Conditions: Leukemia Precursor b-Cell Lymphoblastic Leukemia-Lymphoma ACUTE LYMPHOBLASTIC LEUKEMIA
Keywords: Leukemia Precursor Cell Lymphoblastic Leukemia-Lymphoma ACUTE LYMPHOBLASTIC leukemia inotuzumab ozogamicin Besponsa transplant
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 102
Healthy volunteers: no

Brief summary:
This study will explore 2 different doses of inotuzumab ozogamicin including the dose that is approved and a lower dose. The main purpose of this study is to evaluate whether a dose of inotuzumab ozogamicin, lower than the approved dose, could be recommended for adult patient with relapsed or refractory ALL who may be at higher risk for severe liver problems after inotuzumab ozogamicin treatment and stem cell transplant (a potentially curative therapy that can replace cancer cells with healthy cells). Efficacy and safety of the 2 doses will be evaluated.

Detailed description:

Arms:
arm 1: Inotuzumab ozogamicin at starting dose 1.2 mg/m2/cycle (administered in 3 divided doses). Most patients expected to receive 2 or 3 cycles (cycle length 21 to 28 days) arm 2: Inotuzumab ozogamicin at starting dose 1.8 mg/m2/cycle (administered in 3 divided doses). Most patients expected to receive 2 or 3 cycles (cycle length 21 to 28 days)

Interventions: intervention 1: inotuzumab ozogamicin-dose level 2 intervention 2: Inotuzumab ozogamicin-dose level 1
Intervention descriptions: intervention 1: Inotuzumab ozogamicin (BESPONSA™) is a CD22 targeted antibody drug conjugate (ADC) approved by US FDA for treatment of adults with relapsed or refractory B cell precursor acute lymphoblastic leukemia (ALL). The approved starting dose is 1.8mg/m2/cycle. This treatment arm evaluates a lower starting dose of 1.2mg/m2/cycle. intervention 2: Inotuzumab ozogamicin (BESPONSA™) is a CD22 targeted antibody drug conjugate (ADC) approved by US FDA for treatment of adults with relapsed or refractory B cell precursor acute lymphoblastic leukemia (ALL). The approved starting dose of 1.8mg/m2/cycle is administered in this treatment arm.

Protocol document:
Prot_000.pdf: 
Inotuzumab ozogamicin (PF-05208773)
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Final Protocol 23 May 2018
PFIZER CONFIDENTIAL
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A PHASE 4, OPEN-LABEL, RANDOMIZED STUDY OF TWO INOTUZUMAB 
OZOGAMICIN DOSE LEVELS IN ADULT PATIENTS WITH RELAPSED OR 
REFRACTORY B-CELL ACUTE LYMPHOBLASTIC LEUKEMIA ELIGIBLE FOR 
HEMATOPOIETIC STEM CELL TRANSPLANTATION AND WHO HAVE RISK 
FACTOR(S) FOR VENO-OCCLUSIVE DISEASE
Investigational Product Number:
PF-05208773
Investigational Product Name:
Inotuzumab Ozogamicin
United States Investigational New Drug
(US IND) Number:
European Clinical Trial Database 
(EudraCT) Number:
2018-001557-27
Protocol Number:
B1931030
Phase:
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
Original protocol
23 May 2018
Not applicable


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TABLE OF CONTENTS
LIST OF TABLES.....................................................................................................................7
LIST OF FIGURES ...................................................................................................................7
PROTOCOL SUMMARY.........................................................................................................9
SCHEDULE OF ACTIVITIES................................................................................................14
1. INTRODUCTION ...............................................................................................................20
1.1. Indication.................................................................................................................20
1.2. Background and Rationale ......................................................................................20
1.2.1. Inotuzumab ozogamicin..............................................................................20
1.2.2. Phase 3 Study B1931022............................................................................20
1.2.2.1. Efficacy .....................................................................................20
1.2.2.2. Pharmacokinetics ......................................................................23
1.2.2.3. Safety.........................................................................................23
1.2.3. Phase 1/2 Study B1931010.........................................................................27
1.2.4. Phase 4 Study B1931030............................................................................28
1.2.4.1. Selection of Dose Levels...........................................................29
1.2.4.2. Reference Safety Information ...................................................30
2. STUDY OBJECTIVES AND ENDPOINTS.......................................................................31
3. STUDY DESIGN.................................................................................................................31
4. SUBJECT ELIGIBILTY CRITERIA..................................................................................33
4.1. Inclusion Criteria.....................................................................................................33
4.2. Exclusion Criteria....................................................................................................35
4.3. Life Style Guidelines...............................................................................................37
4.4. Sponsor Qualified Medical Personnel.....................................................................38
5. STUDY TREATMENTS.....................................................................................................39
5.1. Dose Level 1 (Arm 1 of Randomized Phase): Inotuzumab Ozogamicin 
Starting Dose of 1.8 mg/m2/cycle (administered in 3 divided doses) .......................39
5.2. Dose Level 2 (Run-in Phase and Arm 2 of Randomized Phase): Inotuzumab 
Ozogamicin Starting Dose of 1.2 mg/m2/cycle (administered in 3 divided 
doses).........................................................................................................................40
5.3. Study Treatment for Patients Not Proceeding to HSCT ( Dose Levels 1 and 
2)................................................................................................................................41
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5.4. Recommended Dose Modifications (Dose Levels 1 and 2)....................................42
5.4.1. Redosing Criteria and Dose Delays (Dose Levels 1 and 2)........................42
5.4.2. Dose Reductions ( Dose Levels 1 and 2)....................................................43
5.5. Allocation to Treatment ..........................................................................................44
5.6. Subject Compliance.................................................................................................44
5.7. Investigational Supplies ..........................................................................................44
5.7.1. Dosage Form and Packaging ......................................................................44
5.7.2. Preparation and Dispensing........................................................................44
5.7.3. Administration............................................................................................44
5.7.4. Investigational Product Storage..................................................................45
5.7.5. Investigational Product Accountability ......................................................46
5.7.6. Destruction of Investigational Product Supplies ........................................46
5.8. Concomitant Medication(s).....................................................................................46
5.8.1. Prior Medications........................................................................................46
5.8.2. Concomitant Medications...........................................................................46
5.8.3. Permitted Concomitant Medications ..........................................................46
5.8.4. Prohibited Concomitant Medications .........................................................47
5.8.5. Discouraged Concomitant Medications......................................................47
6. STUDY PROCEDURES .....................................................................................................48
6.1. Screening.................................................................................................................48
6.2. Study Period ............................................................................................................49
6.2.1. Day 1...........................................................................................................50
6.2.2. Day 4...........................................................................................................51
6.2.3. Days 8 and 15 .............................................................................................51
6.3. End of Treatment.....................................................................................................51
6.4. Follow-up Visits......................................................................................................52
6.5. Subject Withdrawal.................................................................................................53
7. ASSESSMENTS..................................................................................................................54
7.1. Efficacy Assessments..............................................................................................54
7.2. Safety Assessments .................................................................................................55
7.3. Pregnancy Testing...................................................................................................56
7.4. Pharmacokinetic Measures......................................................................................56


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7.5. Pharmacodynamic Evaluations ...............................................................................56
7.6. Immunogenicity Testing .........................................................................................56
8. ADVERSE EVENT REPORTING......................................................................................58
8.1. Requirements...........................................................................................................58
8.1.1. Additional Details on Recording Adverse Events on the CRF...................59
8.1.2. Eliciting Adverse Event Information..........................................................59
8.1.3. Withdrawal From the Study Due to Adverse Events (see also the 
Subject Withdrawal section)............................................................................59
8.1.4. Time Period for Collecting AE/SAE Information......................................60
8.1.4.1. Reporting SAEs to Pfizer Safety...............................................60
8.1.4.2. Recording Non-serious AEs and SAEs on the CRF .................60
8.1.5. Causality Assessment .................................................................................61
8.1.6. Sponsor’s Reporting Requirements to Regulatory Authorities ..................61
8.2. Definitions...............................................................................................................61
8.2.1. Adverse Events...........................................................................................61
8.2.2. Abnormal Test Findings .............................................................................62
8.2.3. Serious Adverse Events ..............................................................................62
8.2.4. Hospitalization............................................................................................63
8.3. Severity Assessment................................................................................................64
8.4. Special Situations ....................................................................................................65
8.4.1. Protocol-Specified Serious Adverse Events...............................................65
8.4.2. Potential Cases of Drug-Induced Liver Injury............................................66
8.4.3. Potential VOD Cases..................................................................................67
8.4.4. Exposure to the Investigational Product During Pregnancy or 
Breastfeeding, and Occupational Exposure.....................................................69
8.4.4.1. Exposure During Pregnancy......................................................69
8.4.4.2. Exposure During Breastfeeding ................................................71
8.4.4.3. Occupational Exposure .............................................................71
8.4.5. Medication Errors .......................................................................................71
8.4.5.1. Medication Errors......................................................................71
9. DATA ANALYSIS/STATISTICAL METHODS...............................................................72
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9.1. Sample Size Determination.....................................................................................72
9.2. Analysis Populations...............................................................................................74
9.2.1. Intent-to-Treat (ITT)...................................................................................74
9.2.2. Safety Population........................................................................................74
9.2.3. Per Protocol (PP) Population......................................................................74
9.3. Efficacy Analysis ....................................................................................................75
9.3.1. Analysis of the Primary Endpoint...............................................................75
9.3.2. Analysis of Secondary Endpoints...............................................................75
9.4. Analysis of Other Endpoints ...................................................................................76
9.4.1. Population Pharmacokinetic Analysis ........................................................76
9.5. Safety Analysis........................................................................................................77
9.5.1. Analysis of the Primary Endpoint...............................................................77
9.5.2. Analysis of Secondary Endpoints...............................................................77
9.6. Interim Analysis ......................................................................................................77
9.7. Data Monitoring Committee ...................................................................................77
10. QUALITY CONTROL AND QUALITY ASSURANCE.................................................77
11. DATA HANDLING AND RECORD KEEPING .............................................................78
11.1. Case Report Forms/Electronic Data Record .........................................................78
11.2. Record Retention...................................................................................................79
12. ETHICS..............................................................................................................................79
12.1. Institutional Review Board (IRB)/Independent Ethics Committee (IEC) ............79
12.2. Ethical Conduct of the Study ................................................................................80
12.3. Subject Information and Consent..........................................................................80
12.4. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH 
GCP ...........................................................................................................................81
13. DEFINITION OF END OF TRIAL...................................................................................81
13.1. End of Trial in a Member State.............................................................................81
13.2. End of Trial in all Participating Countries ............................................................81
14. SPONSOR DISCONTINUATION CRITERIA ................................................................81
15. PUBLICATION OF STUDY RESULTS..........................................................................82
15.1. Communication of Results by Pfizer ....................................................................82
15.2. Publications by Investigators ................................................................................82


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16. REFERENCES ..................................................................................................................84
LIST OF TABLES
Table 1.
Schedule of Activities...........................................................................................14
Table 2.
Follow-Up.............................................................................................................17
Table 3.
Pharmacokinetics Flowchart.................................................................................18
Table 4.
Safety Laboratory Requirements ..........................................................................19
Table 5.
Study B1931022: Efficacy Findings for CR/CRi, DoR, and MRD 
Negativity .............................................................................................................21
Table 6.
Study B1931022: Association of Patient Baseline Characteristics with 
Occurrence of VOD Post-HSCT in Inotuzumab Ozogamicin Treated 
Patients..................................................................................................................24
Table 7.
Study B1931022: Rate of VOD Post-HSCT for Inotuzumab Ozogamicin 
Treated Patients by Baseline Risk Factors for VOD Post-HSCT.........................25
Table 8.
Study B1931022: Post-HSCT Non-Relapse Mortality Rate by Arm ...................26
Table 9.
Study B1931010: Summary of Hematologic Remission, Time to 
Hematologic Remission, MRD Negativity and Time to MRD Negativity 
for Phase 1 Dose-Escalation Cohorts ...................................................................28
Table 10.
Predicted Efficacy and Safety of Inotuzumab Ozogamicin by Dose Level 
Based on Previously Established Population Pharmacokinetic and 
Exposure-Response Models1 ................................................................................30
Table 11.
Dose Level 1 (Arm 1 of Randomized Phase) Dosing Schedule: Inotuzumab 
Ozogamicin Starting Dose of 1.8 mg/m2/cycle (administered in 3 divided 
doses)....................................................................................................................40
Table 12.
Dose Level 2 (Run-in Phase and Arm 2 of Randomized Phase) Dosing 
Schedule: Inotuzumab Ozogamicin Starting Dose of 1.2 mg/m2/cycle 
(administered in 3 divided doses).........................................................................41
Table 13.
VOD Severity Grading (Patients Belong to the Category that Fulfills Two 
or More Criteria)a..................................................................................................69
Table 14.
Estimated VOD Rate and CR/CRi Rate with 95% Confidence Interval..............74
LIST OF FIGURES
Figure 1.
Study B1931022: Kaplan-Meier Curve for Overall Survival 
(Intent-to-Treat Population)..................................................................................23
Figure 2.
Study B1931030: Study Flow Diagram................................................................33


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APPENDICES
Appendix 1. Outcome Definitions...........................................................................................85
Appendix 2. List of Drugs Known to Predispose to Torsade de Pointes.................................87
Appendix 3. Eastern Cooperative Oncology Group (ECOG) Performance Status .................88
Appendix 4. Recommendation for Patients Proceeding to Transplant and Potential 
VOD Cases ...........................................................................................................89
Appendix 5. Abbreviations......................................................................................................91


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PROTOCOL SUMMARY
Indication
Adults with relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL).
Background and Rationale
Inotuzumab ozogamicin (BESPONSA) is a CD22-targeted antibody-drug conjugate (ADC) 
that is currently approved in the United States (US), the European Union (EU), Switzerland
(approvals granted in 2017), and Japan (approval granted in 2018).  Approval was based on 
demonstration of a positive benefit/risk for the treatment of adults with relapsed or refractory 
B-cell precursor acute lymphoblastic leukemia (ALL).  The approved dosing regimen is a 
starting dose of 1.8 mg/m2/cycle (administered as 3 divided doses on Day 1 [0.8 mg/m2], 
Day 8 [0.5 mg/m2], and Day 15 [0.5 mg/m2]) which is reduced to 1.5 mg/m2/cycle 
(0.5 mg/m2 on Day 1, 8, and 15) once complete remission (CR) or complete remission with 
incomplete hematologic recovery (CRi) is achieved.  Cycle 1 is 3 weeks in duration, but may 
be extended to 4 weeks if the patient achieves a CR/CRi, and/or to allow recovery from 
toxicity. Subsequent cycles are 4 weeks in duration.  For patients proceeding to 
hematopoietic stem cell transplantation (HSCT), the recommended duration of treatment is 
2 cycles.  A third cycle may be considered for those patients who do not achieve CR/CRi and 
minimal residual disease (MRD) negativity after 2 cycles.  For patients not proceeding to 
HSCT, up to a maximum of 6 cycles may be administered.
The activity of inotuzumab ozogamicin using this dosing regimen was demonstrated in a
randomized, open-label, international Phase 3 study (B1931022).  Study B1931022 
compared inotuzumab ozogamicin to Investigator’s choice of chemotherapy (control) as 
Salvage 1 or 2 therapy in adults with relapsed or refractory CD22-positive B-cell ALL.  The 
study had 2 primary endpoints: hematologic remission (CR/CRi, evaluated based on the first 
218 patients randomized, per Endpoint Adjudication Committee assessment) and overall 
survival (OS; based on all 326 randomized patients after 252 OS events were observed). The 
study met the primary objective of CR/CRi, with rates of 80.7% versus 29.4% for 
inotuzumab ozogamicin and control arms, respectively (p-value <0.0001).  The analysis of 
OS did not meet the pre-specified boundary for statistical significance.  At study completion, 
the estimated hazard ratio (HR) for OS was 0.75 (97.5% confidence interval [CI]: 0.57-0.99, 
1-sided p-value 0.0105).
The frequency of hepatic veno-occlusive disease (VOD) (also known as sinusoidal 
obstruction syndrome [SOS]) after a subsequent HSCT was higher in the inotuzumab 
ozogamicin arm compared to the control arm (18/79 patients [23%] versus 3/34 patients 
[9%], respectively).  Baseline characteristics that were identified as potential risk factors for 
VOD post-HSCT in inotuzumab ozogamicin treated patients included ongoing or prior liver 
disease, prior HSCT, increased age, and later salvage lines.  The use of HSCT conditioning 
regimens containing 2 alkylating agents, total bilirubin level greater than or equal to the 
upper limit of normal before HSCT, and a greater number of inotuzumab ozogamicin cycles 
were also associated with greater risk of VOD.


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This Phase 4 study (B1931030) is a post-marketing requirement (PMR) that was requested 
by the US Food and Drug Administration and is designed to evaluate the safety and efficacy 
of 2 inotuzumab ozogamicin dose levels in adults with relapsed or refractory B-cell ALL 
who are eligible for HSCT and who are at higher risk for developing VOD post-HSCT.
Objectives
Primary Objective
The primary objectives are to evaluate the rates of VOD and hematologic remission 
(CR/CRi) for 2 inotuzumab ozogamicin dose levels in adult patients with relapsed or 
refractory B-cell ALL who are eligible for HSCT and who are at higher risk for developing 
VOD post-HSCT.  The study analysis will be descriptive only, without formal hypothesis 
testing.
The primary endpoints are: 

Rate of VOD (total, during study treatment, and post-HSCT); and

Rate of hematologic remission (CR/CRi).
Secondary Objective
The secondary objectives are to evaluate the safety and efficacy of 2 inotuzumab ozogamicin 
dose levels.  Secondary endpoints include the following: adverse events and laboratory 
abnormalities, MRD negativity in patients achieving CR/CRi, duration of remission (DoR) in 
patients achieving a CR/CRi, progression-free survival (PFS), OS, rate of HSCT, post-HSCT
relapse, post-HSCT mortality, post-HSCT non-relapse mortality, post-HSCT relapse-related 
mortality, pharmacokinetic (PK) exposure-response relationships for efficacy and safety, and 
immunogenicity testing for anti-drug antibodies, including neutralizing antibodies.
Study Design
This is an open-label, study of inotuzumab ozogamicin in adults with relapsed or refractory 
B-cell ALL who are eligible for HSCT and who have risk factor(s) for developing VOD with 
inotuzumab ozogamicin treatment. 
The study will be conducted in 2 phases: a run-in phase and a randomized phase.  In total, up 
to approximately 102 patients will be enrolled in the study across the 2 phases. 
Run-in phase: a total of up to 22 patients will be enrolled to receive the starting dose of 
1.2 mg/m2/cycle (dose level 2).  A Simon Two-Stage optimal design will be used.  If 
acceptable efficacy (CR/CRi and MRD negativity) is observed in the run-in phase, the study 
will enter the randomized phase. 


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Randomized phase: if acceptable efficacy is observed in the run-in phase, the study will enter 
the randomized phase.  A total of approximately 80 patients will be randomized (1:1) to 1 of 
2 dose levels of inotuzumab ozogamicin (40 patients per dose level). Patients will be 
stratified at randomization based on age (<55 vs 55 years), salvage status (Salvage 1 vs 2), 
and prior HSCT (yes vs no). 
The treatment period is expected to last, on average, approximately 3 months (ie, 2-3 cycles).  
Safety and disease assessments and PK sample collection will be conducted throughout the 
treatment period.
After inotuzumab ozogamicin treatment, patients will be followed for at least 2 years (from 
randomization).  During the follow-up period, safety and disease assessments will be 
conducted, and information about subsequent ALL treatments (including HSCT) and survival 
status will be collected.  All known cases of VOD, regardless of causality and severity, will 
be reported as serious adverse events (SAEs) throughout the follow-up period.
The study will be conducted at approximately 50 clinical sites and is expected to be 
completed (last patient last visit) in approximately 6 years.
Study Treatments
Dose Level 1 (Arm 1 of Randomized Phase): Patients will be treated with inotuzumab 
ozogamicin at a starting dose of 1.8 mg/m2/cycle (administered in 3 divided doses).  After 
CR/CRi is achieved, the dose will be reduced to 1.5 mg/m2/cycle (administered in 3 divided 
doses).  For patients proceeding to HSCT, 2 cycles are recommended; a third cycle may be 
considered for those patients who do not achieve CR/CRi and MRD negativity after 2 cycles. 
Patients who do not achieve CR/CRi within 3 cycles should discontinue treatment.  The cycle 
length will be 21-28 days.
Dose Level 2 (Run-in Phase and Arm 2 of Randomized Phase): Patients will be treated with 
inotuzumab ozogamicin at a starting dose of 1.2 mg/m2/cycle (administered in 3 divided 
doses).  After CR/CRi is achieved, the dose will be reduced to 0.9 mg/m2/cycle (administered 
in 3 divided doses).  For patients proceeding to HSCT, 2 cycles are recommended; additional 
cycles may be considered for those patients who do not achieve CR/CRi and MRD negativity 
after 2 cycles (maximum of 4 cycles). Patients who do not achieve CR/CRi within 4 cycles 
should discontinue treatment.  The cycle length will be 21-28 days.
Statistical Methods
This study will evaluate the safety and efficacy of 2 inotuzumab ozogamicin dose levels.  
Descriptive analyses, for each dose level will be provided for the primary and secondary 
endpoints. Other than the Simon Two-Stage Design in the run-in phase, no formal 
hypothesis testing will be conducted.


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A total of up to 22 patients will be enrolled in the run-in phase.  In order to minimize the 
expected number of patients enrolled in the event that the lower dose level (1.2 mg/m2/cycle 
of inotuzumab ozogamicin, dose level 2) proves to be of minimal efficacy benefit, a Simon 
Two-Stage optimal design will be used for the run-in phase.  The run-in phase will test the 
null hypothesis (H0) that the CR/CRi rate is 31.2% versus the alternative hypothesis (Ha) 
that the CR/CRi rate is 57% (ie, predicted based on the exposure response model) with a 
significance level of 0.10 and 80% power.
Seven (7) patients will be enrolled in Stage 1. If ≤2 CR/CRi responders are observed in 
Stage 1, accrual will be stopped for further evaluation.  Once at least 3 (ie, 42.9%) CR/CRi 
responders are documented, an additional 15 enrolled patients will be evaluated in Stage 2.  
If 10 CR/CRi responders are observed in the total of 22 patients from both stages, it will be 
concluded that the true CR/CRi rate for the lower dose is higher than the historical control 
(31.2% for Study B1931022 control arm subgroup of patients with risk factors for VOD 
post-HSCT).
The expected MRD negativity rate among the patients who achieve CR/CRi is 70%.  With 
10 CR/CRi responders expected at the end of Stage 2, the expected number of patients with 
MRD negativity among the 22 patients in the run-in phase is 7.  Given a CR/CRi rate of 
57%, predicted by the exposure response model, and 70% expected MRD negativity rate 
among CR/CRi responders, 40% is the expected MRD negativity rate among all patients 
enrolled in the run-in phase.  Twenty-two (22) patients will also provide 80% power to reject 
the null hypothesis of the MRD negativity rate 20% when the alternative hypothesis of the 
true MRD negativity rate is 40% with significance level of 0.10.  There will be 
84% probability to observe a minimum of 7 patients who have achieved MRD negativity if 
the true MRD negativity rate is at least 40%.
To review the totality of the efficacy data, DoR will also be analyzed for the run-in phase.  
Safety data will also be reviewed for the run-in phase. 
Once at least 10 CR/CRi responders and at least 7 patients achieving MRD negativity are 
documented among the 22 patients in the run-in phase, patients enrolled in the randomized 
phase will then be evaluated, with approximately 80 patients randomized (1:1) to the 
approved dose level of 1.8 mg/m2/cycle (dose level 1, Arm 1) or the lower dose level of 
1.2 mg/m2/cycle (dose level 2, Arm 2). 
Until analyses for decision-making are completed, enrollment will continue between Stage 1 
and Stage 2 of the run-in phase and between the run-in and randomized phases of the study.
At the end of the study, descriptive analyses will be conducted.  For the randomized phase, a 
sample size of 40 patients per arm will provide the estimated VOD rate in each dose level 
with a maximum standard error (SE) of 0.08.  The maximum SE estimated for other binary 
endpoints in each dose level (eg, CR/CRi rate) will also be 0.08.  In addition, for summary of 
dose level 2, patients in the run-in phase will be combined with Arm 2 of the randomized 
phase, for a sample size of approximately 62 patients (ie, 22 patients enrolled in the run-in 


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phase and 40 patients enrolled in Arm 2 in the randomized phase) to provide the 
above-mentioned estimated rates with a maximum SE of 0.06.


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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 and
ASSESSMENTS 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
Activity
Screen1
-28 days from 
randomization
Inotuzumab Ozogamicin Treatment Cycle 
End of Treatment
(EOT)2
(All patients: 4 -6 weeks from 
the last dose of study drug)
Study Visit (Window, days)
Day 1 (2)
Day 8 (2)
Day 15 (2)
EOT (3)
Informed Consent1
X
Review study eligibility (inclusion and 
exclusion criteria)
X
CD22 Immunophenotyping3
X
Antibodies to inotuzumab4
X
X
Medical History (including cancer 
history and prior treatments and 
therapies)
X
Weight/height5
X
X
X
Vital Signs and Physical Examination6
X
X
X
X
X
ECOG PS
X
X
Hematology7
X
X
X
X
X
Blood Chemistry7
X
X
X
X
X
Coagulation8
X
X
X
Pregnancy test9
X
X
X
Contraception check10
X
X
X
HbsAg and anti-HCV11
X
ECG12
X (3-28 days prior to 
randomization)
X
X
Pharmacokinetics
See Table 3 for time points
Randomization13
X
Premedications 
X
X
X


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Activity
Screen1
-28 days from 
randomization
Inotuzumab Ozogamicin Treatment Cycle 
End of Treatment
(EOT)2
(All patients: 4 -6 weeks from 
the last dose of study drug)
Study Visit (Window, days)
Day 1 (2)
Day 8 (2)
Day 15 (2)
EOT (3)
Study Treatments
See Protocol Section 5.0
Bone marrow aspirate and clinical 
disease assessments14
X
See table footnote 14
X
Karyotyping/ Immunophenotyping/
MRD / Bone marrow biopsy15
X
Done in patients with suspected CR and/or CRi15
Radiological Assessment16
X
As clinically indicated.  See Appendix 1.
Assessment of CNS disease17
X
As clinically indicated
AE/SAE and concomitant medications18
X
Assessed throughout the study until 9 weeks from last dose of inotuzumab ozogamicin 
 
Abbreviations: AE=adverse event, ANC=absolute neutrophil count; antiHCV=antibody to hepatitis C virus; APTT=activated partial thromboplastin time; 
-HCG=beta-human chorionic gonadotropin; BM=bone marrow; BSA=body surface area; CBC = complete blood count; CD22=cluster of differentiation-22; 
CNS=central nervous system; CR=complete remission; CRF=case report form; CRi=complete remission with incomplete count recovery; CT=computerized 
tomography; ECG=electrocardiogram; ECOG PS=Eastern Cooperative Oncology Group performance status; EMD=extramedullary disease; EOT=end of 
treatment; FACS=fluorescence activated cell sorting; HbsAg=hepatitis B surface antigen; HCV=hepatitis C virus; HSCT = hematopoietic stem cell transplant; 
ICD=informed consent document; IEC = independent ethics committee; IHC= immunohistochemistry; IRB = institutional review board; MRD=minimal 
residual disease; MRI = magnetic resonance imaging; NCI CTCAE = National Cancer Institute Common Terminology Criteria for Adverse Events; 
PK=pharmacokinetic(s); PT=prothrombin time; RNA=ribonucleic acid; SAE=serious adverse event; SOC= standard of care; VOD=veno-occlusive disease. 
Additional procedures or samples may be undertaken as medically required at the discretion of the Investigator.  These data may be recorded on the CRF (eg, 
local MRD analysis if done at the site).  
1.
Assessment(s) and test(s) done according to SOC at the institution prior to the patient signing the ICD can be used to determine patient eligibility if collected within the 
timeframe specified in this protocol.  Results will be recorded in the CRF.  However, before any collected sample is sent to the central vendor, the patient must be consented 
for study participation. 
2.
EOT visits should be performed before starting a new anti-leukemic therapy (including before subsequent HSCT conditioning, other form of consolidation/intensification or 
maintenance therapy).  If a new anti-leukemia therapy will be started, the EOT visit should occur as close as possible to 4 to 6 weeks after the last dose of study drug. 
3.
CD22 immunophenotyping performed at screening on peripheral blood or bone marrow aspirate by local laboratories.  Surface CD22 expression should be measured by 
FACS; IHC analysis is allowed in patients with 1) dry tap or 2) inadequate BM aspirate and/or with insufficient circulating blasts for FACS.
4.
Immune response testing to inotuzumab ozogamicin: blood sample will be collected at Day 1 of every cycle prior to the beginning of inotuzumab ozogamicin infusion and at 
the EOT visit. Analysis will be performed by a central laboratory.
5.
Height required only at screening; patients must be weighed up to 72 hours prior to Day 1 of each cycle and EOT visit.  If the patient experiences a weight loss or gain 
>10% from the prior weight obtained, the BSA and the amount of inotuzumab ozogamicin required for dose preparation must be re-calculated. 
6.
Physical examination performed at screening and at Day 1, 8 and 15 of every cycle prior to inotuzumab ozogamicin administration.  Vital signs (pulse, blood pressure, temp) 
required on every day of dosing for every regimen (see Section 6).
CCI
CCI






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Table 3.
Pharmacokinetics Flowchart
Cycle 1
Cycle Day
1
4
8
15
Time (hours) relative to the start of inotuzumab ozogamicin
administration
0
1
2
4
72
0
1
6
0
1
PK sample collection
X1
X2
X
X
X
X1
X2
X
X1
X2
Cycle 2
Cycle Day
1
8
Time (hours) relative to the start of inotuzumab ozogamicin
administration
0
1
2
0
2
PK sample collection
X1
X2
X
X1
X
Cycles 3 and 43
Cycle Day
1
8
Time (hours) relative to the start of inotuzumab ozogamicin
administration
0
1
0
PK sample collection
X1
X2
X
Abbreviations: PK=pharmacokinetic.
1.
Sample drawn before start of inotuzumab ozogamicin infusion.
2.
Sample drawn immediately before end of inotuzumab ozogamicin infusion.
3.
Cycle 4 for Arm 2 (dose level 2) only.




