseline Disease Characteristics .................................................................... 21 
8.3 
Prior/Concomitant/Follow-up Medications/Procedures/Therapies ......................... 22 
8.3.1 
Prior/Concomitant/Follow-up Medications ................................................... 22 
8.3.2 
Prior/Concomitant/Follow-up Surgeries/Procedures ..................................... 22 
8.3.3 
Prior/Follow-up Anti-Cancer Therapies......................................................... 23 
8.3.4 
Prior/Concomitant/Follow-up Transfusions ................................................... 23 
9 
STUDY DRUG EXPOSURES ......................................................................................... 24 
10 
PROTOCOL DEVIATIONS ............................................................................................. 25 
11 
EFFICACY ANALYSES .................................................................................................. 26 
11.1 
Primary Efficacy Analysis ....................................................................................... 26 
11.2 
Secondary Efficacy Analyses ................................................................................... 27 
11.2.1 
Key Secondary Efficacy Analyses ................................................................. 27 
11.2.2 
Additional Secondary Efficacy Analyses ....................................................... 28 
11.2.3 
Other Secondary Analyses ............................................................................. 29 
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Flotetuzumab 
MacroGenics, Inc. 
CP-MGD006-01: Statistical Analysis Plan 
Version 3.0, 19 April 2021 
 
 
12 
SAFETY ANALYSES ...................................................................................................... 30 
12.1 
Treatment Emergent Adverse Events ....................................................................... 30 
12.2 
Clinical Laboratory Evaluations .............................................................................. 31 
12.3 
Physical Examination............................................................................................... 32 
12.4 
Vital Sign Measurements and Performance Status .................................................. 32 
12.5 
Electrocardiograms .................................................................................................. 32 
12.6 
Left Ventricular Ejection Fraction............................................................................ 33 
12.7 
Pulmonary Function Testing .................................................................................... 33 
13 
INTERIM ANALYSIS ...................................................................................................... 34 
13.1 
General Information ................................................................................................. 34 
13.2 
Data Safety Monitor (DSM) .................................................................................... 34 
13.3 
Independent Data Monitoring Committee ............................................................... 34 
13.4 
Statistical Approaches for Control of Alpha ............................................................ 35 
14 
LIST OF TABLES, LISTINGS, AND FIGURES ............................................................ 36 
15 
REFERENCES ................................................................................................................. 37 
 
LIST OF TABLES  
Table 1 
Meta-analysis Using Bayesian Method .............................................................. 13 
Table 2 
Three Stage Design ............................................................................................. 15 
Table 3 
Key Secondary Endpoints .................................................................................. 17 
Table 4 
Additional Secondary Endpoints ........................................................................ 18 
Table 5 
Stopping Bounds for Excess Toxicity Based on Bayesian Beta 
Binomial Model with Beta (1,1) Prior ................................................................ 35 
 
LIST OF FIGURES  
Figure 1 
Forest Plot for Meta-analysis .............................................................................. 12 
 
LIST OF APPENDICES  
Appendix 1 
International Working Group (IWG) Response Criteria for Acute 
Myeloid Leukemia (AML) Modified for Assessment of AML in this 
Study 
 
 
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CP-MGD006-01: Statistical Analysis Plan 
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Flotetuzumab 
MacroGenics, Inc. 
CP-MGD006-01: Statistical Analysis Plan 
Version 3.0, 19 April 2021 
 
 
LIST OF ABBREVIATIONS  
AE 
adverse event 
AESI 
adverse event of special interest 
AML 
acute myeloid leukemia 
CR 
complete remission (mCR, CRc, or CRm) 
CR1 
initial CR 
CRc 
cytogenetic complete remission 
CRh 
complete remission with partial hematologic recovery 
CRi 
complete remission with incomplete blood cell recovery 
CRm 
molecular complete remission 
CRn 
CR with incomplete neutrophil recovery 
CRp 
CR with incomplete platelet recovery 
CRS 
cytokine release syndrome 
CTCAE 
common terminology criteria for adverse events 
DLT 
dose-limiting toxicity 
DOR 
duration of response  
DSM 
Data Safety Monitor 
EBV 
Epstein-Barr Virus 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 
EFS 
event-free survival 
EOTV 
end of treatment visit 
ER 
early relapse 
FDA 
Food and Drug Administration 
HSCT 
hematopoietic stem cell transplantation 
IDMC 
independent data monitoring committee 
IRR 
infusion related reaction 
IWG 
International Working Group 
mCR 
morphologic CR 
MLFS 
morphologic leukemia-free state 
MRD 
minimal residual disease 
MTD 
maximum tolerated dose 
MTDS 
maximum tolerated dose and schedule 
OS 
overall survival 
PBMC 
peripheral blood mononuclear cell 
PD 
progressive disease 
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Flotetuzumab 
MacroGenics, Inc. 
CP-MGD006-01: Statistical Analysis Plan 
Version 3.0, 19 April 2021 
 
 
PIF 
primary induction failure 
PK 
pharmacokinetics 
PR 
partial remission 
SAE 
serious adverse event 
SD 
stable disease 
SPP 
statistical programming plan 
TLFs 
tables, listings and figures 
TTR 
time to response  
WBC 
white blood cell (count) 
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Flotetuzumab 
MacroGenics, Inc. 
CP-MGD006-01: Statistical Analysis Plan 
Version 3.0, 19 April 2021 
 
 
1 
INTRODUCTION  
Flotetuzumab (MGD006) is a CD123 x CD3 DART protein developed by MacroGenics, Inc., 
designed to target CD123-positive cells (including AML cells) for recognition and elimination 
by CD3-expressing T lymphocytes as effector cells. 
This statistical analysis plan (SAP) provides a detailed and comprehensive description of the 
analysis of the study CP-MGD006-01 entitled “A Phase 1/2, First-in-Human, Dose Escalation 
Study of MGD006, a CD123 x CD3 Dual Affinity Re-Targeting (DART) Bi-Specific Antibody-
Based Molecule, in Patients with Relapsed or Refractory Acute Myeloid Leukemia or 
Intermediate-2/High Risk Myelodysplastic Syndrome”. 
 
