Clinical trial NCT03727750
Conditions: ECG Pharmacokinetics Safety
Keywords: gemtuzumab ozogamicin Mylotarg QT interval prolongation Pharmacokinetics Safety Veno-occlusive disease Anti-drug antibody
Sponsor: Pfizer
Start date: 2019-07-03; Completion date: 2021-04-27
Enrollment: 51 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This is a single-arm, open-label, Phase 4 study evaluating the effect of GO on the QTc, pharmacokinetics, safety, and immunogenicity of GO as a single-agent monotherapy in adult and pediatric patients with relapsed or refractory CD33-positive AML.

Detailed description:
This is a single-arm, open-label, Phase 4 study evaluating the effect of GO on the QTc, pharmacokinetics, safety, and immunogenicity of GO as a single-agent monotherapy in adult and pediatric patients with relapsed or refractory CD33-positive AML. Approximately 50 adult (age \>=18 years) and 6 pediatric (12 years =\< age =\< 17 years) patients who satisfy the study eligibility criteria will be enrolled. Enrolled patients will receive GO 3 mg/m2 up to 2 cycles on Days 1, 4, and 7 at each cycle. The impact of GO on VOD/SOS in the context of previous and subsequent HSCT will also be assessed. Patients enrolled in the study will receive three doses of GO 3 mg/m2 (up to one vial) as a 2-hour intravenous infusion on Cycle 1 Days 1, 4, and 7. A second cycle of GO 3mg/m² (up to one vial) on Cycle 2 Days 1, 4, and 7 will be allowed at the investigator's discretion for patients who meet the following criteria after Cycle 1: Bone marrow with a decrease of blast percentage to at least 25% or a decrease of pretreatment blast percentage by at least 50%; and Blood count with neutrophils \>=1,000/µL, and platelets \>=50,000/µL, except in patients with the bone marrow blasts \>=5%, the decrease in neutrophils and platelets thought to be due to the underlying leukemia. After GO treatment, subsequent anticancer therapy such as consolidation or conditioning regimen and/or HSCT could be considered at the investigator's discretion. A minimum interval of 2 months is recommended between the last dose of GO and HSCT.

Arms: arm 1: Patients will receive three doses of Gemtuzumab Ozogamicin (GO) 3 mg/m2 (up to one vial) as a 2 hour intravenous infusion on Cycle 1 Days 1, 4, and 7. A second cycle of GO 3mg/m² (up to one vial) on Cycle 2 Days 1, 4, and 7 will be allowed at the investigator's discretion for patients who meet the criteria
Interventions: intervention 1: Gemtuzumab Ozogamicin
Intervention descriptions: intervention 1: Three doses of GO 3 mg/m2 (up to one vial) as a 2 hour intravenous infusion on Cycle 1 Days 1, 4, and 7. A second cycle of GO 3mg/m² (up to one vial) on Cycle 2 Days 1, 4, and 7 will be allowed at the investigator's discretion for patients who meet the criteria

Protocol documents:
Prot_000.pdf: 
Gemtuzumab Ozogamicin (MYLOTARG™)
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PFIZER CONFIDENTIAL
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A SINGLE ARM, OPEN-LABEL, PHASE 4 STUDY EVALUATING QT INTERVAL, 
PHARMACOKINETICS, AND SAFETY OF GEMTUZUMAB OZOGAMICIN 
(MYLOTARG™) AS A SINGLE-AGENT REGIMEN IN PATIENTS WITH 
RELAPSED OR REFRACTORY CD33-POSITIVE ACUTE MYELOID LEUKEMIA
Investigational Product Number:
PF-05208747 (CMA-676)
Investigational Product Name:
Gemtuzumab Ozogamicin (MYLOTARG™)
United States (US) Investigational New 
Drug (IND) Number:
European Clinical Trials Database 
(EudraCT) Number:
2018-002619-89
Protocol Number:
B1761031
Phase:
4
This document and accompanying materials contain confidential information belonging to Pfizer.  Except as 
otherwise agreed to in writing, by accepting or reviewing these documents, you agree to hold this information in 
confidence and not copy or disclose it to others (except where required by applicable law) or use it for 
unauthorized purposes.  In the event of any actual or suspected breach of this obligation, Pfizer must be 
promptly notified.
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Document History
Document
Version Date
Summary of Changes and Rationale
Final Protocol
27 June 2018
Not applicable (N/A)


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TABLE OF CONTENTS
LIST OF TABLES.....................................................................................................................7
LIST OF FIGURES ...................................................................................................................7
APPENDICES ...........................................................................................................................7
PROTOCOL SUMMARY.........................................................................................................8
SCHEDULE OF ACTIVITIES................................................................................................12
1. INTRODUCTION ...............................................................................................................18
1.1. Mechanism of Action/Indication.............................................................................18
1.2. Background and Rationale ......................................................................................18
1.2.1. Incidence and Treatment of Acute Myeloid Leukemia (AML)..................18
1.2.2. Gemtuzumab Ozogamicin for Treatment of Acute Myeloid 
Leukemia..........................................................................................................19
1.2.2.1. Regulatory History ....................................................................19
1.2.2.2. Fractionated Dosing of GO .......................................................20
1.2.2.3. Pharmacodynamics, Pharmacokinetics and Dosage .................20
1.2.2.4. Clinical Data for GO in Patients with AML in First 
Relapse ..............................................................................................21
1.2.2.5. Study Rationale .........................................................................21
2. STUDY OBJECTIVES AND ENDPOINTS.......................................................................23
3. STUDY DESIGN.................................................................................................................23
4. PATIENT ELIGIBILITY CRITERIA.................................................................................25
4.1. Inclusion Criteria.....................................................................................................25
4.2. Exclusion Criteria....................................................................................................26
4.3. Lifestyle Requirements ...........................................................................................27
4.3.1. Contraception..............................................................................................27
4.4. Sponsor’s Qualified Medical Personnel..................................................................28
5. STUDY TREATMENT.......................................................................................................29
5.1. Allocation to Treatment ..........................................................................................29
5.2. Patient Compliance .................................................................................................29
5.3. Investigational Product Supplies.............................................................................29
5.3.1. Dosage Form(s) and Packaging..................................................................29
5.4. Administration.........................................................................................................30
5.4.1. Administration of the Premedication..........................................................30


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5.4.2. Administration of GO.................................................................................30
5.4.3. Dosage Modification for Toxicities............................................................30
5.5. Investigational Product Storage ..............................................................................32
5.6. Investigational Product Accountability...................................................................32
5.6.1. Destruction of Investigational Product Supplies ........................................33
5.7. Concomitant Treatment(s).......................................................................................33
6. STUDY PROCEDURES .....................................................................................................33
6.1. Screening.................................................................................................................33
6.2. Study Period ............................................................................................................35
6.2.1. GO Treatment .............................................................................................35
6.2.2. Cycle 1........................................................................................................36
6.2.2.1. Cycle 1 Day 1 (GO Treatment).................................................36
6.2.2.2. Cycle 1 Day 4 and Day 7 (GO Treatment)................................37
6.2.2.3. Cycle 1 Day 10 (Post-GO Period).............................................37
6.2.2.4. Cycle 1 Days 15 and 21 (Post-GO Period) ...............................38
6.2.3. Cycle 2........................................................................................................39
6.2.3.1. Cycle 2 Day 1............................................................................39
6.2.3.2. Cycle 2 Day 4 and Day 7 (GO Treatment)................................40
6.2.3.3. Cycle 2 Day 10 (Post-GO Period).............................................40
6.2.3.4. Cycle 2 Days 15 and 21 (Post-GO Period) ...............................40
6.2.4. The End-of-Treatment (EOT) Visit (36 Days after the Last Dose of 
GO) ..................................................................................................................41
6.2.5. Follow-up Period ........................................................................................42
6.3. Patient Withdrawal..................................................................................................42
7. ASSESSMENTS..................................................................................................................44
7.1. Electrocardiogram Assessment ...............................................................................44
7.1.1. QT Interval Prolongation............................................................................44
7.1.2. Core Laboratory Manual Measurement for ECGs/QTc .............................45
7.2. Pharmacokinetics Assessment.................................................................................45
7.2.1. Pharmacokinetic Samples...........................................................................45
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7.3. Immunogenicity ......................................................................................................46
7.4. Safety Assessments .................................................................................................47
7.4.1. Veno-occlusive Disease Assessments and Sinusoidal Obstruction 
Syndrome.........................................................................................................47
7.5. Response Assessments ............................................................................................49
7.6. Survival ...................................................................................................................50
7.7. Pregnancy Testing...................................................................................................50
7.9. Imaging Assessments ..............................................................................................51
8. ADVERSE EVENT REPORTING......................................................................................52
8.1. Requirements...........................................................................................................52
8.1.1. Additional Details on Recording Adverse Events on the CRF...................53
8.1.2. Eliciting Adverse Event Information..........................................................53
8.1.3. Withdrawal from the Study Due to Adverse Events (see also the 
Patient Withdrawal Section 6.3) ......................................................................53
8.1.4. Time Period for Collecting AE/SAE Information......................................54
8.1.4.1. Reporting SAEs to Pfizer Safety...............................................54
8.1.4.2. Recording Non-serious AEs and SAEs on the CRF .................54
8.1.5. Causality Assessment .................................................................................55
8.1.6. Sponsor’s Reporting Requirements to Regulatory Authorities ..................55
8.2. Definitions...............................................................................................................55
8.2.1. Adverse Events...........................................................................................55
8.2.2. Abnormal Test Findings .............................................................................56
8.2.3. Serious Adverse Events ..............................................................................56
8.2.4. Hospitalization............................................................................................57
8.3. Severity Assessment................................................................................................58
8.4. Special Situations ....................................................................................................59
8.4.1. Protocol-Specified Serious Adverse Events...............................................59
8.4.2. Potential Cases of Drug-Induced Liver Injury............................................60
8.4.3. Potential VOD/SOS Cases..........................................................................61
8.4.4. Exposure to the Investigational Product During Pregnancy or 
Breastfeeding, and Occupational Exposure.....................................................61
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8.4.4.1. Exposure During Pregnancy......................................................62
8.4.4.2. Exposure During Breastfeeding ................................................63
8.4.4.3. Occupational Exposure .............................................................63
8.4.5. Medication Errors .......................................................................................63
8.4.5.1. Medication Errors......................................................................64
9. DATA ANALYSIS/STATISTICAL METHODS...............................................................64
9.1. Sample Size Determination.....................................................................................64
9.2. Analysis Sets ...........................................................................................................65
9.2.1. Full Analysis Set.........................................................................................65
9.2.2. Safety Analysis Set.....................................................................................65
9.2.3. QTc Analysis Set ........................................................................................65
9.2.4. PK Analysis Set ..........................................................................................65
9.2.5. PK/PD Analysis Set....................................................................................65
9.3. Planned Analyses ....................................................................................................65
9.3.1. Analysis of Primary Endpoint ....................................................................65
9.3.2. Analysis of Secondary Endpoints...............................................................66
9.3.2.1. Safety Analysis..........................................................................66
9.3.2.2. Pharmacokinetic Analysis.........................................................67
9.3.2.3. Pharmacokinetic/Pharmacodynamic (PK/PD) Analysis ...........67
9.3.2.4. QTc-Concentration Analysis.....................................................67
9.3.2.5. Immunogenicity ........................................................................68
9.3.2.6. Efficacy Analyses......................................................................68
9.4. Interim Analysis ......................................................................................................68
9.5. Data Monitoring Committee ...................................................................................68
10. QUALITY CONTROL AND QUALITY ASSURANCE.................................................69
11. DATA HANDLING AND RECORD KEEPING .............................................................69
11.1. Case Report Forms/Electronic Data Record .........................................................69
11.2. Record Retention...................................................................................................70
12. ETHICS..............................................................................................................................70
12.1. Institutional Review Board/Ethics Committee......................................................70
12.2. Ethical Conduct of the Study ................................................................................71
12.3. Patient Information and Consent...........................................................................71


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12.4. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH 
GCP ...........................................................................................................................72
13. DEFINITION OF END OF TRIAL...................................................................................73
13.1. End of Trial in a Member State.............................................................................73
13.2. End of Trial in All Other Participating Countries.................................................73
14. SPONSOR DISCONTINUATION CRITERIA ................................................................73
15. PUBLICATION OF STUDY RESULTS..........................................................................73
15.1. Communication of Results by Pfizer ....................................................................73
15.2. Publications by Investigators ................................................................................74
16. REFERENCES ..................................................................................................................76
LIST OF TABLES
Table 1.
Schedule of Activities...........................................................................................12
Table 2.
Schedule of Activities – ECG, Pharmacokinetics, Immunogenicity, 
Pharmacodynamics
.................................16
Table 3.
Dosage Modifications for Non hematologic and Hematologic Toxicities ...........31
Table 4.
EBMT Criteria for VOD/SOS Diagnosis .............................................................48
Table 5.
European Leukemia Net (ELN 2017) Recommendations5...................................50
LIST OF FIGURES
Figure 1.
B1761031 Study Schematic..................................................................................24
APPENDICES
Appendix 1. Abbreviations......................................................................................................79
Appendix 2. Definition of Active Hepatitis Infection .............................................................82
Appendix 3. Laboratory Tests..................................................................................................83
Appendix 4. List of Drugs Known to Predispose to Torsades de Pointes ...............................84
Appendix 5. Definition of Refractory and Relapsed AML (ELN 2017 
Recommendation)5 ...............................................................................................85
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PROTOCOL SUMMARY
Background and Rationale:
Gemtuzumab ozogamicin (GO, MYLOTARG) is an antibody-drug conjugate (ADC) 
composed of the cluster of differentiation 33 (CD33)-directed monoclonal antibody 
hP67.6 (recombinant humanized immunoglobulin [Ig] G4, kappa antibody produced by 
mammalian cell culture in NS0 cells) that is covalently linked to the cytotoxic agent 
N-acetyl-gamma-calicheamicin dimethylhydrazide (DMH), a semisynthetic disulfide 
derivative of calicheamicin.  The antibody portion binds specifically to the CD33 antigen, a 
sialic acid-dependent adhesion protein found on the surface of myeloid leukemic blasts and 
immature normal cells of myelomonocytic lineage, but not on normal hematopoietic stem 
cells.
On 01 September 2017, the US Food and Drug Administration (FDA) approved GO 
(MYLOTARG) for the treatment of adult patients with newly diagnosed CD33-positive 
acute myeloid leukemia (AML) and for the treatment of adult or pediatric patients at least 
2 years of age with relapsed/refractory CD33-positive AML.1  In adults with newly 
diagnosed CD33-positive AML, GO can be administered as part of a combination regimen 
(ie, fractionated dose of 3 mg/m2 on Days 1, 4, and 7 combined with daunorubicin [DNR] 
and cytarabine [Ara-C] during induction) or as a single agent (ie, 6 mg/m2 on Day 1 and 
3 mg/m2 on Day 8 of induction).  In the setting of relapsed/refractory CD33-positive AML in 
patients aged 2 years and older, GO is approved for use as a single agent only using the 
fractionated dosing regimen (ie, 3 mg/m2 on Days 1, 4, and 7).1
During their review of the Biologics License Application (BLA), the FDA issued 
post-marketing requirements (PMRs) that requested additional assessment of the impact of 
the fractionated dosing regimen of GO on the risk of veno-occlusive disease or sinusoidal 
obstruction syndrome (VOD/SOS) in patients with previous or subsequent hematopoietic 
stem cell transplantation (HSCT), hemorrhage, unexpected serious risk of QT interval 
prolongation, and unexpected serious risk of anti-drug antibodies.  Additionally, no clinical 
pharmacokinetics (PK) data for GO, represented by total hP67.6 antibody, have been 
characterized following the fractionated dosing regimen.  The PK profiles included in the 
BLA used for exposure-response modeling of the pivotal Phase 3 trial, ie, Acute Leukemia 
French Association 0701 (ALFA-0701),2 were simulated using population PK modeling 
based on 8 previous clinical trials.  Therefore, B1761031 has been planned to address these 
PMRs. 
On 22 February 2018, the Committee for Medicinal Products for Human Use (CHMP) 
adopted a positive opinion, and on 19 April 2018 the European Commission granted a 
marketing authorization for Mylotarg, indicated for combination therapy with DNR and 
Ara-C for the treatment of patients age 15 years and above with previously untreated, 
de novo CD33-positive acute myeloid leukemia (AML), except acute promyelocytic 
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The CHMP identified several recommendations in the ongoing development of GO, 
including the addition of 
 
6 pediatric 
patients into the FDA issued PMR study.  Therefore, this study will include 6 pediatric 
patients 12-17 years of age (eg, adolescents).  Patients within this defined age group are 
expected to have similar electrocardiogram (ECG)/PK findings, and are deemed acceptable 
for the schedule of assessments and blood draw requirements of this study.
Objectives and Endpoints:
Primary Objective:
Primary Endpoint:
•
To assess the effect of GO on the QTc interval. 
•
Maximum change from baseline in 
corrected QT interval (QTc).
Secondary Objectives:
Secondary Endpoints:
•
To characterize the PK of single-agent GO following 
the fractionated regimen (ie, 3 mg/m² on Days 1, 4, 
and 7).
•
To assess the safety of GO with fractionated dosing 
of 3 mg/m2.
•
To assess the immunogenicity of GO. 
•
To assess response and overall survival.  
•
PK parameters: clearance and volume of 
distribution.
•
Adverse events (AEs) and abnormal 
laboratory findings.
•
Incidence of anti-drug antibody 
(ADA)/neutralizing antibodies (NAb). 
•
Response: complete remission (CR) and 
complete remission with incomplete 
hematologic recovery (CRi) achieved after 
GO.
•
Overall Survival. 
 
 
 
 
 
 
 
 
 
 
 
Study Design:
This is a single-arm, open-label, Phase 4 study evaluating the effect of GO on the QTc, 
pharmacokinetics, safety, and immunogenicity of GO as a single-agent monotherapy in adult 
and pediatric patients with relapsed or refractory CD33-positive AML.  Approximately 
50 adult (age ≥18 years) and 6 pediatric (12 years ≤age ≤17 years) patients who satisfy the 
study eligibility criteria will be enrolled.  Enrolled patients will receive the fractionated 
regimen of GO 3 mg/m2 up to 2 cycles on Days 1, 4, and 7 at each cycle.  The impact of GO 
on VOD/SOS in the context of previous and subsequent HSCT will also be assessed. 
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Treatment Plan
Patients enrolled in the study will receive three doses of GO 3 mg/m2 (up to one vial) as a 
2-hour intravenous infusion on Cycle 1 Days 1, 4, and 7. A second cycle of GO 3mg/m² (up 
to one vial) on Cycle 2 Days 1, 4, and 7 will be allowed at the investigator’s discretion for 
patients who meet the following criteria after Cycle 1: Bone marrow with a decrease of blast 
percentage to at least 25% or a decrease of pretreatment blast percentage by at least 50%;
and Blood count with neutrophils 1,000/µL and platelets 50,000/µL, except in patients 
with the bone marrow blasts 5%, the decrease in neutrophils and platelets thought to be due 
to the underlying leukemia (refer to Section 7.5).
After GO treatment, subsequent anticancer therapy such as consolidation or conditioning 
regimen and/or HSCT could be considered at the investigator’s discretion.  A minimum 
interval of 2 months is recommended between the last dose of GO and HSCT.
Assessments:
QTc Interval
Triplicate ECGs will be performed at screening, baseline (prior to dose on Day 1) and 
immediately preceding serial PK draws on each day of dosing.  A 12-lead tracing will be 
used for all ECGs, including measurements of PR interval, QT interval, RR interval, and 
QRS complex.  All triplicate ECG tracings will be sent to an independent ECG core 
laboratory for blinded manual interval measurements.3
Pharmacokinetics (PK)
Blood samples will be collected from all participating patients for PK analysis according to 
the PK schedule.  Samples will be collected prior to each dose and at time points around the 
maximum concentration (Cmax), ie, at the end of the 2-hour infusion in order to characterize 
the QTc-concentration relationship. 
Safety
Safety will be monitored per the protocol specified schedule.  Safety assessments include 
adverse events (AEs) graded according to the National Cancer Institute Common 
Terminology Criteria for Adverse Events (NCI CTCAE, version 4.03), clinical examination 
(including blood pressure and pulse), ECGs, and laboratory tests (hematology, chemistry, 
coagulation and urinalysis), including hemorrhage-related laboratory data and 
coagulation-related assessments, such as complete blood counts and differential counts, 
prothrombin time (PT), activated partial thrombin time (aPTT), and fibrinogen. 
Any events of veno-occlusive disease (VOD) and sinusoidal obstruction syndrome (SOS) 
will be reported as serious adverse event (SAE) during the study duration.  Details of the 
HSCT will be collected in order to assess the impact of the fractionated regimen of GO on 
the risk of VOD/SOS with previous or subsequent HSCT. 


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Immunogenicity
Anti-drug antibody (ADA) samples will be collected as specified in the protocol.  Samples 
will be analyzed for ADAs using a tiered approach of screening, confirmation, and titer 
determination.4  Samples that test positive for ADA will be further characterized to determine 
whether neutralizing antibodies (NAb) are present.
Efficacy
Efficacy evaluation anddetermination of remission status by blood and bone marrow 
aspiration (and biopsy if applicable) will be conducted at the end of each cycle using 
European Leukemia Net (ELN 2017) recommendations (see Section 7.5).5  Survival status 
for each patient will be collected for the study duration of 12 months. 
 
Statistical Methods:
The sample size is based on ensuring sufficient data to exclude a 20 milliseconds (msec)
mean increase 20 msec in the QT interval using the Fridericia heart rate correction (QTcF).  
If the upper bounds of one-sided 95% confidence intervals of change from baseline in QT 
measurements using the Fridericia’s heart rate correction for each of the QTc sampling time 
points (on Day 4, at 0 hours, and Day 7, at 0, 2, 4, and 6 hours) are below 20 msec, the post-
baseline dose QTc interval will be considered to be “non-inferior” to the baseline.
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SCHEDULE OF ACTIVITIES
The Schedule of Activities table provides an overview of the protocol visits and procedures.  Refer to the STUDY PROCEDURES
(see Section 6) and ASSESSMENTS (see Section 7) sections of the protocol for detailed information on each procedure and 
assessment required for compliance with the protocol.  The investigator may schedule visits (unplanned visits) in addition to those 
listed on the Schedule of Activities table, in order to conduct evaluations or assessments required to protect the well-being of the 
patient.
Table 1.
Schedule of Activities
Screening
Cycle 1
Cycle 2                               
(if administered)
EOT
Follow-up 
Period19
GO Treatment
Post-GO Period
GO Treatment
Post-GO Period
Schedule Day1
<28 days 
prior to 
enrollment
C1
D1
C1
D4
C1
D7
C1
D10
C1
D15
C1
D21
C2
D1
C2
D4
C2
D7
C2
D10
C2
D15
C2
D21
Every 12 weeks
Visit window (Days)
±1
±1
±1
±1
±1
±1
±2
±7
Informed consent & 
assent3
X
Immunophenotyping 
(including CD33)4
X
 
ECG (in triplicate)6
X
X
X
X
X
X
Pharmacokinetic 
samples7
X
X
X
X7
X7
X7
X7
X7
X7
X7
X
Medical history8
X
Body weight
X
X
X
X
X
X
X
Vital signs/PE
X
X
X
X
X
X
X
ECOG PS score9
X
X
X
Imaging
assessment10
X10
X10
X10
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Table 1.
Schedule of Activities
Screening
Cycle 1
Cycle 2                               
(if administered)
EOT
Follow-up 
Period19
GO Treatment
Post-GO Period
GO Treatment
Post-GO Period
Schedule Day1
<28 days 
prior to 
enrollment
C1
D1
C1
D4
C1
D7
C1
D10
C1
D15
C1
D21
C2
D1
C2
D4
C2
D7
C2
D10
C2
D15
C2
D21
Every 12 weeks
Visit window (Days)
1
1
1
1
1
1
2
7
Safety Laboratory11
CBC and differential 
counts 12
X
X
X
X
X
X12
X
X
X
X
X12
X
Chemistry
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X17
Urinalysis
X
X
X
Coagulation
(PT, aPTT, 
fibrinogen)
X
X
X
X
X
X
X
X
X
X
X
Pregnancy test
X13
X20
HIV, Hepatitis B, 
and Hepatitis C 
evaluation14
X
Pre-medication
X
X
X
X
X
X
BM examination  
and disease 
assessments15
X15
X15
Serious and non-
serious adverse event 
monitoring16
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X17
Concomitant 
medications and 
treatment18
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Survival follow-up19
X21
Abbreviations: aPTT = activated partial thromboplastin time; BM = bone marrow; C = Cycle; CAT = computed axial tomography; CBC = complete blood 
counts; D = Day; ECG = electrocardiogram; ECOG PS = Eastern Cooperative Oncology Group performance status; EOT = end of treatment; GO = gemtuzumab 
ozogamicin; HIV = human immunodeficiency virus; MRI = magnetic resonance imaging; PE = physical examination; PT = prothrombin time


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1.
All assessments should be performed prior to dosing with GO on the visit day unless otherwise indicated.  Acceptable time windows for performing each 
assessment are described in the column headers.  The exact enrollment day (Day 1) is the day when patient identifier is assigned with the first GO dose.  The 
EOT is defined as 36 days after the last dose of GO or start of subsequent anticancer therapy, eg, consolidation and/or conditioning regimens.
2.
The second cycle will be allowed at the investigator’s discretion for patients who meet the following criteria after Cycle 1(see also Table 3 describing 
hematologic toxicities): Bone marrow with a decrease of blast percentage to at least 25% or a decrease of pretreatment blast percentage by at least 50%; and 
Blood count with neutrophils ≥1,000/μL and platelets ≥50,000/μL, except in patients with the bone marrow blasts ≥5%, the decrease in neutrophils and 
platelets thought to be due to the underlying leukemia.  Patients who do not meet these response criteria after the first cycle of GO will not be allowed to 
receive a 2nd cycle see Section 7.5). Cycle 2 Day 1 must be started no later than 42 days after the last dose of GO (ie, Cycle 1 Day 7).
3.
Informed Consent and assent for those patients under age 18 (or as specified per local policy/laws).  Must be obtained prior to undergoing any study 
procedure.
4.
CD33 immunophenotyping performed at screening on bone marrow (BM) or of circulating blasts in peripheral blood specimen by local laboratories.  
Surface CD33 expression should be measured by flow cytometry (flow-activated cell sorting, FACS); immunohistochemistry (IHC) analysis is allowed in 
patients with (1) dry tap; or (2) if BM specimen is inadequate and/or with insufficient circulating blasts for FACS. 
 