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1. INTRODUCTION
1.1. Indication
Adults with relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL).
1.2. Background and Rationale
1.2.1. Inotuzumab ozogamicin 
Inotuzumab ozogamicin is a CD22-directed antibody-drug conjugate (ADC) consisting of 
3 components: 1) the recombinant humanized immunoglobulin class G subtype 4 (IgG4) 
kappa antibody inotuzumab, specific for human CD22, 2) N-acetyl-gamma-calicheamicin 
that causes double-stranded DNA breaks, and 3) an acid-cleavable linker composed of the 
condensation product of 4-(4’-acetylphenoxy)-butanoic acid (AcBut) and 
3-methyl-3-mercaptobutane hydrazide (known as dimethylhydrazide) that covalently attaches 
N-acetyl-gamma-calicheamicin to inotuzumab.  Nonclinical data suggest that the anticancer 
activity of inotuzumab ozogamicin is due to the binding of the ADC to CD22-expressing 
tumor cells, followed by internalization of the ADC-CD22 complex, and the intracellular 
release of N-acetyl-gamma-calicheamicin dimethylhydrazide via hydrolytic cleavage of the 
linker.1  Activation of N-acetyl-gamma-calicheamicin dimethylhydrazide induces 
double-strand DNA breaks, subsequently inducing cell cycle arrest and apoptotic cell death. 
Inotuzumab ozogamicin (BESPONSA) is currently approved in the United States (US), the 
European Union (EU), Switzerland (approvals granted in 2017), and Japan (approval granted 
in 2018). Approval was based on demonstration of a positive benefit/risk for the treatment of 
adults with relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL).  The 
approved dosing regimen is a starting dose of 1.8 mg/m2/cycle (administered as 3 divided 
doses on Day 1 [0.8 mg/m2], Day 8 [0.5 mg/m2], and Day 15 [0.5 mg/m2]) which is reduced 
to 1.5 mg/m2/cycle (administered as 3 divided doses on 0.5 mg/m2 on Day 1, 8, and 15) once 
complete remission (CR) or complete remission with incomplete hematologic recovery (CRi) 
is achieved.  Cycle 1 is 3 weeks in duration, but may be extended to 4 weeks if the patient 
achieves a CR/CRi, and/or to allow recovery from toxicity.  Subsequent cycles are 4 weeks in 
duration.  For patients proceeding to hematopoietic stem cell transplantation (HSCT), the 
recommended treatment is 2 cycles.  A third cycle may be considered for those patients who do 
not achieve CR/CRi and minimal residual disease (MRD) negativity after 2 cycles.  For patients 
not proceeding to HSCT, up to a maximum of 6 cycles may be administered.
1.2.2. Phase 3 Study B1931022
1.2.2.1. Efficacy
The activity of the currently approved inotuzumab ozogamicin dosing regimen was 
demonstrated in a randomized (1:1), open-label, international Phase 3 study (B1931022).  
Study B1930122 compared inotuzumab ozogamicin to Investigator’s choice of chemotherapy 
(control) as Salvage 1 or 2 therapy in adults with relapsed or refractory CD22-positive B-cell 
ALL.  Investigator’s choice of chemotherapy was fludarabine + cytarabine + granulocyte 
colony-stimulating factor (FLAG), high-dose cytarabine (HIDAC), or 
mitoxantrone + cytarabine (MXN/AraC).  Patients with Philadelphia chromosome-positive 


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(Ph+) disease must have failed treatment with at least 1 tyrosine kinase inhibitor (TKI) and 
standard chemotherapy.  Patients were stratified at randomization based on duration of first 
remission (<12 versus 12 months), line of salvage (Salvage 1 versus 2), and age (<55 versus 
55 years).2,3
The study had 2 primary endpoints: hematologic remission (CR/CRi, evaluated based on the 
first 218 patients randomized (ITT218 population), per Endpoint Adjudication Committee 
assessment) and overall survival (OS; based on all 326 randomized patients). The secondary 
efficacy endpoints included MRD negativity (defined as <1 abnormal cell/104 nucleated cells 
by flow cytometry per central laboratory analysis), duration of remission (DoR), 
progression-free survival (PFS), and HSCT rate.2,3
The study met the primary objective of CR/CRi, with rates of 80.7% versus 29.4% for the 
inotuzumab ozogamicin and control arms, respectively (p-value <0.0001) (Table 5).  Among 
responders in the ITT218 population, MRD negativity was higher and DoR was longer for 
the inotuzumab ozogamicin arm compared to the control arm (MRD negativity, 78.4% versus 
28.1%, respectively; median DoR, 5.4 months versus 3.5 months, respectively, Table 5). 
Remission, DoR, and MRD negativity results in all 326 randomized patients were consistent 
with those for the first 218 randomized patients (Table 5).2,3
Table 5.
Study B1931022: Efficacy Findings for CR/CRi, DoR, and MRD Negativity
First 218 Patients Randomizeda
All 326 Patients Randomizedb
Inotuzumab 
Ozogamicin
(N=109)
Control: HIDAC, 
FLAG, or 
MXN/Ara-C
(N=109)
Inotuzumab 
Ozogamicin
(N=164)
Control: HIDAC, 
FLAG, or MXN/Ara-C
(N=162)
Responding (CR/CRi) patients
n (%) 
[95% CI]
88 (80.7)
[72.1-87.7]
32 (29.4)
[21.0-38.8]
120 (73.2)
[65.7-79.8]
50 (30.9)
[23.9-38.6]
p-valuec
<0.0001 (primary endpoint)
<0.0001
DoR in responding (CR/CRi) patientsd
N
84
32
120
50
Median, months
[95% CI]
5.4
[4.2-8.0]
3.5
[2.9-6.6]
5.3
[4.2-7.0]
3.6 
[2.9-5.2]
p-valuec
0.0031
0.0052
MRD negativity in responding (CR/CRi) patientse
N
69
9
92
19
Ratef (%)
[95% CI]
69/88 (78.4)
[68.4-86.5]
9/32 (28.1)
[13.7-46.7]
92/120 (76.7)
[68.1-83.9]
19/50 (38.0)
[24.7-52.8]
p-valuec
<0.0001
<0.0001
Abbreviations: CI=confidence interval; CR=complete remission; CRi=complete remission with incomplete 
hematologic recovery; DoR=duration of remission; EAC=Endpoint Adjudication Committee; 
FLAG=fludarabine + cytarabine + granulocyte colony-stimulating factor; HIDAC=high-dose cytarabine; 
MRD=minimal residual disease; MXN/AraC=mitoxantrone + cytarabine; N/n=number of patients; 
PFS=progression-free survival.


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a.
CR/CRi per EAC assessment.  CR was defined as < 5% blasts in the bone marrow and the absence of peripheral 
blood leukemic blasts, full recovery of peripheral blood counts (platelets ≥100 × 109/L and absolute neutrophil 
counts [ANC] ≥1 × 109/L) and resolution of any extramedullary disease.  CRi was defined as < 5% blasts in the bone 
marrow and the absence of peripheral blood leukemic blasts, incomplete recovery of peripheral blood counts 
(platelets < 100 × 109/L and/or ANC < 1 × 109/L) and resolution of any extramedullary disease.  CR/CRi and MRD 
negativity results from planned interim analysis (data cutoff date 02 October 2014). 
b.
CR/CRi per Investigator’s assessment. Data cutoff date 08 March 2016. 
c.
1-sided p-value using Chi-squared test or Fisher’s exact test (if any Chi-squared cell count <5)
d.
DoR, based on a later cutoff date than the CR/CRi (data cutoff date 08 March 2016), was defined for patients who 
achieved CR/CRi per Investigator’s assessment as time since first response of CR/CRi per Investigator’s assessment 
to the date of a PFS event or censoring date if no PFS event was documented. 
e.
MRD negativity was defined by flow cytometry as leukemic cells comprising < 1 × 10-4 (< 0.01%) of bone marrow 
nucleated cells.
f.
Rate was defined as the number of patients who achieved MRD negativity divided by the total number of patients 
who achieved CR/CRi per EAC (first 218 randomized patients) or per Investigator assessment (all 326 randomized 
patients).
In all randomized patients (N = 326) at study completion (last patient last visit), the estimated 
hazard ratio (HR) for PFS was 0.450 (95% confidence interval [CI]: 0.336-0.602) with 
1-sided p<0.0001 in favor of inotuzumab ozogamicin over control based on a stratified 
analysis.
Overall, 79/164 patients (48%) in the inotuzumab ozogamicin arm and 35/162 patients 
(22%) in the control arm had a follow-up HSCT.3 Among the 79 patients in the inotuzumab 
ozogamicin arm who underwent a follow-up HSCT, 71 patients proceeded to HSCT directly 
after inotuzumab ozogamicin treatment (without any intervening induction therapy) with a 
median gap of 4.9 weeks (range: 1-19 weeks) between the last dose of inotuzumab 
ozogamicin and HSCT. 
The analysis of OS did not meet the pre-specified boundary for statistical significance.  At 
study completion (last patient last visit), the estimated HR for OS was 
0.75 (97.5% CI: 0.57-0.99, 1-sided p-value 0.0105) (Figure 1).3


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Figure 1.
Study B1931022: Kaplan-Meier Curve for Overall Survival (Intent-to-Treat 
Population)
1.2.2.2. Pharmacokinetics
Based on pharmacokinetic (PK) data from 163 patients in Study B1931022, mean peak and 
trough exposures of inotuzumab ozogamicin increased with each cycle, due to its long steady 
state elimination half-life (12.3 days).  Mean peak concentrations in serum were observed at 
or near the end of infusion with a highest observed mean peak concentration of 308 ng/mL 
by Cycle 4 Day 1 and the highest observed mean trough concentration of 91.3 ng/mL, by 
Cycle 4 Day 8, compared to a peak of 211 ng/mL at Cycle 1 Day 1 and a trough of 
6.84 ng/mL at Cycle 1 Day 8.
Based on the PK exposure-response analyses of the safety and efficacy data from Phase 3 
Study B1931022 and Phase 1/2 Study B1931010 (see Section 1.2.3), there was a statistically 
significant (p<0.0001) relationship between inotuzumab ozogamicin average serum 
concentration up to the time of response (Cavg) and the probability of CR/CRi and MRD 
negativity.  Furthermore, there was a statistically significant (p<0.05) relationship between 
inotuzumab ozogamicin cumulative total serum exposure during Cycle 1 (cAUCP1) and the 
probability of VOD (VOD per assessment of the independent Hepatic Events Adjudication 
Board for Phase 3 Study B1931022). 
1.2.2.3. Safety
In Study B1931022, 164 patients received inotuzumab ozogamicin.  The median duration of 
treatment was 8.9 weeks (range: 0.1-26.4 weeks), with a median of 3 treatment cycles started 
in each patient.  The most common (2%) serious adverse events reported for patients who 
received inotuzumab ozogamicin were infection, febrile neutropenia, hemorrhage, abdominal 
pain, pyrexia, fatigue, and VOD.3  


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1.2.2.3.1. Hepatotoxicity, Including Veno-occlusive Disease (VOD; also known as 
sinusoidal obstruction syndrome) 
Hepatotoxicity, including severe, life-threatening, and sometimes fatal hepatic VOD was 
observed in 23/164 patients (14%) during or following inotuzumab ozogamicin.  As 
described below, most cases of VOD occurred after subsequent HSCT (following completion 
of inotuzumab ozogamicin treatment).3
VOD was reported in 5/164 patients (3%) during study therapy or in follow-up without an 
intervening HSCT. For these 5 patients, VOD was reported up to 56 days after the last dose
of inotuzumab ozogamicin.3
Among the 79 inotuzumab ozogamicin treated patients who proceeded to a subsequent 
HSCT, VOD was reported in 18/79 patients (23%).  The median time from subsequent HSCT 
to onset of VOD was 15 days (range: 3-57 days).  Five (5) cases of VOD post-HSCT were 
fatal.3 While VOD is a toxicity known to be associated with the hepatotoxic conditioning 
regimens used in HSCT,4 the frequency of VOD post-HSCT was higher in the inotuzumab 
ozogamicin arm compared to the control arm (23% versus 3/34 [9%] patients, respectively).
Baseline characteristics that were identified as potential risk factors for VOD post-HSCT in 
inotuzumab ozogamicin treated patients included ongoing or prior liver disease, prior HSCT, 
increased age, and later salvage lines (Table 6).
Table 6.
Study B1931022: Association of Patient Baseline Characteristics with 
Occurrence of VOD Post-HSCT in Inotuzumab Ozogamicin Treated 
Patients
Subsets, n
Estimate (SE)
Odds Ratio
95% CI
P-value
Univariate Analysis (N=79)
Prior HSCT (yes, no)
11, 68
1.26 (0.68)
3.526
0.931, 13.358
0.064
Salvage status (2 or more, 1)1
20, 58
0.83 (0.58)
2.301
0.744, 7.117
0.148
Age (55, <55 years)
17, 62
1.18 (0.59)
3.245
1.012, 10.406
0.048
Prior history of liver 
disease/hepatitis (yes, no)
21, 58
1.08 (0.57)
2.954
0.970, 8.994
0.057
Abbreviations: CI:=confidence interval; HSCT=hematopoietic stem cell transplant; SE=standard error.
Baseline characteristics to be used in Logistic Regression model may include prior SCT (Yes, No), 
ALT/AST/bilirubin elevation (Yes, No), Salvage Status (2 or more, 1), age (>=55, <55), prior history of liver 
disease/hepatitis (Yes, No), baseline ECOG performance status (2, 0/1).
Data cutoff date 01 September 2016.
1.
Salvage status missing for 1 patient.


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The rates of VOD post-HSCT for inotuzumab ozogamicin treated patients with and without 
potential baseline risk factors is shown in Table 7.
Table 7.
Study B1931022: Rate of VOD Post-HSCT for Inotuzumab Ozogamicin 
Treated Patients by Baseline Risk Factors for VOD Post-HSCT
Baseline Risk Factor for VOD 
post-HSCT
Rate of VOD Post-HSCT
Yes 
% (n/N)
No
% (n/N)
Prior HSCT 
45.5% (5/11)
19.1% (13/68)
Salvage status >11
35.0% (7/20)
19.0%  (11/58)
Age (55 years)
41.2% (7/17)
17.7%  (11/62)
Prior history of liver disease/hepatitis
38.1% (8/21)
17.2% (10/58)
Abbreviations: HSCT=hematopoietic stem cell transplant; N=number of subjects who had follow-up HSCT and 
in each specified category; n=the number of subjects who had VOD as specified among the N patients. 
Percentage is calculated based on N of each category.
Data cutoff date 01 September 2016.
1.
Salvage status missing for 1 patient.
Other characteristics that were identified as potential risk factors for VOD post-HSCT in 
inotuzumab ozogamicin treated patients included conditioning regimens containing 
2 alkylating agents, total bilirubin level greater than or equal to the upper limit of normal 
before HSCT, and a greater number of inotuzumab ozogamicin cycles.  Among the 
79 inotuzumab ozogamicin treated patients who had a subsequent HSCT, 11 (13.9%) patients 
received dual-alkylating conditioning regimens including 5 patients who received busulfan 
and thiotepa containing regimens, and 2 patients who received busulfan and 
cyclophosphamide containing regimens.
Other hepatotoxicity reported for inotuzumab ozogamicin treated patients included abnormal 
liver tests: Grade 3/4 increases in aspartate aminotransferase (AST), alanine aminotransferase 
(ALT), and total bilirubin occurred in 7/160 (4%), 7/161 (4%), and 8/161 patients (5%), 
respectively.3
1.2.2.3.2. Post-HSCT Non-Relapse Mortality
While the overall percentage of patients surviving after HSCT was similar in both arms 
(35.4% vs 34.3%), post-HSCT non-relapse mortality (NRM) rate was higher in the 
inotuzumab ozogamicin arm compared to the control arm (39% versus 23%, respectively, 
Table 8). The most common causes of post-HSCT NRM for inotuzumab ozogamicin treated 
patients included VOD and infections.  Five (5) of the 18 VOD events that occurred 
post-HSCT were fatal. Among patients with ongoing VOD at time of death, 6 patients died 
due to multiorgan failure (MOF) and/or infection (3 patients died due to MOF, 2 patients 
died due to infection, and 1 patient died due to MOF and infection).3


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Table 8.
Study B1931022: Post-HSCT Non-Relapse Mortality Rate by Arm
Rate of VOD Post-HSCT
Inotuzumab ozogamicin
(N=164)
Control
(N=162)
Number of patients who had follow-up HSCT
79 (48.2)
35 (21.6)
Number of patients with post-HSCT non-relapse 
mortality adjusting for competing risksa,b
31 (39.2)
8 (22.9)
Estimated mortality rate at end of 
Day 100 (95% CI)
20.25
(12.19, 29.77)
5.71
(0.99, 16.93)
Estimated mortality rate at end of Month 12
(95% CI)
36.71
(26.14, 47.31)
14.54
(5.18, 28.48)
Patients may have had more than 1 reported reason for the cause of death.  MedDRA (v18.1) coding 
dictionary was applied.
Data cutoff date 01 September 2016.
Abbreviations: CI=confidence interval; HSCT=hematopoietic stem cell transplant; N=number of patients.
a.
Number of patients with post-transplant was used for percent calculation.
b.
Competing risk was defined as relapse from CR/Cri after post-HSCT, or death where mechanism of death = disease 
progression/relapse.  Events that occurred after competing risk were not included in the calculation of cumulative 
incidence rate.
1.2.2.3.3. Myelosuppression
Myelosuppression was observed in patients who received inotuzumab ozogamicin.
Thrombocytopenia and neutropenia were reported in 83/164 (51%) patients and 
81/164 (49%) patients, respectively.  Grade 3 thrombocytopenia and neutropenia were 
reported in 23/164 (14%) patients and 33/164 (20%) patients, respectively.  Grade 4 
thrombocytopenia and neutropenia were reported in 46/164 (28%) patients and 45/164 (27%)
patients, respectively.  Febrile neutropenia, which may be life-threatening, was reported in 
43/164 (26%) patients.  For patients who were in CR/CRi at the end of treatment, the 
recovery of platelet counts to >50,000/mm3 was later than 45 days after the last dose in 
15/164 (9%) patients who received inotuzumab ozogamicin and 3/162 (2%) patients who 
received control therapy (Investigator’s choice of chemotherapy).3
Complications associated with myelosuppression (including infections and 
bleeding/hemorrhagic events) were observed in inotuzumab ozogamicin treated patients. 
Infections, including serious infections, some of which were life-threatening or fatal, were 
reported in 79/164 (48%) patients.  Fatal infections, including pneumonia, neutropenic 
sepsis, sepsis, septic shock, and pseudomonal sepsis, were reported in 8/164 (5%) patients; 
the frequency of fatal infections was the same in the control arm (7/143 patients, 4.9%). 
Bacterial, viral, and fungal infections were reported.3
Hemorrhagic events were reported in 54/164 (33%) patients who received inotuzumab 
ozogamicin. Grade 3 or 4 hemorrhagic events were reported in 8/164 (5%) patients.  One 
Grade 5 (fatal) hemorrhagic event (intra-abdominal hemorrhage) was reported in 1/164 (1%) 
patients. The most common hemorrhagic event was epistaxis which was reported in 
24/164 (15%) patients.3


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1.2.2.3.4. Infusion Related Reactions
Infusion related reactions were observed in patients who received inotuzumab ozogamicin.
Infusion related reactions (all Grade 2) were reported in 4/164 (2%) patients (reported 
symptoms included fever, chills, and hypotension).  Infusion related reactions generally 
occurred in Cycle 1 shortly after the end of the inotuzumab ozogamicin infusion and resolved 
spontaneously or with medical management.3
1.2.2.3.5. QT Interval Prolongation
Increases in QT interval corrected for heart rate using Fridericia’s formula (QTcF) of 
60 msec from baseline were measured in 4/162 (3%) patients who received inotuzumab 
ozogamicin.  No patients had QTcF values greater than 500 msec.  Grade 2 QT prolongation 
was reported in 2/164 (1%) patients.  No Grade 3 QT prolongation or events of Torsade de 
Pointes were reported in inotuzumab ozogamicin treated patients. In the control arm, QTcF 
60 msec from baseline were measured in 3/124 (2%) patients, and 1/124 (1%) patients had 
QTcF values >500 msec.3
Central tendency analysis of the QTcF interval changes from baseline showed that the 
highest mean (upper bound of the 2-sided 90% CI) for QTcF was 15.3 (21.1) msec, which 
was observed at Cycle 4/Day 1/1 hour in the inotuzumab ozogamicin arm.3  Based on the 
latest exposure response analysis, although there was a positive correlation between QTc 
interval with inotuzumab ozogamicin serum concentration, the upper bound of the 
95% confidence interval for the predicted changes from baseline in QTcF and QT interval 
corrected for heart rate using a population-specific method (QTcS), at therapeutic and 
supratherapeutic (1.5 fold therapeutic) concentrations, remained below the 10 msec threshold 
(4.92-8.28 msec).
1.2.3. Phase 1/2 Study B1931010
Study B1931010 was a Phase 1/2 single-arm, 2-stage, multicenter, open-label study
evaluating single-agent inotuzumab ozogamicin for the treatment of relapsed or refractory 
ALL.  Results from this study helped to inform the inotuzumab ozogamicin dosing regimen 
used in Phase 3 Study B1931022.  Key eligibility criteria included age 18 years and 
relapsed or refractory CD22-positive ALL.  For the Phase 2 part of the study, the patients 
must have been due to receive Salvage 2 therapy.  Patients with Ph+ ALL had to have failed 
treatment with at least 1 TKI.5
The Phase 1 dose-escalation portion of Study B1931010 was designed to determine the
recommended Phase 2 dose (RP2D) of weekly inotuzumab ozogamicin.  Twenty-four (24)
patients were treated with inotuzumab ozogamicin at dose levels of 1.2 mg/m2/cycle (n=3), 
1.6 mg/m2/cycle (n=12), or 1.8 mg/m2/cycle (n=9).5


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Remissions (CR/CRi) were observed across all dose levels: the CR/CRi rate was 2/3 (66.7%)
for 1.2 mg/m2/cycle, 8/16 (75.0%) for 1.6 mg/m2/cycle, and 8/9 (88.9%) for 1.8 mg/m2/cycle
(Table 9).  MRD negativity was also achieved among responders in each dose level 
(Table 9); time to MRD negativity was longest for the 1.2 mg/m2/cycle group.5
Table 9.
Study B1931010: Summary of Hematologic Remission, Time to 
Hematologic Remission, MRD Negativity and Time to MRD Negativity 
for Phase 1 Dose-Escalation Cohorts
Phase 1, Dose-Escalation
1.2 mg/m2
1.6 mg/m2
1.8 mg/m2
Number of Patients
(N=3)
(N=12)
(N=9)
Hematologic remission rate (CR/CRi)
n (%)
2 (66.7)
9 (75.0)
8 (88.9)
95% CIa
(9.4, 99.2)
(42.8, 94.5)
(51.8, 99.7)
Time to remission (CR/CRi) (days)
N
2
9
8
Mean
39.0
35.3
42.8
SD
24.0
12.6
19.9
Median
39.0
29.0
38.0
Range
22-56
22-59
22-78
MRD-negativity
n/N (%)b
2/2 (100)
8/9 (88.8)
8/8 (100)
Time to MRD-negativity (days)
Median (range)
98.5
(98-99)
32.0
(22-64)
30.0
(22-141)
Abbreviations: CI=confidence interval; CR=complete response; CRi=complete response with incomplete 
count recovery; N/n=number of patients SD=standard deviation.
Final data from completed study.
aCI created by Exact Binomial approximation.
bPercentages were based on the number of patients with CR/CRi.
1.2.4. Phase 4 Study B1931030
Study B1931030 is a post-marketing requirement (PMR) requested by the US Food and Drug 
Administration (FDA).  The study will evaluate the safety and efficacy of 2 inotuzumab 
ozogamicin dose levels in adults with relapsed or refractory B-cell ALL who are eligible for 
HSCT and who are at higher risk for developing VOD post-HSCT.
In this study, the currently approved inotuzumab ozogamicin dosing regimen and an 
alternative dosing regimen, examining a lower total dose per cycle, will be evaluated to 
assess whether a lower dose improves safety, and specifically reduces the rate of VOD 
post-HSCT, and is efficacious for patients at higher risk for VOD post-HSCT.


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1.2.4.1. Selection of Dose Levels
Dose level 1 (starting dose, 1.8 mg/m2/cycle, administered in 3 divided doses) was chosen to 
evaluate the safety and efficacy of inotuzumab ozogamicin at the approved starting dose in 
patients with a higher risk of developing VOD post-HSCT.  In Study B1931022, among all 
enrolled patients treated with inotuzumab ozogamicin (N=164), the CR/CRi rate was 
73.2% and the percentage of responding patients who achieved MRD negativity was 76.7%.  
In Study B1931022, the percentage of patients who developed VOD post-HSCT was 23%.
Among the subgroup of Study B1931022 inotuzumab ozogamicin treated patients with 
1 risk factors for VOD post-HSCT (prior HSCT, Salvage status >1, age 55 years, and/or 
prior history of liver disease/hepatitis [N=105]), the CR/CRi and VOD post-HSCT rates were 
70.5% and 31.1% (14 /45 patients who underwent HSCT after inotuzumab ozogamicin 
treatment), respectively. 
Dose level 2 (starting dose, 1.2 mg/m2/cycle, administered in 3 divided doses) was chosen to 
evaluate the safety and efficacy of inotuzumab ozogamicin at a lower dose than the approved 
starting dose in order to assess whether a lower dose improves safety, and in particular 
reduces the risk of VOD post-HSCT, and is efficacious in patients with a higher risk of 
developing VOD post-HSCT.  This starting dose was examined in Phase 1/2 
Study B1931010. In Study B1931010, activity of 1.2 mg/m2/cycle was shown as 2 of 
3 patients treated at this dose level achieved CR/CRi (Table 9).  The time to achieve CR/CRi 
was similar across each of the dose groups (1.2 mg/m2/cycle, 1.6 mg/m2/cycle, and 
1.8 mg/m2/cycle, Table 9).  Both patients who achieved CR/CRi with 1.2 mg/m2/cycle
treatment, also achieved MRD negativity, though time to MRD negativity appeared to be 
longer for the 2 responders in this dose group compared to responders in each of the higher 
dose groups (Table 9).
Potential changes to safety and efficacy at this lower dose have also been estimated based on 
population PK exposure-response modeling.  The modeling predictions, which are based on 
Phase 3 Study B1931022 data, are shown in Table 10.  For dose level 2, assuming the same 
number of treatment cycles as that for dose level 1 based on Phase 3 Study B1931022 
experience, the predicted CR/CRi rate is 57% (an absolute difference of 14% lower than for
dose level 1), the predicted MRD negativity rate is 43% (an absolute difference of 17% lower 
than for dose level 1), and the predicted rate of VOD post-HSCT is 16.6% (an absolute 
difference of 6.8% lower than for dose level 1).  The actual efficacy and safety results 
observed will depend on the patients enrolled, the actual dosage of inotuzumab ozogamicin 
received per cycle, the number of cycles received, as well as other treatment and 
HSCT-related factors.  The number of inotuzumab ozogamicin cycles received is expected to 
have an impact on CR/CRi rate as the concentrations of inotuzumab ozogamicin do not reach 
steady state until the beginning of Cycle 4. It is anticipated that patients who do not achieve 
CR/CRi in Cycle 1 and continue to receive the therapy are more likely to achieve CR/CRi at 
later cycles since the average serum concentration is expected to be higher at later cycles, 
compared to Cycle 1, until a steady state concentration is achieved at the beginning of 
Cycle 4. Therefore, it is likely that the extent of observed differences in CR/CRi and MRD 
negativity between dose levels 1 and 2 will be lower than that predicted due to more patients 
being able to continue to receive the therapy at dose level 2 beyond Cycles 1 or 2.






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Run-in phase: up to 22 patients will be enrolled to receive the starting dose of 
1.2 mg/m2/cycle (dose level 2).  A Simon Two-Stage optimal design will be used.  If 
acceptable efficacy (CR/CRi and MRD negativity) is observed in the run-in phase, the study 
will enter the randomized phase (see Section 9.1).
Randomized phase: if acceptable efficacy is observed in the run-in phase (see Section 9.1), 
the study will enter the randomized phase.  A total of approximately 80 patients will be
randomized (1:1) to 1 of 2 dose levels of inotuzumab ozogamicin (40 patients per dose level)
(Figure 2).  Patients will be stratified at randomization based on age (<55 vs 55 years), 
salvage status (Salvage 1 vs 2), and prior HSCT (yes vs no).
Patients will receive inotuzumab ozogamicin treatment, on average, for approximately three 
months (ie, 2-3 cycles).  Safety assessments, disease assessments, and PK sample collections
will be conducted throughout the treatment period.
After inotuzumab ozogamicin treatment, patients will be followed for at least 2 years (from 
randomization).  During the follow-up period, safety and disease assessments will be 
conducted, and information about subsequent ALL treatments (including HSCT) and survival 
status will be collected.  All known cases of VOD, regardless of causality and severity, will 
be reported as serious adverse events (SAEs) throughout the follow-up period.
This study will be conducted at approximately 50 clinical sites and is expected to be 
completed (last patient last visit) in approximately 6.0 years.




