A Phase 3, Randomized, Open-label, Multicenter Study Comparing Ponatinib Versus Imatinib, Administered in Combination With Reduced-Intensity Chemotherapy, in Patients With Newly Diagnosed Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia (Ph+ ALL)
Phase: PHASE3
Conditions: Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia (Ph+ALL)
Sponsor: Takeda

CLINICAL STUDY PROTOCOL 
NCT Number: 
Study Title: 
Study Number: 
NCT03589326
A Phase 3, Randomized, Open-label, Multicenter Study Comparing 
Ponatinib Versus Imatinib, Administered in Combination With 
Reduced-Intensity Chemotherapy, in Patients With Newly 
Diagnosed Philadelphia Chromosome Positive Acute 
Lymphoblastic Leukemia (Ph+ ALL)
Ponatinib-3001
Protocol Version and Date: 
Version 10.0: 29-October-2021
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1.0 TITLE PAGE
PROTOCOL
A Phase 3, Randomized, Open-label, Multicenter Study Comparing Ponatinib Versus 
Imatinib, Administered in Combination With Reduced-Intensity Chemotherapy, in 
Patients With Newly Diagnosed Philadelphia Chromosome–Positive Acute Lymphoblastic 
Leukemia (Ph+ ALL)
Sponsor: 
Takeda Development Center Americas, Inc.
95 Hayden Avenue
Lexington, MA 02421
USA
617-349-0200
Study Number:
Ponatinib-3001
EudraCT Number:
2018-000397-30
Compound:
Ponatinib
Date:
20 October 2021
Amendment Number:
10
Amendment History:
Date
Amendment Number
Amendment Type 
Region
20 October 2021
10
Substantial
Global
07 May 2021
9
Substantial
Global
10 February 2021
8
Substantial
Global
13 August 2019
7
Substantial
Japan
29 July 2019
6
Substantial
Argentina
23 July 2019
5
Substantial
South Korea
09 May 2019
4
Substantial
Global
06 December 2018
3 
Substantial
South Korea
08 November 2018
2
Substantial
Global
22 May 2018
1
Nonsubstantial
Global
12 March 2018
Initial Protocol
Not applicable
Global
CONFIDENTIAL PROPERTY OF TAKEDA
This document is a confidential communication of Takeda. Acceptance of this document constitutes the agreement 
by the recipient that no information contained herein will be published or disclosed without written authorization 
from Takeda except to the extent necessary to obtain informed consent from those persons to whom the drug may be 
administered. Furthermore, the information is only meant for review and compliance by the recipient, his or her 
staff, and applicable institutional review committee and regulatory agencies to enable conduct of the study.
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CONFIDENTIAL
1.0
ADMINISTRATIVE INFORMATION
1.1
Contacts
A separate contact information list will be provided to each site. See the site operations manual 
for more information.
Serious adverse event (SAE) and pregnancy reporting information is presented in Section 10.0, 
as is information on reporting product complaints. The names and contact information for the 
sponsor’s medical monitor/designee and responsible medical officer are in the site operations 
manual.
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CONFIDENTIAL
1.2
Approval
REPRESENTATIVES OF TAKEDA
This study will be conducted with the highest respect for the individual participants in 
accordance with the requirements of this clinical study protocol and also in accordance with the 
following:

The ethical principles that have their origin in the Declaration of Helsinki.

International Council for Harmonisation (ICH) E6 Good Clinical Practice (GCP):
Consolidated Guideline.

All applicable laws and regulations, including, without limitation, data privacy laws, clinical
trial disclosure laws, and regulations.
SIGNATURES
The signature of the responsible Takeda medical officer and other signatures can be found on the 
signature page.
 MPH
Study Clinical Lead
 Oncology Clinical 
Research
Date
PhD
Study Biostatistics Lead
 Oncology Statistics
Date
 PharmD, PhD
Quantitative Clinical Pharmacology
Date
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CONFIDENTIAL
INVESTIGATOR AGREEMENT
I confirm that I have read and that I understand this protocol, the investigator’s brochure, 
prescribing information, and any other product information provided by the sponsor. I agree to 
conduct this study in accordance with the requirements of this protocol and also to protect the 
rights, safety, privacy, and well-being of study subjects in accordance with the following:

The ethical principles that have their origin in the Declaration of Helsinki.

ICH, E6 GCP: Consolidated Guideline.

All applicable laws and regulations, including, without limitation, data privacy laws and
regulations.

Regulatory requirements for reporting SAEs defined in Section 10.0 of this protocol.

Terms outlined in the clinical study site agreement.

Responsibilities of the investigator (Appendix B).
I further authorize that my personal information may be processed and transferred in accordance 
with the uses contemplated in Appendix C of this protocol.
Signature of Investigator
Date
Investigator Name (print or type)
Investigator’s Title
Location of Facility (City, State/Province)
Location of Facility (Country)
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CONFIDENTIAL
1.3
Protocol Amendment 10 Summary of Changes and Rationale
This section describes the changes to the protocol incorporating Amendment 10. The primary 
reason for this amendment is to: 

Update the efficacy analysis to reflect a change in the sample size for the final analysis from
150 patients to 230 patients.
In addition, the protocol was updated to:

Clarify that patients who achieve minimal residual disease (MRD)-negative status with
incomplete complete remission (CRi) at the end of induction may remain on study drug
treatment, at the investigator’s discretion.

Clarify that for MRD-negative complete remission (CR), the analysis will be based on the
intent-to-treat (ITT) population who have been identified with BCR-ABL1 dominant variants
of p190 or p210.

Provide additional guidance to sites regarding survival follow up assessments, timing for end
of treatment (EOT), reporting of mutation status if available at time of relapse, and the time
period for requiring bone marrow (BM) at EOT.
Minor grammatical, editorial, formatting, and administrative changes not affecting the conduct of 
the study are included in this amendment for clarification and administrative purposes only and 
are not listed in the summary of changes below. 
Protocol Amendment 10
Summary of Changes Since the Last Version of the Approved Protocol
Change 
Number
Sections Affected by 
Change
Description of Each Change and Rationale
Location
Description
Rationale
1.
Section 2.0 Study 
Summary
Section 6.1 Overview 
of Study Design
Section 6.3.1 Duration 
of an Individual 
Patient’s Study
Participation
Section 9.4.15.1 BM 
Aspirate
Section 9.5
Completion of Study 
Treatment (for 
Individual Patients)
Section 9.10 Post-
treatment Follow-Up 
Assessments
Clarified that patients who achieve minimal 
residual disease (MRD)-negative status with 
incomplete complete remission (CRi) at end 
of induction may remain on study drug 
treatment, at the investigator’s discretion.
Provide an option for patients 
who may be benefiting from 
therapy as evidenced by the 
MRD-negative status to 
continue study treatment.
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CONFIDENTIAL
Protocol Amendment 10
Summary of Changes Since the Last Version of the Approved Protocol
Change 
Number
Sections Affected by 
Change
Description of Each Change and Rationale
Location
Description
Rationale
2.
Section 2.0 Study 
Summary
Section 6.3.1 Duration 
of an Individual 
Patient’s Study
Participation
Section 9.10 Post-
treatment Follow-Up 
Assessments
Appendix A Schedule 
of Events Table 2
Clarification that alternative therapies are to 
be collected.
Alternative therapies to be 
collected if available and to 
report possible confounding 
factors of event-free survival 
(EFS) endpoint
3.
Section 6.3.1 Duration 
of an Individual 
Patient’s Study
Participation
Clarified that all patients who discontinue 
study treatment will be followed for survival. 
Patients who discontinued without relapse 
from CR will have investigator-reported 
assessment of relapse, wherever available.
Requirement for analysis of 
key secondary endpoint of 
EFS to follow time to relapse 
from CR and/or death.
4.
Section 2.0 Study 
Summary
Section 7.2 Exclusion 
Criteria
Updated exclusion criterion 16 k to state that 
patients with superficial vein thrombosis
(SVT) may be included after discussion with 
the sponsor’s medical monitor/designee.
SVT has a low association 
rate with deep venous 
thrombosis (DVT). Patients 
with a SVT reported at 
screening, which may or may 
not be catheter-related, that 
has resolved or is manageable 
may be considered after 
discussion and review of 
potential risk factors for DVT 
with the medical monitor.
5.
Section 2.0 Study 
Summary
Section 7.2 Exclusion 
Criteria
Language edited and added for exclusion 
criterion 22 with clarification of minimum 
expectation for repeat testing to specify that 
patients with positive serum pregnancy test 
who have undergone a complete abortion in 
the last 60 days may be included after 
discussion with the sponsor’s medical 
monitor/designee and that if positive, a repeat 
test is to be performed 7 to 14 days later and 
must be significantly lower to insure there is 
no active pregnancy for study eligibility.
Clarify that pregnancy test 
requirements for patients who 
may have undergone a 
complete abortion recently but 
presented with a positive 
pregnancy test must have 
repeat testing and review by 
the medical monitor to ensure 
there is no active pregnancy 
before study entry. 
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Protocol Amendment 10
Summary of Changes Since the Last Version of the Approved Protocol
Change 
Number
Sections Affected by 
Change
Description of Each Change and Rationale
Location
Description
Rationale
6.
Section 8.4 Dose 
Modification 
Guidelines for Safety
Language edited to read "Variation from 
these guidelines should be communicated 
with the medical monitor/designee, ideally 
before implementation, and resulting 
agreements/investigator decisions should be 
recorded in source documents."
Investigators are responsible 
for decisions related to 
discontinuation or variation in 
treatments as determined to be 
in the best interest of the 
patient. These decisions 
should be reported to the 
medical monitoring team in a 
timely manner but will not be 
a protocol deviation based on 
a reporting time period.
7.
Section 8.5 Excluded 
Concomitant 
Medications and 
Procedures
Added an exception to permit use of 
ondansetron if an alternative to the antiemetic 
agent is not feasible and the investigator 
considers this the only suitable medication to 
manage symptoms.
Provide additional guidance to 
sites.
8.
Section 9.7
Discontinuation of 
Treatment With Study 
Drug and Patient 
Replacement
Added the following reasons for study drug 
discontinuation: Failure to achieve CR, 
Failure to achieve MRD-negative, 
Progressive disease, Relapse from CR, 
Hematopoietic stem cell transplantation.
Align with reasons for study 
drug discontinuation cited in 
other sections of the protocol.
9.
Section 9.10 Post-
treatment Follow-Up 
Assessments
Added clarification for sentence "Patients 
who discontinue study treatment without 
relapse from CR, will be followed for 
investigator-reported disease status (eg, 
relapse from CR) and survival, and reporting 
of alternative therapies, wherever available"
Alternative therapies are to be 
collected if available to report 
possible confounding factors 
of EFS endpoint. SOE 
footnote ‘q’ already states this 
is collected.
10.
Section 9.10 Post-
treatment Follow-Up 
Assessments
Added sentence "Date of relapse to be 
reported and noted in source documentation."
The date of relapse is required 
for EFS endpoint assessment, 
and for patients who 
discontinued study treatment 
reporting of later relapse 
should be documented in 
sourced notes to verify date 
and method of reporting
relapse (i.e. bone marrow 
report).
11.
Section 9.10 Post-
treatment Follow-Up 
Assessments
Provided clarification to the sentence: 
"Patients who proceed to alternative therapy 
will also be discontinued from study 
treatment and will be followed for 
investigator-reported disease status (eg, 
relapse from CR) and survival." 
Clarified that date of relapse 
from CR is to be reported for 
EFS endpoint analysis and 
source documentation should 
be noted (i.e. bone marrow 
report)
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Protocol Amendment 10
Summary of Changes Since the Last Version of the Approved Protocol
Change 
Number
Sections Affected by 
Change
Description of Each Change and Rationale
Location
Description
Rationale
12.
Section 13.1.3
Efficacy Analysis
Section 13.2 IA and 
Criteria for Early 
Termination
Updated the efficacy analysis to reflect a 
change in the sample size for the final 
analysis from 150 patients to 230 patients and 
to add statistical testing for the endpoints of 
duration of CR, duration of MRD-negative 
CR, overall response rate and overall 
survival.
Change sample size to 
increase the accuracy, 
stability, and power of the 
primary endpoint analysis and 
specify statistical testing for 
other secondary endpoints that 
may be used to make labeling 
claims.
13.
13.1.3 Efficacy 
Analysis
Added that “for MRD-negative CR, the 
analysis will be based on the ITT population 
who have been identified with BCR-ABL1 
dominant variants of p190 or p210.”
Clarify study population to be 
used for the analysis of MRD-
negative CR.
14.
Section 13.3
Determination of 
Sample Size Figure 
13.a Statistical 
Analysis Schema
Updated Figure 13.a to reflect the change in 
the sample size for the final analysis from 
150 to 230 patients and added footnotes 
describing the analyses that are to be 
conducted if the efficacy boundary is crossed.
Change sample size to 
increase the accuracy, 
stability, and power of the 
primary endpoint analysis and 
specify statistical testing for 
other secondary endpoints that 
may be used to make labeling 
claims.
15.
Section 13.3
Determination of 
Sample Size
Updated the determination of sample size to 
reflect the change in sample size for the final 
analysis from 150 to 230 patients.
Change sample size to 
increase the accuracy, 
stability, and of the primary 
endpoint analysis.
16.
Appendix A Schedule 
of Events Table 2
Updated Footnote b to specify “end-of-
treatment (EOT) is within 30 days after a 
patient has discontinued the study drug (last 
dose).” 
Provide additional guidance to 
sites.
17.
Appendix A Schedule 
of Events Table 2
Updated Footnote c to specify that survival 
follow-up assessments will include patients 
who have been discontinued from study drug 
for any reason.
Provide additional guidance to 
sites.
18.
Appendix A Schedule 
of Events Table 2
Added Footnote z to specify time period for 
requiring bone marrow at EOT.
Provide additional guidance to 
sites.
19.
Appendix E Drugs 
With a Risk of TdP
Updated to align with the July 2021 list of 
drugs with a risk of torsades de pointes.
Provide sites with a current 
list of drugs with a risk of 
torsades de pointes.
20.
Appendix M
Enrollment 
Projections at Primary 
Endpoint Analyses
Updated enrollment projections at primary 
endpoint analyses to reflect the change in 
sample size for the final analysis.
Change sample size to 
increase the accuracy, 
stability, and power of the 
primary endpoint analysis.
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TABLE OF CONTENTS
1.0
ADMINISTRATIVE INFORMATION ...........................................................................2
1.1
Contacts.....................................................................................................................2
1.2
Approval....................................................................................................................3
1.3
Protocol Amendment 10 Summary of Changes and Rationale....................................5
2.0
STUDY SUMMARY ....................................................................................................15
3.0
STUDY REFERENCE INFORMATION ......................................................................24
3.1
Study-Related Responsibilities.................................................................................24
3.2
Principal Investigator/Coordinating Investigator ......................................................24
3.3
List of Abbreviations ...............................................................................................25
3.4
Corporate Identification...........................................................................................28
4.0
INTRODUCTION.........................................................................................................29
4.1
Background .............................................................................................................29
4.1.1
Disease State Background................................................................................29
4.1.2
Ponatinib Design and Mechanism of Action ....................................................31
4.1.3
Ponatinib: Nonclinical to Clinical ....................................................................31
4.2
Rationale for the Proposed Study.............................................................................33
4.2.1
Rationale for Ponatinib in Newly Diagnosed Ph+ ALL....................................33
4.2.2
Ponatinib Dose Rationale.................................................................................33
4.2.3
Rationale for Selection of MRD-Negative CR as Primary Endpoint.................34
5.0
STUDY OBJECTIVES AND ENDPOINTS..................................................................36
5.1
Objectives................................................................................................................36
5.1.1
Primary Objectives ..........................................................................................36
5.1.2
Secondary Objectives ......................................................................................36
5.1.3
Safety Objectives.............................................................................................37
5.1.4
Exploratory Objectives ....................................................................................37
5.2
Endpoints.................................................................................................................37
5.2.1
Primary Endpoint.............................................................................................37
5.2.2
Secondary Endpoints .......................................................................................37
5.2.3
Safety Endpoints..............................................................................................38
5.2.4
PK Endpoint ....................................................................................................38
5.2.5
Exploratory Endpoints .....................................................................................38
6.0
STUDY DESIGN..........................................................................................................39
6.1
Overview of Study Design.......................................................................................39
6.2
Number of Patients ..................................................................................................41
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6.3
Duration of Study ....................................................................................................41
6.3.1
Duration of an Individual Patient’s Study Participation....................................41
6.3.2
End of Study/Study Completion Definition and Planned Reporting..................41
6.3.3
Time Frames for Primary and Secondary Endpoints to Support Disclosures.....41
6.3.4
Total Study Duration .......................................................................................43
6.3.5
Posttrial Access ...............................................................................................43
7.0
STUDY POPULATION................................................................................................43
7.1
Inclusion Criteria .....................................................................................................43
7.2
Exclusion Criteria ....................................................................................................45
8.0
STUDY DRUG .............................................................................................................47
8.1
Study Drug Administration......................................................................................47
8.1.1
Investigational Therapy: Ponatinib...................................................................47
8.1.2
Induction Phase (Cycles 1 Through 3) .............................................................48
8.1.3
Consolidation Phase (Cycles 4 Through 9).......................................................49
8.1.4
Maintenance Phase (Cycles 10 Through 20) ....................................................51
8.1.5
Postcycle 20 Therapy.......................................................................................51
8.2
Reference/Control Therapy: Imatinib.......................................................................52
8.3
Dose Modification Guidelines for Efficacy ..............................................................52
8.3.1
Mandatory Dose Reduction for Response ........................................................52
8.3.2
Loss of Response After Dose Reduction for MRD-Negative CR......................52
8.4
Dose Modification Guidelines for Safety .................................................................52
8.4.1
Ponatinib .........................................................................................................53
8.4.2
Imatinib ...........................................................................................................60
8.5
Excluded Concomitant Medications and Procedures ................................................61
8.6
Permitted Concomitant Medications and Procedures................................................61
8.7
Precautions and Restrictions ....................................................................................62
8.8
Management of Clinical Events ...............................................................................62
8.9
Blinding and Unblinding..........................................................................................63
8.10
Description of Investigational Agent........................................................................63
8.10.1
Ponatinib .........................................................................................................63
8.10.2
Imatinib ...........................................................................................................63
8.11
Preparation, Reconstitution, and Dispensation..........................................................64
8.11.1
Ponatinib .........................................................................................................64
8.11.2
Imatinib ...........................................................................................................64
8.12
Packaging and Labeling...........................................................................................64
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8.12.1
Ponatinib .........................................................................................................64
8.12.2
Imatinib ...........................................................................................................64
8.13
Storage, Handling, and Accountability.....................................................................65
8.13.1
Storage ............................................................................................................65
8.13.2
Handling and Accountability ...........................................................................65
8.13.3
Disposition of Used and Unused Study Drug ...................................................66
8.14
Other Protocol-Specified Materials ..........................................................................66
9.0
STUDY CONDUCT......................................................................................................66
9.1
Study Personnel and Organizations..........................................................................66
9.2
Arrangements for Recruitment of Patients................................................................66
9.3
Treatment Group Assignments.................................................................................66
9.4
Study Procedures.....................................................................................................67
9.4.1
Screening Period Procedures............................................................................67
9.4.2
Informed Consent ............................................................................................67
9.4.3
Enrollment and Randomization........................................................................67
9.4.4
Medical/Surgical History and Demographics ...................................................67
9.4.5
Initial Leukemia Diagnosis ..............................................................................68
9.4.6
Pregnancy Test ................................................................................................68
9.4.7
Physical Examination and ECOG Performance Status......................................68
9.4.8
Eye Examinations............................................................................................68
9.4.9
Vital Signs.......................................................................................................68
9.4.10
CV Risk Assessments ......................................................................................68
9.4.11
Echocardiogram...............................................................................................69
9.4.12
Prior and Concomitant Medications and Procedures.........................................69
9.4.13
AEs .................................................................................................................69
9.4.14
Clinical Laboratory Evaluations.......................................................................69
9.4.15
Disease Assessment.........................................................................................70
9.4.16
Quality of Life and Health Outcomes Measures...............................................72
9.4.17
Medical Resource Utilization Data Collection..................................................72
9.4.18
PK Measurements: Ponatinib...........................................................................72
9.4.19
Changes to Study Procedures Due to COVID-19 Pandemic .............................72
9.5
Completion of Study Treatment (for Individual Patients) .........................................74
9.6
Completion of Study (for Individual Patients)..........................................................74
9.7
Discontinuation of Treatment With Study Drug and Patient Replacement................74
9.8
Withdrawal of Patients From Study .........................................................................75
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9.9
Study Compliance....................................................................................................75
9.10
Post-treatment Follow-Up Assessments ...................................................................75
10.0
ADVERSE EVENTS ....................................................................................................76
10.1
Definitions...............................................................................................................76
10.1.1
PTE Definition ................................................................................................76
10.1.2
AE Definition ..................................................................................................76
10.1.3
SAE Definition................................................................................................76
10.1.4
AEs of Special Interest Definitions ..................................................................77
10.2
Procedures for Recording and Reporting AEs and SAEs..........................................79
10.3
Monitoring of AEs and Period of Observation .........................................................80
10.4
Procedures for Reporting Drug Exposure During Pregnancy and Birth Events.........80
10.5
Procedures for Reporting Product Complaints or Medication Errors (Including 
Overdose) ................................................................................................................80
10.6
Safety Reporting to Investigators, IRBs or IECs, and Regulatory Authorities...........81
11.0
STUDY-SPECIFIC COMMITTEES .............................................................................81
11.1
Steering Committee .................................................................................................81
11.2
Independent Data Monitoring Committee ................................................................81
11.3
Cardiovascular Endpoint Adjudication Committee...................................................82
12.0
DATA HANDLING AND RECORDKEEPING............................................................82
12.1
eCRFs......................................................................................................................82
12.2
Record Retention .....................................................................................................83
12.2.1
Japan Record Retention ...................................................................................83
13.0
STATISTICAL METHODS..........................................................................................84
13.1
Statistical and Analytical Plans ................................................................................84
13.1.1
Analysis Sets ...................................................................................................84
13.1.2
Analysis of Demographics and Other Baseline Characteristics.........................85
13.1.3
Efficacy Analysis.............................................................................................85
13.1.4
Safety Endpoints..............................................................................................91
13.1.5
Exploratory Endpoints .....................................................................................91
13.1.6
PK Analysis (Ponatinib) ..................................................................................93
13.1.7
Safety Analysis................................................................................................93
13.2
IA and Criteria for Early Termination ......................................................................93
13.3
Determination of Sample Size..................................................................................94
13.4
Blinding of Trial Management Team for Data Review.............................................96
14.0
QUALITY CONTROL AND QUALITY ASSURANCE...............................................96
14.1
Study Site Monitoring Visits....................................................................................96
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14.2
Protocol Deviations..................................................................................................96
14.2.1
Japan Protocol Deviations................................................................................97
14.3
Quality Assurance Audits and Regulatory Agency Inspections ................................97
15.0
ETHICAL ASPECTS OF THE STUDY........................................................................97
15.1
IRB and/or IEC Approval ........................................................................................98
15.2
Subject Information, Informed Consent, and Subject Authorization .........................98
15.3
Subject Confidentiality ............................................................................................99
15.4
Publication, Disclosure, and Clinical Trial Registration Policy...............................100
15.4.1
Publication.....................................................................................................100
15.4.2
Clinical Trial Registration..............................................................................100
15.4.3
Clinical Trial Results Disclosure....................................................................101
15.5
Insurance and Compensation for Injury..................................................................101
16.0
REFERENCES............................................................................................................102
LIST OF IN-TEXT TABLES
Table 6.a
Primary and Secondary Endpoints for Disclosures .............................................42
Table 8.a
Induction Phase Treatment (Cycles 1 Through 3)...............................................48
Table 8.b
Consolidation Phase Treatment ..........................................................................50
Table 8.c
Maintenance Phase Treatment............................................................................51
Table 8.d
Dose Modifications for Nonhematologic Drug-Related Adverse Events: 
Ponatinib............................................................................................................53
Table 8.e
Dose Modifications for Hematologic Drug-Related Adverse Events: Ponatinib..56
Table 8.f
Dose Modifications for AOEs: Ponatinib ...........................................................58
Table 8.g
Dose Modifications for Venous Thrombotic/Embolic Events: Ponatinib ............59
Table 13.a
Definitions of Efficacy Response Criteria...........................................................89
LIST OF IN-TEXT FIGURES
Figure 13.a
Statistical Analysis Schema................................................................................95
LIST OF APPENDICES
Appendix A
Schedule of Events...........................................................................................106
Appendix B
Responsibilities of the Investigator...................................................................117
Appendix C
Investigator Consent to Use of Personal Information........................................119
Appendix D
ECOG Scale for Performance Status ................................................................120
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Appendix E
Drugs With a Risk of TdP................................................................................121
Appendix F
Drugs That Inhibit or Induce CYP3A...............................................................130
Appendix G
Copy of Framingham Score..............................................................................131
Appendix H
EQ-5D-5L........................................................................................................132
Appendix I
FACT-Leu .......................................................................................................134
Appendix J
Leucovorin (Folinic Acid) Rescue Therapy for Methotrexate...........................137
Appendix K
Cytarabine Dose Adjustments for Creatinine Clearance Values........................138
Appendix L
Management of Tumor Lysis Syndrome...........................................................139
Appendix M
Enrollment Projections at Primary Endpoint Analyses......................................141
Appendix N
Amendment History.........................................................................................142
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2.0
STUDY SUMMARY
Name of Sponsor: Takeda Development Center Americas, Inc.
Compound:
Ponatinib
Title of Protocol: A Phase 3, Randomized, Open-Label, Multicenter 
Study Comparing Ponatinib Versus Imatinib, Administered in 
Combination With Reduced-Intensity Chemotherapy, in Patients 
With Newly Diagnosed Philadelphia Chromosome–Positive Acute 
Lymphoblastic Leukemia (Ph+ ALL)
EudraCT No.: 2018-000397-30
Study Number: Ponatinib-3001
Phase: 3
Study Design: This phase 3 study is designed as an open-label, multicenter, randomized comparison of the tyrosine 
kinase inhibitors (TKIs) ponatinib versus imatinib, when administered as first-line therapy in patients aged 
≥18 years with newly diagnosed Ph+ ALL. The TKIs will be administered in combination with 20 cycles of a 
reduced-intensity chemotherapy regimen (including 3 cycles of induction therapy, 6 cycles of consolidation therapy, 
and 11 cycles of maintenance therapy), followed by single-agent therapy with ponatinib or imatinib, to be 
administered continuously until patients have completed the study, experienced relapse from complete remission 
(CR) or progressive disease (PD), have an unacceptable toxicity, withdraw consent, proceed to hematopoietic stem 
cell transplant (HSCT) or alternative therapy, or the sponsor terminates the study.
The primary endpoint of this study is minimal residual disease (MRD)-negative CR at the end of induction (defined 
in Table 13.a). Patients who achieve the primary endpoint will continue in the study in the consolidation and 
maintenance phases followed by a single-agent therapy phase. As CR must have been maintained for at least 4 
weeks, patients who do not achieve CR by the end of Cycle 2 will be considered as having failed to achieve the 
primary endpoint (see Table 13.a for definitions). Patients who achieve CR or who achieve MRD-negative status 
with incomplete complete remission (CRi) but do not achieve the primary endpoint at the end of induction may, at 
the investigator’s discretion, continue on study treatment. All patients who do not achieve CR at the end of induction 
will be discontinued from study treatment, with the exception of patients who are MRD-negative and CRi at end of 
induction; these patients may remain on study drug treatment at the investigator’s discretion. For all discontinued 
patients, the patient’s treating physician should consider alternative therapy options.
Upon enrollment, patients will be randomized in a 2:1 ratio of ponatinib:imatinib to be taken throughout the study, 
beginning on Cycle 1 Day 1. Patients randomized to Cohort A (ponatinib) will receive 30 mg of oral ponatinib once 
daily (QD), which will be reduced to 15 mg if MRD-negative CR is achieved at the end of induction. If a patient 
loses MRD negativity after dose reduction to 15 mg, re-escalation to 30 mg may be considered after discussion with 
the sponsor’s medical monitor/designee. Dose reductions to 10 mg of ponatinib QD may be considered for safety 
reasons after discussion with the sponsor’s medical monitor/designee (see Section 8.4.1). For patients in the 
ponatinib cohort who achieve CR but do not achieve the primary endpoint at the end of induction and who continue 
in the study at the investigator’s discretion, the dose of ponatinib will be reduced, as described above, at any later 
time point when the patient achieves MRD-negative CR and re-escalated, as described above, upon loss of response. 
Patients randomized to Cohort B (imatinib) will receive 600 mg of oral imatinib QD. Intrathecal therapy will be 
performed twice per month for the first 6 cycles for central nervous system (CNS) disease prophylaxis. At the end of 
the 20 cycles, all patients remaining on study will continue on ponatinib or imatinib (administered as a single agent).
MRD status will be measured using quantitative polymerase chain reaction–based tests validated for the ability to 
detect breakpoint cluster region-Abelson (BCR-ABL1)/ABL1 levels with a minimal sensitivity of 0.01%, with MRD 
negativity defined as ≤0.01% BCR-ABL1/ABL1. Separate tests will be used to assess the p210 and p190 variants of 
BCR-ABL1 (see Section 4.2.3), which comprise >95% of the variants present in adult patients with Ph+ ALL. For 
the p210 test, BCR-ABL1/ABL1 levels will be reported on the International Scale with traceability to the World 
Health Organization (WHO) first International Genetic Reference Panel. For the p190 test, for which there is no 
internationally available reference material, the raw ratio of BCR-ABL1/ABL1 levels will be reported. To ensure 
uniformity of analysis, all samples will be tested using the same methodology in central laboratories. Assessment of 
the primary endpoint at the end of induction will be based on analysis of bone marrow (BM) samples. To minimize 
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the number and volume of BM aspirates required, and in keeping with available recommendations [1] and evidence 
of general concordance between results [2], assessment of BCR-ABL1/ABL1 levels at other time points may use 
peripheral blood samples. Both sample types will be collected at a subset of time points to allow the levels of 
concordance between sample types to be broadly assessed.
The key secondary endpoint for this study is event-free survival (EFS). Other secondary endpoints will include rates 
of CR and incomplete CR (CRi) at the end of Cycle 1, end of Cycle 2, the end of induction, and during or at the end 
of consolidation (end of Cycle 9 or end of study treatment, whichever occurs earlier); rates of molecular response 3-
log reduction (MR3, BCR-ABL1/ABL1 ≤0.1%), molecular response 4-log reduction (MR4, ≤0.01% BCR-
ABL1/ABL1), and molecular response 4.5-log reduction (MR4.5, BCR-ABL1/ABL1 ≤0.0032%) at the end of Cycle 
1, the end of Cycle 2, the end of induction, and during or at the end of consolidation (end of Cycle 9 or end of study 
treatment, whichever occurs earlier); rates of primary induction failure (PIF) and overall response rate (ORR) at the 
end of induction; rates of MRD-negative CR at multiple intervals after the end of induction; duration of 
MRD-negative CR; duration of CR; time to treatment failure; duration of MR4.5 in patients who achieved MR4.5; 
overall survival (OS) and relapse from CR for on-study patients with and without HSCT, and OS. (See Table 13.a
for endpoint definitions.)
Safety and tolerability parameters will be assessed in both cohorts, including incidence of all adverse events (AEs), 
serious adverse events (SAEs), arterial occlusive events (AOEs), and venous thrombotic/embolic events (VTEs); 
rates of discontinuation, dose reductions, and dose interruptions due to AEs; incidence of death while on treatment, 
and changes from baseline in vital signs and laboratory test results. Plasma concentration-time data will also be 
collected for patients receiving ponatinib.
Exploratory endpoints will include change from baseline in patient-reported quality-of-life and medical resource 
utilization (MRU) assessments; time to start of alternative therapy; time to HSCT; and biomarkers of disease 
sensitivity and resistance to ponatinib and imatinib and/or biomarkers affecting ponatinib efficacy or safety.
Primary Objective:
To compare the efficacy of ponatinib versus imatinib, administered as first-line therapy in combination with 
reduced-intensity chemotherapy, in patients with newly diagnosed Ph+ ALL, as measured by the MRD-negative CR 
rate at the end of induction.
Key Secondary Objectives:

To compare EFS between the 2 cohorts.
Other Secondary Objectives:

To compare the rates of CR and CRi between the 2 cohorts, at the end of Cycle 1, the end of Cycle 2, the end of 
induction, and during or at the end of consolidation (end of Cycle 9 or end of study treatment, whichever occurs 
earlier).

To compare the rates of MR3, MR4, and MR4.5 between the 2 cohorts, at the end of Cycle 1, the end of Cycle 
2, the end of induction, and during or at the end of consolidation (end of Cycle 9 or end of study treatment, 
whichever occurs earlier).

To compare the rates of PIF and ORR between the 2 cohorts, at the end of induction.

To compare rates of MRD-negative CR at multiple intervals after the end of induction.

To determine the duration of MRD-negative CR in each of the 2 cohorts.

To determine the duration of CR in each of the 2 cohorts.

To compare the time to treatment failure between the 2 cohorts.

To compare the duration of MR4.5 between the 2 cohorts, in patients who achieved MR4.5.

To compare outcomes in patients with and without HSCT, between the 2 cohorts.

To compare OS between the 2 cohorts.

To characterize the incidence of AEs, SAEs, AOEs, VTEs, and other safety outcomes of interest in each of the 
2 cohorts, using multiple methods.

To compare the tolerability between the 2 cohorts, including the rates of discontinuation, dose reductions, and 
dose interruptions due to AEs.
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
To collect plasma concentration-time data to contribute to population pharmacokinetic (PK) and 
exposure-response analyses of ponatinib.
Subject Population: Male and female patients with newly diagnosed Ph+ ALL, aged 18 years and older
Number of Patients:
Ponatinib treatment group: Approximately 153-156
Imatinib treatment group (active comparator): Approximately 74-77
Estimated total randomized: Approximately 230
Number of Sites:
Estimated total: Approximately 120 sites in 
up to 35 countries globally
Dose Levels:
Ponatinib: 30 mg QD
Imatinib: 600 mg QD
Route of Administration:
Both ponatinib and imatinib are 
administered by mouth.
Duration of Treatment:
All patients will remain on study drug until they are deceased, have 
failed to achieve the primary endpoint of MRD-negative CR at the 
end of induction (patients who do not achieve the primary endpoint 
may remain on study treatment, at the investigator’s discretion, if 
they have achieved CR or MRD-negative status with CRi at the end 
of induction), have experienced relapse from CR or have progressive 
disease, have an unacceptable toxicity, have withdrawn consent, have 
proceeded to HSCT or alternative therapy, or until the sponsor 
terminates the study, whichever occurs first.
Period of Evaluation:
Study data will be evaluated for 
approximately 3-6 years after enrollment of 
the last patient.
Main Criteria for Inclusion:
1.
Male or female patients aged 18 years or older.
2.
Newly diagnosed Ph+ or BCR-ABL1 positive ALL, as defined by the 2017 National Comprehensive Cancer 
Network guidelines.
3.
Eastern Cooperative Oncology Group (ECOG) performance status ≤2.
4.
Clinical laboratory values as follows, within 30 days before randomization:
a)
Total serum bilirubin ≤1.5× the upper limit of normal (ULN), unless due to Gilbert’s syndrome.
b)
Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≤2.5× the ULN.
c)
Serum creatinine ≤1.5× the ULN and estimated creatinine clearance ≥30 mL/minute (Cockcroft-Gault 
formula).
d)
Serum lipase <1.5× the ULN.
5.
Normal QT interval corrected per Fredericia method (QTcF) on screening electrocardiogram, defined as QTcF 
of ≤450 ms in males or ≤470 ms in females.
6.
Female patients who:
a)
Are postmenopausal for at least 1 year before the screening visit, or
b)
Are surgically sterile, or
c)
If they are of childbearing potential, agree to practice 1 highly effective method of contraception (such as 
any form of hormonal contraception, eg, birth control pills or hormonal intra-uterine device [IUD]) and 
1 additional effective (barrier) method at the same time, from the time of signing the informed consent 
through 1 month after the last dose of study drug or a longer period per any local regulation, eg, 35 days for 
patients in France), or
d)
Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the patient. 
(Periodic abstinence [eg, calendar, ovulation, symptothermal, postovulation methods], withdrawal, 
spermicides only, and lactational amenorrhea are not acceptable methods of contraception. Female and 
male condoms should not be used together.)
7.
Male patients, even if surgically sterilized (ie, status postvasectomy), who:
a)
Agree to practice effective barrier contraception during the entire study treatment period and through 
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120 days after the last dose of study drug, or
b)
Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the patient. 
(Periodic abstinence [eg, calendar, ovulation, symptothermal, postovulation methods], withdrawal, 
spermicides only, and lactational amenorrhea are not acceptable methods of contraception. Female and 
male condoms should not be used together.)
8.
Voluntary written consent must be given before performance of any study-related procedure not part of standard 
medical care, with the understanding that consent may be withdrawn by the patient at any time without 
prejudice to future medical care.
9.
Willingness and ability to comply with scheduled visits and study procedures.
Main Criteria for Exclusion:
1.
Patients with a history or current diagnosis of chronic phase, accelerated phase, or blast phase chronic myeloid 
leukemia.
2.
Prior/current treatment with any systemic anticancer therapy (including but not limited to any TKI) and/or 
radiotherapy for ALL, with the exception of an optional prephase therapy or chemotherapy induction (no more 
than one cycle), which should be discussed with the sponsor’s medical monitor/designee.
3.
Treatment with any investigational products within 30 days before randomization or 6 half-lives of the agent, 
whichever is longer.
4.
Currently taking drugs that are known to have a risk of causing prolonged QTc or torsades de pointes (unless 
these can be changed to acceptable alternatives or discontinued) (Appendix E).
5.
Taking any medications or herbal supplements that are known to be strong inhibitors or strong inducers of 
cytochrome P450 3A4 within at least 14 days before the first dose of study drug (Appendix F).
6.
Uncontrolled active serious infections that could, in the investigator’s opinion, potentially interfere with the 
completion of treatment according to this protocol.
7.
Major surgery within 28 days before randomization (minor surgical procedures such as catheter placement or 
BM biopsy are not exclusionary criteria).
8.
Known seropositive HIV, known active hepatitis B or C infection.
9.
History of acute pancreatitis within 1 year of study screening or history of chronic pancreatitis.
10. Uncontrolled hypertriglyceridemia (triglycerides >450 mg/dL).
11. Diagnosed and treated for another malignancy within 5 years before randomization or previously diagnosed 
with another malignancy and have any evidence of residual disease. Patients with nonmelanoma skin cancer or 
carcinoma in situ of any type are not excluded if they have undergone complete resection.
12. History or presence of clinically relevant CNS pathology such as epilepsy, childhood or adult seizure, paresis, 
aphasia, stroke, severe brain injuries, dementia, Parkinson’s disease, cerebellar disease, organic brain syndrome, 
or psychosis.
13. Clinical manifestations of CNS or extramedullary involvement with ALL other than lymphadenopathy or 
hepatosplenomegaly.
14. Autoimmune disease with potential CNS involvement.
15. Known significant neuropathy of Grade ≥2 severity.
16. Clinically significant, uncontrolled, or active cardiovascular, cerebrovascular, or peripheral vascular disease, or 
history of or active VTE disease, including, but not restricted to:
a)
Complete left bundle branch block.
b)
Right bundle branch block plus left anterior hemiblock, or bifascicular block.
c)
History of or presence of clinically significant ventricular or atrial tachyarrhythmias.
d)
Clinically significant resting bradycardia (<50 beats per minute).
e)
Uncontrolled hypertension (HTN; systolic blood pressure [BP] ≥150 mmHg and/or diastolic BP 
≥90 mmHg). Patients with Stage 2 HTN (systolic BP ≥140 mmHg and/or diastolic BP ≥90 mmHg) should 
be under treatment at study entry per the current American Heart Association guidelines to ensure BP 
control. Patients requiring 3 or more antihypertensive medications should have controlled HTN for the past 
6 months. Isolated elevation(s) of systolic and/or diastolic BP during screening are not exclusionary.
f)
Any history of myocardial infarction, unstable angina, coronary artery disease, cerebrovascular accident, 
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ischemic stroke, or transient ischemic attack. Note: Patients with any history of these events, whether 
considered clinically significant or not, are excluded.
g)
History of congestive heart failure (New York Heart Association class III or IV) or left ventricular ejection 
fraction <40%, within 6 months before randomization.
h)
Symptomatic peripheral vascular disease or history of infarction, including visceral infarction.
i)
History of any revascularization procedure, including the placement of a stent.
j)
Patients with documented significant pleural or pericardial effusions unless they are thought to be 
secondary to leukemia.
k)
Any history of venous thromboembolism, including, but not limited to, deep venous thrombosis (DVT) or
pulmonary embolism within 6 months before randomization; patients with catheter-associated DVTs or 
superficial vein thrombosis, which are considered to be resolved/controlled, may be included after 
discussion with the sponsor’s medical monitor/designee.
17. Poorly controlled diabetes. Patients with preexisting, well-controlled diabetes are not excluded.
18. Known gastrointestinal (GI) disease or GI procedure that could interfere with the oral absorption or tolerance of 
study drug, including difficulty swallowing.
19. Ongoing uncontrolled nausea or vomiting of any severity.
20. Have a significant bleeding disorder unrelated to ALL.
21. Life-threatening illness unrelated to cancer, such as severe CNS, pulmonary, renal, or hepatic disease unrelated 
to cancer.
22. Female patients who are lactating or breastfeeding or have a positive serum pregnancy test during the screening 
period or have a positive urine pregnancy test on Day 1 before the first dose of study drug is administered 

Patients with a positive serum pregnancy test who have undergone a complete abortion in the last 60 days 
may be included after discussion with the sponsor’s medical monitor/designee. If the serum test is positive, 
a repeat test is to be performed 7 to 14 days later and must be significantly lower to insure there is no active 
pregnancy for study eligibility.
23. Any serious medical or psychiatric illness that could, in the investigator’s opinion, potentially interfere with the 
completion of treatment according to this protocol.
24. Admission or evidence of illicit drug use, drug abuse, or alcohol abuse.
Main Criteria for Evaluation and Analyses:
Primary efficacy endpoint: MRD-negative CR (BCR-ABL/ABL1 ≤0.01% and meeting criteria for CR) at the end of 
induction (see Table 13.a).
Key secondary efficacy endpoint:

EFS, defined as the dates of randomization until:
–
Death due to any cause.
–
Failure to achieve CR by the end of induction.
–
Relapse from CR.
Other secondary endpoints (defined in Table 13.a):

CR and CRi rates at the end of Cycle 1, the end of Cycle 2, the end of induction, and during or at the end of 
consolidation (end of Cycle 9 or end of study treatment, whichever occurs earlier).

MR3, MR4, and MR4.5 at the end of Cycle 1, the end of Cycle 2, the end of induction, and during or at the end 
of consolidation (end of Cycle 9 or end of treatment, whichever occurs earlier).

Rates of PIF and ORR at the end of induction.

Rates of MRD-negative CR at multiple intervals after the end of induction.

Duration of MRD-negative CR.

Duration of CR.

Time to treatment failure.

Duration of MR4.5 in patients who achieved MR4.5.

OS and rate of relapse from CR for on-study patients with and without HSCT.
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
OS.
Safety and tolerability endpoints:

Incidence and exposure-adjusted incidence rates of AOEs, VTEs, AEs, and SAEs in each of the 2 cohorts.

Incidence of dose reductions, interruptions, and discontinuations due to AEs in each of the 2 cohorts.

Incidence of death on treatment, in each of the 2 cohorts.

Changes from baseline in vital signs (including systolic and diastolic BP and heart rate) and clinical laboratory 
test results, in each of the 2 cohorts.
PK endpoint:

Plasma concentration-time data to contribute to population PK and exposure-response analyses of ponatinib.
Exploratory endpoints:

Change from baseline in patient-reported quality of life (Functional Assessment of Cancer Therapy – Leukemia 
[FACT-Leu] and EuroQOL-5 Dimension-5 Level [EQ-5D-5L]).

Change from baseline in MRU assessments.

Time to start of alternative therapy.

Time to start of HSCT.

Biomarkers of disease sensitivity and resistance to ponatinib and imatinib and/or biomarkers affecting ponatinib 
efficacy or safety.
Statistical Considerations:
Stratification and Test for MRD-negative CR Primary Endpoint
To adjust for the known confounding factors in the study, patients’ randomization assignments will be stratified 
dependent on the following factor:
Ages: 18 through <45 years; ≥45 through <60 years; and ≥60 years.
Statistical Design Considerations
The standard closed sequential testing procedure will be used for testing the primary endpoint of MRD-negative CR, 
the key secondary endpoint of EFS, and other secondary endpoints (duration of CR, duration of MRD-negative CR, 
ORR, and OS) with one planned interim analysis (IA) and one final analysis (FA) for each. If the hypothesis test on 
the primary endpoint of MRD negative CR is statistically significant at either the IA or FA for MRD-negative CR, 
then the test for EFS and other secondary endpoints will be conducted. Each of these endpoints (MRD-negative CR, 
EFS, and other secondary endpoints) will be tested at a 2-sided alpha level of 0.05. To maintain the type I error 
family wise at 2-sided 0.05 level, the O’Brien-Fleming alpha spending function (the Lan-DeMets method) will be 
used to determine the significance level at the IA or FA for MRD-negative CR; the Gamma Family (-1) alpha 
spending function will be used to determine the significance level at IA and FA for EFS; the other secondary 
endpoints will use the same efficacy boundaries determined by EFS at IA and FA. By employing such closed 
sequential testing procedure, the type I error for the primary endpoint, the key secondary endpoint, and other 
secondary endpoints are strongly controlled.
If the analysis of MRD-negative CR achieves statistical significance at the IA or FA for MRD-negative CR, then 
EFS, duration of CR, duration of MRD-negative CR, ORR, and OS will be tested at the IA or FA for EFS. The 
study will continue to enroll patients to achieve the accrual target of 230 patients for the final analysis for MRD-
negative CR and EFS.
Sample Size Justification:
Assuming an effect size ranging from 20% to 28% (40% to 48% and 20% MRD-negative CR rates for the active and 
control arms, respectively), an upfront committed sample size of approximately 230 patients (approximately 153 
versus 77 for the active and control arms, respectively, based on a 2:1 allocation ratio) will provide 84% to 98% 
power for MRD-negative CR at the final analysis using the efficacy boundary of 0.036 according to the group 
sequential testing procedure with the IA performed using data from 116 patients. The O’Brien-Fleming alpha 
spending function (the Lan-DeMets method), will be implemented to determine the significance level at IA and FA 
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for the primary endpoint, with an overall type I error rate at a 2-sided 0.05 level.
Inference for the key secondary endpoint of EFS will be conducted at α = 5% level only if the primary endpoint is 
met either at IA or FA for the MRD-negative CR. Based on 3-year EFS data observed from various phase 2 studies, 
effect size is assumed as 67% versus 46% for EFS at year 3 for the active and control arms, respectively, or 
HR = 0.516 for non-HSCT patients. The effect size is assumed as 53% and 40% for EFS at year 3 for active and 
control arms, respectively or HR = 0.693 for patients who are undertaking HSCT. Also, it is assumed that 50% and 
45% of patients from active and control arms will undertake HSCT, respectively. Based on simulation studies, 
approximately 230 patients will be enrolled to collect long-term EFS data. Among these 230 patients, approximately 
173 events need to be accumulated at FA so that the power will be approximately 80% for the EFS endpoint. It is 
expected that the time of FA for EFS will be approximately 8.5 years after the first patient has been enrolled.
Interim Analyses:
There will be one IA and possibly an FA in the study for the MRD-negative CR primary endpoint using a group 
sequential testing approach. The IA was performed after the end of induction phase data were collected for 
116 patients. The primary endpoint of MRD-negative CR was first tested at the IA with a 2-sided efficacy boundary 
of 0.022 and will be tested again at the FA with a 2-sided efficacy boundary of 0.036 after the end of induction 
phase data have been collected for 230 patients. If the significance boundary is crossed at the FA for MRD-negative 
CR, there will be testing for EFS and other secondary endpoints at a 2-sided alpha level of 0.05 using a group 
sequential testing approach. 
The analyses for the IA and FA for MRD-negative CR, and the IA for EFS will be carried out by an independent 
statistical team in a manner that maintains the blinding of the study results to the team. The independent data 
monitoring committee (IDMC) will review both efficacy and safety data at the time of the IA, and will inform the 
sponsor’s executive committee of its recommendation.
Dosing Regimen:
Upon enrollment, patients will be randomized in a 2:1 ratio (ponatinib:imatinib) to receive either 30 mg of oral 
ponatinib (QD) or 600 mg of oral imatinib (QD), to be taken throughout the study, beginning on Cycle 1 Day 1. All 
patients will receive reduced-intensity chemotherapy, with an initial induction phase (3 cycles). Patients who 
achieve the primary endpoint at the end of induction will continue in a consolidation phase (6 cycles) and a 
maintenance phase (11 cycles), for a possible total of 20 cycles of reduced-intensity chemotherapy. Patients who do 
not achieve the primary endpoint but have achieved CR at the end of induction may also continue on study treatment 
at the discretion of the investigator. At the end of the 20 cycles, patients will remain on ponatinib or imatinib 
(administered as a single agent).
Dose modifications for ponatinib and imatinib will be performed as per dose modification guidelines (defined in 
detail in the protocol Section 8.3 and Section 8.4). After completing the maintenance phase, patients will continue to 
receive only ponatinib or imatinib as long-term therapy. Patients in each cohort will remain on study treatment until 
they are deceased, have failed to achieve the primary endpoint (patients who do not achieve the primary endpoint 
may remain on study drug, at the investigator’s discretion, if they have achieved CR at the end of induction), have 
experienced relapse from CR or have progressive disease, have an unacceptable toxicity, have withdrawn consent, 
have proceeded to HSCT or alternative therapy, or until the sponsor terminates the study, whichever occurs first.
Note: Dose modification guidelines for efficacy are detailed in the protocol Section 8.3 for ponatinib only. Dose 
modification guidelines for adverse drug reactions are detailed in Section 8.4 for both ponatinib and imatinib; 
investigators should refer to current local prescribing information for all other therapies included in the study. 
Patients who discontinued study treatment without relapse from CR, will be followed for investigator-reported 
disease status (eg, relapse from CR) and survival, and collect alternative therapies, wherever available (see also 
footnote q in the Schedule of Events [SOE]). 
Patients who proceed to HSCT will be discontinued from study treatment but will be followed per the on-study data 
collection schedule as specified in the SOE (Table 2) for post-transplantation data collection, including transplant-
related procedures, investigator-reported disease status (eg, relapse from CR), survival, and the use of post-
transplant treatment (chemotherapy, TKI). Patients who proceed to alternative therapy will also be discontinued 
from study treatment but will be followed for investigator-reported disease status (eg, relapse from CR) and 
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survival. All other patients who discontinue study treatment will be followed for survival as specified in the SOE 
(Table 2).
The following table outlines the study dosing regimens.
Induction Phase Treatment (Three 28-Day Cycles; Study Cycles 1, 2 and 3) a,b
Cohort A
Cohort B
Vincristine: 1.4 mg/m2 IV on Days 1 and 14 (capped at 
2 mg)
Vincristine: 1.4 mg/m2 IV on Days 1 and 14 (capped at 
2 mg)
Dexamethasone: 

Patients aged <60 years: 40 mg PO on Days 1-4 and 
Days 11-14.

Patients aged ≥60 years: 20 mg PO on Days 1-4 and 
Days 11-14.
Dexamethasone:

Patients aged <60 years: 40 mg PO on Days 1-4 and 
Days 11-14.

Patients aged ≥60 years: 20 mg PO on Days 1-4 and 
Days 11-14.
Ponatinib c:
Starting dose: 30 mg QD, starting on Cycle 1 Day 1.
Imatinib c:
Starting dose: 600 mg QD, starting on Cycle 1 Day 1.
Consolidation Phase Treatment (Six 28-Day Cycles; Study Cycles 4 - 9) a,b
Cohort A
Cohort B
Alternating methotrexate and cytarabine:

Methotrexate (odd consolidation cycles 1st, 3rd, 
and 5th) Study Cycles 4, 6 and 8:
–
Patients aged <60 years: 
1000 mg/m2 IV Day 1, 24-h infusion.
–
Patients aged ≥60 years: 
250 mg/m2 IV Day 1, 24-h infusion.
–
Rescue: folinic acid (see Appendix J).

Cytarabine (even consolidation cycles 2nd, 4th, and 
6th) Study Cycles 5, 7 and 9: 
–
Patients aged <60 years: 
1000 mg/m2 q12 h IV, Days 1, 3, and 5, 2-h 
infusion (dose adapted by CrCl; see 
Appendix K).
–
Patients aged ≥60 years:
250 mg/m2 q12 h IV, Days 1, 3, and 5, 
2-h infusion (if the patient has impaired renal 
function, reduce the dose or consider 
discontinuing cytarabine).
Alternating methotrexate and cytarabine:

Methotrexate (odd consolidation cycles 1st, 3rd, 
and 5th) Study Cycles 4, 6 and 8:
–
Patients aged <60 years: 
1000 mg/m2 IV Day 1, 24-h infusion.
–
Patients aged ≥60 years: 
250 mg/m2 IV Day 1, 24-h infusion.
–
Rescue: folinic acid (see Appendix J).