 
 
 
6.
ECGs will be in triplicate (3 consecutive ECGs approximately 2 minutes apart).  All ECGs will be sent to an ECG core laboratory vendor.  ECG at screening 
will be used to determine patient eligibility.  Ideally, the patient will be supine or reclined in a semi recumbent position for the entire infusion and for both 
pre- and post- infusion ECGs.  To minimize artifact, the patient should not change position between the pre- and post-infusion ECGs.  Additional ECGs may 
be done if clinically required.  See Table 2 for additional collection time points.
7.
Pharmacokinetic samples: See Table 2 for additional time points.
8.
Medical History: To be collected within 28 days prior to first dose Includes date of initial diagnosis with FAB subtype, prior AML therapies including HSCT 
and outcomes, and cytogenetics.  Also, review study eligibility.
9.
ECOG PS: Assessment is not required on Day 1 if acceptable screening assessment is done within 7 days prior to the start of investigational drug.
10. Patients with suspected extramedullary disease will have imaging assessment (eg, CAT or MRI) of all known disease sites.
11. Days 1, 4, and 7 laboratory samples should be collected prior to dosing.  
12. Three times a week after GO dosing until determination of remission status (see Section 7.5); subsequently CBC and differential counts will be collected 
once weekly until EOT (or until start of Cycle 2 (if administered) or start of subsequent anticancer therapy).
13. Pregnancy test: Required in less than 7 days prior to Day 1.
14. Evaluations of HIV and hepatitis B serological tests and hepatitis C tests (see Section 6.1).
15. Efficacy evaluation anddetermination of remission status by blood and bone marrow aspiration (and biopsy if applicable) after recovery of blood counts is 
observed and/or at a maximum of 36 days after the last dose of GO treatment.
16. Adverse Event (AE) Assessments: Adverse events should be documented and recorded at each visit using NCI CTCAE version 4.03 up to 36 days after the 
last dose of GO or start of subsequent anticancer therapy, (eg, consolidation or conditioning regimen), whichever occurs first.  Patients must be followed for 
AEs according to Section 8.  Sites should report related SAEs including VOD/SOS as warranted.  Any occurrence of VOD/SOS is to be reported as SAE to 
Pfizer Safety and recorded in the case report form (CRFsee Section 7.4.1).
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17. Occurrence of VOD/SOS will be monitored for the study duration of 12 months for each patient (see Section 7.4.1). During Follow-up period, blood 
chemistry sampling should be collected only in case of occurrence of VOD/SOS.
18. Concomitant Medications/Treatments: Concomitant medications and treatments will be recorded from 28 days prior to the start of study treatment and up to 
36 days post the last dose of study treatment or starting subsequent anticancer therapy (eg, consolidation or conditioning regimen).  During the follow-up 
period concomitant medications only related to follow-up therapy/HSCT and the management of VOD/SOS are to be collected (see Section 7.4.1).  Also, the 
patient will be informed of the need to use 2 highly effective methods of contraception consistently and correctly and document the conversation, and the 
patient’s affirmation, in the patient’s chart (see Section 4.3.1). 
19. Post BM assessment and determination of response: Consolidation as well as the decision of subsequent HSCT will be at physician’s discretion.  The study 
duration for each patient is 12 months.  The survival data will be collected for each patient for the study duration.  Patients who undergo HSCT subsequent 
to GO regimen will undergo relevant laboratory tests for safety monitoring per institutional standards for suspected or diagnosed VOD/SOS. 
20. Pregnancy test (see Section 7.7).
21. For any patients who may not be able to visit the study site at the protocol designated time, telephone contact is acceptable method for survival follow-up 
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Table 2.
Schedule of Activities – ECG, Pharmacokinetics, Immunogenicity
 
Assessments
Cycle 1
Cycle 2 (if administered)
EOTl
(±2 
days)
Follow-up 
Period
D1
D4
D7
D10
(±1 
day)
D15
(±1 
day)
D21
(±1 
day)
D1
D7
D15
(±1 
day)
D21
(±1 
day)
Time (hours) relative to the 
start of the GO infusion
0
1
2
4
6
24
0
2
0
2
4
6
NA
NA
NA
0
2
0
2
6
NA
NA
NA
NA
Blood sample for PKa
Xb Xd Xc Xd Xd Xj Xb Xc Xb Xc Xd Xd
Xe
Xe
Xe
Xb Xc Xb Xc Xd
Xe
Xe
Xe
 
 
Blood sample for ADA/NAbc
Xb
Xe
Xe
Xe
Xe
Xe
Xm
Triplicate 12-lead ECGf
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
 
 
 
ADA = anti-drug antibody; D = Day; ECG = electrocardiogram; EOT = end of treatment; GO = gemtuzumab ozogamicin; NA = not applicable;
NAb = neutralizing antibody; PD = pharmacodynamics; PK = pharmacokinetics 
a.
PK samples collected during infusion should be taken from the arm OPPOSITE to the IV infusion site. 
PK sample should ALWAYS be collected AFTER ECG.
If the dosing day is delayed, the PK and PD samples must be collected on the same day as dosing.
PK collections on Day 4 and Day 10 for all patients.
b.
Pre-dose samples to be collected right before the start of GO infusion. 
c.
2-hour, post-dose samples are to be drawn right before the infusion ends (maximum window of ±10 minutes allowed). 
d.
These post-dose samples to be drawn within ±10 minutes of the designated time.
e.
Samples on Days 10, 15, 21, and EOT visit may be collected at any time during the visit.
f.
Triplicate 12-lead ECG: At each time-point, three consecutive 12-lead ECGs will be performed approximately 2 minutes apart, but within 15 minutes for all 
ECGs, to determine the mean QTc.  ECGs will be collected at Screening and on dosing Days 1, 4, and 7.  It is preferable that the machine used has the 
capacity to calculate the standard intervals automatically.  ECG interval readings by the ECG recorder’s algorithm will be read and interpreted at the 
investigational site for eligibility determination.  Additional ECGs will be performed as clinically indicated for patient safety monitoring and documentation 
stored in the source documents.  ECG measurements will include PR interval, QT interval, RR interval and QRS complex.  
 
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j.
24-hour, post dose samples for PK 
 to be drawn from 24 to 30 hours of the designated time.
l.
EOT is defined as 36 days after the last dose of GO.
m. The follow-up for patients who are ADA positive at the EOT visit (36 days after last dose) consists of visits approximately every 90 days until ADA titers 
are no longer detectable, return to baseline, stabilize at a level acceptable to the investigator and sponsor, or up to 1 year after their first visit in the main 
study, whichever comes first.
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1. INTRODUCTION
1.1. Mechanism of Action/Indication
The CD33 (cluster of differentiation) antigen is a cell surface protein expressed on the 
external surface of normal and leukemic myeloid cells, and leukemic blasts in more than 
80-90% of patients with acute myeloid leukemia (AML).  The antigen is not expressed on the 
pluripotent stem cells, normal precursor hematopoietic cells.6
Gemtuzumab ozogamicin (GO; MYLOTARG) is an antibody-drug conjugate (ADC) 
composed of the CD33-directed monoclonal antibody (recombinant humanized 
immunoglobulin [Ig] G4, kappa antibody produced by mammalian cell culture in NS0 cells) 
that is covalently linked to the cytotoxic agent N-acetyl gamma calicheamicin 
dimethylhydrazide (DMH), a semisynthetic disulfide derivative of calicheamicin.  The 
antibody portion binds specifically to the CD33 antigen, a sialic acid-dependent adhesion 
protein found on the surface of myeloid leukemic blasts and immature normal cells of 
myelomonocytic lineage, but not on normal hematopoietic stem cells.  After binding to the 
CD33 antigen, GO is internalized within the leukemic cell, thus delivering the calicheamicin 
derivative.7  Activation of N-acetyl gamma calicheamicin DMH induces double-strand 
deoxyribonucleic acid (DNA) breaks, subsequently inducing cell cycle arrest and apoptotic 
cell death.8  GO, the only approved AML therapy that targets CD33 antigen, is indicated for 
the treatment of newly-diagnosed CD33-positive acute myeloid leukemia (AML) in adults, 
and relapsed or refractory CD33-positive AML in adults and in pediatric patients 2 years and 
older.1
1.2. Background and Rationale
1.2.1. Incidence and Treatment of Acute Myeloid Leukemia (AML)
Acute myeloid leukemia (AML) is the most common type of acute leukemia in adults and 
accounts for ~80% of all cases of acute leukemia.  Each year there are approximately 
260,000 new cases of AML worldwide with incidence 4.2 per 100,000; of these about 
21,380 cases are estimated in US.9  The average age of a patient with AML is about 68 years 
and it is relatively uncommon before the age of 45.  Incidence increases with age and peaks 
in adults 65 years of age or older; slightly more than half of all patients are 60 years of age or 
older.  Thus, AML is an orphan disease of older people. 
AML is a genetically heterogeneous malignancy characterized by multiple genetic mutations 
at the time of diagnosis that evolve with treatment, resulting in treatment resistance, disease 
relapse, and reduced survival.  Standard of care induction chemotherapies such as 
anthracycline plus cytarabine, or hypomethylating agents (eg, decitabine and azacitidine) can 
induce complete remissions in 5-70% of patients; however, remissions are not durable and 
disease relapse occurs in up to 60% of patients.10  The most effective consolidation therapy is 
allogeneic stem cell transplantation, but this carries a high risk of initial mortality and a 
significant risk of long-term morbidity associated with chronic graft-versus-host disease, 
which tends to offset the therapeutic benefits of a low likelihood of relapse.  But the risk of 
disease recurrence of chemotherapeutic-based approaches, with or without autologous stem 
cell rescue, still remains high.  Patients with relapsed AML have a particularly poor 


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prognosis.  A number of cytotoxic agents and combination regimens have been used for 
salvage chemotherapy and remission rates from 20–70% have been described.  However, the 
period of remission typically lasts only 4-6 months. 
1.2.2. Gemtuzumab Ozogamicin for Treatment of Acute Myeloid Leukemia
1.2.2.1. Regulatory History
Gemtuzumab ozogamicin originally received accelerated approval with dose of 
9 mg/m² x 2 (14 days apart) given as a single-agent treatment for patients with CD33-positive 
AML in first relapse who are 60 years of age or older and who are not considered candidates 
for cytotoxic chemotherapy in the United States (US) on 17 May 2000 and as a monotherapy 
for the treatment of patients with relapsed or refractory CD33-positive AML in Japan in 
2005.  A Phase 3 study (Southwest Oncology Group [SWOG] S0106) evaluating GO in 
combination with chemotherapy in patients with previously untreated de novo AML was 
subsequently conducted as a post-market requirement (PMR) from 2004 to 2009 to confirm 
the clinical benefit of GO in order to convert the accelerated approval to full approval.  
S0106 was a randomized trial comparing treatment with DNR and Ara-C with or without GO 
6 mg/m2 for treatment of patients <60 years old with newly-diagnosed AML.  The primary 
endpoint was complete remission (CR) rate post induction and disease-free survival (DFS) 
post consolidation.  There were 637 patients randomized.  The study showed no 
improvement in CR, DFS or overall survival (OS) with the addition of GO.  In addition, there 
was a higher rate of fatal induction toxicities in the GO arm (5.8% versus 1.3%).  FDA 
concluded that clinical benefit was not confirmed and that there was a potential safety issue 
due to the increase in early deaths.  In addition, GO was associated with hepatic 
veno-occlusive disease (VOD), which has substantial morbidity and mortality.  Therefore, 
Pfizer voluntarily withdrew Mylotarg from the US market in October 2010.  Nevertheless, 
GO continued to be marketed for the treatment of patients with relapsed or refractory 
CD33-positive AML in Japan, hematologists requested compassionate-use GO for their 
AML patients, and investigators continued to evaluate GO in patients with AML.
On 01 September 2017 the US FDA approved Mylotarg for adults with newly diagnosed 
CD33-positive AML, and for adults and children 2 years and older with relapsed or 
refractory CD33-positive AML.  Study ALFA-0701 supported use of GO in combination 
with chemotherapy in newly diagnosed AML, EORTC (European Organisation for Research 
and Treatment of Cancer) - GIMEMA (Gruppo Italiano Malattie Ematologiche dell' Adulto) 
AML-19 Study supported use of single-agent GO in newly diagnosed AML,23 and Study 
MyloFrance-1 supported use of single-agent GO in relapsed or refractory AML.  The 
approved dosage is as follows:1

Combination regimen in newly-diagnosed AML: Induction with 3 mg/m2 on Days 1, 
4, and 7 in combination with DNR and Ara-C, followed by consolidation with 
3 mg/m2 on Day 1 in combination with DNR and Ara-C.

Single-agent regimen in newly-diagnosed AML: Induction with 6 mg/m2 on Day 1 
and 3 mg/m2 on Day 8, followed by continuation for patients without evidence of 
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•
Single-agent regimen in relapsed or refractory AML: 3 mg/m2 on Days 1, 4, and 7. 
On 22 February 2018, the Committee for Medicinal Products for Human Use (CHMP) 
adopted a positive opinion, and on 19 April 2018, The European Commission (EC) granted a 
marketing authorisation approval for Mylotarg, indicated for combination therapy with DNR 
and Ara-C for the treatment of patients age 15 years and above with previously untreated, 
de novo CD33-positive acute myeloid leukemia (AML), except acute promyelocytic 
leukemia (APL).
1.2.2.2. Fractionated Dosing of GO
Based on in vitro studies, which showed rapid re-expression of CD33 antigenic sites on the 
cell surface of blasts cells after exposure to GO, it was hypothesized that fractionated doses 
of GO may be efficacious and better tolerated.11  It was hypothesized that fractionated dose 
on Days 1, 4, and 7 may increase GO activity by binding to re-expressed CD33, thereby 
increasing GO uptake into leukemic blasts.  In vitro data indicated that at least 90% of CD33 
saturation is required for efficient killing of AML blasts .12 The initial dose-escalation 
Study 101 (N=40) in relapsed AML evaluated CD33 site saturation of GO over a dose range 
of 0.25 to 9 mg/m2.  Based on these results, a dose of 3 mg/m2 is estimated to produce 
90% to 95% saturation of CD33.13  Based on exposure-response modeling, lower fractionated 
dosing of GO was predicted to retain efficacy and improve safety.  This is particularly 
important in patients who undergo hematopoietic stem cell transplantation (HSCT), a 
significant risk factor of VOD/SOS.
The safety and efficacy of the fractionated dose GO monotherapy regimen of 3 mg/m2 on 
Days 1, 4, and 7, in patients with CD33-positive AML in first relapse has been demonstrated 
in a Phase 2 study (MyloFrance-1).14
1.2.2.3.
 Pharmacokinetics and Dosage
GO was originally approved for use in patients with CD33-positive relapsed AML.  Three 
registrational Phase 2 studies (0903B1-201, 0903B1-202, 0903B1-203) were conducted.15  
The approved regimen was 2 doses of GO at 9 mg/m2, administered at least 14 days apart.  
The 14-day interval between doses was selected on the basis of near total clearance of the 
antibody portion of GO, hP67.6, within this time period.  Based on the non-compartmental 
analysis (NCA) following a 9 mg/m2 dose on Days 1 and 14, the half-life of hP67.6 was 
62 hours after the first dose and 90 hours after the second dose.
Since no clinical pharmacokinetic (PK) data are available for the fractionated dosing regimen 
for GO (3 mg/m2 administered on Days 1, 4, and 7), PK profiles for this regimen were 
simulated, using the PK model developed based on prior clinical studies, in patients with 
relapsed or refractory AML or de novo AML.  The model predicted that, while the total dose 
of the fractionated dosing regimen is half of that of the original dosing regimen (9 versus 
18 mg/m2), total area under curve (AUC) of hP67.6 over the course of treatment is 25%, and 
maximum concentration (Cmax) is 24% of the original dosing regimen.  Since the Cmax has 
been associated with the risk of certain AEs (eg, VOD/SOS, bilirubin elevation, aspartate 
aminotransferase [AST] elevation), the fractionated regimen is expected to have improved 
safety profile than the previously used regimen.13
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1.2.2.4. Clinical Data for GO in Patients with AML in First Relapse
Studies 201, 202, and 203 were single-arm studies in adult patients with CD33-positive AML 
in first relapse that supported the original accelerated approval of Mylotarg by the FDA in 
May 2000 .15  These studies shared a similar design and used an identical GO dosing regimen 
of 9 mg/m2 on Days 1 and 15.  The primary objective of these studies was to assess the 
efficacy (based on the number of patients achieving CR or complete remission with 
incomplete platelet recovery [CRp]) and safety of GO monotherapy.  A pooled analysis of 
these 3 pivotal Phase 2 studies (N=277) reported an objective response rate of 35% (based on 
International Working Group [IWG] criteria).16  The evidence from these studies indicated 
that patients receiving GO had a high incidence of myelosuppression, manifested by delayed 
recovery time for neutrophils and platelet counts, and over time, hepatic VOD (SOS) 
emerged. 
A Phase 2 study (MyloFrance-1) used the fractionated regimen of single-agent GO (3 mg/m2
on Days 1, 4, and 7), followed by consolidation with high-dose cytarabine in patients with 
AML in first relapse.  Of 57 patients who received GO, 15 patients (26%) achieved CR and 
four patients (7%) achieved CRp.  In the 19 patients who achieved a response in the
MyloFrance-1 study, the median times to recovery of neutrophil count to 500/mm3 and of 
platelet count to 50,000/mm3 were 23 and 20 days, respectively, approximately half the 
median time to recovery observed in Studies 201/202/203 (40.5 days and 51 days, 
respectively).  Grade 3 treatment emergent adverse events (TEAEs) reported in >1% patients 
in the MyloFrance-1 study included sepsis (31.5%), fever (15.8%), rash (10.5%), 
pneumonia (7.0%), bleeding (7.0%), mucositis (3.5%), and diarrhea, headaches, tachycardia, 
and edema (1.8% each).  Grade 3 or 4 liver toxicity was not reported; also, there were no 
reports of VOD/SOS, including in 7 patients who underwent HSCT subsequent to GO 
treatment.14  
Additional information for this compound may be found in the single reference safety 
document (SRSD), which for this study is the investigator brochure (IB).
1.2.2.5. Study Rationale 
Results from the studies evaluating treatment with GO in patients with CD33-positive AML 
in first relapse, described in Section 1.2.2.4, provide evidence that fractionated regimen of 
GO has enhanced safety profile than the original dosing regimen, without hampering the 
efficacy. 
The effect of GO on the QT interval has not been evaluated clinically because the regulatory 
guidelines when the original studies (201, 202, and 203) were conducted did not require 
quantitative QT data to be collected.  However, tests evaluating the effect of N-acetyl gamma 
calicheamicin DMH on the human ether-a-go-go-related gene (hERG) potassium channel at 
concentrations up to 6.77 uM resulted in <1% inhibition of the hERG current amplitude and 
there were no effects of GO on ECG parameters in dogs at any dose (range 4 to 40 mg/m2) or 
in monkeys in the 6-week repeat-dose studies.  Additionally, no PK data are available for the 
fractionated dosing regimen (3 mg/m2 on Days 1, 4, and 7) of GO.  Therefore, FDA has 
requested a PMR study to characterize the effect of the fractionated dosing regimen of GO as 


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a single-agent treatment in patients with relapsed or refractory CD33-positive AML on QT 
interval, PK, and safety. In addition, the CHMP identified several recommendations in the 
ongoing development of GO, including
 
 
 inclusion of 6 pediatric patients into the FDA issued PMR study.  The 6 pediatric 
patients in this study will be between 12 and 17 years of age (eg, adolescents), a defined 
group of pediatric patients expected to have similar ECG/PK findings and for whom the 
schedule of assessments and blood draw requirements would be acceptable in order not to 
exceed 3% of total blood volume within 4 weeks.
A sample size of 50 patients 18 years or older should allow for collection of sufficient data to 
characterize the effect of GO on the QT interval, as well as to enhance the understanding of 
GO following the fractionated regimen in patients with relapsed or refractory AML.  
Six (6) pediatric patients (12 years ≤age ≤17 year) will be included based on agreement with 
CHMP.  This study includes the collection of hemorrhage-related laboratory data and 
coagulation-related assessments, such as complete blood counts (CBC) and differential 
counts, prothrombin time (PT), activated partial thromboplastin time (aPTT), and fibrinogen.  
The impact of GO on VOD/SOS in the context of previous and subsequent HSCT, and 
anti-drug antibody (ADA) formation will also be assessed.  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
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2. STUDY OBJECTIVES AND ENDPOINTS
Primary Objective:
Primary Endpoint:
•
To assess the effect of GO on the QTc interval. 
•
Maximum change from baseline in 
corrected QT interval (QTc).
Secondary Objectives:
Secondary Endpoints:
•
To characterize the PK of single-agent GO following 
the fractionated regimen (ie, 3 mg/m² on Days 1, 4, 
and 7).
•
To assess the safety of GO with fractionated dosing 
of 3 mg/m2.
•
To assess the immunogenicity of GO. 
•
To assess response and overall survival.  
•
PK parameters: clearance and volume of 
distribution.
•
Adverse events (AEs) and abnormal 
laboratory findings.
•
Incidence of anti-drug antibody 
(ADA)/neutralizing antibodies (NAb). 
•
Response: complete remission (CR) and 
complete remission with incomplete 
hematologic recovery (CRi) achieved after 
GO.
•
Overall Survival. 
 
 
 
 
 
 
 
 
 
 
 
3. STUDY DESIGN
This is a single-arm, open-label, Phase 4 study evaluating the effect of GO on the QT, 
pharmacokinetics, safety, and immunogenicity of GO as a single-agent monotherapy in adult
and pediatric patients with relapsed or refractory CD33-positive AML.  Approximately 
50 adult patients (age ≥18 years) and 6 pediatric (12 years ≤age ≤17 years) patients who 
satisfy the study eligibility criteria will be enrolled and treated with the fractionated regimen 
of GO 3 mg/m2 on Days 1, 4, and 7 (up to 2 cycles).  Triplicate ECGs will be performed at 
screening, baseline (prior to dose on Day 1) and right before serial PK draws on each day of 
dosing.  All triplicate ECG tracings will be sent to an independent ECG core laboratory for 
blinded manual interval measurements. The active safety monitoring duration will be up to 
36 days after the last dose of GO or starting of subsequent anticancer therapy, including 
consolidation and/or conditioning regimens.  This study includes the collection of 
hemorrhage-related laboratory data and coagulation-related assessments, such as CBC and 
differential counts, PT, aPTT, and fibrinogen.  Any event of VOD/SOS will continue to be 
reported as SAE during the entire study duration. 
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After receiving the study treatment (Cycle 1 and Cycle 2, if administered), blood cell and 
differential counts will be examined 3 times a week after GO dosing until having 
determination of remission status (see Section 7.5); subsequently CBC and differential counts 
will be collected once weekly until 36 days after the last dose of GO or until start of 
subsequent anticancer therapy, eg, consolidation or conditioning regimen.  Efficacy 
evaluation and final determination of remission status by blood and bone marrow aspiration 
(and biopsy if applicable) will be conducted after recovery of blood counts is observed or at a 
maximum of 36 days after the last dose of GO treatment (EOT).  Study duration for each 
patient is a total of 12 months from enrollment, survival data will be collected for the study 
duration of 12 months. 
Treatment Plan
Patients enrolled in the study will be receive three doses of GO 3 mg/m2 (up to one vial) as a 
2-hour intravenous infusion on Cycle 1 Days 1, 4, and 7.  A second cycle 3mg/m² (up to one 
vial) on Cycle 2 Days 1, 4, and 7 will be allowed at the investigator’s discretion for patients 
who meet the following criteria after Cycle 1: Bone marrow with a decrease of blast 
percentage to at least 25% or a decrease of pretreatment blast percentage by at least 50%;
and Blood count with neutrophils 1,000/µL and platelets 50,000/µL, except in patients 
with the bone marrow blasts 5%, the decrease in neutrophils and platelets thought to be due 
to the underlying leukemia (see Section 7.5).
After GO treatment, subsequent anticancer therapy such as consolidation or conditioning 
regimen and/or HSCT could be considered at the investigator’s discretion.  A minimum 
interval of 2 months is recommended between the last dose of GO and HSCT. 
Figure 1.
B1761031 Study Schematic
Confirmed 
refractory or 
relapsed CD33-
positive AML 
Age 12 years 
ECOG PS 0 to 2
Prior HSCT 
allowed (2 months 
prior to enrollment)
Treatment
Monotherapy with GO 
2-hour intravenous (IV)
infusion of 3 mg/m2 (up to 
one vial) on Days 1, 4, and 7 
(1-2 cycles) 
Assessments: 
QTc, PK, Safety, 
immunogenicity, and 
Efficacy
After GO Treatment 
Subsequent anticancer 
therapy at the discretion 
of the investigator 
(eg, consolidation and/or 
HSCT)
HSCT allowed (2 months 
recommended between 
last dose GO and HSCT)
Pre-
medication


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4. PATIENT ELIGIBILITY CRITERIA
This study can fulfill its objectives only if appropriate patients are enrolled.  The following 
eligibility criteria are designed to select patients for whom participation in the study is 
considered appropriate.  All relevant medical and nonmedical conditions should be taken into 
consideration when deciding whether a particular patient is suitable for this protocol. 
Patient eligibility should be reviewed and documented by an appropriate member of the 
investigator’s study team before patients are included in the study. 
4.1. Inclusion Criteria
Patients must meet all of the following inclusion criteria to be eligible for enrollment into the 
study:
1. Refractory or relapsed (ie, bone marrow blasts 5%) CD33-positive AML.
2. Age 12 years. 
3. Eastern Cooperative Oncology Group (ECOG) Performance Status 0 to 2.
4. Initial peripheral white blood cells (WBC) counts <30,000/L; patients with a higher 
WBC count should undergo cytoreduction.
5. Adequate renal/hepatic functions, ie: 

Serum creatinine 1.5 x upper limit of normal (ULN) or any serum creatinine 
level associated with a measured or calculated creatinine clearance of 
40 mL/min;

Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) 
<2.5×ULN; total bilirubin <2×ULN.
6. Negative serum or urine pregnancy (human chorionic gonadotropin [hCG]) test 
within 1 week before treatment for women of child bearing potential.
7. Evidence of a personally signed and dated informed consent document and obtaining 
proper pediatric assent in addition to consent according to local regulations (by the 
caregivers or legally acceptable representative [eg, parents] in the pediatric patients) 
indicating that the patient [or a legally acceptable representative/parent(s)/legal 
guardian] has been informed of all pertinent aspects of the study.
8. Willing and able to comply with scheduled visits, treatment plan, laboratory tests, and 
other study procedures.


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9. Female patients of non-childbearing potential must meet at least 1 of the following 
criteria:

Achieved postmenopausal status, defined as follows: cessation of regular menses 
for at least 12 consecutive months with no alternative pathological or 
physiological cause; status may be confirmed with a serum follicle-stimulating 
hormone (FSH) level confirming the postmenopausal state;

Have undergone a documented hysterectomy and/or bilateral oophorectomy;

Have medically confirmed ovarian failure. 
All other female patients (including female patients with tubal ligations) are considered to be 
of childbearing potential. 
4.2. Exclusion Criteria
Patients with any of the following characteristics/conditions will not be included in the study:
1. Patients with prior treatment with GO.
2. Patients with prior history of VOD/SOS.
3. Prior HSCT is not allowed, if it was conducted within 2 months prior to study 
enrollment.
4. Patients with known active central nervous system (CNS) leukemia.
5. Uncontrolled or active infectious status.
6. Any of the following within the 3 months prior to starting study treatment: 
myocardial infarction, severe/unstable angina, coronary/peripheral artery bypass 
graft, congestive heart failure, or cerebrovascular accident including transient 
ischemic attack, or symptomatic pulmonary embolism.
7. Uncontrolled cardiac dysrhythmias of NCI CTCAE Grade 2, uncontrolled atrial 
fibrillation of any grade.
8. Sero-positivity to human immunodeficieny virus (HIV).
9. Active hepatitis B or hepatitis C infection (see Appendix 2).
10. Chemotherapy, radiotherapy, or other anti-cancer therapy (except hydroxyurea as 
cytoreduction) within 2 weeks prior to enrollment in the study.
11. Major surgery within 4 weeks prior to enrollment.
12. Diagnosis of any other malignancy within 3 years prior to enrollment, except for 
adequately treated basal cell or squamous cell skin cancer, or carcinoma in situ of the 
cervix.