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d. Ongoing or prior hepatic disease which may include a prior history of hepatitis or 
drug-induced liver injury, as well as hepatic steatosis, nonalcoholic 
steatohepatitis, baseline elevations of bilirubin > upper limit of normal (ULN) and 
1.5 x ULN.
3. Ph+ ALL patients must have failed treatment with at least 1 second or third 
generation tyrosine kinase inhibitor and standard multi-agent induction 
chemotherapy.
4. Patients in Salvage 1 with late relapse should be deemed poor candidates for 
reinduction with initial therapy.
5. Patients with lymphoblastic lymphoma and bone marrow involvement 
5% lymphoblasts by morphologic assessment.
6. Age 18 years to 75 years.
7. Eastern Cooperative Oncology Group (ECOG) performance status 0-2.
8. Adequate liver function, including total serum bilirubin 1.5 x ULN unless the patient 
has documented Gilbert syndrome, and aspartate and alanine aminotransferase 
(AST and ALT) 2.5 x ULN.
9. Serum creatinine 1.5 x ULN or any serum creatinine level associated with a 
measured or calculated creatinine clearance of 40 mL/min.
10. Male and female patients of childbearing potential and at risk for pregnancy must 
agree to use a highly effective method of contraception throughout the study and for a 
minimum of 8 months (females) and 5 months (males) after the last dose of assigned 
treatment.  A patient is of childbearing potential if, in the opinion of the Investigator, 
he/she is biologically capable of having children and is sexually active.  Female 
subjects of nonchildbearing potential must meet at least 1 of the following criteria:
a.
Achieved postmenopausal status, defined as follows: cessation of regular menses 
for at least 12 consecutive months with no alternative pathological or 
physiological cause; and have a serum follicle-stimulating hormone (FSH) level 
confirming the postmenopausal state;
b. Have undergone a documented hysterectomy and/or bilateral oophorectomy; 
c.
Have medically confirmed ovarian failure. 
All other female subjects (including female subjects with tubal ligations) are considered to be 
of childbearing potential. 


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11. Evidence of a personally signed and dated informed consent document indicating that 
the subject has been informed of all pertinent aspects of the study; patients with 
mental capacity which requires the presence of a legally authorized representative 
will be excluded from the study.
12. Willing and able to comply with scheduled visits, treatment plan, laboratory tests, and 
other study procedures.
4.2. Exclusion Criteria
Subjects with any of the following characteristics/conditions will not be included in the 
study:
1. Isolated extramedullary relapse (ie, testicular or central nervous system).
2. Burkitt’s or mixed phenotype acute leukemia based on the WHO 2008 criteria.6
3. Active central nervous system (CNS) leukemia, as defined by unequivocal 
morphologic evidence of lymphoblasts in the cerebrospinal fluid (CSF), use of 
CNS-directed local treatment for active disease within the prior 28 days, symptomatic 
CNS leukemia (ie, cranial nerve palsies or other significant neurologic dysfunction) 
within 28 days. Prophylactic intrathecal medication is not a reason for exclusion.
4. Prior chemotherapy within 2 weeks before randomization with the following 
exceptions: 
a.
To reduce the circulating lymphoblast count or palliation: ie, steroids, 
hydroxyurea or vincristine;
b. For ALL maintenance: mercaptopurine, methotrexate, vincristine, thioguanine, 
and/or tyrosine kinase inhibitors.
Patients must have recovered from acute non hematologic toxicity (to Grade 1) of 
all previous therapy prior to enrollment.
5. Prior monoclonal antibodies within 6 weeks of randomization, with the exception of 
rituximab which must be discontinued at least 2 weeks prior to randomization.
6. Prior inotuzumab ozogamicin treatment or other anti-CD22 immunotherapy 
6 months before randomization.
7. Prior allogeneic hematopoietic stem cell transplant (HSCT) 90 days before 
randomization.  Patients must have completed immunosuppression therapy for 
treatment of graft versus host disease (GvHD) prior to enrollment.  At randomization, 
patients must not have Grade 2 acute GvHD, or extensive chronic GvHD.


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8. Peripheral absolute lymphoblast count 10,000/L (treatment with hydroxyurea
and/or steroids/vincristine is permitted within 2 weeks of randomization to reduce the 
white blood cell [WBC] count).
9. Known systemic vasculitides (eg, Wegener’s granulomatosis, polyarteritis nodosa, 
systemic lupus erythematosus), primary or secondary immunodeficiency (such as 
human immunodeficiency virus [HIV] infection or severe inflammatory disease).
10. Active hepatitis B infection as evidenced by hepatitis B surface antigen, active 
hepatitis C infection (must be anti-hepatitis C antibody negative or hepatitis C 
ribonucleic acid negative), or known seropositivity for HIV.  HIV testing may need to 
be performed in accordance with local regulations or local practice.
11. Major surgery within 4 weeks before randomization.
12. Unstable or severe uncontrolled medical condition (eg, unstable cardiac function or 
unstable pulmonary condition).
13. Concurrent active malignancy other than non-melanoma skin cancer, carcinoma in 
situ of the cervix, or localized prostate cancer that has been definitely treated with 
radiation or surgery.  Patients with previous malignancies are eligible provided that 
they have been disease free for 2 years.
14. Patients with active heart disease or the presence of New York Heart Association 
(NYHA) stage III or IV congestive heart failure.
15. QTcF >470 msec (based on the average of 3 consecutive electrocardiogram [ECGs]).
16. Myocardial infarction 6 months before randomization.
17. History of clinically significant ventricular arrhythmia, or unexplained syncope not 
believed to be vasovagal in nature, or chronic bradycardic states such as sinoatrial 
block or higher degrees of atrioventricular (AV) block unless a permanent pacemaker 
has been implanted.
18. Uncontrolled electrolyte disorders that can compound the effects of a QTc prolonging 
drug (eg, hypokalemia, hypocalcemia, hypomagnesemia).
19. Prior confirmed or ongoing hepatic veno-occlusive disease (VOD) or sinusoidal 
obstruction syndrome (SOS), or other serious or current ongoing liver disease such as 
cirrhosis or nodular regenerative hyperplasia.
20. Administration of live vaccine 6 weeks before randomization.
21. Evidence of uncontrolled current serious active infection (including sepsis, 
bacteremia, fungemia) or patients with a recent history (within 4 months) of deep 
tissue infections such as fascitis or osteomyelitis.


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22. Patients who have had a severe allergic reaction or anaphylactic reaction to any 
humanized monoclonal antibodies.
23. Pregnant female subjects; breastfeeding female subjects; fertile male subjects and 
female subjects of childbearing potential who are unwilling or unable to use highly 
effective contraception as outlined in this protocol for the duration of the study and 
for a minimum of 8 months (females) and 5 months (males) after the last dose of 
investigational product.
24. Investigative site staff members directly involved in the conduct of the study and their 
family members, site staff members otherwise supervised by the Investigator, or 
subjects who are Pfizer employees, including their family members, directly involved 
in the conduct of the study.
25. Participation in other studies involving investigational drug(s) within 2 weeks prior to 
study entry and/or during study participation (up through the end of treatment visit).
26. 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 subject inappropriate for entry into this 
study.
4.3. Life Style Guidelines
All fertile male subjects and female subjects who are of childbearing potential as applicable 
to the study who are, in the opinion of the Investigator, sexually active and at risk for 
pregnancy with their partner(s), must agree to use a highly effective method of contraception 
consistently and correctly for the duration of the active treatment period and for at least 8 
months (females) and for at least 5 months (males) after the last dose of investigational 
product.  The Investigator or his or her designee, in consultation with the subject, will 
confirm that the subject has selected an appropriate method of contraception for the 
individual subject from the permitted list of contraception methods (see below), and will 
confirm that the subject has been instructed in its consistent and correct use.  At time points 
indicated in the Schedule of Activities, the Investigator or designee will inform the subject of 
the need to use highly effective contraception consistently and correctly and document the 
conversation and the subject’s affirmation in the subject’s chart (subjects needs to affirm 
their consistent and correct use of at least 1 of the selected methods of contraception).  In 
addition, the Investigator or designees will instruct the subject to call immediately if the 
selected contraception method is discontinued or if pregnancy is known or suspected in the 
subject or the 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:


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1. Established use of hormonal methods of contraception associated with inhibition of 
ovulation (eg, oral, inserted, injected, implanted, transdermal) provided the subject or 
male subject’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.
2. Correctly placed copper-containing intrauterine device (IUD). 
3. 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.
4. Male sterilization with absence of sperm in the post-vasectomy ejaculate.
5. Bilateral tubal ligation/bilateral salpingectomy or bilateral tubal occlusive procedure 
(provided that occlusion has been confirmed in accordance with the device’s label).
NOTE: Sexual abstinence, defined as completely and persistently refraining from all 
heterosexual intercourse (including during the entire period of risk associated with the study 
treatments) may obviate the need for contraception ONLY if this is the preferred and usual
lifestyle of the subject.
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 at least 5 months after the 
last dose of the investigational product.
4.4. Sponsor 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 Pfizer team SharePoint site.
To facilitate access to appropriately qualified medical personnel on study-related medical 
questions or problems, subjects are provided with a contact card. The contact card contains, 
at a minimum, protocol and investigational product identifiers, subject study numbers, 
contact information for the investigational 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 
subject’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 
advice on medical questions or problems that may arise during the study. The contact
number is not intended for use by the subject directly, and if a subject calls that number, he 
or she will be directed back to the Investigator site.


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5. STUDY TREATMENTS
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 inotuzumab ozogamicin.
All patients must be weighed within 72 hours prior to every cycle Day 1 dosing to ensure 
they did not experience either a weight loss or gain >10% from the prior weight used to 
calculate the amount of inotuzumab ozogamicin required for dose preparation.  A decision to 
recalculate the dose of inotuzumab ozogamicin based on the weight obtained at each cycle 
can be in accordance with institutional practice; however, if the patient has experienced 
either a weight loss or gain >10% (with no other evidence or clinical concern for VOD), the
required amount of inotuzumab ozogamicin needed for study drug preparation and 
administration must be recalculated using this most recent weight/body surface area (BSA)
obtained.  If the dose administered is 10% greater or lower than the one prescribed, it will be 
reported as a dosing medication error.
Prophylactic CNS chemotherapy (intrathecal) is strongly recommended during study 
participation.
Premedication is required for all subjects.  Pre-medicate with a corticosteroid, antipyretic, 
and antihistamine.  Premedication may also include antiemetics (see Section 5.7.3.)
See Section 5.4 for re-dosing criteria and recommended dose delays/reductions.
5.1. Dose Level 1 (Arm 1 of Randomized Phase): Inotuzumab Ozogamicin Starting 
Dose of 1.8 mg/m2/cycle (administered in 3 divided doses)
The dosing schedule for dose level 1 is shown in Table 11.
For dose level 1, the starting dose of inotuzumab ozogamicin is 1.8 mg/m2/cycle
(administered in 3 divided doses).  After CR/CRi is achieved, the dose is reduced to 
1.5 mg/m2/cycle (administered in 3 divided doses).  The cycle length will be 21-28 days.  
Inotuzumab ozogamicin is administered on Day 1, 8, and 15.
For patients proceeding to HSCT, 2 cycles of inotuzumab ozogamicin are recommended.  A
third cycle may be considered for those patients who do not achieve CR/CRi and MRD 
negativity after 2 cycles.
Patients who do not achieve a CR/CRi within 3 cycles should discontinue treatment. 






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5.4. Recommended Dose Modifications (Dose Levels 1 and 2)
Every effort should be made to administer study treatment on the planned dose and schedule.
In the event of toxicity, dosing may be delayed as described below.  In the event of multiple 
toxicities, dose modification should be based on the worst toxicity observed.  Patients are to 
be instructed to notify Investigators at the first occurrence of any adverse symptom.
Dose modifications may occur as follows:

Within a cycle: dose interruption until adequate recovery or omission of a dose during 
a given treatment cycle.

Between cycles: next cycle administration may be postponed due to toxicity in the 
previous cycle.
In the next cycle: dose reduction based on worst toxicity observed in the previous cycle.
5.4.1. Redosing Criteria and Dose Delays (Dose Levels 1 and 2)
Unless patients meet the following criteria prior to the start of each cycle, inotuzumab 
ozogamicin treatment will be delayed.
1. No evidence of progressive disease (PD).  See Appendix 1 for outcome definitions.  
Study treatment may be continued in patients with isolated CNS relapse, at the 
Investigator’s discretion.
2. Decrease in blast percentage or stable disease (50% increase in blast percentage) 
based on the most recent peripheral blood counts and bone marrow evaluation.
3. Recovery to Grade 1 or baseline non-hematologic investigational product-related 
toxicity (except alopecia) (prior to each dose of inotuzumab ozogamicin).
4. Serum bilirubin 1.5 x ULN, and AST, ALT 2.5 x ULN irrespective of the causality 
(prior to each dose of inotuzumab ozogamicin).  Exception: Hyperbilirubinemia in the 
setting of documented Gilbert’s disease.
5. Serum creatinine 2 x ULN or estimated creatinine clearance 40 mL/min as 
calculated using the method standard for the institution (prior to each dose of 
inotuzumab ozogamicin).
6. For patients with pre-treatment absolute neutrophil counts (ANC) 1 x 109/L: ANC 
1 x 109/L.
7. For patients with pre-treatment platelets 50 x 109/L: platelets 50 x 109/L.
8. For patients with baseline ANC <1 x 109/L and/or platelets <50 x 109/L: ANC and 
platelets must recover at least to baseline values obtained for the prior cycle, or


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ANC 1 x 109/L and platelets 50 x 109/L, or the most recent bone marrow must 
demonstrate stable or improved disease, and the ANC and platelets are believed to be 
low due to disease, not investigational product.
9. QTcF 470 msec (average of 3 ECGs).  Note: QTcF must be confirmed prior to 
Day 1 of Cycles 1, 2, 3 and 4 (irrespective of the causality, dosing must be held if 
average QTcF >470 msec).
10. Any hypocalcemia, hypokalemia, or hypomagnesemia must be corrected according to 
standard of care prior to dosing.
While doses given within a treatment cycle (ie, Days 8 and/or 15) need not be delayed due to 
neutropenia or thrombocytopenia, dose delays within a cycle are required for 
non-hematologic toxicity (see #s 3, 4, 5, 9, and 10 above).  Platelet transfusions should be 
given if clinically indicated, but cannot be used to meet dosing criteria prior to start of 
subsequent cycles.
Inotuzumab ozogamicin dosing should be permanently discontinued for any patient with 
possible, probable or confirmed VOD or other severe liver toxicity. Dose delays due to 
inotuzumab ozogamicin-related toxicity 7 days during a treatment cycle are permitted.  If 
dose delay is >7 days, it will result in omission of the next dose within the cycle; the patient 
remains eligible to receive the subsequent planned dose assuming all dosing criteria are met.  
If a dose within a cycle is delayed (ie, Day 8 or 15 dose is delayed), the next dose should also 
be delayed. A minimum of 6 days should be maintained between doses.  Reason for any 
dose delays must be reported on dosing case report form (CRF).  If a treatment interruption 
continues beyond Day 28 of the current cycle, then the day when treatment is restarted will 
be considered Day 1 of the next cycle.  If the beginning of the next cycle is delayed by more 
than 28 days due to inotuzumab ozogamicin-related toxicity, (eg, delay of Day 1 dosing 
beyond 42 days from prior cycle Day 15 dosing) study treatment will be permanently 
discontinued unless otherwise agreed by Sponsor and Investigator.  All toxicity grades are 
according to National Cancer Institute Common Terminology Criteria for Adverse Events 
version 3.0 (NCI CTCAE v3.0).
5.4.2. Dose Reductions ( Dose Levels 1 and 2)
Dose reductions may be required based on the worst toxicity experienced in the previous 
cycle. Patients experiencing a treatment interruption due to inotuzumab ozogamicin-related 
toxicity 14 days will resume dosing with a single 25% reduction (total dose) in inotuzumab 
ozogamicin for the subsequent cycle once adequate recovery is achieved.  If further dose 
modification is indicated after a 25% dose reduction (total dose), the number of doses within 
the cycle should be reduced to two for subsequent cycles. Dose reduction of inotuzumab 
ozogamicin (total dose) by 25% are recommended for patients with CRi, whose platelet 
counts have not recovered to those values obtained prior to the start of the previous cycle.
Once a patient has a dose reduction for an inotuzumab ozogamicin-related toxicity, the dose 
will not be re-escalated.  Patients who are unable to tolerate a 25% dose reduction followed 


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by a decrease in the number of doses per cycle to two doses will be withdrawn from 
treatment unless otherwise agreed between the Investigator and the Sponsor.
5.5. Allocation to Treatment
Once the patient has signed the informed consent, the Investigator or designee will contact 
the randomization system (see study manual) 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 
randomization system.  Instructions on how to use the randomization system will be provided 
in the study manual.  No patient will receive study drug therapy until the entire 
enrollment/randomization process has been completed.
5.6. Subject Compliance
All doses of inotuzumab ozogamicin will be administered by the appropriately designated 
study staff at the Investigator site.
5.7. Investigational Supplies
Study centers will receive a supply of the inotuzumab ozogamicin after site activation.  
Re-supplies will be made during the course of the study.  The study monitor should be 
contacted for any issues related to inotuzumab ozogamicin supplies.
5.7.1. Dosage Form and Packaging
Inotuzumab ozogamicin is provided as a lyophilized, unpreserved white to off-white powder
in a single-dose vial for reconstitution and further dilution for intravenous injection.  It is 
light sensitive.
5.7.2. Preparation and Dispensing
See the Investigational Product Manual for instructions on how to prepare inotuzumab 
ozogamicin for administration.
Inotuzumab ozogamicin 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.
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.
5.7.3. Administration
See the Investigational Product Manual for instructions on how to administer inotuzumab 
ozogamicin. 


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Premedication is required for all subjects.  Pre-medicate with a corticosteroid, antipyretic, 
and antihistamine. Premedication may also include antiemetics.  In cases of infusion related 
reactions, interrupt the infusion and institute appropriate medical management.  Depending 
on the severity of the infusion related reaction, consider discontinuation of the infusion or 
administration of steroids and antihistamines.  For severe or life-threatening infusion 
reactions, permanently discontinue treatment.
5.7.4. Investigational Product Storage 
See the Investigational Product Manual for instructions on how to store inotuzumab 
ozogamicin.  It should be stored at 2 to 8C (36 to 46F).
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 Investigational 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 


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considered a protocol deviation. Specific details regarding information the site should report 
for each excursion will be provided to the site.
5.7.5. 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.
5.7.6. 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.
5.8. Concomitant Medication(s)
5.8.1. Prior Medications
The start date, stop date, dose, and best response to all prior therapies/procedures for 
treatment of the patient’s cancer will be recorded on the CRF.  In addition, the start date, stop 
date, and indication for all treatments and/or therapies and medications received within 
28 days before the first dose of investigational product (including herbal supplements or 
herbal teas, if applicable) will be recorded on the CRF.
5.8.2. Concomitant Medications
The start date, stop date, and indication for concomitant treatments and/or therapies and 
medications received from the first dose of investigational product until 4 to 6 weeks after 
the last dose of investigational product (ie, through end of treatment visit) will be recorded on 
the CRF. Treatment and/or therapies for adverse events will be recorded on the CRF up 
through 9 weeks after the last dose of inotuzumab ozogamicin (see Section 6.3).  In the 
Follow-up period, select concomitant medications including antifungals, 
prophylaxis/treatment for graft versus host disease, and prophylaxis/treatment for VOD 
(including ursodeoxycholic acid or defibrotide) will be collected in the CRF for up to at least 
100 days after a subsequent HSCT (Section 6.4).  Also, in case of severe liver toxicity 
following subsequent HSCT warranting an SAE report, include details regarding these 
concomitant medications such as the actual dose used, start and stop dates and clinical 
response to their use.  Data collected in the context of their use will be provided as part of the 
final clinical study report.
5.8.3. Permitted Concomitant Medications
Any medication for a concurrent medical condition is permitted and will be supplied by the 
study site.
The use of hydroxyurea is permitted for temporary control of WBC elevations in patients
with aggressive disease both prior and during the first 5 days of study treatment.  Reduction 


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of peripheral blast counts to at least 10,000/L is required for randomization and may 
improve the initial PK profile of inotuzumab ozogamicin.  Hydroxyurea may be given at 
1 to 5 grams daily for up to 5 days in Cycle 1.
Concurrent therapy for CNS prophylaxis/treatment is strongly encouraged (eg, intrathecal 
methotrexate).
Growth factors such as granulocyte-colony stimulating factor (G-CSF), including 
pegfilgrastim, and granulocyte macrophage-colony stimulating factor (GM-CSF) may be 
used in accordance with local guidelines and medical practice.
Platelet transfusions should be given if clinically indicated, but cannot be used to meet 
dosing criteria prior to start of subsequent cycles.
Corticosteroids are allowed for cytoreduction, CNS prophylaxis/treatment, as premedications 
for up to 1 day, to treat hypersensitivity reactions for up to 1 day, and as antiemetic for up to 
8 days/cycle as supportive care.  Intranasal, inhaled, or topical corticosteroids are allowed, as 
are low doses of corticosteroids (10 mg or less of prednisone or equivalent/day) throughout 
study participation.  Higher doses of steroids are discouraged if alternative therapy is 
available.  It is crucial to enter dosing details for systemic corticosteroids administered in the 
CRF due to their possible influence on the study endpoints.
5.8.4. Prohibited Concomitant Medications
Craniospinal radiation (CSXRT) is prohibited during study treatment.  If CSXRT is clinically 
indicated, the patient should be withdrawn from study therapy.
Anti-cancer therapy other than as defined/allowed in this protocol and other investigational 
agents are prohibited throughout the treatment period of the study.
5.8.5. Discouraged Concomitant Medications
Patients should be strongly encouraged to avoid herbal supplements throughout the treatment 
period of the study.
Concomitant use of inotuzumab ozogamicin with drugs known to prolong the QT interval or 
induce Torsades de Pointes may increase the risk of a clinically significant QTc interval 
prolongation.  Discontinue or use alternative concomitant drugs that do not prolong QT/QTc 
interval during inotuzumab ozogamicin treatment.  When it is not feasible to avoid 
concomitant use of drugs known to prolong QT/QTc, obtain ECGs and electrolytes prior to 
the start of treatment, after initiation of any drug known to prolong QTc, and periodically 
monitor as clinically indicated during treatment.  See Appendix 2 for a list of medications.
At clinically relevant concentrations, N-acetyl-gamma-calicheamicin (which is released from 
inotuzumab ozogamicin followng hydrolytic cleavage of the ADC linker) had a low potential 
to inhibit or induce cytochrome P450 enzymes,  inhibit uridine glucuronyltransferase (UGT) 
enzymes, or inhibit drug transporters (p-glycoprotein, breast cancer resistance protein
(BCRP), organic anion transporter (OAT)1 and OAT3, organic cation transporter (OCT)2, 


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and organic anion transporting polypeptide (OATP)1B1 and OATP1B3. At clinically 
relevant concentrations, inotuzumab ozogamicin had a low potential to inhibit or induce 
cytochrome P450 enzymes.
6. STUDY PROCEDURES 
The same study procedures are conducted for both arms.  Please refer to the SCHEDULE OF 
ACTIVITIES (Table 1) and additional tables provided within the protocol.
SAE/AE will be reported throughout the study, as described in the specific section of the 
protocol (see Section 8).
6.1. Screening
Screening procedures will occur within 28 days before randomization unless otherwise noted.  
Informed consent document (ICD): an Institutional Review Board (IRB) or Independent 
Ethics Committee (IEC) approved ICD must be signed and dated before any study-specific 
procedures are done.  Results from laboratory tests or assessments, performed as a standard 
of care, prior to the date of informed consent but within the allowed timeframe for screening 
procedures, can be used for determining the patient’s eligibility and will be entered in the 
CRF.  Use of pre-consent results to support inclusion/exclusion criteria must be clearly 
documented in the patient’s source documents.
The following will be collected at screening:

Sign informed consent form.

Review study eligibility (inclusion and exclusion criteria).

Locally obtained characterization of leukemia, including CD22 immunophenotyping 
(flow cytometry) from peripheral blood or bone marrow aspirate obtained within
28 days of randomization. However, local results will be reported in the CRF.  IHC
is allowed in patients with a dry tap or otherwise inadequate bone marrow aspirate in 
the absence of circulating blasts.

Medical history.  Presence of chronic conditions and/or medical history of 
significance including relevant surgical procedures.  A prior history of confirmed 
VOD must be excluded.  Investigators must be rigorous in evaluation to rule out 
presence of any potential of VOD at baseline.

Cancer history and treatment.  Current and initial cancer diagnosis, prior cancer 
therapies and treatments.

Prior treatments and/or therapies and medications (including herbal supplements or 
herbal teas, if applicable) as described in the Prior Medications section.

Eastern Cooperative Oncology Group (ECOG) performance status (Appendix 3).


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
Focused physical examination performed with clinical judgment evaluating potential 
areas of ALL 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 height, weight, blood pressure, pulse and temperature.

Laboratory evaluations as described in Safety Laboratory Requirements (Table 4).

For women of childbearing potential, a beta-human chorionic gonadotropin (-HCG) 
serum or urine pregnancy test must be done up to 72 hours prior to dosing.

Confirm appropriate contraception usage (see Section 4.3).

Hepatitis B (HbsAg) and C (anti-HCV antibody, HCV ribonucleic acid) tests.

Bone marrow aspirate (including bone marrow biopsy if available) and clinical 
disease assessments.  Disease assessments to include liver and spleen assessments.  
The value for blast percentage in the bone marrow and blood (see Safety Laboratory 
Requirements, Table 4) must be confirmed prior to the patient’s first dose.  
Karyotyping to be performed locally.

Bone marrow aspirate (peripheral blood sample if BM aspirate is inadequate) will be 
sent to a central laboratory for immunophenotyping and MRD assessment. The 
leukemic phenotype and/or genotype may also be evaluated by other test methods at 
the discretion of the Sponsor.

Patients with suspected extramedullary disease will have radiographic assessment 
(ie, computerized tomography [CT] or magnetic resonance imaging [MRI]) of all 
known disease sites, as clinically indicated.  Liver, spleen and testes can be assessed 
by palpation; assessment of CNS disease (eg, lumbar puncture) will be done in 
patients with signs or symptoms suggestive of CNS disease or if any prior history of 
CNS leukemia.

Electrocardiogram (ECG).  ECGs will be collected to determine patient eligibility.

Following successful completion of the pre-study assessment and screening 
procedures and confirmation of eligibility, patients may be randomized.

Collection of adverse events. 
6.2. Study Period
The ‘study treatment period’ is defined as the period starting with the first dose of 
investigational product up to and including the end-of-treatment visit.