 
 
 
 
 
 
. 
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MacroGenics, Inc. 
CP-MGD006-01: Statistical Analysis Plan 
Version 3.0, 19 April 2021 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Flotetuzumab 
MacroGenics, Inc. 
CP-MGD006-01: Statistical Analysis Plan 
Version 3.0, 19 April 2021 
 
 
3 
STUDY OBJECTIVES  
3.1 
Primary Objectives  
To assess the anti-neoplastic activity of flotetuzumab in patients with PIF/ER AML, as 
determined by the proportion of patients who achieve CR/CRh. 
3.2 
Secondary Objective(s)  
Collectively, the secondary objectives of this study are: 
• Assessment of CR rate, CRh rate, overall complete response rate (CR, CRh, CRi 
[CRn, CRp], or MLFS), objective response rate (CR, CRh, CRi [CRn, CRp], MLFS, 
or PR), time to response and duration of response (DOR). 
• To measure early mortality rates, overall survival (OS) and event-free survival (EFS). 
• To determine the rate of eligible patients, per institution criteria, that transition to 
successful stem cell transplant after achieving complete response (CR, CRh, CRi 
[CRn, CRp], or MLFS). 
• To assess rate of conversion to and maintenance of transfusion independence. 
• To evaluate duration of initial hospitalization for flotetuzumab administration. 
• To evaluate incidence and duration of hospitalizations subsequent to initial discharge. 
• To monitor the safety and tolerability of flotetuzumab. 
• To characterize the PK and immunogenicity of flotetuzumab. 
• To determine safety and efficacy of tocilizumab in the treatment of IRR/CRS. 
3.3 
Exploratory Objectives  
The exploratory objectives of the study are: 
• To evaluate CD123 expression on blast cells  
• To evaluate circulating cytokine levels at baseline and over time 
• To evaluate circulating leukemic and normal cells at baseline and over time 
• To evaluate circulating T lymphocyte populations and activation markers at baseline 
and over time  
• To evaluate leukemic cells, leukemic stem cells, normal progenitor cells and T 
lymphocytes at baseline and over time in the bone marrow 
• To evaluate molecular markers of minimal residual disease (MRD) 
• To examine changes in T lymphocyte repertoire 
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• To evaluate the correlation between cytogenetic abnormalities with responses to 
flotetuzumab immunotherapy. 
• To study adaptive immune changes during flotetuzumab treatment. 
• To study the tumor microenvironment immune contexture. 
• Ruxolitinib Cohort Objectives: 
o To characterize the onset, duration, and severity of IRR/CRS on an 
exploratory, pilot basis in flotetuzumab-treated patients receiving ruxolitinib 
and compare that to historical experience in patients not receiving ruxolitinib. 
o To measure and compare cytokine profile and T-lymphocyte populations in 
patients receiving the combination of ruxolitinib and flotetuzumab vs 
flotetuzumab alone. 
o To determine the safety and tolerability of the combination of ruxolitinib and 
flotetuzumab. 
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4 
STUDY DESIGN AND PLAN  
4.1 
Overall Study Design and Plan  
This is an open-label, multi-dose, single-arm, multi-center, Phase 1/2, dose-escalation and 
expansion study. As of Protocol Amendment 11 the trial design was updated to a single arm 
pivotal study going forward to evaluate efficacy and safety of flotetuzumab for PIF/ER AML 
patients. 
 
4.2 
Sample Size Determination  
The planned sample size for the pivotal portion of the study as of Protocol Amendment 11 is 170 
patients, based on a three-stage design. 
To determine the sample size under inclusion criteria, historical reference response rates to 
standard treatments were ascertained through a meta-analysis based on 5 published studies that 
included PIF/ER AML patients selected from 963 publications identified through database 
search (1; 2; 3; 6; 7). The response rate identified by the meta-analysis is based on a random 
intercept logistic regression model, yielding a combined CR/CRh rate for PIF/ ER AML of 
11.8%, with a 95% confidence interval of 9.4% to 14.7% (Figure 1). 
Figure 1 
Forest Plot for Meta-analysis  
 
The result obtained with the Bayesian method is consistent with the result of the random 
intercept logistic regression model (Table 1). 
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Table 1 
Meta-analysis Using Bayesian Method  
Assumption 
Point Estimate 
95% Credible 
Intervals 
(Highest Posterior 
Density) 
95% Credible 
Intervals 
(Equal-tail) 
Normal prior, 
normal 
(0, var=10000) 
11.7% 
(9.3%, 14.7%) 
(9.2%, 14.6%) 
Beta prior, beta 
(1, 1) 
11.9% 
(9.4%, 14.6%) 
(9.4%, 14.7%) 
 
The upper 95% CI of 14.7% was chosen as the rate for the null hypothesis (H0) and a target of 
23% CR/CRh was established as a clinically meaningful endpoint in this patient population. 
A three-stage design with two interim analyses was employed to test the null hypothesis (H0) of 
CR/CRh rate = 14.7% against the alternative hypothesis (H1) of CR/CRh rate = 23%. 
Demonstration of CR/CRh rate improvement (H1) by rejecting H0 at a 1-sided type I error of 
0.025 with adequate power (80%) in a sequential design requires 170 patients. Specifically, the 
planned number of patients and the futility and efficacy boundaries at each stage are as follows: 
a. First interim analysis: The first interim analysis will be performed after 40 patients have 
been enrolled and either have had their responses evaluated or were discontinued for any 
reason from study treatment prior to their first response assessments. This interim 
analysis is for futility only, that is, the study enrollment will continue if at least 5 (12.5%) 
out of 40 patients have response of CR/CRh. 
b. Second interim analysis: If the enrollment continues after the first interim analysis, a 
second interim analysis will be performed after additional 60 patients have been enrolled 
(100 patients in total) and either have had their response evaluated or were discontinued 
for any reason from study treatment prior to their first response assessment. This interim 
analysis is for both futility and efficacy. Specifically, 
i. If the number of CR/CRh is less than 15 (15%) out of 100 patients, then the 
study is considered futile and enrollment will be stopped. 
ii. If the number of CR/CRh is 15 (15%) or greater out of 100 patients, then 
enrollment will continue. 
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iii. If the number of CR/CRh is 25 (25%) or greater out of 100 patients, then H0 
is rejected and the study is considered positive. The enrollment will still 
continue. 
c. Final analysis: If enrollment continues after the second interim, then the final analysis 
will be performed after additional 70 patients have been enrolled (170 patients in total) 
and either have had their response evaluated or were discontinued for any reason from 
study treatment prior to their first response assessments. If the number of CR/CRh is at 
least 35 (20.6%) out of the total of 170 patients, then H0 is rejected and the study is 
considered positive. 
The above design yields a 1-sided alpha of 0.005 for the efficacy boundary at the second interim 
analysis and an overall 1-sided alpha of 0.024 with approximately 80% power at the final 
analysis (Table 2). The probability of early termination under H0 (futility) in the first two stages 
is 55%. 
 