Cytarabine (even consolidation cycles 2nd, 4th, and 
6th) Study Cycles 5, 7 and 9: 
–
Patients aged <60 years: 
1000 mg/m2 q12 h IV, Days 1, 3, and 5, 2-h 
infusion (dose adapted by CrCl; see 
Appendix K).
–
Patients aged ≥60 years:
250 mg/m2 q12 h IV, Days 1, 3, and 5, 
2-h infusion (if the patient has impaired renal 
function, reduce the dose or consider 
discontinuing cytarabine).
Ponatinib c: Start with the last induction phase dose; 
modify dose based on MRD-negative CR results (see 
Section 8.3).
Imatinib c: Start with the last induction phase dose.
Maintenance Phase Treatment (Eleven 28-Day Cycles; Study Cycles 10 - 20)
Cohort A
Cohort B
Vincristine: 1.4 mg/m2 IV injected over 1 minute on 
Day 1 of each maintenance phase cycle (1 injection/mo; 
capped at 2 mg)
Vincristine: 1.4 mg/m2 IV injected over 1 minute on Day 
1 of each maintenance phase cycle (1 injection/mo; 
capped at 2 mg)
Prednisone d:
Patients aged <60 years: 200 mg/d PO on Days 1-5
Prednisone d:
Patients aged <60 years: 200 mg/d PO on Days 1-5
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Patients aged ≥60-69 years: 100 mg/d PO on Days 1-5
Patients aged ≥70 years: 50 mg/d PO on Days 1-5
Patients aged ≥60-69 years: 100 mg/d PO on Days 1-5
Patients aged ≥70 years: 50 mg/d PO on Days 1-5
Ponatinib c: Start with the last consolidation phase dose; 
modify dose based on MRD-negative CR results (see 
Section 8.3).
Imatinib c: Start with the last consolidation phase dose.
Post–Cycle 20 Therapy
Ponatinib monotherapy:
Patients will continue on the last maintenance phase 
dose (or dose modified based on MRD-negative CR 
results) until they are deceased, have experienced 
relapse from CR or have progressive disease, have an 
unacceptable toxicity, have withdrawn consent, have
proceeded to HSCT or alternative therapy, or until the 
sponsor terminates the study, whichever occurs first.
Imatinib monotherapy:
Patients will continue on the last maintenance phase dose 
until they are deceased, have experienced relapse from 
CR or have progressive disease, have an unacceptable 
toxicity, have withdrawn consent, have proceeded to 
HSCT or alternative therapy, or until the sponsor 
terminates the study, whichever occurs first.
Abbreviations: CNS, central nervous system; CR, complete remission; CrCl, creatinine clearance; HSCT, 
hematopoietic stem cell transplant; IV, intravenously; MRD, minimal residual disease; PO, by mouth; q, every; QD, 
once daily.
Note: Alternative dose modifications/schedules may be recommended after discussion with the investigator and 
sponsor’s medical monitor/designee to maximize exposure of study treatment while protecting patient safety.
a Lumbar punctures will be performed to test cerebrospinal fluid for CNS disease on Day 1 and Day 14 of the 3 
induction phase cycles and the first 3 consolidation phase cycles (total: 6 cycles, 12 samples), and additionally as 
clinically indicated.
b CNS prophylaxis will be administered on Day 1 and Day 14 of the 3 induction phase cycles and the first 
3 consolidation phase cycles (total: 6 cycles, 12 intrathecal injections) and comprises a triple intrathecal injection of 
methotrexate, cytarabine, and corticosteroids (recommended: dexamethasone) as per current practice in each center. 
If patients move to the maintenance phase directly from the induction phase or before completing the consolidation 
phase, they will still be required to receive the complete course of intrathecal CNS prophylaxis to complete the total 
of 12 intrathecal injections.
c Ponatinib and imatinib will be dispensed to patients on Day 1 of each cycle.
d Prednisolone can be used instead of prednisone if prednisone is not available.
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3.0
STUDY REFERENCE INFORMATION
3.1
Study-Related Responsibilities
The sponsor will perform all study-related activities with the exception of those identified in the 
clinical study supplier list in the site operations manual. The identified vendors will perform 
specific study-related activities either in full or in partnership with the sponsor.
3.2
Principal Investigator/Coordinating Investigator
Takeda will select a signatory coordinating investigator from the investigators who participate in 
the study. Selection criteria for this investigator will include significant knowledge of the study 
protocol, the study medication, their expertise in the therapeutic area and the conduct of clinical 
research, and study participation. The signatory coordinating investigator will be required to 
review and sign the clinical study report (CSR) and by doing so agrees that it accurately 
describes the results of the study.
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3.3
List of Abbreviations
AE
adverse event
AESI
adverse events of special interest
ALL
chromosome-positive acute lymphoblastic leukemia
ALT
alanine aminotransferase
ANC
absolute neutrophil count
AP
accelerated phase
AOE
arterial occlusive event
AST
aspartate aminotransferase
BCR
breakpoint cluster region
BCR-ABL
breakpoint cluster region-Abelson
BM
bone marrow
BNP
B-type natriuretic peptide
BP
blood pressure
BSA
body surface area
CAD
coronary artery disease
CHF
congestive heart failure
CMH
Cochran-Mantel-Haenszel
CML
chronic myeloid leukemia
CNS
central nervous system
COVID-19
coronavirus disease 2019
CP
chronic phase
CP-CML
chronic phase chronic myeloid leukemia
CR
complete remission (complete response)
CRi
incomplete complete remission
CrCl
creatinine clearance
CRO
contract research organization
CSF
cerebrospinal fluid
CSR
clinical study report
cTnI
cardiac troponin-I
CV
cardiovascular
CVA
cerebrovascular accident
CVEAC
cardiovascular endpoint adjudication committee
DTP
direct-to-patient
CYP
cytochrome P450
DVT
deep venous thrombosis
ECG
electrocardiogram
ECHO
echocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic case report form
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EDC
electronic data capture
EFS
event-free survival
EMA
European Medicines Agency
EOT
end of treatment
EQ-5D-5L
EuroQOL-5 Dimension-5 Level
ESMO
European Society for Medical Oncology
FA
final analysis
FACT-Leu
Functional Assessment of Cancer Therapy – Leukemia
FDA
Food and Drug Administration
GCP
Good Clinical Practice
GI
gastrointestinal
HR
hazard ratio
HbA1c
glycosylated hemoglobin
HDPE
high-density polyethylene
HLT
High Level Term
HRQOL
health-related quality of life
HSCT
hematopoietic stem cell transplantation
HTN
hypertension
hyper-CVAD
hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone
IA
interim analysis
IC50
half-maximal inhibitory concentration
ICF
informed consent form
ICH
International Council for Harmonisation
IDMC
independent data monitoring committee
IEC
independent ethics committee
IS
International Scale
IRB
institutional review board
IRT
interactive response technology
ITT
intent-to-treat
K-M
Kaplan-Meier
LBBB
left bundle branch block
LVEF
left ventricular ejection fraction
MaHR
major hematologic response
MCyR
major cytogenetic response
MedDRA
Medical Dictionary for Regulatory Activities
MHRA
Medicines and Healthcare products Regulatory Agency
MI
myocardial infarction
MR3
molecular response 3-log reduction (BCR-ABL1/ABL1 ≤0.1%)
MR4
molecular response 4-log reduction (BCR-ABL1/ABL1 ≤0.01%)
MR4.5
molecular response 4.5-log reduction (BCR-ABL1/ABL1 ≤0.0032%)
MRD
minimal residual disease
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MRU
medical resource utilization
NCCN
National Comprehensive Cancer Network
NCI CTCAE
National Cancer Institute Common Terminology Criteria for Adverse Events
NT-proBNP
N-terminal pro-brain natriuretic peptide
ORR
overall response rate
OS
overall survival
PCR
polymerase chain reaction
PD
progressive disease (disease progression)
Ph+ ALL
Philadelphia chromosome–positive acute lymphoblastic leukemia
PIF
primary induction failure
PK
pharmacokinetic
PMDA
Pharmaceuticals and Medical Devices Agency of Japan
PP
per-protocol
PO
by mouth (orally)
PT
Preferred Term
PTE
pretreatment event
QD
once daily
qPCR
quantitative polymerase chain reaction
QTcF
QT interval corrected per Fredericia method
rSDR
remote source data review
rSDV
remote source data verification
SAE
serious adverse event
SAP
statistical analysis plan
SOC
System Organ Class
SOE
Schedule of Events
SUSARs
suspected unexpected serious adverse reactions
TdP
torsades de pointes
TEAE
treatment-emergent adverse event
TIA
transient ischemic attack
TKI
tyrosine kinase inhibitor
TLS
tumor lysis syndrome
UK
United Kingdom
ULN
upper limit of normal
URL
upper reference limit
US
United States
VTE
venous thrombotic/embolic event
WBC
white blood cell
WHO
World Health Organization
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3.4
Corporate Identification
TDC Americas
Takeda Development Center Americas, Inc
TDC Japan
Takeda Development Center Japan
TDC Asia
Takeda Development Center Asia, Pte Ltd
TDC Europe
Takeda Development Centre Europe Ltd
TDC
TDC Japan, TDC Asia, TDC Europe and/or TDC Americas, as applicable
Takeda
TDC Japan; TDC Asia; TDC Europe and/or TDC Americas; as applicable
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4.0
INTRODUCTION
4.1
Background
4.1.1
Disease State Background
4.1.1.1
Ph+ ALL
Philadelphia chromosome–positive acute lymphoblastic leukemia (Ph+ ALL) is a rare 
malignancy of the blood and bone marrow (BM), constituting approximately 20% to 30% of 
adult ALL [3,4]. ALL occurs at an age-adjusted incidence in the United States (US) of 1.58 per 
100,000 individuals per year. In 2014, the estimated prevalence of Ph+ ALL was approximately 
16,367 to 24,551 (20% to 30% of total ALL prevalence in 2014). Ph+ ALL is mainly a disease of 
adults, accounting for only approximately 3% of pediatric cases of ALL [3,4].
Ph+ ALL results from a translocation of chromosomes 9 and 22, referred to as the Philadelphia 
chromosome, which leads to the fusion of the breakpoint cluster region (BCR) coding sequence 
with the tyrosine kinase coding region of Abelson1 (ABL1). The consequence is expression of a 
BCR-ABL1 fusion oncoprotein with constitutive activation of ABL1 tyrosine kinase activity, 
which in turn activates cell signaling pathways promoting cell proliferation and survival. The 
constitutive ABL1 kinase activity is both necessary and sufficient for induction of both Ph+ ALL 
and chronic myeloid leukemia (CML) [5].
4.1.1.2
Treatment for Ph+ ALL
Ph+ ALL has been historically associated with very poor prognosis [6]. Before the introduction 
of tyrosine kinase inhibitors (TKIs), the outcome of treatment for patients with Ph+ ALL was 
poor. While treatment with chemotherapy alone (in the absence of a TKI) resulted in complete 
remission (CR) in many patients initially (45% to 90%), the median duration of CR was short 
(approximately 10 months), and most patients later relapsed, leading to few long-term survivors 
[7-9].
The National Comprehensive Cancer Network (NCCN) guidelines [4] contain widely accepted 
recommendations for the treatment of Ph+ ALL in the US. NCCN guidelines first recommend 
treatment of Ph+ ALL patients in a clinical study. If that is not possible, the guidelines then 
generally recommend first-line treatment of Ph+ ALL with a TKI, along with chemotherapy 
(which usually includes vincristine, and may also include doxorubicin or daunorubicin and/or 
cyclophosphamide) and/or a steroid (generally dexamethasone or prednisone). Similarly, the 
European Society for Medical Oncology (ESMO) has published clinical practice guidelines for 
treating Ph+ ALL in adults with TKIs; ESMO recommends that a TKI should be administered 
continuously and should be combined with chemotherapy in front-line therapy [10]. Central 
nervous system (CNS) prophylaxis is also recommended to be administered throughout 
treatment. HSCT is performed in some patients, depending on factors such as availability of a 
suitable donor and the suitability of the patient to withstand the procedure. HSCT, however, may 
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have some limitations, as it is an option for only a limited number of patients (particularly 
younger patients) and is associated with significant rates of both mortality and relapse [9].
4.1.1.3
Use of TKIs and Unmet Medical Need
All regimens recommended by NCCN guidelines [4] include a TKI; however, in the US, no TKI 
has yet received regulatory approval for newly diagnosed Ph+ ALL in adult patients. In the US, 
imatinib (a first-generation BCR-ABL1 TKI) is approved for pediatric patients with newly 
diagnosed Ph+ ALL in combination with chemotherapy and for relapsed or refractory Ph+ ALL 
in adult patients; dasatinib (a second-generation BCR-ABL1 TKI) is approved for adults with 
Ph+ ALL with resistance or intolerance to prior therapy; and ponatinib (a third-generation 
BCR-ABL1 TKI) is approved for adult patients with Ph+ ALL for whom no other TKI therapy is 
indicated or who are T315I–mutation-positive.
First-line use of first- or second-generation TKIs in combination with chemotherapy results in 3-
and 5-year overall survival (OS) rates of approximately 46% to 56% and 43%, respectively [11-
13]. These relatively modest OS rates are generally due to relapse after achievement of an initial 
CR by hematologic criteria and create opportunity for considerable improvement in the treatment 
of Ph+ ALL. Relapse in Ph+ ALL is generally associated with TKI resistance, which can occur 
by multiple mechanisms. The most common mechanism of resistance to the first- and second-
generation TKIs is single mutations in the ABL1 kinase domain [3,14,15]. While the second-
generation TKIs are more potent inhibitors of BCR-ABL1 compared with imatinib and have 
inhibitory activity against most imatinib-resistant mutations, several mutations such as T315I, 
V299L, and F317L are also resistant to dasatinib [4]. Of these, the T315I mutation is the most 
common mutation associated with resistance to both imatinib and dasatinib [14,15]. In one study 
with dasatinib, the T315I mutation was observed in 75% of relapsed patients on whom mutation 
analysis by Sanger sequencing was performed [15].
Rationale therefore exists that there is an unmet medical need for a more potent TKI that can 
suppress the development of mutations and is also active against the single mutations associated 
with resistance to the early generation TKIs. This more potent TKI could result in deeper and 
more durable responses in the first-line treatment of Ph+ ALL compared with the earlier 
generation TKIs.
There also remains an unmet medical need for effective treatment regimens in older patients with 
Ph+ ALL and in patients who are unable to tolerate intensive chemotherapy regimens. Increasing 
age is a risk factor for the development of Ph+ ALL, and generally the older the patient, the 
worse the prognosis [4,14,16]. In older patients (aged ≥65 years), NCCN guidelines recommend 
either reduced-intensity chemotherapy or no chemotherapy (steroid only) in combination with a 
TKI. Even among younger adults, the use of a TKI along with reduced-intensity chemotherapy 
may have a more favorable benefit-risk profile compared with more intensive regimens such as 
hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone 
(hyper-CVAD). The combination of a more potent TKI (ponatinib) with a chemotherapy 
regimen that is more intensive than steroids but less intensive than chemotherapy such as 
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hyper-CVAD, may be a good option for the first-line treatment of Ph+ ALL and warrants further 
investigation in a broad Ph+ ALL patient population.
In summary, the increased potency of ponatinib compared with the early generation TKIs, along 
with ponatinib’s activity toward the single mutations associated with resistance to the early 
generation TKIs and its ability to suppress the development of resistance mutations, forms the 
rationale for the use of ponatinib in combination with less intensive chemotherapy in the 
treatment of first-line Ph+ ALL in this phase 3 study.
4.1.2
Ponatinib Design and Mechanism of Action
Ponatinib is the product of a computational and structure-based approach to the design of a 
small-molecule TKI [17]. Ponatinib was designed to optimally inhibit native BCR-ABL1 and 
mutant forms of the protein that cause resistance to other TKIs, including the T315I gatekeeper 
mutation that confers resistance to all approved BCR-ABL1 inhibitors other than ponatinib 
(ie, imatinib, nilotinib, dasatinib, and bosutinib).
A critical feature of ponatinib’s design is the incorporation of multiple contact points with the 
ABL1 kinase domain, which balances and distributes overall binding affinity [18]. This leads not 
only to high-affinity binding to ABL1, but also renders binding less susceptible to disruption by 
any single amino acid mutation. A second critical structural feature is a carbon-carbon triple 
bond linkage that allows ponatinib to make a productive hydrophobic contact with the bulky 
isoleucine residue present in the T315I mutation rather than being sterically hindered by it.
Through direct inhibition of native BCR-ABL1 and its variants, ponatinib inhibits aberrant 
downstream signaling by reducing phosphorylated CRKL (pCRKL), thereby promoting 
apoptosis and cell death in BCR-ABL1–positive cells [17].
4.1.3
Ponatinib: Nonclinical to Clinical
Nonclinical studies have demonstrated that ponatinib potently inhibits native BCR-ABL1, and all 
single-mutation variants, at clinically relevant concentrations [17,19]. In a cell line expressing 
native BCR-ABL1, ponatinib inhibited viability with a half-maximal inhibitory concentration 
(IC50) <1 nM, which is more than 200-fold lower than that of imatinib. Ponatinib also potently 
inhibited viability (with IC50s <40 nM) of cell lines expressing 14 major clinically observed 
imatinib-resistant BCR-ABL1 mutations, including T315I. Ponatinib exhibited potent in vivo 
activity in 2 mouse tumor models expressing the T315I mutation of BCR-ABL1. Using an in 
vitro mutagenesis screen approach that has successfully predicted mutations that confer clinical 
resistance to imatinib and nilotinib and dasatinib [20], a concentration between 20 nM and 
40 nM of ponatinib was found to suppress the emergence of any resistant BCR-ABL1 mutation 
[17].
While nonclinical studies have shown that no single BCR-ABL1 mutation can cause resistance 
to ponatinib, it has been shown that certain compound mutations (2 mutations in the same 
BCR-ABL1 protein) can confer resistance [17,21]. For example, the presence of a T315I 
mutation on the same allele with Y253H or E255K can confer nonclinical resistance to 
ponatinib, though ponatinib is able to inhibit each of those mutants individually. Development of 
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compound mutations is a risk associated with sequential use of BCR-ABL1 TKIs [22], whereby 
expansion of a leukemic progenitor cell that has a single resistance mutation provides a template 
on which a second mutation can develop.
The association between ponatinib efficacy and BCR-ABL1 mutation status in patients has been 
studied most extensively in the phase 2 PACE study (Study AP24534-10-201), the pivotal study 
upon which full marketing approval was granted by the US Food and Drug Administration 
(FDA) for the indications described in the current Iclusig label. The PACE study enrolled 
449 heavily pretreated patients, including 267 patients with chronic phase CML (CP-CML) and 
32 patients with Ph+ ALL [23]. All patients previously had been treated with at least 1 approved 
BCR-ABL1 inhibitor, with the majority having been treated with 3 or more. A starting dose of 
45 mg was used, which was the recommended dose established in the phase 1 study 
(Study AP24534-07-101) [24].
Though response rates were high in heavily pretreated patients with CP-CML or Ph+ ALL, 
long-term outcomes differed substantially [23]. Among patients with CP-CML, 56% of patients 
achieved the primary endpoint of a major cytogenetic response (MCyR), and these responses 
were durable: The estimated rate of a sustained MCyR for at least 12 months was 91%. Among 
patients with Ph+ ALL, 41% achieved the primary endpoint of a major hematologic response 
(MaHR); however, these responses were not durable: The estimated rate of a sustained MaHR of 
at least 12 months was 8%. It is important to note that short- and long-term outcomes in patients 
with CP-CML and Ph+ ALL could be rationalized based on the relationship between 
BCR-ABL1 mutation status and ponatinib efficacy, as assessed in these patients.
First, analysis of efficacy based on baseline mutation status demonstrated that high response 
rates were observed in patients regardless of BCR-ABL1 mutation status (ie, in patients with or 
without BCR-ABL1 mutations), and responses were observed for each of the 15 mutations 
present in more than 1 patient with CP-CML at baseline. Thus, high initial response rates 
observed in patients with CP-CML and Ph+ ALL are likely explained by the ability of ponatinib 
to potently inhibit native and single-mutation variants of BCR-ABL1 that exist before ponatinib 
therapy and which constitute most of the leukemic cell population.
Second, analysis of BCR-ABL1 mutation status at the end of ponatinib treatment revealed that 
the acquisition of compound mutations was rare in patients with CP-CML but common in 
patients with Ph+ ALL treated with ponatinib [23,25]. Among 130 patients with CP-CML, 
19 patients (15%) were found to have acquired any mutation at the end of treatment (EOT) that 
was not detected at baseline, and 4 patients (3%) were found to have acquired a compound 
mutation. In contrast, among 20 patients with Ph+ ALL, 13 patients (65%) were found to have 
acquired any mutation, and 12 patients (60%) were found to have acquired a compound 
mutation. In all the patients who acquired a compound mutation, 1 of the mutations was detected 
at baseline.
In summary, nonclinical and clinical data consistently indicate that ponatinib is a highly potent 
and a “pan” BCR-ABL1 inhibitor, defined as having the ability to inhibit all single BCR-ABL1 
mutations. This likely explains the high degree of efficacy initially observed in patients with 
CP-CML and Ph+ ALL, even if they had been heavily pretreated. However, certain compound 
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mutations, which emerge during prior treatment with a non–pan-BCR-ABL1 inhibitor, can 
confer resistance to ponatinib. Development of compound mutations is common in Ph+ ALL but 
not in CP-CML, likely explaining the durable response induced by ponatinib in heavily 
pretreated patients with CP-CML but not in patients with Ph+ ALL.
4.2
Rationale for the Proposed Study
4.2.1
Rationale for Ponatinib in Newly Diagnosed Ph+ ALL
As described previously (Section 4.1.1.3), in newly diagnosed patients with Ph+ ALL treated 
with first- or second-generation TKIs, the development of secondary resistance mutations in 
BCR-ABL1 is strongly associated with disease progression. When these patients with relapsed or 
refractory Ph+ ALL are then treated with ponatinib, many have developed a second (compound) 
mutation in BCR-ABL1. Some of these compound mutations may be resistant to ponatinib and 
to the first- and second-generation TKIs. Options for further treatment with TKIs are then 
exhausted.
The rationale for use of ponatinib in the first-line treatment of Ph+ ALL is that, by suppressing 
all single BCR-ABL1 resistance mutations, the predominant mechanism by which a leukemic 
cell is expected to develop a BCR-ABL1-mediated mechanism of resistance to ponatinib would 
be to develop 2 independent mutations simultaneously. The decreased likelihood of this 
occurring in patients only treated with ponatinib, compared with patients treated with a first- or 
second-generation TKI and then ponatinib, leads to the hypothesis of more durable responses in 
patients with newly diagnosed Ph+ ALL treated with ponatinib compared with sequential 
treatment with first- or second-generation TKIs followed by ponatinib.
On the basis of this rationale, the data summarized in Section 4.1.3, and the greater potency of 
ponatinib compared with the earlier generation TKIs, the sponsor hypothesizes that ponatinib 
treatment in patients with newly diagnosed Ph+ ALL will lead to superior outcomes compared 
with those treated with first- or second-generation TKIs. In contrast to heavily pretreated patients 
with Ph+ ALL, where long-term outcomes were limited by development of compound resistance 
mutations, this is not expected to be the case in newly diagnosed patients. Preliminary clinical 
data are consistent with this hypothesis.
Ph+ ALL is a fast and aggressive disease for which the long-term prognosis remains poor, even 
when treated with the first- and second-generation TKIs. An improvement in long-term outcome 
may justify the risk of using a more potent TKI (ponatinib) in patients with newly diagnosed 
Ph+ ALL. Furthermore, if clinical data suggest that a more potent TKI could allow for the use of 
less intensive chemotherapy, the first-line use of ponatinib in adult patients with newly 
diagnosed Ph+ ALL may be additionally justified.
4.2.2
Ponatinib Dose Rationale
Clinical information on the safety and efficacy of different doses of ponatinib comes from 
multiple sources which, taken together, led to the selection of 30 mg as the starting dose for this 
protocol, with a dose reduction to 15 mg upon achievement of minimal residual disease 
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(MRD)-negative CR and re-escalation to 30 mg if response is lost, as permitted by safety and 
tolerability in individual patients. Although a starting dose of 45 mg is recommended in the 
current prescribing information for ponatinib, it is acknowledged that the optimal dose of 
ponatinib remains to be defined; this is the objective of an ongoing, phase 2, dose-ranging study 
(Study AP24534-14-203) evaluating the efficacy and safety of starting doses of 15 mg, 30 mg, or 
45 mg once daily (QD) in patients with resistant CP-CML. The proposed starting dose of 30 mg 
QD for the current protocol is based upon consideration of the expected superior benefit-risk 
balance at 30 mg versus 45 mg, informed by previously conducted dose intensity-response 
analyses of data from the completed Studies AP24534-07-101 and AP24534-10-201.
Logistic regression analyses of dose intensity-AE relationships in patients with CP-CML in the 
phase 2 Study AP24534-10-201 indicated a dose-dependent increase in AEs, and notably in 
arterial occlusive event (AOE) rates, which are of specific importance for ponatinib. Dose 
intensity was a statistically significant predictor of AOE rates in that multivariate analysis after 
adjustment for known cardiovascular (CV) risk factors, leading to the expectation that the 30 mg 
QD dose will have a superior safety profile compared with 45 mg QD, thus supporting 30 mg 
QD selection as the starting dose.
In addition, a dose intensity-efficacy logistic regression analyses in Study AP24534-10-201 
demonstrated a statistically significant relationship between dose intensity and the probability of 
achieving MCyR at 12 months. These analyses clearly indicated that 30 mg (versus 15 mg) is 
within the dynamic range of the inferred dose-response relationship, with the estimated 
probability of MCyR by 12 months at 30 mg (~60%) being meaningfully greater than at 15 mg 
(~25%), and both the 30 mg and 15 mg doses are likely to be biologically active on the basis of 
data that demonstrated average plasma concentrations exceeding the IC50 for all BCR-ABL1 
mutations at the 30 mg dose, and for most BCR-ABL1 mutations at the 15 mg dose. Although a 
direct translation of exposure-efficacy relationships in a resistant CP-CML population to a 
previously untreated Ph+ ALL population is not possible, the estimated dose intensity-efficacy 
relationship in Study AP24534-10-201 nevertheless provides valuable prior information 
regarding expectations of dose-response relationships for efficacy of ponatinib in BCR-ABL1–
driven hematologic malignancies. Accordingly, the results of these analyses provide the 
supporting rationale for selecting the 30 mg QD starting dose for this phase 3 protocol.
4.2.3
Rationale for Selection of MRD-Negative CR as Primary Endpoint
Treatment guidelines for patients with ALL [4] recommend an initial minimal threshold for 
response to be the achievement of a CR (also referred to as complete response), with no 
recurrence for 4 weeks, by the end of the induction phase.
More important, the absence of MRD has been found to have strong long-term prognostic power 
in patients with ALL, with a large body of evidence demonstrating a strong correlation between 
MRD negativity and improved event-free survival (EFS) and OS [4,26]. Consistent with most 
studies, NCCN guidelines recommend that MRD be assessed upon completion of the initial 
induction [4]. MRD assessment relies on accurate and sensitive detection of the relative 
proportion of leukemic cells, with an assay sensitivity of at least 0.01% (ie, the ability to detect 
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1 ALL cell among at least 10,000 normal cells) generally being required to consider a sample to 
be MRD-negative [4,27].
In Ph+ ALL, MRD status can be assessed by detecting the specific genetic abnormality that 
defines the leukemic cells (ie, the presence of the BCR-ABL1 fusion gene transcript). In this 
approach, quantitative polymerase chain reaction (qPCR) is used to measure BCR-ABL1 levels 
(present in leukemic cells) relative to ABL1 levels (present in normal cells and leukemic cells) to 
assess disease levels.
In a meta-analysis that included 5 studies conducted in adult Ph+ ALL patients, MRD negativity 
at the end of induction was associated with significantly improved EFS and OS [26]. In the study 
most pertinent to the phase 3 study described here, Short performed a retrospective analysis to 
test the association between achievement of MRD negativity and long-term outcomes in 85 
patients with newly diagnosed Ph+ ALL treated with 1 of 3 TKIs (imatinib [N = 23], dasatinib 
[N = 39], or ponatinib [N = 23]) and a hyper-CVAD chemotherapy backbone, who did not 
undergo allogeneic stem cell transplantation. In this study, achievement of MRD negativity at 3 
months, which was defined as absence of detectable BCR-ABL1 transcripts with a sensitivity of 
0.01%, was associated with significantly longer OS and relapse-free survival. Importantly, 
though rates of MRD negativity were different according to the TKI (eg, 39% and 87% for 
patients receiving imatinib and ponatinib, respectively), among patients who achieved MRD 
negativity at 3 months, there was no impact on either OS or relapse-free survival according to the 
TKI received [28].
Given the reliance of this test on assessment of the genetic abnormality underlying Ph+ ALL, the 
assay used to assess BCR-ABL1 levels must be able to quantify the variants present in most 
patients with Ph+ ALL. More specifically, differences in the location of the BCR breakpoint 
result in 2 major variants of the BCR-ABL1 fusion transcript [29], which require separate 
polymerase chain reaction (PCR) primers for detection. In the variant present in the majority 
(~75%) of adult patients with Ph+ ALL, the first exon of the BCR gene is fused to the second 
exon of the ABL1 gene, resulting in a fusion transcript that encodes a 190 kDa oncoprotein. 
These are referred to as the e1a2 or p190 variants. In the second most common variant (~25% of 
patients), exons 13 or 14 (also known as exons b2 or b3) of the BCR gene are fused to the second 
exon of the ABL1 gene, resulting in a fusion transcript that encodes a 210 kDa oncoprotein. 
These are referred to as the e13a2 (or b2a2), e14a2 (or b3a2), or p210 variants. Thus, assessment 
of BCR-ABL1 levels in patients with Ph+ ALL requires use of 2 separate assays able to 
quantitatively measure levels of p190 and p210 variants, with a minimal sensitivity of at least 
0.01%.
In summary, current treatment guidelines and multiple retrospective analyses support assessment 
of MRD negativity at the end of the induction phase of treatment as a meaningful surrogate for 
long-term efficacy (coupled with achievement of CR for at least 4 weeks). These studies also 
support defining MRD negativity as BCR-ABL1/ABL1 levels ≤0.01% (also referred to as 
molecular response 4-log reduction [MR4]) and measuring MRD negativity with appropriately 
qualified assays. Assessment of alternate residual disease thresholds, including 
BCR-ABL1/ABL1 levels ≤0.1% (molecular response 3-log reduction [MR3]) and ≤0.0032% 
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(molecular response 4.5-log reduction [MR4.5]), at multiple timepoints, may further inform 
response milestones that may help guide future optimization of treatment regimens.
5.0
STUDY OBJECTIVES AND ENDPOINTS
5.1
Objectives
5.1.1
Primary Objectives
The primary objective of the study is to compare the efficacy of ponatinib versus imatinib, 
administered as first-line therapy in combination with reduced-intensity chemotherapy, in 
patients with newly diagnosed Ph+ ALL, as measured by the MRD-negative CR rate at the end 
of induction (see Table 13.a for the definitions of MRD negativity and CR).
5.1.2
Secondary Objectives
The key secondary objective is to compare EFS between the 2 cohorts.
Other secondary objectives are:

To compare the rates of CR and incomplete CR (CRi) between the 2 cohorts, at the end of 
Cycle 1, the end of Cycle 2, the end of induction, and during or at the end of consolidation 
(end of Cycle 9 or end of study treatment, whichever occurs earlier).