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Unplanned laboratory assessments will be recorded in the CRF only if clinically significant 
(eg, associated with an AE).
6.2.1. Day 1

Laboratory evaluations will be conducted as described in Table 1 and Table 4.  
Laboratory tests can be done up to 72 hours prior to dosing. Results of complete 
blood counts, serum chemistry, coagulation tests, and pregnancy tests must be 
available before dosing;

Blood sample collected prior to inotuzumab ozogamicin administration for the 
measurement of antibodies to inotuzumab ozogamicin;

Patients will be weighed up to 72 hours prior to the beginning of a new cycle and if 
needed the BSA should be recalculated (see Section 5);

Urine or serum pregnancy test in all females of childbearing potential at every cycle 
prior to dosing; a pregnancy test is required up to 72 hours prior to Cycle 1 Day 1;

Confirm appropriate contraception usage (see Section 4.3);

Focused physical examination performed with clinical judgment evaluating potential 
areas of ALL 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, liver, spleen, and 
lymph nodes; including worsening of medical history conditions;

Vital signs including blood pressure, pulse and temperature.  Performed on all days 
that inotuzumab ozogamicin is administered for all cycles (predose and 1 hour after 
the end of each inotuzumab ozogamicin infusion; also performed 2 hours after the 
end of inotuzumab ozogamicin infusion for Cycle 1 Day 1 dose);

Bone marrow aspirate and clinical disease assessments will be conducted as described 
in Table 1;

MRD assessment and karyotyping for patients with CR/CRi; MRD samples will be 
sent to central vendor while karyotyping will be performed locally;

Bone marrow biopsy collected at least once in patients with CRi (ANC <1 x109/L 
and/or platelets <100 x 109/L) to assess cellularity at the study site as described in 
Table 1;

Patients with extramedullary disease at screening will have radiographic assessment 
(ie, CT or MRI) to confirm CR or CRi, and as medically indicated.  Use the same 
method of assessment for each evaluation (eg, CT scan);

Pharmacokinetic evaluations will be conducted as described in Table 3;




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tests continue to be collected in the CRF through at least 9 weeks after the last dose of study 
inotuzumab ozogamicin unless a new anti-cancer therapy is given.  Adverse events and 
associated concomitant medications must continue to be collected in the CRF through at least 
9 weeks after the last dose of study inotuzumab ozogamicin unless a new anti-cancer therapy 
is given; thereafter, serious adverse events (SAEs) are reported as described in Section 8.1.4.  
VOD cases will be reported as SAEs (Section 8.4.3) and recorded in the CRF for the entire 
duration of study participation, including the Follow-up period, regardless if new anti-cancer 
therapy is given.  The end-of-treatment visit procedures and tests include the following:

Blood sample collected for the measurement of antibodies to inotuzumab ozogamicin;

ECOG performance status;

Focused physical examination performed with clinical judgment evaluating potential 
areas of ALL 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, temperature and weight;

Laboratory evaluations will be conducted as described in Table 1 and Table 4;

For women of childbearing potential, a beta-human chorionic gonadotropin (-HCG) 
pregnancy test must be done;

Confirm appropriate contraception usage (see Section 4.3);

Disease assessment (see Section 7.1), including bone marrow aspirate, which should 
be done prior to the start of new anti-cancer treatment;

Electrocardiogram (ECG).
6.4. Follow-up Visits
Disease assessments will be conducted for all patients whose disease has not progressed
(including patients undergoing stem-cell transplant or other subsequent anti-leukemic
therapy) until disease progression for up to at least 2 years after randomization (every 
12 weeks up to 1 year from randomization and every 24 weeks between year 1 and 2).  Visits 
for disease assessment are planned starting approximately 12 weeks after the last disease 
assessment then continuing until the patient completes at least 2 years (relative to the day of 
randomization) or has documented disease progression, whichever occurs first (see Table 2).  
Visits for disease assessment will include the following evaluations:


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
Laboratory evaluations which include complete blood count (CBC) with differential, 
total bilirubin, alkaline phosphatase, ALT, AST, gamma-glutamyl transpeptidase 
(GGT), and albumin, hematology.  Evaluations will be done up to a year from 
randomization or until a new cancer treatment has started. For patients in disease 
follow up beyond a year from randomization, CBC with differential and platelets are 
required until disease progression;

Bone marrow aspirate (and biopsy if indicated per standard of care) and 
extramedullary disease assessments.  Disease assessments to include testicular, liver 
and spleen assessments.  No bone marrow aspirate is necessary if non-response or 
progressive disease can be diagnosed from peripheral blood evaluation; required 
every 12 weeks (1 week) for one year from randomization, then every 24 weeks 
(2 weeks) for the second year; all disease assessments should be recorded on CRF 
until relapse/disease progression unless consent is withdrawn;

Reporting of follow-up anticancer therapy.  Medication name, surgical or 
radiotherapy procedure, start/stop dates will be collected for 2 years (total, relative to 
the day of randomization). Also at least the first post-study salvage therapy 
(re-induction) and response to the first post-study salvage therapy (re-induction) will 
be reported in the CRF (refractory or responsive disease).  Post-study transplant 
information including conditioning treatments will be collected for up to 2 years from 
randomization.  Follow-up anticancer therapy and response will be recorded for all 
randomized patients (even if the patient was never treated on study);

Select concomitant medications including antifungals, prophylaxis/treatment for graft 
versus host disease, and prophylaxis/treatment for VOD (including ursodeoxycholic 
acid or defibrotide) will be collected in the CRF for up to at least 100 days after a 
subsequent HSCT.
All randomized patients (including patients undergoing stem-cell transplant) will be followed 
for survival for at least 2 years.  Follow-up limited to survival status will start approximately 
12 weeks after the completion of the disease follow-up period.  Follow-up for survival can be 
conducted every 12 weeks either by telephone interview or email.  Also, information about 
other anticancer therapy will be collected.
All known cases of VOD must be reported in the CRF for the entire duration of study 
participation, including the Follow-up period, irrespective of causality.  Also, cases of VOD
will be reported as SAEs as detailed in Section 8.4.3.
6.5. Subject Withdrawal
Prior to randomization, Investigators should ensure the consent process includes full 
disclosure of the risks and procedures. 
The patient should not be randomized unless they understand and accept the chance of being 
randomized to either arm (dose level).


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Subjects 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 (see also the Subject Withdrawal
section) section) or behavioral reasons, or the inability of the subject to comply with the 
protocol-required schedule of study visits or procedures at a given study site.
If a subject does not return for a scheduled visit, every effort should be made to contact the 
subject.  Every effort should be made to schedule an end of treatment visit and to complete 
all the assessments required.  This visit should take place 4 to 6 weeks after the last dose of 
study treatment.  If a patient does not return for a scheduled visit, every effort should be 
made to contact the patient for 1 year before declaring a patient lost to follow-up.  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 subject return for 
a final visit, if applicable, and follow-up with the subject regarding any unresolved adverse 
events (AEs), disease progression and survival.
If the subject 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.
7. ASSESSMENTS
The same assessments are conducted for both arms.  Please refer to the Schedule of Activities
(Table 1) and additional tables provided within the protocol.
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 subject.  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. Efficacy Assessments
Assessment of response and progression status will be evaluated according to a modified 
Cheson Criteria described in Appendix 1. Disease assessments are determined using 
information from bone marrow evaluations, laboratory assessments (eg, hematology), clinical
and radiological information (eg, extramedullary disease).  No bone marrow aspirate is 
necessary if non-response or progressive disease can be diagnosed from peripheral blood 
evaluation or radiological/clinical assessment.  Patients with extramedullary disease prior to 


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randomization will have radiographic assessment (CT or MRI) to confirm a CR or CRi using 
the same method of assessment, unless contraindicated.
Bone marrow aspirate (or biopsies if clinically indicated) and disease assessments (see
Appendix 1) will be performed at screening, once at day 16-28 of Cycles 1 and 2, or until 
CR/CRi and MRD negativity are achieved, then after every 1-2 cycles as clinically indicated,
at the end-of-treatment visit (unless previously done within 28 days), and during follow-up
visits (see Section 6.4).
Bone marrow aspirates will be analyzed at the study site. A BM biopsy is recommended at 
the time of bone marrow aspirates and will be done during treatment at least to evaluate 
cellularity in patients achieving CRi.
CBC with differential and platelets, bone marrow aspirate, bone marrow biopsy as clinically 
indicated, plus re-evaluation of pre-existing or suspected extramedullary disease as clinically 
indicated should be completed at the time of each disease assessment.  If a CNS disease 
assessment was indicated during screening, reassessments will be done as clinically indicated
(Table 1).
At any time point, an additional aspirate or biopsy may be required if the original aspirate is 
inadequate for disease assessment.

For patients requiring baseline cytoreduction or palliation (eg, hydroxyurea, steroids 
and/or vincristine), a post-cytoreduction BM assessment is not required prior to 
randomization;

If a patient receives a more aggressive chemotherapy regimen (ie, another salvage 
attempt), the patient must repeat the entire screening process and must meet all 
eligibility criteria prior to randomization;

G-CSF should be discontinued at least 72 hours prior to every bone marrow
assessments;
Karyotyping will be performed locally in all patients at screening and at least once in patients 
achieving morphologic CR or CRi and who had abnormal cytogenetics at baseline. It is 
recommended that 20 or more metaphases be counted for local cytogenetics analysis.
For determination of MRD, bone marrow aspirate will be sent to a central laboratory and 
analyzed by flow cytometry for cell surface markers associated with B-ALL. The leukemia 
phenotype and/or genotype may also be evaluated by other test methods at the discretion of 
the Sponsor.
7.2. Safety Assessments
Safety endpoints include adverse events (graded according to the National Cancer Institute 
Common Terminology Criteria for Adverse Events [NCI CTCAE] version 3.0), clinical 
examination (including blood pressure and pulse), laboratory tests (hematology, chemistry, 
and coagulation) and 12-lead electrocardiograms (ECGs).


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Additional procedures or samples may be undertaken as medically required at the discretion 
of the Investigator.
7.3. Pregnancy Testing
For female subjects of childbearing potential, a serum or urine pregnancy test, with 
sensitivity of at least 25 mIU/mL, will be performed at screening, 72 hours prior to every 
cycle Day 1, and at the end of treatment visit (to confirm the patient has not become pregnant 
during the study) (Table 1).  A negative pregnancy result is required before the patient may 
receive the investigational product.  Pregnancy tests will also be done whenever one 
menstrual cycle is missed during the active treatment period (or when potential pregnancy is 
otherwise suspected).  Pregnancy tests may also be repeated as per request of IRB/IECs or if 
required by local regulations.
7.4. Pharmacokinetic Measures
In order to correctly utilize the PK data, it is critical that the actual time and date of 
inotuzumab ozogamicin administration and PK sample collection is recorded on the CRF.  
Concentrations of inotuzumab ozogamicin and free calicheamicin in serum will be 
determined by validated bioanalytical assays.  These analyses will be performed at a central 
laboratory designated by the Sponsor.  Sample collection, labeling, storage and shipping 
information for central laboratory analyses can be found in the Study Manual.
7.5. Pharmacodynamic Evaluations
Bone marrow aspirate, collected at screening and for remission status, will be sent to the 
central vendor, for immunophenotyping and assessment of MRD.  MRD will be assessed by 
flow cytometry for CD22 and other cell surface markers associated with B-cell ALL.  The 
leukemia phenotype and/or genotype may also be evaluated by other test methods at the 
discretion of the sponsor.  MRD analysis will be done at least once in patients with prior 
assessment of CR or CRi.  A peripheral blood sample must be provided to the central vendor 
if a patient has an inadequate aspirate at screening.
7.6. Immunogenicity Testing
To assess the immunogenicity of inotuzumab ozogamicin, blood sample will be collected at 
Day 1 of every cycle prior to the inotuzumab ozogamicin infusion and at the 
End-of-Treatment visit (Table 1, Schedule of Activities). 
The immunogenicity of inotuzumab ozogamicin will be evaluated using a validated 
electrochemiluminescence (ECL)-based immunoassay.  For patients whose sera tests positive 
for anti-inotuzumab ozogamicin antibodies, a validated cell-based luminescence assay will 
be performed to test for neutralizing antibodies. 
In patients who test positive for anti-inotuzumab ozogamicin antibodies, the impact of 
anti-inotuzumab ozogamicin antibodies on clearance, safety, and efficacy will be assessed.






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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 
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 
subject 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, 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 subject.  In addition, each study subject 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 Subject
Withdrawal section)
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 subject 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 subject begins from the time the subject provides informed consent, which 
is obtained before the subject’s participation in the study (ie, before undergoing any 
study-related procedure and/or receiving investigational product), through and including a 
minimum of 9 weeks after the last administration of the investigational product.
The “active collection period” for VOD is the entire duration of study participation, 
including the Follow-up period, regardless of whether new anti-cancer treatment is 
initiated.  All cases of VOD must be reported as SAEs (recorded on the CRF and CT 
SAE Report Form).
For subjects who are screen failures, the active collection period ends when screen failure 
status is determined.
8.1.4.1. Reporting SAEs to Pfizer Safety
All SAEs occurring in a subject during the active collection period are reported to Pfizer 
Safety on the CT SAE Report Form.
SAEs occurring in a subject 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 begins a new anticancer therapy, SAEs occurring during the above-indicated 
active collection period must still be reported to Pfizer Safety irrespective of any intervening 
treatment.
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 subject 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 subject 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;


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
Same-day surgeries (as outpatient/same-day/ambulatory procedures).
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, subject 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 subject;

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
GRADE
Clinical Description of Severity
0 
No change from normal or reference range (This grade is not included in the 
Version 3.0 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


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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.
8.4. Special Situations
8.4.1. Protocol-Specified Serious Adverse Events
Unless the Investigator believes that there is a causal relationship between the 
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 ALL.  However, these events should still be recorded
as AEs on the CRF.
Protocol-specified SAEs that will not normally be reported to Pfizer Safety in an expedited 
manner, unless Grade 5 (or with an outcome of fatal) or if a causal relationship with the 
investigational product is considered at least reasonable:

Febrile neutropenia;

Neutropenic sepsis;

The following occurring post-HSCT and after discontinuation of inotuzumab 
ozogamicin:

Acute graft versus host disease (GvHD);

Infection requiring IV antibiotics; 

Hemorrhage/bleeding;

Weight loss/anorexia;

Acute kidney injury;

Nausea/vomiting/diarrhea;

Thrombocytopenia/anemia. 
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 subjects, transaminase elevations are a harbinger of a more 
serious potential outcome.  These subjects fail to adapt and therefore are "susceptible" to 
progressive and serious liver injury, commonly referred to as drug-induced liver injury 
(DILI).  Subjects 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 subject’s 
individual baseline values and underlying conditions.  Subjects 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:

Subjects 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 subjects 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 subject 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 Cases
All cases of veno-occlusive disease (VOD), also known as sinusoidal obstruction syndrome 
(SOS), regardless of causality, severity and treatment arm must also be reported as an SAE 
for the entire duration of study participation, including the Follow-up period (Table 2).  
Events of VOD which occur thereafter should be reported following the SAE reporting 
criteria.  In the event of serious or severe hepatic adverse events, patients should have a 
hepatology consultation and work-up including (but not limited to), weights, infectious 
hepatitis testing (A, B, C).  When evaluating liver toxicity, inform the radiologist of the 
potential for hepatic vascular disease.  When VOD 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).  
Assessment of abdominal tumor(s); collection of alcohol use information (historical, 
current); prior hepatitis or a related condition (either infectious or non-infectious, including 
non-alcoholic steatohepatitis [NASH, also known as non-alcoholic fatty liver or NAFL] and 
alcoholic steatohepatitis [ASH]), laboratory tests (including, but not limited to, conventional 


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liver function tests, INR/ prothrombin time (PT), albumin, and ammonia levels), and 
information from liver biopsy or autopsy if performed.
Results of all assessments, signs and symptoms should be recorded in the CRF (including 
imaging results, biopsy results, vital signs [including changes in weight], detailed pertinent 
physical exam, laboratory values, non-study medications [including herbal supplements and 
herbal teas, if applicable], sites of disease other adverse events particularly recent and/or 
concurrent infections, and other non-study treatments); unplanned CRF pages can be used if 
necessary.  Assessment (recording) of weights in a patient experiencing any hepatic event is 
important because it can help in the differential diagnosis, given the association of fluid 
retention with portal hypertension and VOD.  One of the major distinctions between most 
acute liver disorders in oncology patients and VOD is the presence of portal hypertension, 
which leads to renal retention of salt and water, and thus, to abrupt gains in weight.
For this study, criteria for VOD (also known as sinusoidal obstruction syndrome [SOS]) is 
defined as:7
a.
Classical VOD (first 21 days after HSCT): 

Bilirubin 2 mg/dL and two (or more) of the following criteria must also be 
present;

Painful hepatomegaly;

Weight gain >5%;

Ascites.
b.
Late onset VOD (>21 days after HSCT):

Classical VOD beyond Day 21;
or

Histologically proven VOD;
or

Two or more of the following criteria must be present:

Bilirubin >2 mg/Dl;

Painful hepatomegaly;

Weight gain >5%;

Ascites.
AND hemodynamical and/or ultrasound evidence of VOD.


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For this study, severity of VOD is defined as follows (Table 13).7
Table 13.
VOD Severity Grading (Patients Belong to the Category that Fulfills Two 
or More Criteria)a
Mild
(Grade 1)b
Moderate
(Grade 2)b
Severe
(Grade 3)
Very severe
(Grade 4)c
Time since first 
clinical symptomsd
>7 days
5-7 days
4 days
Any time
Bilirubin (mg/dL)
2 and <3
3 and <5
5 and <8
8
Bilirubin (umol/L)
34 and <51
51 and <85
85 and <136
136
Bilirubin kinetics
doubling 48 hr
Transaminases
2 X ULN
>2 and 5 x ULN
>5 and 8 x ULN
>8 x ULN
Weight increase
<5%
5% and <10%
5% and <10%
>10%
Renal Function
<1.2 x baseline 
at HSCT
1.2 and <1.5 x 
baseline at HSCT
1.2 and <1.5 x 
baseline at HSCT
2 x baseline at 
HSCT or other 
signs of 
MOD/MOF
Abbreviations:hr=hour; HSCT=hematopoietic stem cell transplant; MOD=multi-organ dysfunction;
MOF=multi-organ failure; ULN=upper limit of normal.
a.
If patients fulfill two or more criteria in two different categories, they must be classified in the most severe 
category. Patients weight increase 5% and <10% is considered by default as a criterion for severe VOD; 
however, if patients do not fulfill other criteria for severe VOD, weight increase 5% and <10% is therefore 
considered as a criterion for moderate VOD. 
b.
In the case of presence of two or more risk factors for VOD, patients should be in the upper grade. 
c.
Patients with multi-organ dysfunction must be classified as very severe. 
d.
Time from the date when the first signs/symptoms of VOD began to appear (retrospectively determined).
e.
and the date when the symptoms fulfilled VOD diagnostic criteria.
See also Appendix 4 for guidance about recommendation for patients proceeding to HSCT 
and potential VOD cases.
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.
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;


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
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 subject or subject’s partner becomes or is found to be pregnant during the subject’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 subject 
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]), 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;

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.


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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 subject with the Pregnant Partner Release of Information Form 
to deliver to his partner.  The Investigator must document in the source documents that the 
subject 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 subject 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
8.4.5.1. Medication Errors
Medication errors may result from the administration or consumption of the investigational 
product by the wrong subject, or at the wrong time, or at the wrong dosage strength.
Medication errors include:

Medication errors involving subject exposure to the investigational product;


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
Potential medication errors or uses outside of what is foreseen in the protocol that do 
or do not involve the participating subject.
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 
will be documented 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 objective of this study is to evaluate safety and efficacy of two inotuzumab ozogamicin 
dose levels through descriptive analyses.  A total of up to approximately 102 patients will be 
enrolled in the study: up to 22 patients in the run-in phase (dose level 2) and 80 patients 
(40 patients per dose level arm) in the randomized phase if acceptable efficacy is observed 
for dose level 2 in the run-in phase.
The observed CR/CRi rate for the subgroup of patients with factors for higher risk of VOD 
post-HSCT in Phase 3 Study B1931022 was 70.5% for the inotuzumab ozogamin arm and 
31.2% for the control arm.  However, the true response rates for this subgroup could be 
lower, depending on the prognostic factors of the patients in this group; the response rate for 
inotuzumab ozogamin could be as low as 57% in this patient population based on the 
exposure response model.  Based on these results, the run-in phase will test the null 
hypothesis (H0) that the CR/CRi rate is 31.2% versus the alternative hypothesis (Ha) that 
the CR/CRi rate is 57% .  In order to minimize the expected number of patients enrolled in 
the event that the lower dose level (1.2 mg/m2/cycle of inotuzumab ozogamicin, dose level 2) 
proves to be of minimal efficacy benefit, a Simon Two-Stage optimal design will be used for 
the run-in phase.  A total of up to 22 patients will be enrolled in the run-in phase.  This 
sample size will provide 80% power to reject the null hypothesis with significance level of 
0.10 if the true CR/CRi rate is 57%.


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Seven (7) patients will be enrolled in Stage 1.  If 2 CR/CRi responders are observed in 
Stage 1, accrual will be stopped for further evaluation.  Once at least 3 (ie, 42.9%) CR/CRi 
responders are documented, an additional 15 enrolled patients will be evaluated in Stage 2.
If 10 CR/CRi responders are observed in the total of 22 patients from both stages, it will be 
concluded that the true CR/CRi rate for the lower dose is higher than the historical control 
(31.2% for Study B1931022 control arm subgroup of patients with risk factors for VOD 
post-HSCT).
The expected MRD negativity rate among the patients who achieve CR/CRi is 70%.  With 
10 CR/CRi responders expected at the end of Stage 2, the expected number of patients with 
MRD negativity among the 22 patients in the run-in phase is 7.  Given a CR/CRi rate of 
57%, predicted by the exposure response model, and an expected MRD negativity rate of 
70% among CR/CRi responders, 40% is the expected MRD negativity rate among all the 
patients enrolled in the run-in phase.  Twenty-two (22) patients will also provide 80% power 
to reject the null hypothesis of the MRD negativity rate 20% when the alternative 
hypothesis of the true MRD negativity rate is 40% with significance level of 0.10.  There 
will be 84% probability to observe a minimum of 7 patients who have achieved MRD 
negativity if the true MRD negativity rate is at least 40%.
To review the totality of the efficacy data, DoR will also be analyzed for the run-in phase.  
Safety data will also be reviewed for the run-in phase.
Once at least 10 CR/CRi responders and at least 7 patients achieving MRD negativity are 
documented among the 22 patients in the run-in phase, patients enrolled in the randomized 
phase will then be evaluated, with approximately 80 patients randomized (1:1) to the 
approved dose level of 1.8 mg/m2/cycle (dose level 1, Arm 1) or the lower dose level of 
1.2 mg/m2/cycle (dose level 2, Arm 2). 
Until analyses for decision-making are completed, enrollment will continue between Stage 1 
and Stage 2 of the run-in phase and between the run-in and randomized phases of the study.
At the end of the study, descriptive analyses will be conducted by dose level.  For the 
randomized phase, a sample size of 40 patients per arm will provide the estimated VOD rate 
in each dose level with a maximum standard error (SE) of 0.08.  The maximum SE estimated 
for other binary endpoints in each dose level (eg, CR/CRi rate) will also be 0.08.  In addition, 
for summary of dose level 2, patients in the run-in phase will be combined with Arm 2 of the 
randomized phase, for a sample size of approximately 62 patients (ie, 22 patients enrolled in 
the run-in phase and 40 patients enrolled in Arm 2 in the randomized phase) to provide the 
above-mentioned estimated rates with a maximum SE of 0.06.
Table 14 shows the possible estimated VOD rate and CR/CRi rate with 95% CI with a 
sample size of 40 patients and 62 patients, respectively.


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Table 14.
Estimated VOD Rate and CR/CRi Rate with 95% Confidence Interval
VOD/ Sample 
Size
VOD Rate
% (95% CI)
Responders/ Sample Size
CR/CRi rate
% (95% CI)
40 patients
4/40
10% (2.8-23.7)
16/40
40% (24.9-56.7)
6/40
15% (5.7-29.8)
20/40
50% (33.8-66.2)
8/40
20% (9.1-35.6)
24/40
60% (43.3-75.1)
10/40
25% (12.7-41.2)
28/40
70% (53.5-83.4)
12/40
30% (16.6-46.5)
32/40
80% (64.4-90.9)
62 patients
6/62
10% (3.6-19.9)
25/62
40% (28.1-53.6)
9/62
15% (6.9-25.8)
31/62
50% (37.0-63.0)
13/62
21% (11.7-33.2)
37/62
60% (46.4-71.9)
16/62
26% (15.5-38.5)
44/62
71% (58.1-81.8)
19/62
31% (19.6-43.7)
50/62
81% (68.6-89.6)
Abbreviations: CI=confidence interval; CR=complete remission; CRi=complete remission with incomplete 
hematologic recovery; VOD=veno-occlusive disease
9.2. Analysis Populations
This study is designed to enroll patients who are eligible for HSCT.  Patients must be eligible 
for HSCT at the time of enrollment (see Section 4.1).  Patients who are eligible for HSCT at 
enrollment but who subsequently are not able to proceed to HSCT will not be replaced.  
Analyses will be performed for the Intent-to-Treat, Safety Population, and Per Protocol 
Populations as described below.
9.2.1. Intent-to-Treat (ITT) 
The ITT population will include all patients who are enrolled into the study, with study drug 
assignment designated according to initial randomization.
9.2.2. Safety Population
The safety population includes all enrolled patients who receive at least 1 dose of 
investigational product (inotuzumab ozogamicin), with treatment assignments designated 
according to actual treatment received.
Safety post-HSCT will also be evaluated. The HSCT safety population includes all enrolled
patients who receive at least 1 dose of investigational product (inotuzumab ozogamicin), with 
treatment assignments designated according to actual treatment received, and who undergo 
HSCT after inotuzumab ozogamicin treatment.
9.2.3. Per Protocol (PP) Population
All patients who meet all of the following criteria:
1. Randomized and receive at least one dose of investigational product (inotuzumab 
ozogamicin), with treatment assignments designated according to actual treatment 
received.


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2. No major protocol violations.  Major violations include failure to satisfy major entry 
criteria or life-threatening dosing error. 
3. An adequate baseline disease assessment.
4. Proceeds to follow-up HSCT.
9.3. Efficacy Analysis
All analyses will be done by dose level and by study phase (ie, run-in phase, Arm 1 of 
randomization phase , and Arm 2 of the randomization phase will be summarized separately).  
In addition, for the summary of dose level 2, patients enrolled in the run-in phase will be 
combined with Arm 2 of the randomization phase. 
9.3.1. Analysis of the Primary Endpoint
Hematologic response, defined as complete remission (CR) + complete remission with 
incomplete hematologic recovery (CRi), will be summarized in the ITT population.  
Descriptive analyses (ie, the number, percent of patients achieving CR/CRi along with 
2-sided 95% confidence interval [CI]) without formal hypothesis testing will be provided.  A 
sensitivity analysis will also be conducted for CR/CRi in the PP population.
CR is defined as a disappearance of leukemia as indicated by <5% marrow blasts and the 
absence of peripheral blood leukemic blasts, with recovery of hematopoiesis defined by 
absolute neutrophil count (ANC) 1000/l and platelets 100,000/l.  Absence of
extramedullary disease status is required.  CRi is defined as CR except with absolute 
neutrophil count (ANC) <1000/l and/or platelets <100,000/l (see Appendix 1).
9.3.2. Analysis of Secondary Endpoints
MRD negativity (in patients who achieved CR/CRi) will be defined as the minimum MRD 
percentage between the date of CR/CRi and end of treatment test is <0.01%. Descriptive 
analyses (ie, the number, percent of patients achieving MRD negativity along with 2-sided 
95% CI) will be provided for both ITT and PP populations.
DoR will be defined as time from date of first response in responders (CR/CRi) to the date of 
disease progression or death due to any cause, whichever occurs first.  DoR will be 
summarized descriptively using Kaplan-Meier methods and displayed graphically where 
appropriate in both ITT and PP populations.
PFS will be defined as time from date of randomization to the date of disease progression or 
death due to any cause, whichever occurs first. PFS will be summarized descriptively using 
Kaplan-Meier methods and displayed graphically where appropriate in both ITT and PP
populations.
OS will be defined as the time from date of randomization to the date of death due to any 
cause. OS will be summarized descriptively using Kaplan-Meier methods and displayed 
graphically where appropriate in both ITT and PP populations.


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Rate of HSCT will be summarized by descriptive analyses (ie, the number, percent of 
patients underwent HSCT along with 2-sided 95% CI) in ITT population and PP population.
Post-HSCT relapse will be defined as the time from date of HSCT to the date of first relapse 
post-HSCT.  Post-HSCT relapse will be summarized descriptively using competing-risks 
analyses and displayed graphically where appropriate in both ITT and PP populations.
Post-HSCT mortality will be defined as the time from date of HSCT to the date of death due 
to any cause. Post-HSCT mortality will be summarized descriptively using Kaplan-Meier 
methods and displayed graphically where appropriate in both ITT and PP populations.
Post-HSCT non-relapse mortality (NRM) will be defined as time from date of HSCT to the 
date of death due to any cause without prior relapse/progression post-HSCT. Post-HSCT 
NRM will be summarized descriptively using competing-risks analyses and displayed 
graphically where appropriate in both ITT and PP populations.
Post-HSCT relapse-related mortality (RRM) will be defined as time from date of HSCT to 
the date of death due to any cause with prior relapse/progression post-HSCT. Post-HSCT 
RRM will be summarized descriptively using competing-risks analyses and displayed 
graphically where appropriate in both ITT and PP populations.
The immunogenicity of inotuzumab ozogamicin will be summarized descriptively.
9.4. Analysis of Other Endpoints
9.4.1. Population Pharmacokinetic Analysis
Analysis of bioanalytical measures for inotuzumab ozogamicin (and unconjugated 
calicheamicin, if possible) will be performed using a nonlinear mixed-effects model and a 
previously defined base model structure of drug disposition which takes into account the 
nonlinear drug disposition which has been observed following inotuzumab ozogamicin 
administration.
Using a Bayesian post-hoc approach, individual patient PK parameters based on the final 
population PK model and individual patient contributions to the model may be generated.  
These parameters would serve as input for PK predictions and for exposure response 
analyses with respect to key safety (eg, VOD, ALT, AST, bilirubin) and efficacy (CR/CRi, 
MRD negativity) endpoints.  The exposure response analyses will be only performed if the 
study enters the randomized phase.
The results of population PK analysis and exposure response analyses with respect to safety 
and efficacy endpoints of interest (if applicable) will be provided separately as part of a 
population modeling analysis report.


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9.5. Safety Analysis
Similar to efficacy analyses, safety analyses will be done by dose level and by study phase 
(ie, run-in phase, Arm 1 of randomization phase , and Arm 2 of the randomization phase will 
be summarized separately).  In addition, for the summary of dose level 2, patients enrolled in 
the run-in phase will be combined with Arm 2 of the randomization phase. 
9.5.1. Analysis of the Primary Endpoint
Rate of VOD (total, on-study treatment, and post-HSCT) will be summarized for each arm in 
the safety population and PP population.  Descriptive analyses (ie, the number, percent of 
patients with VOD along with 2-sided 95% CI) without formal hypothesis testing will be 
performed.  A subgroup analysis will also be conducted for VOD in the HSCT safety
population.  Analyses in this subgroup will include an assessment of VOD in all patients with 
a subsequent HSCT as well as in patients who proceed to HSCT directly after inotuzumab 
ozogamicin treatment (without an intervening induction therapy).  All known cases of VOD, 
regardless of causality and severity, will be reported as SAEs for the entire duration of study 
participation, including the Follow-up period (recorded on the CRF and the CT SAE Report 
Form, see Table 2 and Section 8.1.4).
9.5.2. Analysis of Secondary Endpoints
The safety analysis will be conducted on the safety population, the HSCT safety population, 
and the PP population.  AEs will be presented with and without regard to causality based on 
the Investigator’s judgment.  The frequency of overall toxicity, categorized by toxicity 
Grades 1 through 5, will be described.  Additional summaries will be provided for AEs that 
are observed with higher frequency.
9.6. Interim Analysis
This study is designed to have one interim analysis for Stage 1 of the run-in phase and one 
interim analysis at the end of the run-in phase to allow early stopping due to insufficient 
efficacy for dose level 2.  See Section 9.1 for details. 
9.7. Data Monitoring Committee 
This study will use an internal review committee (IRC).  The IRC will review run-in phase
results and provide recommendations about the conduct of the study (see Section 9.1).  
During the randomization phase, the IRC will review safety data for both arms at regular 
intervals during the study.  The IRC will be comprised of 3 members who are not directly 
involved in the study, including a statistician and two medically qualified individuals.
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.