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Table 2 
Three Stage Design  
H0 
(Benchmark 
CR/CRh 
rate) 
H1 
(Target 
CR/CRh 
rate) 
Stage 1 
Stage 2 
Efficacy interim 
analysis at the end of 
Stage 2 
Stage 3 
1-Sided 
alpha 
for 
rejecting 
H0 
Power 
under 
H1 
14.7% 
23% 
N1 
Move to 
Stage 2 if 
# (%) of 
CR/CRh ≥ 
N2 
N1+N2 
Move to 
Stage 3 if 
# (%) of 
CR/CRh ≥ 
Trial 
success if 
# (%) of 
CR/CRh ≥ 
1-sided 
alpha 
for 
rejecting 
H0 
N3 
Total 
(N1+N2+N3) 
Trial 
success if 
# (%) of 
CR/CRh ≥ 
0.024 
80% 
40 
5 (12.5%) 
60 
100 
15 (15.0%) 
25 (25.0%) 
0.005 
70 
170 
35(20.6%) 
 
 
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5 
STUDY POPULATIONS  
Three populations will be used for analysis, the efficacy population, safety population and the 
evaluable population, as defined below: 
• Efficacy population – All patients that have been enrolled under protocol 
amendment 11 or later and treated with flotetuzumab at the MTD of 500 ng/kg/day as 
a continuous 7-day per week IV infusion during Cycle 1, have received any portion of 
one dose of flotetuzumab, and met the definition of PIF/ER AML based on 
Amendment 11 inclusion criteria 
. This 
population will be used for the primary analysis of efficacy endpoints. 
• Safety population – All patients who received any portion of any dose of 
flotetuzumab. AML and MDS will be analyzed as pooled and separate populations for 
safety and PK. The analysis of all safety endpoints will be based on the safety 
population. 
• Response evaluable population – All patients in the efficacy population that have a 
baseline bone marrow assessment, have at least one post-infusion assessment of their 
disease status or were removed from the study for reason of documented evidence of 
disease progression, death, or treatment-related adverse event. This population will be 
used in the summary of response rate as a secondary analysis. 
Patients who die before having a post-infusion disease assessment will be considered evaluable 
for OS and EFS analyses. 
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6 
STUDY ENDPOINTS  
6.1 
Primary Efficacy Endpoint  
The primary efficacy endpoint for the PIF/ER AML pivotal expansion cohort is the rate of 
CR/CRh as assessed by the study investigators. 
6.2 
Secondary Efficacy Endpoints  
Key secondary endpoints are listed in Table 3. 
Table 3 
Key Secondary Endpoints  
Name 
Description 
Duration of response (DOR) 
Time of initial documentation of response to the time of disease relapse or 
death due to any cause, whichever occurs first. 
Rate of post-baseline transfusion 
independence  
Rate of no transfusion during any consecutive 56-day period on-study. 
Rate of HSCT 
Rate of successful HSCT through study treatment. 
Incidence and duration of 
hospitalization 
Duration of initial hospitalization as well as incidence, number and 
durations of subsequent hospitalizations following the initial discharge, 
number of days hospitalized, and reasons for hospitalization. 
CR rate 
Rate of complete remission. 
CRh rate 
Rate of complete remission with partial hematologic recovery. 
 
The additional secondary endpoints are listed in Table 4. 
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Table 4 
Additional Secondary Endpoints  
Name 
Description 
Overall complete response rate 
Rate of achievement of BM blast of < 5%, CR+CRh+CRi [CRn, 
CRp]+MLFS according to IWG AML response criteria. 
Objective response rate 
Rate of CR+CRh+CRi [CRn, CRp]+MLFS+PR according to IWG AML 
response criteria. 
Overall survival (OS) 
Time from first dose to death from any cause. 
Event-free survival (EFS) 
Time from first dose to the date of relapse after CR/CRh/CRi [CRn, CRp], 
or death from any cause, whichever occurs first. 
Time to response (TTR) 
Time from first dose to the first CR, CRh, CRi (CRn, CRp), or MLFS. 
Mortality rate at 30, 60, 90 and 180 
days 
Rate of death from any cause within 30, 60, 90, 180 days of first study 
dose. 
Six-month survival rate 
Probability of survival at 6 months from first study dose. 
One-year survival rate 
Probability of survival at 1 year from first study dose. 
Immunogenicity 
Proportion of patients who become positive for anti-drug antibody 
production. 
Pharmacokinetics 
Evaluation of serum concentration of flotetuzumab and its relationships 
with efficacy, safety and correlative endpoints. 
 
6.3 
Safety Endpoint  
Safety assessments include evaluation of type, frequency, severity, and relationship to 
flotetuzumab treatment of AEs, SAEs and AESIs. These events will be recorded by the 
Investigators in the electronic case report forms (eCRFs). Verbatim terms will be coded to lower-
level terms in the Medical Dictionary for Regulatory Activities (MedDRA) and graded by the 
National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) 
version 4.0, except for infusion related reaction/cytokine release syndrome events which are 
defined by the modified criteria proposed by Lee et al (5). The most current version of MedDRA 
will be used. Additionally, the safety evaluation includes clinical laboratory evaluations, death, 
physical examination, vital signs, ECOG performance status, electrocardiogram (ECG) and 
concomitant medications/surgeries/procedures/therapies. 
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7 
STATISTICAL METHODOLOGY  
7.1 
General Considerations  
Safety and efficacy summaries will be provided for each dose level cohort. 
Unless otherwise specified, the following general considerations are applied in data analyses: 
• All statistical tests will preserve a significance level of 0.05 for two-sided tests, unless 
otherwise specified. 
• The baseline value is defined as the latest value at the time of or prior to the first dose 
of study treatment. 
• Categorical data will be summarized by the number and percent of patients falling 
within each category. 
• Continuous variables will be summarized by descriptive statistics, including mean, 
standard deviation, median, minimum, and maximum. 
• Time-to-event endpoints will be summarized by the number and percent of the event, 
median time and corresponding 95% confidence interval (CI), and event free rate and 
corresponding 95% CI at the specified time points of interest. 
• To summarize safety/efficacy data by visit, the post-baseline results will be 
summarized by the scheduled visit or the derived visit as appropriate. 
• In general, the derived visit is the same as the scheduled visit in the protocol which is 
defined by study day; data that is closest to derived visit (before and after) will be 
used as the value for that visit. In case that two data collected at the equal distance to 
the derived visit, the later one will be used. 
• Summaries in the Safety Population will be reported by dose cohort and total 
population; summaries in the Efficacy Population will be reported by PIF, ER and the 
combined PIF/ER total population. 
• The impact of COVID-19 may be assessed and analyzed on a case by case basis. In 
particular, the following analyses may be performed if there are enough COVID-19 
positive patients to render the analyses meaningful: 
o Number of patients discontinued study treatment and/or discontinued from 
study due to COVID-19, if such reason is collected 
o Summary of tumor response, PFS and OS 
o Summary of study drug interruption, delay or withdraw due to COVID-19, if 
such reason is collected 
o Listing of protocol deviation due to COVID-19 separately 
 