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13. QTc interval >470 milliseconds (msec) using the Fridericia (QTcF) (based on the 
mean value of the triplicate electrocardiograms [ECGs]), family or personal history of 
long or short QT syndrome, Brugada syndrome or known history of QTc 
prolongation, or Torsade de Pointes (TdP).
14. The use of medications known to predispose to Torsades de Pointes within 2 weeks 
prior to enrollment (see Appendix 4).
15. History of allergic reactions attributed to compounds of similar chemical or biologic 
composition to GO.
16. Investigator site staff members directly involved in the conduct of the study and their 
family members, site staff members otherwise supervised by the investigator, or 
patients who are Pfizer employees, including their family members, directly involved 
in the conduct of the study.
17. Participation in other studies involving investigational drug(s) within 2 weeks prior to 
study entry and/or during study participation.
18. Other acute or chronic medical or psychiatric condition including recent (within the 
past year) or active suicidal ideation or behavior or laboratory abnormality that may 
increase the risk associated with study participation or investigational product 
administration or may interfere with the interpretation of study results and, in the 
judgment of the investigator, would make the patient inappropriate for entry into this 
study.
19. Pregnant female patients; breastfeeding female patients; fertile male patients and 
female patients of childbearing potential who are unwilling or unable to use 2 highly 
effective methods of contraception as outlined in this protocol for the duration of the 
study and for 7 months after the last dose of investigational product. 
4.3. Lifestyle Requirements
4.3.1. Contraception
In this study, fertile male patients and female patients who are of childbearing potential as 
applicable to the study will receive GO, which has been associated with demonstrated 
teratogenicity/fetotoxicity.  Patients who are, in the opinion of the investigator, sexually 
active and at risk for pregnancy with their partner(s) must agree to use 2 methods of highly 
effective contraception throughout the study and for at least 7 months after the last dose of 
GO in female patients of reproductive potential, and for at least 4 months after the last dose 
of GO in male patients with female partners of reproductive potential.  The investigator or his 
or her designee, in consultation with the patient, will confirm that the patient has selected 
2 appropriate methods of contraception for the individual patient and his/her partner(s) from 
the list of permitted contraception methods (see below) and will confirm that the patient has 
been instructed in their consistent and correct use.  At time points indicated in the Schedule 
of Activities, the investigator or designee will inform the patient of the need to use 2 highly 
effective methods of contraception consistently and correctly and document the conversation, 


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and the patient’s affirmation, in the patient’s chart.  In addition, the investigator or designee 
will instruct the patient to call immediately if 1 or both of the selected contraception methods 
is discontinued or if pregnancy is known or suspected in the patient or partner. 
Highly effective methods of contraception are those that, alone or in combination, result in a 
failure rate of less than 1% per year when used consistently and correctly (ie, perfect use) and 
include the following:

Established use of hormonal methods of contraception associated with inhibition of 
ovulation (eg, oral, inserted, injected, implanted, transdermal), provided the patient or 
male patient’s female partner plans to remain on the same treatment throughout the 
entire study and has been using that hormonal contraceptive for an adequate period of 
time to ensure effectiveness.  

Correctly placed copper-containing intrauterine device (IUD).

Male condom or female condom used WITH a separate spermicide product (ie, foam, 
gel, film, cream, or suppository).  For countries where spermicide is not available or 
condom plus spermicide is not accepted as highly effective contraception, this option 
is not appropriate.

Male sterilization with absence of sperm in the postvasectomy ejaculate. 

Bilateral tubal ligation/bilateral salpingectomy or bilateral tubal occlusive procedure 
(provided that occlusion has been confirmed in accordance with the device’s label).

All sexually active male subjects must agree to prevent potential transfer to and 
exposure of partner(s) to drug through ejaculate by using a condom consistently and 
correctly, beginning with the first dose of investigational product and continuing for 
36 days after the last dose of GO. 
4.4. Sponsor’s Qualified Medical Personnel
The contact information for the sponsor's appropriately qualified medical personnel for the 
study is documented in the study contact list located in the investigator file. 
To facilitate access to appropriately qualified medical personnel on study-related medical 
questions or problems, patients are provided with a contact card.  The contact card contains, 
at a minimum, protocol and investigational product identifiers, patient study numbers, 
contact information for the investigator site, and contact details for a contact center in the 
event that the investigator site staff cannot be reached to provide advice on a medical 
question or problem originating from another healthcare professional not involved in the 
patient’s participation in the study.  The contact number can also be used by investigator staff 
if they are seeking advice on medical questions or problems; however, it should be used only 
in the event that the established communication pathways between the investigator site and 
the study team are not available.  It is therefore intended to augment, but not replace, the 
established communication pathways between the investigator site and the study team for 


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advice on medical questions or problems that may arise during the study.  The contact 
number is not intended for use by the patient directly, and if a patient calls that number, he or 
she will be directed back to the investigator site.
5. STUDY TREATMENT
For the purposes of this study, and per International Conference on Harmonisation (ICH) 
guidelines, investigational product is defined as a pharmaceutical form of an active 
ingredient or placebo being tested or used as a reference/comparator in a clinical trial, 
including a product with a marketing authorization when used or assembled (formulated or 
packaged) in a way different from the approved form, or when used for an unapproved 
indication, or when used to gain further information about an approved use (ICH E6 1.33). 
For this study, the investigational product is gemtuzumab ozogamicin (GO).
5.1. Allocation to Treatment
Once the patient has signed the informed consent (and assent for pediatric patients), the 
investigator or designee will contact the interactive response technology (IRT) system to 
obtain a patient identification number (patient ID).  Following full assessment and 
determination that a patient meets all eligibility criteria, the investigator or designee will 
enroll the patient into the study using the IRT system.  Instructions on how to use the IRT 
system will be provided in the study manual.  No patient will receive study drug therapy until 
the entire enrollment process has been completed.
The study-specific IRT reference manual will provide the contact information and further 
details on the use of the IRT system. 
5.2. Patient Compliance
All doses of investigational product will be administered by the appropriately designated 
study staff at the investigator site.
The site will complete required dosage Preparation Record located in the study manual.  The 
use of the Preparation Record is preferred but it does not preclude the use of an existing 
appropriate clinical site documentation system.  The existing clinical site's documentation 
system should capture all pertinent/required information on the preparation and 
administration of the dose.  This may be used in place of the Preparation Record after 
approval from the Pfizer monitor.
5.3. Investigational Product Supplies
Study centers will receive a supply of GO after site activation.  Resupplies will be made 
during the course of the study.  The study monitor should be contacted for any issues related 
to GO supplies.
5.3.1. Dosage Form(s) and Packaging
GO for injection is supplied as a white to off-white, unpreserved, lyophilized cake or powder 
in a single-dose 20-mL Type I amber glass vial with rubber closure and flip-off cap.  Vials 
will be labeled in accordance with local requirements.


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Preparation and Dispensing
The investigational product will be dispensed using an IRT drug management system on 
Days 1, 4, and 7 per cycle.  Only qualified personnel who are familiar with procedures that 
minimize undue exposure to themselves and to the environment should undertake the 
preparation, handling, and safe disposal of chemotherapeutic agents including GO. 
See the Investigational Product Manual (IP manual), for instructions on how to prepare the 
investigational product for administration.  Investigational product should be prepared and 
dispensed by an appropriately qualified and experienced member of the study staff 
(eg, physician, nurse, physician’s assistant, nurse practitioner, pharmacy assistant/technician, 
or pharmacist) as allowed by local, state, and institutional guidance. 
5.4. Administration
5.4.1. Administration of the Premedication
Premedication is required for all patients.
Patients will be pre-medicated with acetaminophen 650 mg orally and diphenhydramine 
50 mg orally or intravenously 1 hour prior to GO dosing and 1 mg/kg methylprednisolone or 
an equivalent dose of an alternative corticosteroid within 30 minutes prior to infusion of GO 
(given prior to GO infusion may ameliorate infusion-related symptoms).
Follow standard practice of the institution to prevent tumor lysis syndrome.
Vital signs should be monitored during infusion and for 2 hours following infusion.
5.4.2. Administration of GO
Three doses of GO 3 mg/m2 (up to one vial per dose) will be administered at investigational 
site as a 2-hour intravenous infusion after premedication on Days 1, 4, and 7 at each cycle. 
Patients will receive 1 or 2 cycles of GO. The second cycle of GO will be allowed at the 
investigator’s discretion for patients who meet selected dosing criteria after the first cycle.
(see Section 7.5).
Use appropriate aseptic technique for the reconstitution and dilution procedures.  Protect the 
reconstituted and diluted GO solution from light.  See the IP manual for instructions on how 
to administer GO.
5.4.3. Dosage Modification for Toxicities

Every effort should be made to administer study medication on the planned dose and 
schedule.  Patients are to be instructed to notify investigators at the first occurrence of 
any adverse symptom.  In the event of multiple toxicities, dose modification should 
be based on the worst toxicity observed. 

Full recovery from hematologic toxicities is not a requirement for administration of the 
second or third dose on Day 4 or 7, respectively.  


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
In the event of non-hematologic toxicities, dosing may be delayed, omitted or 
discontinued as described below (Table 3) by monitoring chemistries especially total 
bilirubin, AST, ALT, and other severe or life-threatening non-hematologic toxicities 
through recovery from treatment-related toxicities. 

In the event of persistent hematologic toxicities after Cycle 1, conditional Cycle 2 
dosing may be delayed or discontinued as described below (Table 3) by monitoring 
blood counts through recovery from treatment-related toxicities.
Table 3.
Dosage Modifications for Non hematologic and Hematologic Toxicities
Non-hematologic Toxicities
Recommended Actions
VOD/SOS

Discontinue GO. 
Total bilirubin greater than 2×ULN, 
or AST and/or ALT greater than 
2.5×ULN

Delay treatment with GO until recovery of total bilirubin to less 
than or equal to 2 × upper normal limit (ULN) and AST and 
ALT to less than or equal to 2.5 × ULN prior to each dose.

Omit scheduled dose if delayed more than 2 days between 
sequential infusions.
Infusion-related reactions

Interrupt the infusion and institute appropriate medical 
management.

Administer acetaminophen, diphenhydramine and/or 
methylprednisolone, if needed.

Provide supportive care measures as needed.

For mild, moderate or severe infusion related reactions, once 
symptoms resolve, consider resuming the infusion at no more 
than half the rate at which the reaction occurred.  Repeat the 
procedure above in the event of recurrence of symptoms.

Permanently discontinue GO upon occurrence of a severe 
infusion reaction or for any life-threatening infusion reaction. 
Other severe or life-threatening 
non-hematologic toxicities

Delay treatment with GO until recovery to a severity of no more 
than mild (Grade 1).

Omit scheduled dose if delayed more than 2 days between 
sequential infusions.
Hematologic Toxicities
Recommended Actions
Persistent thrombocytopenia

If platelet count does not recover to greater than or equal to 
50,000 /µL within 42 days after the last dose of GO in the first 
cycle, DO NOT administer the 2nd cycle.*
Persistent neutropenia

If neutrophil count does not recover to greater than or equal to 
1,000/µL within 42 days after the last dose of GO in the first 
cycle, DO NOT administer the 2nd cycle.*
* except in patients with the bone marrow blasts 5%,  the decrease in neutrophils and platelets thought to be due to the 
underlying leukemia.


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5.5. Investigational Product Storage
The investigator or an approved representative, eg, pharmacist, will ensure that all 
investigational products are stored in a secured area with controlled access under required 
storage conditions and in accordance with applicable regulatory requirements.
Investigational products should be stored in their original containers and in accordance with 
the labels.  
See the investigator product manual for storage conditions of the product once reconstituted 
and/or diluted. 
Any storage conditions stated in the SRSD will be superseded by the storage conditions 
stated on the product label.
Site systems must be capable of measuring and documenting (for example, via a log), at a 
minimum, daily minimum and maximum temperatures for all site storage locations (as 
applicable, including frozen, refrigerated, and/or room-temperature products).  This should 
be captured from the time of investigational product receipt throughout the study.  Even for 
continuous-monitoring systems, a log or site procedure that ensures active evaluation for 
excursions should be available.  The intent is to ensure that the minimum and maximum 
temperature is checked each business day to confirm that no excursion occurred since the last 
evaluation and to provide the site with the capability to store or view the minimum/maximum 
temperature for all non-working days upon return to normal operations.  The operation of the 
temperature monitoring device and storage unit (for example, refrigerator), as applicable, 
should be regularly inspected to ensure they are maintained in working order. 
Any excursions from the product label storage conditions should be reported to Pfizer upon 
discovery.  The site should actively pursue options for returning the product to the storage 
conditions described in the labeling, as soon as possible.  Deviations from the storage 
requirements, including any actions taken, must be documented and reported to Pfizer. 
Once an excursion is identified, the investigational product must be quarantined and not used 
until Pfizer provides permission to use the investigational product.  It will not be considered a 
protocol deviation if Pfizer approves the use of the investigational product after the 
temperature excursion.  Use of the investigational product prior to Pfizer approval will be 
considered a protocol deviation.  Specific details regarding information the site should report 
for each excursion will be provided to the site.
Receipt of materials, door opening and closing, and other routine handling operations where 
the products are briefly out of the temperature range described in the labeling are not 
considered excursions.
5.6. Investigational Product Accountability 
The investigator site must maintain adequate records documenting the receipt, use, loss, or 
other disposition of the investigational product supplies.  All investigational products will be 
accounted for using a drug accountability form/record. 


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5.6.1. Destruction of Investigational Product Supplies 
The sponsor or designee will provide guidance on the destruction of unused investigational 
product (eg, at the site).  If destruction is authorized to take place at the investigator site, the 
investigator must ensure that the materials are destroyed in compliance with applicable 
environmental regulations, institutional policy, and any special instructions provided by 
Pfizer, and all destruction must be adequately documented.
5.7. Concomitant Treatment(s)
All concomitant medications required to clinically manage patients while they are receiving 
GO therapy are permitted, including any palliative and supportive care for cancer related 
symptoms.  Investigational drugs, anti-cancer therapy (except hydroxyurea as cytoreduction), 
and radiation (eg, cranial irradiation for CNS leukemia) are prohibited 2 weeks prior to study 
entry, during the GO treatment period, and before the determination of remission status by 
bone marrow (BM) assessment. 
The patients treated with medications that are known to predispose to Torsades de Pointes 
should discontinue the drugs at least 2 weeks prior to enrollment.  Medications that are 
known to cause QT prolongation should be avoided whenever possible during the GO 
treatment period and the post-GO period, but allowed after EOT visit.  Refer to Appendix 4
for assessing drugs known to predispose to Torsades de Pointes.
All concomitant medications, including prescription and nonprescription drugs, nondrug 
treatment, and dietary supplements and herbal preparations, will be entered on the case report 
form (CRF).  Concomitant medications and treatments will be recorded from 28 days prior to 
the start of study treatment and up to 36 days post the last dose of study treatment or starting 
subsequent anticancer therapy (eg, consolidation or conditioning regimen).
6. STUDY PROCEDURES 
The enrollment (study entry) day is defined as Day 1, when patient identifier is assigned with 
the first GO dosed.
6.1. Screening
Informed consent document (ICD) approved by an Institutional Review Board (IRB) or 
Independent Ethics Committee (IEC) must be signed and dated before any study-specific 
procedures are conducted.  Screening procedures for evaluating eligibility and baseline data 
will be completed within 28 days prior to dosing on Day 1 unless otherwise noted. 
The following will be collected at screening:

Sign informed consent form and obtain documentation of assent at screening for those 
patients under age 18 (or as specified per local policy/laws).

Review study eligibility (inclusion and exclusion criteria).


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•
Evidence of CD33 positivity for eligibility at screening, eg, by immunophenotyping 
of bone marrow or leukemia blasts in the peripheral bloodperformed by local 
laboratory using a validated assay and obtained within 28 days of enrollment will be 
collected and recorded in the CRF.  Surface CD33 expression should be measured by 
flow cytometry (flow-activated cell sorting, FACS); immunohistochemistry (IHC) 
analysis is allowed in patients with (1) dry tap; or (2) if BM specimen is inadequate 
and/or with insufficient circulating blasts for FACS.
 
 
•
Medical history: To be collected within 28 days prior to first dose.  
•
Chronic conditions and/or medical history of significance including alcohol use 
and relevant radiation and surgical procedures; 
•
Any other previous cancer diagnosis; 
•
Patients with prior HSCT are allowed in the study but those with history of 
VOD/SOS are not allowed.  Medical history must be reviewed for evidence of 
VOD/SOS (eg, weight gain, elevated bilirubin, tender hepatomegaly, and ascites 
may indicate underlying VOD/SOS), especially if a patient received high-dose 
chemotherapy followed by HSCT; 
•
Current disease: Initial AML diagnosis, relevant information for conclusive 
morphologically documented, refractory or relapsed CD33-positive AML, Eastern 
Cooperative Oncology Group performance status (ECOG PS) will be assessed.  
(Definition of refractory and relapsed AML as per ELN 2017 recommendation,5
see Appendix 5). 
•
Focused physical examination performed with clinical judgment evaluating potential 
areas of AML relapse and any clinically significant abnormalities which may include 
the following body systems: general appearance, skin, head/eyes/ears/nose/throat, 
heart, lungs, testes, abdomen, extremities, neurological, back/spinal, and lymph 
nodes; including worsening of medical history conditions.
•
Imaging Assessment: Patients with suspected extramedullary disease will have 
imaging assessment (eg, computed axial tomography [CAT] or magnetic resonance 
imaging [MRI]) of relevant sites.
•
Vital signs including height, weight, blood pressure, pulse, and temperature.  ECOG 
PS will also be assessed. 
•
Laboratory evaluations as described in Section 7.4, Appendix 3, and Schedule of 
Activities (Table 1).
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
For women of childbearing potential, a beta-human chorionic gonadotropin (-hCG) 
urine or serum pregnancy test must be conducted as specified in Section 7.7.  

ECG at screening will be collected in triplicate within 28 days prior to enrollment.  
The results will be read and interpreted at the investigational site for eligibility 
determination; results of QTcF assessment are to be available prior to enrollment.

Patients may be enrolled following successful completion of the pre-study 
assessments, screening procedures, and confirmation of eligibility. 

Evaluations of HIV and hepatitis B serological tests and hepatitis C tests will be 
conducted (see Appendix 2).

Adverse events should be documented and recorded using NCI CTCAE version 4.03 
(see Section 8).  
6.2. Study Period 
The total study period at each cycle is comprised of following periods:

GO Treatment: Starts with the first dose of GO (Day 1) and ends with the last dose of 
GO (usually Day 7). 

Post-GO Period: Starts on the day after the last dose of GO and ends on 36 days after 
the last dose of GO or start of subsequent anticancer therapy, including consolidation 
and/or conditioning regimen.  This period ends with End-of-Treatment (EOT) visit.

If the optional second cycle of GO is administered, the same GO Treatment and Post-
GO Periods are repeated starting once when Cycle 1 remission status is determined.  
The second cycle must be started no later than 42 days after the last dose of GO.  This 
period ends with End-of-Treatment (EOT) visit.

Follow-up Period: Starts on the day after EOT visit and ends when a patient 
completes 12 months on the study or death, whichever occurs first.  This is end of 
study for each patient. 
6.2.1. GO Treatment
Each cycle includes an active GO treatment phase (Days 1, 4, and 7) and a post GO treatment 
phase (Day 10 to 21).
The second cycle is allowed at the investigator’s discretion for patients who meet the 
following dosing criteria after Cycle 1(refer also to Table 3 describing hematologic 
toxicities): Bone marrow with a decrease of blast percentage to at least 25%, or a decrease of 
pretreatment blast percentage by at least 50%; and blood count with neutrophils 1,000/µL 
and platelets 50,000/µL, except in patients with the bone marrow blasts 5%, the decrease 
in neutrophils and platelets thought to be due to the underlying leukemia. 


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Patients who don’t meet these criteria after the first cycle of GO are not allowed to receive 
the 2nd cycle. Cycle 2 Day 1 must be started no later than 42 days after the last dose of GO 
(ie, Cycle 1 Day 7).
6.2.2. Cycle 1
6.2.2.1. Cycle 1 Day 1 (GO Treatment)
•
On Day 1 patients may be admitted at the site for 24 hours for 
pharmacokinetic/pharmacodynamic (PK/PD) sampling at investigator’s discretion.  
Hospitalization beyond Day 1 is per standard of practice and investigator judgment. 
If there is prolongation of hospitalization, consider if SAE criteria are met (see 
Section 8.2.4). 
•
Laboratory specimen will be collected per the Schedule of Activities (and assessed 
per Section 7.  Results of complete blood counts, and serum chemistry tests must be 
checked before dosing.  Patients will have a blood sample collected prior to GO 
administration for the measurement of  immunogenicity (antibodies to GO [ADA] 
and neutralizing antibody [NAb]). 
 
•
Patients will be weighed for body surface area (BSA) calculation. 
•
Physical examination (PE) performed with clinical judgment evaluating potential 
areas of AML relapse and any clinically significant abnormalities which may include 
the following body systems: general appearance, skin, head/eyes/ears/nose/throat, 
heart, lungs, testes, abdomen, extremities, neurological, back/spinal, and lymph 
nodes; including worsening of medical history conditions.
•
Vital signs including blood pressure, pulse, and body temperature will be performed 
prior to GO infusion and 2 hours after the infusion is complete (see Table 1). ECOG 
PS assessment will be conducted if acceptable screening assessment is not done 
within 7 days prior to the start of investigational drug.  
•
Pre-medication should be given before GO infusion.  See Section 5.4.1 and 
Section 5.4.2 for administration of premedication and GO, respectively.
•
Electrocardiograms (ECGs) will be collected in all patients according to Schedule of 
Activities (Table 2) and as described in Section 7.1.  The ECGs will be collected in 
triplicate (3 consecutive ECGs approximately 2 minutes apart).  Predose ECGs will 
be performed prior to GO dosing, after administration of premedications.  Triplicate 
ECGs will also be performed prior to selected serial PK draws, around the time when 
the Cmax is expected and immediately before the end of the infusion, ie, prior to the 
Hour 2 PK sample collection (within 15 minutes).3
C
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•
Pharmacokinetic (all patients)
 
 PK collections will include predose (Hour 0), 
Hour 1, 2, 4, 6, and 24 as described in Schedule of Activities (Table 2).  
 
  Adverse events 
should be documented and recorded using NCI CTCAE version 4.03 (see Section 8).
•
Concomitant medications and treatments will be recorded.  
6.2.2.2. Cycle 1 Day 4 and Day 7 (GO Treatment)
•
Laboratory tests, PE, and vital signs will be conducted as described in Schedule of 
Activities (Table 1). Vital signs will also be performed 2 hours after the infusion is 
complete. 
•
For the dose calculation and adjustment of GO, if the patient experiences a weight 
loss or gain >10% from the prior record of weight, the body surface area (BSA) and 
the amount of GO required for dose preparation must be re-calculated (maximum 
dosage up to one vial). 
•
Full recovery from hematologic toxicities is not a requirement for administration of 
the second or third dose on Days 4 and 7, respectively. 
•
Pre-medication should be given before dosing.  See Section 5.4.1 and Section 5.4.2
for administration of premedication and GO, respectively.  
•
Pharmacokinetic (all patients
 
and triplicate ECGs 
will be collected according to Schedule of Activities (Table 2).  If the dosing day is 
delayed beyond Day 4, these samples are to be collected on the day of dosing.
•
Adverse events should be documented and recorded using NCI CTCAE version 4.03 
(see Section 8).
•
Concomitant medications and treatments will be recorded.  
6.2.2.3. Cycle 1 Day 10 (Post-GO Period)
•
Laboratory tests, PE, body weight, and vital signs will be conducted according to 
Schedule of Activities (Table 1).
C
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•
Pharmacokinetic (all patients), pharmacodynamic (only for patients 18 years or 
older), and metabolic profiling (only for patients 18 years or older) samples will be 
collected according to Schedule of Activities (Table 2).
•
Patients with suspected extramedullary disease will have imaging assessment 
(eg, CAT or MRI) of all known disease sites.
•
Adverse events should be documented and recorded using NCI CTCAE version 4.03 
(see Section 8).
•
Concomitant medications and treatments will be recorded.  
6.2.2.4. Cycle 1 Days 15 and 21 (Post-GO Period)
•
Laboratory tests (except CBC and differential counts) will be conducted according to 
Schedule of Activities (Table 1).
•
Starting with Day 15, CBC and differential counts will be examined 3 times a week 
until having determination of remission status (see Section 7.5); subsequently CBC 
and differential counts will be collected once weekly until EOT visit (ie, 36 days after 
the last dose of GO) or until start of subsequent anticancer therapy, eg, Cycle 2, 
consolidation and/or conditioning regimen (see Schedule of Activities Table 1).
•
Pharmacokinetic (all patients)
 
 according to Schedule of Activities (Table 2). 
•
Blood sample will be collected for the measurement of antibodies to GO (ADA) and 
neutralizing antibody (NAb) on Days 15 and 21.
•
Patients with extramedullary disease during screening or clinically suspicious after 
GO near the scheduled day for bone marrow aspiration (and biopsy if applicable) will 
have imaging assessment (eg, CAT or MRI). (Day 21)
•
Efficacy evaluation and determination of remission status will be assessed by 
peripheral blood andbone marrow aspiration (and biopsy if applicable) after recovery 
of blood counts is observed, typically between Day 21 and Day 28. This evaluation 
should be conducted prior to Cycle 2 (if administered) or EOT (ie, 36 days after last 
the dose of GO).
•
Adverse events should be documented and recorded using NCI CTCAE version 4.03 
(see Section 8).
•
Concomitant medications and treatments will be recorded.  
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6.2.3. Cycle 2
The second cycle will be allowed at the investigator’s discretion for patients who meet 
selected dosing criteria after Cycle 1 (see Section 7.5). Cycle 2 Day 1 must be started no 
later than 42 days after the last dose of GO (ie, Cycle 1 Day 7).
6.2.3.1. Cycle 2 Day 1

On Day 1 patients may be admitted at the site for 24 hours as per investigator’s 
discretion.  Hospitalization beyond Day 1 will be per standard practice and 
investigator judgment. If there is prolongation of hospitalization, consider if SAE 
criteria are met (see Section 8.2.4).

Laboratory specimen will be collected per the Schedule of Activities (Table 1) and 
assessed per Section 7.  Results of complete blood counts, and serum chemistry tests 
must be checked before dosing.  Patients will be weighed for BSA calculation.
Physical examination (PE) performed with clinical judgment evaluating potential 
areas of AML relapse and any clinically significant abnormalities which may include 
the following body systems: general appearance, skin, head/eyes/ears/nose/throat, 
heart, lungs, testes, abdomen, extremities, neurological, back/spinal, and lymph 
nodes; including worsening of medical history conditions.

Vital signs including blood pressure, pulse and temperature will be performed prior to 
GO infusion and 2 hours after the infusion is complete (see Table 1).

Pre-medication should be given before GO infusion.  Section 5.4.1 and Section 5.4.2
for administration of premedication and GO, respectively.

Electrocardiograms (ECGs) will be collected in all patients according to Schedule of 
Activities (Table 2) and as described in Section 7.1.  The ECGs will be collected in 
triplicate (3 consecutive ECGs approximately 2 minutes apart).  Predose ECGs will 
be performed prior to GO dosing, after administration of premedications.  Triplicate 
ECGs will also be performed prior to selected serial PK draws, around the time when 
the Cmax is expected and immediately before the end of the infusion, ie, prior to the 
Hour 2 PK sample collection (within 15 minutes).3

PK collections (all patients) will include predose (Hour 0) and Hour 2 as described in 
Schedule of Activities (Table 2).  

Adverse events should be documented and recorded using NCI CTCAE version 4.03 
(see Section 8).

Concomitant medications and treatments will be recorded.  


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6.2.3.2. Cycle 2 Day 4 and Day 7 (GO Treatment)

Laboratory tests, PE, and vital signs will be conducted as described in Schedule of 
Activities (Table 1).  Vital signs will also be performed 2 hours after the infusion is 
complete. 

For the dose calculation and adjustment of GO, if the patient experiences a weight 
loss or gain >10% from the prior record of weight, the body surface area (BSA) and 
the amount of GO required for dose preparation must be re-calculated (Maximum 
dosage will be up to one vial). 

Full recovery from hematologic toxicities is not a requirement for administration of 
the second or third dose on Day 4 or 7, respectively. 

Pre-medication should be given before dosing.  See Section 5.4.1 and Section 5.4.2
for administration of premedication and GO, respectively.  

Pharmacokinetic (all patients) and triplicate ECGs will be collected on Day 7 
according to Schedule of Activities (Table 2).  If the dosing day is delayed beyond 
Day 4, these samples are to be collected on the day of dosing.

Adverse events should be documented and recorded using NCI CTCAE version 4.03 
(see Section 8).

Concomitant medications and treatments will be recorded.  
6.2.3.3. Cycle 2 Day 10 (Post-GO Period)

Laboratory tests will be conducted according to Schedule of Activities (Table 1).

Patients with suspected extramedullary disease will have imaging assessment 
(eg, CAT or MRI) of all known disease sites. 

Adverse events should be documented and recorded using NCI CTCAE version 4.03 
(see Section 8).