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During study conduct and/or after study completion, the Investigator site may be subject 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 subject'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 subject.  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 and/or paper form and will 
be password protected or secured in a locked room 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 
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 subject chart.  In these 
cases, data collected on the CRFs must match the data in those charts. 


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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 subjects 
(sufficient information to link records, eg, CRFs and hospital records), all original signed 
informed consent 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 (IRB)/Independent Ethics Committee (IEC)
It is the responsibility of the Investigator to have prospective approval of the study protocol, 
protocol amendments, informed consent 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.
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 subjects.  In 
that event, the Investigator must notify the IRB/EC and Pfizer in writing immediately after 
the implementation.


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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.
12.3. Subject 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 subject personal data.  Such 
measures will include omitting subject names or other directly identifiable data in any 
reports, publications, or other disclosures, except where required by applicable laws. 
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, subject 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 subjects who participated in the 
study, linking each subject’s numerical code to his or her actual identity.  In case of data 
transfer, Pfizer will maintain high standards of confidentiality and protection of subjects’ 
personal data consistent with the Clinical Study Agreement and applicable privacy laws.
The informed consent documents and any subject recruitment materials must be in 
compliance with ICH GCP, local regulatory requirements, and legal requirements, including 
applicable privacy laws.
The informed consent documents used during the informed consent process and any subject 
recruitment materials must be reviewed and approved by Pfizer, approved by the IRB/EC 
before use, and available for inspection.
The Investigator must ensure that each study subject is fully informed about the nature and 
objectives of 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 subject’s personal 
data.  The Investigator further must ensure that each study subject 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.


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The Investigator, or a person designated by the Investigator, will obtain written informed 
consent from each subject before any study-specific activity is performed.  The Investigator 
will retain the original of each subject's signed consentdocument.
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 subjects against any immediate hazard, and of 
any serious breaches of this protocol or of ICH GCP that the Investigator becomes aware of.
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 subjects 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 Participating Countries
End of trial in all participating countries is defined as last patient last visit.
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 
inotuzumab ozogamicin at any time.
If a study is prematurely terminated, Pfizer will promptly notify the Investigator.  After 
notification, the Investigator must contact all participating subjects and the hospital pharmacy 
(if applicable) within a timeframe agreed at the time with the Sponsor and in accordance with 
local and regulations and/or IEC/IRBs.  As directed by Pfizer, all study materials must be 
collected and all CRFs completed to the greatest extent possible.


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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.
PCD is defined as the date that the final subject 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 


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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, subject to the other 
requirements of this section.
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 for in the CSA between Pfizer and the 
institution.  In this section entitled Publications by Investigators, the defined terms shall have 
the meanings given to them in the CSA.
If there is any conflict between the CSA and any attachments to it, the terms of the CSA 
control.  If there is any conflict between this protocol and the CSA, this protocol will control 
as to any issue regarding treatment of study subjects, and the CSA will control as to all other 
issues.


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16. REFERENCES

Dijoseph JF, Dougher MM, Armellino DC, et al. Therapeutic potential of 
CD22-specific antibody-targeted chemotherapy using inotuzumab ozogamicin 
(CMC-544) for the treatment of acute lymphoblastic leukemia. Leukemia 
2007;21(11):2240-5.

Kantarjian HM, DeAngelo DJ, Stelljes M, et al.Inotuzumab ozogamicin versus standard 
therapy for acute lymphoblastic leukemia. N Engl J Med 2016; 375: 740–53.

United States package insert, BESPONSA™(inotuzumab ozogamicin) for injection, for 
intravenous use. Initial U.S. Approval: 2017.

Carreras E, Bertz H, Arcese W, Vernant J-P, Tomas J-F, et al, Incidence and outcome of 
hepatic veno-occlusive disease after blood or marrow transplantation: a prospective 
cohort study of the European Group for blood and marrow transplantation.  Blood.  
1998; 92: 3599-3604.

DeAngelo DJ, Stock W, Stein AS, et al. Inotuzumab ozogamicin in adults with relapsed 
or refractory CD22-positive  acute lymphoblastic leukemia: a phase 1/2 study. Blood 
Advances 2017; 1(15):1167-1180.

Swerdlow SH, Campo E, Harris NL, et al. WHO Classification of Tumours of 
Haematopoietic and Lymphoid Tissues. Lyon, France: IARC Press; 2008.

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 Blood 
Marrow Transplantation. 2016; 51: 906-912.


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APPENDICES
Appendix 1. Outcome Definitions
The below outcome definitions will be used for reporting of disease assessments:

Complete response (CR) is defined as a disappearance of leukemia as indicated by 
<5% marrow blasts and the absence of peripheral blood leukemic blasts, with 
recovery of hematopoiesis defined by absolute neutrophil count (ANC) 1000/l and 
platelets 100,000/l.  C1 extramedullary disease status is required.

Complete response with incomplete count recovery (CRi) is defined as CR except 
with absolute neutrophil count (ANC) <1000/l and/or platelets <100,000/l.

Partial response (PR) is defined as an improved or no worsening of ALL as indicated 
by no peripheral blood blasts, neutrophils 1000/l, platelets 100,000/l, and either 
or both of the following:

At least a 50% decrease in the marrow blast percentage, compared to the 
pretreatment value, and marrow blast percentage 5% and 25%.

C2 extramedullary disease status.

Treatment failures are defined as patients who fail to achieve CR, CRi or PR will be 
classified according to the type of failure:

Resistant disease: Patient survives 7 days following completion of initial 
treatment course and has persistent leukemia in the most recent peripheral blood 
smear or bone marrow and/or persistent disease involvement at any 
extramedullary site after completion of therapy.

Death during aplasia: Patient survives 7 days following completion of initial 
treatment course then dies while cytopenic, with the last post-induction bone 
marrow without leukemic blasts.

Indeterminate:

Patient survives <7 days after completion of initial treatment course.

Patient survives 7 days following completion of initial treatment course then 
dies with no persistent leukemia in the peripheral smear but no post-induction 
bone marrow examination or extramedullary disease examination.

Relapse from CR or CRi:

Appearance of leukemic blasts in the peripheral blood.


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
Appearance of extramedullary disease.

5% blasts in the bone marrow not attributable to another cause (eg, recovery of 
normal cells following chemotherapy-induced aplasia).  If there are no circulating 
blasts and no extramedullary disease and the bone marrow blast percentage is 
5% but <20%, then a repeat bone marrow performed at least 7 days after the first 
marrow examination and documenting bone marrow blast percentage is 5% is 
necessary to establish relapse.

Progressive disease (PD) is defined as a doubling of peripheral blasts with an absolute 
increase of >5 x 109/L and/or appearance of or progression of extramedullary disease.
The following criteria will be used for evaluation of extramedullary disease:

Measurable extramedullary disease: Lesions that can be accurately measured in two 
dimensions by CT, MRI, medical photograph (skin or oral lesion), or other 
conventional technique and a greatest transverse diameter of 1 cm or greater; or 
palpable lesions with both diameters 2 cm.  Note: although CT scans remain the 
standard for evaluation of nodal disease, radiographic scans are not required for 
patients with easily palpable/superficial nodes.

Non-measurable extramedullary disease: All other lesions including unidimensional 
lesions, lesions too small to be considered measurable, pleural or pericardial 
effusions, ascites, bone disease, leptomeningeal disease, lymphangitis, pulmonitis, 
abdominal masses not confirmed or followed by imaging techniques or disease 
documented by indirect evidence only (eg, lab values).
Extramedullary disease status:

C1: Complete disappearance of all measurable and non-measurable extramedullary 
disease with the exception of lesions for which the following must be true: For 
patients with at least one measurable lesion, all nodal masses >1.5 cm in greatest 
transverse diameter (GTD) at baseline must have regressed to 1.5 cm in GTD and all 
nodal masses 1 cm and 1.5 cm in GTD at baseline must have regressed to <1 cm 
GTD or they must have reduced by 75% in sum of products of greatest diameters 
(SPD).  No new lesions.  Spleen and other previously enlarged organs must have 
regressed in size and must not be palpable.  All disease must be assessed using the 
same technique as at baseline.

C2: Patient does not qualify for C1 status
Modified from: Cheson et. al., Revised recommendations of the International Working Group for Diagnosis, 
Standardization of Response Criteria, Treatment Outcomes, and Reporting Standards for Therapeutic Trials in 
Acute Myeloid Leukemia. J Clin Oncol. 2003 Dec 15;21(24):4642-9.


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Appendix 2. List of Drugs Known to Predispose to Torsade de Pointes
Generic Name
Brand Name(s)
Amiodarone
Cordarone®, Pacerone®
Arsenic trioxide
Trisenox®
Astemizole
Hismanal®
Azithromycin
Zithromax®
Bepridil
Vascor®
Chloroquine
Aralen®
Chlorpromazine
Thorazine®
Cisapride
Propulsid®
Citalopram
Celexa®
Clarithromycin
Biaxin®
Disopyramide
Norpace®
Dofetilide
Tikosyn®
Domperidone
Motilium®
Droperidol
Inapsine®
Erythromycin
Erythrocin®, E.E.S.®
Escitalopram
Lexapro®
Flecainide
Tambocor®
Halofantrine
Halfan®
Haloperidol
Haldol®
Ibutilide
Corvert®
Levomethadyl
Orlaam®
Mesoridazine
Serentil®
Methadone
Dolophine®, Methadose®
Moxifloxacin
Avelox®
Ondensetron*
Zofran ®
Pentamidine
Pentam®, NebuPent®
Pimozide
Orap®
Probucol
Lorelco®
Procainamide
Pronestyl®, Procan®
Quinidine
Cardioquin®, Quinaglute®
Sevoflurane
Ulane®, Sojourn®
Sotalol
Betapace®
Sparfloxacin
Zagam®
Terfenadine
Seldane®
Thioridazine
Mellaril®
Vandetanib
Zactima®
Reference: "Torsades List: Drugs with a Risk of Torsades de Pointes," drugs that are generally accepted by the 
QTdrugs.org Advisory Board to carry a risk of Torsades de Pointes on the University of Arizona CERT 
website: http://crediblemeds.org/everyone/composite-list-all-qtdrugs .  See website for current list and refer to 
the relevant package insert.
* Zofran: intraveneous (IV) dose >16 mg (reference, 29Jun2012 FDA Drug Safety Communication; FDA 
website http://www fda.gov/Drugs/DrugSafety/ucm310190.htm)




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Appendix 4. Recommendation for Patients Proceeding to Transplant and Potential 
VOD Cases

For patients planning to receive HSCT, it is recommended that treatment with 
inotuzumab ozogamicin be limited to 2 cycles or the fewest number of cycles 
required to achieve a CR/CRi (if CR/CRi not achieved after 2 cycles). See
Section 5.1 and Section 5.2 for recommendations for dose level 1 and dose level 2, 
respectively.

The risk of relapse must be balanced against the potential risk of toxicity associated 
with beginning HSCT soon after the last dose of inotuzumab ozogamicin.  In Phase 3 
Study B1931022, the median time between last dose of inotuzumab ozogamicin and 
HSCT was 4.9 weeks (range: 1-19 weeks).

Healthcare providers should use their clinical judgment to determine the most 
appropriate course of therapy for prophylactic treatment of VOD before the start of 
conditioning therapy according to standard of care (eg, prophylactic ursodeoxycholic 
acid* [proprietary names include Actigall, Urso, and Ursodiol] at 
12-15 mg/kg/day, beginning 2 weeks before the start of conditioning therapy.1,2

Use the least hepatotoxic conditioning regimen and, specifically, avoid using 
regimens that contain 2 alkylating agents and or that combine an alkylating agent 
with higher dose TBI (defined as >12 Gy). 

If using a busulfan-containing conditioning regimen, please consider using 
pharmacokinetically-dosed busulfan.3

When possible, avoid the concomitant use of hepatotoxic drugs peri-transplant.

If significant liver toxicity occurs, consult a gastroenterology and/or hepatology 
service.

When evaluating liver toxicity, inform the radiologist of the potential for hepatic 
vascular disease. When VOD 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 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).


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
Defibrotide** may be used in the setting of severe VOD.4 In Phase 3 
Study B1931022, 4/8 inotuzumab ozogamicin treated patients who had Grade 3 or 4
VOD after a follow-up HSCT and who were treated with defibrotide recovered.  The
median duration of defibrotide treatment was 20 days.  Of note, inotuzumab 
ozogamicin treated patients with Grade 3 or 4 VOD after a follow-up HSCT and not 
treated with defibrotide did not recover.

If a patient will proceed to HSCT under the care of different physicians, these 
recommendation should be reviewed with the new treating physicians.
*Ursodeoxycholic acid is not authorised for use by regulatory authorities in this setting.
** Defibrotide is not authorized for use by all regulatory authorities in this setting.  

Ruutu T, Eriksson B, Remes K, et al, Ursodeoxycholic acid for the prevention of hepatic complications in allogeneic 
stem cell transplantation. Blood. 2002, Sep 15; 100 (6): 1977-83.

Ruutu T, Juvonen E, Remberger M, et al, Improved survival with ursodeoxycholic acid prophylaxis in allogeneic 
stem cell transplantation: long-term follow-up of a randomized study. Biol Blood Marrow Transplant. 2014 Jan; 
20(1): 135-8.

Yeh RF, Pawlikowski MA, Blough DK, et al. Accurate targeting of daily intravenous busulfan with 8-hour blood 
sampling in hospitalized adult hematopoietic cell transplant recipients. Biol Blood Marrow Transplant. 
2012;18:265-272.

Richardson PG, Soiffer RJ, Antin JH, et al, Defibrotide for the treatment of severe hepatic veno-occlusive disease and 
multiorgan failure after stem cell transplantation: a multicenter, randomized, dose-finding trial. Biol Blood Marrow 
Transplant. 2010 Jul; 16(7): 1005-17.


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Appendix 5. Abbreviations
Abbreviation
Term
ADC
Antibody-drug conjugate
AE
Adverse event
ALL
Acute lymphocytic leukemia
ALT
Alanine aminotransferase
ANC
Absolute neutrophil count
ASH
Alcoholic steatohepatitis
AST
Aspartate aminotransferase
AUC
Area under the concentration-time curve
AV block
Atrioventricular block
-HCG
Beta-human chorionic gonadotropin
BSA
Body surface area
BM
Bone marrow
BMA
Bone marrow aspirate
CalichDHE
N-acetyl -calicheamicin dimethyl hydrazide
CBC
Complete blood count
CI
Confidence interval
CK
Creatine kinase
CMC-544
Inotuzumab ozogamicin; investigational product composed of 
a conjugate of a humanized IgG4 anti-CD22 antibody. 
CNS
Central nervous system
CR
Complete response
CRi
Complete response with incomplete count recovery
CRF
Case report form (including electronic case report forms)
CSA
Clinical study agreement
CSF
Cerebrospinal fluid
CSXRT
Craniospinal radiation
CT
Computed tomography
CTA
Clinical trial application
CTCAE
Common Terminology Criteria for Adverse Events
DILI
Drug-induced liver injury
DNA
Deoxyribonucleic acid
DoR
Duration of remission
EAC
Endpoint Adjudication Committee
EC
Ethics committee
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
EDP
Exposure during pregnancy
EDTA
Edetic acid (ethylenediaminetetraacetic acid)
EOT
End of treatment
EU
European Union
CCI


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Abbreviation
Term
EudraCT
European Clinical Trials Database
FACS
Fluorescence activated cell sorting
FDA
Food and Drug Administration
FLAG
Fludarabine, cytarabine, G-CSF
FSH
Follicle-stimulating hormone
G544
A humanized IgG4 anti-human CD22 monoclonal antibody
GCP
Good Clinical Practice
G-CSF
Granulocyte colony-stimulating factor
GGT
Gamma glutamyl transpeptidase
GM-CSF
Granulocyte-macrophage colony-stimulating factor
GVHD
Graft versus host disease
HbsAg
Hepatitis B surface antigen
HCV
Hepatitis C virus
HIDAC
high-dose cytarabine
HIV
Human immunodeficiency virus
HR
Hazard ratio
HSCT
Hematopoietic stem cell transplant
hyper-CVAD
Cyclophosphamide, vincristine, doxorubicin, dexamethasone
ICD
Informed consent document
ICH
International Conference on Harmonisation
ID
Identification
IEC
Independent ethics committee
IHC
Immunohistochemistry
IND
Investigational new drug application
INR
International normalization rate
IRB
Institutional review board
IRC
Internal review committee
ITT
Intent to treat
IUD
Intrauterine device
IV
Intravenous, intravenously
K2EDTA
Dipotassium ethylenediaminetetraacetic acid
LDH
Lactate dehydrogenase
LFT
Liver function test
mAb
Monoclonal antibody
MOF
Multiorgan failure
MRD
Minimal residual disease
MRI
Magnetic resonance imaging
MXN/AraC
Mitoxantrone + cytarabine
NASH
Non-alcoholic steatohepatitis
NCCN
National Comprehensive Cancer Network
NCI
National Cancer Institute
NYHA
New York Heart Association
OS
Overall survival


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Abbreviation
Term
PCD
Primary completion date
PD
Progressive disease
PE
Physical exam
PFS
Progression-free survival
Ph+
Philadelphia chromosome positive
PI
Principal investigator
PK
Pharmacokinetics
PMR
Post-marketing requirement
PP
Per protocol
PT
Prothrombin time
QTc
QT interval corrected for heart rate
QTcF
QT interval corrected for heart rate using Fridericia’s formula
QTcS
QT interval corrected for heart rate using a 
population-specific method
RNA
Ribonucleic acid
SAE
Serious adverse event
SAP
Statistical analysis plan
SOC
Standard of care
SE
Standard error
SOS
Sinusoidal obstruction syndrome 
SRSD
Single reference safety document
SUSAR
Suspected unexpected serious adverse drug reaction
TKI
Tyrosine kinase inhibitor
TBili
Total bilirubin
ULN
Upper limit of normal
US
United States
USPI
United States package insert
VOD
Veno-occlusive disease
VS
Vital signs
WBC
White blood cell 
WHO
World Health Organization

SAP_001.pdf: 
Inotuzumab ozogamicin (Besponsa) 
Study B1931030 
Statistical Analysis Plan Amendment 2  
PFIZER CONFIDENTIAL 
Page 1 
 
 
 
 
 
 
 
 
 
 
 
Protocol B1931030 
 
 
A PHASE 4, OPEN-LABEL, RANDOMIZED STUDY OF TWO 
INOTUZUMAB OZOGAMICIN DOSE LEVELS IN ADULT PATIENTS 
WITH RELAPSED OR REFRACTORY B-CELL ACUTE 
LYMPHOBLASTIC LEUKEMIA ELIGIBLE FOR HEMATOPOIETIC 
STEM CELL TRANSPLANTATION AND WHO HAVE RISK FACTOR(S) 
FOR VENO-OCCLUSIVE DISEASE 
 
 
 
 
Statistical Analysis Plan 
(SAP) 
 
 
 
 
 
 
 
 
 
 
 
 
Version: 
3.0 
 
Date: 
29-Apr-2022 


Inotuzumab ozogamicin (Besponsa) 
Study B1931030 
Statistical Analysis Plan Amendment 2  
PFIZER CONFIDENTIAL 
Page 2 
 
 
 
TABLE OF CONTENTS 
LIST OF TABLES .......................................................................................................................... 5 
LIST OF FIGURES ........................................................................................................................ 5 
LIST OF ABBREVIATIONS ........................................................................................................ 6 
1. VERSION HISTORY ................................................................................................................ 7 
2. INTRODUCTION ...................................................................................................................... 8 
2.1. Study Objectives ............................................................................................................ 9 
2.1.1. Primary Objectives ........................................................................................... 9 
2.1.2. Secondary Objectives ....................................................................................... 9 
2.2. Study Design ................................................................................................................ 10 
3. ENDPOINTS AND BASELINE VARIABLES: DEFINITIONS AND CONVENTIONS12 
3.1. Primary Endpoints ....................................................................................................... 12 
3.1.1. Efficacy ........................................................................................................... 12 
3.1.2. Safety............................................................................................................... 12 
3.2. Secondary Endpoints ................................................................................................... 12 
3.3. Baseline Variables ....................................................................................................... 16 
3.3.1. Baseline Covariates ........................................................................................ 17 
3.3.2. Stratification Factors....................................................................................... 18 
3.3.3. Study Treatment Exposure ............................................................................. 19 
3.4. Safety Endpoints .......................................................................................................... 19 
3.4.1. Adverse Events ............................................................................................... 20 
3.4.1.1. Treatment Emergent Adverse Events ......................................... 20 
3.4.1.2. Adverse Events of Special Interest .............................................. 20 
3.4.2. Laboratory Data .............................................................................................. 21 
3.4.3. Other Safety Endpoints .................................................................................. 21 
4. ANALYSIS SETS .................................................................................................................... 21 
4.1. Full Analysis Set .......................................................................................................... 22 
4.2. Per-Protocol Analysis Set............................................................................................ 22 
4.3. Safety Analysis Set ...................................................................................................... 22 
4.4. PK Analysis Set ........................................................................................................... 23 
4.5. Immunogenicity Analysis Set ..................................................................................... 23 


Inotuzumab ozogamicin (Besponsa) 
Study B1931030 
Statistical Analysis Plan Amendment 2  
PFIZER CONFIDENTIAL 
Page 3 
 
 
5. GENERAL METHODOLOGY AND CONVENTIONS ...................................................... 23 
5.1. Hypotheses and Decision Rules.................................................................................. 23 
5.1.1. Hypotheses and Sample Size ......................................................................... 23 
5.1.1.1. Run-in Phase ................................................................................. 23 
5.1.1.2. Randomized Phase ....................................................................... 24 
5.1.2. Decision Rules ................................................................................................ 25 
5.2. General Methods .......................................................................................................... 26 
5.2.1. Pooling of Data by Center .............................................................................. 26 
5.2.2. Nominal Timepoints....................................................................................... 26 
5.2.3. Definition of Study Day ................................................................................. 26 
5.2.4. Date of Last Contact ....................................................................................... 26 
5.2.5. ALL Disease Assessment Date ..................................................................... 27 
5.2.6. Unscheduled Assessments ............................................................................. 27 
5.2.7. Standard Derivations and Reporting Conventions ....................................... 27 
5.2.8. Analyses of Continuous Endpoints ............................................................... 27 
5.2.9. Analyses of Categorical Endpoints ............................................................... 28 
5.2.10. Analyses of Time to Event Endpoints......................................................... 28 
5.2.11. Competing-Risks Analyses of Time to Event Endpoints ........................... 28 
5.3. Methods to Manage Missing Data .............................................................................. 28 
5.3.1. Missing Dates ................................................................................................. 28 
5.3.2. Missing Toxicity Grade of Adverse Events .................................................. 31 
5.3.3. Missing ECG Data .......................................................................................... 32 
6. ANALYSES AND SUMMARIES .......................................................................................... 32 
6.1. Primary Endpoints ....................................................................................................... 32 
6.1.1. CR/CRi Rate ................................................................................................... 32 
6.1.1.1. Primary Analysis .......................................................................... 32 
6.1.1.2. Sensitivity Analysis ...................................................................... 33 
6.1.2. VOD Rate ........................................................................................................ 33 
6.2. Secondary Endpoints ................................................................................................... 35 
6.2.1. MRD-Negativity ............................................................................................. 35 
6.2.2. DoR ................................................................................................................. 35 


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Inotuzumab ozogamicin (Besponsa) 
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6.2.3. PFS .................................................................................................................. 36 
6.2.4. OS .................................................................................................................... 37 
6.2.5. Rate of HSCT ................................................................................................. 37 
6.2.6. Post-HSCT Relapse ........................................................................................ 37 
6.2.7. Post-HSCT Mortality ..................................................................................... 38 
6.2.8. Non-Relapse Mortality ................................................................................... 38 
6.2.9. Relapse-Related Mortality ............................................................................. 38 
6.2.10. Immune Response to Inotuzumab ............................................................... 39 
6.3. PK Exposure-Response for Efficacy and Safety Endpoints...................................... 39 
6.4. Subset Analyses ........................................................................................................... 39 
6.5. Baseline and Other Summaries ................................................................................... 39 
6.5.1. Baseline Summaries ....................................................................................... 39 
6.5.1.1. Demographic and Baseline Characteristics ................................ 39 
6.5.1.2. Medical History ............................................................................ 40 
6.5.1.3. Disease Characteristics ................................................................ 40 
6.5.1.4. Prior Anti-Cancer Therapies ........................................................ 40 
6.5.2. Study Conduct and Patient Disposition......................................................... 41 
6.5.2.1. Patient Disposition ....................................................................... 41 
6.5.2.2. Protocol Deviations ...................................................................... 41 
6.5.3. Study Treatment Exposure ............................................................................. 41 
6.5.3.1. Exposure to Inotuzumab Ozogamicin ......................................... 41 
6.5.3.2. Dose Reductions and Delays ....................................................... 42 
6.5.4. Concomitant Medications .............................................................................. 42 
6.5.5. Follow-up Systemic Therapies ...................................................................... 42 
6.6. Safety Summaries and Analyses ................................................................................. 42 
6.6.1. Adverse Events ............................................................................................... 42 
6.6.1.1. Adverse Events of Special Interest .............................................. 43 
6.6.2. Deaths .............................................................................................................. 43 
6.6.3. Laboratory Data .............................................................................................. 43 
6.6.4. Vital Signs and Physical Examination .......................................................... 44 
6.6.5. Electrocardiograms......................................................................................... 44 


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Inotuzumab ozogamicin (Besponsa) 
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6.6.6. Other Safety Analysis ..................................................................................... 45 
7. INTERIM ANALYSES............................................................................................................ 46 
8. REFERENCES ......................................................................................................................... 47 
9. APPENDICES .......................................................................................................................... 48 
 
 
LIST OF TABLES 
Table 1. Summary of Major Changes in SAP Amendments ....................................................... 7 
Table 2. 95% CI for Different Estimated VOD Rates and CR/CRi Rates ...............................24 
 
 
LIST OF FIGURES 
Figure 1. Study B1931030: Study Design .................................................................................. 11 


PFIZER CONFIDENTIAL 
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Inotuzumab ozogamicin (Besponsa) 
Study B1931030 
Statistical Analysis Plan Amendment 2  
 
 
LIST OF ABBREVIATIONS 
 
Abbreviation 
Definition 
ADA 
anti-inotuzumab ozogamicin antibodies 
AE 
adverse event 
AEoSI 
adverse events of special interest 
ALL 
acute lymphoblastic leukemia 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
ATC 
Anatomical Therapeutic Chemical 
BSA 
body surface area 
BMI 
body mass index 
CI 
confidence interval 
CR 
complete remission 
CRi 
complete remission with incomplete hematologic recovery 
CRF 
clinical report form 
CTCAE 
Common Terminology Criteria for Adverse Events 
DI 
dose intensity 
DoR 
duration of remission 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eDISH 
evaluation of drug-induced serious hepatotoxicity 
EOT 
end of treatment 
HR 
heart rate 
HSCT 
hematopoietic stem cell transplantation 
IOTA 
investigator overall tumor assessment 
ITT 
intent-to-treat 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRD 
minimal residual disease 
Nab 
neutralizing antibodies 
NCI 
National Cancer Institute 
OS 
overall survival 
PFS 
progression-free survival 
PK 
pharmacokinetic 
PP 
Per-Protocol 
PT 
preferred term 
PMAR 
population modeling analysis report 
QT 
time from the beginning of the QRS complex to the end of the T wave 
QTc 
corrected QT 
QTcB 
QTc corrected using Bazett’s formula 
QTcF 
QTc corrected using Fridericia’s formula 
RDI 
relative dose intensity 
RR 
R is a point corresponding to the peak of the QRS complex of ECG wave and 
RR is the interval between successive Rs 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SE 
standard error 
SOC 
System Organ Class 
TEAE 
treatment emergent adverse event 
ULN 
upper limit of normal 
VOD 
veno-occlusive disease 


PFIZER CONFIDENTIAL 
Page 7 
Inotuzumab ozogamicin (Besponsa) 
Study B1931030 
Statistical Analysis Plan Amendment 2  
 
 
 
1. VERSION HISTORY 
This amended Statistical Analysis Plan (SAP) for Study B1931030 is the second amendment of 
the original SAP version 1.0 dated 29 May 2018. This amendment is based on the original 
version of the protocol (dated 23 May 2018). 
 