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• All data summaries and tabulations will be conducted using SAS® software Version 
9.3 or higher. 
7.2 
Missing Data  
Data that are reported as missing will be treated as missing in all data summaries. Imputation 
rules for partially recorded dates, in cases where complete dates were required to carry out an 
analysis, will be described in the Statistical Programming Plan (SPP). In descriptive summaries 
for safety, observations that appear spurious (extreme values relative to the majority of the data) 
will not be altered or removed from the summary. 
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8 
PATIENT DISPOSITION AND BASELINE CHARACTERISTICS  
8.1 
Patient Disposition  
For patient disposition, the number and percentage of patients who reach various study 
milestones are summarized: All screened patients are broken down by screen failures (with 
reasons if collected) and enrolled. Then the category of enrolled patients is broken down by 
“never treated” (with reasons if collected) and “treated”. The category of treated patients will 
further be broken down by “treatment ongoing” and “treatment discontinued” (with reasons for 
discontinuation, which also include protocol-defined treatment completion, if any). 
A summary of patient disposition will be presented for both safety and efficacy population. 
8.2 
Patient Demographics and Baseline Characteristics  
8.2.1 
Demographics  
Age (year), height (cm), weight (kg), body mass index (kg/m2), and other continuous baseline 
characteristics will be summarized using descriptive statistics (N, mean, standard deviation, 
median, minimum, maximum), while age group (< 70 years, ≥ 70 years), gender, ethnicity, race, 
geographic region and other categorical variables will be provided  using frequency tabulations 
(count, percent) for both safety and efficacy population. 
Age or year of birth will be recorded on the eCRF. Where age is not recorded, age will be 
calculated as follows: Age = year of informed consent– year of birth + 1. 
Body mass index (BMI) will be calculated as follows: BMI (kg/m2) = weight in kg/height in m2. 
8.2.2 
Baseline Disease Characteristics  
Baseline disease characteristics will be summarized using descriptive statistics. 
1. Eastern Cooperative Oncology Group (ECOG) performance status; 
2. Prior AML therapies; 
3. Primary induction failure (yes versus no); 
4. Early relapse (yes versus no), if yes, duration of initial CR (CR1); 
5. Relapse (yes versus no); 
6. Initial AML subclassification; 
7. Genetic and cytogenetics abnormalities at baseline; 
8. Prior chemotherapy/immunotherapy (not related to study indication, for patients with 
treatment-related secondary AML) (yes versus no); 
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9. Prior radiotherapy therapies (Not Related to Study Indication, for patients with 
treatment-related secondary AML) (yes versus no); 
10. Prior surgery/procedure (Not Related to Study Indication) (yes versus no); 
11. Bone marrow blasts (%) and category (< 20%; 20% to < 30%; 30% to < 50%; ≥ 50%) 
from the screening bone marrow aspirate sample; 
12. Peripheral blood blast (%); 
13. Baseline values of the following lab parameters: hemoglobin, platelet count, absolute 
neutrophil count (ANC), white blood cells (WBC);  
14. Number of red blood cell (RBC) transfusions and number of units transfused, and 
number of platelet transfusions and number of units transfused within 28 days prior to 
first dose; 
15. The medical and surgical history will be summarized by the Medical Dictionary for 
Regulatory Activities (MedDRA) latest version by system organ class (SOC) and 
preferred term (PT). 
8.3 
Prior/Concomitant/Follow-up Medications/Procedures/Therapies  
Prior medications/procedures/transfusions are defined as medications/procedures/transfusions 
that were started prior to first dose or have start dates missing. 
Concomitant medications/procedures/transfusions are defined as non-study 
medications/procedures/transfusions that are started on or after first dose but before EOTV date or 
started before the start of the study treatment and ended or remain ongoing during the study 
treatment. Medication/procedure/transfusion with missing start date but end date on or after first 
dose date and before EOTV date or with both missing start date and end date is also considered as 
concomitant medication/procedure/transfusion. 
Follow-up medications/transfusions are defined as non-study medications/transfusions that are 
started after EOTV date. 
8.3.1 
Prior/Concomitant/Follow-up Medications  
All prior, concomitant and follow-up medications will be summarized in frequency tabulations 
(patient counts and percentages) and by World Health Organization ATC first level and PT. All 
tables described in this section will be produced for both safety and efficacy population. 
8.3.2 
Prior/Concomitant/Follow-up Surgeries/Procedures  
All prior, concomitant and follow-up procedures/surgeries will be summarized in frequency 
tabulations (patient counts and percentages) and by SOC and PT. All tables described in this 
section will be produced for both safety and efficacy population. 
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8.3.3 
Prior/Follow-up Anti-Cancer Therapies  
Anti-cancer therapies include radiotherapy, induction/consolidation/ maintenance/salvage 
therapies, chemotherapy and immunotherapy. A listing will be provided for anti-cancer therapies. 
8.3.4 
Prior/Concomitant/Follow-up Transfusions  
The number of patients receiving any transfusion product, and the number of patients receiving 
any transfusion type (red blood cells (PRBCs), whole blood, platelets, plasma, other) will be 
summarized by dose cohort groups. Prior /concomitant/follow-up transfusions will be 
summarized in separate tables for both safety and efficacy population. 
Transfusion type, number of units, reasons for taking transfusion, and dates of transfusions will 
be listed in a listing. 
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9 
STUDY DRUG EXPOSURES  
All analyses of treatment exposure will be conducted using the safety and efficacy population. 
The summary of study drug exposure will include descriptive statistics as well as frequency 
counts for the number of doses or cycles received, the total dose actually administered as well as 
the total dose intended, and the dose intensity, which is calculated as percentage of total dose 
actually administrated divided by total dose intended during whole treatment period up to the last 
dose of study drug. Dose intensity by cycle will be summarized. 
Duration of study treatment exposure in days will be calculated as: date of EOTV – first dose 
date + 1 for patients who have discontinued treatment; date of data cutoff – first dose date + 1 for 
patients whose treatment is ongoing. 
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10 
PROTOCOL DEVIATIONS  
Critical protocol deviations will be identified prior to database lock for final analysis and will be 
listed and summarized. 
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11 
EFFICACY ANALYSES  
Disease activity will be assessed by the study investigators by using CBC and peripheral blood 
cell morphological examination, examination of bone marrow aspiration (or biopsy if required), 
and physical examination. Modifications to the Revised Recommendations of the International 
Working Group for Diagnosis (IWG), Standardization of Response Criteria, Treatment 
Outcomes, and Reporting Standards for Therapeutic Trials in Acute Myeloid Leukemia will be 
used (Appendix 1). Response assessment will be based on bone marrow aspirate/biopsy and the 
best CBC up to 14 days post bone marrow aspirate/biopsy. Responses will be categorized as: 
• CR: mCR (morphologic CR], CRc (cytogenic CR], or CRm (molecular CR); 
• CRh (CR with partial hematologic recovery); 
• CRi (CR with incomplete blood count recovery): CRn (CR with incomplete 
neutrophil recovery) or CRp (CR with incomplete platelet recovery); 
• MLFS (morphologic leukemia free state); 
• PR (partial response); 
• OB (other benefit); 
• SD (stable disease); 
• PD (progressive disease). 
The number and percent of PIF/ER AML patients will be summarized by best overall response. 
Efficacy analyses will be based on the PIF/ER AML population 
 