Concomitant medications and treatments will be recorded.  
6.2.3.4. Cycle 2 Days 15 and 21 (Post-GO Period)

Laboratory tests (except CBC and differential counts) will be conducted according to 
Schedule of Activities (Table 1). 

Starting with Day 15, blood cell and differential counts will be examined 3 times a 
week until having determination of remission status (see Section 7.5); subsequently 
CBC and differential counts will be collected once weekly until EOT visit 
(ie, 36 days after the last dose of GO) or until start of subsequent anticancer therapy, 
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
Blood sample will be collected for PK assessment and the measurement of antibodies 
to GO (ADA) and neutralizing antibody (NAb) on Days 15 and 21.

Patients with extramedullary disease during screening or clinically suspicious after 
GO near the scheduled day for bone marrow aspiration (and biopsy if applicable) will 
have imaging assessment (eg, CAT or MRI). 

Determination of remission status will be assessed by peripheral blood and the bone 
marrow aspiration (and biopsy if applicable) after recovery of blood counts is 
observed, , typically between Day 21 and Day 28. This evaluation should be 
conducted prior to EOT (ie, 36 days after the last dose of GO). 

Adverse events should be documented and recorded using NCI CTCAE version 4.03 
(see Section 8).

Concomitant medications and treatments will be recorded.  
6.2.4. The End-of-Treatment (EOT) Visit (36 Days after the Last Dose of GO)

This visit is required for all patients.  It occurs 36 days after the last dose of GO.
However, in the event that a patient requires initiation of a consolidation treatment or 
another anti-cancer therapy, the end-of-treatment visit, including procedures 
(laboratory tests, PE, sampling for PK and ADA/NAb assays), should be performed 
before the initiation of a consolidation treatment or subsequent anti-cancer therapy.  
Adverse events, safety laboratory tests, and associated concomitant medications must 
continue to be collected in the CRF through at least 36 days after the last dose of GO 
or start of subsequent therapy, eg, consolidation and/or conditioning regimen, 
whichever occurs first. 

Adverse Event (AE) Assessments should be documented and recorded at each visit 
using NCI CTCAE version 4.03 up to EOT visit, or start of subsequent anticancer 
therapy, eg, consolidation and/or conditioning regimen, whichever occurs first. 

Concomitant medications and treatments will be recorded up to 36 days after the last 
dose of study treatment or starting subsequent anticancer therapy (eg, consolidation or 
conditioning regimen).

EOT visit procedures and tests include the following:

Blood sample collection for PK assessment and ADA/NAb measurement;

Limited physical examination, with clinical judgment to evaluate potential areas 
of AML relapse and any clinically significant abnormalities which may include 
the following body systems: general appearance, skin, head/eyes/ears/nose/throat, 
heart, lungs, testes, abdomen, extremities, neurological, back/spinal, and lymph 
nodes; including worsening of medical history conditions;


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
Laboratory evaluations, including pregnancy test, according to the Schedule of 
Activities (Table 1).

Disease assessment for final determination of remission status should be 
conducted no later than 36 days after last dose of GO (EOT) or/and prior to the 
start of subsequent anticancer therapy (eg, consolidation and/or conditioning 
regimen).
6.2.5. Follow-up Period
Each patient will visit the study site every 12 weeks during study duration of 12 months after 
enrollment; for procedures to be followed during these visits see Schedule of Activities
(Table 1).  For any patients who may not be able to visit the study site at the protocol 
designated time, telephone contact is acceptable method for survival follow-up for study 
duration of 12 months.  Any occurrences of VOD/SOS will be recorded in the CRF for entire 
study duration of 12 months regardless of causality, subsequent anticancer therapy or HSCT. 
Following information will be collected during the follow-up period:

Blood sample collection for ADA/NAb measurement for patients known to be ADA 
positive at the EOT visit: Samples will be collected every 12 weeks until ADA titers
that are no longer detectable, return to baseline, or stabilize at a level acceptable to 
the investigator and sponsor; or up to 1 year after their enrollment in the study, 
whichever comes first.

Subsequent anticancer therapy information (eg, consolidation and/or conditioning 
regimens, type of HSCT).

Concomitant medication for graft-versus-host disease (GVHD) prophylaxis and 
VOD/SOS prophylaxis.

Survival including causes of death. 
6.3. Patient Withdrawal 
Reasons for discontinuation of study treatment may include:

Withdrawal of consent and/or assent;

Adverse events of unacceptable toxicity as determined by the investigator, or need for 
treatment delay or continuous interruption of the second study dose beyond 2 days 
after the scheduled day of dosing due to study treatment related non-hematologic 
toxicity; 

Global deterioration of health status requiring discontinuation;

Lost to follow-up;


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
Patient refused further treatment;

Study terminated by Sponsor;

Death.
Withdrawal of consent:
Patients who request to discontinue study treatment will remain in the study and must 
continue to be followed for protocol specified follow-up procedures.  The only exception to 
this is when a patient specifically withdraws consent for any further contact with him or her 
or persons previously authorized by the patient to provide this information.  Patients should 
notify the investigator in writing of the decision to withdraw consent from future follow-up, 
whenever possible.  The withdrawal of consent should be explained in detail in the medical 
records by the investigator, as to whether the withdrawal is only from further receipt of 
investigational product or also from study procedures and/or posttreatment study follow-up, 
and entered on the appropriate CRF page.  In the event that vital status (whether the patient is 
alive or dead) is being measured, publicly available information should be used to determine 
vital status only as appropriately directed in accordance with local law.
Lost to follow-up: 
All reasonable efforts must be made to locate patients to determine and report their ongoing 
status.  This includes follow-up with persons authorized by the patient as noted above.  Lost 
to follow-up is defined by the inability to reach the patient after a minimum of 2 documented 
phone calls, faxes, or e-mails as well as lack of response by the patient to 1 registered mail 
letter.  All attempts should be documented in the patient’s medical records.  If it is 
determined that the patient has died, the site will use locally permissible methods to obtain 
the date and cause of death.  If the investigator’s use of a third-party representative to assist 
in the follow-up portion of the study has been included in the patient’s informed consent, 
then the investigator may use a sponsor-retained third-party representative to assist site staff 
with obtaining the patient’s contact information or other public vital status data necessary to 
complete the follow-up portion of the study.  The site staff and representative will consult 
publicly available sources, such as public health registries and databases, in order to obtain 
updated contact information.  If, after all attempts, the patient remains lost to follow-up, then 
the last-known-alive date as determined by the investigator should be reported and 
documented in the patient’s medical records.
Patients may withdraw from the study at any time at their own request, or they may be 
withdrawn at any time at the discretion of the investigator or sponsor for safety (see also the 
Withdrawal From the Study Due to Adverse Events Section 8.1.3) or behavioral reasons, or 
the inability of the patient to comply with the protocol-required schedule of study visits or 
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If a patient does not return for a scheduled visit, every effort should be made to contact the 
patient.  All attempts to contact the subject and information received during contact attempts 
must be documented in the subject’s medical record.  In any circumstance, every effort 
should be made to document patient outcome, if possible.  The investigator should inquire 
about the reason for withdrawal, request that the patient return for a final visit, if applicable, 
and follow up with the patient regarding any unresolved adverse events.
If the patient withdraws from the study, and also withdraws consent for disclosure of future 
information, no further evaluations should be performed, and no additional data should be 
collected.  The sponsor may retain and continue to use any data collected before such 
withdrawal of consent.
Patients who withdraw from the study may be replaced at the discretion of the investigator 
upon consultation with the sponsor.
7. ASSESSMENTS
Every effort should be made to ensure that the protocol-required tests and procedures are 
completed as described.  However, it is anticipated that from time to time there may be 
circumstances outside of the control of the investigator that may make it unfeasible to
perform the test.  In these cases the investigator will take all steps necessary to ensure the 
safety and well-being of the patient.  When a protocol-required test cannot be performed, the 
investigator will document the reason for this and any corrective and preventive actions that 
he or she has taken to ensure that normal processes are adhered to as soon as possible.  The 
study team will be informed of these incidents in a timely manner.
For samples being collected and shipped, detailed collection, processing, storage, and 
shipment instructions and contact information will be provided to the investigator site prior 
to initiation of the study.
7.1. Electrocardiogram Assessment 
7.1.1. QT Interval Prolongation
As indicated in the Schedule of Activities (Table 2), triplicate ECGs will be performed at 
screening, baseline (prior to dose on Day 1) and on each day of dosing (Days 1, 4, and 7 of at
cycle).  ECGs will be paired with PK blood sampling and collected immediately prior to the 
PK blood sample collection, such that the blood sample is collected at the nominal planned 
time.  Ideally, the patient will be supine or reclined in a semi recumbent position for the 
entire infusion and for both pre and post infusion ECGs.  To minimize artifact, the patient 
should not change position between the pre and post infusion ECGs.  If a patient experiences 
a cardiac or neurologic AE (specifically syncope, dizziness, seizures, or stroke) triplicate 
ECGs should be obtained at the time of the event.  Additional ECGs will be performed as 
clinically indicated for patient safety monitoring and documentation stored in the source 
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A 12-lead (with a 10-second rhythm strip) tracing will be used for all ECGs.  ECG 
measurements will include PR interval, QT interval, RR interval, and QRS complex.  For 
triplicate measures, at each time point, three consecutive ECGs will be performed 
approximately 2 minutes apart, but within 15 minutes for all 3 ECGs.  It is preferable that the 
machine used has a capacity to calculate the standard intervals automatically. 
All ECGs will be sent to the ECG core laboratory for independent reading and interpretation. 
7.1.2. Core Laboratory Manual Measurement for ECGs/QTc
Core ECG laboratory, which acts like a central laboratory (vendor) for reading ECGs, 
performing manual interval measurement will carry out independent reading and 
interpretation of QTc interval.3
The ECG core laboratory will follow the below directions for the ECGs assessments:

Blinding of ECG reader to time, and day identifiers.

Review of ECGs from a particular patient should be performed by a single reader.

Pre-specification of the lead for interval measurements.

Baseline and on-treatment ECGs should be based on the same lead.
7.2. Pharmacokinetics Assessment 
7.2.1. Pharmacokinetic Samples 
Blood samples for pharmacokinetic analysis will be collected from all participating patients 
at the times indicated in Schedule of Activities (Table 2), during infusion and from the arm 
opposite to the infusion site, according to the procedures in the lab manual.
Later samples (Days 10 to EOT visit) are collected primarily to assess immunogenicity (with 
a companion PK sample).
All efforts will be made to obtain the pharmacokinetic samples at the exact nominal time 
relative to dosing.  However, some flexibility in sampling times has been provided to allow 
for variation in assessment schedules.  Samples obtained within the specified time windows 
will not be captured as a protocol deviation, as long as the exact time of the sample collection 
is noted on the source document and data collection tool (eg, CRF).  During the trial, actual 
collection times may change but the number of samples will remain the same.18
PK samples will be assayed for total hP67.6 antibody, conjugated calicheamicin, and 
unconjugated calicheamicin, using validated analytical methods in compliance with Pfizer 
standard operating procedures.  Details regarding the storage and shipping of plasma samples 
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7.3. Immunogenicity
Anti-drug antibody (ADA) samples will be collected according to Schedule of Activities
(Table 2). Procedures related to the handling, storage and shipments will be described in the 
laboratory manual.
Samples will be analyzed for anti-drug antibodies using an electrochemiluminescent method, 
with a tiered approach of screening, confirmation, titer determination and additional 
specificity (characterization in the presence of purified hP67.6 (naked antibody) and 
Calicheamicin (Payload). Samples that test positive for ADA may be further characterized 
for specificity to the unconjugated naked antibody and Payload and to determine whether 
neutralizing antibodies (NAb) are present.
Samples collected for detecting ADA and NAb will be retained in accordance with local 
regulations and, if not used in the timeframe, will be destroyed.  Additional exploratory 
testing of samples may be performed to further characterize the ADA response.
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7.4. Safety Assessments 
Safety assessments include adverse events (AEs) graded according to the National Cancer 
Institute Common Terminology Criteria for Adverse Events (NCI CTCAE, version 4.03), 
clinical examination (including blood pressure and pulse), ECGs, and laboratory tests 
(hematology, chemistry, coagulation and urinalysis).
Additional (unscheduled) assessments should be conducted if laboratory values are abnormal 
(or if clinically indicated) and repeated until resolution, until return to baseline, or until NCI 
CTCAE Grade 1.  
Safety assessments will be conducted until patient discontinues from the study or as protocol 
specified for 36 days after the last dose of GO or start of subsequent anticancer therapy such 
as consolidation and/or conditioning regimen (Schedule of Activities Table 1). Survival 
status will be collected for the study duration of 12 months for each patient. 
The laboratory tests specified in Appendix 3 will be conducted.
7.4.1. Veno-occlusive Disease Assessments and Sinusoidal Obstruction Syndrome
Patients with prior history of VOD/SOS will be excluded from enrollment.  Investigators 
must be vigilant when reviewing medical history for any evidence of VOD/SOS that might 
not have been formally evaluated for diagnosis, and must be rigorous in evaluation to rule out 
presence of any potential of VOD/SOS at baseline.  VOD/SOS may present as a constellation 
of signs and symptoms such as weight gain, elevated bilirubin, tender hepatomegaly, and 
ascites.  As it is sometimes a complication of high-dose chemotherapy (conditioning therapy) 
given before HSCT, careful evaluation in the context of previous and subsequent HSCT is 
essential.  Table 4 provides European Group for Blood and Marrow Transplantation (EBMT) 
criteria of VOD/SOS for recommended reference.21,21  In the event of serious or severe 
hepatic adverse events, patients should have a hepatology consultation and work-up 
including (but not limited to) hepatic function test monitoring (eg, AST, ALT, and total 
bilirubin), ultrasound evaluation, weight gain monitoring, and active hepatitis evaluation, eg, 
viral autoimmune, etc.
All cases of VOD/SOS, regardless of causality or severity, must be reported as a SAE within 
the entire study duration of 12 months (see Section 8.1.4). 


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Table 4.
EBMT Criteria for VOD/SOS Diagnosis
EBMT Criteria for VOD/SOS Diagnosis in Adults21
Classical VOD/SOS
In the ﬁrst 21 days after HSCT
(Baltimore Criteria)
Late onset VOD/SOS 
>21 Days after HSCT

Bilirubin 2 mg/dL and two of the following 
criteria must be present:

Hepatomegaly (painful hepatomegaly);

Ascites;

Weight gain >5% from baseline.

Classical VOD/SOS beyond Day 21,
OR

Histologically proven VOD/SOS,
OR

Presence of two or more of the following 
criteria AND hemodynamic or/and ultrasound 
evidence of SOS/VOD:

Bilirubin 2 mg/dL (or 34 mol/L) Painful 
hepatomegaly;

Weight gain >5%;

Ascites.
EBMT Criteria for VOD/SOS Diagnosis in Pediatrics21

No limitation for time of onset of SOS/VOD.

The presence of two or more of the following:a

Unexplained consumptive and transfusion-refractory thrombocytopenia;b

Otherwise unexplained weight gain on three consecutive days despite the use of diuretics or a 
weight gain >5% above baseline value;

Hepatomegaly (best if conﬁrmed by imaging) above baseline value;c

Ascites (best if conﬁrmed by imaging) above baseline value;c

Rising bilirubin from a baseline value on 3 consecutive days or bilirubin 2 mg/dL within 72 hours.
a.
With the exclusion of other potential differential diagnoses. 
b.
1 weight-adjusted platelet substitution/day to maintain institutional transfusion guidelines. 
c.
Suggested: imaging (ultrasonography, CAT, or MRI) immediately before HSCT to determine baseline 
value for both hepatomegaly and ascites.
Doppler Ultrasonography for Clinical Suspicion for VOD/SOS
When VOD/SOS is in the differential diagnosis, a right upper quadrant ultrasound with color 
flow Doppler (including resistive indices to hepatic artery flow and evaluation of hepatic 
venous outflow) should be performed.  In addition, the radiology report should describe 
common bile duct, the degree of gall bladder wall thickening in millimeters, and the volume 
of ascites should be estimated as closely as possible (ie, small and localized, moderate and 
generalized, or large and generalized). 
Assessments and Laboratory Tests
Any of the following assessments, used to diagnose VOD/SOS, should be reported.

Biopsy; 


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
Doppler ultrasonography; 

Measurement of venous pressures;

Laboratory tests must include liver function tests (LFTs), eg, total bilirubin, 
AST/ALT, ALK-P (alkaline phosphatase), PT/INR (prothrombin ratio/international 
normalized ratio), aPTT, fibrinogen, and creatinine level.
Risk factors for VOD/SOS or other factors affecting liver function such as GVHD 
prophylaxis and/or treatment, and anti-infectives used as treatment or prophylaxis should be 
reported.  The information on HSCT (eg, allogeneic, matched, or related/unrelated) with 
conditioning regimens will be collected. 
Management of VOD/SOS
The diagnosis of VOD/SOS, interpretation of severity, and appropriate management of the 
event will be medically determined by investigator per institutional standard(s). 
Treatment of VOD/SOS must be described and entered into the CRF (eg, defibrotide). 
7.5. Response Assessments
Response assessment will be determined as follows: 

Starting with Day 15, blood cell and differential counts will be examined 3 times a 
week after GO dosing until determination of remission status; subsequently CBC and 
differential counts will be collected once weekly until EOT visit (ie, 36 days after the 
last dose of GO), or until start of Cycle 2 (if administered), or until start of subsequent 
therapy (eg, consolidation and/or conditioning regimen).  

Efficacy evaluation and determination of remission status by blood and bone marrow 
aspiration (and biopsy if applicable) will be conducted at the end of each cycle after 
blood count recovery (neutrophils 500/L and platelet 50,000/L) is observed or at 
a maximum of 36 days after the last dose of GO regimen.  

A bone marrow aspirate is required to assess response to treatment, and a bone 
marrow biopsy is also recommended to confirm response and to assess cellularity and 
is required in case of a dry tap.
The second cycle will be allowed at the investigator’s discretion for patients who meet the 
following dosing criteria after Cycle 1(refer also to Table 3 describing hematologic 
toxicities):

Bone marrow with a decrease of blast percentage to at least 25% or a decrease of 
pretreatment blast percentage by at least 50%; and


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•
Blood count with neutrophils ≥1,000/μL and platelets ≥50,000/μL, except in patients 
with the bone marrow blasts ≥5%, the decrease in neutrophils and platelets thought to 
be due to the underlying leukemia.
Patients who don’t meet these criteria after the first cycle of GO will not be allowed to 
receive the 2nd cycle.
Response will be assessed using European Leukemia Net (ELN 2017) recommendations 
(Table 5).5
Table 5.
European Leukemia Net (ELN 2017) Recommendations5
Complete Remission 
(CR)
•
Bone marrow blasts <5%; absence of circulating blasts and blasts with 
Auer rods; absence of extramedullary disease;
•
ANC ≥1x109/L (1000/μL); platelet count ≥1x109/L (100,000/mL).
CR with incomplete 
hematologic recovery
(CRi)
•
All CR criteria except for residual neutropenia; ANC <1x109/L 
(1000/μL); or thrombocytopenia; platelet count <1x109/L 
(100,000/mL).
7.6. Survival
Survival status will be followed for all patients for the study duration.  For any enrolled 
patient who may not be able to visit the study site at the protocol designated time, telephone 
contact is acceptable method for survival follow-up, plus collecting cause(s) of death. 
7.7. Pregnancy Testing
For female patients of childbearing potential, a serum or urine pregnancy test, with 
sensitivity of at least 25 mIU/mL and assayed in a certified laboratory, will be performed on 
2 occasions prior to starting administration of study medication —once at the start of 
screening and once at the baseline visit, immediately before starting the study treatment.  
Following a negative pregnancy test result at screening, appropriate contraception must be 
commenced and a second negative pregnancy test result will be required at the baseline visit 
before the patient may receive the study medication.  Pregnancy tests will be repeated at at 
the end of study treatment, and additionally whenever 1 menstrual cycle is missed or when 
potential pregnancy is otherwise suspected.  Additional pregnancy tests may also be 
undertaken if requested by institutional review boards (IRBs)/ethics committees (ECs) or if 
required by local regulations.  In the case of a positive confirmed pregnancy, the patient will 
be withdrawn from administration of investigational product but may remain in the study. 
 
 
 
 
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7.9. Imaging Assessments 
•
Patients with suspected extramedullary disease will have imaging assessment 
(eg, CAT or MRI) of relevant disease sites during screening.  Imaging assessment 
will be repeated during the post-GO period (Schedule of Activities Table 1).
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
For imaging assessment using Doppler sonography in patients with suspected 
VOD/SOS, please see Section 7.4.1.
8. ADVERSE EVENT REPORTING
8.1. Requirements
The table below summarizes the requirements for recording safety events on the CRF and for 
reporting safety events on the Clinical Trial (CT) Serious Adverse Event (SAE) Report Form 
to Pfizer Safety.  These requirements are delineated for 3 types of events: (1) SAEs; 
(2) non-serious adverse events (AEs); and (3) exposure to the investigational product under 
study during pregnancy or breastfeeding, and occupational exposure. 
Safety Event
Recorded on the CRF
Reported on the CT SAE 
Report Form to Pfizer 
Safety Within 24 Hours of 
Awareness
SAE
All
All
Non-serious AE
All
None
Exposure to the 
investigational product 
under study during 
pregnancy or 
breastfeeding, and 
occupational exposure
All (regardless of whether 
associated with an AE), 
except occupational 
exposure
Exposure during pregnancy, 
exposure via breastfeeding, 
occupational exposure 
(regardless of whether 
associated with an AE)
All observed or volunteered events regardless of treatment group or suspected causal 
relationship to the investigational product will be reported as described in the following 
paragraphs.
Events listed in the table above that require reporting to Pfizer Safety on the CT SAE Report 
Form within 24 hours of awareness of the event by the investigator are to be reported 
regardless of whether the event is determined by the investigator to be related to an 
investigational product under study.  In particular, if the SAE is fatal or life-threatening, 
notification to Pfizer Safety must be made immediately, irrespective of the extent of available 
event information.  This time frame also applies to additional new (follow-up) information on 
previously forwarded reports.  In the rare situation that the investigator does not become 
immediately aware of the occurrence of an event, the investigator must report the event 
within 24 hours after learning of it and document the time of his/her first awareness of the 
event.
For each event, the investigator must pursue and obtain adequate information both to 
determine the outcome and to assess whether it meets the criteria for classification as an SAE 
(see the Serious Adverse Events section below).  In addition, the investigator may be 
requested by Pfizer Safety to obtain specific follow-up information in an expedited fashion.  
This information is more detailed than that recorded on the CRF.  In general, this will include 
a description of the event in sufficient detail to allow for a complete medical assessment of 


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the case and independent determination of possible causality.  Any information relevant to 
the event, such as concomitant medications and illnesses, must be provided.  In the case of a 
patient death, a summary of available autopsy findings must be submitted as soon as possible 
to Pfizer Safety.  Any pertinent additional information must be reported on the CT SAE 
Report Form; additional source documents (eg, medical records, CRF, laboratory data) are to 
be sent to Pfizer Safety ONLY upon request.
As part of ongoing safety reviews conducted by the sponsor, any non-serious AE that is 
determined by the sponsor to be serious will be reported by the sponsor as an SAE.  To assist 
in the determination of case seriousness, further information may be requested from the 
investigator to provide clarity and understanding of the event in the context of the clinical 
study.
As noted in the Protocol-Specified Serious Adverse Events section (Section 8.4.1), should an 
investigator judge one of the identified protocol-specified SAEs to have a causal relationship 
with the investigational product, the investigator must report the SAE to Pfizer Safety within 
24 hours of investigator awareness.
8.1.1. Additional Details on Recording Adverse Events on the CRF
All events detailed in the table above will be recorded on the AE page(s) of the CRF.  It 
should be noted that the CT SAE Report Form for reporting of SAE information is not the 
same as the AE page of the CRF.  When the same data are collected, the forms must be 
completed in a consistent manner.  AEs should be recorded using concise medical 
terminology and the same AE term should be used on both the CRF and the CT SAE Report 
Form for reporting of SAE information.
8.1.2. Eliciting Adverse Event Information
The investigator is to record on the CRF all directly observed AEs and all AEs spontaneously 
reported by the study patient/legally acceptable representative.  In addition, each study 
patient/legally acceptable representative will be questioned about the occurrence of AEs in a 
non-leading manner.
8.1.3. Withdrawal from the Study Due to Adverse Events (see also the Patient 
Withdrawal Section 6.3)
Withdrawal due to AEs should be distinguished from withdrawal due to other causes, 
according to the definition of AE noted below, and recorded on the CRF. 
When a patient withdraws from the study because of an SAE, the SAE must be recorded on 
the CRF and reported, as appropriate, on the CT SAE Report Form, in accordance with the 
Requirements section above.


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8.1.4. Time Period for Collecting AE/SAE Information
The time period for actively eliciting and collecting AEs and SAEs (“active collection 
period”) for each patient begins from the time the patient provides informed consent, which 
is obtained before the patient’s participation in the study (ie, before undergoing any 
study-related procedure and/or receiving investigational product)  through and including a 
minimum of 36 calendar days after the last administration of the investigational product. 
For patients who are screen failures, the active collection period ends when screen failure 
status is determined. 
Any patient with VOD/SOS will be monitored for the study duration of 12 months from 
enrollment as described in Section 7.4.1. 
8.1.4.1. Reporting SAEs to Pfizer Safety
All SAEs occurring in a patient during the active collection period are reported to Pfizer 
Safety on the CT SAE Report Form.
SAEs occurring in a patient after the active collection period has ended are reported to Pfizer 
Safety if the investigator becomes aware of them; at a minimum, all SAEs that the 
investigator believes have at least a reasonable possibility of being related to investigational 
product must be reported to Pfizer Safety.  Follow up by the investigator continues 
throughout and after the active collection period and until the event or its sequelae resolve or 
stabilize at a level acceptable to the investigator, and Pfizer concurs with that assessment.
If a patient starts a subsequent anticancer therapy (eg, consolidation, and/or conditioning 
regimen, or HSCT), SAEs occurring during the above-indicated active collection period 
(ie, within 36 days of last dose of GO) must still be reported to Pfizer Safety irrespective of 
any intervening treatment and causality.
Incidence of VOD/SOS will be reported for the entire study duration of 12 months, 
regardless of causality, or start of subsequent anticancer therapy (eg, consolidation and/or 
conditioning regimen, or HSCT).  All cases of VOD/SOS must be reported as SAEs 
(recorded on the CRF and CT SAE Report Form).
8.1.4.2. Recording Non-serious AEs and SAEs on the CRF 
During the active collection period, both non-serious AEs and SAEs are recorded on the 
CRF.
Follow-up by the investigator may be required until the event or its sequelae resolve or 
stabilize at a level acceptable to the investigator, and Pfizer concurs with that assessment.
If a patient begins a new anticancer therapy, the recording period for non-serious AEs ends at 
the time the new treatment is started; however, SAEs must continue to be recorded on the 
CRF during the above-indicated active collection period.