Table 1. Summary of Major Changes in SAP Amendments 
 
SAP Version 
Change 
Rationale 
1 
Not Applicable 
Not Applicable 
2 
• 
The data cutoff for the primary analysis 
was revised to 12 months following 
randomization of the last patient; 
• 
The time intervals for summarizing safety 
endpoints were clarified in Section 3.1.2 
for VOD rate and Section 3.4 for AEs and 
laboratory abnormalities; 
• 
Minor revisions were incorporated for PK 
analyses (Section 3.2) and 
PK/Immunogenicity analysis set (Section 
4.4 and 4.5) for clarification purpose; 
• 
Tumor assessment was revised to ALL 
disease assessment in Section 5.2.5; 
• 
Methods for handling ECG data not being 
collected in triplicate was added in Section 
5.3.3; 
• 
More details were added in summary of 
patient disposition in Section 6.5.2.1; 
• 
Summary of exposure to inotuzumab in 
Section 6.5.3.1 was revised to account for 
its administration schedule; 
• 
A summary of post-HSCT SAEs was 
added in Section 6.6.1; 
• 
A section for AE summaries (required for 
basic results disclosure in EU and US) in 
Section 6.6.1 was removed; 
• 
Summaries of PR and QRS were removed 
in Section 6.6.5; 
• 
Explicit references to any specific CRF 
pages were removed. 
• 
Considering the clinical 
circumstances where nearly all 
post-SCT VOD would occur within 
100 days of transplant the sponsor 
expected that all data to assess 
CR/CRi and nearly all VOD cases 
are likely to occur within one year 
from the last patient randomized; 
• 
To align with the protocol 
3 
General 
• 
Replaced “during study treatment” with 
“on-treatment” for the primary safety 
endpoint. 
• 
Added Appendix 2 to document additional 
analyses that may be undertaken to assess 
the impact of COVID-19 pandemic. 
Table 1 
• 
Modified rationale for primary analysis 
cutoff time change for version 2. 
Section 3.1 
• 
Remove the unnecessary analyses 
• 
Clarify the endpoint definitions and 
analysis details. 
• 
Incorporating clinical consideration 
for primary analysis cutoff time 
change. 


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• 
Clarified that primary efficacy endpoint 
only accounted for CR/CRi prior to EOT. 
Section 3.2 
• 
Changed the start dates for PFS/OS from 
date of randomization to date of first dose. 
• 
Removed the secondary endpoint PFS 
according to standard definition. Added a 
sensitivity analysis of PFS with an 
alternative censoring rule in Section 6.2.3, 
which is equivalent to the analysis of PFS 
according to standard definition. 
• 
Clarified the definition of DoR, PFS, OS, 
rate of HSCT, post-HSCT relapse, post- 
HSCT mortality, post-HSCT non-relapse 
mortality, and post-HSCT relapse-related 
mortality. 
Section 3.3 
• 
Clarified the definition of baseline. 
• 
Clarified baseline variables for the 
analysis. 
• 
Moved the definition of study treatment 
exposure variables from Section 6.5.3 to 
Section 3.3.3. 
• 
Clarified lab parameters for the analysis in 
Section 3.4.2. 
• 
Added definitions of other safety 
endpoints in Section 3.4.3. 
Section 4.2 
• 
Clarified the definition of per-protocol 
analysis set. 
Section 5.2 
• 
Removed unnecessary details on Pfizer 
standard methods for data derivation. 
Section 5.3 
• 
Clarified the approach for imputing 
missing ECG data. 
Section 6 
• 
Removed unnecessary details on Pfizer 
standard analyses. 
• 
Added details for the non-standard 
analyses. 
Section 6.1.2 
• 
Added analyses of association of baseline 
and patient characteristics at the time of 
HSCT with occurrence of VOD post- 
HSCT. 
 
 
2. INTRODUCTION 
This SAP provides the detailed methodology for summary and statistical analyses of the data to 
be collected in Study B1931030. This document may modify the plan outlined in the protocol; 


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however, any major modifications of the primary endpoint definition or its analysis will also be 
reflected in a protocol amendment. Any deviations from this SAP will be described in the 
clinical study report (CSR). 
 
The data cutoff for the primary analysis will be 12 months following randomization of the last 
patient. All summaries and analyses will include all data pertaining to visits/assessments 
performed up to and including the data cutoff date. 
 
2.1. Study Objectives 
2.1.1. Primary Objectives 
The primary objectives of the study are to evaluate the rates of veno-occlusive disease (VOD) 
and hematologic remission (complete remission [CR]/complete remission with incomplete 
hematologic recovery [CRi]) following treatment at 2 inotuzumab ozogamicin dose levels in 
adult patients with relapsed or refractory B-cell acute lymphoblastic leukemia (ALL) who are 
eligible for hematopoietic stem cell transplantation (HSCT) and who are at higher risk for 
developing VOD post-HSCT after inotuzumab ozogamicin treatment. 
 
The study analyses will be descriptive only, without conducting formal hypothesis testing. 
The primary endpoints include the following: 
• Rate of VOD (total, during study treatment, and post-HSCT); and 
 
• Rate of hematologic remission (CR/CRi). 
 
2.1.2. Secondary Objectives 
The secondary objectives of the study are to evaluate the safety and efficacy following treatment 
at 2 inotuzumab ozogamicin dose levels. 
 
The secondary endpoints include the following: 
 
• Adverse events (AEs) and laboratory abnormalities (grade, timing, seriousness, 
relatedness) during study treatment and post-HSCT; 
 
• Minimal residual disease (MRD) negativity in patients achieving CR/CRi; 
 
• Duration of remission (DoR) in patients achieving a CR/CRi; 
 
• Progression-free survival (PFS); 
 
• Overall survival (OS); 
 
• Rate of HSCT; 
 
• Post-HSCT relapse; 


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• Post-HSCT mortality; 
 
• Post-HSCT non-relapse mortality; 
 
• Post-HSCT relapse-related mortality; 
 
• Pharmacokinetic (PK) exposure-response relationships for efficacy and safety; and 
 
• Immunogenicity testing for anti-inotuzumab ozogamicin antibodies (ADA) and 
neutralizing antibodies (Nab). 
 
2.2. Study Design 
This open-label study will evaluate 2 inotuzumab ozogamicin dose levels in adults with relapsed 
or refractory B-cell ALL who are eligible for HSCT and who are at higher risk for developing 
VOD post-HSCT after inotuzumab ozogamicin treatment. Figure 1 shows the study design. 
 
The 2 dose levels are as follows: 
 
• Dose Level 1: Patients will be treated with inotuzumab ozogamicin at a starting dose of 
1.8 mg/m2/cycle administered over 3 divided doses. After CR/CRi is achieved, the dose 
will be reduced to 1.5 mg/m2/cycle administered over 3 divided doses.  For patients 
proceeding to HSCT, 2 cycles are recommended; a third cycle may be considered for 
those patients who do not achieve CR/CRi and MRD-negativity after 2 cycles. Patients 
who do not achieve CR/CRi within 3 cycles should discontinue treatment.  The cycle 
length will be 21-28 days. 
 
• Dose Level 2: Patients will be treated with inotuzumab ozogamicin at a starting dose of 
1.2 mg/m2/cycle administered over 3 divided doses. After CR/CRi is achieved, the dose 
will be reduced to 0.9 mg/m2/cycle administered over 3 divided doses. For patients 
proceeding to HSCT, 2 cycles are recommended; additional cycles may be considered for 
those patients who do not achieve CR/CRi and MRD-negativity after 2 cycles (maximum 
of 4 cycles). Patients who do not achieve CR/CRi within 4 cycles should discontinue 
treatment.  The cycle length will be 21-28 days. 


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+ / 
Statistica l Analysis Plan Amendment 2  
 
 
 
 
 
 
 
Figure 1. Study B1931030: Study Design 
 
 
Run-in Phase 
 
 
 
 
End  of Run-in Phase 
Proceed to randomized phase 
or stop study enrollment if 
futility if reached 
  
 
 
 
 I 
Arm 1(Dose Level 1) 
I 
 
 r. Follow-up:2 years (from 
Randomized Phase 
N=40 patients 
randomization) 
Randomize (1:1) 
N=80 patients 
 
Assessments: Safety, disease 
status, ALL therapy 
(including HSCT), and 
Arm 2 (Dose Level 2)   rt  smvival status 
N= 40 patients 
 
 
The study will be conducted in 2 phases: a nm-in phase and a randomized phase. Up to 
approximately 102 patients will be enrolled in the study across these 2 phases. 
 
Run-in phase: Up to 22 patients will be enrolled and receive a staiiing dose of 1.2 mg/m2/cycle 
(dose level 2). A Simon Two-Stage optimal design will be used.  Ifacceptable efficacy (CR/CRi 
and MRD-negativity) is observed in the nm-in phase, patients will be enrolled into the 
randomized phase (see Section 5.1.2). 
 
Randomized phase: Ifacceptable efficacy is observed in the nm-in phase (see Section 5.1.2), 
patients will be randomized (1:1) to 1of 2 dose levels of inotuzumab ozogamicin (40 patients per 
dose level): 
 
• Ann 1 of Randomized Phase: Dose level 1; 
 
• Ann 2 of Randomized Phase: Dose level 2. 
 
A total of approximately 80 patients will be strntified at randomization based on age (<55 vs  55 
yeai·s), salvage status (Salvage 1 vs   2), and prior HSCT (yes vs no). 
 
Patients will receive an average of approximately 3 months (i.e., 2-3 cycles) of inotuzumab 
ozogamicin treatment. Safety assessments, disease assessments, and PK sample collections will 
be conducted throughout the treatment period. 
Follow-up:2 years (from 
randomization) 
Assessments: Safety, disease 
status, ALL therapy 
(including HSCT), and 
smvival status 
Dose Level 2 
Simon Two-Stage Design 
N=up to 22 patients 
-Stage 1: 7 patients 
-Stage 2: 15 patients 
I 
.. 
I I 


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After inotuzumab ozogamicin treatment, patients will be followed for at least 2 years from the 
time of randomization. During the follow-up period, safety and disease assessments will be 
conducted, and information about subsequent ALL treatments (including HSCT) and survival 
status will be collected.  All known cases of VOD, regardless of causality and severity, will be 
reported as serious adverse events (SAEs) throughout the follow-up period. 
 
This study will be conducted at approximately 50 clinical sites and is expected to be completed 
(last patient last visit) in approximately 6 years. 
 
3. ENDPOINTS AND BASELINE VARIABLES: DEFINITIONS AND CONVENTIONS 
3.1. Primary Endpoints 
3.1.1. Efficacy 
The primary efficacy endpoint is CR/CRi rate. CR/CRi rate is defined as the percentage of 
patients with a best overall response of CR or CRi until the End of Treatment (EOT) based on 
investigator assessments (according to the modified Cheson Criteria defined in Study B1931030 
Protocol Appendix 1). Patients without a documented CR or CRi until the EOT will be 
considered as non-responders. 
 
3.1.2. Safety 
The primary safety endpoint is VOD rate. The criteria for VOD are defined in Study B1931030 
Protocol Section 8.4. 
 
VOD rate will be summarized based on patients experiencing VOD by overall study period, on- 
treatment or in follow-up without HSCT period and post-HSCT period. The definitions of those 
periods are described in Section 3.4. 
 
3.2. Secondary Endpoints 
Secondary endpoints include, and are defined, as follows: 
 
Adverse Events (AEs) and Laboratory Abnormalities 
• Definition: AEs and laboratory abnormalities characterized by grade, timing, seriousness, 
relatedness, and time of occurrence (i.e., on-treatment or post-HSCT) (see Section 3.4). 
 
• All known cases of VOD, regardless of causality and severity, will be reported as 
serious adverse events (SAEs) throughout the follow-up period. 
 
MRD Negativity 
• Definition: In patients who achieve CR/CRi, a patient will be considered to be MRD 
negative if the minimum MRD (%) between the date of achieving CR/CRi and the EOT 
test is <0.01%. 


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DoR 
• Definition: Time from date of first response in responders (patients who achieved 
CR/CRi) to the date of disease progression (i.e., objective progression, relapse from 
CR/CRi, including post-study treatment follow-up disease assessments) or death due to 
any cause, whichever occurs first. 
 
• Censorship: 
 
• Patients without a DoR event at time of analysis will be censored at the date of last 
adequate post-baseline disease assessment including follow-up disease assessment. 
 
• Patients with documentation of a DoR event after an unacceptably long interval (>28 
weeks) since the previous adequate post-baseline disease assessment will be censored 
at the date of the previous assessment. 
 
• Adequate post-baseline disease assessment is defined as an assessment where a 
response has been provided and analyzed by the investigator. Timepoints at which the 
response is not evaluable, or no assessment was performed will not be used for 
determining the censoring date. 
 
• Duration (months): [date of event/ censoring−date of first response+1]/30.4375. 
 
PFS 
• Definition: Time from date of first dose of study treatment to the date of disease 
progression (i.e., objective progression, relapse from CR/CRi, including post-study 
treatment follow-up disease assessments), death due to any cause, or starting new 
induction therapy/post-therapy HSCT without achieving CR/CRi, whichever occurs first. 
 
• Censorship: 
 
• Patients without a PFS event at time of analysis will be censored at the date of last 
adequate post-baseline disease assessment. 
 
• Patients with documentation of a PFS event after an unacceptably long interval (>28 
weeks if there was adequate post-baseline disease assessment, or >12 weeks if there 
was no adequate post-baseline assessment) since the previous adequate disease 
assessment will be censored at the date of the previous assessment (date of first dose 
of study treatment if no adequate post-baseline assessment). 
 
• Patients without adequate baseline assessment will be censored at the date of first 
dose of study treatment. 
 
• Adequate baseline is defined using the following criteria: 


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• All baseline assessments must be within 28 days prior to and including the date of 
first dose of study treatment, 
 
• Bone marrow biopsy or aspirate with blasts ≥5%, OR hematology test with 
presence of blast cells (% or absolute). 
 
• Adequate post-baseline disease assessment is defined as an assessment where a 
response has been provided and analyzed by the investigator. Timepoints at which the 
response is not evaluable, or no assessment was performed will not be used for 
determining the censoring date. 
 
• For patients in the randomized phase who did not receive the randomly assigned study 
treatment, the date of first dose of study treatment will be missing. This missing date will 
be imputed using the date of randomization and such patient will be censored at the date 
of randomization. 
 
• Duration (months): [date of event/ censoring−date of first dose +1]/30.4375. 
 
OS 
• Definition: Time from date of first dose of study treatment to death due to any cause. 
 
• Censorship: Patients without confirmation of death will be censored at the date that the 
patient is last known to be alive (see Section 5.2.4 for derivation of date of last contact). 
 
• For patients in the randomized phase who did not receive the randomly assigned study 
treatment, the date of first dose of study treatment will be missing. This missing date will 
be imputed using the date of randomization and such patient will be censored at the date 
of randomization. 
 
• Duration (months): [date of death/ last known to be alive−date of first dose +1]/30.4375. 
 
Rate of HSCT 
• Definition: Percentage of patients who undergo HSCT after inotuzumab ozogamicin 
treatment and prior to post induction therapy. 
 
Post-HSCT Relapse 
• Definition: Time from date of first HSCT after inotuzumab ozogamicin treatment to the 
date of first relapse post-HSCT. 
 
• Event: first relapse post-HSCT. 
 
• Competing event: any deaths post-HSCT without prior relapse. 


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• If a cause of death is relapse/progression, it should be assumed that relapse occurred 
prior to death. 
 
• Censorship: Patients without confirmation of relapse/death will be censored at the date 
that the patient was last known to be alive (see Section 5.2.4 for derivation of date of last 
contact). 
 
• Duration (months): [date of event/ competing event/ last known to be alive−date of first 
transplant after study treatment +1]/30.4375. 
 
Post-HSCT Mortality 
• Definition: Time from date of first HSCT after inotuzumab ozogamicin treatment to 
death due to any cause. 
 
• Censorship: Patients without confirmation of death will be censored at the date that the 
patient was last known to be alive (see Section 5.2.4 for derivation of date of last 
contact). 
 
• Duration (months): [date of death/ last known to be alive−date of first transplant after 
study treatment +1]/30.4375. 
 
Non-relapse Mortality 
• Definition: Time from date of first HSCT after inotuzumab ozogamicin treatment to 
death due to any cause without prior relapse. 
 
• Event: Death post-HSCT without any prior relapse. 
 
• Competing event: Relapse post-HSCT or any death post-HSCT related to relapse, 
whichever occurs first. 
 
• If a cause of death is relapse/progression, it should be assumed that relapse occurred 
prior to death. 
 
• Censorship: Patients without confirmation of death will be censored at the date that the 
patient was last known to be alive (see Section 5.2.4 for derivation of date of last 
contact). 
 
• Duration (months): [date of event/ competing event/ last known to be alive−date of first 
transplant after study treatment +1]/30.4375. 
 
Relapse-related Mortality 
• Definition: time from date of first HSCT after inotuzumab ozogamicin treatment to death 
due to any cause with prior relapse. 


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• Event: Death post-HSCT with prior relapse. 
 
• Competing event: Death post-HSCT without any prior relapse/progression. 
 
• If a cause of death is relapse/progression, it should be assumed that relapse occurred 
prior to death. 
 
• Censorship: Patients without confirmation of death will be censored at the date that the 
patient was last known to be alive (see Section 5.2.4 for derivation of date of last 
contact). 
 
• Duration (months): [date of event/ competing event/ last known to be alive−date of first 
transplant after study treatment +1]/30.4375. 
 
PK Exposure-Response Relationships for Efficacy and Safety 
• PK serum concentrations for inotuzumab ozogamicin and unconjugated calicheamicin. 
 
• Relationships between PK exposure and efficacy endpoints, including CR/CRi and 
MRD-negativity. This will be provided separately as part of a population modeling 
analysis report (PMAR). 
 
• Relationships between PK exposure and safety endpoints, including rate of VOD and 
hepatic events (i.e., Grade ≥3 and/or serious hepatotoxicity) as well as Grade ≥3 elevated 
bilirubin, elevated aspartate aminotransferase (AST), elevated alanine aminotransferase 
(ALT), thrombocytopenia, and neutropenia rate. This will be provided separately as part 
of a PMAR. 
 
Immunogenicity 
• Incidence and titer of ADA, including Nab. 
 
• Impact of ADA/Nab on inotuzumab ozogamicin clearance, safety, and efficacy, if data 
permit. 
 
3.3. Baseline Variables 
• Start and end dates of study treatment 
 
• The date of first dose (start date) of study treatment is the earliest date of non-zero dosing 
of the study drug. 
 
• The date of last dose of study treatment is the latest date of non-zero dosing of the study 
drug. 
 
• Definition of baseline: 


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• For efficacy endpoints and baseline characteristics associated with disease assessments, 
unless otherwise specified, the last assessment prior to first dose of study treatment will 
serve as the baseline assessment. 
 
• For post-HSCT efficacy endpoints, the last assessment prior to first transplant after 
study treatment will serve as the baseline assessment. 
 
• For safety (including Eastern Cooperative Oncology Group [ECOG] performance status) 
and immunogenicity, unless otherwise specified, the last assessment performed on or 
prior to the date of the first dose of study treatment will serve as the baseline assessment. 
If there are no observations meeting these criteria, then baseline will be considered as 
‘missing’. 
 
• For electrocardiograms (ECGs), as triplet ECG will be collected; therefore the baseline 
for each ECG measurement is the average of the measurements prior to the first dose of 
study treatment. 
 
Notes: 
 
• No ‘windowing’ will be applied when defining baseline. Values from the assessments 
performed outside the protocol-specified window will not be excluded when determining 
baseline assessments. Any deviations from the protocol-specified window will be 
documented as protocol deviations. 
 
3.3.1. Baseline Covariates 
1. Demographic characteristics including age, race, sex, and ethnicity, where age is calculated 
following Pfizer data standards as age in years. 
 
2. Physical measurements at baseline include height (cm), body weight (kg), body mass index 
(BMI), and body surface area (BSA), where baseline is defined as the last assessment prior to 
first dose of study treatment. 
 
• BMI (kg/m2) will be computed as Height (cm)/Weight (kg) x 100. 
 
• BSA (m2) will be computed using Du Bois Formula: 0.007184 x Weight (kg)0.425 x 
Height (cm)0.725. 
 
3. Other baseline patient characteristics, including: 
 
• Enrollment geographical region (eg, North America, Western Europe, Eastern Europe, 
and Asia) and country within each region. 
 
• VOD risk factors collected at the screening visit, including age (<55, ≥55 years), salvage 
status (Salvage 1, ≥2), prior HSCT (yes, no) and ongoing/prior hepatic disease (yes, no). 


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• ECOG performance status collected at the screening visit. 
 
4. Significant medical history, including diseases or syndromes that are ongoing at, or stopped 
before, the screening visit. The Medical Dictionary for Regulatory Activities (MedDRA) will 
be used to code the disease/syndrome. 
 
• Medical history for hepatic medical conditions, including ascites, cholelithiasis, 
gallbladder disorder, hepatic steatosis, nodular hepatic disease, VOD/SOS and neoplasm 
not otherwise specified (NOS). 
 
5. Disease characteristics, including: 
 
• Duration since onset (months), defined as (date of first dose – date of onset of current 
episode)/30.4375. 
 
• Local/central CD22 expression in percentage at the screening visit. 
 
• Local cytogenetics including number of metaphases analyzed, karyotype (abnormal, 
normal, not evaluable), and chromosomal abnormality, at the screening visit. 
 
6. Prior anticancer therapy, including: 
 
• Prior systemic/induction/radiation therapy for primary diagnosis. 
 
• Responses to most recent prior induction regimen, to prior regimen 1 and 2. 
 
• Duration of first remission (months), defined as (date of relapse – date of best overall 
response +1)/30.4375 in the first regimen with best overall response of CR. 
 
3.3.2. Stratification Factors 
In the randomized phase, randomization will be stratified by the following VOD risk factors 
collected at the screening visit, 
 
• Age (<55 vs ≥55 years), 
 
• Salvage status (Salvage 1 vs ≥2), 
 
• Prior HSCT (yes vs no). 
 
Unless otherwise specified, stratified analyses will utilize strata as defined in the randomization 
system. 


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3.3.3. Study Treatment Exposure 
Inotuzumab ozogamicin will be administered at a starting dose of 1.8 mg/m2/cycle (Dose Level 
1) or 1.2 mg/m2/cycle (Dose Level 2) over 3 divided doses (Section 2.2). The cycle length will 
be 21-28 days. 
 
1. Treatment exposure to inotuzumab ozogamicin, including 
 
• Treatment cycles, 
 
• Treatment duration (weeks), defined as (last dose date – first dose date + 1)/7, 
 
• Actual overall dose (mg/m2), defined as the sum of the actual dose that the patient 
received across all cycles, 
 
• Actual dose (mg/m2) in a cycle is defined as total dose administered within a 
cycle[mg]/BSA [m2], where BSA will be calculated based on the last available weight 
on or prior to the date of first dose of a cycle. 
 
• Actual dose intensity (mg/m2/cycle), defined as [actual overall dose (mg/m2)]/[number of 
cycles], 
 
• Relative dose intensity (%), defined as the actual dose intensity divided by the planned 
dose intensity. 
 
• Planned dose intensity (mg/m2/cycle) is defined as [planned overall dose 
(mg/m2)]/[number of  cycles]. 
 
2. Dose modification, including 
 
• Dose reduction, defined as a nonzero dose that is less than the prior dose. 
 
• Dose delay, defined as ≥3 days of delay of the actual to the planned treatment 
administration day relative to the previous treatment administration date (1-2 days of 
delays will not be considered as dose delay). 
 
3.4. Safety Endpoints 
AEs and laboratory abnormalities, including the VOD rate, will be summarized based on the 
overall study period. The overall study period will be defined as the period starting with the first 
dose of study treatment through end of study follow-up (including on-treatment period and post- 
HSCT period). 
 
• On-treatment period will be defined as the period starting with the first dose of study 
treatment drug through 63 days after last dose or one day before start day of new anti- 
cancer therapy, whichever occurs first. 


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• Post-HSCT will be defined as the period starting from the first transplant after 
inotuzumab ozogamicin treatment and including the entire duration of subsequent follow- 
up; this assessment will not be applicable for patient not proceeded to HSCT after study 
treatment. 
 
Other safety endpoints will be summarized based on the on-treatment period unless otherwise 
specified. 
 
3.4.1. Adverse Events 
AEs will be classified using the Medical Dictionary for Regulatory Activities (MedDRA) coding 
dictionary. The severity of the toxicities will be graded according to the National Cancer Institute 
(NCI) Common Terminology Criteria for Adverse Events (CTCAE), version 3.0 (v3.0). For 
other Aes without specific NCI CTCAE v3.0 definitions, results will be identified according to 
NCI CTCAE v3.0 “other” categories. 
 
In both dose levels, patients will be followed for AEs for a minimum of 9 weeks (63 calendar 
days) after the last dose of study treatment. All AEs will be followed until the event or its 
sequelae resolve or stabilize at a level acceptable to the Investigator assuming Pfizer concurs 
with that assessment. 
 
All known cases of VOD, regardless of causality or severity, will be reported in the clinical 
report form (CRF) and as SAEs for the entire duration of study participation and the follow-up 
period. 
 
An AE will be considered treatment related if the investigator considers the AE to be related to 
the study treatment. 
 
3.4.1.1. Treatment Emergent Adverse Events 
Treatment emergent AEs (TEAEs) will be defined as AEs that commence on or after Cycle 1 
Day 1 but within 63 days of last dose (non-related) or any time after Cycle 1 Day 1 (treatment- 
related). All VOD events within 2 years of randomization date regardless of causal attribution to 
study treatment will be included. 
 
3.4.1.2. Adverse Events of Special Interest 
AEs of special interest (AESI) are as follows: 
 
• GRADE ≥3 HEPATOTOXICITY AND/OR SERIOUS HEPATOTOXICITY, 
INCLUDING VOD/SOS; 
 
• MYELOSUPPRESSION/CYTOPENIA (including Infections and Haemorrhage); 
 
• INTERSTITIAL LUNG DISEASE; 
 
• INFLAMMATORY GASTROINTESTINAL EVENT; 


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• PANCREATITIS; 
 
• SECONDARY PRIMARY MALIGNANCY; 
 
• REPRODUCTIVE AND DEVELOPMENT TOXICITY; 
 
• NEPHROTOXICITY; and 
 
• NEUROTOXICITY. 
 
These events are defined in Appendix 1. 
 
Note: Prior to data analysis, the AEoSI list may be updated if required. 
 
3.4.2. Laboratory Data 
Relevant hematology and chemistry parameters (on-treatment and post-HSCT) will be 
programmatically graded according to the NCI CTCAE v3.0. Parameters which cannot be graded 
will be summarized relative to the normal range (i.e., higher or lower than normal range). 
Additional details are provided in Section 6.6.3. 
 
3.4.3. Other Safety Endpoints 
• Physical examination: if any finding on the physical examination is considered by the 
investigator to be ‘clinically significant’, the event is to be recorded as medical history 
(preexisting) or an AE (treatment emergent), as appropriate. 
 
• Vital signs: vital sign parameters include body weight, height, body temperature, pulse rate, 
and blood pressure (systolic and diastolic). 
 
• Electrocardiogram (ECG): triplicate ECGs produce the following parameters: heart rate, PR, 
QT, QRS complex, corrected QT intervals (QTcB corrected using Bazett’s formula, and 
QTcF corrected using Fridericia’s formula), and RR. 
 
• Triplicate ECGs will be performed at screening, at baseline (prior to dose on Day 1), 
prior to the start of each cycle, and at the EOT. A 12 lead tracing will be used for all 
ECGs, including measurements of PR interval, QT interval, QRS complex and, RR 
interval. 
 
• Hospitalization: status and date as collected in the CRF. 
 
4. ANALYSIS SETS 
This study is designed to enroll patients who are eligible for HSCT.  Patients must be eligible for 
HSCT at the time of randomization (see Study B1931030 Protocol Section 4.1). Patients who are 
eligible for HSCT at randomization but who subsequently are not able to proceed to HSCT will 
not be replaced. Analyses will be performed based on the intent-to-treat (ITT) population (full 


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analysis set), Per-Protocol population (per protocol analysis set), and Safety population (safety 
analysis set) as described below. 
 
4.1. Full Analysis Set 
The Full Analysis Set will be based on the ITT population which will include all patients who 
are randomized into the study with study drug assignment based on randomization. 
 
4.2. Per-Protocol Analysis Set 
The Per-Protocol (PP) Analysis Set will be based on the PP population which will be a subset of 
the ITT population and will include all patients who meet all of the following criteria: 
 
• Patients who were randomized and received at least one dose of study drug with 
treatment assignments designated according to actual treatment received. 
 
• Patients with no major protocol violations; major violations include, 
 
• Failure to satisfy major entry criteria, include the following: Inclusion criteria 1, 2, 6, 
11; exclusion criteria 1, 2, 3, 13, 19. 
 
• Life-threatening dosing error, defined as taking wrong study treatment (ie, 
randomized to Dose Level 1 but took study drug for Dose Level 2; OR randomized to 
Dose Level 2 but took study drug for Dose Level 1). 
 
• Patients with an adequate baseline disease assessment. A patient will have an adequate 
baseline disease assessment if the patient has one of the following two procedures at 
screening: 
 
• Bone marrow biopsy or aspirate with blasts ≥5%, 
 
• Hematology test with presence of blast cells (% or absolute). 
 
• Patients who proceed to follow-up HSCT. 
 
4.3. Safety Analysis Set 
The Safety Analysis Set will be based on the safety population which includes all randomized 
patients who receive at least 1 dose of study drug, with treatment assignments designated 
according to actual treatment received. 
 
Safety will also be evaluated post-HSCT in the HSCT safety population. The HSCT safety 
population will include all randomized patients who receive at least 1 dose of study drug, with 
treatment assignments designated according to actual treatment received, and who undergo 
HSCT after inotuzumab ozogamicin treatment. In addition, subgroup analysis will be performed 
for patients who undergo HSCT directly without new induction therapy. 