. All efficacy results will be summarized by PIF, ER and the total 
combined PIF/ER populations. 
11.1 
Primary Efficacy Analysis  
The primary efficacy endpoint for the AML expansion cohort is the CR/CRh rate, calculated as 
the proportion of patients in the efficacy population that has achieved a best response of CR 
(mCR, CRc, or CRm) or CRh at any point during treatment by investigator’s assessment, 
according to IWG AML response criteria (Appendix 1). CR/CRh rate will be summarized for 
total combined PIF/ER patients as the primary analysis, as well as for PIF and ER patients, 
separately, and for PIF/ER patients in the response evaluable population as a sensitivity analysis. 
A two-sided exact 95% confidence interval will be calculated around response rates. 
For the second interim analysis of 100 patients, as well as for the final analysis of 170 patients, 
all treated patients will be followed for at least 6 months or death from any cause, whichever 
comes first, prior to data cut off for the analysis. If the trial passes the pre-specified efficacy 
boundary (25% observed CR/CRh rate) at the second interim analysis, a two-sided exact 95% 
confidence interval described by Jennison and Turnbull (44) will be produced to account for the 
bias in the conventional exact confidence interval for fixed sample test. 
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11.2 
Secondary Efficacy Analyses  
Counts, percentages, and two-sided exact 95% confidence intervals will be used to describe 
categorical secondary variables. Kaplan-Meier (KM) methods will be used to estimate time-to-
event endpoints, unless otherwise specified. All secondary efficacy endpoints will be 
summarized in both efficacy and response evaluable population by PIF, ER, and total. 
11.2.1 
Key Secondary Efficacy Analyses  
The key secondary efficacy endpoints include CR rate, CRh rate, duration of response, post-
baseline transfusion independence rate, HSCT rate and incidence and duration of hospitalization. 
Duration of response (DOR) will be calculated from the time of initial documentation of 
response to the time of disease relapse or death due to any cause, whichever occurs first. Patients 
who are still in response at study completion without alternative therapies will be censored at the 
time of their last disease assessment. 
Duration of response will be calculated for patients who achieve the first evidence of CR or CRh 
as primary analysis. A separate exploratory analysis will be conducted for patients who achieve 
the first evidence of complete response (CR, CRh, CRi [CRn, CRp], or MLFS). 
DOR (months) = (date of event [disease relapse or death] or date of censoring –date of first 
evidence of response + 1) / (365.25/12) 
Sensitivity analyses will be done for duration of response by using the additional censoring rules 
below: 
• Censored at the date of HSCT. 
• Censored at the date of other alternative therapies such as surgery, procedure, 
radiation and subsequent antileukemic therapy, etc. 
• Patients with two or more consecutive missing response assessments prior to event 
will be censored at the last date of response assessment before the missing 
assessments. 
The duration of response will be analyzed using the KM method. The 25th percentile, median and 
75th percentile time (including two-sided 95% CI) will be summarized. 
Post-baseline transfusion independence is defined as no transfusion during any consecutive 
56-day period on-study. Post-baseline transfusion independence will be summarized for RBC 
and platelet transfusion separately and in total. Transfusion dependence at baseline is defined as 
any red blood cell or platelet transfusions during the 28 days prior to the first dose of study drug. 
The rate of conversion from transfusion dependence to transfusion independence will be 
calculated. The rate of patients who are transfusion independent at baseline and remain 
independent during any 56-day post-baseline period will also be calculated. 
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HSCT rate is defined as rate of successful HSCT through study treatment. Patients who received 
other therapies (except for conditioning therapy) for AML after discontinuation of study drug and 
later undergo a subsequent HSCT will not be included. Number and percentage of patients with 
HSCT will be summarized. 
Incidence and Duration of Hospitalization, summaries will be provided for the efficacy 
population, as well as independently for patients who achieved CR or CRh. Summaries will 
include duration of initial hospitalization as well as incidence, number and duration of 
subsequent hospitalizations following the initial discharge, number of days hospitalized, and the 
reasons for hospitalization. 
11.2.2 
Additional Secondary Efficacy Analyses  
Additional secondary efficacy endpoints include overall complete response rate, objective 
response rate, subgroup analyses of CR/CRh, CR, CRh and overall complete response rates, 
overall survival, event-free survival, time to response, mortality rate at 30, 60, 90, and 180 days, 
six-month and one-year survival.  
Overall complete response rate is defined as the rate of CR+CRh+CRi [CRn, CRp]+MLFS 
according to IWG AML response criteria (Appendix 1), and includes any response which 
achieves < 5% BM blasts by morphology. 
Objective response rate is defined as the rate of CR+CRh+CRi [CRn, CRp]+MLFS+PR 
according to IWG AML response criteria (Appendix 1). 
Subgroup analyses of CR/CRh, CR, CRh, and overall complete response rates will be 
performed by baseline disease characteristic (e.g., age group [< 70, ≥ 70], gender, cytogenetic 
risk status [high, intermediate, low], prior line of therapy [1, 2, 3], TP53 gene mutations) 
Overall survival (OS) is defined as the time between the date of the first dose of study drug and 
death from any cause. Patients who are alive or whose death status is unknown will be censored 
at the last date known alive on or before data cutoff date. The last known-to-be-alive date is the 
last non-imputed date of any subject record in the study database. This date may be the last visit 
date or last contact date that the subject is known to be alive. 
OS (months) = (date of death or last known alive – first dose date +1) / (365.25/12) 
Event-free survival (EFS) is defined as the time from the first dose of study drug until date of 
evidence of relapse from CR, CRh, or CRi (CRn, CRp), or death from any cause, whichever 
occurs first. Patients who are not known to have any of these events at study completion will be 
censored at the date of the last disease assessment. 
EFS (months) = (date of event [relapse or death] or date of censoring – first dose date + 1) / 
(365.25/12) 
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Sensitivity analysis of OS and EFS: patients will be censored for alternative therapies or 
procedures such as surgery, HSCT, radiation and subsequent antileukemic therapy, etc. If a 
patient begins a subsequent antileukemic therapy prior to event, the patient will be censored at 
the date of last assessment before starting the new anti-cancer therapy. For EFS, patients with 
two or more consecutive missing response assessments prior to event will be censored at the last 
date of response assessment before the missing assessments. 
Time to response (TTR) is defined as time from first dose of study drug to first CR, CRh, CRi 
(CRn, CRp), or MLFS and will be summarized with descriptive statistics. Time to CR/CRh and 
time to best overall response will be calculated. 
Mortality rate is defined as rate of death from any cause within 30, 60, 90, or 180 days of first 