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8.1.5. Causality Assessment
The investigator’s assessment of causality must be provided for all AEs (serious and 
non-serious); the investigator must record the causal relationship on the CRF, and report such 
an assessment in accordance with the SAE reporting requirements, if applicable.  An 
investigator’s causality assessment is the determination of whether there exists a reasonable 
possibility that the investigational product caused or contributed to an AE; generally the facts 
(evidence) or arguments to suggest a causal relationship should be provided.  If the 
investigator does not know whether or not the investigational product caused the event, then 
the event will be handled as “related to investigational product” for reporting purposes, as 
defined by the sponsor.  If the investigator's causality assessment is “unknown but not 
related” to investigational product, this should be clearly documented on study records. 
In addition, if the investigator determines that an SAE is associated with study procedures, 
the investigator must record this causal relationship in the source documents and CRF, and 
report such an assessment in the dedicated section of the CT SAE Report Form and in 
accordance with the SAE reporting requirements.
8.1.6. Sponsor’s Reporting Requirements to Regulatory Authorities
AE reporting, including suspected unexpected serious adverse reactions, will be carried out 
in accordance with applicable local regulations.
8.2. Definitions
8.2.1. Adverse Events
An AE is any untoward medical occurrence in a study patient administered a product or 
medical device; the event need not necessarily have a causal relationship with the treatment 
or usage.  Examples of AEs include, but are not limited to: 

Abnormal test findings;

Clinically significant signs and symptoms;

Changes in physical examination findings;

Hypersensitivity;

Drug abuse;

Drug dependency.
Additionally, AEs may include signs and symptoms resulting from:

Drug overdose;

Drug withdrawal;


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
Drug misuse; 

Drug interactions;

Extravasation;

Exposure during pregnancy (EDP);

Exposure via breastfeeding;

Medication error;

Occupational exposure.
Worsening of signs and symptoms of the malignancy under study should be recorded as AEs 
in the appropriate section of the CRF.  Disease progression assessed by measurement of 
malignant lesions on radiographs or other methods should not be reported as AEs.
8.2.2. Abnormal Test Findings
Abnormal objective test findings should be recorded as AEs when any of the following 
conditions are met: 

Test result is associated with accompanying symptoms; and/or

Test result requires additional diagnostic testing or medical/surgical intervention; 
and/or

Test result leads to a change in study dosing (outside of any protocol-specified dose 
adjustments) or discontinuation from the study, significant additional concomitant 
drug treatment, or other therapy; and/or

Test result is considered to be an AE by the investigator or sponsor.
Merely repeating an abnormal test, in the absence of any of the above conditions, does not 
constitute an AE.  Any abnormal test result that is determined to be an error does not require 
recording as an AE.
8.2.3. Serious Adverse Events
A serious adverse event is any untoward medical occurrence at any dose that:

Results in death;

Is life-threatening (immediate risk of death);

Requires inpatient hospitalization or prolongation of existing hospitalization;


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
Results in persistent or significant disability/incapacity (substantial disruption of the 
ability to conduct normal life functions);

Results in congenital anomaly/birth defect.
Or that is considered to be:

An important medical event.
Medical and scientific judgment is exercised in determining whether an event is an important 
medical event.  An important medical event may not be immediately life-threatening and/or 
result in death or hospitalization.  However, if it is determined that the event may jeopardize 
the patient or may require intervention to prevent one of the other AE outcomes, the 
important medical event should be reported as serious.  Examples of such events are 
intensive treatment in an emergency room or at home for allergic bronchospasm; blood 
dyscrasias or convulsions that do not result in hospitalization; or development of drug 
dependency or drug abuse.
Progression of the malignancy under study (including signs and symptoms of progression) 
should not be reported as an SAE unless the outcome is fatal within the active collection 
period.  Hospitalization due to signs and symptoms of disease progression should not be 
reported as an SAE.  If the malignancy has a fatal outcome during the study or within the 
active collection period, then the event leading to death must be recorded as an AE on the 
CRF, and as an SAE with Common Terminology Criteria for Adverse Events (CTCAE) 
Grade 5 (see the Severity Assessment section).
8.2.4. Hospitalization
Hospitalization is defined as any initial admission (even less than 24 hours) in a hospital or 
equivalent healthcare facility, or any prolongation of an existing admission.  Admission also 
includes transfer within the hospital to an acute/intensive care unit (eg, from the psychiatric 
wing to a medical floor, medical floor to a coronary care unit, or neurological floor to a 
tuberculosis unit).  An emergency room visit does not necessarily constitute a hospitalization; 
however, the event leading to the emergency room visit is assessed for medical importance.
Hospitalization does not include the following:

Rehabilitation facilities;

Hospice facilities;

Respite care (eg, caregiver relief);

Skilled nursing facilities;

Nursing homes;

Same-day surgeries (as outpatient/same-day/ambulatory procedures).


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Hospitalization or prolongation of hospitalization in the absence of a precipitating clinical 
AE is not in itself an SAE.  Examples include:

Admission for treatment of a preexisting condition not associated with the 
development of a new AE or with a worsening of the preexisting condition (eg, for 
workup of a persistent pretreatment laboratory abnormality);

Social admission (eg, patient has no place to sleep);

Administrative admission (eg, for yearly physical examination);

Protocol-specified admission during a study (eg, for a procedure required by the study 
protocol);

Optional admission not associated with a precipitating clinical AE (eg, for elective 
cosmetic surgery);

Hospitalization for observation without a medical AE;

Preplanned treatments or surgical procedures.  These should be noted in the baseline 
documentation for the entire protocol and/or for the individual patient;

Admission exclusively for the administration of blood products.
Diagnostic and therapeutic noninvasive and invasive procedures, such as surgery, should not 
be reported as SAEs.  However, the medical condition for which the procedure was 
performed should be reported if it meets the definition of an SAE. For example, an acute 
appendicitis that begins during the reporting period should be reported if the SAE 
requirements are met, and the resulting appendectomy should be recorded as treatment of the 
AE.
8.3. Severity Assessment
If required on the AE page of the CRF, the investigator will use the adjectives MILD, 
MODERATE, or SEVERE to describe the maximum intensity of the AE.  For purposes of 
consistency, these intensity grades are defined as follows:
MILD
Does not interfere with subject's usual function.
MODERATE
Interferes to some extent with subject's usual function.
SEVERE
Interferes significantly with subject's usual function.
Note the distinction between the severity and the seriousness of an AE.  A severe event is not 
necessarily an SAE.  For example, a headache may be severe (interferes significantly with 
the subject's usual function) but would not be classified as serious unless it met one of the 
criteria for SAEs, listed above.


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Investigators should report AEs using concise medical terminology (verbatim) as well as 
collect on the CRF the appropriate Common Terminology Criteria for Adverse Events 
(CTCAE) (Version 4.03, Publish Date: 14 June 2010, NCI CTCAE) listed in the Cancer 
Therapy Evaluation Program.  New protocols of projects that have been utilizing a previous 
version may continue to use that version.
If required on the AE page of the CRF, the investigator will use the following definitions of 
severity in accordance with the current CTCAE version to describe the maximum intensity of 
the adverse event.  
Grade
Clinical Description of Severity
0
No change from normal or reference range (This grade is not included in the 
Version 4.03 CTCAE document but may be used in certain circumstances.)
1
MILD adverse event
2
MODERATE adverse event
3
SEVERE adverse event
4
LIFE-THREATENING consequences; urgent intervention indicated
5
DEATH RELATED TO adverse event
8.4. Special Situations
8.4.1. Protocol-Specified Serious Adverse Events
Unless the investigator believes that there is a causal relationship between investigational 
product and an event specified below, these events should not be reported to Pfizer Safety by 
the investigator as SAEs.  These events are anticipated to occur commonly in a population 
with AML.  However, these events should still be recorded as adverse events on the case 
report Form (CRF).
Protocol-specified SAEs that will not normally be reported to Pfizer Safety in an expedited 
manner: 

Febrile neutropenia (unless Grade 5).

Neutropenic sepsis (unless Grade 5).
Should an aggregate analysis indicate that these prespecified events occur more frequently 
than expected, eg, based on epidemiological data, literature, or other data, then this will be 
submitted and reported in accordance with Pfizer’s safety reporting requirements.  Aggregate 
analyses of safety data will be performed on a regular basis per internal standard operating 
procedures.  


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8.4.2. Potential Cases of Drug-Induced Liver Injury
Humans exposed to a drug who show no sign of liver injury (as determined by elevations in 
transaminases) are termed “tolerators,” while those who show transient liver injury, but adapt 
are termed “adaptors.”  In some patients, transaminase elevations are a harbinger of a more 
serious potential outcome.  These patients fail to adapt and therefore are “susceptible” to 
progressive and serious liver injury, commonly referred to as drug induced liver injury 
(DILI).  Patients who experience a transaminase elevation above 3 times the upper limit of 
normal (× ULN) should be monitored more frequently to determine if they are an “adaptor” 
or are “susceptible.”
In the majority of DILI cases, elevations in aspartate aminotransferase (AST) and/or alanine 
aminotransferase (ALT) precede total bilirubin (TBili) elevations (>2 × ULN) by several 
days or weeks.  The increase in TBili typically occurs while AST/ALT is/are still elevated 
above 3 × ULN (ie, AST/ALT and TBili values will be elevated within the same lab sample).  
In rare instances, by the time TBili elevations are detected, AST/ALT values might have 
decreased.  This occurrence is still regarded as a potential DILI.  Therefore, abnormal 
elevations in either AST OR ALT in addition to TBili that meet the criteria outlined below 
are considered potential DILI (assessed per Hy’s law criteria) cases and should always be 
considered important medical events, even before all other possible causes of liver injury 
have been excluded.
The threshold of laboratory abnormalities for a potential DILI case depends on the patient’s 
individual baseline values and underlying conditions.  Patients who present with the 
following laboratory abnormalities should be evaluated further as potential DILI (Hy’s law) 
cases to definitively determine the etiology of the abnormal laboratory values:

Patients with AST/ALT and TBili baseline values within the normal range who 
subsequently present with AST OR ALT values >3 × ULN AND a TBili value 
>2 × ULN with no evidence of hemolysis and an alkaline phosphatase value 
<2 × ULN or not available;

For patients with baseline AST OR ALT OR TBili values above the ULN, the 
following threshold values are used in the definition mentioned above, as needed, 
depending on which values are above the ULN at baseline:

Preexisting AST or ALT baseline values above the normal range: AST or ALT 
values >2 times the baseline values AND >3 × ULN; or >8 × ULN (whichever is 
smaller);

Preexisting values of TBili above the normal range: TBili level increased from 
baseline value by an amount of at least 1 × ULN or if the value reaches >3 × ULN 
(whichever is smaller).
Rises in AST/ALT and TBili separated by more than a few weeks should be assessed 
individually based on clinical judgment; any case where uncertainty remains as to whether it 
represents a potential Hy’s law case should be reviewed with the sponsor. 


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The patient should return to the investigator site and be evaluated as soon as possible, 
preferably within 48 hours from awareness of the abnormal results.  This evaluation should 
include laboratory tests, detailed history, and physical assessment. 
In addition to repeating measurements of AST and ALT and TBili, laboratory tests should 
include albumin, creatine kinase (CK), direct and indirect bilirubin, gamma glutamyl 
transferase (GGT), prothrombin time (PT)/international normalized ratio (INR), total bile 
acids, alkaline phosphatase and acetaminophen drug and/or protein adduct levels.  
Consideration should also be given to drawing a separate tube of clotted blood and an 
anticoagulated tube of blood for further testing, as needed, for further contemporaneous 
analyses at the time of the recognized initial abnormalities to determine etiology.  A detailed 
history, including relevant information, such as review of ethanol, acetaminophen (either by 
itself or as a coformulated product in prescription or over the counter medications), 
recreational drug, supplement (herbal) use and consumption, family history, sexual history, 
travel history, history of contact with a jaundiced person, surgery, blood transfusion, history 
of liver or allergic disease, and potential occupational exposure to chemicals, should be
collected.  Further testing for acute hepatitis A, B, C, D, and E infection and liver imaging 
(eg, biliary tract) may be warranted. 
All cases demonstrated on repeat testing as meeting the laboratory criteria of AST/ALT and 
TBili elevation defined above should be considered potential DILI (Hy’s law) cases if no 
other reason for the LFT abnormalities has yet been found.  Such potential DILI (Hy’s law) 
cases are to be reported as SAEs, irrespective of availability of all the results of the 
investigations performed to determine etiology of the LFT abnormalities. 
A potential DILI (Hy’s law) case becomes a confirmed case only after all results of 
reasonable investigations have been received and have excluded an alternative etiology.
8.4.3. Potential VOD/SOS Cases
All cases of VOD/SOS with or without previous HSCT, regardless of causality and severity 
must be reported as an SAE for entire study duration of 12 months from enrollment, 
regardless of subsequent anticancer therapy (eg, consolidation and/or conditioning regimen, 
or HSCT). 
The assessment and management of VOD/SOS will be up to physician’s discretion and per 
institutional standards of practice.  All the assessments and management (eg, prophylaxis 
and/or treatment) should be recorded in the CRF.  In this study, the diagnosis of VOD/SOS is 
as described in Section 7.4.1.
8.4.4. Exposure to the Investigational Product During Pregnancy or Breastfeeding, and 
Occupational Exposure
Exposure to the investigational product under study during pregnancy or breastfeeding and 
occupational exposure are reportable to Pfizer Safety within 24 hours of investigator 
awareness.


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8.4.4.1. Exposure During Pregnancy
For both unapproved/unlicensed products and for marketed products, an exposure during 
pregnancy (EDP) occurs if:

A female becomes, or is found to be, pregnant either while receiving or having been 
exposed (eg, because of treatment or environmental exposure) to the investigational 
product; or the female becomes or is found to be pregnant after discontinuing and/or 
being exposed to the investigational product.

An example of environmental exposure would be a case involving direct contact with 
a Pfizer product in a pregnant woman (eg, a nurse reports that she is pregnant and has 
been exposed to chemotherapeutic products).

A male has been exposed (eg, because of treatment or environmental exposure) to the 
investigational product prior to or around the time of conception and/or is exposed 
during his partner’s pregnancy. 

If a patient or patient’s partner becomes or is found to be pregnant during the 
patient’s treatment with the investigational product, the investigator must report this 
information to Pfizer Safety on the CT SAE Report Form and an EDP supplemental 
form, regardless of whether an SAE has occurred.  In addition, the investigator must 
submit information regarding environmental exposure to a Pfizer product in a 
pregnant woman (eg, a patient reports that she is pregnant and has been exposed to a 
cytotoxic product by inhalation or spillage) to Pfizer Safety using the EDP 
supplemental form.  This must be done irrespective of whether an AE has occurred 
and within 24 hours of awareness of the exposure.  The information submitted should 
include the anticipated date of delivery (see below for information related to 
termination of pregnancy).
Follow-up is conducted to obtain general information on the pregnancy and its outcome for 
all EDP reports with an unknown outcome.  The investigator will follow the pregnancy until 
completion (or until pregnancy termination) and notify Pfizer Safety of the outcome as a 
follow-up to the initial EDP supplemental form.  In the case of a live birth, the structural 
integrity of the neonate can be assessed at the time of birth.  In the event of a termination, the 
reason(s) for termination should be specified and, if clinically possible, the structural 
integrity of the terminated fetus should be assessed by gross visual inspection (unless 
pre-procedure test findings are conclusive for a congenital anomaly and the findings are 
reported).
If the outcome of the pregnancy meets the criteria for an SAE (ie, ectopic pregnancy, 
spontaneous abortion, intrauterine fetal demise, neonatal death, or congenital anomaly [in a 
live-born baby, a terminated fetus, an intrauterine fetal demise, or a neonatal death]), then the 
investigator should follow the procedures for reporting SAEs.
Additional information about pregnancy outcomes that are reported to Pfizer Safety as SAEs 
follows: 

Spontaneous abortion includes miscarriage and missed abortion.


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
Neonatal deaths that occur within 1 month of birth should be reported, without regard 
to causality, as SAEs.  In addition, infant deaths after 1 month should be reported as 
SAEs when the investigator assesses the infant death as related or possibly related to 
exposure to the investigational product.

Additional information regarding the EDP may be requested by the sponsor.  Further 
follow-up of birth outcomes will be handled on a case-by-case basis (eg, follow-up on 
preterm infants to identify developmental delays).  In the case of paternal exposure, 
the investigator will provide the patient with the Pregnant Partner Release of 
Information Form to deliver to his partner.  The investigator must document in the 
source documents that the patient was given the Pregnant Partner Release of 
Information Form to provide to his partner.
8.4.4.2. Exposure During Breastfeeding
Scenarios of exposure during breastfeeding must be reported, irrespective of the presence of 
an associated SAE, to Pfizer Safety within 24 hours of the investigator’s awareness, using the 
CT SAE Report Form.  An exposure during breastfeeding report is not created when a Pfizer 
drug specifically approved for use in breastfeeding women (eg, vitamins) is administered in 
accord with authorized use.  However, if the infant experiences an SAE associated with such 
a drug’s administration, the SAE is reported together with the exposure during breastfeeding.
8.4.4.3. Occupational Exposure
An occupational exposure occurs when, during the performance of job duties, a person 
(whether a healthcare professional or otherwise) gets in unplanned direct contact with the 
product, which may or may not lead to the occurrence of an AE.
An occupational exposure is reported to Pfizer Safety within 24 hours of the investigator’s 
awareness, using the CT SAE Report Form, regardless of whether there is an associated 
SAE.  Since the information does not pertain to a patient enrolled in the study, the 
information is not recorded on a CRF; however, a copy of the completed CT SAE Report 
Form is maintained in the investigator site file.
8.4.5. Medication Errors
Other exposures to the investigational product under study may occur in clinical trial settings, 
such as medication errors. 
Safety Event
Recorded on the CRF
Reported on the CT SAE 
Report Form to Pfizer Safety 
Within 24 Hours of Awareness
Medication errors 
All (regardless of whether 
associated with an AE)
Only if associated with an SAE


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8.4.5.1. Medication Errors
Medication errors may result from the administration or consumption of the investigational 
product by the wrong patient, or at the wrong time, or at the wrong dosage strength. 
•
Medication errors include:
•
Medication errors involving patient exposure to the investigational product;
•
Potential medication errors or uses outside of what is foreseen in the protocol that 
do or do not involve the participating patient.
Such medication errors occurring to a study participant are to be captured on the medication 
error page of the CRF, which is a specific version of the AE page.
In the event of a medication dosing error, the sponsor should be notified immediately.
Whether or not the medication error is accompanied by an AE, as determined by the 
investigator, the medication error is recorded on the medication error page of the CRF and, if 
applicable, any associated AE(s), serious and non-serious, are recorded on an AE page of the 
CRF.
Medication errors should be reported to Pfizer Safety within 24 hours on a CT SAE Report 
Form only when associated with an SAE.
9. DATA ANALYSIS/STATISTICAL METHODS
Detailed methodology for summary and statistical analyses of the data collected in this study 
is outlined here and further detailed in a statistical analysis plan (SAP), which will be 
maintained by the sponsor.  The SAP may modify what is outlined in the protocol where 
appropriate; however, any major modifications of the primary endpoint definitions or their 
analyses will also be reflected in a protocol amendment.
9.1. Sample Size Determination
The QTc analysis will be based on a non-inferiority hypothesis testing framework. 
If the upper bounds of one-sided 95% confidence intervals of change from baseline in QT 
measurements using Fridericia’s heart rate correction for each of the QTc sampling time 
points (Day 4, 0 hours, and Day 7, at 0, 2, 4 and 6 hours) are below 20 msec, the post-
baseline dose QTc interval will be considered to be “non-inferior” to the baseline; the QTc 
effect of GO will be concluded to be not unacceptable.
Thus with an overall 1-sided significance level of 0.05 and a non-inferiority margin of 
20 msec, assuming a standard deviation of 18.8 msec and a mean change from baseline for 
QTcF up to 10 msec, 50 patients will provide 90 % power for assessing the 5 QTc sampling 
timepoints using paired difference in means with the t distribution.
 
 
 
CCI


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If the upper bounds of one-sided 95% confidence intervals of change from baseline in QT 
measurements using Fridericia’s heart rate correction for each of the QTc sampling time 
points (on Day 4, at 0 hours, and Day 7, at 0, 2, 4, and 6 hours) are below 20 msec, the post-
baseline dose QTc interval will be considered to be “non-inferior” to the baseline.
The inclusion of 6 pediatric patients was determined based on agreement with CHMP.
9.2. Analysis Sets
9.2.1. Full Analysis Set
The full analysis set will include all enrolled patients, and will be the primary analysis set for 
evaluating all efficacy endpoints and patient characteristics.
9.2.2. Safety Analysis Set
The safety analysis set will include all enrolled patients who receive at least 1 dose of study 
medication.  The safety analysis set will be the primary analysis set for evaluating treatment 
administration/compliance and safety.
9.2.3. QTc Analysis Set
The QTc analysis set will include all patients in the safety analysis set who have a baseline 
ECG and at least one post-dose ECG. 
9.2.4. PK Analysis Set
All patients who are treated with GO and contribute at least one PK sample will be included 
in the PK analysis set. 
9.2.5. PK/PD Analysis Set
QTc PKPD analysis set: All patients who are treated with GO and contribute at least one PK 
sample who have a baseline ECG and at least one post-dose ECG.
Safety and Efficacy PKPD analysis set: All patients who are treated with GO and contribute 
at least one PK sample.
9.3. Planned Analyses
Separate summaries for adult and pediatric patients will be presented. Combined summaries 
of adult and pediatric patients will also be presented.
9.3.1. Analysis of Primary Endpoint 
ECG measurements from the ECG core laboratory (an average of the triplicate 
measurements) will be used for the statistical analysis and all data presentations.  Only the 
scheduled ECGs will be used in the primary analysis.  The last available planned triplicate 
measurements prior to first dose will be used as baseline.


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QT measurements will be corrected by heart rate (QTc) including Bazzett’s (QTcB) and 
Fridericia’s (QTcF) methods, and a study-specific correction method (QTcS) will be 
evaluated according to the observed data.  QTcF will be used for the primary analysis. 
The absolute corrected QT interval and changes in QTc (QTcB, QTcF, and/or QTcS) from 
baseline will be summarized using descriptive statistics by nominal time point. 
A random effect model with the nominal timepoints as a fixed effect and patients as a 
random effect will be used for the primary analysis to estimate the mean change in QTcF 
(primary endpoint) at the post baseline nominal timepoints (Day 4, 0 hours, and Day 7, at 0, 
2, 4 and 6 hours) along with 2-sided 90% confidence interval for the mean.  The maximum 
increase in QTc from baseline will be computed over all time points.  The maximum increase 
from baseline will be summarized with descriptive statistics. 
Categorical analysis of changes in QTc (QTcB, QTcF, and/or QTcS) from baseline including 
absolute QTc interval prolongation and maximum increase will be provided.  Interval 
measurements from unscheduled ECGs will be included in the categorical analyses.
Baseline versus worst on treatment QTc according to maximum CTCAE grade will be 
summarized using a shift table.
9.3.2. Analysis of Secondary Endpoints
9.3.2.1. Safety Analysis
9.3.2.1.1. Adverse Events
AEs will graded by the investigator according to the CTCAE version 4.03 and coded using 
the Medical Dictionary for Regulatory Activities (MedDRA).  The focus of AE summaries 
will be on Treatment Emergent Adverse Events, those with initial onset or increasing in 
severity after the first dose of study medication.  The number and percentage of patients who 
experienced any AE, SAE, treatment related AE, and treatment related SAE will be 
summarized according to worst toxicity grades. 
 
9.3.2.1.2. Laboratory Test Abnormalities
The number and percentage of patients who experienced laboratory test abnormalities will be 
graded according to CTCAE version 4.03 and summarized according to worst toxicity grade 
observed for each laboratory test. 
For laboratory tests without CTCAE grade definitions, results will be categorized as normal, 
abnormal, or not done.
For patients who respond, time to neutrophil recovery (>500/μl) and time to platelet recovery 
(>50,000/μl) will be summarized using Kaplan-Meier methods.
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9.3.2.1.3. Deaths 
The number of deaths (and the cause of death) during the study periods will be summarized.
9.3.2.1.4. VOD/SOS
Incidence and timing of VOD/SOS and HSCT will be summarized.
9.3.2.2. Pharmacokinetic Analysis
These analyses will be conducted in the PK analysis set.
The pharmacokinetics of three analytes will be measured in patient samples in this study: 
total hP67.6 antibody, conjugated calicheamicin, and unconjugated calicheamicin.  The 
primary analyte representing GO PK is the total hP67.6 antibody.  Noncompartmental 
analysis (NCA) will be performed to characterize the clearance and volume of distribution of 
total hP67.6 antibody following the fractionated regimen (secondary endpoint). 
Population PK analysis, using nonlinear mixed effects modeling methodology as 
implemented in NONMEM® Version 7.3.0 (ICON Development Solutions, Ellicott City,
MD), will also be conducted and reported separately.  A population modeling approach will 
be used to further characterize the PK of total hP67.6 antibody, conjugated calicheamicin, 
and unconjugated calicheamicin, as well as to assess intrinsic and extrinsic covariates that 
may account for some of the interindividual variability of population PK parameters. 
9.3.2.3. Pharmacokinetic/Pharmacodynamic (PK/PD) Analysis
Population PK/PD modeling analyses will be explored, as necessary, based on emerging 
safety/clinical response data.  The results of these population modeling analyses will be 
reported separately from the clinical study report.
 
9.3.2.4. QTc-Concentration Analysis
Concentration data of total hP67.6 antibody and unconjugated calicheamicin (if feasible) will 
be listed by patient and by actual collection time and day.
The relationship between observed drug concentration (total hP67.6 antibody and 
unconjugated calicheamicin) to changes in QT/QTc will be evaluated to further characterize 
the effect on QT interval.  QTc- concentration- analysis will be conducted using linear 
regression, ie, a linear mixed effects model.  If appropriate, other models may also be 
examined.  Exploratory analyses (via graphical displays and/or model fitting) may include 
accounting for a delayed effect and the justification for the choice of pharmacodynamics 
model.  Diagnostic evaluation will be included to explore the adequacy of the model.  The 
results of these modeling analyses may be reported separately from the clinical study report.3
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9.3.2.5. Immunogenicity
The percentage of patients with positive ADA and neutralizing antibodies will be 
summarized.  For patients with positive ADA and neutralizing antibodies, the magnitude 
(titer), time of onset, and duration of ADA response will also be described, as data permit.  In 
addition, potential effects of ADA formation on the PK profile of GO will be examined 
individually, and evaluated between the groups with and without positive ADA.
Because the observed incidence of ADA is highly dependent on multiple factors including 
the assays used for ADA detection, timing of sample collection and immune status of the 
patients, the incidence of ADA observed in the planned study may differ from the incidence 
reported in historical clinical trials.
These analyses will be conducted in the Safety Analysis Set.
Samples will be analyzed for ADAs using a tiered approach of screening, confirmation, and 
titer determination. Samples that test positive for ADA will be further characterized to 
determine whether neutralizing antibodies (NAb) are present.
9.3.2.6. Efficacy Analyses 
Efficacy evaluation anddetermination of remission status by blood and bone marrow 
aspiration (and biopsy if applicable) will be conducted at the end of each cycle using 
European Leukemia Net (ELN 2017) recommendations (see Section 7.5).  Survival status for 
each patient will be collected for the study duration of 12 months. 
9.3.2.6.1. Response
The proportion of the patients who respond (CR + CRi [CR with incomplete hematologic 
recovery] according to best response) and a 95% confidence interval will be reported. 
9.3.2.6.2. Overall Survival 
Overall survival rate at 12 months with a 95% confidence interval will be estimated using 
Kaplan Meier methods and presented graphically. 
9.4. Interim Analysis
No formal interim analysis will be conducted for this study.  However, as this is an 
open-label study, the sponsor may conduct unblinded reviews of the data during the course of 
the study for the purpose of safety assessment, facilitating dose-escalation decisions, 
facilitating pharmacokinetic (PK)/pharmacodynamic (PD) modeling, and/or to support 
clinical development. 
9.5. Data Monitoring Committee 
This study will not use a data monitoring committee. 