To compare the rates of MR3, MR4, and MR4.5 between the 2 cohorts, at the end of Cycle 1, 
the end of Cycle 2, the end of induction, and during or at the end of consolidation (end of 
Cycle 9 or end of study treatment, whichever occurs earlier).

To compare the rates of primary induction failure (PIF) and overall response rate (ORR) 
between the 2 cohorts, at the end of induction.

To compare rates of MRD-negative CR at multiple intervals after the end of induction.

To determine the duration of MRD-negative CR in each of the 2 cohorts.

To determine the duration of CR in each of the 2 cohorts.

To compare the time to treatment failure between the 2 cohorts.

To compare the duration of MR4.5 between the 2 cohorts, in patients who achieved MR4.5.

To compare outcomes in patients with and without HSCT, between the 2 cohorts.

To compare OS between the 2 cohorts.

To collect plasma concentration-time data to contribute to population pharmacokinetic (PK) 
and exposure-response analyses of ponatinib.
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5.1.3
Safety Objectives
The safety objectives are:

To characterize the rates of AEs/SAEs, AOEs, venous thrombotic/embolic events (VTEs), 
and other safety outcomes of interest in the 2 cohorts, using multiple methods.

To compare the tolerability between the 2 cohorts, including the rates of discontinuation, 
dose reductions, and dose interruptions due to AEs.
5.1.4
Exploratory Objectives
The exploratory objectives are:

To compare patient-reported quality of life (Functional Assessment of Cancer Therapy –
Leukemia [FACT-Leu] and EuroQOL-5 Dimension-5 Level [EQ-5D-5L]) results between 
the 2 cohorts.

To compare medical resource utilization (MRU) results between the 2 cohorts.

To compare the time to start of alternative therapy between the 2 cohorts.

To compare the time to HSCT between the 2 cohorts.

To explore biomarkers of disease sensitivity and resistance to ponatinib and imatinib and/or 
biomarkers affecting ponatinib efficacy or safety.
5.2
Endpoints
5.2.1
Primary Endpoint
The primary endpoint is MRD-negative CR at the end of induction (see Table 13.a for the 
definitions of MRD negativity and CR).
5.2.2
Secondary Endpoints
5.2.2.1
Key Secondary Endpoints
The key secondary endpoint is:

EFS, defined as the dates of randomization until:
–
Death due to any cause.
–
Failure to achieve CR by the end of induction.
–
Relapse from CR.
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5.2.2.2
Other Secondary Endpoints
Other secondary endpoints (defined in Table 13.a) are:

CR and CRi rates at the end of Cycle 1, the end of Cycle 2, the end of induction, and during 
or at the end of consolidation (end of Cycle 9 or end of study treatment, whichever occurs 
earlier).

Molecular response rates (MR3, MRD negativity [MR4], and MR4.5) at the end of Cycle 1, 
the end of Cycle 2, the end of induction, and during or at the end of consolidation (end of 
Cycle 9 or end of study treatment, whichever occurs earlier).

Rates of PIF and ORR at the end of induction.

Rates of MRD-negative CR at multiple intervals after the end of induction.

Duration of MRD-negative CR.

Duration of CR.

Time to treatment failure.

Duration of MR4.5 in patients who achieved MR4.5.

OS and rate of relapse from CR for on-study patients with and without HSCT.

OS.
5.2.3
Safety Endpoints
The safety endpoints are:

Incidence and exposure-adjusted incidence rates of AOEs, VTEs, AEs, and SAEs, in each of 
the 2 cohorts.

Incidence of dose reductions, interruptions, and discontinuations due to AEs, in each of the 
2 cohorts.

Incidence of death on treatment, in each of the 2 cohorts.

Changes from baseline in vital signs (including systolic and diastolic blood pressure [BP] and 
heart rate) and clinical laboratory test results, in each of the 2 cohorts.
5.2.4
PK Endpoint
The PK endpoint is plasma concentration-time data to contribute to population PK and exposure-
response analyses of ponatinib.
5.2.5
Exploratory Endpoints
The exploratory endpoints are (see Table 13.a for the definitions):

Change from baseline in patient-reported quality of life (FACT-Leu and EQ-5D-5L).
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
Change from baseline in MRU assessments.

Time to start of alternative therapy.

Time to start of HSCT.

Biomarkers of disease sensitivity and resistance to ponatinib and imatinib and/or biomarkers 
affecting ponatinib efficacy or safety.
6.0
STUDY DESIGN
6.1
Overview of Study Design
This phase 3 study is designed as an open-label, multicenter, randomized comparison of the TKIs 
ponatinib versus imatinib, when administered as first-line therapy in patients aged ≥18 years with 
newly diagnosed Ph+ ALL. The TKIs will be administered in combination with 20 cycles of a 
reduced-intensity chemotherapy regimen (including 3 cycles of induction therapy, 6 cycles of 
consolidation therapy, and 11 cycles of maintenance therapy), followed by single-agent therapy 
with ponatinib or imatinib, to be administered continuously. Patients will remain on study 
treatment until they are deceased, have failed to achieve the primary endpoint at the end of 
induction (patients who do not achieve the primary endpoint may remain on study drug, at the 
investigator’s discretion, if they have achieved CR or MRD-negative status with CRi at the end 
of induction), have experienced relapse from CR or have progressive disease, have an 
unacceptable toxicity, have withdrawn consent, have proceeded to HSCT or alternative therapy, 
or until the sponsor terminates the study, whichever occurs first. 
The primary endpoint of this study is MRD-negative CR at the end of induction (defined in 
Table 13.a). Patients who achieve the primary endpoint will continue in the study in the
consolidation and maintenance phases followed by a single-agent therapy phase. As CR must 
have been maintained for at least 4 weeks, patients who do not achieve CR by the end of Cycle 2 
(ie, C3D1) will be considered as having failed to achieve the primary endpoint (see Table 13.a
for definitions). Patients who achieve CR but do not achieve MRD-negative status or who 
achieve MRD-negative status with CRi at the end of induction may continue on study treatment 
at the investigator’s discretion. All other patients will be discontinued from study drug. For all 
discontinued patients, the patient’s treating physician should consider alternative therapy options.
Upon enrollment, patients will be randomized in a 2:1 ratio of ponatinib:imatinib to be taken 
throughout the study, beginning on Cycle 1 Day 1. Patients randomized to Cohort A (ponatinib) 
will receive 30 mg of oral ponatinib QD, which will be reduced to 15 mg if MRD-negative CR is 
achieved at the end of induction. If a patient loses MRD negativity after dose reduction to 15 mg, 
re-escalation to 30 mg may be considered after discussion with the sponsor’s medical 
monitor/designee. Dose reductions to 10 mg of ponatinib QD may be considered for safety 
reasons after discussion with the sponsor’s medical monitor/designee (see Section 8.4.1). For 
patients in the ponatinib cohort who achieve CR or MRD-negative CRi but do not achieve the 
primary endpoint at the end of induction and who continue in the study at the investigator’s 
discretion, the dose of ponatinib will be reduced, as described above, at any time when the 
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patient achieves MRD-negative CR and re-escalated, as described above, upon loss of response. 
Patients randomized to Cohort B (imatinib) will receive 600 mg of oral imatinib QD. Intrathecal 
therapy will be performed twice per month for the first 6 cycles for CNS disease prophylaxis. At 
the end of the 20 cycles, all patients remaining on study will remain on ponatinib or imatinib 
(administered as a single agent).
MRD status will be measured using qPCR-based tests validated for the ability to detect 
BCR-ABL1/ABL1 levels with a minimal sensitivity of 0.01%, with MRD negativity defined as 
≤0.01% BCR-ABL1/ABL1. Separate tests will be used to assess the p210 and p190 variants of 
BCR-ABL1 (see Section 4.2.3), which comprise >95% of the variants present in adult patients 
with Ph+ ALL. For the p210 test, BCR-ABL1/ABL1 levels will be reported on the International 
Scale (IS) with traceability to the World Health Organization (WHO) first International Genetic 
Reference Panel. For the p190 test, for which there is no internationally available reference 
material, the raw ratio of BCR-ABL1/ABL1 levels will be reported. To ensure uniformity of 
analysis, all samples will be tested using the same methodology in central laboratories. 
Assessment of the primary endpoint at the end of induction will be based on analysis of BM 
samples, but in rare cases where the BM samples are not evaluable or not available, blood 
samples could also be used. To minimize the number and volume of BM aspirates required, and 
in keeping with available recommendations [1] and evidence of general concordance between 
results [2], assessment of BCR-ABL1/ABL1 levels at other time points may use peripheral blood 
samples. Both sample types will be collected at a subset of time points to allow the levels of 
concordance between sample types to be broadly assessed.
The key secondary endpoint for this study is EFS. Other secondary endpoints will include rates 
of CR and CRi at the end of Cycle 1, Cycle 2, the end of induction, and during or at the end of 
consolidation (end of Cycle 9 or end of study treatment, whichever occurs earlier); rates of MR3, 
MR4, and MR4.5 at the end of Cycle 1, the end of Cycle 2, the end of induction and during or at 
the end of consolidation (end of Cycle 9 or end of study treatment, whichever occurs earlier); 
rates of MRD-negative CR at multiple intervals after the end of induction; rates of PIF and ORR 
at the end of induction; duration of MRD-negative CR; duration of CR; time to treatment failure; 
duration of MR4.5 in patients who achieved MR4.5; OS and rate of relapse from CR for 
on-study patients with and without HSCT, and OS. (See Table 13.a for endpoint definitions.)
Safety and tolerability parameters will be assessed in both cohorts, including incidence of all 
AEs, SAEs, AOEs, and VTEs; rates of discontinuation, dose reductions, and dose interruptions 
due to AEs; incidence of death while on treatment, and changes from baseline in vital signs and 
laboratory test results. Plasma concentration-time data will also be collected for patients 
receiving ponatinib.
Exploratory endpoints will include change from baseline in patient-reported quality-of-life and 
MRU assessments; time to start of alternative therapy; time to HSCT; and biomarkers of disease 
sensitivity and resistance to ponatinib and imatinib and/or biomarkers affecting ponatinib 
efficacy or safety.
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6.2
Number of Patients
Approximately 230 patients will be enrolled in this study from approximately 120 study sites 
globally. Enrollment is defined as randomized to study drug.
6.3
Duration of Study
6.3.1
Duration of an Individual Patient’s Study Participation
All patients will remain on study treatment until they are deceased, have failed to achieve the 
primary endpoint of MRD-negative CR at the end of induction (patients who fail the primary 
endpoint may remain on study drug, at the investigator’s discretion, if they have achieved CR or 
MRD-negative status with CRi at the end of induction), have experienced relapse from CR or 
have progressive disease, have an unacceptable toxicity, have withdrawn consent, have 
proceeded to HSCT or alternative therapy, or until the sponsor terminates the study, whichever 
occurs first.
All patients who discontinue study treatment will be followed for survival as specified in the 
SOE. Patients who discontinued study treatment without relapse from CR, will be followed for 
investigator-reported disease status (eg, relapse from CR) and survival, and reporting of 
alternative therapies, wherever available. Patients who proceed to HSCT will be discontinued 
from study treatment but will be followed per the on-study data collection schedule as specified 
in the Schedule of Events (SOE) for post-transplantation data collection, including transplant-
related procedures, investigator-reported disease status (eg, relapse from CR), survival, and the 
use of post-transplant treatment (chemotherapy, TKI). Patients who proceed to alternative 
therapy will also be discontinued from study treatment and will be followed for 
investigator-reported disease status (eg, relapse from CR) and survival.
After disease progression, all patients will be contacted every 3 months for survival follow-up. 
Patients will be followed until completion of the study or until the patient’s death has been 
reported.
6.3.2
End of Study/Study Completion Definition and Planned Reporting
The study will be considered completed when the death of all patients has been recorded or when 
the study has been terminated by the sponsor.
Study results will be reported in a CSR.
6.3.3
Time Frames for Primary and Secondary Endpoints to Support Disclosures
Table 6.a provides disclosures information for all primary and secondary endpoints.
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Table 6.a
Primary and Secondary Endpoints for Disclosures
Endpoint
Definition
Maximum Time Frame
Primary: MRD-negative CR
BCR-ABL1/ABL1 ratio ≤0.01% and meeting criteria 
for CR (see Table 13.a)
The end of induction, ie, 
approximately 3 months
Key Secondary: EFS
The dates of randomization until:

Death due to any cause.

Failure to achieve CR by the end of induction.

Relapse from CR.
Approximately 3-6 years; 
EFS is event-driven, exact 
time period to be specified 
in statistical analysis plan
Secondary: CR and CRi
See Table 13.a
At approximately 1 month, 
2 months, 3 months, and up 
to 9 months
Secondary: Molecular 
response rates (MR3, MR4, 
and MR4.5)
MR3 is defined as molecular response 3-log 
reduction (≤0.1% BCR-ABL1), or undetectable 
BCR-ABL1 transcripts in cDNA with ≥1000 ABL1 
transcripts;
MR4 is defined as molecular response 4-log 
reduction (≤0.01% BCR-ABL1), or undetectable 
BCR-ABL1 transcripts in cDNA with ≥10,000 
ABL1 transcripts;
MR4.5 is defined as molecular response 4.5-log 
reduction (≤0.0032% BCR-ABL1), or undetectable 
BCR-ABL1 transcripts in cDNA with ≥32,000 
ABL1 transcripts.
At approximately 1 month, 
2 months, 3 months, and up 
to 9 months
Secondary: PIF and ORR
See Table 13.a for definition of PIF.
ORR is defined as CR + CRi.
At approximately 3 months
Secondary: MRD-negative 
CR
BCR-ABL1/ABL1 ratio ≤0.01% and meeting criteria 
for CR (see Table 13.a).
Up to approximately 
3-6 years
Secondary: Duration of 
MRD-negative CR
The interval between the first assessment at which 
the criteria for MRD-negative CR are met until the 
earliest date at which loss of MRD negativity or 
relapse from CR occurs.
Up to approximately 
3-6 years
Secondary: Duration of CR
The interval between the first assessment at which 
the criteria for CR are met until the earliest date at 
which relapse from CR occurs.
Up to approximately 
3-6 years
Secondary: Time to treatment 
failure
Time to end of study-randomized treatment (except 
for HSCT without loss of MRD-negative CR) due to 
safety and/or efficacy reasons.
Up to approximately 
3-6 years
Secondary: MR4.5, including 
best response
MR4.5 is defined as ≤0.0032% BCR-ABL1.
Up to approximately 
3-6 years
Secondary: Duration of 
MR4.5 in patients who 
achieved MR4.5
The interval between the first assessment at which 
the criteria for MR4.5 are met until the earliest date 
at which loss of MR4.5 occurs.
Up to approximately 
3-6 years
Secondary: OS and relapse 
from CR for on-study 
patients with and without 
HSCT
See Table 13.a for a definition of relapse from CR.
OS: The interval between randomization and death 
due to any cause, censored at the last contact date 
when the patient was alive.
Up to approximately 3-6 
years
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Table 6.a
Primary and Secondary Endpoints for Disclosures
Endpoint
Definition
Maximum Time Frame
Secondary: OS
The interval between randomization and death due to 
any cause.
Up to approximately 3-6 
years
Abbreviations: AEs, adverse events; BCR-ABL, breakpoint cluster region-Abelson; cDNA, complementary DNA; 
CR, complete remission; CRi, incomplete CR; EFS, event-free survival; HSCT, hematopoietic stem cell transplant; 
MR3, molecular response 3-log reduction; MR4, molecular response 4-log reduction; MR4.5, molecular response 
4.5-log reduction; MRD, minimal residual disease; ORR, overall response rate; OS, overall survival; PD, 
progressive disease; PIF, primary induction failure.
6.3.4
Total Study Duration
The duration of the study will be approximately 6 to 9 years, including approximately 36 months 
for enrollment and approximately 3-6 years of follow-up from the date that the last patient 
enrolled.
6.3.5
Posttrial Access
Participants who have met the primary (and/or secondary) endpoints of the study and, in the 
opinion of the investigator and confirmed by the sponsor, experienced a clinically important 
benefit from ponatinib may continue to receive ponatinib in an extension phase of this study or a 
separate open-label rollover study. 
Continued access to ponatinib for participants will be terminated for those individuals who no 
longer benefit from ponatinib (eg, they have completed the recommended course of therapy or 
their disease has resolved), the benefit-risk no longer favors the individual, if ponatinib becomes 
available either commercially or via another access mechanism, or when an alternative 
appropriate therapy becomes available. Posttrial access may be terminated in a country or 
geographical region where marketing authorization has been rejected, the development of 
ponatinib has been suspended or stopped by the sponsor, or ponatinib can no longer be supplied.
7.0
STUDY POPULATION
The study population will include male and female adult patients aged 18 years and older who 
have newly diagnosed Ph+ ALL.
7.1
Inclusion Criteria
Each patient must meet all the following inclusion criteria to be enrolled in the study and 
randomized to treatment:
1. Male or female patients aged 18 years or older.
2. Newly diagnosed Ph+ or BCR-ABL1-positive ALL, as defined by the 2017 NCCN 
guidelines.
3. Eastern Cooperative Oncology Group (ECOG) performance status of ≤2.
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4. Clinical laboratory values as follows, within 30 days before randomization:
a) Total serum bilirubin ≤1.5× the upper limit of normal (ULN), unless due to Gilbert’s 
syndrome.
b) Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≤2.5× the ULN.
c) Serum creatinine ≤1.5× the ULN and estimated creatinine clearance (CrCl) 
≥30 mL/minute (Cockcroft-Gault formula).
d) Serum lipase <1.5× the ULN.
5. Normal QT interval corrected per Fridericia method (QTcF) on screening electrocardiogram 
(ECG), defined as QTcF of ≤450 ms in males or ≤470 ms in females.
6. Female patients who:
a) Are postmenopausal for at least 1 year before the screening visit, OR
b) Are surgically sterile, OR
c) If they are of childbearing potential, agree to practice 1 highly effective method of 
contraception (such as any form of hormonal contraception, eg, birth control pills or 
hormonal intra-uterine device [IUD]) and 1 additional effective (barrier) method at the 
same time, from the time of signing the informed consent through 1 month after the last 
dose of study drug or a longer period per any local regulation, eg, 35 days for patients in 
France), OR
d) Agree to practice true abstinence, when this is in line with the preferred and usual 
lifestyle of the patient. (Periodic abstinence [eg, calendar, ovulation, symptothermal, 
postovulation methods], withdrawal, spermicides only, and lactational amenorrhea are 
not acceptable methods of contraception. Female and male condoms should not be used 
together.)
7. Male patients, even if surgically sterilized (ie, status postvasectomy), who:
a) Agree to practice effective barrier contraception during the entire study treatment period 
and through 120 days after the last dose of study drug, OR
b) Agree to practice true abstinence, when this is in line with the preferred and usual 
lifestyle of the patient. (Periodic abstinence [eg, calendar, ovulation, symptothermal, 
postovulation methods], withdrawal, spermicides only, and lactational amenorrhea are 
not acceptable methods of contraception. Female and male condoms should not be used 
together.)
8. Voluntary written consent must be given before performance of any study-related procedure 
not part of standard medical care, with the understanding that consent may be withdrawn by 
the patient at any time without prejudice to future medical care.
9. Willingness and ability to comply with scheduled visits and study procedures.
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7.2
Exclusion Criteria
Patients meeting any of the following exclusion criteria are not to be enrolled in the study or 
randomized to treatment.
1. Patients with a history or current diagnosis of chronic phase, accelerated phase, or blast phase 
CML.
2. Prior/current treatment with any systemic anticancer therapy (including but not limited to any 
TKI) and/or radiotherapy for ALL, with the exception of an optional prephase therapy or 
chemotherapy induction (no more than 1 cycle), which should be discussed with the 
sponsor’s medical monitor/designee.
3. Treatment with any investigational products within 30 days before randomization or 6 half-
lives of the agent, whichever is longer.
4. Currently taking drugs that are known to have a risk of causing prolonged QTc or torsades de 
pointes (TdP) (unless these can be changed to acceptable alternatives or discontinued) 
(Appendix E).
5. Taking any medications or herbal supplements that are known to be strong inhibitors or 
strong inducers of cytochrome P450 (CYP)3A4 within at least 14 days before the first dose 
of study drug (Appendix F).
6. Uncontrolled active serious infections that could, in the investigator’s opinion, potentially 
interfere with the completion of treatment according to this protocol.
7. Major surgery within 28 days before randomization (minor surgical procedures such as 
catheter placement or BM biopsy are not exclusionary criteria).
8. Known HIV seropositivity, known active hepatitis B or C infection.
9. History of acute pancreatitis within 1 year of study screening or history of chronic 
pancreatitis.
10. Uncontrolled hypertriglyceridemia (triglycerides >450 mg/dL).
11. Diagnosed and treated for another malignancy within 5 years before randomization or 
previously diagnosed with another malignancy and have any evidence of residual disease. 
Patients with nonmelanoma skin cancer or carcinoma in situ of any type are not excluded if 
they have undergone complete resection.
12. History or presence of clinically relevant CNS pathology such as epilepsy, childhood or adult 
seizure, paresis, aphasia, stroke, severe brain injuries, dementia, Parkinson’s disease, 
cerebellar disease, organic brain syndrome, or psychosis.
13. Clinical manifestations of CNS or extramedullary involvement with ALL other than 
lymphadenopathy or hepatosplenomegaly.
14. Autoimmune disease with potential CNS involvement.
15. Known significant neuropathy of Grade ≥2 severity.
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16. Clinically significant, uncontrolled, or active cardiovascular, cerebrovascular, or peripheral 
vascular disease, or history of or active VTE disease, including, but not restricted to:
a) Complete left bundle branch block.
b) Right bundle branch block plus left anterior hemiblock, or bifascicular block.
c) History of or presence of clinically significant ventricular or atrial tachyarrhythmias.
d) Clinically significant resting bradycardia (<50 beats per minute).
e) Uncontrolled hypertension (HTN); systolic BP ≥150 mmHg and/or diastolic BP 
≥90 mmHg). Patients with Stage 2 HTN (systolic BP ≥140 mmHg and/or diastolic BP 
≥90 mmHg should be under treatment at study entry per the current American Heart 
Association guidelines to ensure BP control. Patients requiring 3 or more 
antihypertensive medications should have controlled HTN for the past 6 months. Isolated 
elevation(s) of systolic and/or diastolic BP during screening are not exclusionary.
f)
Any history of myocardial infarction (MI), unstable angina, coronary artery disease 
(CAD), cerebrovascular accident (CVA), ischemic stroke, or transient ischemic attack 
(TIA). Note: Patients with any history of these events, whether considered clinically 
significant or not, are excluded.
g) History of congestive heart failure (CHF) (New York Heart Association class III or IV) 
or left ventricular ejection fraction (LVEF) <40%, within 6 months before randomization.
h) Symptomatic peripheral vascular disease or history of infarction, including visceral 
infarction.
i)
History of any revascularization procedure, including the placement of a stent.
j)
Patients with documented significant pleural or pericardial effusions unless thought to be 
secondary to leukemia.
k) Any history of venous thromboembolism, including, but not limited to, deep venous 
thrombosis (DVT) or pulmonary embolism within 6 months before randomization; 
patients with catheter-associated DVTs or superficial vein thrombosis, which are 
considered to be resolved/controlled, may be included after discussion with the sponsor’s 
medical monitor/designee.
17. Poorly controlled diabetes. Patients with preexisting, well-controlled diabetes are not 
excluded.
18. Known gastrointestinal (GI) disease or GI procedure that could interfere with the oral 
absorption or tolerance of study drug, including difficulty swallowing.
19. Ongoing uncontrolled nausea or vomiting of any severity.
20. Have a significant bleeding disorder unrelated to ALL.
21. Life-threatening illness unrelated to cancer, such as severe CNS, pulmonary, renal, or hepatic 
disease unrelated to cancer.
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22. Female patients who are lactating or breastfeeding or have a positive serum pregnancy test 
during the screening period or have a positive urine pregnancy test on Day 1 before the first 
dose of study drug is administered 
–
Patients with positive serum pregnancy test who have undergone a complete abortion in 
the last 60 days may be included after discussion with the sponsor’s medical 
monitor/designee. If the serum test is positive, a repeat test is to be performed 7 to 14 
days later and must be significantly lower to insure there is no active pregnancy for study 
eligibility.
23. Any serious medical or psychiatric illness that could, in the investigator’s opinion, potentially 
interfere with the completion of treatment according to this protocol.
24. Admission or evidence of illicit drug use, drug abuse, or alcohol abuse.
8.0
STUDY DRUG
Investigational therapy: Ponatinib
Reference therapy: Imatinib
Backbone (reduced-intensity) chemotherapy:

Induction phase: Three 28-day cycles of vincristine and dexamethasone.

Consolidation phase: Six 28-day cycles of alternating cytarabine (even-numbered cycles) and 
methotrexate (odd-numbered cycles).