dose of study drug. Number and percentage of deaths at 30, 60, 90, or 180 days will be 
summarized.  
Six-month survival rate is defined as the probability of survival at 6 months from first dose of 
study drug. 
One-year survival rate is defined as the probability of survival at 1 year from first dose of study 
drug. 
Six-month and one-year survival rates will be evaluated by KM estimate with 95% CI. 
11.2.3 
Other Secondary Analyses  
Immunogenicity 
Anti-drug antibody production will be monitored using a bridging ELISA method. The 
proportion of patients who become positive in this assay will be reported. 
Pharmacokinetics 
Serum concentrations of flotetuzumab will be monitored using an electrochemiluminescence-
based sandwich assay. PK analyses will be performed using industry standard software. 
Population PK modeling will be performed, and an appropriate model and model parameters will 
be described. This analysis will be performed by an outside consultant. 
Safety and Efficacy with Use of Tocilizumab 
The number of patients who received tocilizumab in treatment of infusion related reaction (IRR) 
and or cytokine release syndrome (CRS) will be reported. The incidence, severity, and duration 
of IRR/CRS will be summarized and will be broken down by patients who received or not 
received tocilizumab.  
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12 
SAFETY ANALYSES  
12.1 
Treatment Emergent Adverse Events  
Only treatment-emergent AEs, defined as any event that is temporally associated with 
administration of study product, will be summarized in tables. Events prior to treatment (e.g., 
due to study-related procedure) will be listed in an appendix to the final study report. DLTs will 
be listed.  
The following tables of AE data will be created to summarize the number and percent of patients 
who experience at least one event of each of the following types: 
• All AEs 
• Drug-related AEs 
• AEs by CTCAE Grade 
• Drug related AEs by CTCAE Grade 
• AEs with CTCAE Grade severity ≥ Grade 3 
• Drug-related AEs with CTCAE Grade severity  Grade 3 
• SAEs (this may be a listing if there are few events) 
• Drug-related SAEs 
• Fatal AEs (this may be a listing if there are few events) 
• AEs that result in study discontinuation 
• AEs that lead to withdrawal of study drug 
• AEs categorized as AESI and/or IREs 
Tabulated data will display the number and percent of patients that experience individual events 
by System Organ Class (SOC) and Preferred Term (PT). Events will be displayed alphabetically 
for SOC and in descending order of overall PT incidence within each SOC. 
An overall summary of AEs will display the number and percent of patients who experience at 
least one event of each of the following types: 
• Any AE 
• Any drug-related AE 
• Any AE with CTCAE Grade severity  Grade 3 
• Any drug-related AE with CTCAE Grade severity  Grade 3 
• Any SAE 
• Any drug-related SAE 
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• Any AE that results in study or study drug discontinuation 
• Any fatal AE 
• Any AESI 
• Any IREs 
The following AESI will be summarized: 
• All cytokine release syndrome or infusion related reaction events 
• Grade 2 or greater immune-related AEs including, but not limited to, events of 
pneumonitis, colitis, autoimmune hepatitis, arthritis, glomerulonephritis, myocarditis 
and cardiomyopathy, hypophysitis, or thyroiditis 
• Tumor lysis syndrome (TLS) 
• Neutropenic sepsis/fungemia 
• Grade 2 or greater neurological events. 
• Capillary leak syndrome 
• Epstein-Barr Virus (EBV) reactivation 
The following summaries will be provided for AESI: 
• All AESI 
• Study drug related AESI 
• Serious AESI 
• Study drug related serious AESI 
• AESI with CTCAE grade of Grade ≥ 3 
• Study drug related AEs with CTCAE severity Grade ≥ 3 
12.2 
Clinical Laboratory Evaluations  
Summaries of laboratory values will display descriptive statistics for numerically quantified labs. 
Summaries will be grouped by lab panel (e.g., hematology, blood chemistry, and urinalysis) and 
will be displayed by visit for each lab parameter. Graphs of mean values over time or individual 
values at each time point may be used. 
Shift tables will be used to display the percent of patients who have a shift in their lab values 
from normal at baseline to each post-baseline visit by CTCAE v4.0 severity Grade. 
Listings of all clinical laboratory data with abnormal flags will be provided by patients and tests. 
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12.3 
Physical Examination  
Physical examination will be performed at screening, at the end of each treatment cycle, and at 
the EOTV. Descriptive statistics for height (screening only) and weight, and examination of skin, 
HEENT (head, eyes, ears, nose, and throat), lymph nodes, heart, chest, lungs, abdomen, 
extremities, and neurologic system, both observed values and changes from baseline (weight) 
will be summarized. 
12.4 
Vital Sign Measurements and Performance Status  
Evaluation of vital signs includes include blood pressure, heart rate, respirations, pulse oximetry, 
and temperature at scheduled visits. 
Vital sign measurements and Eastern Cooperative Oncology Group (ECOG) will be listed for 
each patient and by scheduled visit. Descriptive statistics for vital signs and ECOG, both 
observed values and changes from baseline, will be summarized. 
12.5 
Electrocardiograms  
Twelve-lead ECGs will be obtained according to the schedules outlined in the latest version of 
the protocol in order to evaluate the potential cardiac effects of study drug, including QT interval 
prolongation. Recorded values of ECG parameters and change from baseline values will be 
summarized at each scheduled visit. 
In addition, at baseline and maximum post-baseline visits, the proportion of patients having 
absolute QTc Fridericia value (QTcF) and QTcF interval (ΔQTcF) of the following categories 
will be presented: 
• ≤ 450 ms 
• > 450 ms to ≤ 480 ms 
• > 480 to ≤ 500 ms 
• > 500 ms 
At maximum post-baseline visits, the proportion of patients who have an increase from baseline 
in ΔQTcF of the following categories will be presented: 
• ≤ 30 ms 
• > 30 to ≤ 60 ms 
• > 60 ms 
Central interpretation of ECGs will be used for data analysis purposes and will be summarized 
by presenting the shift from baseline to worst by cycle. The overall ECG interpretation will be 
displayed in cross–tabulations by dose cohort. 
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12.6 
Left Ventricular Ejection Fraction  
If the patient has a history or signs and symptoms of cardiac disease, an echocardiogram (or 
multiple-gated acquisition scan [MUGA] if indicated) will be obtained during the screening 
period, if one was not performed within 30 days before the start of treatment (Cycle 1 Day 1). An 
echocardiogram (or MUGA if indicated) may also be conducted during the study if clinically 
indicated. A listing will be provided at patient level. 
12.7 
Pulmonary Function Testing  
PFT, including DLCO and FEV1, will be conducted during the screening period if testing was 
not performed within 30 days before the start of treatment (Cycle 1 Day 1). PFT may also be 
conducted during the study if clinically indicated. listings will be provided at patient level. 
• During the COVID-19 pandemic, if PFT equipment is not available, a correlative 
stair-climbing test may be conducted instead, together with lung CT and 
echocardiogram irrespective of cardiac history. The patient must pass the stair-
climbing test, with O2 saturation ≥ 95%, lung CT with normal appearing lung 
parenchyma, and normal echocardiogram 
 