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10. QUALITY CONTROL AND QUALITY ASSURANCE
Pfizer or its agent will conduct periodic monitoring visits during study conduct to ensure that 
the protocol and Good Clinical Practices (GCPs) are being followed.  The monitors may 
review source documents to confirm that the data recorded on CRFs are accurate.  The 
investigator and institution will allow Pfizer monitors/auditors or its agents and appropriate 
regulatory authorities direct access to source documents to perform this verification.  This 
verification may also occur after study completion.
During study conduct and/or after study completion, the investigator site may be patient to 
review by the IRB/EC, and/or to quality assurance audits performed by Pfizer, or companies 
working with or on behalf of Pfizer, and/or to inspection by appropriate regulatory 
authorities.
The investigator(s) will notify Pfizer or its agents immediately of any regulatory inspection 
notification in relation to the study.  Furthermore, the investigator will cooperate with Pfizer 
or its agents to prepare the investigator site for the inspection and will allow Pfizer or its 
agent, whenever feasible, to be present during the inspection.  The investigator site and 
investigator will promptly resolve any discrepancies that are identified between the study 
data and the patient's medical records.  The investigator will promptly provide copies of the 
inspection findings to Pfizer or its agent.  Before response submission to the regulatory 
authorities, the investigator will provide Pfizer or its agents with an opportunity to review 
and comment on responses to any such findings.
It is important that the investigator(s) and their relevant personnel are available during the 
monitoring visits and possible audits or inspections and that sufficient time is devoted to the 
process.
11. DATA HANDLING AND RECORD KEEPING
11.1. Case Report Forms/Electronic Data Record
As used in this protocol, the term CRF should be understood to refer to either a paper form 
or an electronic data record or both, depending on the data collection method used in this 
study.
A CRF is required and should be completed for each included patient.  The completed 
original CRFs are the sole property of Pfizer and should not be made available in any form to 
third parties, except for authorized representatives of Pfizer or appropriate regulatory 
authorities, without written permission from Pfizer.  The investigator shall ensure that the 
CRFs are securely stored at the study site in encrypted electronic form and will be password 
protected to prevent access by unauthorized third parties.
The investigator has ultimate responsibility for the collection and reporting of all clinical, 
safety, and laboratory data entered on the CRFs and any other data collection forms (source 
documents) and ensuring that they are accurate, authentic/original, attributable, complete, 
consistent, legible, timely (contemporaneous), enduring, and available when required.  The 
CRFs must be signed by the investigator or by an authorized staff member to attest that the 


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data contained on the CRFs are true.  Any corrections to entries made in the CRFs or source 
documents must be dated, initialed, and explained (if necessary) and should not obscure the 
original entry. 
In most cases, the source documents are the hospital or the physician patient chart.  In these 
cases, data collected on the CRFs must match the data in those charts. 
In some cases, the CRF may also serve as the source document.  In these cases, a document 
should be available at the investigator site and at Pfizer that clearly identifies those data that 
will be recorded on the CRF, and for which the CRF will stand as the source document.
11.2. Record Retention
To enable evaluations and/or inspections/audits from regulatory authorities or Pfizer, the 
investigator agrees to keep records, including the identity of all participating patients 
(sufficient information to link records, eg, CRFs and hospital records), all original signed 
informed consent/assent documents, copies of all CRFs, safety reporting forms, source 
documents, and detailed records of treatment disposition, and adequate documentation of 
relevant correspondence (eg, letters, meeting minutes, and telephone call reports).  The 
records should be retained by the investigator according to the ICH guidelines, according to 
local regulations, or as specified in the clinical study agreement (CSA), whichever is longer.  
The investigator must ensure that the records continue to be stored securely for so long as 
they are retained.
If the investigator becomes unable for any reason to continue to retain study records for the 
required period (eg, retirement, relocation), Pfizer should be prospectively notified.  The 
study records must be transferred to a designee acceptable to Pfizer, such as another 
investigator, another institution, or an independent third party arranged by Pfizer. 
Investigator records must be kept for a minimum of 15 years after completion or 
discontinuation of the study or for longer if required by applicable local regulations.
The investigator must obtain Pfizer's written permission before disposing of any records, 
even if retention requirements have been met.
12. ETHICS
12.1. Institutional Review Board/Ethics Committee
It is the responsibility of the investigator to have prospective approval of the study protocol, 
protocol amendments, informed consent/assent documents, and other relevant documents, eg, 
recruitment advertisements, if applicable, from the IRB/EC.  All correspondence with the 
IRB/EC should be retained in the investigator file.  Copies of IRB/EC approvals should be 
forwarded to Pfizer.


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The only circumstance in which an amendment may be initiated prior to IRB/EC approval is 
where the change is necessary to eliminate apparent immediate hazards to the patients.  In 
that event, the investigator must notify the IRB/EC and Pfizer in writing immediately after 
the implementation.
12.2. Ethical Conduct of the Study
The study will be conducted in accordance with the protocol, legal and regulatory 
requirements, and the general principles set forth in the International Ethical Guidelines for 
Biomedical Research Involving Human Subjects (Council for International Organizations of 
Medical Sciences 2002), ICH Guideline for Good Clinical Practice, and the Declaration of 
Helsinki.  In addition, the study will be conducted in accordance with applicable local 
regulatory requirements and laws.
12.3. Patient Information and Consent
All parties will comply with all applicable laws, including laws regarding the implementation 
of organizational and technical measures to ensure protection of patient personal data.  Such 
measures will include omitting patient names or other directly identifiable data in any 
reports, publications, or other disclosures, except where required by applicable law. 
The personal data will be stored at the study site in encrypted electronic and/or paper form 
and will be password protected or secured in a locked room to ensure that only authorized 
study staff have access.  The study site will implement appropriate technical and 
organizational measures to ensure that the personal data can be recovered in the event of 
disaster.  In the event of a potential personal data breach, the study site shall be responsible 
for determining whether a personal data breach has in fact occurred and, if so, providing 
breach notifications as required by law.
To protect the rights and freedoms of natural persons with regard to the processing of 
personal data, when study data are compiled for transfer to Pfizer and other authorized 
parties, patient names will be removed and will be replaced by a single, specific, numerical 
code, based on a numbering system defined by Pfizer.  All other identifiable data transferred 
to Pfizer or other authorized parties will be identified by this single, subject-specific code.  
The investigator site will maintain a confidential list of patients who participated in the study, 
linking each patient’s numerical code to his or her actual identity.  In case of data transfer, 
Pfizer will maintain high standards of confidentiality and protection of patients’ personal data 
consistent with the Clinical Study Agreement and applicable privacy laws.
The informed consent/assent documents and any patient recruitment materials must be in 
compliance with ICH GCP, local regulatory requirements, and legal requirements, including 
applicable privacy laws.
The informed consent/assent documents used during the informed consent process and any 
patient recruitment materials must be reviewed and approved by Pfizer, approved by the 
IRB/EC before use, and available for inspection.


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The investigator must ensure that each study patient, or his or her legally acceptable 
representative, is fully informed about the nature and objectives of the study, the sharing of 
data relating to the study , the sharing of data relating to the study  and possible risks 
associated with participation, including the risks associated with the processing of the 
patient’s personal data.  The investigator further must ensure that each study patient, or his or 
her legally acceptable representative, or parent(s) or legal guardian if a minor, is fully 
informed about his or her right to access and correct his or her personal data and to withdraw 
consent for the processing of his or her personal data. 
Whenever consent is obtained from a patient’s legally acceptable representative, the patient’s 
assent (affirmative agreement) must subsequently be obtained when the patient has the 
capacity to provide assent, as determined by the IRB/EC.  If the investigator determines that 
a patient’s decisional capacity is so limited he/she cannot reasonably be consulted, then, as 
permitted by the IRB/EC and consistent with local regulatory and legal requirements, the 
patient’s assent may be waived with source documentation of the reason assent was not 
obtained.  If the study patient does not provide his or her own consent, the source documents 
must record why the patient did not provide consent (eg, decisionally impaired adult), how 
the investigator determined that the person signing the consent was the patient’s legally 
acceptable representative, the consent signer’s relationship to the study patient (eg, parent, 
spouse), and that the patient’s assent was obtained or waived.  If assent is obtained verbally, 
it must be documented in the source documents.  
If the study includes minor patients who reach the age of majority during the study, as 
recognized under local law, they must reconsent as adults to remain in the study.  If the 
enrollment of emancipated minors is permitted by the study age criteria, the IRB/EC, and 
local law, they must provide documentation of legal status to give consent without the 
permission of a parent or legal guardian.  
The investigator, or a person designated by the investigator, will obtain written informed 
consent from each patient or the patient's legally acceptable representative and the patient’s 
assent, when applicable, before any study-specific activity is performed.  The investigator 
will retain the original of each patient's signed consent/assent document.
12.4. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH GCP
In the event of any prohibition or restriction imposed (ie, clinical hold) by an applicable 
regulatory authority in any area of the world, or if the investigator is aware of any new 
information that might influence the evaluation of the benefits and risks of the investigational 
product, Pfizer should be informed immediately. 
In addition, the investigator will inform Pfizer immediately of any urgent safety measures 
taken by the investigator to protect the study patients against any immediate hazard, and of 
any serious breaches of this protocol or of ICH GCP that the investigator becomes aware of.


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13. DEFINITION OF END OF TRIAL
13.1. End of Trial in a Member State 
End of trial in a Member State of the European Union is defined as the time at which it is 
deemed that a sufficient number of patients have been recruited and completed the study as 
stated in the regulatory application (ie, clinical trial application [CTA]) and ethics application 
in the Member State.  Poor recruitment (recruiting less than the anticipated number in the 
CTA) by a Member State is not a reason for premature termination but is considered a 
normal conclusion to the study in that Member State.
13.2. End of Trial in All Other Participating Countries 
End of trial in all other participating countries is defined as last patient last visit (LPLV). 
14. SPONSOR DISCONTINUATION CRITERIA
Premature termination of this study may occur because of a regulatory authority decision, 
change in opinion of the IRB/EC, or investigational product safety problems, or at the 
discretion of Pfizer.  In addition, Pfizer retains the right to discontinue development of GO at 
any time.
If a study is prematurely terminated, Pfizer will promptly notify the investigator.  After 
notification, the investigator must contact all participating patients and the hospital pharmacy 
(if applicable) within 4 weeks.  As directed by Pfizer, all study materials must be collected 
and all CRFs completed to the greatest extent possible.
15. PUBLICATION OF STUDY RESULTS
15.1. Communication of Results by Pfizer
Pfizer fulfills its commitment to publicly disclose clinical trial results through posting the 
results of studies on www.clinicaltrials.gov (ClinicalTrials.gov), the European Clinical Trials 
Database (EudraCT), and/or www.pfizer.com, and other public registries in accordance with 
applicable local laws/regulations. 
In all cases, study results are reported by Pfizer in an objective, accurate, balanced, and 
complete manner and are reported regardless of the outcome of the study or the country in 
which the study was conducted.
www.clinicaltrials.gov
Pfizer posts clinical trial US Basic Results on www.clinicaltrials.gov for Pfizer-sponsored 
interventional studies (conducted in patients) that evaluate the safety and/or efficacy of a 
Pfizer product, regardless of the geographical location in which the study is conducted.  US 
Basic Results are submitted for posting within 1 year of the primary completion date (PCD) 
for studies in adult populations or within 6 months of the PCD for studies in pediatric 
populations.


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PCD is defined as the date that the final patient was examined or received an intervention for 
the purposes of final collection of data for the primary outcome, whether the clinical study 
concluded according to the prespecified protocol or was terminated.
EudraCT
Pfizer posts European Union (EU) Basic Results on EudraCT for all Pfizer-sponsored
interventional studies that are in scope of EU requirements.  EU Basic Results are submitted 
for posting within 1 year of the PCD for studies in adult populations or within 6 months of 
the PCD for studies in pediatric populations.
www.pfizer.com
Pfizer posts Public Disclosure Synopses (clinical study report synopses in which any data 
that could be used to identify individual patients has been removed) on www.pfizer.com for 
Pfizer-sponsored interventional studies at the same time the US Basic Results document is 
posted to www.clinicaltrials.gov.
15.2. Publications by Investigators
Pfizer supports the exercise of academic freedom and has no objection to publication by the 
principal investigator (PI) of the results of the study based on information collected or 
generated by the PI, whether or not the results are favorable to the Pfizer product.  However, 
to ensure against inadvertent disclosure of confidential information or unprotected 
inventions, the investigator will provide Pfizer an opportunity to review any proposed 
publication or other type of disclosure of the results of the study (collectively, “publication”) 
before it is submitted or otherwise disclosed.
The investigator will provide any publication to Pfizer at least 30 days before it is submitted 
for publication or otherwise disclosed.  If any patent action is required to protect intellectual 
property rights, the investigator agrees to delay the disclosure for a period not to exceed an 
additional 60 days. 
The investigator will, on request, remove any previously undisclosed confidential 
information before disclosure, except for any study- or Pfizer product-related information 
necessary to the appropriate scientific presentation or understanding of the study results.
If the study is part of a multicenter study, the investigator agrees that the first publication is 
to be a joint publication covering all investigator sites, and that any subsequent publications 
by the PI will reference that primary publication.  However, if a joint manuscript has not 
been submitted for publication within 12 months of completion or termination of the study at 
all participating sites, the investigator is free to publish separately, patient to the other 
requirements of this section.


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For all publications relating to the study, the institution will comply with recognized ethical 
standards concerning publications and authorship, including Section II - “Ethical 
Considerations in the Conduct and Reporting of Research” of the Uniform Requirements for 
Manuscripts Submitted to Biomedical Journals, http://www.icmje.org/index.html#authorship, 
established by the International Committee of Medical Journal Editors.
Publication of study results is also provided in the CSA between Pfizer and the institution.  In 
this section entitled Publications by Investigators, the defined terms shall have the meanings 
assigned to them in the CSA.
If there is any conflict between the CSA and its attachments to it, the terms of the CSA take 
precedence.  If there is any conflict between this protocol and the CSA, this protocol will 
take precedence as to any issue regarding treatment of study patients, and the CSA take 
precedence as to all other issues.


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Guidance for industry: E14 clinical evaluation of QT/QTc interval prolongation and 
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Sievers EL, Larson RA, Stadtmauer EA, et al. Efficacy and safety of gemtuzumab 
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U.S. Department of Health and Human Services, Food and Drug Administration, 
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Taksin AL, Legrand O, Raffoux E, et al. High efficacy and safety profile of fractionated 
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Larson RA, Sievers EL, Stadtmauer EA, et al. Final report of the efficacy and safety of 
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Cheson BD, Bennett JM, Kopecky KJ, et al. Revised recommendations of the 
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eliminate transmission of hepatitis B virus infection in the United States: 
recommendations of the Advisory Committee on Immunization Practices (ACIP); 
Part 1: immunization of infants, children, and adolescents.  MMWR 2005; 
54(RR-16):1-34.
20.
Getchell JP, Wroblewski KE, DeMaria A Jr, et al. Testing for HCV infection: an update 
of guidance for clinicians and laboratorians. MMWR Morb Mortal.  Wkly Rep 2013; 
62(18):362-5.


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21.
Mohty M, Malard F, Abecassis M, et al. Revised diagnosis and severity criteria for 
sinusoidal obstruction syndrome/veno-occlusive disease in adult patients: a new 
classification from the European Society for Blood and Marrow Transplantation.  Bone 
Marrow Transplant 2016; 51(7):906-12.
22.
Corbacioglu S, Carreras E, Ansari M, et al. Diagnosis and severity criteria for sinusoidal 
obstruction syndrome/veno-occlusive disease in pediatric patients: a new classification 
from the European society for blood and marrow transplantation.  Bone Marrow 
Transplant. 2018 Feb;53(2):138-145.
23.
Amadori S, Suciu S, Selleslag D, et al. Gemtuzumab Ozogamicin Versus Best 
Supportive Care in Older Patients With Newly Diagnosed Acute Myeloid Leukemia 
Unsuitable for Intensive Chemotherapy: Results of the Randomized Phase III 
EORTC-GIMEMA AML-19 Trial.  J Clin Oncol. 2016 Mar 20; 34(9):972-9.


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Appendix 1. Abbreviations 
This following is a list of abbreviations that may be used in the protocol. 
Abbreviation
Term
ADA
anti drug antibody
ADC
antibody drug conjugate
AE
adverse event
ALFA
Acute Leukemia French Association
ALK-P
alkaline phosphatase
ALT
alanine aminotransferase
AML
acute myeloid leukemia
APL
acute promyelocytic leukemia
Ara-C
cytarabine
aPTT
activated partial thromboplastin time
AST
aspartate aminotransferase
AUC
area under curve
BSA
body surface area
BLA
Biologics License Application
BM
bone marrow
BUN
blood urea nitrogen
CAT
computed axial tomography
CBC
complete blood counts
CD33
cluster of differentiation 33
CERT
Center for Education and Research on Therapeutics
CHMP
Committee for Medicinal Products for Human Use
CK
creatine kinase
Cmax
maximum concentration
CNS
central nervous system
CR
complete remission
CRF
case report form
CRi
complete remission with incomplete hematologic recovery
CRMDR
complete remission without minimal residual disease
CRp
complete remission with incomplete platelet recovery
CSA
clinical study agreement
CSF
cerebrospinal fluid
CSR
clinical study report
CT
clinical trial
CTA
clinical trial application
CTCAE
Common Terminology Criteria for Adverse Events
DFS
disease free survival
DILI
drug-induced liver injury
DMH
dimethylhydrazide
CCI


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Abbreviation
Term
DNA
deoxyribonucleic acid
DNR
daunorubicin
DU
dispensable unit
EBMT
European Group for Blood and Marrow Transplantation
EC
ethics committee
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
EDP
exposure during pregnancy
EOT
end of treatment
ELN
European Leukemia Net
EORTC
European Organisation for Research and Treatment of Cancer
EU
European Union
EudraCT
European Clinical Trials Database
FACS
flow activated cell sorting
FDA
Food and Drug Administration
FSH
follicle-stimulating hormone
GCP
Good Clinical Practice
GGT
gamma-glutamyl transferase
GIMEMA
Gruppo Italiano Malattie EMatologiche dell'Adulto
GO
gemtuzumab ozogamicin
GVHD
graft-versus-host disease
hCG
human chorionic gonadotropin
HCV
hepatitis C virus 
HCV RNA
Quantitative hepatitis C virus RNA measurement
hERG
human ether-a-go-go-related gene
HIV
human immunodeficiency virus
HRQL
health-related quality of life
HSCT
hematopoietic stem cell transplantation
IB
investigator’s brochure
ICD
informed consent document
ICH
International Conference on Harmonisation
ID
identification
IEC
Independent Ethics Committee
Ig
immunoglobulin
IHC
immunohistochemistry
IND
investigational new drug application
INR
international normalized ratio
IP
investigational product
IRB
institutional review board
IRC
internal review committee
IRT
interactive response technology
IUD
intrauterine device
IV
intravenous


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Abbreviation
Term
IWG
International Working Group
IWR
interactive web response
LDH
Lactate dehydrogenase
LFT
liver function test
LPLV
last patient last visit 
MedDRA
Medical Dictionary for Regulatory Activities
MRI
magnetic resonance imaging
msec
millisecond 
N/A
not applicable
NAb
neutralizing antibodies
NCA
non compartmental analysis
NCI
National Cancer Institute
OS
overall survival
PCD
primary completion date
PD
Pharmacodynamics(s)
PE
physical examination
PI
principal investigator
PK
Pharmacokinetic
PMR
post marketing requirements
PS
performance status
PT
prothrombin time
QTc
corrected QT interval
QTcF
QT interval using the Fridericia heart rate correction
QTcS
QT interval using a study-specific heart rate correction method 
RBC
red blood cells
RNA
ribonucleic acid
SAE
serious adverse event
SAP
statistical analysis plan
SOP
standard operating procedure
SOS
sinusoidal obstruction syndrome
SRSD
single reference safety document
SUSAR
suspected unexpected serious adverse reaction
SWOG
Southwest Oncology Group
TBili
total bilirubin
TdP
Torsades de Pointes
TEAEs
treatment emergent adverse event
ULN
upper limit of normal
US
United States
VOD
veno-occlusive disease 
WBC
white blood cells
CCI


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Appendix 2. Definition of Active Hepatitis Infection

Hepatitis B serological tests and definition of active infection.19
Serological Test
Test outcomes
Interpretation
HBsAg
anti-HBc
IgM anti-HBc
anti-HBs
positive
positive
positive
negative
Acutely infected
HBsAg
anti-HBc
IgM anti-HBc
anti-HBs
positive
positive
negative
negative
Chronically infected
HBsAg: Hepatitis B surface antigen  
anti-HBs: Hepatitis B surface antibody 
anti-HBc: Total hepatitis B core antibody 

IgM anti-HBc: IgM antibody to hepatitis B core antigen. 
Hepatitis C tests and Definition of active hepatitis C.20
Test
Test outcomes
Interpretation
HCV antibody 
HCV RNA
Reactive
Detected
Current HCV infection
HCV antibody: antibody to hepatitis C virus
HCV RNA: Quantitative hepatitis C virus RNA measurement


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Appendix 3. Laboratory Tests
Hematology Panel
Chemistry Panel
Coagulation Panel
Urinalysis
WBC/differential counts 
including blast
RBC count
Hemoglobin
Hematocrit
Platelet count
Sodium
Potassium
Magnesium
Total calcium
Creatinine
Albumin
Alanine 
aminotransferase (ALT)
Aspartate 
aminotransferase (AST)
Glucose
Total Bilirubin 
Blood urea nitrogen 
(BUN) 
Uric acid or urate
Alkaline phosphatase 
(ALK-P)
Lactate dehydrogenase 
(LDH)
international normalized 
ratio/prothrombin time 
(INR/PT)
Activated Partial 
thromboplastin time 
(aPTT)
Fibrinogen
pH
Protein/albumin
Glucose
Blood/hemoglobin
Ketones/acetone


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Appendix 4. List of Drugs Known to Predispose to Torsades de Pointes
The medications which are known to be associated with a risk of TdP and known to prolong 
the QTc interval are listed in the CredibleMedsTdP risk category 
(https://www.crediblemeds.org). 
(CredibleMedsis associated with University of Arizona Cancer Center for Education and
Research on Therapeutics [CERT]: “Torsades List: Drugs with a Risk of Torsades de
Pointes,” Advisory Board).


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Appendix 5. Definition of Refractory and Relapsed AML (ELN 2017 
Recommendation)5
Refractory Disease: 

No complete remission (CR) or CR with incomplete hematologic recovery (CRi) after 
2 courses of intensive induction treatment; excluding patients with death in aplasia or 
death due to indeterminate cause. 
Relapsed Disease: 

After CR without minimal residual disease (CRMDR-), CR, or CRi, bone marrow 
blasts 5%; or reappearance of blasts in the blood; or development of extramedullary 
disease.

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Protocol B1761031 (PF-05208747 (CMA-676)) Statistical Analysis Plan 
PFIZER CONFIDENTIAL 
Page 5 
 
 
6.6.1.2. Basic Results ................................................................... 40 
6.6.2. Deaths ............................................................................................... 40 
6.6.3. Laboratory Data ................................................................................ 40 
6.6.3.1. Time To Recovery ........................................................... 42 
6.6.3.2. Hy’s Law Assessment ..................................................... 43 
6.6.4. Vital Signs ........................................................................................ 43 
6.6.5. Electrocardiogram ............................................................................. 44 
6.6.5.1. Assessment of Correction Factors ................................... 44 
6.6.5.2. ECG Parameter Results ................................................... 44 
6.6.5.3. Change from baseline ...................................................... 44 
6.6.5.4. Absolute QTc interval prolongation ................................ 45 
6.6.5.5. Maximum increase from baseline QTc ........................... 45 
6.6.6. Physical Examination ....................................................................... 45 
7. INTERIM ANALYSES ............................................................................................. 45 
8. APPENDICES ........................................................................................................... 46 
 
LIST OF TABLES 
Table 1. Summary of Major Changes in SAP Amendments ........................................... 6 
Table 2. PK Parameters to be Summarized Descriptively ............................................. 28 
Table 3. Noncompartmental PK Parameters .................................................................. 46 
 
APPENDICES 
Appendix 1. SUMMARY OF PK ANALYSES ............................................................ 46 
Appendix 2. AESI Definitions ....................................................................................... 47 
 
 
 


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Protocol B1761031 (PF-05208747 (CMA-676)) Statistical Analysis Plan 
PFIZER CONFIDENTIAL 
Page 7 
 
 
SAP 
Version 
Version 
Date 
Change 
Rationale 
reported separately from 
pediatric patients. 
The last cycle defintion was 
updated to the min (last dose 
+36, start of subsequent 
anticancer therapy) 
The change is consistent with the safety 
reporting period, and standard 
definitions that considers start of 
subsequent anticancer therapy. 
Additional categorizations ECG 
parameters were added to 
summaries.  Clarification was 
added whether triplicate 
averages or individual replicates 
are included in summaries. 
Given the focus on ECGs, the additional 
categorizations were felt to be relevant.  
The clarifcations about replicates was 
based on standards. 
Derivation of QTcS: The 
estimated slope was clarified to 
be based on individual replicates 
and changed to be based on only 
the individual replicates selected 
as baseline. 
It was felt to be most relevant to derive 
QTcS based on only the individual 
replicates selected as baseline. 
Statistical details for LS means, 
SE, and CI  were provided and 
was updated to include only data 
from Cycle 1. 
Further details for the linear model were 
provided for clarity. Only data from 
Cycle 1 will be included because Cycle 
2 was optional and at the investigator’s 
discretion. 
Analyses for impact of COVID-
19 pandemic were added. 
Since study enrollment and conduct was 
ongoing during the COVID-19 
pandemic, conventions and analyses 
were added per company guidance  
Missing PK data conventions 
were clarified. 
The clarifications were made consistent 
with standards. 
References to listings were 
modified. 
Consistent with standards changes, the 
focus is on listings required for an ICH 
CSR. 
Plots of PK parameters were 
removed. 
The plots were to contain summaries for 
adult and pediatric patients, but 
pediatric enrollment has not completed  
Descriptive statistics summary 
of PK concentrations were 
added.  Mean plots were 
removed. 
The descriptive summary was 
indavertantly omitted from SAP version 
1.  Consistent with current reporting 
guidance some outputs were omitted to 
streamline reporting. 
Graphical summary of change in 
QTcF from baseline was added. 
A graphical summary for the primary 
endpoint was added to streamline the 
presentation in the CSR. 
The descriptions of the 
immunogenicity summaries 
were modified. 
Updates are consistent with current 
standard summaries. 


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Protocol B1761031 (PF-05208747 (CMA-676)) Statistical Analysis Plan 
PFIZER CONFIDENTIAL 
Page 11 
 
 
 
3. ENDPOINTS AND BASELINE VARIABLES: DEFINITIONS AND 
CONVENTIONS 
3.1. Primary Endpoint 
3.1.1. QTc interval 
Change from baseline in corrected QT interval (QTc) using Fridericia’s heart rate correction.  
Refer to Section 5.2.8 for details of derivations. 
3.2. Secondary Endpoints 
3.2.1. PK parameters 
The following PK parameters will be calculated for GO (represented by total hP67.6 
antibody, conjugated calicheamicin, and unconjugated calicheamicin) from the 
concentration-time values using standard noncompartmental methods: AUClast, AUC0-72, 
AUC0-336, Cmax, Tmax, and if data permits AUCinf, t1/2, CL, VSS.  A tabular summary of these 
noncompartmental PK parameters and analyses is presented in Table 3.  
3.2.2. Immunogenicity  
Samples for ADA will be analyzed using a tiered approach of screening, confirmation, and 
titer determination.  Samples that test positive for ADA to GO will be further tested for 
specificity (in presence of purified hP67.6 naked antibody and in the presence of 
calicheamicin payload) and characterized to determine whether NAb are present or absent. 
ADA will be classified as negative if the titer value is less than the minimum required 
dilution, i.e., titer <75, and positive otherwise (titer 75 or greater). 
NAb will be classified as negative if the titer value is less than the minimum required 
dilution, i.e., titer <20, and positive otherwise (titer 20 or greater). 
 
3.2.3. Best Response 
Efficacy evaluation and determination of remission status by blood and bone marrow 
aspiration (and biopsy if applicable) per the investigator will be classified according to 
European Leukemia Net (ELN 2017) recommendations according to the following 
categories.   Thus the bone marrow will be assessed by the investigator after each cycle when 
blood count recovery (neutrophils ≥500/µL and platelet ≥50,000/µL) is observed or at a 
maximum of 36 days after the last dose of GO regimen.  The date of response is also 
dependent on the observation of the peripheral blood recovery mentioned in the criteria 
below.  If Cycle 2 is to be administered, note that the Cycle 1 assessment is required to be 
conducted prior to the start of Cycle 2.   


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Protocol B1761031 (PF-05208747 (CMA-676)) Statistical Analysis Plan 
PFIZER CONFIDENTIAL 
Page 14 
 
 
CRF, time will not be collected on the AE CRF.  Refer to Section 5.3.1, for details, but 
adverse events occurring on the same day as the first dose of study treatment will be 
considered to have occurred during the on-treatment period. 
 