Maintenance phase: Eleven 28-day cycles of vincristine and prednisone.
8.1
Study Drug Administration
8.1.1
Investigational Therapy: Ponatinib
Ponatinib will be supplied by the sponsor as 10 mg (oval-shaped), 15 mg, and 30 mg 
(round-shaped), white, film-coated tablets. All protocol-specific criteria for administration of 
ponatinib must be met and documented before ponatinib administration. Study drug will be 
administered only to eligible patients under the supervision of the investigator or identified 
subinvestigator(s).
Ponatinib will be self-administered by the patient on a daily schedule at a starting dose of 30 mg 
by mouth (PO) QD. Each 28-day dosing period is referred to as 1 Cycle. Patients should be 
instructed to take the prescribed number of tablets with water, with or without food, at 
approximately the same time each day, continuously throughout the study, and not to take more 
than the prescribed dose at any time. Patients should swallow the study medication whole and 
not chew it or manipulate it in any way before swallowing.
Patients will be provided a diary or equivalent where the date and time of administration will be 
recorded; complete instructions will be provided with the site operations manual.
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Patients who forget to take their dose more than 6 hours after it is due should not make up the 
missed dose. Any missing doses should be recorded, and subsequent training of patients should 
be documented in the appropriate source record (eg, clinic chart) and in the electronic case report 
form (eCRF).
If severe emesis or mucositis prevents the patient from taking a ponatinib dose, that dose will be 
skipped. Under no circumstance should a patient repeat a dose or double-up doses.
8.1.2
Induction Phase (Cycles 1 Through 3)
The induction phase will begin on Day 1 of the study (Cycle 1 Day 1) and will comprise three 
28-day cycles, including ponatinib (Cohort A; study drug; 30 mg QD), imatinib (Cohort B; 
active comparator; 600 mg QD), and reduced-intensity chemotherapy (Table 8.a).
Table 8.a
Induction Phase Treatment (Cycles 1 Through 3)
Induction Phase Treatment (Three 28-Day Cycles) a,b
Cohort A
Cohort B
Vincristine: 1.4 mg/m2 IV on Days 1 and 14 (capped at 
2 mg)
Vincristine: 1.4 mg/m2 IV on Days 1 and 14 (capped at 
2 mg)
Dexamethasone: 
Patients aged <60 years: 40 mg PO on Days 1-4 and 
Days 11-14
Patients aged ≥60 years: 20 mg PO on Days 1-4 and 
Days 11-14
Dexamethasone: 
Patients aged <60 years: 40 mg PO on Days 1-4 and 
Days 11-14
Patients aged ≥60 years: 20 mg PO on Days 1-4 and 
Days 11-14
Ponatinib c
Starting dose: 30 mg QD, starting on Cycle 1 Day 1
Imatinib c
Starting dose: 600 mg QD, starting on Cycle 1 Day 1
Abbreviations: IV, intravenous; PO, by mouth; QD, once daily.
Administration guidelines are provided for ponatinib only in this protocol; investigators should refer to current local 
prescribing information for all other therapies included in this protocol. Alternative dose modifications/schedules 
may be recommended after discussion with the investigator and medical monitor/designee to maximize exposure of 
study treatment while protecting patient safety.
a Lumbar punctures will be performed to test CSF for CNS disease on Day 1 and Day 14 of the 3 induction phase 
cycles and the first 3 consolidation phase cycles (total: 6 cycles, 12 samples), and additionally as clinically 
indicated.
b CNS prophylaxis will be administered on Day 1 and Day 14 of the 3 induction phase cycles and the first 
3 consolidation phase cycles (total: 6 cycles, 12 intrathecal injections) and comprises a triple intrathecal injection of 
methotrexate, cytarabine, and corticosteroids (recommended: dexamethasone) as per current practice in each center. 
If patients move to the maintenance phase directly from the induction phase or before completing the consolidation 
phase, they will still be required to receive the complete course of intrathecal CNS prophylaxis to complete the total 
of 12 intrathecal injections.
c Ponatinib and imatinib will be dispensed to patients on Day 1 of each cycle.
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8.1.3
Consolidation Phase (Cycles 4 Through 9)
The consolidation phase will begin after Cycle 3 of the induction phase is complete and will 
comprise six 28-day cycles, including ponatinib or imatinib and alternating cytarabine 
(even-numbered cycles) and methotrexate (odd-numbered cycles) (Table 8.b).
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Table 8.b
Consolidation Phase Treatment
Consolidation Phase Treatment (Six 28-Day Cycles; Study Cycle 4-9) a,b
Cohort A
Cohort B
Alternating methotrexate and cytarabine:

Methotrexate (odd consolidation cycles 1st, 3rd, and 
5th) Study Cycles 4, 6 and 8:
–
Patients aged <60 years: 
1000 mg/m2 IV Day 1, 24-h infusion.
–
Patients aged ≥60 years: 
250 mg/m2 IV Day 1, 24-h infusion.
–
Rescue: folinic acid (see Appendix J).

Cytarabine (even consolidation cycles 2nd, 4th, and 
6th) Study Cycles 5, 7 and 9:
–
Patients aged <60 years: 
1000 mg/m2 q12 h IV, Days 1, 3, and 5, 
2-h infusion (dose adapted by CrCl; see 
Appendix K).
–
Patients aged ≥60 years:
250 mg/m2 q12 h IV, Days 1, 3, and 5, 
2-h infusion
(if the patient has impaired renal function, 
reduce the dose or consider discontinuing 
cytarabine).
Alternating methotrexate and cytarabine:

Methotrexate (odd consolidation cycles 1st, 3rd, and 
5th) Study Cycles 4, 6 and 8:
–
Patients aged <60 years: 
1000 mg/m2 IV Day 1, 24-h infusion.
–
Patients aged ≥60 years: 
250 mg/m2 IV Day 1, 24-h infusion.
–
Rescue: folinic acid (see Appendix J).

Cytarabine (even consolidation cycles 2nd, 4th, and 
6th) Study Cycles 5, 7 and 9:
–
Patients aged <60 years: 
1000 mg/m2 q12 h IV, Days 1, 3, and 5, 
2-h infusion (dose adapted by CrCl; see 
Appendix K).
–
Patients aged ≥60 years:
250 mg/m2 q12 h IV, Days 1, 3, and 5, 
2-h infusion (if the patient has impaired renal 
function, reduce the dose or consider 
discontinuing cytarabine).
Ponatinib c Start with the last induction phase dose; 
modify dose based on MRD-negative CR results (see 
Section 8.3).
Imatinib c Start with the last induction phase dose.
Abbreviations: CrCl, creatinine clearance; IV, intravenous; PO, by mouth; q, every; QD, once daily.
Administration guidelines are provided for ponatinib only in this protocol; investigators should refer to current local 
prescribing information for all other therapies included in this protocol. Alternative dose modifications/schedules 
may be recommended after discussion with the investigator and medical monitor/designee to maximize exposure of 
study treatment while protecting patient safety.
a Lumbar punctures will be performed to test CSF for CNS disease on Day 1 and Day 14 of the 3 induction phase 
cycles and the first 3 consolidation phase cycles (total: 6 cycles, 12 samples), and additionally as clinically 
indicated.
b CNS prophylaxis will be administered on Day 1 and Day 14 of the first 3 consolidation phase cycles (total with the 
induction phase administration: 6 cycles, 12 intrathecal injections) and comprises a triple intrathecal injection of 
methotrexate, cytarabine, and corticosteroids (recommended: dexamethasone) as per current practice in each center. 
If patients move to the maintenance phase directly from the induction phase or before completing the consolidation 
phase, they will still be required to receive the complete course of intrathecal CNS prophylaxis to complete the total 
of 12 intrathecal injections.
c Ponatinib and imatinib will be dispensed to patients on Day 1 of each cycle.
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8.1.4
Maintenance Phase (Cycles 10 Through 20)
The maintenance phase will begin after Cycle 9 of the consolidation phase is complete and will 
comprise eleven 28-day cycles, including the following (Table 8.c):
Table 8.c
Maintenance Phase Treatment
Maintenance Phase Treatment (Eleven 28-Day Cycles)
Cohort A
Cohort B
Vincristine:
1.4 mg/m2 IV injected over 1 minute on Day 1 of each 
maintenance phase cycle (1 injection/mo; capped at 
2 mg)
Vincristine:
1.4 mg/m2 IV injected over 1 minute on Day 1 of each 
maintenance phase cycle (1 injection/mo; capped at 
2 mg)
Prednisone a
Patients aged <60 years: 200 mg/d PO on Days 1-5
Patients aged ≥60-69 years: 100 mg/d PO on Days 1-5
Patients aged ≥70 years: 50 mg/d PO on Days 1-5
Prednisone a
Patients aged <60 years: 200 mg/d PO on Days 1-5
Patients aged ≥60-69 years: 100 mg/d PO on Days 1-5
Patients aged ≥70 years: 50 mg/d PO on Days 1-5
Ponatinib b: Start with the last consolidation phase dose; 
modify dose based on MRD-negative CR results (see 
Section 8.3).
Imatinib b: Start with the last consolidation phase dose.
Abbreviations: IV, intravenous; PO, by mouth; QD, once daily.
Administration guidelines are provided for ponatinib only in this protocol; investigators should refer to current local 
prescribing information for all other therapies included in this protocol. Alternative dose modifications/schedules 
may be recommended after discussion with the investigator and medical monitor/designee to maximize exposure of 
study treatment while protecting patient safety.
a Prednisolone can be used instead of prednisone if prednisone is not available.
b Ponatinib and imatinib will be dispensed to patients on Day 1 of each cycle.
8.1.5
Postcycle 20 Therapy
Patients will continue on the last maintenance phase dose (or dose modified based on 
MRD-negative CR results) of TKI alone until they are deceased, have experienced relapse from 
CR or have progressive disease, have an unacceptable toxicity, have withdrawn consent, have 
proceeded to HSCT or alternative therapy, or until the sponsor terminates the study, whichever 
occurs first. During this single-agent therapy phase, study drug will be dispensed at each visit 
(ie, every 3 months).
Patients who proceed to HSCT will be discontinued from study treatment but will be followed 
per the on-study data collection schedule as specified in the SOE for post-transplantation data 
collection, including transplant-related procedures, investigator-reported disease status (eg, 
relapse from CR), survival, and the use of post-transplant treatment (chemotherapy, TKI). 
Patients proceeding to alternative therapy will also be discontinued from study treatment but will 
be followed for investigator-reported disease status (eg, relapse from CR) and survival. All other 
patients who discontinue study treatment will be followed for survival as specified in the SOE 
(Table 2).
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8.2
Reference/Control Therapy: Imatinib
The active comparator in this study is imatinib, to be administered at 600 mg PO QD 
continuously during the study. Imatinib was chosen primarily because it is currently the most 
widely used standard of care throughout the world in the first-line treatment of adult patients 
with Ph+ ALL. The use of imatinib in combination with the reduced-intensity chemotherapy 
proposed in this phase 3 study is consistent with the recommended NCCN treatments for both 
adolescent and young adults and adult patients [4].
Patients will be provided a diary or equivalent where the date and time of administration will be 
recorded; complete instructions will be provided with the site operations manual.
Investigators should refer to the current local prescribing information for details on imatinib 
therapy. 
8.3
Dose Modification Guidelines for Efficacy
8.3.1
Mandatory Dose Reduction for Response
The primary endpoint of this study will be achievement of MRD-negative CR at the end of 
induction (as defined in Section 13.1.3.4). Ponatinib dose reductions to 15 mg QD will be 
implemented in patients who achieve MRD-negative CR after completion of the induction phase. 
In patients who achieve CR or MRD-negative status with CRi but do not achieve the primary 
endpoint at the end of induction therapy and continue in the study at the investigator’s discretion, 
ponatinib dose reductions to 15 mg QD will be implemented at any later time point when the 
patient achieves MRD-negative CR. No dose reductions for response will be implemented for 
patients in the imatinib cohort.
All patients who do not achieve CR at the end of induction will be discontinued from study 
treatment (both ponatinib and imatinib), after which the patient’s treating physician should 
consider alternative therapy options.
Note: It is recommended that the mandatory dose reduction for response be implemented as soon 
as feasible (preferably within 2-3 weeks from the time the investigator is made aware of the 
response results). Unscheduled visits may be performed to implement the dose reduction.
8.3.2
Loss of Response After Dose Reduction for MRD-Negative CR
Patients in the ponatinib cohort who achieve MRD-negative status (defined in Table 13.a), 
undergo dose reduction, and subsequently lose MRD-negative status at a single time point, can 
have dose re-escalation to 30 mg upon review and agreement with the sponsor’s medical 
monitor/designee and in the absence of AEs requiring dose modification.
8.4
Dose Modification Guidelines for Safety
Dose modification guidelines detailed in this section are for ponatinib and imatinib only. 
Investigators should refer to the current local prescribing information for all other therapies 
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included in this study. In instances where local prescribing information is not available, the 
sponsor will provide dose modification guidelines to the sites.
These guidelines should be followed by clinical investigators; however, for an individual patient, 
dose interruptions, reductions, and treatment discontinuation and any variation from these 
guidelines can also be based on the clinical circumstance (eg, the investigator assesses that the 
potential benefit outweighs the risk of continued therapy). Variation from these guidelines 
should be communicated with the medical monitor/designee, ideally before implementation, and 
resulting agreements/investigator decisions should be recorded in source documents. 
8.4.1
Ponatinib
8.4.1.1
Dose Reduction for Drug-Related Adverse Events
Dose reduction guidelines for ponatinib are summarized in Table 8.d and Table 8.e, and adverse 
events (AEs) should be graded according to National Cancer Institute Common Terminology 
Criteria for Adverse Events (NCI CTCAE), version 5.0 [30].
Grade 4 nonhematologic toxicities (considered related to treatment) will, in general, require that 
treatment with study drug be permanently discontinued. If, in the opinion of the investigator and 
the sponsor’s medical monitor or designee, it is in the patient’s best interest to continue treatment 
with study drug, then the dose of study drug will be reduced by at least 1 dose level in 
subsequent cycles of treatment after recovery of the toxicity or toxicities in question to Grade 1 
or to baseline values.
Dose reduction below 10 mg QD is not permitted (see Table 8.d, Table 8.e, Table 8.f, and 
Table 8.g). Doses may be interrupted for study drug-related toxicities for up to 28 days; longer 
interruptions need to be discussed with the sponsor’s medical monitor/designee.
See Section 8.4.1.3 for dose re-escalation guidelines after the resolution of drug-related AEs.
Table 8.d
Dose Modifications for Nonhematologic Drug-Related Adverse Events: 
Ponatinib
General Toxicities
Modification
Grade 1 or transient Grade 2
No intervention
Grade 2 lasting ≥7 days with optimal care
First occurrence a at any dose level:
Hold until event is Grade ≤1, or has returned to baseline
Resume at current dose level
Recurrence b at 30 mg:
Hold until event is Grade ≤1, or has returned to baseline
Resume at 15 mg
Recurrence b at 15 mg:
Hold until event is Grade ≤1, or has returned to baseline
Resume at 10 mg
Recurrence b at 10 mg
Discontinue ponatinib 
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Table 8.d
Dose Modifications for Nonhematologic Drug-Related Adverse Events: 
Ponatinib
Grade 3 or 4
Occurrence a at 30 mg:
Hold until event is Grade ≤1, or has returned to baseline
Resume at 15 mg
Occurrence a at 15 mg:
Hold until event is Grade ≤1, or has returned to baseline
Resume at 10 mg
Occurrence a at 10 mg
Discontinue ponatinib
Pancreatitis and Elevation of Lipase
Modification
Asymptomatic Grade 1 or 2 elevation of serum lipase
Consider interruption or dose reduction of ponatinib
Asymptomatic Grade 3 elevation of lipase 
(>5 × the ULN), or symptomatic Grade 3 
(>2 × the ULN), or asymptomatic radiologic pancreatitis 
(Grade 2 pancreatitis)
Occurrence a at 30 mg:
Hold until event is Grade ≤1, or has returned to baseline
Resume at 15 mg
Occurrence a at 15 mg:
Hold until event is Grade ≤1, or has returned to baseline
Resume at 10 mg
Occurrence a at 10 mg
Discontinue ponatinib
Grade 4 elevation of lipase (>5 × the ULN and with 
signs or symptoms), or symptomatic Grade 3 
pancreatitis (severe pain, vomiting, medical intervention 
indicated [eg, analgesia, nutritional support])
Occurrence a at 30 mg:
Hold until complete resolution of symptoms and after 
recovery of lipase elevation to Grade ≤1
Resume at 15 mg
Occurrence a at 15 mg:
Hold until event is Grade ≤1, or has returned to baseline
Resume at 10 mg
Occurrence a at 10 mg
Discontinue ponatinib
Grade 4 pancreatitis
Discontinue ponatinib
Hepatic Toxicity
Modification
Elevation of liver transaminase >3 × ULN (Grade 2 or 
higher)
Occurrence a at 30 mg:
Hold ponatinib and monitor hepatic function until event 
is Grade ≤1 (≤3× the ULN) or has returned to baseline
Resume at 15 mg
Occurrence a at 15 mg:
Hold until event is Grade ≤1, or has returned to baseline
Resume at 10 mg
Occurrence a at 10 mg:
Discontinue ponatinib
Elevation of AST or ALT >3× the ULN concurrent with 
an elevation of bilirubin >2× the ULN and ALP <2× the 
ULN
Discontinue ponatinib
LVEF/CHF c
Modification
Grade 1
No dose adjustment
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Table 8.d
Dose Modifications for Nonhematologic Drug-Related Adverse Events: 
Ponatinib
Grade 2
Monitor by ECHO
First occurrence a at any dose level:
Hold until event is Grade ≤1, or has returned to baseline
Resume at current dose level
Recurrence b at 30 mg:
Hold until event is Grade ≤1, or has returned to baseline 
Resume at 15 mg
Recurrence b at 15 mg:
Hold until event is Grade ≤1, or has returned to baseline
Resume at 10 mg
Recurrence b at 10 mg:
Discontinue ponatinib
Grade 3
Monitor by ECHO
Occurrence a at 30 mg:
Hold until event is Grade ≤1, or has returned to baseline
Resume at 15 mg
Occurrence a at 15 mg:
Hold until event is Grade ≤1, or has returned to baseline
Resume at 10 mg
Occurrence a at 10 mg:
Discontinue ponatinib
Grade 4
Discontinue ponatinib
Skin Rash
Modification
Grade 1
No intervention
Grade 2 persistent despite optimal symptomatic therapy
First occurrence at any dose level:
Hold until event is Grade ≤1, or has returned to baseline
Resume at current dose level
Recurrence b at 30 mg:
Hold until event is Grade ≤1, or has returned to baseline
Resume at 15 mg
Recurrence b at 15 mg:
Hold until event is Grade ≤1, or has returned to baseline
Resume at 10 mg
Recurrence b at 10 mg:
Discontinue ponatinib
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Table 8.d
Dose Modifications for Nonhematologic Drug-Related Adverse Events: 
Ponatinib
Grade 3 persistent despite optimal symptomatic therapy
First occurrence at any dose level:
Hold until event is Grade ≤1, or has returned to baseline
Resume at current dose level
Recurrence b at 30 mg:
Hold until event is Grade ≤1, or has returned to baseline
Resume at 15 mg
Recurrence b at 15 mg:
Hold until event is Grade ≤1, or has returned to baseline
Resume at 10 mg
Recurrence b at 10 mg:
Discontinue ponatinib
Grade 4
Discontinue ponatinib
Abbreviations: ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; CHF, 
congestive heart failure; ECHO, echocardiogram; LVEF, left ventricular ejection fraction; ULN, upper limit of 
normal.
a “Occurrence” means the first time an AE is encountered by a patient at a given dose level.
b “Recurrence” means the second time an AE is encountered by a patient at a given dose level.
c For Grade 2: LVEF <50%-40%, Grade 3: LVEF <39-20%, Grade 4: refractory CHF or LVEF <20%.
Note: NCI CTCAE, version 5.0, 2018 criteria should be used to interrupt or discontinue study drug for Grades 2, 3, 
or 4 events considered to be study drug–related.
Table 8.e
Dose Modifications for Hematologic Drug-Related Adverse Events: 
Ponatinib
Drug-Related ANC/Platelets
Modification
Grade 1 or 2
No dose adjustment
Grade 3 or 4
First occurrence a at any dose level:
Hold until event is Grade ≤1, or has returned to baseline
Resume at current dose level
Recurrence b at 30 mg:
Hold until event is Grade ≤1, or has returned to baseline
Resume at 15 mg
Recurrence b at 15 mg:
Hold until event is Grade ≤1, or has returned to baseline
Resume at 10 mg
Recurrence b at 10 mg:
Discontinue ponatinib
Abbreviation: ANC, absolute neutrophil count.
NCI CTCAE, v5.0, 2018 criteria should be used to interrupt or discontinue study drug for Grades 2, 3, or 4 events 
considered to be study drug–related.
a “Occurrence” means the first time an AE is encountered by a patient at a given dose level.
b “Recurrence” means the second time an AE is encountered by a patient at a given dose level.
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8.4.1.2
Dose Modifications for AOEs and VTEs
AOEs and VTEs are broadly defined in Section 10.1.4. Additionally, the sponsor has a list of a 
broad range of nonspecific terms that could meet the criteria for AOEs and VTEs. The sponsor 
will periodically look at the safety data and inform the site if any AE qualifies for AOEs/VTEs 
as per that criteria. Dose modification guidelines presented here also apply to these 
sponsor-identified AOEs/VTEs.
Investigator discretion should be used to judge the event as a vascular pathology when applying 
these dose-modifying schemes.
8.4.1.2.1
AOEs 
In patients suspected of developing any serious or clinically significant AOE requiring urgent 
intervention or hospitalization, ponatinib should be immediately interrupted. Ponatinib should 
not be re-administered to these patients with serious or clinically significant AOEs unless the 
investigator assesses that the potential benefit outweighs the risk of continued therapy.
Patients should be discontinued from ponatinib in the event of MI, unstable angina, CVA, TIA, 
or revascularization procedures. For all other AOEs, dose modification guidelines are outlined in 
Table 8.f.
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Table 8.f
Dose Modifications for AOEs: Ponatinib
Arterial Occlusion: Cardiovascular and Cerebrovascular Events
Grade 1 
Consider interruption or dose reduction of ponatinib until the event resolves.
Grade 2
First occurrence a at any dose level:
Hold until event is Grade ≤1, or has returned to baseline
Resume at current dose level
Recurrence b at 30 mg: 
Hold until event is Grade ≤1, or has returned to baseline
Resume at 15 mg
Recurrence b at 15 mg: 
Hold until event is Grade ≤1, or has returned to baseline
Resume at 10 mg
Recurrence b at 10 mg: 
Discontinue ponatinib
Grade 3 and 4
Discontinue ponatinib.
Other Arterial Occlusions, including Peripheral Vascular Events
Grade 1 
Consider interruption or dose reduction of ponatinib until the event resolves.
Grade 2 
First occurrence a at any dose level:
Hold until event is Grade ≤1, or has returned to baseline
Resume at current dose level
Recurrence b at 30 mg:
Hold until event is Grade ≤1, or has returned to baseline
Resume at 15 mg
Recurrence b at 15 mg:
Hold until event is Grade ≤1, or has returned to baseline
Resume at 10 mg
Recurrence c at 10 mg:
Discontinue ponatinib
Grade 3
Occurrence a at 30 mg:
Hold until event is Grade ≤1, or has returned to baseline 
Resume at 15 mg
Occurrence a at 15 mg: 
Hold until event is Grade ≤1, or has returned to baseline
Resume at 10 mg
Occurrence a at 10 mg:
Discontinue ponatinib
Any recurrence b at any dose level: discontinue ponatinib
Grade 4
Discontinue ponatinib
Abbreviations: AOE, arterial occlusive event; CVA, cerebrovascular accident; MI, myocardial infarction; TIA, 
transient ischemic attack.
Patients should be discontinued from ponatinib in the event of MI, unstable angina, CVA or TIA, or 
revascularization procedures.
a “Occurrence” means the first time an AOE is encountered by a patient at a given dose level.
b “Recurrence” means the second time any AOE is encountered by a patient at a given dose level, not necessarily 
recurrence of the same AOE.
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8.4.1.2.2
VTEs 
In patients suspected of developing any serious or clinically significant VTE requiring urgent 
intervention or hospitalization, ponatinib should be immediately interrupted. Ponatinib should 
not be re-administered to these patients with serious or clinically significant VTEs unless the 
investigator assesses that the potential benefit outweighs the risk of continued therapy. Patients 
should be discontinued from study drug in the event of life-threatening pulmonary embolism or 
retinal vein thrombosis.
For all other VTEs, dose modification guidelines are outlined in Table 8.g.
Table 8.g
Dose Modifications for Venous Thrombotic/Embolic Events: Ponatinib
Venous Thrombotic/Embolic Events
Grade 1 
Consider interruption or dose reduction of ponatinib until the event resolves
Grade 2 
First occurrence a at any dose level: 
Hold until event is Grade ≤1, or has returned to baseline
Resume at current dose level
Recurrence b at 30 mg:
Hold until event is Grade ≤1, or has returned to baseline
Resume at 15 mg
Recurrence b at 15 mg:
Hold until event is Grade ≤1, or has returned to baseline
Resume at 10 mg
Recurrence b at 10 mg:
Discontinue ponatinib
Grade 3
Occurrence a at 30 mg:
Hold until event is Grade ≤1, or has returned to baseline
Resume at 15 mg
Occurrence a at 15 mg:
Hold until event is Grade ≤1, or has returned to baseline
Resume at 10 mg
Occurrence a at 10 mg: 
Discontinue ponatinib
Grade 4
Discontinue ponatinib.
Abbreviation: VTE, venous thrombotic/embolic event.
a “Occurrence” means the first time a VTE is encountered by a patient at a given dose level.
b “Recurrence” means the second time any VTE is encountered by a patient at a given dose level, not necessarily 
recurrence of the same VTE.
8.4.1.3
Dose Re-Escalation after Drug-Related AEs
After dose reductions for toxicity, the dose of ponatinib can be re-escalated from the reduced 
dose level to the previously administered dose level if either of the following criteria is met:

All Grade ≥2 nonhematologic toxicities have recovered to Grade ≤1 for at least 1 month, or
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
All Grade ≥3 hematologic and nonhematologic toxicities have recovered to Grade ≤2 and are 
manageable with supportive therapy.
Patients may receive stepwise dose escalations (eg, 10 mg QD to 15 mg QD to 30 mg QD) up to 
the starting dose if the above criteria continue to be met. In no circumstances should a patient 
receive a ponatinib dose higher than 30 mg QD.
Note: Patients with Grade ≥3 left ventricular dysfunction, CHF, or arterial occlusion are not 
eligible for dose re-escalation after resolution of their symptoms.
8.4.2
Imatinib
Doses of imatinib should be modified for toxicities according to standard practice and current 
local prescribing information. General guidelines are presented below.
8.4.2.1
Hepatotoxicity and Nonhematologic Drug-Related AEs
If patients experience bilirubin >3× the ULN or liver transaminases >5× the ULN, imatinib 
should be withheld until bilirubin levels have returned to <1.5× the ULN and transaminase levels 
to <2.5× the ULN. Treatment with imatinib may then continue at a reduced daily dose (ie, 600 to 
400 mg or 400 to 300 mg if a patient experiences an adverse reaction at a daily dose of 400 mg).
If patients experience a severe nonhematologic adverse reaction (such as severe hepatotoxicity or 
severe fluid retention), imatinib should be withheld until the event has resolved. Thereafter,
treatment can be resumed as appropriate depending on the initial severity of the event and local 
practice.
8.4.2.2
Hematologic Drug-Related AEs
If patients experience severe neutropenia or thrombocytopenia (ie, absolute neutrophil count 
[ANC] <0.5 × 109/L and/or platelets <10 × 109/L):
1. Check if cytopenia is related to leukemia (marrow aspirate or biopsy)
2. If cytopenia is unrelated to leukemia, reduce imatinib dose to 400 mg
3. If cytopenia persists for 2 weeks, reduce further to 300 mg
4. If cytopenia persists for 4 weeks and is still unrelated to leukemia, stop imatinib until ANC 
≥1× 109/L and platelets ≥20× 109/L, then resume treatment at 300 mg
8.4.2.3
Dose Re-Escalation after Resolution of Drug-Related AEs
The dose of imatinib can be re-escalated from the reduced dose level to the previously 
administrated dose level if the following criteria are met:

All Grade ≥2 non-hematologic toxicities have recovered to Grade ≤1 for at least 1 month

All Grade ≥3 hematologic and non-hematologic toxicities have recovered to Grade ≤2 and 
are manageable with supportive therapy
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Patients may receive stepwise dose escalations (eg, 300 mg QD to 400 mg QD to 600 mg QD) 
up to the starting dose if the above criteria continue to be met. In no circumstances should a 
patient receive an imatinib dose higher than 600 mg QD.
8.5
Excluded Concomitant Medications and Procedures
The following concurrent medications and treatments are prohibited:

Other anticancer therapies (except for optional prephase treatment, protocol-defined 
combination treatment [Section 8.1])

Other investigational drugs or devices

Herbal preparations or related over-the-counter preparations containing herbal ingredients

Elective surgery requiring inpatient care that can be postponed until study completion
The following concurrent medications should be avoided while taking ponatinib:

Medications that are strong inhibitors or inducers of CYP3A4 should be avoided, but are not 
prohibited (Appendix F) in patients assigned to the ponatinib arm. Consider alternatives to 
strong CYP3A4 inhibitors or inducers. If coadministration of ponatinib with strong inhibitors 
of CYP3A4 is unavoidable, a dose reduction is recommended; the ponatinib dose is to be 
lowered by 1 dose level from the current dose (that is, 15 mg for a patient receiving 30 mg, 
or 10 mg for a patient receiving 15 mg).