. 
 
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13 
INTERIM ANALYSIS  
13.1 
General Information  
Following a three-stage design, the interim analyses will be performed after 40 and 100 patients 
have been enrolled and either have had their responses evaluated or discontinued for any reason 
from study treatment prior to their first response assessments. The first interim analysis is for 
futility only and the second interim analysis is for both futility and efficacy. See Section 4.2 for 
more details. 
13.2 
Data Safety Monitor (DSM)  
Prior to Protocol Amendment 13, an independent DSM (with disease-specific and/or 
immunotherapy expertise) was involved in all decisions regarding transition from the Single 
Patient Dose Escalation Segment to the Multi-patient Dose Escalation Segment and regarding the 
definition of MTDS and transition to the MTDS Cohort Expansion Segment of the study. In the 
Single Patient Dose Escalation Segment, safety data from all patients followed through Study 
Day 28 (Cycle 2 Day 1) was reviewed. Safety data from each dose escalation cohort in the 
Multi-patient Dose Escalation Segment was made available to the DSM after each cohort of 
patients had been followed for a minimum of 28 Study Days. 
Safety evaluations was conducted on an ongoing basis during the Cohort Expansion Segment of 
the study. Review by Principal Investigators (or designee), the Medical Monitor and the DSM 
was conducted in regular intervals. The interval analysis utilized data from all cycles of 
treatment. If during the conduct of the interval cohort analysis, the Bayesian posterior probability 
is greater than 80% that the DLT event rate is more than 20%, enrollment would be paused and 
an ad hoc meeting of the Principal Investigators (or designee), the Medical Monitor, and the 
DSM would be held to consider dose reduction or study termination.  
13.3 
Independent Data Monitoring Committee  
Starting with Protocol Amendment 13, an independent data monitoring committee (IDMC) is 
formed to conduct regular independent safety review. This replaces the independent DSM in 
place prior to this amendment. 
At each IDMC safety review meeting, IDMC will receive and review aggregate safety data. The 
IDMC will determine whether the enrollment should be paused based on Bayesian posterior 
probability evaluation of DLT event rate. This posterior probability is calculated based on the 
following Bayesian binomial model: Suppose that the DLT rate p follows non-informative prior 
Beta(1,1), and that r out of n treated patients have experienced DLTs, then the posterior 
distribution for p is Beta(1+r, 1+n-r). Then, for each n in 8 patient segments, the number of 
patients with DLTs that would result in a pause of enrollment is the smallest integer r, satisfying 
P(p>20%|n, r)>80%, where p~Beta(1+r, 1+n-r). Table 5 below shows the number of patients 
with DLTs that would result in a pause of enrollment to assess toxicity. 
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Table 5 
Stopping Bounds for Excess Toxicity Based on Bayesian Beta 
Binomial Model with Beta (1,1) Prior 
  
Number of patients treated (n) 
Number of patients with DLTs that would result in 
a pause of enrollment (r) 
8 
3 
16 
5 
24 
7 
32 
9 
40 
10 
48 
12 
56 
14 
64 
16 
72 
17 
80 
19 
88 
21 
94 
22 
 