Because the protocol requires collection of VOD/SOS for the entire duration of the study, all 
collected AEs that start after the first dose of study treatment will be included as treatment 
emergent.   
3.5.1.1. Adverse Events of Special Interest (AESI) 
Certain AEs will be grouped together to support discussion of AEs of Special Interest, these 
will be reported as clusters using the MedDRA coding as follows with the specific definitions 
provided in Appendix 2:  
• MYELOSUPPRESSION 
• HEAMORRHAGE  
• INFECTION (Grade >3  and/or serious infection) 
• HEPATOTOXICITY (Grade ≥3 and/or serious hepatotoxicity including all 
VOD/SOS)  
• INFUSION RELATED REACTIONS (including Anaphylaxis):  From start of 
infusion to within 24 hours of end of infusion 
• TUMOUR LYSIS SYNDROME 
• CARDIAC CONDUCTION 
 
3.5.2. Laboratory Data 
Laboratory data will be graded programmatically according to the NCI CTCAE v4.03 
severity grade (including low and high values if both are defined for the parameter) for the 
following safety laboratory parameters:  
• Hematology tests: hemoglobin, white blood cells, platelets, neutrophils, lymphocytes. 
• Chemistry tests: sodium, potassium, magnesium, glucose, creatinine, total calcium, , 
albumin, total bilirubin, AST, ALT, alkaline phosphatase (ALP).  For laboratory tests 
that can be either abnormally high or abnormally low, both directions will be 
computed. 
• Coagulation tests: prothrombin time, international normalized ratio (INR), activated 
partial thromboplastin time, fibrinogen. 
• Urinalaysis test: protien 
 
The non-CTC graded laboratory tests red blood cells, hematocrit, BUN, LDH, uric acid or 
urate along with urinalysis tests (pH), will be categorized as below normal limit, within 
normal limits, and above normal limits.  The remaining urinalysis tests (albumin, glucose, 
blood/hemoglobin, ketones/acetone) will be categorized as negative or positive. 
 


Protocol B1761031 (PF-05208747 (CMA-676)) Statistical Analysis Plan 
PFIZER CONFIDENTIAL 
Page 15 
 
 
3.5.2.1. Time to Recovery of Neutrophils 
For patients who respond, time to recovery of neutrophils for each cycle will be defined as 
the date of first dose of study treatment to the date that the absolute neutrophils recover to 
counts of 500/µl after each cycle.  During each cycle, the nadir will be calculated.  Recovery 
is not considered to have occurred until after the date of this nadir.  If the nadir equals or 
exceeds the target level of recovery, the date of recovery is defined as the first date after the 
final dose in the cycle on which the target level was reached. Patients not achieving the target 
levels of neutrophil recovery are censored at the last laboratory evaluation prior to the next 
cycle, first follow-up anti-cancer treatment, or death, whichever comes first. 
3.5.2.2. Time to Recovery of Platelets 
For patients who respond, time to recovery of platelets for each cycle will be defined as the 
date of first dose of study treatment to the date that the platelets recover to counts of 
50,000/µl after each cycle.  During each cycle, the nadir will be calculated.  Recovery is not 
considered to have occurred until after the date of this nadir.  Also, patients are required to be 
platelet transfusion independent on the date of recovery.  Platelet transfusion independence 
will be defined as no platelet transfusion for at least 7 days prior to the assessment.  If the 
nadir equals or exceeds the target level of recovery, the date of recovery is defined as the first 
date after the final dose in the cycle on which the target level was reached and the patient was 
transfusion independent. Patients not achieving the target levels of platelet recovery are 
censored at the last laboratory evaluation prior to the next cycle, first follow-up anti-cancer 
treatment, or death, whichever comes first.  
4. ANALYSIS SETS 
Data for all subjects will be assessed to determine if subjects meet the criteria for inclusion in 
each analysis population prior to releasing the database and classifications will be 
documented per standard operating procedures. 
4.1. Full Analysis Set 
The full analysis set will include all enrolled patients, and will be the primary analysis set for 
evaluating all efficacy endpoints and patient characteristics. 
4.2. Per Protocol Analysis Set  
Not applicable. 
4.3. Safety Analysis Set 
The safety analysis set will include all enrolled patients who receive at least 1 dose of study 
medication.  The safety analysis set will be the primary analysis set for evaluating treatment 
administration/compliance and safety. 


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Protocol B1761031 (PF-05208747 (CMA-676)) Statistical Analysis Plan 
PFIZER CONFIDENTIAL 
Page 18 
 
 
5.2.2. Unscheduled Assessments 
ECG parameters:  Only the scheduled ECGs will be used in the primary analyses. Interval 
measurements from unscheduled ECGs will be included in some of the categorical analyses, 
refer to Section 5.2.8.4 for further details. 
5.2.3. Definition of Study Day 
The study day for assessments occurring on or after the first dose of study treatment (e.g., 
adverse event start date) will be calculated as: 
Study day = Date of the assessment/event - start date of study treatment + 1.  
The study day for assessments occurring prior to the first dose of study treatment (e.g., 
baseline characteristics, medical history) will be negative and calculated as: 
Study day = Date of the assessment/event –start date of study treatment. 
The study day will be displayed in all relevant data listings. 
5.2.4. Definition of Cycle and Cycle Day 
For Cycle 1 and Cycle 2 the actual start date for each patient will be determined from the first 
start date of dosing from the respective CRF exposure page with a dose recorded. 
 
If Cycle 2 is administered, then the actual stop date for Cycle 1 will be calculated as the start 
date of Cycle 2 minus one day. 
 
For the last Cycle, actual stop date will be calculated as the minimum of the last dose + 36 
and the start date of subsequent anticancer therapy. 
The cycle day will be calculated as Cycle day = Date of the assessment/event – cycle start 
date + 1.  
The cycle day will be displayed in all relevant data listings. 
5.2.5. Assignment to Cycles 
Data collected in log pages, such as adverse events, and laboratory results, will be assigned to 
cycles.  Cycles are defined in Section 5.2.4.   For adverse events, the assignment will be 
based on the start date.  Adverse events that start after the end of the last cycle will be 
assigned to a cycle called Follow-up.   
5.2.6. Date of Last Contact 
The date of last contact will be derived for patients not known to have died using the latest 
complete date (i.e. imputed dates will not be used in the derivation) among the following: 


Protocol B1761031 (PF-05208747 (CMA-676)) Statistical Analysis Plan 
PFIZER CONFIDENTIAL 
Page 19 
 
 
• All patient assessment dates including local laboratory assessment dates,  vital signs, 
performance status, ECG, bone marrow assessments, extramedullary disease 
assessment), 
• Start and stop dates of concomitant therapies including non-drug treatments or 
procedures, including transfusions, 
• Start and end dates of anti-cancer treatments administered after study treatment 
discontinuation including systemic therapy, radiation, and HSCT, 
• AE start and end dates, 
• Last date of contact collected on the ‘Survival Follow-up’ CRF (do not use date of 
survival follow-up assessment unless status is ‘alive’), 
• Study treatment start and end dates, 
• Enrollment date, and 
• Date of discontinuation on disposition CRF pages (do not use if reason for 
discontinuation is lost to follow-up or death). 
5.2.7. Standard Derivations and Reporting Conventions 
The following conversion factors will be used to convert days into weeks, months or years:   
1 week = 7 days, 1 month = 30.4375 days, 1 year = 365.25 days. 
Percentages will be reported to one decimal place. The rounding will be performed to closest 
integer / first decimal using the common mid-point between the two consecutive values. E.g., 
5.1 to 5.4 will be rounded to an integer of 5, and 5.5 to 5.9 will be rounded to an integer of 6. 
Duration calculations such as Overall Survival (defined in Section 3.2.4) will be reported in 
months will use +1 thus OS = ((death date or censoring date) – start date +1)/ 30.4375. 
5.2.8. ECG Derivation Details 
5.2.8.1. Corrected QT interval derivation 
Fridericia’s heart rate correction: 
3 60 HeartRate
QT
 
 
Bazzett’s heart rate correction: 
HeartRate
QT
60
 
The ECG core laboratory (vendor) will provide the corrected QT intervals according to the 
Fridericia’s and Bazzett’s corrections.   


Protocol B1761031 (PF-05208747 (CMA-676)) Statistical Analysis Plan 
PFIZER CONFIDENTIAL 
Page 20 
 
 
A study specific correction for adult patients will be derived as QT/(RR)S where S is 
determined as follows: 
The study specific QT correction factor (ICH E14 Step 4, May 12, 2005) will be derived for 
adult patients in the QTc analysis set using  the individual replicates from the selected 
baseline (baseline is defined in Section 3.4) QT and RR.  
No study specific QT correction factor will be assessed for the 6 pediatric patients. 
Prior to estimating the regression, QT and RR will be transformed by the natural logarithm to 
Ln(QT) and Ln(RR), respectively.  Ln (RR) will be treated in the regression as the 
explanatory variable with Ln (QT) as the response variable.  The regression equation will be 
as follows: 
Ln(QT) = Intercept + S × Ln(RR) + Error 
Where  S = slope of the regression line. 
Once (S) is estimated, it will be used to derive the study specific QT correction, QTcS, for 
adult patients in the QTc analysis set. 
5.2.8.2. Averaging of triplicate ECG parameter measurements 
After the above variables have been derived within each patient and scheduled timepoint, 
each ECG parameter (including QTcF, QTcB, QTcS, QT, HR, PR, RR, QRS) should each be 
averaged as follows:  (1st measurement + 2nd measurement + 3rd measurement) / 3.  All 
summary statistics, analyses and figures will be based on the triplicate averaged data from 
the ECG core laboratory. 
5.2.8.3. Change from baseline 
The change from baseline calculations for ECG parameter measurements is derived from the 
triplicate averaged measurements.  Change from baseline is defined as a patient’s parameter 
value at a particular timepoint minus baseline value (value - baseline value). Change from 
baseline calculations should only use post-dose ECG measurements at the scheduled nominal 
timepoints (Day 1 at 1, 2, 4 hours; Day 4 at 0, 2 hours; Day 7 at 0, 2, 4, 6 for Cycle 1; and in 
Cycle 2 Day 1 at 0, 2 hours; Day 7 at 0, 2 6 hours).  Baseline is defined in Section 3.4.  
5.2.8.4. Categorization of ECG parameters 
The categorization of QTc will be per ICH E14 guidance: 
The absolute QTc interval (QTcF and QTcS) value for each patient will be categorized as 
<=450; >450 - <=480, >480 - <=500; >500 msec, using the maximum value post baseline 
(considering both cycles) based on the averaged triplicate values.  Similarly, the absolute 
values of HR, PR and QRS will be categorized as follows:  HR <= 50 bpm, HR >= 120 bpm, 
PR >= 220 msec and QRS >= 120 msec. 
 


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Protocol B1761031 (PF-05208747 (CMA-676)) Statistical Analysis Plan 
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Page 23 
 
 
 
5.3. Methods to Manage Missing Data 
5.3.1. Missing Dates 
In data listings, dates will reflect the information provided by the investigator on the CRF, if 
any imputation was applied to data presented in listings, such data will be clearly marked as 
imputed. 
5.3.1.1. Missing or Partial Adverse Event dates/times 
Complete adverse event dates are needed to determine treatment emergence, and to assign 
adverse events to cycles, therefore missing or partial dates will be imputed.  Completely 
missing AE dates will be imputed as follows with the end result that the events will be 
considered treatment emergent.  
AE Start Date: If the AE start date is missing, and if the date of first dose is less than AE 
end date, then the start date will be assigned as the date of first dose. Otherwise if the date of 
first dose is after the AE end date then the AE start date will be imputed as the earliest of 
non-missing AE end date or informed consent date.  
AE Stop Date: If the AE end date is missing then the end date will be imputed as the latest 
of the Subject Withdrawal/Completion date, death date, last dose of study treatment, or AE 
start date. 
5.3.1.2. Missing or Partial Death Dates:  
Missing or partial death dates will be imputed based on the last contact date: 
• If the entire date is missing it will be imputed as the day after the date of last contact 
(see derivation of date of last contact in Section 5.2.6); or 
• If the day or month is missing, death will be imputed to the maximum of the full 
(non-imputed) day after the date of last contact and the following: 
- Missing day: 1st day of the month and year of death, or 
- Missing day and month: January 1st of the year of death. 
5.3.1.3. Missing or Partial Anti-cancer Treatment dates  
Incomplete dates for new (follow-up) anti-cancer treatment will be imputed as follows: 


Protocol B1761031 (PF-05208747 (CMA-676)) Statistical Analysis Plan 
PFIZER CONFIDENTIAL 
Page 24 
 
 
• The end date of new anti-cancer therapy will be included in the imputation for start date 
of new anti-cancer therapy.  If the end data of new anti-cancer therapy is: 
o completely missing then it will be ignored in the imputations below,  
o partially missing with only year available then the imputations below will 
consider 31DECYYYY as the end date of the new anti-cancer therapy, or 
o partially missing with only month and year available then the imputations below 
will consider the last day of the month for MMMYYYY as the end date of the 
new anti-cancer therapy. 
• If the start date of new anti-cancer therapy is completely or partially missing then the 
imputed start date of new anti-cancer therapy will be: 
= 31DECYYYY, if only Year is available and Year < Year of min (last dose of 
study treatment + 1, end date of new anti-cancer therapy) 
= Last day of the month, if both Year and Month are available and  
Year = Year of min (last dose of study treatment + 1, end date of new 
anti-cancer therapy) 
Month < Month of min (last dose of study treatment + 1 day, end date 
of new anti-cancer therapy) 
= min (last dose of study treatment + 1, end date of new anti-cancer therapy), 
for all other cases. 
5.3.1.4. General concomitant medications and concomitant non-drug procedures 
If start dates of concomitant medications or concomitant non-drug treatments are completely 
missing, the medications and non-drug treatments/procedures will be considered concomitant 
unless the medication stop date is prior to first study treatment.  If only partial information 
are available, (e.g. only a month and year or only a year) dates will be imputed (see Section 
5.3.1.5) and thus if the imputed dates based on the partial information provides sufficient 
information to indicate the dates are prior to the start of study treatment (e.g. month/year less 
than month/year of first dose) then these will be considered to have started prior to treatment; 
otherwise these will be considered to have started after treatment. 
5.3.1.5. Other Missing or Partial Dates   
Imputation methods for other missing or partial dates which will be used in computations of 
durations will be as follows (e.g. date of diagnoses):  
• If the day of the month is missing for a start date used in a calculation, the first day 
of the month will be used to replace the missing date.  


Protocol B1761031 (PF-05208747 (CMA-676)) Statistical Analysis Plan 
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Page 25 
 
 
• If both the day and month are missing, the first day of the year is used.  
• For stop dates, the last day of the month, or last day of the year is used if the day or 
day and month are missing, respectively.  
• If the date is completely missing, no imputation will be performed (other than as 
explicitly described in this section). 
5.3.2. Missing Toxicity Grades of Adverse Events 
In summaries which present maximum toxicity grade, the maximum of non-missing grades 
will be displayed.  A patient will be counted as a missing grade only when all occurrences for 
a particular event are reported as missing.  
5.3.3. Missing absolute WBC differential counts and Normal Ranges  
For WBC differential counts (total neutrophil [including bands], lymphocyte counts), the 
absolute value will be used when the results are reported in this manner. When only 
percentages are available the absolute value will be derived as follows:  
Derived differential absolute count = (WBC count) × (Differential % value / 100) 
If both the absolute and % value for Neutrophils or Lymphocytes are reported from the same 
laboratory sample date and patient, only the absolute value will be graded.  The % value will 
not be graded in this scenario.    
If the % value is converted to the differential absolute count for grading and the LLN for the 
differential absolute count is not available (only LLN for % is available) then Grade 1 will be 
assigned if the following conditions are met:  
• Lymphocyte count decreased:   
- derived absolute count does not meet Grade 2-4 criteria, and 
- % value < % LLN value, and 
- derived absolute count  ≥ 800/mm3 
• Neutrophil count decreased  
- derived absolute count does not meet Grade 2-4 criteria, and 
- % value < % LLN value, and 
- derived absolute count  ≥ 1500/mm3 
5.3.4. Missing Pharmacokinetic (PK) Data 
In all data presentations (except listings), concentrations below the limit of quantification 
(BLQ) will be set to zero. (In listings BLQ values will be reported as “<LLQ”, where LLQ 


Protocol B1761031 (PF-05208747 (CMA-676)) Statistical Analysis Plan 
PFIZER CONFIDENTIAL 
Page 26 
 
 
will be replaced with the value for the lower limit of quantification.)  If a summary statistic is 
a BLQ value, it will also be reported as zero. 
In summary tables and plots of median profiles, concentrations will be set to missing if one 
of the following cases is true: 
• A concentration has been reported as ND (i.e., not done) or NS (i.e., no sample); 
• A deviation in sampling time is of sufficient concern or a concentration has been 
flagged as anomalous by the clinical pharmacologist. 
Summary statistics will not be presented at a particular timepoint if more than 50% of the 
data are missing.  Actual PK sampling times will be used in the derivation of PK parameters.   
If a PK parameter cannot be derived from the concentration data, the parameter will be coded 
as NC (i.e. not calculated). NC values will not be generated beyond the day that a patient 
discontinues. 
In summary tables of PK parameters, statistics will be calculated by setting NC values to 
missing; and statistics will not be presented if more than 50% of the data are NC and 
statistics will be presented for ≥3 evaluable measurements .   
If an individual patient has a known biased estimate of a PK parameter, this will be footnoted 
in summary tables and will not be included in the calculation of summary statistics. 
5.3.5. Missing ECG Data 
For ECG parameters, no values will be imputed for missing replicates within a scheduled 
assessment.  Thus if the three triplicate measurements for an ECG parameter are not 
available, then the average will not be computed.   
 
6. ANALYSES AND SUMMARIES 
If both adult and pediatric patients enrollment are completed and respective LPLV are 
included in the same same database release,  all summary tables will have separate 
tabulations (columns) for adult and pediatric patients, and also a total column combining 
adult and pediatric patients, unless noted otherwise.  If adult and pediatric patients are to be 
reported at different times, for example if adult LPLV is reached while pediatric enrollment 
is still ongoing, with pediatric patients summary to be reported at a later database release then 
summary tables may not contain a total column.  
Listings will be provided as required for an ICH CSR.  Additional details for some data 
listings are described for some data types in the following sections.  As relevant, listings or 
summary tables focused on COVID-19 will be provided such as participants affected by 
COVID-19 related study disruption, protocol deviations, COVID-19 related deaths, COVID-
19 related discontinuations. 


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Page 27 
 
 
 
6.1. Primary Endpoint 
6.1.1. Change in QTcF from baseline 
ECG measurements from the ECG core laboratory (an average of the triplicate 
measurements) will be used for the statistical analysis and all data presentations.  Only the 
scheduled ECGs from adult patients in Cycle 1 and the particular timepoints of Day 4, 0 
hours, and Day 7 at 0, 2, 4, and 6 hours will be interpreted for the primary analysis.   The last 
available planned triplicate measurements prior to first dose will be used as baseline.   
QT measurements will be corrected by heart rate (QTc) according to Fridericia’s (QTcF) 
method.   
 
A linear model (for adult patients and pediatric patients separately) with the Cycle 1 nominal 
timepoints as a fixed effect and unstructured variance/covariance to account for the repeated 
measurements from patients will be used for the primary analysis to estimate the mean 
change in QTcF (primary endpoint) at the post baseline nominal timepoints for Cycle 1 along 
with the estimated least squares means and 2-sided 90% confidence interval for the mean.  
Confidence intervals will use the approximate t distribution with degrees of freedom by 
Kenward Rogers method.  Refer to Section 5.2.8 for further details of derivations.  Although 
the 90% CI for the mean change in QTcF from the Cycle 1 Day 4, 0 hours, and Cycle 1 Day 
7, at 0, 2, 4 and 6 hours summarized for adult patients will be interpreted (see Section 5.1), 
all Cycle 1 timepoints will be included in the estimation.  
  
Summary will be for the QTc analysis set.  The least squares mean and its 90 % confidence 
interval will be displayed graphically. 
Additional summaries of QT interval data are described in Section 6.6.5 along with the 
summary of other ECG data. 
6.2. Secondary Endpoints 
6.2.1. Pharmacokinetc Endpoints 
6.2.1.1. Non-Compartmental Analysis 
To assess the pharmacokinetics of GO (represented by total hP67.6 antibody, conjugated 
calicheamicin, and unconjugated calicheamicin if possible), the PK parameters detailed in 
Section 3.2.1  will be summarized for subjects in the PK analysis set (as defined in Section 
4.4.2).  Missing values will be handled as detailed in Section 5.3.4.   
Each PK parameter for each analyte (total hP67.6 antibody, conjugated calicheamicin, and 
unconjugated calicheamicin) will be summarized using the set of descriptive statistics as 
specified in the table below: 


Protocol B1761031 (PF-05208747 (CMA-676)) Statistical Analysis Plan 
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Page 28 
 
 
Table 2. PK Parameters to be Summarized Descriptively 
Parameter 
Summary Statistics 
AUClast, AUC0-72, 
AUC0-336, AUCinfa, 
Cmax, CL*,a and Vss*,a 
N, arithmetic mean, median, cv%, standard deviation, minimum, 
maximum, geometric mean and geometric cv%. 
Tmax 
N, median, minimum, maximum. 
t1/2a 
N, arithmetic mean, median, cv%, standard deviation, minimum, 
maximum. 
*for total hP67.6 antibody only 
a if data permit 
 
Supporting data from the estimation of t½  and AUCinf will be listed by analyte or provided in 
data sets where applicable:  terminal phase rate constant (kel); goodness of fit statistic from the 
log-linear regression (r2); the percent of AUCinf based on extrapolation (AUCextrap%); the first, 
last, and number of time points used in the estimation of kel.   
Presentations for plasma concentrations of GO (total hP67.6 antibody, conjugated 
calicheamicin, and unconjugated calicheamicin) will include: 
• Listings will be consistent with ICH CSR requirements and may include: A listing of 
all concentrations sorted by participant ID, cycle, day and nominal time postdose. The 
concentration listing will also include the actual times. Deviations from the nominal 
time will be given in a separate listing. 
• A summary of concentrations by nominal time postdose, where the set of descriptive 
statistics will include n, mean, median, standard deviation, coefficient of 
variation(cv), minimum, maximum and the number of concentrations above the lower 
limit of quantification. 
• Median concentrations time plots (on both linear and semi-log scales) against 
nominal time postdose for Cycle 1 Day 1 and Cycle 1 Day 7 . 
 
For summary statistics, median plots by sampling time, the nominal PK sampling time will 
be used, for individual participant plots by time, the actual PK sampling time will be used. 
 
6.2.1.2. Population Pharmacokinetics/Pharmacodynamics 
Population PK/PD modeling analyses will be explored, as necessary, based on emerging 
safety/clinical response data. The results of these population modeling analyses will be 
reported separately from the clinical study report. 
6.2.2. Immunogenicity 
Immunogenicity will be summarized for the immunogenicity analysis set (as defined in 
Section 4.4.4). 
 


Protocol B1761031 (PF-05208747 (CMA-676)) Statistical Analysis Plan 
PFIZER CONFIDENTIAL 
Page 29 
 
 
The percentage of patients with positive ADA and NAb will be summarized (eg. at baseline, 
treatment-induced (positive for the first time after dosing), and treatment-boosted (pre-
existing positive titers that were at a higher level post-baseline), and overall (treatment-
induced + treatment-boosted).  The overall percentage will be computed excluding baseline 
positive patients without any post-dose assessment.  The other percentages will be based on 
the number of patients in the immunogenecity analysis set. 
 
For patients with positive ADA/NAb, the magnitude of the titer will be described with 
summary statistics (median, Q1, Q3) for positive baseline titers, peak titer for treatment-
induced and treatment-boosted, and titer fold increase for treatment-boosted (calculated as 
the ratio of peak post-dose titer to baseline titer), if data permit. 
For patients with treatment induced ADA/NAb, time of onset, and duration will also be 
described with summary statistics (median, Q1, Q3), if data permit.  Onset of ADA/NAb will 
be calculated as date of date of first positive result – date of first dose +1.  Duration of 
ADA/NAb will be calculated as date of last positive result – date of first positive result +1.  
The number and percent of transient and persistent positive ADA/NAb will be summarized 
out of the number of patients with treatment-induced ADA/NAb. 
Transient ADA/NAb will be defined as treatment-induced ADA/NAb meeting the following 
conditions: 
• detected only at one sampling time point during the treatment or follow-up 
(excluding the last sampling time point which will be considered persistent 
unless shown to be undetectable at a later time) or 
• detected at two or more sampling time points during the treatment (including 
follow-up), where the first and last positive samples (irrespective of any 
negative samples in between) are separated by a period less than 16 weeks, 
and the last sampling time point is negative 
 
Persistent ADA/Nab will be defined as treatment-induced ADA/NAb meeting the following 
conditions: 
• detected at two or more sampling time points during the treatment (including follow-
up), where the first and last positive samples (irrespective of any negative samples in 
between) are separated by a period of 16 weeks or longer or 
• detected only in the last treatment sampling time point or at a sampling time point 
with less than 16 weeks before a negative last sample. 
 
Analyses to assess the impact of ADA on safety are described in Section 6.6.1. The 
impact of ADA on PK will be assessed in population PK analysis and will be reported 
separately. 


Protocol B1761031 (PF-05208747 (CMA-676)) Statistical Analysis Plan 
PFIZER CONFIDENTIAL 
Page 30 
 
 
6.2.3. Best Response 
Best response will be summarized for the full analysis set. 
Best response is derived from the cycle 1 and cycle 2 disease assessments according to the 
investigator (Section 3.2.3).  The summary will include response (CR+CRi), along with the 
subcategories CR, CRi, and no response. 
Best response will be summarized as a binary variable using frequency counts, percentages, 
and will additionally include a 95% Clopper-Pearson CI for the rate. 
Additionally, summaries of the disease assessment for each cycle (Cycle 1 and Cycle 2) 
summarizing the categories as collected on the CRF with the exception that CR will be used 
(combining any CRF category with CR in the label).  The denominator will include only 
patients who received that cycle.   
6.2.4. Overall Survival 
Overall Survival will be summarized for the full analysis set. 
Overall survival is defined as the time from the start date to the date of death due to any 
cause.  Patients last known to be alive as censored at the date of last contact (Section 5.2.6).   
Overall survival will be reported in months and derived as ((death date or censoring date) – 
start date +1)/ 30.4375. 
The summary will include the number of deaths as well the cause of death, the number of 
censored patients as well as the reason for censoring (Withdrawal of consent, Lost to Follow-
up, Alive). 
Overall survival will be summarized using the Kaplan-Meier method.  The quartiles and 
probabilities of an event at 6 months and 12 months will be estimated by the Kaplan-Meier 
method.  Confidence intervals (95 %) for quartiles will be based on the Brookmeyer-Crowley 
method.  Confidence intervals (95%) for the estimated probability of event at 12 months will 
be generated using the log(-log) method with back transformation to a confidence interval on 
the untransformed scale.  
The estimated overall survival curves will be displayed graphically, with one graph including 
estimates for the adult and pediatric patients separately,. Graphs will describe the number of 
patients at risk over time.  
Deaths related to COVID-19 will be presented in listings, if there are < 5 COVID-19 related 
deaths. 
  