Medications with a known risk of TdP (see Appendix E):
–
Medications that are associated with the prolongation of the QT interval may interact 
with ponatinib and imatinib as well. Some medications associated with QT prolongation 
also interact with CYP3A4.
–
Medications that prolong the QT interval, but are not associated with a known risk of 
TdP, should be avoided, but are not prohibited. If such medications are necessary and 
used while a patient is on study, additional ECG monitoring should be performed as 
clinically indicated. Exception, if an alternative to the antiemetic agent ondansetron is not 
feasible and the investigator considers this the only suitable medication to manage 
symptoms then additional ECG monitoring should be performed and documented. 
Consult the medical monitor to discuss study drug discontinuation if any possible cardiac 
changes are noted.
Please refer to the current local prescribing information for information regarding drug 
interactions with imatinib and the other components of chemotherapy.
8.6
Permitted Concomitant Medications and Procedures
All treatments/therapy received within 30 days before the first dose of study drug will be 
recorded as prior treatments.
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All concomitant medications administered from the time of informed consent signature through 
the EOT visit (either the last dose of study drug or the investigator/patient decision to 
discontinue, whichever occurs later) are to be reported on the appropriate eCRF for each patient.
All routine and appropriate supportive care (including blood products, and hematopoietic growth 
factors) will be allowed during this study, as clinically indicated, and in accordance with 
standard-of-care practices. Clinical judgment should be exercised in the treatment of any AE 
experienced by an individual patient.
Information on all concomitant medications, administered blood products, and interventions 
occurring during the study must be recorded on each patient’s eCRF. Among other treatments for 
concurrent illnesses, the following therapies are allowed:

Medical or surgical treatment necessary for the patient’s well-being

Where appropriate, treatment with hematopoietic growth factors

Antiplatelet agents and anticoagulants are permitted with caution in patients who may be at 
risk of bleeding events
8.7
Precautions and Restrictions
To participate in this study, female and male patients must qualify for the study per the inclusion 
and exclusion criteria (Section 7.1 and Section 7.2, respectively).
It is not known what effects the study therapies have on human pregnancy or development of the 
embryo or fetus. Therefore, female patients participating in this study should avoid becoming 
pregnant, and male patients should avoid impregnating a female partner. Before starting 
treatment, male patients considering reproduction should be advised to seek counseling on sperm 
storage, and female patients considering pregnancy should be advised to seek counseling on egg 
storage. Nonsterilized female patients of reproductive age group and male patients should use 
effective methods of contraception through defined periods during and after study treatment. 
Lactating females should be advised not to breast feed. All patients must meet the inclusion 
criteria for female and male patients as outlined in Section 7.1.
8.8
Management of Clinical Events
Although the study excludes patients with active hepatitis B at the time of screening, both 
imatinib and ponatinib have been associated with reactivation of hepatitis B. It is recommended 
to consult an expert in liver disease before initiating treatment of patients with evidence of prior 
hepatitis B infection, and monitor these patients for clinical and laboratory signs of hepatitis B 
virus reactivation or hepatitis during study drug treatment and for several months following 
treatment discontinuation.
Patients with ALL are at increased risk of tumor lysis syndrome (TLS) with cytotoxic/cytolytic 
therapy. In patients with ALL, those with white blood cell (WBC) count ≥100,000 are 
considered high risk, and those with WBC count 50,000 to 100,000 are considered intermediate 
risk. Pre-existing uremia or hyperuricemia, decreased urinary flow or acidic urine, dehydration, 
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oliguria, anuria, and renal insufficiency or renal failure may increase the risk of TLS. 
Consequences of TLS include hyperphosphatemia, hyperkalemia, hypocalcemia, and uremia. 
Clinical manifestations of TLS may include nausea, vomiting, diarrhea, anorexia, lethargy, 
edema, fluid overload, hematuria, congestive heart failure, cardiac dysrhythmias, seizures, 
muscle cramps, tetany, syncope, and possible sudden death. If clinically presented, TLS should 
be managed according to local practice and guidelines, including prophylaxis where indicated. 
Guidelines on prophylaxis and management are included in Appendix L.
Refer to the current local ponatinib prescribing information for details on management of 
patients who have or who develop the following conditions: AOEs; VTEs; HTN; neuropathy; 
hepatotoxicity; CHF or left ventricular dysfunction; serious ocular toxicities; pancreatitis or 
lipase/amylase elevations; ocular toxicity, bleeding events; fluid retention/edema; cardiac 
arrhythmias; myelosuppression; tumor lysis syndrome; posterior reversible encephalopathy 
syndrome; compromised wound healing; or GI perforation.
Note: Monitor and manage BP elevations during the study and treat hypertension to normalize 
BP.
In patients with persistent elevation of cardiac troponin-I (cTnI) or N-terminal pro-brain 
natriuretic peptide (NT-proBNP)/B-type natriuretic peptide (BNP), performing an 
echocardiogram and/or consulting a cardiologist should be considered.
For all other therapies to be administered per this protocol, investigators should refer to the 
current local prescribing information for specific drugs for management of clinical events.
8.9
Blinding and Unblinding
This is an open-label study; patients and investigators will know the identity of each patient’s 
study drug. However, to protect study integrity, the study team (except a few members who are 
included in the patient management) will be blinded to the treatment assignment for data review.
8.10
Description of Investigational Agent
8.10.1
Ponatinib
Ponatinib investigational drug product is supplied as white, oval or round, film-coated tablets for 
oral administration. Each tablet contains 10 mg, 15 mg, or 30 mg of active ingredient. Other 
ingredients are typical pharmaceutical excipients: lactose monohydrate, microcrystalline 
cellulose, sodium starch glycolate, colloidal silicon dioxide, magnesium stearate, and a tablet 
coating comprised of polyethylene glycol, talc, polyvinyl alcohol, and titanium dioxide.
8.10.2
Imatinib
Imatinib 100 mg is supplied as the following 2 formulations:

A round, biconvex with beveled edges, film-coated tablet, scored on one side with letters S 
and A on each side of the score and “NVR” on the other side. The color is very dark yellow 
to brownish orange. Each tablet contains 100 mg of active ingredient.
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
Dark yellow to brownish-orange round film-coated tablets, embossed with “I” and “1” on 
both sides of the notch on one side and smooth on the other side of the tablet. The round 
tablets have a diameter of 7.65 mm x 0.20 mm. Each tablet contains 100 mg of active 
ingredient.
Imatinib 400 mg is supplied as the following 2 formulations:

A biconvex, ovaloid film-coated tablet with beveled edges and is unscored. The color is very 
dark yellow to brownish orange with “glivec” on one side. Each tablet contains 400 mg of 
active ingredient. 

Dark yellow to brownish-orange oval film-coated tablets, embossed with “I” and “2” on both 
sides of the notch on one side and smooth on the other side of the tablet. The oval tablets are 
15.15 mm x 0.20 mm long and 8.15 mm x 0.20 mm wide. The tablet can be divided into 
2 equal doses. Each tablet contains 400 mg of active ingredient.
8.11
Preparation, Reconstitution, and Dispensation
8.11.1
Ponatinib
Ponatinib tablets should be swallowed whole with water and should not be crushed or dissolved 
in liquid [31].
8.11.2
Imatinib
Imatinib is dispensed as film-coated tablets, as described in the local prescribing information.
8.12
Packaging and Labeling
8.12.1
Ponatinib
Ponatinib tablets will be supplied as follows:

10 mg tablets: 30 count in white high-density polyethylene (HDPE) bottles with foil 
induction seal and cap

15 mg tablets: 30 count in white HDPE bottles with foil induction seal and cap

30 mg tablets: 30 count in white HDPE bottles with foil induction seal and cap
Bottle labels will bear the appropriate label text as required by governing regulatory agencies. At 
a minimum, such text will include product name, product strength, number of tablets, and lot 
number.
8.12.2
Imatinib
Imatinib will either be dispensed from local supplies or provided by Takeda according to country 
regulatory requirements. If provided by Takeda, imatinib will be supplied as 100 mg and 400 mg 
film-coated tablets in appropriate packaging.
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8.13
Storage, Handling, and Accountability
8.13.1
Storage
Ponatinib and imatinib should be stored as described on the study drug labels.
8.13.2
Handling and Accountability
8.13.2.1
Ponatinib
The study pharmacist or designee at the investigative site will be responsible for handling and 
dispensing study drug and completing associated documentary paperwork.
Ponatinib supplies are shipped to the investigative site at appropriate intervals, depending on 
patient accrual. Supply shipping will be managed by interactive response technology (IRT). The 
site must use either an appropriate dispensing log/accountability form provided by the sponsor or 
an acceptable substitute. Each time study medication is dispensed for a patient, the following 
information is recommended to be recorded: the patient’s study number, tablet strength, the 
number of tablets dispensed (with the corresponding lot number), and the initials of the person 
dispensing the drug. These logs are to be maintained by the study pharmacist in the pharmacy 
throughout the duration of the study (or as per local legal requirements), and will be periodically 
verified by a representative of the sponsor. The investigator is responsible for ensuring that the 
patient diary and study drug provided to the patient and returned from the patient are accounted 
for and noted in source documentation.
In the event that a patient cannot visit the site to obtain the study drug due to unavoidable 
circumstances such as the coronavirus disease 2019 (COVID-19) pandemic, sites should contact 
the sponsor’s medical monitor/designee to arrange for an alternate mechanism 
(eg, direct-to-patient [DTP] shipping).
8.13.2.2
Imatinib
The study pharmacist or designee at the investigative site will be responsible for handling and 
dispensing study drug and completing associated documentary paperwork.
The site must use either an appropriate dispensing log/accountability form provided by the 
sponsor or an acceptable substitute. Each time study medication is dispensed for a patient, the 
following information is recommended to be recorded: the patient’s study number, tablet 
strength, the number of tablets dispensed (with the corresponding lot number), and the initials of 
the person dispensing the drug. These logs are to be maintained by the study pharmacist in the 
pharmacy throughout the duration of the study (or as per local legal requirements), and will be 
periodically verified by a representative of the sponsor. The investigator is responsible for 
ensuring that the patient diary and study drug provided to the patient and returned from the 
patient are accounted for and noted in source documentation.
In the event that a patient cannot visit the site to obtain the study drug due to unavoidable 
circumstances such as the COVID-19 pandemic, sites should contact the sponsor’s medical 
monitor/designee to arrange for an alternate mechanism (eg, DTP shipping).
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8.13.3
Disposition of Used and Unused Study Drug
No other use of ponatinib in this study is authorized by the sponsor. The principal investigator or 
designee will be responsible for the appropriate handling and disposition of residual study drug.
During the study and at termination, patients must return all unused study drug supplies and the 
return of these unused study drug supplies must be recorded. Returned supplies must not be 
redispensed.
Periodically throughout and at the conclusion of the study, a representative of the sponsor will 
conduct an inventory of unused study drug. At the completion of the study, a final study drug 
accountability review will be conducted, and any discrepancies must be investigated. All used 
and unused bottles or packs of study drug must be destroyed in an appropriate manner according 
to the standard practice at each study center (ie, destroyed at the site or returned to the local 
distribution center). Destruction of such supplies will be documented, and a representative of the 
sponsor will verify disposition records.
8.14
Other Protocol-Specified Materials
No other drugs or ancillary material are supplied for use in this study, unless otherwise required 
by national local law or regulations.
9.0
STUDY CONDUCT
This study will be conducted in compliance with the protocol, GCP, applicable regulatory 
requirements, and ICH guidelines.
9.1
Study Personnel and Organizations
The contact information for the sponsor’s medical monitor/designee for this study, the central 
laboratories, the coordinating investigator, and any other vendors may be found in the site 
operations manual. For 24-hour contact information, please refer to the site operations manual or 
equivalent.
9.2
Arrangements for Recruitment of Patients
Recruitment and enrollment strategies for this study may include recruitment from the 
investigator’s local practice or referrals from other physicians. If advertisements become part of 
the recruitment strategy, they will be reviewed by the institutional review board 
(IRB)/independent ethics committee (IEC) and Takeda (or designee).
It is not envisioned that prisoners (or other populations that might be subject to coercion or 
exploitation) will be enrolled into this study.
9.3
Treatment Group Assignments
The randomization scheme will be generated by an independent statistician at Takeda. Prior to 
dosing, a randomization number will be assigned to each patient. The randomization assignment 
will be implemented by IRT.
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9.4
Study Procedures
Refer to the SOE (Appendix A, Table 1 and Table 2) for timing of assessments. Additional 
details are provided as necessary in the sections that follow and in the SOE footnotes.
Tests and procedures should be performed on schedule, but occasional changes may be allowed 
for holidays, vacation, and other administrative reasons. If the study schedule is shifted, both 
assessments and dosing must be shifted to ensure collection of assessment is completed before 
dosing.
9.4.1
Screening Period Procedures
Screening tests and procedures are used to establish eligibility of the patient for the study. If any 
given procedure or laboratory test is repeated before randomization, patients must continue to 
maintain laboratory values within eligibility parameters. Any patient who is re-screened after 
screen failure must, in addition to the failed test, repeat only those screening tests that have fallen 
outside the specified screening period, as outlined in the SOE (Appendix A, Table 1). See 
Appendix A, Table 1 for all screening procedures. 
9.4.2
Informed Consent
Each patient must provide written informed consent by signing and dating an IRB/IEC-approved 
informed consent form (ICF) before any study-required procedures are conducted, unless those 
procedures are performed as part of the patient’s standard care.
During the consent process, the person obtaining consent must inform the patient of all elements 
of informed consent. Adequate time must be allowed for questions and for the patient to make a 
voluntary decision.
9.4.3
Enrollment and Randomization
Enrollment is defined as randomization to a treatment cohort. See Appendix A, Table 1 for 
enrollment procedures. Specific instructions for randomization will be supplied in the site 
operations manual. Randomization procedures should be performed following complete 
eligibility assessments and just before the initiation of the assigned dose cohort.
Patients will be randomized in a 2:1 ratio to receive oral ponatinib or imatinib (Cohort A and 
Cohort B, respectively) QD throughout the study. Study drug administration is detailed in 
Section 8.1. Each cycle of therapy will comprise 28 days of treatment, regardless of dose.
This study is open-label; patients and investigators will know the identity of each patient’s study 
drug. However, to protect study integrity, the study team (except a few members who are 
included in the patient management) will be blinded to the treatment assignment for data review. 
9.4.4
Medical/Surgical History and Demographics
During the screening period, demographic data and a complete medical and surgical history will 
be compiled for each patient. Details of the data to be collected are specified in the SOE 
footnotes (Appendix A, Table 1).
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9.4.5
Initial Leukemia Diagnosis
The initial leukemia diagnosis must be recorded during the screening period. Only patients who 
are newly diagnosed with Ph+ ALL or BCR-ABL1-positive ALL are eligible for this study.
9.4.6
Pregnancy Test
The screening pregnancy test must be a serum beta-human chorionic gonadotropin test and must 
be performed as specified in the SOE (Appendix A, Table 1). Monthly urine pregnancy testing 
will be performed during the study (through the first 20 cycles); from that point forward, urine 
pregnancy tests will be performed at quarterly patient visits (serum pregnancy test may be 
instead performed at the discretion of the investigator, upon request of an IEC/IRB, or if required 
by local regulations) (Appendix A, Table 1 and Table 2). Additional pregnancy testing may be 
performed at the discretion of the investigator, upon request of an IEC/IRB, or if required by 
local regulations.
9.4.7
Physical Examination and ECOG Performance Status
Complete physical examinations (including weight) will be completed as specified in the SOE 
(Appendix A, Table 1 and Table 2). Sites should calculate body surface area (BSA) from the 
weight and height measured at baseline as specified in the SOE (Appendix A, Table 1) and the 
additional weight assessments will be documented in the eCRF without the need to calculate the 
BSA. Height will be measured at screening only.
The ECOG performance status should be evaluated during each complete physical examination, 
as specified in the SOE (Appendix A, Table 1 and Table 2). Patients must have an ECOG 
performance status ≤2 to be eligible for this study. Additional details on assessing ECOG status 
are provided in the site operations manual.
9.4.8
Eye Examinations
A detailed eye history and eye examinations must be performed as specified in the SOE
(Appendix A, Table 1 and Table 2).
9.4.9
Vital Signs
Vital sign measurements will include systolic and diastolic BP, heart rate, respiratory rate, and 
body temperature. Vital sign measurements will be assessed as specified in the SOE 
(Appendix A, Table 1 and Table 2) and the SOE footnotes.
9.4.10
CV Risk Assessments
9.4.10.1
Framingham Score
The Framingham risk score (Appendix G) estimates the risk of various CV disease outcomes, 
and will be performed as specified in the SOE (Appendix A, Table 1 and Table 2). Details of 
assessing the Framingham risk scores are provided in the site operations manual.
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9.4.10.2
Ankle-Brachial Index
An assessment of the ankle-brachial index (ABI) will be performed to assess patients for the risk 
of peripheral arterial disease, as specified in the SOE (Appendix A, Table 1 and Table 2). 
Additional details on assessing the ABI are provided in the site operations manual.
9.4.10.3
12-Lead ECG
All ECGs must be 12-lead ECGs, performed as specified in the SOE (Appendix A, Table 1 and
Table 2). If medications known to prolong the QTcF interval are used while a patient is on study, 
then additional ECG monitoring should be performed as clinically indicated.
If the timing of a PK blood sample or other blood draw coincides with the timing of an ECG, the 
ECG should be performed first, followed by the blood draw.
9.4.11
Echocardiogram
An echocardiogram for assessment of LVEF must be performed as specified in the SOE
(Appendix A, Table 1 and Table 2).
9.4.12
Prior and Concomitant Medications and Procedures
All medications/therapies and therapeutic procedures used/completed by the patient within 
30 days before the first dose of study drug will be recorded as prior medication in the eCRF. All 
medications/therapies and therapeutic procedures used/completed by the patients from the 
signing of the ICF until the EOT visit (30 days after the last dose) will be recorded in the eCRF 
as concomitant medications, as specified in the SOE (Appendix A, Table 1 and Table 2). See 
Section 8.5 and Section 8.6 for a list of medications and therapies that are prohibited and/or 
allowed during the study.
9.4.13
AEs
Monitoring of AEs, serious and nonserious, will be conducted throughout the study, starting on 
the date of signed ICF, and continuing until the 30-day EOT visit, as specified in the SOE
(Appendix A, Table 1 and Table 2). Refer to Section 10.0 for details regarding definitions, 
documentation, and reporting of AEs and SAEs.
It is expected that new and updated AEs and concomitant medications will be reported within the 
treatment period; ongoing AEs thought to be at least possibly study drug–related; and all ongoing 
SAEs should be followed at least every 4 weeks until they resolve to baseline (or to NCI 
CTCAE, version 5.0, Grade ≤1), stabilize, or are considered to be chronic/irreversible.
9.4.14
Clinical Laboratory Evaluations
Clinical laboratory evaluations will be performed as specified in the SOE (Appendix A, Table 1
and Table 2). Laboratory test results should be assessed before dosing. Handling and shipment of 
clinical laboratory samples will be outlined in the laboratory manual.
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9.4.14.1
Hematology
Blood samples for complete blood count with differential will be obtained as specified in the 
SOE (Appendix A, Table 1 and Table 2), or more frequently as clinically indicated.
9.4.14.2
Serum Analysis
a) Chemistry
The full chemistry panel must be obtained as specified in the SOE (Appendix A, Table 1
and Table 2), or more frequently as clinically indicated.
If CrCl is to be estimated, the Cockcroft-Gault formula will be employed as follows:
Estimated CrCl = [(140 - Age) * weight (kg)] / [72 * serum creatinine (mg/dL)]
For female patients, the result of the formula above should be multiplied by 0.85.
b) Fasting Glucose, Cholesterol, Lipids, and Glycosylated Hemoglobin (HbA1c)
Fasting glucose, glycosylated hemoglobin (HbA1c), and serum lipid panel (total, 
high-density lipoprotein, and low-density lipoprotein), including triglycerides, must be 
collected during screening and at subsequent time as specified in the SOE (Appendix A, 
Table 1 and Table 2), or more frequently as clinically indicated.
c) C-Reactive Protein, cTnI, and NT-proBNP or BNP
C-reactive protein, cTnI, and NT-proBNP or BNP assessments must be performed as 
specified in the SOE (Appendix A, Table 1 and Table 2), or more frequently as clinically 
indicated.
d) Hepatitis B Serology
At the time of screening and during the study if clinically indicated, blood serum must be 
tested for hepatitis B surface antigen, hepatitis B core antibody, and hepatitis B surface 
antibody, at minimum, as specified in the SOE (Appendix A, Table 1 and Table 2).
9.4.15
Disease Assessment
9.4.15.1
BM Aspirate
BM samples needed to assess the MRD-negative CR rate at the end of induction and other 
efficacy endpoints will be collected as specified in the SOE (Appendix A, Table 1 and Table 2). 
The optimal sample for MRD assessment is the first pull or early pull of the BM aspirate. 
Additional details regarding handling, shipping, and analysis of BM aspirates are provided in the 
laboratory manual.
Note: The BM aspirate on Cycle 3 Day 1 is only required in patients who have not achieved CR 
at Cycle 2 Day 1 (see Table 13.a for the definition of CR). Patients who achieve CR but do not 
achieve MRD-negative status or who achieve MRD-negative status with CRi at the end of 
induction (ie, end of Cycle 3) may continue on study treatment at the investigator’s discretion.
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All other patients will be discontinued from the study drug. For all discontinued patients, the 
patient’s treating physician should consider alternative therapy options.
Quantitative assessment of BCR-ABL1/ABL1 levels will be performed by a central molecular 
diagnostics laboratory, and the results will be reported to the participating investigator. For 
patients with the p190 BCR-ABL1 variant, the absolute ratio of BCR-ABL1 to ABL1 transcripts 
will be reported. For patients with the p210 BCR-ABL1 variant, the ratio of BCR-ABL1 to 
ABL1 transcripts will be reported on the IS (see Table 13.a for the definition of MRD 
negativity).
While BM samples will be sent to a central laboratory for molecular assessment, a portion of the 
BM aspirate sample will also be sent to a local laboratory for CR and relapse from CR 
assessments. A portion of the BM aspirate sample may also be used for exploratory biomarker 
assessments as described in Section 9.4.15.2.
BM aspirates may be performed at other times when clinically indicated. Results from the local 
laboratory testing of any BM aspirate, whether scheduled or unscheduled, must be recorded in 
the patient’s eCRF.
9.4.15.2
Peripheral Blood Samples for Molecular Response, CR and Exploratory Biomarker 
Assessments
Peripheral blood samples needed to assess molecular response and exploratory biomarkers will 
be collected as specified in the SOE (Appendix A, Table 1 and Table 2). Details of handling, 
shipping, and analysis of peripheral blood samples are provided in the laboratory manual.
Quantitative assessment of BCR-ABL1 levels (ie, molecular response assessments) will be 
performed by a central molecular diagnostics laboratory, and the results will be reported to the 
participating investigator. For patients with the p190 BCR-ABL1 variant, the absolute ratio of 
BCR-ABL1 to ABL1 transcripts will be reported. For patients with the p210 BCR-ABL1 variant, 
the ratio of BCR-ABL1 to ABL1 transcripts will be reported on the IS.
Peripheral blood samples will also be collected for local laboratory CR and relapse from CR 
assessments, and results from the local laboratory testing, whether scheduled or unscheduled, 
must be recorded in the patient’s eCRF.
Exploratory biomarker assessments will include analysis of molecular determinants of response 
or resistance to ponatinib and imatinib, including those present at the initiation of study drug or 
those that develop during study treatment. Exploratory biomarker assessments could also include 
analysis of biomarkers affecting ponatinib efficacy or safety. This testing will include, but may 
not be limited to, analysis of BCR-ABL1 mutation status.
9.4.15.3
Extramedullary Disease
Extramedullary disease assessments will be performed locally as clinically indicated and will 
include lumbar punctures to test cerebrospinal fluid (CSF) for CNS disease as specified in the 
SOEs (Appendix A, Table 1 and Table 2). Additional assessments for other extramedullary 
involvement (ie, lymphadenopathy, splenomegaly, skin/gum infiltration, testicular mass) should 
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be performed as clinically indicated throughout the study. Results from local laboratory testing, 
whether scheduled or unscheduled, must be recorded in the patient’s eCRF.
9.4.16
Quality of Life and Health Outcomes Measures
Both the EQ-5D-5L and the FACT-Leu forms are validated and self-administered forms. The 
EQ-5D-5L is a general questionnaire of health-related quality of life (HRQOL) issues, developed 
by the EuroQOL Group. The FACT-Leu questionnaire was developed specifically for patients 
with leukemia by the Functional Assessment of Chronic Illness Therapy Measurement System 
(www.facit.org) which manages administration, scoring, and interpretation of questionnaires that 
measure HRQOL for people with chronic illnesses. Patients for whom a validated translation 
exists in a language in which they are fluent will complete the EQ-5D-5L and the FACT-Leu 
during study visits, as specified in the SOE (Appendix A, Table 1 and Table 2) [32-35]. Details 
on administration of the EQ-5D-5L are provided in the site operations manual.
9.4.17
Medical Resource Utilization Data Collection
All medical care encounters will be collected for all patients until study closure, as specified in 
the SOE (Appendix A, Table 1 and Table 2).
9.4.18
PK Measurements: Ponatinib
Blood samples for plasma PK assessments will be collected as specified in the SOE 
(Appendix A, Table 1 and Table 2) in patients assigned to the ponatinib cohort. Details on 
sample collection times are provided in the SOE footnotes. Details of collection and handling of 
plasma PK samples are provided in the laboratory manual. The date and exact time of dosing of 
the 2 preceding doses of ponatinib before all PK sample collections, and the date and exact time 
of collection of all the PK samples should be recorded in the eCRF.
9.4.19
Changes to Study Procedures Due to COVID-19 Pandemic
The following information provides guidance regarding changes to the study procedures that 
could be implemented for study participants or study sites which are affected by the COVID-19 
pandemic. This guidance takes references from the FDA Guidance on Conduct of Clinical Trials 
of Medical Products during COVID-19 Public Health Emergency - Guidance for Industry, 
Investigators, and Institutional Review Boards, March 2020, updated 02 July 2020, and the EMA 
Guidance on the Management of Clinical Trials During the COVID 19 (Coronavirus) Pandemic, 
Version 3 (28 April 2020).
As the COVID-19 pandemic may peak in different regions at different times and restrictions 
implemented by local laws and recommendations may vary, any decision on procedural changes 
should be made on a case-by-case basis by the investigator in consultation with the study team 
and the medical team sponsor’s medical monitor/designee as needed, while maintaining patient 
safety and confidentiality as the priority.
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Procedural changes due to COVID-19 may include the following: 

Informed Consent Procedure: If necessary, informed consent from a potential or current 
study participant may be obtained via alternate methods, including but not limited to, 
electronic informed consent (eIC), remote consenting process, or an electronic face-to-face 
consent interview (if approved by IRB/IEC) when these individuals are unable to travel to the 
site.