The IDMC will also hold a minimum of two safety and efficacy review meetings for two planned 
interim analyses (additional ad hoc meetings will be held as needed). At each meeting, in 
addition to above safety evaluation, IDMC will also receive and review aggregate efficacy data 
to determine whether enrollment should continue based on futility and efficacy boundaries 
described in Section 4.2. The details of IDMC formation and meeting conduct is described in a 
the IDMC Charter. 
13.4 
Statistical Approaches for Control of Alpha  
The type I error rate will be controlled at the overall one-sided 0.025 level by using 3-stage 
design. The decision rules are as follows: 
First stage: the study enrollment will continue if at least 5 (12.5%) out of 40 patients have 
response of CR/CRh. 
Second stage: the study enrollment will continue if at least 15 (15%) out of 100 patients have 
response of CR/CRh.  
Claim success if at least 25 (25%) out of 100 patients have response of CR/CRh at the second 
stage or at least 35 (20.6%) out of the total of 170 patients have response of CR/CRh at the final 
stage. 
The 3-stage design yields a 1-sided alpha of 0.005 for the efficacy boundary at the second 
interim analysis and an overall 1-sided alpha of 0.024 with approximately 80% power at the final 
analysis. The probability of early termination under H0 (futility) in the first two stages is 55%. 
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14 
LIST OF TABLES, LISTINGS, AND FIGURES  
The list of tables, listings, and figures (TLFs) and associated shells planned for the clinical study 
report based on the analyses described in this SAP will be provided in a separate SPP, which will 
also include data reporting conventions and programming specifications for the development of 
these TLFs. 
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15 
REFERENCES  
1. DiNardo CD, Rausch CR, Benton C, Kadia T, Jain N, Pemmaraju N, et al. Clinical 
experience with the BCL2-inhibitor venetoclax in combination therapy for relapsed and 
refractory acute myeloid leukemia and related myeloid malignancies. Am J Hematol. 
2018;93:401-407. 
2. Faderl S, Wetzler M, Rizzieri D, Schiller G, Jagasia M, Stuart R, et al. Clofarabine plus 
cytarabine compared with cytarabine alone in older patients with relapsed or refractory acute 
myelogenous leukemia: results from the CLASSIC I Trial. J Clin Oncol. 2012;30(20):2492-
9. 
3. FDA. Xospata (gilteritinib) label. Accessed 01 June 2020. Available from: 
https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/211349s001lbl.pdf 
4. Jennison C and Turnbull BW. Group Sequential Methods with Applications to Clinical 
Trials. Boca Raton, Florida: Chapman & Hall/CRC. 2000;235-244. 
5. Lee DW, Gardner R, Porter DL, Louis CU, Ahmed N, Jensen M, et al. Current concepts 
in the diagnosis and management of cytokine release syndrome. Blood 2014;10;124(2):188-
95 
6. Medeiros BC, Tanaka TN, Balaian L, Bashey A, Guzdar A, Li H, et al. A phase I/II trial 
of the combination of azacitidine and gemtuzumab ozogamicin for treatment of relapsed 
acute myeloid leukemia. Clin Lymphoma Myeloma Leuk. 2018;18(5):346-352. 
7. Ravandi F, Ritchie EK, Sayar H, Lancet JE, Craig MD, Vey N, et al. Vosaroxin plus 
cytarabine versus placebo plus cytarabine in patients with first relapsed or refractory acute 
myeloid leukaemia (VALOR): a randomised, controlled, double-blind, multinational, phase 3 
study. Lancet Oncol. 2015;16(9):1025-36. 
 
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Appendix 1 
International Working Group (IWG) Response Criteria for Acute Myeloid Leukemia 
(AML) Modified for Assessment of AML in this Study 
Response Criterion 
Time of 
Assessment 
Neutrophils* 
(µL) 
Platelets* 
(µL) 
Bone Marrow Blasts (%) 
Other 
Complete Remission (CR) 
Day 25 + 3 days 
(each cycle) 
≥ 1,000 
≥ 100,000 
< 5 
Transfusion# 
Extramedullary disease 
(EMD) 
• 
Morphologic CR (mCR) Day 25 + 3 days 
(each cycle) 
≥ 1,000 
≥ 100,000 
< 5 
Transfusion# EMD 
• 
Cytogenetic CR (CRc) 
Day 25 + 3 days 
(each cycle) 
≥ 1,000 
≥ 100,000 
< 5 
Cytogenics – normal, 
EMD 
• 
Molecular CR (CRm) 
Day 25 + 3 days 
(each cycle) 
≥ 1,000 
≥ 100,000 
< 5 
Molecular – negative, 
EMD 
CR with partial hematologic 
recovery (CRh) 
Day 25 + 3 days 
(each cycle) 
≥ 500 
≥ 50,000 
< 5 
Transfusion$ EMD 
CR with incomplete blood 
count recovery (CRi) 
Day 25 + 3 days 
(each cycle) 
< 1,000 
< 100,000 
< 5 
Transfusion$ EMD 
• 
CR with incomplete 
neutrophil recovery 
(CRn) 
Day 25 + 3 days 
(each cycle) 
< 1,000 
≥ 100,000 
< 5 
Transfusion$ EMD 
• 
CR with incomplete 
platelet recovery (CRp) 
Day 25 + 3 days 
(each cycle) 
≥ 1,000 
< 100,000 
< 5 
Transfusion$ EMD 
Morphologic leukemia-free 
state (MLFS) 
Day 25 + 3 days 
(each cycle) 
NA 
NA 
< 5 
EMD 
Partial remission (PR) 
Day 25 + 3 days 
(each cycle) 
> 1,000 
> 100,000 
> 50% decrease or  
decrease to 5-25 
Blasts < 5% if Auer rod 
positive 
Other benefit (OB) 
Day 25 + 3 days 
(each cycle) 
NA 
NA 
> 30% decrease 
NA 
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Response Criterion 
Time of 
Assessment 
Neutrophils* 
(µL) 
Platelets* 
(µL) 
Bone Marrow Blasts (%) 
Other 
Stable disease (SD) 
Day 25 + 3 days 
(each cycle) 
NA 
NA 
Absence of CR, CRh, CRi, PR, MLFS, 
OB, and criteria for PD not met 
NA 
Progressive disease 
NA 
NA 
NA 
Evidence for an increase in bone 
marrow blast percentage and/or increase 
of absolute blast counts in the blood: 
• 
> 50% increase in 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 mo; 
without at least a 100% 
improvement in ANC to an 
absolute level (>0.5 x 109/L 
[500/mL], and/or platelet count to 
>50 x 109/L [50 000/mL] non-
transfused); or 
• 
> 50% increase in peripheral blasts 
(WBC x % blasts) to > 25 x 109/L 
(> 25 000/mL) (in the absence of 
differentiation syndrome)†; or 
• 
New extramedullary disease 
In general, at least 2 
cycles of flotetuzumab 
should be administered 
to determine 
“progressive disease”. 
“Progressive disease” is 
usually accompanied by a 
decline in ANC and 
platelets, increased 
transfusion requirement, 
and decline in 
performance status or 
increase in symptoms 
Recurrence/relapse 
Relapse after CR is defined as a reappearance of leukemic blasts in the peripheral blood and ≥ 5% blasts in the bone marrow 
not attributable to any other cause (e.g., bone marrow regeneration after consolidation therapy) 
CR = complete remission (includes mCR, CRc, CRm). 
CRi = includes neutrophil count ≥ 1000 or platelet count ≥ 100,000. 
*Assessment is quantitated by BM biopsy and best CBC (up to 28 days post BM biopsy). 
# No RBC and/or platelet transfusion within 5 days prior to response assessment. 
$ No platelet transfusion within 5 days prior to response assessment 
† Certain targeted therapies, for example, those inhibiting mutant IDH proteins, may cause a differentiation syndrome, that is, a transient increase in the percentage of bone marrow 
blasts and an absolute increase in blood blasts; in the setting of therapy with such compounds, an increase in blasts may not necessarily indicate PD. 
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