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4.4. PK Analysis Set 
The PK Analysis Set will be based on the PK population which includes all treated patients who 
received at least 1 dose of study drug and had at least one PK sample collected and analyzed. 
 
4.5. Immunogenicity Analysis Set 
The Immunogenicity Analysis Set will be based on the immunogenicity population which 
includes all treated patients who received at least 1 dose of study drug and had at least one 
ADA/Nab sample collected and analyzed for immunogenicity. 
 
5. GENERAL METHODOLOGY AND CONVENTIONS 
5.1. Hypotheses and Decision Rules 
5.1.1. Hypotheses and Sample Size 
A total of up to approximately 102 patients will be enrolled in the study:  up to 22 patients in the 
run-in phase (dose level 2) and 80 patients (40 patients per dose level) in the randomized phase if 
acceptable efficacy is observed at dose level 2 in the run-in phase. 
 
5.1.1.1. Run-in Phase 
The primary objective of the run-in phase is to allow for the potential to stop the study early if 
insufficient efficacy (see Section 5.1.2) is observed at the lower dose level (1.2 mg/m2/cycle 
[dose level 2]). 
 
The run-in phase is designed to test: 
 
• The null hypothesis H10: CR/CRi rate ≤31.2% versus the alternative hypothesis H1a: 
CR/CRi rate ≥57%; 
 
• The null hypothesis H20: MRD-negativity rate ≤20% versus the alternative hypothesis 
H2a: MRD-negativity rate ≥40%. 
 
In Phase 3 Study B1931022, patients that had ≥1 factor for a higher risk of VOD post-HSCT had 
an observed CR/CRi rate of 70.5% in the inotuzumab ozogamicin arm and 31.2% in the control 
arm. 
 
In the current study, based on the exposure-response modeling from Study B1931022 and 
depending on the actual prognostic factors of the enrolled patients, the true response rates for 
patients that have ≥1 factor for a higher risk of VOD post-HSCT might be as low as 57%. 
Therefore, in the current study, the null hypothesis H10 has been selected to be 31.2% and the 
alternative hypothesis H1a has been selected to be 57%. 
 
In the current study, the MRD-negativity rate among patients who achieve CR/CRi is expected to 
be ≥70%. Given an expected CR/CRi rate of 57% and an expected MRD-negativity rate of ≥ 
70% among CR/CRi responders, the MRD-negativity rate among all the patients enrolled in the 


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run-in phase is expected to be 40%. Therefore, an MRD-negativity rate of 40% has been selected 
as the alternative hypothesis H2a. 
 
A total of up to 22 patients will be enrolled in the run-in phase. This sample size will provide 
80% power to reject the null hypothesis with a significance level of 0.10 if the true CR/CRi rate 
is 57%. This sample size will also provide 80% power to reject the null hypothesis of an MRD- 
negativity rate of ≤20% when the alternative hypothesis for the true MRD-negativity rate is ≥ 
40% with a significance level of 0.10. 
 
5.1.1.2. Randomized Phase 
The primary purpose of the randomized phase is to evaluate the safety and efficacy of two 
inotuzumab ozogamicin dose levels through descriptive analyses. There is no hypothesis testing 
for either primary or secondary endpoints. 
 
Assuming the study proceeds beyond the run-in phase to the randomized phase, approximately 
80 patients will be randomized (1:1) to either 1.8 mg/m2/cycle (dose level 1, Arm 1) or 1.2 
mg/m2/cycle (dose level 2, Arm 2). A sample size of 40 patients per dose level will provide the 
estimated VOD rates shown in Table 2 at each dose level with a maximum standard error (SE) of 
0.08. The maximum SE estimated for other binary endpoints in each dose level (e.g., CR/CRi 
rate) will also be 0.08. 
 
In addition, for dose level 2, data from patients included in the run-in phase (i.e., who were 
treated with 1.2 mg/m2/cycle) will be combined with data from patients from Arm 2 of the 
randomized phase, leading to a sample size of approximately 62 patients (i.e., 22 patients 
enrolled in the run-in phase and 40 patients enrolled in Arm 2 in the randomized phase) to 
provide the above-mentioned estimated rates with a maximum SE of 0.06. 
 
Table 2 shows the possible estimated VOD rates and CR/CRi rates with 95% confidence interval 
(CI) with a sample size of 40 patients and 62 patients, respectively. 
 
Table 2.  95% CI for Different Estimated VOD Rates and CR/CRi Rates 
 
VOD/Sample Size 
VOD Rate 
% (95% CI) 
Responders/Sample Size 
CR/CRi rate 
% (95% CI) 
40 patients 
4/40 
10 (2.8-23.7) 
16/40 
40% (24.9-56.7) 
6/40 
15 (5.7-29.8) 
20/40 
50% (33.8-66.2) 
8/40 
20 (9.1-35.6) 
24/40 
60% (43.3-75.1) 
10/40 
25 (12.7-41.2) 
28/40 
70% (53.5-83.4) 
12/40 
30 (16.6-46.5) 
32/40 
80% (64.4-90.9) 
62 patients 
6/62 
10 (3.6-19.9) 
25/62 
40% (28.1-53.6) 
9/62 
15 (6.9-25.8) 
31/62 
50% (37.0-63.0) 
13/62 
21 (11.7-33.2) 
37/62 
60% (46.4-71.9) 
16/62 
26 (15.5-38.5) 
44/62 
71% (58.1-81.8) 
19/62 
31 (19.6-43.7) 
50/62 
81% (68.6-89.6) 


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Table 2.  95% CI for Different Estimated VOD Rates and CR/CRi Rates 
 
VOD/Sample Size 
VOD Rate 
% (95% CI) 
Responders/Sample Size 
CR/CRi rate 
% (95% CI) 
Abbreviations: CI=confidence interval; CR=complete remission; CRi=complete remission with incomplete 
hematologic recovery; VOD=veno-occlusive disease. 
5.1.2. Decision Rules 
Overall, the study is designed have a run-in phase to assess for potential futility at the lower 
inotuzumab ozogamicin dose level (1.2 mg/m2/cycle, dose level 2) and a follow-up randomized 
phase (descriptive analyses) in which patients will receive inotuzumab ozogamicin dose levels of 
1.8 mg/m2/cycle or 1.2 mg/m2/cycle. 
 
For the run-in phase, a Simon Two-Stage optimal design will be used to minimize the expected 
number of patients enrolled if the lower dose proves to have insufficient efficacy. Therefore, 
overall, the study is designed to have 2 interim analyses for futility. 
 
The first interim analysis will be performed at the end of Stage 1 of the run-in phase, i.e. after 7 
patients have been enrolled with a minimum of 3 months follow-up from randomization. 
Meanwhile, patient enrollment will continue between Stage 1 and Stage 2 until analyses for 
decision-making are completed. Once ≥3 (i.e., 42.9%) CR/CRi responders being documented, an 
additional 15 enrolled patients will be evaluated in the second interim analysis. If, at the first 
interim analysis, <3 CR/CRi responders are documented for the 7 patients enrolled in Stage 1, 
patient enrollment will be stopped for further evaluation (see Section 7 for the derivations). 
 
If the decision is made to proceed after the first interim analysis, enrollment will continue, and 
the second interim analysis will be conducted. 
 
The second interim analysis will be performed at the end of the run-in phase, i.e. after a total of 
22 patients have been enrolled with a minimum of 3 months follow-up from randomization. 
Meanwhile, patient enrollment will continue into the randomized phase while analyses for 
decision-making are being completed. If there are ≥10 CR/CRi responders and ≥7 patients 
achieving MRD-negativity documented among the 22 patients in the run-in phase, the enrollment 
will further continue until randomized phase has completed. Subsequently, patients enrolled in 
the randomized phase will be evaluated in the final analysis. If, at the second interim analysis, 
<10 CR/CRi responders or <7 patients achieving MRD-negativity are documented for the 22 
patients enrolled in the run-in phase, patient enrollment will be stopped for further evaluation 
(see Section 7 for the derivations). DoR and safety will also be analyzed at the end of the run-in 
phase. 
 
If the decision is made to proceed after the second interim analysis, enrollment will continue, and 
the final analysis will be conducted as planned. 


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5.2. General Methods 
All analyses will be based on descriptive statistics without hypothesis testing and with 95% CI 
provided for each of the estimate. No p-values will be provided. Additional analyses may be 
performed if deemed appropriate. 
 
5.2.1. Pooling of Data by Center 
In order to provide overall estimates of treatment effects, data will be pooled across centers 
(clinical sites). A variable for ‘center’ will not be included in statistical models or for subset 
analyses since it is anticipated that there will be a high number of participating centers with a 
small number of patients randomized/treated at each center. 
 
5.2.2. Nominal Timepoints 
For all algorithms and analyses, visit labels as specified on the clinical report form (CRF) will be 
used as the nominal timepoint (i.e. assessment will not be slotted). 
 
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 onset, tumor measurement) will be calculated as: 
 
Study day = Date of the assessment/event – start date of study treatment + 1. 
The start date of study treatment is the date of Cycle 1 Day 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. Date of Last Contact 
The date of last contact will be derived for patients not known to have died at the data cutoff date 
using the latest complete date (i.e., imputed dates will not be used in the derivation) among the 
following: 
 
• All patient assessment dates (e.g., blood draws [laboratory, PK]), vital signs, physical 
exam, performance status, ECG, disease assessments); 
 
• Start and stop dates of concomitant therapies including non-drug treatments or 
procedures; 
 
• Start and end dates of anti-cancer therapies administered after study treatment 
discontinuation including systemic therapy, radiation, and surgeries; 


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• AE start and end dates; 
 
• Last date of contact collected by subsequent follow-up (do not use date of survival 
follow-up assessment unless status is ‘alive’); 
 
• Study treatment start and end dates; 
 
• Randomization date; 
 
• Date of discontinuation (do not use if reason for discontinuation is lost to follow-up or 
death). 
 
Only dates associated with actual examinations of the patient will be used in the derivation. 
Dates associated with a technical operation unrelated to patient status such as the date a blood 
sample was processed, or dates data were entered into the CRF will not be used. Assessment 
dates after the data cutoff date will not be applied to derive the last contact date. 
 
5.2.5. ALL Disease Assessment Date 
The ALL disease assessment date at each nominal timepoint will be utilized for respective 
analyses. 
 
5.2.6. Unscheduled Assessments 
Unless otherwise specified, unscheduled assessments will not be displayed in summary tables by 
nominal visit/timepoint. Unscheduled assessments will be used when deriving baseline and worst 
case on-treatment for safety (except where noted for baseline ECGs). Additionally, unscheduled 
assessments will be used for efficacy analyses (e.g. defining date of progression/censoring, 
hematologic remission, date of last contact). 
 
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 1 decimal place. Rounding will be performed to the closest 
integer/first decimal using the common mid-point between 2 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. 
 
5.2.8. Analyses of Continuous Endpoints 
Continuous variables will be summarized using descriptive statistics i.e., mean, standard 
deviation, median, minimum, maximum and number of patients. The difference in mean values 
between two arms with CI calculated based on the t-distribution will be displayed. 


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5.2.9. Analyses of Categorical Endpoints 
Categorical variables will be summarized using frequency counts and percentages. Unless 
otherwise specified, the calculation of proportions will include the missing category. Therefore 
counts of missing observations will be included in the denominator and presented as a separate 
category. In addition, appropriate Cis will be calculated using the normal approximation or the 
exact method (Collett D, 1991). 
 
The difference in percentages between two arms with CI calculated using the normal 
approximation or the exact method (Collett D, 1991) will be displayed. 
 
5.2.10. Analyses of Time to Event Endpoints 
Time to event endpoints (i.e., DoR, OS, PFS and post-HSCT mortality) will be summarized 
using the Kaplan-Meier method and estimated time to event curves will be displayed graphically 
when appropriate. The median, quartiles, and probabilities of an event at a particular timepoint 
will be estimated using the Kaplan-Meier method. CIs for medians and quartiles will be 
calculated using the method described by Brookmeyer R and Crowley J (1982). CIs for the 
estimated probability of event at a particular timepoint will be generated using the log(-log) 
method with back transformation to a CI on the untransformed scale. Summaries of the number 
and percentages of patients with an event will also be provided in summary tables and figures. 
 
5.2.11. Competing-Risks Analyses of Time to Event Endpoints 
Time to event endpoints associated with competing events (i.e., post-HSCT relapse, non-relapse 
mortality and relapse-related mortality) will be summarized using competing-risks analyses and 
estimated cumulative incidence plot will be displayed graphically when appropriate. Cumulative 
incidence rates of an event at a particular timepoint will be estimated with the CI calculated 
based on the cumulative incidence function using the method described by Kalbfleisch RL and 
Prentice JD (1980). Summaries of the number and percentages of patients with an event and 
patients with a competing event will also be provided in summary tables and figures, 
respectively. 
 
5.3. Methods to Manage Missing Data 
Unless otherwise specified, all data will be evaluated as observed, and no imputation method for 
missing values will be used. 
 
Any imputations will occur at the analysis dataset level. In all patient data listings imputed 
values will be presented and flagged as imputed. 
 
5.3.1. Missing Dates 
For time to event endpoints, missing date will be handled by censoring as described in their 
definitions in Section 3.2. 
 
For purposes of data listings, dates will reflect only the information provided by the Investigator 
on the CRF. 


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If start dates for AEs or concomitant medications are completely missing, a worst case approach 
will be taken whereby the events will be considered treatment emergent and the medications will 
be considered concomitant. If only partial information are available (e.g. only a month and year 
or only a year) and the partial information provide 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 a similar worst case 
approach will apply and these will be considered to have started after treatment. 
 
No imputation will be done for first dose date. The date of last dose of study treatment, if 
unknown or partially unknown, will be imputed as follows: 
 
• If the last date of study treatment is completely missing and there is no End of Treatment 
(EOT) visit and no death date, the patient should be considered to be ongoing and use the 
data cutoff date for the analysis as the last dosing date; or 
 
• If the last date of study treatment is completely or partially missing and there is EITHER an 
EOT visit OR a death date available (on or prior to the data cutoff date), then impute this date 
as the last dose date: 
 
• 
= 31DECYYYY, if only Year is available and Year < Year of min (EOT date, death 
date); 
 
• 
= Last day of the month, if both Year and Month are available and Year = Year of min 
(EOT date, death date) and Month < the month of min (EOT date, death date); or 
 
• 
= min (EOT date, death date), for all other cases. 
 
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 5.2.3); 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. 
 
Incomplete dates for new anti-cancer therapy will be imputed as follows and will be used to 
determine censoring dates for efficacy analyses: 
 
• 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: 
 
• Completely missing then it will be ignored in the imputations below; 


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• Partially missing with only year available then the imputations below will consider 
31DECYYYY as the end date of the new anti-cancer therapy; or 
 
• 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. 
 
• For patients who have not discontinued study treatment at the time of the data cutoff date, the 
last dose of study treatment will be set to the data cutoff date in the imputations below. 
 
• 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 [max 
(progression/relapse date + 1, 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 [max (progression/relapse date + 1, last dose of study treatment + 
1), end date of new anti-cancer therapy] 
 
• Month < Month of min [max (progression/relapse date + 1 day, last dose of study 
treatment + 1 day), end date of new anti-cancer therapy] 
 
• 
= min [max (progression/relapse date + 1, last dose of study treatment + 1), end date of 
new anti-cancer therapy], for all other cases. 
 
The following imputation rules apply if the event is unique for a patient or it is the first of a 
series of similar events; otherwise, the AE Onset Date will not be imputed: 
 
• If the AE Collection Date is not missing, is less than the Date of First Exposure to Treatment, 
and is less than the AE Stop Date, then AE Onset Date will be set to the Date of AE 
Collection; 
 
• If the Previous Visit Date is greater than the Date of First Exposure to Treatment and less 
than the AE Stop Date, the AE Start Date will be set to the previous visit date; 
 
• If the Date of First Exposure to Treatment is greater than the previous visit date and less than 
the AE Stop Date, the AE Onset Date will be set to the Date of First Exposure to Treatment; 
 
• Otherwise the AE Onset date will be set to the AE Stop date. 
 
Ongoing events will have the AE Stop Date set to 1 of the following values: 
 
• Date of Death, if the patient died and a date of death exists; 


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• Maximum of Patient Withdraw Date, AE Onset Date, or AE Collection Date if the patient 
withdrew from the study and a date of withdraw exists; 
 
• Maximum of AE Onset Date, Subject Summary Collection Date, or AE Collection Date if a 
date of subject summary collection exists but a date of withdraw does not exist; 
 
• Maximum of Last Treatment Date or AE Onset Date if a date of subject summary collection 
does not exist. 
 
Imputation will only occur if event is unique for the patient, or it is the last of a series of similar 
events; otherwise the Stop Date will not be imputed. AEs are deemed similar if they have the 
same verbatim term. 
 
Resolved events will have the AE Stop Date set to the maximum of the AE collection date and 
the AE Onset date. 
 
Imputation methods for other partial dates will be as follows: 
 
• 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; 
 
• If both the day and month are missing, the first day of the year will be used; 
 
• For stop dates, the last day of the month, or last day of the year will be used if the day or day 
and month are missing, respectively; 
 
• If the date is completely missing, no imputation will be performed. 
 
5.3.2. Missing Toxicity Grade of Adverse Events 
Prior to Study Treatment: If no toxicity grade is available or the grade is reported as unknown for 
an adverse event prior to the first study treatment, then Grade 1 will be assumed for purposes of 
defining a baseline grade for assessing if further occurrences are treatment emergent. However, 
if the patient experiences multiple episodes of the same AE prior to study treatment, then the 
maximum toxicity grade observed prior to study treatment will be utilized in assessing if further 
occurrences are treatment emergent. 
 
During Study Treatment: If no toxicity grade is available or the grade is reported as unknown for 
an adverse event during the study treatment, then the event will be considered treatment 
emergent unless a baseline event was reported as Grade 4. 
 
In summaries which present maximum toxicity grade, the maximum of non-missing grades will 
be displayed. Missing grade will only be displayed for cases where a patient reported only 1 
event and the grade is missing. 


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5.3.3. Missing ECG Data 
For QTc analyses, no values will be imputed for missing data. If one or two of the triplicate 
measurements for an ECG parameter are missed, the average of the remaining two measurements 
or the single measurement can be used in the analyses. If all triplicate measurements are missing 
at a timepoint for an ECG parameter, no values will be imputed for this timepoint.  If the 
triplicate needs to be repeated because of an artifact, then the repeated triplicate will be reported 
on an unscheduled CRF page.  Based on a review of the data these unscheduled assessments may 
be used in place of the assessments at the nominal time. Data review and consultation with the 
study team is required to flag these cases. 
 
6. ANALYSES AND SUMMARIES 
This study is designed to have 2 phases, the run-in phase and the randomized phase. All efficacy 
and safety analyses will be done by dose level and by study phase (i.e., the run-in phase, Arm 1 
of the randomization phase (Dose Level 1), and Arm 2 of the randomization phase (Dose Level 
2) will be summarized separately).  In addition, patients enrolled in the run-in phase will be 
combined with Arm 2 of the randomization phase for the summary of Dose Level 2. 
 
6.1. Primary Endpoints 
6.1.1. CR/CRi Rate 
6.1.1.1. Primary Analysis 
The primary analysis of CR/CRi rate will be based on the ITT population. 
 
The frequency (number and percentage) of patients with CR, and CRi, and not met CR or CRi 
will be tabulated for Dose Level 2 (run-in), Dose Level 1 (randomized), Dose Level 2 
(randomized), and Dose Level 2 (run-in & randomized combined). Not met CR or CRi includes 
three categories, 
 
1. Not post baseline samples: define as patients did not have any post baseline aspirate 
collected (non-response confirmed by peripheral blasts only), 
 
2. Patients with ≥5% blasts, 
 
3. Patients with <5% blasts: define as patients with less than 5% bone marrow blasts but did 
not meet criteria for CR or CRi due to the presence of peripheral blasts, EMD, or missing 
assessments. 
 
CR/CRi rate will be calculated along with the two-sided 95% CI using the normal approximation 
or the exact method (Collett D, 1991) for Dose Level 2 (run-in), Dose Level 1 (randomized), 
Dose Level 2 (randomized), and Dose Level 2 (run-in & randomized combined). The unstratified 
and stratified difference in response rates between two dose levels of the randomized phase 
(Dose Level 1 – Dose Level 2) along with the 2-sided 95% CI for the difference will be provided 
as a descriptive statistic. 


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In addition, time to remission (in months), defined as time from the date of first dose of study 
treatment to the date of first remission (CR/CRi), will be summarized using descriptive statistics 
for patients achieving CR/CRi for Dose Level 2 (run-in), Dose Level 1 (randomized), Dose 
Level 2 (randomized), and Dose Level 2 (run-in & randomized combined). Length of duration 
(months) will be calculated as [date of first remission−date of first dose+1]/30.4375. 
 
6.1.1.2. Sensitivity Analysis 
A sensitivity analysis will be performed based on the PP population to explore the robustness of 
the primary analysis results. CCI 
be a repeat of the primary analysis described in Section 6.1.1.1. 
The sensitivity analysis will 
 
6.1.2. VOD Rate 
The primary analysis of VOD rate will be based on the Safety population for the following 
periods: 
 
• Overall study period, 
 
• On-treatment or in follow-up without HSCT period, and 
 
• Post-HSCT period. 
 
VOD rate will be calculated along with the 2-sided 95% CI using the normal approximation or 
the exact method (Collett D, 1991) for Dose Level 2 (run-in), Dose Level 1 (randomized), Dose 
Level 2 (randomized), and Dose Level 2 (run-in & randomized combined). The difference 
(unstratified) in incidence between two dose levels of overall patients of the randomized phase 
(Dose Level 1 – Dose Level 2) along with the two-sided 95% CI for the difference will be 
provided as a descriptive statistic. 
 
In addition, similar analyses will be conducted for VOD rate for the two subsets: 
 
1. HSCT safety population, 
 
2. Patients who proceed to HSCT directly after inotuzumab ozogamicin treatment without 
an intervening induction therapy in the HSCT safety population. 
 
Time to VOD post-HSCT (from date of first HSCT after inotuzumab ozogamicin treatment) will 
be summarized using descriptive statistics for patients having experienced VOD post-HSCT in 
the above two subsets. 
 
Subset Analyses by VOD Risk Factors 
For Dose Level 1 (randomized) and Dose Level 2 (randomized), the VOD rates by dose levels 
and rate differences (Dose Level 1 – Dose level 2) along with the 2-sided 95% CI will be 
provided for 
 
1.  Safety population, 


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2. HSCT safety population, and 
 
3. Patients who proceed to HSCT directly after inotuzumab ozogamicin treatment without 
an intervening induction therapy in the HSCT safety population, 
 
respectively, in subsets per VOD risk factors as listed below: 
 
• Age <55 years vs ≥55 years, 
 
• Salvage 1 vs ≥2, 
 
• Prior HSCT (yes vs no), 
 
• Prior history of liver disease/hepatitis (yes vs no). 
 
Analyses of Association of Baseline Characteristics and Patient Characteristics at the Time 
of HSCT with Occurrence of VOD Post-HSCT 
Both univariate and multivariate logistic regression analyses will be performed to evaluate the 
potential influences of baseline characteristics and patient characteristics at the time of HSCT 
with occurrence on VOD occurrence post-HSCT for HSCT safety population. The covariates for 
baseline characteristics of interest are: 
 
• Age (<55 years, ≥55 years), 
 
• Salvage status (1, ≥2), 
 
• Prior HSCT (yes, no), 
 
• Prior history of liver disease/hepatitis (yes, no), 
 
• Number of treatment cycles received (continuous). 
 
The covariates for patient characteristics at the time of HSCT of interest are: 
 
• Use of HSCT conditioning regimens containing alkylating agents (single, dual), 
 
• Last bilirubin prior to conditioning therapy (<ULN, ≥ULN), 
 
• Last bilirubin prior to follow-up HSCT (<ULN, ≥ULN). 
 
Covariates for other baseline characteristics and patient characteristics at the time of HSCT, if 
interested, may be included in the univariate and multivariate logistic regression analyses. 
 
For each univariate analysis, number of patients, number of patients in each subset if the 
covariate is binary, estimated odds ratio along with the 95% CI and two-sided p-values will be 
provided for Dose Level 1 (randomized), Dose Level 2 (runin & randomized) and all patients 


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combined from 2 dose levels (in this case, an additional covariate of dose level will be included 
in the analysis). 
 
For each multivariate analysis, a stepwise selection procedure will serve to identify these 
covariates of potential prognostic values. Covariates are entered into and removed from the 
model in such a way that each forward selection step can be followed by one or more backward 
elimination steps. The stepwise selection process terminates if no further covariate can be added 
to the model or if the covariate just entered into the model is the only covariate removed in the 
subsequent backward elimination. The level of significance for an explanatory variable to enter 
the model is set to 0.3 and the significance level for removing it is set to 0.1. For Dose Level 1 
(randomized) and Dose Level 2 (runin & randomized), those covariates selected by the stepwise 
procedure will be reported using number of patients in each subset if the covariate is binary, and 
estimated odds ratio along with the 95% CI and two-sided p-values. 
 
6.2. Secondary Endpoints 
The primary analyses of the follow secondary endpoints will be based on the ITT population. In 
addition, the sensitivity analyses will be performed to explore the robustness of the primary 
analyses results. CCI 
repeat the primary analyses on the PP population. 
The sensitivity analyses will 
 
6.2.1. MRD-Negativity 
MRD-negativity per central lab (qualitative result) will be summarized using frequency (counts 
and percentages) with 2-sided 95% CI for Dose Level 2 (run-in), Dose Level 1 (randomized), 
Dose Level 2 (randomized), and Dose Level 2 (run-in & randomized combined) in patients 
achieving CR/CRi. The difference (unstratified) in percentages between two dose levels of the 
randomized phase (Dose Level 1 – Dose Level 2) along with the 2-sided 95% CI for the 
difference will be provided as a descriptive statistic. 
 
Patients without any post-baseline central MRD results up to end of treatment will be 
summarized using frequency (counts and percentages) in patients achieving CR/CRi for Dose 
Level 2 (run-in), Dose Level 1 (randomized), Dose Level 2 (randomized), and Dose Level 2 
(run-in & randomized combined). 
 
Minimum MRD percentage per central lab (quantitative result) from post-baseline to 7 days 
post-EOT will be summarized using descriptive statistics in patients achieving CR/CRi for Dose 
Level 2 (run-in), Dose Level 1 (randomized), Dose Level 2 (randomized), and Dose Level 2 
(run-in & randomized combined). 
 
Same summary will be performed in patients achieving CR and CRi separately. 
 
6.2.2. DoR 
Number and percentage of patients with a remission (CR/CRi), and remission status (in patients 
with a remission) will be provided for Dose Level 2 (run-in), Dose Level 1 (randomized), Dose 


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Level 2 (randomized), and Dose Level 2 (run-in & randomized combined). Remission statuses 
include, 
 
• Patients with a remission (CR/CRi) and subsequently progressed or died due to any cause 
while on study, and 
 
• Patients with a remission (CR/CRi) who had not progressed or died due to any cause 
while on study. 
 
Median Q1, and Q3 of DoR will be estimated using the Kaplan-Meier method and will be 
reported with 2-sided 95% CI for Dose Level 2 (run-in), Dose Level 1 (randomized), Dose Level 
2 (randomized), and Dose Level 2 (run-in & randomized combined). 
 
The Kaplan-Meier curves for Dose Level 2 (run-in), Dose Level 1 (randomized), Dose Level 2 
(randomized), and Dose Level 2 (run-in & randomized combined) will be displayed graphically. 
 
Additional sensitivity analyses for DoR will be performed in both ITT population and PP 
population where patients without a DoR event at time of analysis will be censored at the date of 
last valid disease assessment (including follow-up disease assessment) or the date of last 
laboratory test showing no blasts, whichever occurs last. 
 
6.2.3. PFS 
Number and percentage of patients with events (including type of event) and patients censored 
(including reason for censoring) will be provided for Dose Level 2 (run-in), Dose Level 1 
(randomized), Dose Level 2 (randomized), and Dose Level 2 (run-in & randomized combined). 
 
Median, Q1 and Q3 of PFS will be estimated using the Kaplan-Meier method and will be 
reported with 2-sided 95% CI for Dose Level 2 (run-in), Dose Level 1 (randomized), Dose Level 
2 (randomized), and Dose Level 2 (run-in & randomized combined). 
 
PFS rates will be computed at months 3, 6, 9, 12 and 15 using the Kaplan-Meier method, and 
will be reported with 2-sided 95% CI for Dose Level 2 (run-in), Dose Level 1 (randomized), 
Dose Level 2 (randomized), and Dose Level 2 (run-in & randomized combined). 
 
The Kaplan-Meier curves will be displayed graphically for Dose Level 2 (run-in), Dose Level 1 
(randomized), Dose Level 2 (randomized), and Dose Level 2 (run-in & randomized combined). 
 
Additional sensitivity analyses for PFS will be performed in both ITT population and PP 
population where patients experiencing events of starting new induction therapy/post-therapy 
HSCT without achieving CR/CRi will be censored at the date of starting new induction 
therapy/post-therapy HSCT. 


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6.2.4. OS 
Number and percentage of patients with events and patients censored (including reason for 
censoring) will be provided for Dose Level 2 (run-in), Dose Level 1 (randomized), Dose Level 2 
(randomized), and Dose Level 2 (run-in & randomized combined). 
 
Median, Q1 and Q3 of OS will be estimated using the Kaplan-Meier method and will be reported 
with 2-sided 95% CI for Dose Level 2 (run-in), Dose Level 1 (randomized), Dose Level 2 
(randomized), and Dose Level 2 (run-in & randomized combined). 
 