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Protocol B1761031 (PF-05208747 (CMA-676)) Statistical Analysis Plan 
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For the patients with a prior HSCT, a summary of the following characteristics (number and 
percentage) using patients with a prior HSCT as the denominator will be provided.  Each of 
the following aspects will be summarized according to the categories collected on the CRF. 
• Time of transplant relative to first GO dose (<2 mos or ≥2 mos before the first dose of 
GO) 
• Type of transplant  
• Donor relatedness  
• HLA compatibility  
• Stem Cell Source  
• Type of conditioning 
• Disease Risk at Transplant 
 
6.5.2. Study Conduct and Subject Disposition 
Evaluation Groups:  A summary of the number of patients screened, the number of screen 
failures, the number of patients enrolled, and the number treated and not treated with 
percentages for the last two items based on the number of patients enrolled.  Additionally, the 
number of patients in each analysis set will be summarized. 
Protocol Devations:  Protocol deviations will be compiled prior to database closure and 
categories will be assigned by the study clinician.  Potentially important protocol deviations 
will be summarized by category (number and percent) (full analysis set).    As relevant, 
important protocol deviations due to COVID-19 will be included.  Protocol deviations related 
to COVID-19 will be presented in listings. 
Disposition: Disposition events will be summarized for each phase (screening, treatment, 
and follow-up (representing end of study)) with number and percentage.  Within a phase, a 
summary of the reason for discontinuation as collected on the CRF, and the number 
completed that phase.  (full analysis set)  Discontinuations related to COVID-19 will be 
presented in a separate summary table. 
Inclusion and Exclusion Criteria:  The number and percentage of patients who did not meet 
at least one of these criteria will be summarized.  Additionally, the number and percentage of 
patients who did not meet each criterion will be summarized. (full analysis set and screen 
failure patients) 
Impact of COVID-19 on Missed ECG Assessments:  Impact to Cycle 1 ECG assessments 
will be assessed by showing assessments completed before and after the anchor date (Section 
5.2.14) and planned assessments (relative to the first dose date).   
 
6.5.3. Study Treatment Exposure 
Study treatment exposure (GO dosing) will be summarized for the safety analysis set. 


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The following will be summarized with frequencies and percentages for each cycle: 
• Patients receiving each dose (GO on Day 1, Day 4, Day 7) according to nominal 
timepoint. 
• Patients receiving all doses in the cycle. 
• Duration of treatment of GO computed from the first dose to the last dose within the 
cycle and categorized as <7 days, 7 days, >7 days. 
For patients receiving Cycle 2, the study day for the start (first GO dose) in Cycle 2 
categorized as Before Day 28, Day 28 to Day 34, Day 35 to Day 42, Day 43 to Day 
49, After Day 50 will be summarized with number and percentage. 
Exposure including all cycles received in terms of total number GO doses categorized as <3, 
3, 4, 5, 6 doses which will be summarized with number and percentage. 
6.5.4. Concomitant Medications and Non-Drug Treatments 
Per protocol, all concomitant medications, including prescription and nonprescription drugs, 
nondrug treatment, and dietary supplements and herbal preparations, will be entered on the 
case report form (CRF).  Concomitant medications and treatments will be recorded from 
28 days prior to the start of study treatment and up to 36 days post the last dose of study 
treatment or start of subsequent anticancer therapy (e.g., consolidation or conditioning 
regimen).  Medications and treatments for the managements of VOD/SOS during the follow-
up period are also to be collected. 
Concomitant medications and non-drug treatments received by patients during the study will 
be summarized for the safety analysis set. 
Concomitant medications refer to all medications which started prior to first dose of study 
treatment but continued during the on-treatment period (see Section 3.5) as well as those 
started during the on-treatment period (including starting on the date of the first dose of study 
drug).  Concomitant medications will be coded in the WHO Drug coding dictionary and will 
be tabulated by Anatomical Therapeutic Chemical (ATC) Classification level 2 and preferred 
term in alphabetical order. A patient will be counted only once within a given drug class and 
within a given drug name, even if the same medication was received at different times.  
Preferred Terms will be reported under each ATC class that it is included under within WHO 
Drug (since no primary path is available in WHO Drug). 
Concomitant non-drug treatments refer to all non-drug treatments administered during 
the on-treatment period (including on the date of the first dose of study drug).  Non-drug 
treatments will be MedDRA coded and will be summarized by MedDRA SOC and PT 
alphabetical order.  Patients will be counted only once per PT even if the same treatment 
was received multiple times. 
 


Protocol B1761031 (PF-05208747 (CMA-676)) Statistical Analysis Plan 
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Any medications which were only administered prior to treatment start will be 
summarized for the safety analysis set by WHO Drug coding dictionary preferred term 
in alphabetical order.  
Any non-drug treatments, aside from anti-cancer treatments described in Section 6.5.1.4, 
which were only administered prior to treatment start will be listed as needed to be 
compliant with ICH required listings but not summarized. 
Transfusions: for each of the two transfusion types (Packed RBC and Platelets) the number 
of days with a transfusion during the on-treatment period for each cycle will be computed for 
each patient.  For each cycle, each transfusion type will be summarized with summary 
statistics (n, mean, median, standard deviation, minimum, and maximum) of the number of 
days with transfusion.  Additionally, the number of days will be categorized as (<=7 days, 8-
14, 15-21, 22-28, 29-36, >36) and the number and percent of patients in each category will be 
summarized. 
 
6.5.5. Follow-up Anti-cancer Treatments 
Summaries will be for the full analysis set. 
Follow-up anti-cancer systemic therapies will be identified as therapies with start date after 
the last dose of study treatment.   
A summary of number of follow-up regimens according to the number and percentage of 
patients with 1, 2, 3, or >3 induction regimens will be provided. 
A summary of the number and percentage of patients with at least one follow-up regimen, 
and the number of patients with at least one induction regimen, at least one conditioning 
regimen, at least one consolidation or intensification regimen, and at least one maintenance 
regimen will be provided. 
Follow-up radiation treatments will be identified by start date after the last dose of study 
treatment.  A summary of the number and percentage of patients with at least one follow-up 
radiation treatment given for conditioning, and the number and percentage of patients with at 
least one follow-up radiation treatment for other reasons will be provided. 
Follow-up HSCT will be identified by start date after to the last dose of study treatment. The 
number and percentage of patients with at least one follow-up HSCT and a summary of 
patients according to the number of follow-up HSCT (1, >1) (number and percentage) will be 
provided.  Follow-up HSCT will be identified by HSCT date after the last dose of study 
treatment. If a patient has more than one follow-up HSCT, then the first HSCT after to study 
treatment will be included in the summary. 
For the patients with a follow-up HSCT a summary of the following characteristics (number 
and percentage) using patients with a follow-up HSCT as the denominator will be provided.  


Protocol B1761031 (PF-05208747 (CMA-676)) Statistical Analysis Plan 
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Page 37 
 
 
Each of the following aspects will be summarized according to the categories collected on 
the CRF. 
 
• Time of transplant relative to last GO dose (< 2 mos or ≥ 2 mos after the last dose of 
GO)  
• Type of transplant  
• Donor relatedness  
• HLA compatibility  
• Stem Cell Source  
• Type of conditioning  
• Disease Risk at Transplant 
 
6.6. Safety Summaries and Analyses 
Safety (AE and other parameters) summaries will be provided for the safety analysis set 
unless otherwise specified. 
6.6.1. Adverse Events 
The following general considerations will be applied to AE summaries: 
All analyses will be based on treatment emergent events unless otherwise specified.  
Treatment emergent is defined in Section 3.5.1.  AEs not considered treatment emergent will 
be flagged in data listings (as applicable to listings needed to be compliant with ICH required 
listings). 
• For summaries including CTCAE grade, patients will be counted according to the worst 
grade for the particular PT or SOC and will also include a total across grades. 
• For summaries including toxicity grade, as described in Section 5.3.2, in the case that a 
patient has events with missing and non-missing toxicity grades, the maximum of the non-
missing grade will be displayed.   Missing grade will only be displayed in the event that 
only one event has been reported for a patient and the grade is missing. 
• There will also be a row for the number and percentage of patients reporting at least 1 AE. 
• For summaries including SOC, the number and percentage of patients with at least 1 AE 
in that SOC will be reported. 
• The denominator for percentages will be the number of patients treated in the group being 
summarized. 
• Each patient will be counted only once within each SOC and PT.   
• In summaries of treatment related AEs, if the relationship to study treatment is missing on 
the CRF, it will be assumed to be related to treatment. 
A high level summary of adverse events (all causality and also for treatment related events) 
will include the number and percentage of patients with: 
• Any Adverse Event 
• Serious AE 


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• Treatment Emergent Adverse Events Leading to Study Drug Withdrawal (ie based on 
last action taken for study drug; not study discontinuation) (All causality) by 
Maximum CTCAE grade showing at least Grade 5. 
• Treatment Emergent Adverse Events Leading to Study Drug Withdrawal (ie based on 
last action taken for study drug; not study discontinuation) (Treatment Related) by 
Maximum CTCAE grade showing at least Grade 5. 
• Treatment Emergent Adverse Events Leading to Study Drug Interruption (All 
causality) 
• Treatment Emergent Adverse Events Leading to Study Drug Interruption (Treatment 
Related) 
• Treatment Emergent Adverse Events by Maximum CTCAE Grade (All Causality) 
with grouped grades such as Grade 1-2; Grade 3-4; Grade 5; Grade ≥3 with a cutoff 
such as ≥10% of any patient group 
• Treatment Emergent Adverse Events by Maximum CTCAE Grade (Treatment 
Related) with grouped grades such as Grade 1-2; Grade 3-4; Grade 5; Grade ≥3 with 
a cutoff such as ≥10% of any patient group 
• Serious Treatment Emergent Events (All Causality) with a cutoff such as  ≥ 2 adult 
patients 
• Serious Treatment Emergent Events (Treatment Related) with a cutoff such as ≥ 2 
adult patients 
 
6.6.1.1. VOD 
Summaries focused on VOD/SOS (The MedDRA PTs of Venoocclusive liver disease and 
Venoocclusive disease) will include the following number and percentage of patients out of 
the following groups (denominator): 
• Any VOD with denominator of safety analysis set 
• VOD before  (first) follow-up HSCT with denominator of safety analysis set 
• VOD before (first) follow-up HSCT with denominator of safety analysis set with a 
prior HSCT 
• VOD after follow-up HSCT with denominator of safety analysis set with a follow-up 
HSCT 
• VOD after follow-up HSCT with denominator of safety analysis set with both a prior 
and a follow-up HSCT. 
 
Timing relative to study treatment and HSCT (days):  The timing of the first VOD relative to 
the nearest prior GO dose will be summarized with descriptive statistics (VOD start date – 
nearest GO dose date +1).  The timing of the first HSCT relative to the nearest VOD after the 


Protocol B1761031 (PF-05208747 (CMA-676)) Statistical Analysis Plan 
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Page 40 
 
 
HSCT date  (days) will be summarized with descriptive statistics (VOD start date – first 
HSCT date +1). 
6.6.1.2. Basic Results 
The following additional summaries required for basic results disclosures in the US and EU 
will be provided: 
• Treatment Emergent Non Serious Adverse Events by SOC and PT (All Causality) in >5% 
of patients in either group; 
 
• Treatment Emergent Non Serious Adverse Events by SOC and PT (All Causality); 
 
• Treatment Emergent Serious Adverse Events by SOC and PT; and  
 
• Fatal Adverse Events by SOC and PT (based on safety database). 
Each of the above summaries for EU will include a count of the number of occurrences of all 
causality events and the number of occurrences of treatment related events. 
6.6.2. Deaths 
The frequency (number and percentage) of patients in the safety analysis set who died and 
who died within 36 days after last dose of study treatment as well as the cause of death, will 
be tabulated based on information from the ‘Notice of Death’ CRFs.   
The frequency (number and percentage) of patients in the safety analysis set who died within 
30 days of first dose of study treatment will also be provided. 
Date and cause of death will be provided in individual patient data listing (as needed to be 
compliant with ICH required listings) together with selected GO dosing information (date of 
first / last administration). 
Refer to Section 6.2.4 for the description of the summaries of all deaths observed in the 
study. 
6.6.3. Laboratory Data 
Laboratory results will be converted to International System of Units (Système International 
d'unités, SI) units which will be used for applying toxicity grades and for all summaries.  
Laboratory data will be graded programmatically according to the NCI CTCAE v4.03 
severity grade (including low and high values if both are defined for the parameter). Non-
numeric qualifiers will not be taken into consideration in the derivation of grade (e.g. 
hypokalemia Grade 1 and Grade 2 are only distinguished by a non-numerical qualifier and 
therefore Grade 2 will not be derived). In summaries the number and percentage of patients 
corresponding to grades that only include non-quantitative criteria will be displayed as a 


Protocol B1761031 (PF-05208747 (CMA-676)) Statistical Analysis Plan 
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Page 41 
 
 
blank or NA (not assessed).  If there is any overlap between grade criteria (e.g. CTCAE 
grading criteria for Creatinine Increased – a value can fall into one range based on 
comparison to ULN and another range based on comparison to baseline), the highest (worst) 
grade would be assigned to that record. Grade 5 is defined in the CTCAE criteria guidance as 
an event with an outcome of death. Since laboratory data does not collect an outcome, Grade 
5 is not used when programmatically grading laboratory data. 
Grade 0 or Outside Toxicity Reference (OTR) is not defined specifically by in the CTCAE 
guidance. However, programmatically this is used as a category to represent those patients 
who did not meet any of the Grades 1 to 4 criteria.  If the laboratory value is evaluable for 
CTCAE criteria grading (numeric value is present, valid units and ranges are present as 
required to allow conversion to standard units and grading), and does not qualify for any of 
the Grade 1-4 criteria for a given laboratory test, then the value is assigned as Grade 0 or 
OTR. 
For WBC differential counts (total neutrophil [including bands], lymphocyte counts), the 
absolute value will be used when the results are reported in this manner. When only 
percentages are available the absolute value will be derived as follows:  
Derived differential absolute count = (WBC count) × (Differential %value / 100) 
If both the absolute and % value for Neutrophils or Lymphocytes are reported from the same 
laboratory sample date and patient, ONLY the absolute value will be graded.  The % value 
will not be graded in this scenario.   Further details of the grading of the computed absolute 
values are provided in Section 5.3.3. 
Several laboratory tests have bi-directional grading criteria defined so that both low (hypo) 
and high (hyper) values will be graded separately.  Each criterion will be summarized 
separately.  In the cases where a value is graded as a Grade 1, 2, 3, or 4 for one of the 
directions, that value will also be assigned as a Grade 0 for the opposite direction for that 
test.  For example, a value meeting the criteria for Grade 3 Hypercalcemia will be classified 
as a Grade 0 Hypocalcemia. 
The following summaries will be provided for the safety analysis set. 
The denominator for percentages will be the number of patients treated in the group being 
summarized with at least 1 post baseline assessment of the laboratory parameter. 
Displays will be organized by laboratory category: Hematology parameters including 
coagulation parameters will be summarized together, chemistry parameters will be 
summarized together, and urinalysis parameters will be summarized together.    Laboratory 
parameters with CTCAE grades will be summarized separately from laboratory parameters 
with no CTCAE grades. 
For each CTCAE term, patients will be counted according to the worst (maximum) CTCAE 
grade on treatment (excluding baseline values).  Baseline is defined in Section 3.4.  If there 
are multiple assessments that meet the baseline definition on the same day without the ability 


Protocol B1761031 (PF-05208747 (CMA-676)) Statistical Analysis Plan 
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Page 42 
 
 
to determine which was truly last, then the worst CTC grade will be assigned as the baseline 
CTC grade.   
The following summary tables will be created: 
• Shift summary of laboratory parameters of baseline CTCAE grade by maximum post 
baseline CTCAE grade.   
• Shift summary of laboratory parameters from ≤ Grade 2 at baseline to ≥ Grade 3 
post-baseline.  
The non-CTC graded laboratory tests (red blood cells, hematocrit, BUN, LDH) along with 
urinalysis test (pH) will be presented according to the following categories overall:  below 
normal limit, within normal limits, and above normal limits. In the unlikely event that for a 
given participant, clinically significant abnormalities are noted in both directions (eg, > ULN 
and < LLN), then both abnormalities are counted.  The remaining urinalysis tests (albumin, 
glucose, blood/hemoglobin, ketones/acetone) will be categorized as negative or positive. 
 
A shift summary of laboratory test results with no CTCAE criteria of baseline assessment by 
worst on-treatment assessment will be created. . 
 
6.6.3.1. Time To Recovery  
The analysis of Time to Recovery of Neutrophils and the analysis of Time to Recovery of 
Platelets will be similar, therefore this section is written generically as “Time to Recovery”.   
Time to Recovery for responders will be reported in days and derived as ((recovery date or 
censoring date) – date of first dose +1) for each cycle (for responders in that cycle). 
The summary will include the number of patients recovered to the level of interest and the 
number of patients not recovered and reported for the safety analysis set. 
Time to Recovery will be summarized using the Kaplan-Meier method. The quartiles will be 
estimated by the Kaplan-Meier method.  Confidence intervals (95%) for quartiles will be 
based on the Brookmeyer-Crowley method.   
The estimated survival curves will be displayed graphically (unless there are < 5 responders) 
with one graph including estimates for the adult and pediatric patients separately. Graphs will 
describe the number of patients at risk over time.  
Prolonged Cytopenias (Neutrophils and Platelets): For each cycle, patients with Time to 
Recovery longer than 42 days will be considered prolonged and summarized for the safety 
analysis set.  The percentage will be based on a denominator that will exclude patients 
without data to determine the status at Day 42 relative to the cycle start.  Thus prolonged 
cyotopenias applies only to patient who are responders in the respective cycle. 


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Page 43 
 
 
6.6.3.2.  Hy’s Law Assessment 
Liver function tests: Alanine aminotransferase (ALT), aspartate aminotransferase (AST), 
Alkaline Phosphatase (ALP), and total bilirubin (TBILI) are used to assess possible drug 
induced liver toxicity.    
An evaluation of drug-induced serious hepatotoxicity (eDISH) by scatterplots of using all 
data from the on treatment period will be produced to assess hepatotoxicity and to identify 
any potential Hy’s Law cases.  This summary does NOT indicate actual Hy’s law cases.  
• Maximum serum ALT vs maximum total bilirubin including reference lines at 
ALT=3×ULN and total bilirubin=2×ULN.  
• Maximum serum AST) vs maximum total bilirubin including reference lines at 
AST=3×ULN and total bilirubin=2×ULN.  
In addition, a listing of all total bilirubin, ALT, AST and alkaline phosphatase values for 
patients with a post-baseline total bilirubin ≥ 2×ULN, ALT ≥ 3×ULN or AST ≥ 3×ULN will 
be provided. 
Summary of liver function tests will include the following categories.  The number and 
percentage of patients with each of the following during the on-treatment period will be 
summarized: 
• 
ALT ≥ 3×ULN, ALT ≥ 5xULN, ALT ≥ 10×ULN, ALT ≥ 20×ULN 
• 
AST ≥ 3×ULN, AST ≥ 5xULN, AST ≥ 10×ULN, AST ≥ 20×ULN 
• 
(ALT or AST) ≥ 3×ULN, (ALT or AST) ≥ 5×ULN, (ALT or AST) ≥ 10×ULN, 
(ALT or AST) ≥ 20×ULN 
• 
TBILI ≥ 2×ULN 
• 
Concurrent  ALT ≥ 3×ULN and TBILI ≥ 2×ULN 
• 
Concurrent AST ≥ 3×ULN and TBILI ≥ 2×ULN 
• 
Concurrent (ALT or AST) ≥ 3×ULN and TBILI ≥ 2×ULN  
• 
Concurrent (ALT or AST) ≥ 3×ULN and TBILI ≥ 2×ULN and ALP > 2×ULN 
• 
Concurrent (ALT or AST) ≥ 3×ULN and TBILI ≥ 2×ULN and ALP ≤ 2×ULN or 
missing 
Concurrent measurements are those occurring on the same date. 
Categories will be cumulative, i.e., a participant with an elevation of AST ≥10×ULN will 
also appear in the categories ≥5×ULN and ≥3×ULN. Liver function elevation and possible 
Hy’s Law cases will be summarized using frequency counts and percentages.  
Summary of liver function tests will also be provided by Cycle (1, 2, Follow-up). 
6.6.4. Vital Signs 
Vital sign data will  be listed as needed to be compliant with ICH required listings and not 
summarized. 


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6.6.5. Electrocardiogram 
This section describes all ECG parameter summaries including secondary analyses of 
changed from baseline in QTc.  Refer to Section 6.1.1 for the primary endpoint analysis.  As 
noted in Section 5.2, separate summaries for adult and pediatric patients will be presented.  
As noted in Section 5.2.8.1, a study specific QT interval correction will be evaluated only for 
adult patients.  All analyses will be provided for the QTc analysis set.  All summaries will be 
based on the ECG core laboratory (vendor) results for ECG parameters.   
6.6.5.1. Assessment of Correction Factors 
Scatterplots of QTc (QTcB, QTcF, QTcS) versus RR interval (msec) using individual 
replicates (non-averaged) from the timepoint selected as baseline including the linear 
regression line with description including slope and its 95% CI, intercept, and coefficient of 
determination (R2) will be presented. 
6.6.5.2. ECG Parameter Results 
The absolute corrected QT interval (QTcB, QTcF, and/or QTcS) will be summarized using 
descriptive statistics (n, mean, median, standard deviation (SD), minimum, maximum and a 
90% confidence interval for the mean) by cycle and nominal time point within cycle 
(Screening, Cycle 1: Day 1 at 0, 1, 2, 4 hours; Day 4 at 0, 2 hours; Day 7 at 0,  2, 4, 6, and 
Cycle 2 Day 1 at 0, 2 hours; Day 7 at 0, 2, 6.  The 90% CI for the mean will be calculated 
using the t-distribution and the observed standard deviation from the particular timepoint. 
In addition to QTc, the ECG parameters of HR, PR interval, QRS interval, QT interval will 
be summarized similarly with descriptive statistics (n, mean, median, standard deviation 
(SD), minimum, maximum). 
6.6.5.3. Change from baseline 
The change in QTc (QTcF, QTcB and/or QTcS) from baseline will be summarized using 
descriptive statistics (n, mean, median, standard deviation (SD), minimum, maximum for 
each cycle and nominal time point within cycle.  
A linear model (for adult patients and pediatric patients separately) with the Cycle 1 nominal 
timepoints as a fixed effect and unstructured variance/covariance to account for the repeated 
measurements from patients will be used to estimate the mean change from baseline (in 
QTcB and/or QTcS) at the post baseline nominal timepoints for Cycle 1 along with the 
estimated least squares means and 2-sided 90% confidence interval for the mean.  
Confidence intervals will use the approximate t distribution with degrees of freedom by 
Kenward Rogers method.   
In addition to QTc, the change from baseline in ECG parameters of HR, PR interval, QRS 
interval, QT interval will be summarized similarly with descriptive statistics (n, mean, 
median, standard deviation (SD), minimum, maximum). 


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6.6.5.4. Absolute QTc interval prolongation 
Categorical analysis of absolute QTc interval prolongation for QTc (QTcF and/or QTcS) 
according the maximum post-baseline value per patient will be summarized.  .  As described 
in Section 5.2.8.4, the categories of <=450; >450 - <=480, >480 - <=500; >500 msec will be 
used to classify post baseline values and the number and percentage of patients in each 
category will be summarized.  A similar categorical analysis of HR, PR and QRS will be 
provided (HR <= 50 bpm, HR >= 120 bpm, PR >= 220 msec and QRS >= 120 msec). 
Additionally a shift summary will be presented using CTCAE grade, where the baseline 
value will also be classified into the same categories and cross classified with the post 
baseline values.  Baseline is based on the triplicate average, but worst post baseline interval 
measurements will based based on individual repliates including values from unscheduled 
ECGs. The baseline versus the worst on treatment QTc will be summarized. 
6.6.5.5. Maximum increase from baseline QTc 
Categorical analysis of maximum increase from baseline in QTc (QTcF and/or QTcS) and 
will be summarized.  . As described in Section 5.2.8.4, the categories of <=30 msec, >30 - 
<=60 msec and >60 msec will be used and the number and percentage of patients in each 
category will be summarized.  A similar categorical analysis of HR and PR will be provided 
(HR increase from baseline >= 20 bpm and PR increase from baseline >=20 msec). 
6.6.6. Physical Examination 
Physical examination data will be  be listed as needed to be compliant with ICH required 
listings and not summarized. 
7. INTERIM ANALYSES 
Not applicable. 


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8. APPENDICES  
Appendix 1. SUMMARY OF PK ANALYSES 
The following PK parameters will be calculated for GO (represented by total hP67.6 
antibody, conjugated calicheamicin, and unconjugated calicheamicin) (if possible) from the 
concentration-time values using standard noncompartmental methods (Table 3). 
Appendix 1. Table 3. Noncompartmental PK Parameters 
Parameter 
Analysis 
Scale 
Total hP67.6 
antibody 
Conjugated  
calicheamicin 
Unconjugated 
calicheamicin 
AUCinf* 
Ln 
D 
D 
D 
AUClast 
Ln 
D 
D 
D 
AUC0-72 
Ln 
D 
D 
D 
AUC0-336 
Ln 
D 
D 
D 
Cmax 
Ln 
D 
D 
D 
Tmax 
R 
D 
D 
D 
t1/2* 
R 
D 
D 
D 
CL* 
Ln 
D 
D 
D 
Vss* 
Ln 
D 
D 
D 
Key: D=displayed with descriptive statistics, ln=natural-log transformed, R=raw 
(untransformed), *=if data permits. 
 


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Appendix 2. AESI Definitions 
HEPATOTOXICITY: (Severe (Grade ≥3) and/or serious hepatotoxicity including all 
VOD/SOS) encoded to MedDRA preferred terms (PTs) within the following Standardised 
MedDRA Query SMQ and PTs: 
 
SMQs: 
• Cholestasis and jaundice of hepatic origin (SMQ narrow) 
• Hepatic failure, fibrosis and cirrhosis and other liver damage-related conditions (SMQ 
narrow) 
• Hepatitis, noninfectious (SMQ narrow) 
• Liver related investigations, signs and symptoms (SMQ narrow and broad) 
PTs: 
Hepatic vein occlusion  
Hepatic vein thrombosis 
Portal vein thrombosis 
Portal vein occlusion 
Budd-Chiari syndrome 
 
All AES encoded to the following MedDRA PTs: 
• Venoocclusive liver disease 
• Venoocclusive disease 
 
HEAMORRHAGE:  
SMQ: 
Haemorrhage terms (excluding laboratory terms) (SMQ narrow) 
MYELOSUPPRESSION: AEs encoded to MedDRA preferred terms (PTs) within the 
following  SMQ: 
• Haematopoietic thrombocytopenia (SMQ narrow and broad) 
• Haematopoietic leukopenia (SMQ narrow) 
• Haematopoietic erythropenia (SMQ narrow and broad) 
• Haematopoietic cytopenias affecting more than one type of blood cell (SMQ narrow) 
 
INFECTIONS: Grade >3 AEs and/or serious AEs encoded to MedDRA preferred terms 
(PTs) within the following SOC and HLT 
SOC (General infections):  
• 
Infections and Infestations SOC 
HLTs (Lung infections): 
• 
Bacterial lower respiratory tract infections  
• 
Fungal lower respiratory tract infections 
• 
Lower respiratory tract infections NEC 


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• 
Respiratory tract infections NEC 
• 
Viral lower respiratory tract infections 
 
INFUSION RELATED REACTIONS (including Anaphylaxis):  From start of infusion to 
within 24 hours of end of infusion: 
Include events that occurred from start of infusion to within 24 hours of end of infusion: 
SMQ: 
• Anaphylactic reaction (SMQ narrow) 
• Angioedema (SMQ narrow) 
• Hypersensitivity (SMQ narrow) 
PT: 
• Cytokine release syndrome 
• Infusion related reaction 
• Chills 
• Pyrexia 
• Hot flush 
• Flushing 
• Feeling hot 
• Hyperhidrosis 
• Dizziness 
• Dyspnoea 
• Wheezing 
• Tachycardia 
• Hypotension 
 
Thus only AEs that start within a window according to the treatment exposure records of the 
start of the GO infusion in terms of date and time to 24 hours after the date and time of the 
stop of the infusion.   Since the AE CRF collects only AE start date and not start time, the AE 
start date will be compared to the date part only of the exposure window (rather than using 
imputed time of AE start. 
 
TUMOUR LYSIS SYNDROME: 
SMQ: 
Tumour lysis syndrome (SMQ narrow) 
 
CARDIAC CONDUCTION: 
SMQ Cardiac arrhythmias; Torsade de pointes/QT prolongation (SMQ narrow and broad)