Survival probabilities will be computed at months 6, 12 and 24 using the Kaplan-Meier method, 
and will be reported with 2-sided 95% CI for Dose Level 2 (run-in), Dose Level 1 (randomized), 
Dose Level 2 (randomized), and Dose Level 2 (run-in & randomized combined). 
 
The Kaplan-Meier curves will be displayed graphically for Dose Level 2 (run-in), Dose Level 1 
(randomized), Dose Level 2 (randomized), and Dose Level 2 (run-in & randomized combined). 
 
6.2.5. Rate of HSCT 
Patients who undergo HSCT and patients who undergo HSCT directly without new induction 
therapy will be summarized using frequency counts and percentages in the ITT population for 
Dose Level 2 (run-in), Dose Level 1 (randomized), Dose Level 2 (randomized), and Dose Level 
2 (run-in & randomized combined). 
 
Type of transplant (allogeneic and autologous) and type of conditioning therapy (myeloablative 
and reduced intensity) will be summarized using frequency counts and percentages in patients 
who undergo HSCT for Dose Level 2 (run-in), Dose Level 1 (randomized), Dose Level 2 
(randomized), and Dose Level 2 (run-in & randomized combined). 
 
No sensitivity analysis will be performed in the PP population. 
 
6.2.6. Post-HSCT Relapse 
Number and percentage of patients who undergo HSCT and patients with post-HSCT relapse 
adjusted for competing risk will be provided for Dose Level 2 (run-in), Dose Level 1 
(randomized), Dose Level 2 (randomized), and Dose Level 2 (run-in & randomized combined). 
 
The cumulative incidence rate of post-HSCT relapse will be computed at Day 180 and other 
clinical meaningful timepoints using a method adjusting competing-risks and will be reported 
with 2-sided 95% CI for Dose Level 2 (run-in), Dose Level 1 (randomized), Dose Level 2 
(randomized), and Dose Level 2 (run-in & randomized combined). 
 
The cumulative incidence plot will be displayed for Dose Level 2 (run-in), Dose Level 1 
(randomized), Dose Level 2 (randomized), and Dose Level 2 (run-in & randomized combined). 


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6.2.7. Post-HSCT Mortality 
Number and percentage of patients who undergo HSCT and patients with post-HSCT mortality 
will be provided for Dose Level 2 (run-in), Dose Level 1 (randomized), Dose Level 2 
(randomized), and Dose Level 2 (run-in & randomized combined). 
 
The cumulative incidence rate of post-HSCT mortality will be computed at Day 180 and other 
clinical meaningful timepoints using the Kaplan-Meier method and will be reported with 2-sided 
95% CI for Dose Level 2 (run-in), Dose Level 1 (randomized), Dose Level 2 (randomized), and 
Dose Level 2 (run-in & randomized combined). 
 
The cumulative incidence plot (i.e., 1 minus the Kaplan-Meier curve) will be displayed for Dose 
Level 2 (run-in), Dose Level 1 (randomized), Dose Level 2 (randomized), and Dose Level 2 
(run-in & randomized combined). 
 
6.2.8. Non-Relapse Mortality 
Number and percentage of patients who undergo HSCT and patients with post-HSCT non- 
relapse mortality adjusted for competing risk will be provided for Dose Level 2 (run-in), Dose 
Level 1 (randomized), Dose Level 2 (randomized), and Dose Level 2 (run-in & randomized 
combined). 
 
The cumulative incidence rate of non-relapse mortality will be computed at Day 180 and other 
clinical meaningful timepoints using a method adjusting competing-risks and will be reported 
with 2-sided 95% CI for Dose Level 2 (run-in), Dose Level 1 (randomized), Dose Level 2 
(randomized), and Dose Level 2 (run-in & randomized combined). 
 
The cumulative incidence plot will be displayed for Dose Level 2 (run-in), Dose Level 1 
(randomized), Dose Level 2 (randomized), and Dose Level 2 (run-in & randomized combined). 
 
6.2.9. Relapse-Related Mortality 
Number and percentage of patients who undergo HSCT and patients with post-HSCT relapse- 
related mortality adjusted for competing risk will be provided for Dose Level 2 (run-in), Dose 
Level 1 (randomized), Dose Level 2 (randomized), and Dose Level 2 (run-in & randomized 
combined). 
 
The cumulative incidence rate of relapse-related mortality will be computed at Day 180 and 
other clinical meaningful timepoints using a method adjusting competing-risks and will be 
reported with 2-sided 95% CI for Dose Level 2 (run-in), Dose Level 1 (randomized), Dose Level 
2 (randomized), and Dose Level 2 (run-in & randomized combined). 
 
The cumulative incidence plot will be displayed for Dose Level 2 (run-in), Dose Level 1 
(randomized), Dose Level 2 (randomized), and Dose Level 2 (run-in & randomized combined). 


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6.2.10. Immune Response to Inotuzumab 
In patients who test positive for anti-inotuzumab ozogamicin antibodies and neutralizing 
antibodies, the effect of anti-inotuzumab ozogamicin antibodies and neutralizing antibodies on 
inotuzumab ozogamicin safety, efficacy, and clearance will be examined and descriptively 
summarized. 
 
6.3. PK Exposure-Response for Efficacy and Safety Endpoints 
Analysis of bioanalytical measures for inotuzumab ozogamicin (and unconjugated calicheamicin, 
if possible) will be performed using a nonlinear mixed effects model and a previously defined 
base model structure of drug disposition which accounts for the nonlinear drug disposition which 
has been observed following inotuzumab ozogamicin administration. 
 
Using a Bayesian post-hoc approach, individual patient PK parameters based on the final 
population PK model and individual patient contributions to the model may be generated. These 
parameters would serve as input for PK predictions and for exposure response analyses with 
respect to key safety (e.g., VOD, ALT, AST, bilirubin) and efficacy (CR/CRi, MRD-negativity) 
endpoints. 
 
The results of population PK analysis and exposure response analyses with respect to safety and 
efficacy endpoints of interest will be provided separately as part of a population modeling 
analysis report. However, the exposure response analyses described previously will be only 
performed if the study moves into its randomized phase. 
 
The listings and descriptive statistics for the observed concentrations of the inotuzumab 
ozogamicin and unconjugated calicheamicin by dose level, cycle, day, and nominal time will be 
provided as part of the CSR. 
 
6.4. Subset Analyses 
Subgroup analysis for safety will be conducted for all patients in the HSCT safety population as 
well as only patients who undergo HSCT directly without new induction therapy. 
 
6.5. Baseline and Other Summaries 
6.5.1. Baseline Summaries 
Baseline demographic and baseline variables will be summarized for ITT population. 
 
6.5.1.1. Demographic and Baseline Characteristics 
1. Demographic characteristics will be summarized for Dose Level 2 (run-in), Dose Level 1 
(randomized), Dose Level 2 (randomized), and overall. Age categories to display are ≥18 to 
<45 years, ≥45 to 65 years, and ≥65 years. 
 
2. Enrollment geographical region and country will be summarized for Dose Level 2 (run-in), 
Dose Level 1 (randomized), Dose Level 2 (randomized), and overall. 


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3. Baseline physical measurement (including height, body weight, BMI, and BSA) will be 
summarized for Dose Level 2 (run-in), Dose Level 1 (randomized), Dose Level 2 
(randomized), and overall, according to Pfizer data standards. 
 
4. Baseline VOD risk factors and ECOG performance status will be summarized using number 
and percentage for Dose Level 2 (run-in), Dose Level 1 (randomized), Dose Level 2 
(randomized), and overall. 
 
6.5.1.2. Medical History 
Significant medical history and medical history for hepatic medical conditions will be 
summarized for Dose Level 2 (run-in), Dose Level 1 (randomized), Dose Level 2 (randomized), 
and overall according to Pfizer data standards. 
 
6.5.1.3. Disease Characteristics 
1. Duration since onset (months) will be summarized using descriptive statistics for Dose Level 
2 (run-in), Dose Level 1 (randomized), Dose Level 2 (randomized), and overall. 
 
2. Baseline local/central CD22 expression (%) will be summarized using descriptive statistics 
for Dose Level 2 (run-in), Dose Level 1 (randomized), Dose Level 2 (randomized), and 
overall. 
 
3. Baseline cytogenetics listed below will be summarized using number and percentage for 
Dose Level 2 (run-in), Dose Level 1 (randomized), Dose Level 2 (randomized), and overall. 
 
• Total number of metaphases analyzed in categories of ≥20, ≥10 to <20, <10, and 
missing/unknow, 
 
• Karyotype per local lab (normal, abnormal, not evaluable, missing), and 
 
• Chromosomal abnormality for Ph+, t(4:11), and others. 
 
6.5.1.4. Prior Anti-Cancer Therapies 
The following categories will be summarized using number and percentage for Dose Level 2 
(run-in), Dose Level 1 (randomized), Dose Level 2 (randomized), and overall: 
 
• Salvage status (derived): 1, 2, 3, 4, 5, etc (derived based on the number of relapses and 
treatment failures of prior induction therapies) 
 
• Prior induction therapy for primary diagnosis: yes, no, 
 
• Number of regimens: 1, 2, 3, etc. 
 
• Prior radiation therapy for primary diagnosis: yes, no, 


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• Responses to most recent prior induction regimen, to first induction regimen, to prior 
induction regimen 2: CR, PR, treatment failure, N/A (adjuvant only), 
 
• Duration of first remission: <12 months and ≥12 months. 
 
6.5.2. Study Conduct and Patient Disposition 
6.5.2.1. Patient Disposition 
1. The number of randomized participants in the below analysis sets/populations (defined in 
Section 4) will be summarized for Dose Level 2 (run-in), Dose Level 1 (randomized), Dose 
Level 2 (randomized), and overall according to Pfizer data standards, 
 
• ITT population, 
 
• PP population, 
 
• Safety population, 
 
• Post-HSCT safety population, 
 
• PK population, 
 
• Immunogenicity population. 
 
2. Patient disposition at screening, end of treatment, and disease/survival follow-up will be 
summarized for Dose Level 2 (run-in), Dose Level 1 (randomized), Dose Level 2 
(randomized), and overall, according to Pfizer data standards. 
 
3. Medication errors will be listed according to Pfizer data standards. 
 
6.5.2.2. Protocol Deviations 
Protocol deviations will be compiled prior to database closure and will be summarized by 
categories (number and percentage) for Dose Level 2 (run-in), Dose Level 1 (randomized), Dose 
Level 2 (randomized), and overall, according to Pfizer data standards. Categories will be 
assigned by the study clinician. 
 
6.5.3. Study Treatment Exposure 
Exposure will be summarized for the safety population. 
 
6.5.3.1. Exposure to Inotuzumab Ozogamicin 
1. Number of cycles started and duration of treatment (weeks) will be summarized using 
descriptive statistics for Dose Level 2 (run-in), Dose Level 1 (randomized), and Dose Level 2 
(randomized). Number and percentage will be provided for 
 
• 
Duration categories (weeks): 0 -<4, 4 -<8, 8 -<12, 12 -<16, 16 -<20, 20 -<24, and >24, 


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• Cycle number categories: any cycle, 1 cycle, 2 cycles, 3 cycles, 4, cycles, ≥5 cycles. 
 
2. The actual overall dose (mg/m2), actual dose intensity (mg/m2/cycle) and the relative dose 
intensity (%) of inotuzumab ozogamicin will be summarized using descriptive statistics for 
Dose Level 2 (run-in), Dose Level 1 (randomized), and Dose Level 2 (randomized). 
 
6.5.3.2. Dose Reductions and Delays 
Number and percentages will be provided for patients with dose reduction and dose delay for 
Dose Level 2 (run-in), Dose Level 1 (randomized), and Dose Level 2 (randomized). 
 
6.5.4. Concomitant Medications 
Concomitant drug treatments received by patients during the study will be summarized by 
Anatomical Therapeutic Chemical Classification level 2 (ATC2) and preferred term (PT) for 
Dose Level 2 (run-in), Dose Level 1 (randomized), Dose Level 2 (randomized), and overall, 
according to Pfizer data standards. 
6.5.5. Follow-up Systemic Therapies 
The number and percentage of patients with follow-up systemic therapies (overall and induction 
therapy only), and number of regimens (1, 2 , ≥3) , will be provided for Dose Level 2 (run-in), 
Dose Level 1 (randomized), and Dose Level 2 (randomized). 
 
Follow-up systemic therapy (overall and induction therapy only) medications will be coded using 
the WHO Drug coding dictionary and will be tabulated by ACT2 and PT in descending order of 
frequency for Dose Level 2 (run-in), Dose Level 1 (randomized), Dose Level 2 (randomized), 
and overall according to Pfizer data standards. 
 
Follow-up HSCT will be summarized as described in Section 6.2.4. 
 
6.6. Safety Summaries and Analyses 
Safety endpoints will be analyzed by dose level based on the safety population for overall safety, 
the HSCT safety population and subpopulation only including patients who undergo HSCT 
directly without new induction therapy for safety post-HSCT. No adjustment for multiple 
comparisons will be made when analyzing safety endpoints. 
 
6.6.1. Adverse Events 
AEs will be coded using the MedDRA dictionary. Toxicity will be graded according to the NCI 
CTCAE v3.0.  All analyses will be based on treatment emergent events unless otherwise 
specified. Treatment emergent is defined in Section 3.4. AEs not considered treatment emergent 
will be flagged in data listings. 
 
Overview of TEAEs, all causality and treatment-related, will be provided using number and 
percentage for Dose Level 2 (run-in), Dose Level 1 (randomized), and Dose Level 2 
(randomized), and Dose Level 2 (run-in & randomized combined) according to Pfizer data 
standards. 


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Incidence of TEAEs, all causality and treatment-related, during the on-treatment period will be 
summarized for Dose Level 2 (run-in), Dose Level 1 (randomized), and Dose Level 2 
(randomized), and Dose Level 2 (run-in & randomized combined) by 
 
• SOC, PT and maximum CTCAE grade, 
 
• PT and maximum CTCAE grade of any grade in ≥10% patients by the categories of all 
grades and grade ≥3 (in decreasing order based on the observed frequencies of all grades 
in Dose Level 1). 
 
Incidence of TEAEs, all causality and treatment-related, leading to permanent 
discontinuation/dose reduction/ dose interruption of study drug and death will be summarized by 
PT for Dose Level 2 (run-in), Dose Level 1 (randomized), and Dose Level 2 (randomized), and 
Dose Level 2 (run-in & randomized combined). 
 
Incidence of SAEs (all causality and treatment-related) and post-HSCT SAEs will be 
summarized for Dose Level 2 (run-in), Dose Level 1 (randomized), and Dose Level 2 
(randomized), and Dose Level 2 (run-in & randomized combined), by 
 
• SOC and PT, 
 
• PT in ≥10% patients (in decreasing order based on the observed frequencies in Dose 
Level 1). 
 
Each patient will be counted only once within each SOC and PT. 
 
6.6.1.1. Adverse Events of Special Interest 
AEoSI (see Section 3.4.1.2) will be summarized to present the incidence of patients with all- 
causality events for Dose Level 2 (run-in), Dose Level 1 (randomized), and Dose Level 2 
(randomized), and Dose Level 2 (run-in & randomized combined). 
 
6.6.2. Deaths 
The number and percentage of patients in the safety population who died and who died within 63 
days after last dose of study treatment as well as the primary reason for death, will be tabulated. 
 
The date and cause of death will be provided in an individual patient data listing together with 
selected dosing information (study treatment received, date of first/last administration, dose). 
 
6.6.3. Laboratory Data 
Laboratory results will be converted to units using the International System of Units (Système 
International d'unités [SI]) which will be used for applying toxicity grades and for all summaries. 
 
Quantitative data will be summarized by dose level using simple descriptive statistics (mean, 
standard deviation, median, quartiles, minimum, and maximum) of actual values and change 


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from baseline for each nominal visit over time (i.e., unscheduled assessments will be excluded). 
Summary will only include data from local laboratories. The total number of patients for change 
from baseline will include all patients who have both a baseline and a value at the nominal visit. 
 
Results collected as strict inequalities (e.g., >10, <10) will be converted to numeric values 
subtracting a factor of 0.001. Expressions of the form “≥” or “≤” will be converted to the end 
point. These numeric values will be evaluated for clinically significant abnormalities but will not 
be included in calculations of summary statistics. 
 
Laboratory abnormalities will be summarized and programmatically classified according to NCI 
CTCAE v3.0. Additional laboratory results that are not part of NCI CTCAE will be presented 
according to the following categories: below normal limit, within normal limits, and above 
normal limits. All summaries will be based on local laboratory data. 
 
Change from baseline in hematology and chemistry parameters during on-treatment period will 
be summarized using shift tables for Dose Level 2 (run-in), Dose Level 1 (randomized), and 
Dose Level 2 (randomized), and Dose Level 2 (run-in & randomized combined) according to 
Pfizer data standards, 
 
• By maximum CTCAE grade for all grades at baseline to all grades post-baseline, 
 
• By maximum CTCAE grade for Grade ≤2 at baseline to Grade 3 or 4 post-baseline, and 
 
• By worst on-treatment assessment for no CTCAE criteria. 
 
Parameters of liver function test during the on-treatment period will be summarized for Dose 
Level 2 (run-in), Dose Level 1 (randomized), and Dose Level 2 (randomized), and Dose Level 2 
(run-in & randomized combined) according to Pfizer data standards. 
 
A plot showing an evaluation of drug-induced serious hepatotoxicity (eDISH) for liver function 
tests, as defined in Study B1931030, Protocol, Section 8.4, will be presented according to Pfizer 
data standards. 
 
6.6.4. Vital Signs and Physical Examination 
No specific data summaries will be provided for vital signs and physical examinations. Any 
findings considered by the investigator to be ‘clinically significant’ will be recorded as adverse 
events and will be included in the adverse event summaries. 
 
6.6.5. Electrocardiograms 
Triplicate ECGs were required at each assessment. ECG summaries will include all ECG 
assessments during on-treatment period. 
 
Absolute values and changes from baseline in ECG parameters during on-treatment period will 
be summarized for Dose Level 2 (run-in), Dose Level 1 (randomized), and Dose Level 2 
(randomized), and Dose Level 2 (run-in & randomized combined) by the categories, 


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• HR interval: 
 
• ≤50 bpm and decrease from baseline ≥20 bpm, 
 
• ≥220 bpm and increase from baseline ≥20 bpm. 
 
• QTc interval: 
 
• Increase from baseline >30 msec, 
 
• Increase from baseline >60 msec, 
 
• 
>450 to 480 msec, 
 
• 
>480 to 500 msec, 
 
• 
>500 msec. 
 
• QTcB interval: Same as QTc interval. 
 
• QTcF interval: Same as QTc interval. 
 
• QRS complex: 
 
• Increase from baseline >30 msec, 
 
• Increase from baseline >60 msec, 
 
• 
≥120 msec. 
 
• PR interval: ≥220 msec and increase from baseline ≥20 msec. 
 
Values of ECG parameters in the above categories will be listed according to Pfizer data 
standards. 
 
6.6.6. Other Safety Analysis 
Number and percentage of patients with hospitalization from first dose of study treatment until 
the end of Cycle 1 and until the EOT will be provided for Dose Level 2 (run-in), Dose Level 1 
(randomized), and Dose Level 2 (randomized), and Dose Level 2 (run-in & randomized 
combined). 
 
Hospitalization duration from first dose of study treatment until the end of Cycle 1 and until the 
EOT will be summarized using descriptive statistics (mean, standard deviation, median, 
quartiles, minimum, and maximum) for Dose Level 2 (run-in), Dose Level 1 (randomized), and 
Dose Level 2 (randomized), and Dose Level 2 (run-in & randomized combined). 


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7. INTERIM ANALYSES 
This study is designed to have two interim analyses to allow the potential for the study to be 
stopped early due to insufficient efficacy at the lower dose level (1.2 mg/m2/, dose level 2). 
 
The first interim analysis will be performed at the end of Stage 1 of the run-in phase, i.e. after 7 
patients have been enrolled with a minimum of 3 months follow-up from randomization. 
Meanwhile, patient enrollment will continue between Stage 1 and Stage 2 until analyses for 
decision-making are completed. Once ≥3 CR/CRi responders are documented, an additional 15 
enrolled patients will be evaluated in the second interim analysis. If, at the first interim analysis, 
<3 CR/CRi responders are documented for the 7 patients enrolled in Stage 1, patient enrollment 
will be stopped for further evaluation. 
 
As the run-in phase is a Simon Two-Stage optimal design (with 22 patients being enrolled and 
the hypothesis test H10: CR/CRi rate ≤31.2% versus H1a: CR/CRi rate ≥57%), the number of 
enrolled patients and the decision rule for Stage 1 (i.e., the first interim analysis) are set at 7 and 
≥3/7, respectively, so that the expected sample size of the run-in phase will be minimized if dose 
level 2 has insufficient efficacy subject to constraints that the hypothesis test H10 versus H1a for 
the run-in phase will have 80% power to reject H10 with significance level of 0.10 if the true 
CR/CRi rate is 57%. 
 
If the decision is made to proceed after the first interim analysis, enrollment will continue and 
the second interim analysis will be conducted. 
 
The second interim analysis will be performed at the end of the run-in phase, i.e. after a total of 
22 patients have been enrolled with a minimum of 3 months follow-up from randomization. 
Meanwhile, patient enrollment will continue into the randomized phase while the analyses for 
decision-making are being completed. If there are ≥10 CR/CRi responders and ≥7 patients 
achieving MRD-negativity documented among the 22 patients in the run-in phase, patient 
enrollment will further continue until randomized phase has completed. Subsequently, patients in 
the randomized phase will be evaluated in the final analysis. If, at the second interim analysis, 
<10 CR/CRi responders or <7 patients achieving MRD-negativity are documented for the 22 
patients enrolled in the run-in phase, patient enrollment will be stopped for further evaluation. 
 
Based on H1a (i.e., CR/CRi rate ≥57%), the decision rule per CR/CRi is set at ≥10/22 for the 
second interim analysis, so that there will be less than 10% chance of observing <10 responders 
out of 22 patients if the true response rate is at least 57% using the exact binomial distribution. 
 
As the MRD-negativity rate among CR/CRi responders is expected to be ≥70% in the current 
study, the number of patients achieving MRD-negativity among the 22 enrolled patients in the 
run-in phase is expected to be ≥7 if there are ≥10 CR/CRi responders documented in those 
patients. Therefore, the decision rule per MRD-negativity is set at ≥7 patients achieving MRD- 
negativity in the second interim analysis. In addition, there will be 84% probability to observe a 
minimum of 7 patients achieving MRD-negativity if the true MRD-negativity rate is at least 40% 
(per H2a). 


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DoR and safety data will also be analyzed at the end of the run-in phase. 
 
8. REFERENCES 
Brookmeyer R and Crowley J. A Confidence Interval for the Median Survival Time. Biometrics. 
1982:38: 29–41. 
 
Collett D. Modelling Binary Data, London: Chapman & Hall, 1991. 
 
Kalbfleisch RL and Prentice JD. The Statistical Analysis of Failure Time Data, New York: 
Willey, 1980. 


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9. APPENDICES 
Appendix 1. Definitions of Adverse Events of Special Interest 
 
IMPORTANT IDENTIFIED RISKS 
• Grade ≥3 hepatotoxicity and/or serious hepatotoxicity, including VOD/SOS 
 
GRADE ≥3 HEPATOTOXICITY AND/OR SERIOUS HEPATOTOXICITY, INCLUDING 
VOD/SOS AEs will be defined as: 
 
• Grade ≥3 AEs and/or SAEs retrieved by applying the following MedDRA SMQs : 
Cholestasis and jaundice of hepatic origin (SMQs narrow); Hepatic failure, fibrosis, 
cirrhosis, and other liver damage related conditions (SMQs narrow); Hepatitis, non- 
infections (SMQs narrow); Liver related investigations signs and symptoms (SMQs 
narrow and broad) 
 
• Grade ≥3 AEs and/or SAEs encoded to the following MedDRA PTs: Hepatic vein 
occlusion, Hepatic vein thrombosis, Portal vein thrombosis, Budd-Chiari Syndrome, 
Chronic graft-versus-host disease in liver, and Acute graft-versus-host disease in liver 
 
• All AEs encoded to the following MedDRA PTs: Venoocclusive liver disease and 
Venoocclusive disease 
 
• Myelosuppression/cytopenia 
 
MYELOSUPPRESSION/CYTOPENIA AEs will be defined as: 
 
• Any reported PTs retrieved by applying the following MedDRA SMQs: Haematopoietic 
thrombocytopenia (SMQ narrow and broad), Haematopoietic leukopenia (SMQ narrow), 
Haematopoietic erythropenia (SMQ narrow and broad), and Haematopoietic cytopenias 
affecting more than one type of blood cell (SMQ narrow) 
 
INFECTION AEs (not considered a separate risk, but considered to be complications of 
myelosuppression/cytopenia) will be defined as: 
 
• Any reported PTs retrieved by applying the MedDRA SOC: Infections and Infestations 
 
HAEMORRHAGE AEs (not considered a separate risk, but considered to be complications 
of myelosuppression/cytopenia) will be defined as: 
 
• Any reported PTs retrieved by applying the MedDRA SMQ: Haemorrhage terms 
(excluding laboratory terms) (SMQ narrow) 
 
IMPORTANT POTENTIAL RISKS 
• Interstitial lung disease (ILD) 


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INTERSTITIAL LUNG DISEASE AEs will be defined as 
 
• Any reported PTs retrieved by applying the MedDRA SMQ: Interstitial lung disease 
(SMQ narrow) 
 
• All AEs encoded to the following MedDRA PT: Graft versus host disease in lung 
 
• Inflammatory gastrointestinal events 
 
INFLAMMATORY GASTROINTESTINAL EVENT AEs will be defined as 
 
• Any reported PTs retrieved by applying the MedDRA Version SMQ Gastrointestinal 
nonspecific inflammation (SMQ narrow), 
 
• All AEs retrieved by applying the MedDRA higher level term (HLT) Colitis (excluding 
infective) (all paths) and Stomatitis and ulceration (all paths) 
 
• All AEs encoded to the following MedDRA PTs: Oral pain, Oropharyngeal pain, and 
Mucosal inflammation 
 
• Pancreatitis 
 
PANCREATITIS AEs will be defined as 
 
• Any reported PTs retrieved by applying the MedDRA Version SMQ: Acute pancreatitis 
(SMQ narrow) 
 
• All AEs encoded to the following MedDRA PTs: Amylase abnormal, Amylase creatinine 
clearance ratio abnormal, Amylase increased, Lipase abnormal, Lipase increased, Lipase 
urine increased, Pancreatic enzyme abnormality, Pancreatic enzymes abnormal, and 
Pancreatic enzymes increased 
 
• Second primary malignancy 
 
SECONDARY PRIMARY MALIGNANCY AEs will be defined as: 
 
• Any reported PTs retrieved by applying the MedDRA SOC: Neoplasms benign, 
malignant and unspecified (including cysts and polyps). 
 
• Reproductive and developmental toxicity (post exposure during pregnancy and while 
breast feeding) 
 
REPRODUCTIVE AND DEVELOPMENT TOXICITY AEs will be defined as 
 
• Any reported PTs retrieved by applying the following MedDRA SMQs: Termination of 
pregnancy and risk of abortion (SMQ narrow), Fertility disorders (SMQ narrow and 


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broad), Foetal disorders (SMQ narrow and broad), Neonatal disorders (SMQ narrow and 
broad), Congenital, familial, and genetic disorders (SMQ narrow) 
 
• All AEs encoded to the following MedDRA PTs: Pregnancy of partner, Exposure via 
father, Foetal exposure during pregnancy, and Maternal exposure during pregnancy 
 
• Nephrotoxicity 
 
NEPHROTOXICITY AEs will be defined as: 
 
• Any reported PTs retrieved by applying the following MedDRA SMQ: Acute renal 
failure (SMQ narrow and broad) 
 
• Neurotoxicity 
 
NEUROTOXICITY AEs will be defined as 
 
• Any reported PTs retrieved by applying the following MedDRA SMQs: Demyelination 
(SMQ narrow and broad) and Peripheral neuropathy (SMQ narrow and broad) and by 
searching for the following specific PTs under the higher level term: Cranial nerve 
disorders NEC (all paths) 
 
Appendix 2. Analyses to Assess the Impact of COVID-19 Pandemic 
 
The study enrollment started before the COVID-19 pandemic period and the study is ongoing 
during the pandemic period. The following data summaries and analyses may be performed to 
assess the impact of COVID-19 on the trial population and study data. Additional analyses may 
be added in a SAP amendment if they are considered necessary to evaluate the outcome of the 
trial. Details of these summaries and analyses are included in the respective sections. 
 
• A listing of all participants affected by COVID-19 related study disruption. 
 
• A listing of protocol deviations related to COVID-19. 
 
• COVID-19 related AEs and deaths. 
 
• Summary of missing ALL disease assessments due to COVID-19. 
 
If additional analyses are needed to assess the impact of COVID-19 on the trial population and 
the study data, an anchor date will be used as a start date for COVID-19 pandemic related 
periods based on Pfizer guidance and standard operating procedure (SOP): 
 
• For global pandemic reference date: Use the date the World Health Organization designated 
COVID-19 as a global pandemic - March 11, 2020. 


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• For China reference date: Use the date COVID-19 was identified as the causative agent of 
outbreak in Wuhan by the China Center for Disease Control and Prevention - January 9, 
2020. 
 
When producing data summaries intended to show the potential impacts of COVID-19 on the 
study, data will be presented as “before” and “during,” where the anchor date is included in the 
“during” group. 
 
A different anchor date may be used for purposes of regulatory submission should the regulatory 
authority requests.