During the first 20 cycles of treatment (induction, consolidation, and maintenance phases), it 
is expected that the patient will visit the site at least once per cycle for chemotherapy drug 
administration (as they are administered intravenously) and/or bone marrow aspiration or any 
other procedures critical for patient management. Other visits may be conducted at the clinic 
or by home health care visits to extend flexibility to patients during the COVID-19 
pandemic. The data collected from home health care visits may be handled differently in the 
final data analysis, with this documented in the statistical analysis plan (SAP). 

All attempts should be made to perform the assessments with the patient present at the site. 
However, in cases where patient’s visit to the site is not feasible (patient cannot travel to the 
site or in cases where the investigator believes that is best for patient’s and site staff’s safety 
not to visit to the site), alternative evaluation such as local laboratories and/or telehealth (the 
ability to connect a physician to a patient)/telemedicine (remote clinical assessments) or 
home health care (performing some assessments in a patient’s home by a qualified health 
care professional) will be allowed if permitted by local laws and regulations. 
–
For home health care visits, collection of clinical laboratory samples (blood specimen 
collection or other diagnostic tests) may be performed by the investigator or qualified 
health care professional who can visit the study participant’s residence.
–
ECG procedures: For home health care visits, ECGs may be performed by a qualified 
health care professional who is authorized/certified to perform such tests routinely.
–
Remote visits via virtual communications (eg, telehealth application) may be performed 
as a safety check on patient well-being.

Deviations from the protocol-specified procedures (eg, not collecting a protocol-specified 
specimen, such as postdose bloodwork) will be recorded as related to COVID-19.

Allow the use of alternate means to capture patient-reported outcomes/quality-of-life data 
(eg, a paper-based or web-based questionnaire) as a back-up only if these data cannot be 
captured on tablet devices at site.

Allow transfer of study participants to investigational sites away from risk zones or closer to 
their home to sites already participating in the study or new ones.

Alternate study drug delivery mechanisms, eg, dispensing additional study drug at clinic 
visits or DTP delivery of the study drug from the investigational site to patients in 
compliance with national laws or temporary national emergency measures and Takeda 
processes (Section 8.13.2 Handling and Accountability).
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9.5
Completion of Study Treatment (for Individual Patients)
All patients will be considered to have completed study treatment when they are deceased, have 
failed to achieve the primary endpoint at the end of induction (patients who do not achieve the 
primary endpoint may remain on study treatment, at the investigator’s discretion, if they have 
achieved CR or MRD-negative status with CRi at the end of induction), have experienced 
relapse from CR or have progressive disease, have an unacceptable toxicity, have withdrawn 
consent, have proceeded to HSCT or alternative therapy, or until the sponsor terminates the 
study, whichever occurs first.
9.6
Completion of Study (for Individual Patients)
The study will be completed for individual patients when death occurs, or the study has been 
terminated by the sponsor.
9.7
Discontinuation of Treatment With Study Drug and Patient Replacement
Discontinuation of treatment with study drug is to be reviewed and confirmed by the sponsor’s 
medical monitor or designee.
Study drug must be discontinued immediately for patients who become pregnant. 
Treatment with study drug may also be discontinued for any of the following reasons:

AE

Protocol deviation

Study terminated by sponsor

Withdrawal by patient

Lost to follow-up

Failure to achieve CR

Failure to achieve MRD-negative

Progressive disease

Relapse from CR

HSCT

Other
Patients who discontinue study drug will not be replaced.
Once study drug has been permanently discontinued, all study procedures outlined for the EOT 
visit will be completed as specified in the SOE (Table 2). The primary reason for study drug 
discontinuation will be recorded on the eCRF. Investigators should refer to the current local 
prescribing information for details on criteria for discontinuing imatinib therapy. Regardless of 
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the duration of treatment, all patients will remain on study for follow-up as described in 
Section 9.10.
9.8
Withdrawal of Patients From Study
Study participation by individual sites or the entire study may be prematurely terminated if, in 
the opinion of the investigator or sponsor, there is sufficient reasonable cause. Written 
notification documenting the reason for study termination will be provided to the investigator or 
sponsor by the terminating party.
A patient may be withdrawn from the study for any of the following reasons; the reason for 
withdrawal from the study must be documented in the eCRF:

Death

Study terminated by sponsor

Withdrawal by patient

Lost to follow-up

Other
9.9
Study Compliance
Study drug will be administered or dispensed only to eligible patients under the supervision of 
the investigator or identified subinvestigator(s). The appropriate study personnel will maintain 
records of study drug receipt and dispensing. (See also Section 8.13.2 and Section 8.13.3.) 
Patients will be provided a diary or equivalent where the date and time of ponatinib and imatinib 
administration will be recorded; complete instructions will be provided with the site operations 
manual.
9.10
Post-treatment Follow-Up Assessments
Patients who stop study treatment due to failure to achieve the primary endpoint (patients who do 
not achieve the primary endpoint may remain on study drug, at the investigator’s discretion, if 
they have achieved CR or MRD-negative status with CRi at the end of induction), withdrawal of 
informed consent, having relapse from CR or having progressive disease, proceeding to HSCT or 
alternative therapy, or until the patient’s death will be followed for OS. Survival data will be 
collected every 3 months ±14 days, starting after the last dose of study drug or the 
investigator/patient decision to discontinue treatment (whichever occurs later).
All patients who discontinue study treatment will be followed for survival as specified in the 
SOE (Table 2). Patients who discontinue study treatment without relapse from CR, will be 
followed for investigator-reported disease status (eg, relapse from CR) and survival, and 
reporting of alternative therapies, wherever available. Date of relapse to be reported and noted in 
source documentation. Patients who discontinue study treatment due to HSCT will be followed 
per the on-study data collection schedule as specified in the SOE for posttransplantation data
collection, including transplant-related procedures, investigator-reported disease status (eg, 
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relapse from CR), survival, and the use of post-transplant treatment (chemotherapy, TKI). 
Patients who proceed to alternative therapy will also be discontinued from study treatment and 
will be followed for investigator-reported disease status (eg, relapse from CR) and survival.
Survival, HSCT, and the start of alternative therapy data may be collected by methods that 
include, but are not limited to, telephone, email, mail, and retrieval from online social security 
indexes and other public records as permitted by local regulations. The EOS eCRF page is to be 
completed at the time the patient discontinues from the survival follow-up period. See the SOE 
for appropriate assessments during follow-up.
Note: Related SAEs occurring during the posttreatment period must be reported to the Global 
Pharmacovigilance department or designee. This includes deaths that the investigator considers 
related to study drug that occur during the post-treatment follow-up period. Refer to Section 10.0
for details regarding definitions, documentation, and reporting of SAEs.
10.0
ADVERSE EVENTS
10.1
Definitions
10.1.1
PTE Definition
Pretreatment event is any untoward medical occurrence in a patient or subject who has signed 
informed consent to participate in a study but before administration of any study medication; it 
does not necessarily have to have a causal relationship with study participation.
10.1.2
AE Definition
Adverse event means any untoward medical occurrence in a patient or subject administered a 
pharmaceutical product; the untoward medical occurrence does not necessarily have a causal 
relationship with this treatment. An AE can therefore be any unfavorable and unintended sign 
(including an abnormal laboratory finding), symptom, or disease temporally associated with the 
use of a medicinal (investigational) product whether or not it is related to the medicinal product. 
This includes any newly occurring event, or a previous condition that has increased in severity or 
frequency since the administration of study drug.
An abnormal laboratory value will not be assessed as an AE unless that value leads to 
discontinuation or delay in treatment, dose modification, therapeutic intervention, or is 
considered by the investigator to be a clinically significant change from baseline.
10.1.3
SAE Definition
Serious adverse event means any untoward medical occurrence that at any dose:

Results in death.

Is life-threatening (refers to an AE in which the patient was at risk of death at the time of the 
event. It does not refer to an event which hypothetically might have caused death if it were 
more severe).
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
Requires inpatient hospitalization or prolongation of an existing hospitalization (see 
clarification in the paragraph in Section 10.2 on planned hospitalizations).

Results in persistent or significant disability or incapacity. (Disability is defined as a 
substantial disruption of a person’s ability to conduct normal life functions).

Is a congenital anomaly/birth defect.

Is a medically important event. This refers to an AE that may not result in death, be 
immediately life-threatening, or require hospitalization, but may be considered serious when, 
based on appropriate medical judgment, may jeopardize the patient, require medical or 
surgical intervention to prevent 1 of the outcomes listed above, or involves suspected 
transmission via a medicinal product of an infectious agent. Examples of such medical events 
include allergic bronchospasm requiring intensive treatment in an emergency room or at 
home, blood dyscrasias or convulsions that do not result in inpatient hospitalization, or the 
development of drug dependency or drug abuse; any organism, virus, or infectious particle 
(eg, prion protein transmitting transmissible spongiform encephalopathy), pathogenic or 
nonpathogenic, is considered an infectious agent.
In this study, intensity for each AE, including any laboratory abnormality, will be determined 
using the NCI CTCAE, version 5.0, 2018 [30]. Clarification should be made between an SAE 
and an AE that is considered severe in intensity (Grades 3 or 4), because the terms serious and 
severe are NOT synonymous. The general term severe is often used to describe the intensity 
(severity) of a specific event; the event itself, however, may be of relatively minor medical 
significance (such as a Grade 3 headache). This is NOT the same as serious, which is based on 
patient/event outcome or action criteria described above, and is usually associated with events 
that pose a threat to a patient’s life or ability to function. A severe AE (Grades 3 or 4) does not 
necessarily need to be considered serious. For example, a white blood cell count of 1000/mm3 to 
less than 2000/mm3 is considered Grade 3 (severe) but may not be considered serious. 
Seriousness (not intensity) serves as a guide for defining regulatory reporting obligations.
10.1.4
AEs of Special Interest Definitions
AOEs and VTEs have been identified as AEs of special interest (AESIs) for ponatinib. These 
include serious or nonserious arterial and venous thrombotic and occlusive AEs.
The sponsor has determined that the events in the following list should be considered AESIs:

MI: The Third Universal Definition of Myocardial Infarction [36] is to define MI. Acute MI 
is used when there is evidence of myocardial necrosis in a clinical setting consistent with 
myocardial ischemia. Any one of the following:
–
A rise and/or fall of cardiac biomarker values (preferably cardiac troponin [cTn]) with at 
least 1 value above the 99th percentile upper reference limit (URL) and with at least 1 of 
the following:

Symptoms of ischemia.
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
New or presumed new significant ST-segment T-wave changes or new left bundle 
branch block (LBBB).

Development of pathological Q waves in the ECG.

Imaging evidence of new loss of viable myocardium or new regional wall motion 
abnormality.

Identification of an intracoronary thrombus by angiography or autopsy.
–
Cardiac death with symptoms suggestive of myocardial ischemia and presumed new 
ischemic ECG changes or new LBBB, but death occurred before cardiac biomarkers were 
obtained or would be increased.
–
Percutaneous coronary intervention-related MI was arbitrarily defined by elevation of 
cTn values (>5 × 99th percentile URL) in patients with normal baseline values 
(≤99th percentile URL) or a rise of cTn values >20% if the baseline values were elevated 
and were stable or falling. In addition, either (1) symptoms suggestive of myocardial 
ischemia, (2) new ischemic ECG changes, (3) angiographic findings consistent with a 
procedural complication, or (4) imaging demonstration of new loss of viable myocardium 
or new regional wall motion abnormality were required.
–
Stent thrombosis associated with MI when detected by coronary angiography or autopsy 
in the setting of myocardial ischemia and with a rise and/or fall of cardiac biomarker 
values with at least 1 value above the 99th percentile URL.
–
Coronary artery bypass grafting-related MI was arbitrarily defined by elevation of cardiac 
biomarker values (>10 × 99th percentile URL) in patients with normal baseline cTn 
values (<99th percentile URL). In addition, either (1) new pathological Q waves or new 
LBBB, (2) angiographic documented new graft or new native coronary artery occlusion, 
or (3) imaging evidence of new loss of viable myocardium or new regional wall motion 
abnormality.

Angina (newly diagnosed or worsening of existing or unstable angina).

CAD (newly diagnosed or worsening of existing CAD) or symptoms that may reflect CV 
disease [36].

Cerebrovascular ischemic disease, including ischemic or hemorrhagic stroke, vascular 
stenosis, TIA, cerebrovascular occlusive disease documented on diagnostic neuroimaging, or 
symptoms that may reflect cerebrovascular disease [37].

New onset or worsening of peripheral artery occlusive disease (eg, of the renal artery, 
mesenteric artery, or femoral artery) or symptoms that may reflect peripheral vascular 
disease.

Retinal vascular thrombosis, both venous and arterial.
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
Venous thromboembolism that could result in significant compromise of organ function or 
other significant consequences (eg, pulmonary embolism, portal vein thrombosis, or renal 
vein thrombosis), or symptoms that may reflect venous thrombosis.

Additionally, the sponsor has a list of a broad range of nonspecific terms that could meet the 
criteria for AOEs and VTEs. The sponsor will periodically look at the safety data and inform 
the site if any AE qualifies for AOEs/VTEs as per that criteria. Dose modification guidelines 
for AOEs/VTEs are presented in Section 8.4.1.2.
–
AOEs and VTEs will be documented in both cohorts for comparison.
10.2
Procedures for Recording and Reporting AEs and SAEs
All AEs spontaneously reported by the patient and/or in response to an open question from study 
personnel or revealed by observation, physical examination, or other diagnostic procedures will 
be recorded on the appropriate page of the eCRF (see Section 10.3 for the period of observation). 
Any clinically relevant deterioration in laboratory assessments or other clinical finding is 
considered an AE. When possible, signs and symptoms indicating a common underlying 
pathology should be noted as a single comprehensive event.
Regardless of causality, SAEs must be reported by the investigator to the Takeda Global 
Pharmacovigilance department or designee within 24 hours of becoming aware of the event. 
Reporting details and contact information are provided in the site operations manual.
If information not available at the time of the first report becomes available at a later date, then 
the investigator will transmit a follow-up electronic data capture (EDC) SAE report (or a 
paper-based SAE form if an EDC SAE report is not feasible) or provide other documentation 
immediately within 24 hours of receipt. Copies of any relevant data from the hospital notes 
(eg, ECGs, laboratory tests, discharge summary, postmortem results) should be sent to the 
addressee, if requested.
All SAEs should be followed up until resolution or permanent outcome of the event. The 
timelines and procedure for follow-up reports are the same as those for the initial report.
Planned hospital admissions or surgical procedures for an illness or disease that existed before 
study drug was given are not to be considered AEs unless the condition deteriorated in an 
unexpected manner during the study (eg, surgery was performed earlier or later than planned).
For both serious and nonserious AEs, the investigator must determine both the severity (toxicity 
grade) of the event and the relationship of the event to study drug administration.
Severity (toxicity grade) for each AE, including any laboratory abnormality, will be determined 
using the NCI CTCAE, version 5.0, 2018 [30]. The criteria are provided in the site operations 
manual.
Relationship of the event to study drug administration (ie, its causality) will be determined by 
the investigator responding yes (related) or no (unrelated) to this question: Is there a reasonable 
possibility that the AE is associated with the study drug?
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10.3
Monitoring of AEs and Period of Observation
AEs, both nonserious and serious, will be monitored throughout the study as follows:

AEs will be reported from the signing of the ICF through 30 days after administration of the 
last dose of study drug and recorded in the eCRFs. AEs should be monitored until they are 
resolved or return to baseline or are clearly determined to be due to a patient’s stable or 
chronic condition or intercurrent illness(es); the exception is peripheral neuropathy, which 
will be followed monthly until (1) resolution of peripheral neuropathy, (2) the start of a 
second-line alternative antineoplastic treatment, or (3) 6 months after PD has occurred, 
whichever occurs first.

SAEs will be reported to the Takeda Global Pharmacovigilance department or designee from 
the signing of informed consent through 30 days after administration of the last dose of study 
drug and recorded in the eCRF. After this period, only related SAEs must be reported to the 
Takeda Global Pharmacovigilance department or designee. SAEs should be monitored until 
they are resolved, return to baseline, or are clearly determined to be due to a patient’s stable 
or chronic condition or intercurrent illness(es).
10.4
Procedures for Reporting Drug Exposure During Pregnancy and Birth Events
If a female study participant or a female partner of a male study participant becomes pregnant or 
suspects that she is pregnant during this study, the sponsor must be contacted immediately. 
Reporting details and contact information are provided in the site operations manual.
Study drug must be discontinued immediately for patients who become pregnant (see 
Section 9.7). 
10.5
Procedures for Reporting Product Complaints or Medication Errors (Including 
Overdose)
A product complaint is a verbal, written, or electronic expression that implies dissatisfaction 
regarding the identity, strength, purity, quality, or stability of a drug product. Individuals who 
identify a potential product complaint situation should immediately report this via the phone 
numbers or email addresses provided in the pharmacy manual for ponatinib and imatinib (refer to 
local guidelines or labeling instructions for backbone chemotherapy agents).
A medication error is a preventable event that involves an identifiable patient and that leads to 
inappropriate medication use, which may result in patient harm. Whereas overdoses and 
underdoses constitute medication errors, doses missed inadvertently by a patient do not. 
Individuals who identify a potential medication error (including overdose) situation should 
immediately report this via the phone numbers or email addresses provided in the pharmacy 
manual for ponatinib and imatinib (refer to local guidelines or labeling instructions for backbone 
chemotherapy agents).
Product complaints and medication errors in and of themselves are not AEs. If a product 
complaint or a medication error results in an SAE, the SAE should be reported. Medication 
errors should also be documented accurately in the patient diary.
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10.6
Safety Reporting to Investigators, IRBs or IECs, and Regulatory Authorities
The sponsor will be responsible for reporting all suspected unexpected serious adverse reactions 
(SUSARs) and any other applicable SAEs to regulatory authorities, including the European 
Medicines Agency (EMA), investigators and IRBs or IECs, as applicable, in accordance with 
national regulations in the countries where the study is conducted. Relative to the first awareness 
of the event by/or further provision to the sponsor or sponsor’s designee, SUSARs will be 
submitted to the regulatory authorities as an expedited report within 7 days for fatal and life-
threatening events and within 15 days for other serious events, unless otherwise required by 
national regulations. The sponsor will also prepare an expedited report for other safety issues 
where these might materially alter the current benefit-risk assessment of an investigational 
medicinal product or that would be sufficient to consider changes in the investigational 
medicinal product’s administration or in the overall conduct of the study. The investigational site 
also will forward a copy of all expedited reports to his or her IRB or IEC in accordance with 
national regulations.
11.0
STUDY-SPECIFIC COMMITTEES
11.1
Steering Committee
The steering committee will comprise medical experts involved in the study, the sponsor, and an 
independent statistician. The steering committee will remain blinded to treatment assignments 
throughout the conduct of the study. The steering committee will oversee the conduct and 
reporting of the study, ensuring expert clinical guidance and a high standard of scientific quality, 
and making any necessary modifications to the protocol. The Steering Committee Charter will 
define the responsibilities of the committee.
11.2
Independent Data Monitoring Committee
An independent data monitoring committee (IDMC) supported by an independent statistician 
will review safety and efficacy data at the planned primary analysis and at regular intervals 
outlined in the charter and make recommendations on study conduct if needed. The IDMC will 
review the outcomes at the interim and final analyses for MRD-negative CR, EFS, and the 
futility analysis for OS.
The IDMC will provide a recommendation regarding study continuation based on the safety and 
efficacy parameters. If the study is terminated early based on the IDMC recommendation, 
Takeda will notify the appropriate regulatory authorities. In addition, the IDMC will periodically 
review safety data at regularly scheduled meetings prespecified in the IDMC charter.
Study accrual will not be interrupted because of the scheduled safety reviews. The IDMC or 
study team may request an ad hoc meeting for any reason, including a significant unexpected 
safety event, follow-up of an observation during a planned IDMC meeting, or a report external to 
the study, such as publication of study results from a competing product. At each review, patient 
incidence rates of AEs (including all SAEs, treatment-related AEs, serious treatment-related 
events, and events requiring the discontinuation of study drug) will be tabulated by System 
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Organ Class (SOC), Preferred Term, and severity grade. Listings and/or narratives of on-study 
deaths and other serious and significant AEs, including any early withdrawals because of AEs, 
will be provided. Records of all meetings will be archived. The IDMC will communicate major 
safety concerns and recommendations regarding study modification or termination to Takeda.
Details of the IDMC will be captured in a charter before the start of the study. Further details 
will be provided in the IDMC charter.
11.3
Cardiovascular Endpoint Adjudication Committee
The cardiovascular endpoint adjudication committee (CVEAC) will comprise independent 
experts with experience and training appropriate for reviews of the CV AOE and VTE endpoints. 
They will review all CV events defined as AOEs and VTEs reported by the sites (ie, initial 
diagnoses, laboratory values, results of procedures, hospital discharge summaries) to determine 
the occurrence of CV endpoints. The adjudication of these events will be performed based on the 
CVEAC adjudication charter, which will document details for performing adjudication, to be 
written before the start of the study. The CVEAC’s assessment of each potential CV endpoint 
will be documented and will be used in the endpoint analysis. The process will be coordinated by 
the contract research organization (CRO), and the CVEAC charter will define the endpoints and 
the responsibilities of the committee.
12.0
DATA HANDLING AND RECORDKEEPING
The full details of procedures for data handling will be documented in the data management plan. 
If selected for coding, AEs, medical history, and concurrent conditions will be coded using the 
Medical Dictionary for Regulatory Activities (MedDRA). Drugs will be coded using the WHO 
Drug Dictionary.
12.1
eCRFs
Completed eCRFs are required for each patient who signs an ICF.
The sponsor or its designee will supply investigative sites with access to eCRFs and will make 
arrangements to train appropriate site staff in the use of the eCRF. These forms are used to 
transmit the information collected in the performance of this study to the sponsor, CRO partners, 
and regulatory authorities. Investigative sites must complete eCRFs in English.
After completion of the entry process, computer logic checks will be run to identify items, such 
as inconsistent dates, missing data, and questionable values. Queries may be issued by Takeda 
personnel (or designees) and will be answered by the site.
Any change of, modification of, or addition to the data on the eCRFs should be made by the 
investigator or appropriate site personnel. Corrections to eCRFs are recorded in an audit trail that 
captures the old information, the new information, identification of the person making the 
correction, the date the correction was made, and the reason for change.
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The principal investigator must review the eCRFs for completeness and accuracy and must sign 
and date the appropriate eCRFs as indicated. Furthermore, the principal investigator must retain 
full responsibility for the accuracy and authenticity of all data entered on the eCRFs.
Electronic CRFs will be reviewed for completeness and acceptability at the study site during 
periodic visits by study monitors. The sponsor or its designee will be permitted to review the 
patient’s medical and hospital records pertinent to the study to ensure accuracy of the eCRFs. 
The completed eCRFs are the sole property of the sponsor and should not be made available in 
any form to third parties, except for authorized representatives of appropriate governmental 
health or regulatory authorities, without written permission of the sponsor.
12.2
Record Retention
The following procedure applies to all countries except for Japan (Section 12.2.1). The 
investigator agrees to keep the records stipulated in Section 12.1 and those documents that 
include (but are not limited to) the study-specific documents, the identification log of all 
participating patients, medical records, temporary media such as thermal-sensitive paper, source 
worksheets, all original signed and dated ICFs, patient authorization forms regarding the use of 
personal health information (if separate from the ICFs), electronic copy of eCRFs, including the 
audit trail, and detailed records of drug disposition to enable evaluations or audits from 
regulatory authorities, the sponsor or its designees. Any source documentation printed on 
degradable thermal-sensitive paper should be photocopied by the site and filed with the original 
in the patient’s chart to ensure long-term legibility. Furthermore, ICH E6 Guideline, 
Section 4.9.5, requires the investigator to retain essential documents specified in ICH E6 
(Section 8) until at least 2 years after the last approval of a marketing application for a specified 
drug indication being investigated or, if an application is not approved, until at least 2 years after 
the investigation is discontinued and regulatory authorities are notified. In addition, ICH E6 
Section 4.9.5 states that the study records should be retained until an amount of time specified by 
applicable regulatory requirements or for a time specified in the Clinical Study Site Agreement 
between the investigator and sponsor.
Refer to the Clinical Study Site Agreement for the sponsor’s requirements on record retention. 
The investigator should contact and receive written approval from the sponsor before disposing 
of any such documents.
12.2.1
Japan Record Retention
The following procedure applies to Japanese sites only.
The investigator and the head of the institution agree to keep the records stipulated in 
Section 12.1 and those documents that include (but are not limited to) the study-specific 
documents, the identification log of all participating patients, medical records, temporary media 
such as thermal-sensitive paper, source worksheets, all original signed and dated informed 
consent forms, patient authorization forms regarding the use of personal health information (if 
separate from the informed consent forms), copies of all paper CRFs and query 
responses/electronic copy of eCRFs, including the audit trail, and detailed records of drug 
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disposition to enable evaluations or audits from regulatory authorities, the sponsor or its 
designees. Any source documentation printed on degradable thermal-sensitive paper should be 
photocopied by the site and filed with the original in the patient’s chart to ensure long-term 
legibility. Furthermore, International Council for Harmonisation (ICH) E6 Section 4.9.5 requires 
the investigator and the head of the institution to retain essential documents specified in ICH E6 
(Section 8) until at least 2 years after the last approval of a marketing application for a specified 
drug indication being investigated or, if an application is not approved, until at least 2 years after 
the investigation is discontinued and regulatory authorities are notified. In addition, ICH E6 
Section 4.9.5 states that the study records should be retained until an amount of time specified by 
applicable regulatory requirements or for a time specified in the Clinical Study Site Agreement 
between the investigator and/or the head of the institution and sponsor.
Refer to the Clinical Study Site Agreement for the sponsor’s requirements on record retention. 
The investigator and the head of the institution should contact and receive written approval from 
the sponsor before disposing of any such documents.
13.0
STATISTICAL METHODS
13.1
Statistical and Analytical Plans
Further details regarding the definition of analysis variables and analysis methodology to address 
all study objectives will be provided in the SAP.
In general, summary tabulations will be presented by treatment arm and will display the number 
of observations, mean, standard deviation, median, minimum, and maximum for continuous 
variables, and the number and percent per category for categorical data. The Kaplan-Meier 
(K-M) survival curves and 25th, 50th (median), and 75th percentiles will be provided along with 
their 2-sided CIs for time-to-event data. In case survival distributions cannot be summarized 
appropriately, alternative approaches will be defined in the SAP.
The SAP will be written by Takeda and will be finalized before the planned interim analysis 
(IA). Deviations from the statistical analyses outlined in this protocol will be indicated in the 
SAP; the sensitivity analyses and the imputation rules of missing data due to COVID-19 
pandemic will also be specified in the SAP; any further modifications will be noted in the final 
CSR.
13.1.1
Analysis Sets
13.1.1.1
Intent-to-Treat Population
The intent-to-treat (ITT) population is defined as all patients who are randomized. Patients will 
be analyzed according to the treatment they were randomized to receive, regardless of any errors 
of dosing.
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13.1.1.2
Per-Protocol Population
The per-protocol (PP) population is a subset of the ITT population. The PP population consists of 
all patients who do not violate the terms of the protocol in a way that would affect the study 
outcome significantly, as determined by the sponsor’s medical monitor/designee. All decisions to
exclude patients from the PP population will be made before the database lock for the analyses.
The PP population will be used as a sensitivity analysis of the ITT population for the efficacy 
endpoints as needed if more than 5% of patients are excluded from this analysis.
13.1.1.3
Safety Population
The safety population is defined as all patients who receive at least 1 dose of any study drug. 
Patients will be analyzed according to the treatment actually received. That is, those patients who 
are randomized to the active arm but received the regimen in the control arm will be included in 
the control arm; those patients who are randomized to the control arm but received the regimen 
in the active arm will be included in the active arm for safety analyses.
13.1.2
Analysis of Demographics and Other Baseline Characteristics
Demographic and baseline characteristics will be summarized using frequency distributions and 
summary statistics based on the ITT population for each treatment cohort and for all patients 
combined.
13.1.3
Efficacy Analysis
The standard closed sequential testing procedure will be used for testing the selected efficacy 
endpoints with the following testing order:
1. MRD-negative CR rate will be tested at the IA or FA at the significance level determined by 
the O’Brien-Fleming alpha spending function (the Lan-DeMets method [38]) using the group 
sequential testing approach. At the IA, alpha = 0.022 with an efficacy boundary of 0.022 
given that 116 patients have been observed, and at the FA, alpha = 0.028 with an efficacy 
boundary of 0.036 if the number of patients is 230 [39].
2. EFS will be tested at the IA or FA at the significance level determined by the Gamma Family 
(-1) alpha spending function using group sequential testing approach [40]. At the IA, alpha = 
0.033 with an efficacy boundary of 0.033, and the FA, alpha = 0.017 with an efficacy 
boundary of 0.034 for EFS if the observed number of events at the IA and FA are 130 and 
173, respectively. If the efficacy boundary is crossed at either the IA or FA for EFS, the 
following endpoints will be tested in the order listed below using the same boundaries 
(0.033 for IA and 0.034 for FA) [41]:
a) Duration of CR
b) Duration of MRD-negative CR
c) ORR
d) OS
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Therefore, the overall type I error rate for these 2 endpoints is strongly controlled at a 2-sided 
0.05 alpha level.
The boundaries for hypothesis testing for MRD-negative CR and EFS will be updated according 
to the observed data in the IA and FA, using the prespecified alpha spending function.
For the secondary endpoint of OS, a futility analysis will be conducted at the time of the IA for 
EFS. The hazard ratio and corresponding 95% CI for the OS analysis will be calculated and 
reviewed by the IDMC. If the HR is >1.2, the IDMC will review the totality of the data and 
provide a recommendation to the sponsor’s executive committee regarding study continuation.
All other efficacy endpoints, if tested, will be at a 2-sided alpha level of 0.05.
For MRD-negative CR, the analysis will be based on the ITT population who have been 
identified with BCR-ABL1 dominant variants of p190 or p210. Other efficacy analyses will be 
conducted in the ITT population, unless otherwise specified.
MRD negativity will be based on the central laboratory results, and CR status will be based on 
the investigator’s assessment Table 13.a. See the SOE (Appendix A, Table 1 and Table 2) for 
details.
13.1.3.1
Primary Efficacy Endpoint Assessment
The primary endpoint is defined as achievement of MRD-negative CR (BCR-ABL/ABL1 
≤0.01% and meeting criteria for CR) at the end of induction (see Table 13.a for endpoint 
definitions). The analysis of the primary efficacy endpoint will test for differences comparing the 
proportion of patients who achieve the primary endpoint at the end of induction in the ponatinib 
arm versus the imatinib arm. 
There will be one IA and possibly an FA in the study for the primary endpoint of MRD-negative 
CR in the ITT population who have been identified with BCR-ABL1 dominant variants of p190 
or p210.
The IA is planned to be performed after the end of induction phase data have been collected for 
115 patients. The power is approximately 82% at the IA with 115 patients enrolled (2-sided 
alpha=0.021) corresponding to a minimal detectable effect size of 22% (48% and 26% 
MRD-negative CR rates for the active and control arms, respectively).
If the MRD-negative CR does not achieve the significance boundary at the IA, the study will 
continue and the FA will be triggered after the end of induction phase data have been collected 
for approximately 230 patients. The significance boundary at the FA with 230 patients enrolled 
would be 0.036 (2-sided) using a group sequential testing approach, which corresponds to a 
minimal detectable effect size of 14% (48% and 34% MRD-negative CR rates for the active and 
control arms, respectively).
The primary analysis for MRD-negative CR will be conducted using a Cochran-Mantel-Haenszel 
(CMH) chi-square test. The CMH chi-square p-value and the relative risk along with its 95% 
2-sided CI will be provided. 
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Sensitivity analyses for the primary endpoint may be performed, including:
1. MRD-negative CR will be analyzed in the PP population if more than 5% of patients are 
excluded from this analysis
2. MRD-negative CR will be analyzed with nonmissing observed cases
Subgroup analyses will be performed for the primary endpoint relative to the baseline 
randomization stratification factor (age); demographic data, such as sex and race; and disease 
characteristics, as appropriate. 
Further details on the analyses of primary endpoint will be discussed in the SAP.
13.1.3.2
Key Secondary Efficacy Endpoint Assessment
The key secondary endpoint is EFS, defined as the date of randomization until:

Death due to any cause

Failure to achieve CR by the end of induction

Relapse from CR
EFS will be tested only if the primary endpoint comparison achieves statistical significance at the 
IA or FA for MRD-negative CR. EFS endpoint will be tested at the 5% level at IA or FA for 
EFS, per the closed sequential testing procedure, to maintain the family-wise type I error rate at 
5% level.
One IA and one FA will be planned for EFS. When approximately 130 EFS events are observed 
(75% of the total 173 expected EFS events), an IA will be performed. The FA will be performed 
when approximately 173 EFS events have been observed. The test significance for the IA and 
FA of EFS will be determined using Gamma Family (-1) boundaries. Based on the projected 
number of EFS events, the formal hypothesis testing will be stopped for overwhelming efficacy 
if the 2-sided p-value crosses the efficacy boundary of 0.033 at IA. The final analysis will be 
tested at 2-sided alpha level of efficacy boundary 0.034 (corresponding to nominal alpha of 
0.017).
The power for the EFS analysis is estimated based on 3-year EFS data observed from various 
phase 2 studies [12,28]. The primary analysis for EFS will be based on time-to-event analysis. 
Since it is expected that a subset of patients who achieve MRD-negative CR after the induction 
phase will proceed to HSCT, the number of events needed for EFS analysis may change 
depending on how HSCT cases are handled in the EFS. The primary analysis of EFS will not 
consider censoring at the time of HSCT or initiation of alternative therapy. Other analysis 
methods will also be considered and specified in the SAP.
Sensitivity analyses for EFS may be considered, including:
1. EFS will be analyzed in the PP population if more than 5% of patients are excluded from this 
analysis
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2. A different approach will be used in dealing with HSCT cases from the one used in the 
primary analysis for the EFS endpoint
3. Inverse Probability of Censoring Weighted analysis of EFS will be used, adjusting for 
possible confounding caused by informative censoring from imbalance in the proportion of 
HSCT between the 2 cohorts
Subgroup analyses will be performed for EFS relative to the baseline randomization stratification 
factor age; demographic data, such as sex and race; and disease characteristics, as appropriate.
Further details on the key secondary endpoint analyses will be discussed in the SAP.
13.1.3.3
Other Secondary Efficacy Endpoint Assessments
The following other secondary endpoints will be analyzed (see Table 13.a for endpoint 
definitions):

CR and CRi rates at the end of Cycle 1, the end of Cycle 2, the end of induction, and during 
or at the end of consolidation (end of Cycle 9 or end of study treatment, whichever occurs 
earlier)

Molecular response rates (MR3, MRD negativity [MR4], and MR4.5), at the end of Cycle 1, 
the end of Cycle 2, the end of induction, and during or at the end of consolidation (end of 
Cycle 9 or end of study treatment, whichever occurs earlier)

Rates of PIF and ORR at the end of induction

Rates of MRD-negative CR at multiple intervals after the end of induction

Duration of MRD-negative CR

Duration of CR

Time to treatment failure

Duration of MR4.5 in patients who achieved MR4.5

OS and rate of relapse from CR for on-study patients with and without HSCT

OS
If the efficacy boundary is crossed at either IA or FA for EFS, the following secondary endpoints 
will be tested in the order listed below using the same boundaries (0.033 for IA and 0.034 for 
FA):
a) Duration of CR
b) Duration of MRD-negative CR
c) ORR
d) OS
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The remaining secondary efficacy endpoints may be tested at α = 0.05 level in a nonhierarchical 
fashion without adjustments for multiplicity, as appropriate.
For analysis of time-to-event endpoints (eg, time to treatment failure, OS), 2-sided, stratified 
log-rank tests will be used to compare the treatment groups with respect to the endpoints. In 
addition, an unadjusted stratified Cox model will be used to estimate the hazard ratio (HR) and 
its 95% CIs for the treatment effect using the stratification factor. K-M survival curves and K-M 
medians (if appropriate and estimable), along with their 2-sided 95% CIs, will also be provided 
for each treatment group.
For the secondary endpoint of OS, a futility analysis with be conducted at the time of the IA for 
EFS. The hazard ratio and corresponding 95% CI for the OS analysis will be calculated and 
reviewed by the IDMC. If the HR is >1.2, the IDMC will review the totality of the data and 
provide a recommendation to the sponsor’s executive committee regarding study continuation.
OS results are expected to be confounded by alternative therapies after patients discontinue from 
the study assigned drug. Thus, sensitivity analyses will be outlined in the SAP for OS analysis 
adjusting for time depending on confounding factors occurring due to taking alternative 
therapies. In addition, a post-transplantation competing risk analysis for disease-related and non-
relapse mortality will be conducted and details of this analysis will be outlined in the SAP.
The primary analysis for duration of MRD-negative CR will be based on time-to-event analysis. 
The primary analysis for duration MRD-negative CR will not consider censoring at the time of 
HSCT or alternative therapies. Sensitivity analyses handling censoring for HSCT or alternative 
therapies may be considered and will be specified in the SAP.
The proportion-based other secondary endpoints (eg, CR, and CRi rates) will be analyzed in the 
same fashion as the primary endpoint. The CMH chi-square p-value and the relative risk, along 
with its 95% 2-sided CI, will be provided. 
Further details on the analyses of other secondary endpoints will be discussed in the SAP.
13.1.3.4
Definitions of Response Criteria
Definitions of response criteria for the purpose of efficacy analyses are provided in Table 13.a.
Table 13.a
Definitions of Efficacy Response Criteria
Term
Definition
CNS-1
CNS-1: No lymphoblasts in the CSF regardless of WBC count.
CNS-2
WBC count <5 leukocytes/µl in the CSF with the presence of blasts.
CNS-3 a
WBC count of ≥5 leukocytes/µl with the presence of blasts.
CNS disease remission
No lymphoblasts in CSF regardless of WBC count in a patient with 
CNS-2 or CNS-3 at diagnosis.
CNS relapse
Development of CNS-3 status or development of clinical signs of CNS 
leukemia (eg, facial nerve palsy, brain/eye involvement, hypothalamic 
syndrome).
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Table 13.a
Definitions of Efficacy Response Criteria
Term
Definition
CR
Complete remission; meeting all the following for at least 4 weeks (ie, 
no recurrence):

No circulating blasts and <5% blasts in the BM.

Normal maturation of all cellular components in the BM.

No extramedullary disease (CNS involvement, lymphadenopathy, 
splenomegaly, skin/gum infiltration, testicular mass).

ANC >1000/µl (or >1.0 × 109/L).

Platelets >100,000/µl (or >100 × 109/L). 
CRi
Hematologic complete remission with incomplete hematologic recovery. 
Meets all criteria for CR except platelet count and/or ANC.
Duration of CR
The interval between the first assessment at which the criteria for CR are 
met until the time at which relapse from CR occurs.
Duration of MR4.5
The interval between the first assessment at which the criteria for MR4.5 
are met until the earliest date at which loss of MR4.5 occurs.
Duration of MRD negativity
The interval between the first assessment at which the criteria for MRD 
negativity are met until the earliest date at which loss of MRD negativity 
occurs or relapse from CR occurs.
Duration of MRD-negative CR
The interval between the first assessment at which the criteria for MRD-
negative CR are met until the earliest date at which loss of MRD 
negativity or relapse from CR occurs.
EFS
Event-free survival (EFS), defined as the dates of randomization until:

Death due to any cause.

Failure to achieve CR by the end of induction.

Relapse from CR.
Loss of MR3
An increase to >0.1% BCR-ABL1/ABL1.
Loss of MR4.5
An increase to >0.0032% BCR-ABL1/ABL1. This result must be 
confirmed at the subsequent visit, unless it is associated with loss of 
MR3 or relapse from CR.
Loss of MRD negativity
An increase to ≥0.01% BCR-ABL1/ABL1. This result must be 
confirmed within 4 weeks with either a BM aspirate (optional) or 
peripheral blood, unless it is associated with loss of MR3 or relapse from 
CR.
MR3
Molecular response 3-log reduction (≤0.1% BCR-ABL1/ABL1), or 
undetectable BCR-ABL1 transcripts in cDNA with ≥1000 ABL1 
transcripts.
MR4.5
Molecular response 4.5-log reduction (≤0.0032% BCR-ABL1/ABL1), or 
undetectable BCR-ABL1 transcripts in cDNA with ≥32,000 ABL1 
transcripts.
MRD-negative CR
Meeting the criteria for both MRD negativity and CR.
MRD negativity (MR4)
≤0.01% BCR-ABL1/ABL1, or undetectable BCR-ABL1 transcripts in 
cDNA with ≥10,000 ABL1 transcripts. Also referred to as MR4.
ORR
Overall response rate: CR + CRi.
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Table 13.a
Definitions of Efficacy Response Criteria
Term
Definition
OS
Overall survival. The interval between randomization and death due to 
any cause.
PD
Progressive disease. Increase of at least 25% in the absolute number of 
circulating or BM blasts or development of extramedullary disease.
PIF
Primary induction failure: Patients who received treatment for ALL but 
never achieved CR or CRi by the end of induction. PIF is not limited by 
the number of unsuccessful treatments; this disease status only applies to 
recipients who have never been in CR or CRi.
Relapse from CR
Reappearance of blasts in the blood or BM (≥5%) or in any 
extramedullary site after a CR.
Time to treatment failure
Time to end of study-randomized treatment (except for HSCT without 
loss of MRD-negative CR) due to safety and/or efficacy reasons.
Abbreviations: ANC, absolute neutrophil count; BCR-ABL, breakpoint cluster region-Abelson; BM, bone marrow; 
CNS, central nervous system; CSF, cerebrospinal fluid; CR, complete remission; CRi, incomplete blood count 
recovery; HSCT, hematopoietic stem cell transplant; MR3, molecular response 3-log reduction (BCR-ABL1/ABL1 
≤0.1%); MR4, molecular response 4-log reduction (BCR-ABL1/ABL1 ≤0.01%); MR4.5, molecular response 4.5-log 
reduction (BCR-ABL1/ABL1 ≤0.0032%); MRD, minimal residual disease; ORR, overall response rate; OS, overall 
survival; PD, progressive disease; Ph+ ALL, Philadelphia chromosome–positive acute lymphoblastic leukemia; 
RBC, red blood cell; WBC, white blood cell.
a If the patient has leukemic cells in the peripheral blood and the lumbar puncture is traumatic and WBC ≥5/μL in 
CSF with blasts, then compare the CSF WBC/RBC ratio to the blood WBC/RBC ratio. If the CSF ratio is at least 2-
fold greater than the blood ratio, then the classification is CNS-3; if not, then it is CNS-2.
13.1.4
Safety Endpoints
The safety endpoints are:

Incidence and exposure-adjusted incidence rates of AOEs, VTEs, AEs, and SAEs, in each of 
the 2 cohorts.

Incidence of dose reductions, interruptions, and discontinuations due to AEs, in each of the 
2 cohorts.

Incidence of death on treatment, in each of the 2 cohorts.

Changes from baseline in vital signs (including systolic and diastolic BP, and heart rate) and 
clinical laboratory test results, in each of the 2 cohorts.
13.1.5
Exploratory Endpoints
The exploratory endpoints are:

Change from baseline in patient-reported HRQOL (FACT-Leu and EQ-5D-5L).

Change from baseline in MRU assessments.

Time to start of alternative therapy.
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
Time to HSCT.

Biomarkers of disease sensitivity and resistance to ponatinib and imatinib and/or biomarkers 
affecting ponatinib efficacy or safety.
Further details on the exploratory endpoint analyses will be discussed in the SAP.
13.1.5.1
Time-to-Next-Treatment and Time-to-HSCT Analyses
Time to subsequent antineoplastic therapy will be defined as the time from randomization to the 
date of first documentation of subsequent antineoplastic therapy or the last contact date for 
patients who never received subsequent antineoplastic therapy.
Likewise, time to HSCT will be defined as the time from randomization to the date of first 
documentation of HSCT or the last contact date for patients who did not receive an HSCT.
A Cox regression model with treatment as explanatory variable will be used for the time-to-event 
analyses. Median follow-up will be calculated by K-M method.
13.1.5.2
Patient-Reported Outcomes Analysis
Quality of life and health outcomes measures are being collected using the EQ-5D-5L and 
FACT-Leu instruments. Means and medians of scores of these questionnaires will be 
summarized for each cohort by time point, overall, and for each domain. Assessments based on 
the FACT-Leu will be analyzed to determine if treatments affect all domains.
Analyses of HRQOL scores, including global health status, will be performed using longitudinal 
models for scores and change from baseline scores. All subscales and individual item scores will 
be tabulated. Descriptive summaries of observed data will be provided at each scheduled 
assessment time point.
Initially, the manuals published for FACT-Leu will be used for scoring and handling missing 
data. Further investigation of missing patterns and details of imputation will be discussed in the 
SAP.
EQ-5D-5L scores will be summarized in descriptive statistics for treatment groups. Both utility 
scores and change from baseline scores will be assessed across time using longitudinal models.
13.1.5.3
Health Economics Analysis Using Medical Resource Utilization
Medical resource utilization data will be summarized in descriptive statistics for hospitalization 
(length of stay, inpatient, outpatient, and reason), number of missing days from work or other 
activities, by patient and caregiver, and by treatment group.
13.1.5.4
Biomarkers of Disease Sensitivity and Resistance to Ponatinib and Imatinib
The mutation status of BCR-ABL1 and other genes implicated in tumor biology and/or drug 
metabolism will be determined, as clinically needed, through analyses of tumor cells collected at 
study entry, on study, and/or at EOT. Analysis methodologies include, but are not limited to, 
DNA sequencing, digital PCR, and mass spectrometry. 
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13.1.6
PK Analysis (Ponatinib)
The PK data collected in this study are intended to contribute to future population PK analyses of 
ponatinib. These population PK analyses may additionally include data collected in other 
ponatinib clinical studies. The analysis plan for the population PK analysis will be defined 
separately and the results of these analyses will be reported separately.
13.1.7
Safety Analysis
The safety analysis will be carried out at interim and final analyses. In addition, an extended 
safety analysis for the study will be carried out at study completion.
Safety evaluations will be based on incidence, severity, and type of AEs; clinically significant 
changes or abnormalities in the patient’s physical or neurological examinations; vital signs; and 
clinical laboratory test results.
Descriptive statistics will be calculated. Treatment-emergent adverse events (TEAEs) will be 
tabulated by primary SOC, High Level Term (HLT), and preferred term (PT). MedDRA will be 
used for coding AEs. A TEAE is defined as any AE that occurs after administration of the first 
dose of any study drug and through 30 days after the last dose of any study drug.
To summarize the number of patients with AEs, patients reporting the same event more than 
once will have that event counted only once within each SOC, HLT, and PT. Events that are 
considered related to treatment will also be tabulated. AEs will also be summarized by intensity. 
Deaths, AEs, SAEs, AOEs, VTEs, and events resulting in study discontinuation, if present, will 
be presented in separate data listings.
Additionally, a descriptive safety analyses of OS will be conducted at the IA (or FA, as 
applicable) for MRD-negative CR if there are a sufficient number of deaths to perform such an 
analysis. The details of this analysis will be provided in the SAP.
13.2
IA and Criteria for Early Termination
MRD-negative CR
There will be one IA and possibly an FA in the study for the MRD-negative CR primary 
endpoint using a group sequential testing approach.
The IA was performed after the end of induction phase data were collected for 116 patients. The 
primary endpoint of MRD-negative CR was first tested at the IA with a 2-sided efficacy 
boundary of 0.022 and will be tested again at the FA with a 2-sided efficacy boundary of 0.036 
after the end of induction phase data have been collected for 230 patients. If the significance 
boundary is crossed at the FA for MRD-negative CR, there will be testing for EFS and other 
secondary endpoints at a 2-sided alpha level of 0.05 using a group sequential testing approach.
The boundaries for hypothesis testing for MRD-negative CR will be updated according to the 
observed data in the IA and FA using the prespecified alpha spending function.
Enrollment projections for patients anticipated to be enrolled at the time of the planned analyses 
are provided in Appendix M.
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EFS
There will be one IA and possibly an FA in the study for the key secondary endpoint EFS using a 
group sequential testing approach.
When approximately 130 EFS events are observed (75% of the total 173 expected EFS events), 
an IA will be performed. The IA is expected to occur approximately 5.5 years after the first 
patient is enrolled. The FA is expected to be performed approximately 8.5 years after the first 
patient enrolled, when all approximately 173 EFS events have been observed. 
The test of significance for the IA and FA of EFS will be determined using Gamma Family (-1) 
boundaries. Based on the projected number of EFS events, the formal hypothesis testing will be 
stopped for overwhelming efficacy if the 2-sided p-value crosses the efficacy boundary 
(p = 0.033) at IA and this will be the FA for EFS for statistical testing purposes. If EFS does not 
achieve statistical significance at the IA, the final analysis will be tested at 2-sided alpha level of 
efficacy boundary 0.034 (corresponding to nominal alpha of 0.017).
If the efficacy boundary is crossed at either IA or FA for EFS, the following secondary endpoints 
will be tested in the order listed below using the same boundaries (0.033 for IA and 0.034 for 
FA):
a) Duration of CR.
b) Duration of MRD-negative CR.
c) ORR.
d) OS.
The boundaries for hypothesis testing for EFS will be updated according to the observed data in 
the IA and FA using the prespecified alpha spending function.
Overall Survival
For the secondary endpoint of OS, a futility analysis will be conducted at the time of the IA for 
EFS. The hazard ratio and corresponding 95% CI for the OS analysis will be calculated and 
reviewed by the IDMC. If the HR is >1.2, the IDMC will review the totality of the data and 
provide a recommendation to the sponsor’s executive committee regarding study continuation.
The IA and FA for MRD-negative CR and the IA for EFS will be carried out by an independent 
statistical center in a manner that maintains the blinding of the study results to the team (see 
Section 13.4). The IDMC will review both efficacy and safety data at the time of the IA, and will 
inform the sponsor’s executive committee of their recommendation.
13.3
Determination of Sample Size
Assuming an effect size ranging from 20% to 28% (40% to 48% and 20% MRD-negative CR 
rates for the active and control arms, respectively), an upfront committed sample size of 
approximately 230 patients (approximately 153 versus 77 for the active and control arms, 
respectively, based on a 2:1 allocation ratio) will provide 84% to 98% power for MRD-negative 
CR at the final analysis using the efficacy boundary of 0.036 according to the group sequential 
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testing procedure with the IA performed using data from 116 patients [39]. The O’Brien-Fleming 
alpha spending function (the Lan-DeMets method [38]) will be implemented to determine the 
significance level at IA and FA for the primary endpoint, with an overall type I error rate at a 
2-sided 0.05 level.
Inference for the key secondary endpoint of EFS will be conducted at α = 5% level only if the 
primary endpoint is met either at IA or FA for the MRD-negative CR (Figure 13.a). Based on 
3-year EFS data observed from various phase 2 studies [12,28], effect size is assumed as 67% 
versus 46% for EFS at year 3 for the active and control arms, respectively, or HR = 0.516 for 
non-HSCT patients. The effect size is assumed as 53% and 40% for EFS at year 3 for active and 
control arms, respectively, or HR = 0.693 for patients who are undertaking HSCT. Also, it is 
assumed that 50% and 45% of patients from active and control arms will undertake HSCT, 
respectively. Based on simulation studies, approximately 230 patients will be enrolled to collect 
long-term EFS data. Among these 230 patients, approximately 173 events need to be 
accumulated at FA so that the power will be approximately 80% for the EFS endpoint. It is 
expected that the time of EFS will be approximately 8.5 years after first patient has been 
enrolled.
Figure 13.a
Statistical Analysis Schema
Abbreviations: Cont.: continue; CP: conditional probability; CR: complete response; EFS: event-free survival; FA: 
final analysis; IA: interim analysis; LPI: last patient in; MRD: minimal residual disease; ORR: overall response rate; 
OS: overall survival.
*If the efficacy boundary is crossed at the IA, it is the final analysis, and no formal hypothesis testing will be 
performed.
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**If the efficacy boundary is crossed at either the IA or FA for EFS, the following endpoints will be tested in the 
following order using the same boundaries: a) Duration of CR; b) Duration of MRD-negative CR; c) ORR; and 
d) OS.
13.4
Blinding of Trial Management Team for Data Review
This is an open-label study. To protect study integrity, the study team will be blinded to 
treatment assignment for aggregate efficacy-related data, unless publicly released, as well as 
individual patient-level data (except a few members who are included in patient management and 
monitoring of the study; however, generation of any aggregate summary of efficacy data by 
treatment arm is not allowed). Details will be specified in a separate data and blinding plan, 
which will be finalized prior to the IA.
14.0
QUALITY CONTROL AND QUALITY ASSURANCE
14.1
Study Site Monitoring Visits
Monitoring visits to the study site will be made periodically during the study to ensure that all 
aspects of the protocol are followed. Source documents will be reviewed for verification of data 
recorded on the eCRFs. Source documents are defined as original documents, data, and records. 
The investigator and institution guarantee access to source documents by the sponsor or its 
designee (CRO) and by the IRB or IEC. In the event a monitor cannot visit the site in a timely 
manner due to the COVID-19 pandemic or other limited circumstances defined in the monitoring 
plan, alternative monitoring approaches such as remote source data verification (rSDV), remote 
source data review (rSDR), or telephone contact may be used to ensure data quality and integrity 
and maintain patient safety. Local regulations and guidances are to be followed regarding rSDV 
and rSDR.
All aspects of the study and its documentation will be subject to review by the sponsor or 
designee (as long as blinding is not jeopardized), including but not limited to the investigator’s 
binder, study medication, patient medical records, informed consent documentation, 
documentation of subject authorization to use personal health information (if separate from the 
ICFs), and review of eCRFs and associated source documents. It is important that the 
investigator and other study personnel are available during the monitoring visits and that 
sufficient time is devoted to the process.
14.2
Protocol Deviations
The investigator should not deviate from the protocol, except where necessary to eliminate an 
immediate hazard to study patients. Should other unexpected circumstances arise that will 
require deviation from protocol-specified procedures, the investigator should consult with the 
sponsor or designee (and IRB or IEC, as required) to determine the appropriate course of action. 
In unavoidable circumstances such as the COVID-19 pandemic, deviations from the protocol 
specified procedures will be recorded as related to COVID-19. There will be no exemptions (a 
prospectively approved deviation) from the inclusion or exclusion criteria.
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The sponsor will assess any protocol deviation; if it is likely to affect to a significant degree the 
safety and rights of a patient or the reliability and robustness of the data generated, it may be 
reported to regulatory authorities as a serious breach of GCP and the protocol.
The site should document all protocol deviations in the patient’s source documents. In the event 
of a significant deviation, the site should notify the sponsor or its designee (and IRB or IEC, as 
required). Significant deviations include, but are not limited to, those that involve fraud or 
misconduct, increase the health risk to the patient, or confound interpretation of primary study 
assessment.
The investigator should document all protocol deviations.
14.2.1
Japan Protocol Deviations
The procedure below applies to patients enrolled at Japanese sites only. 
The investigator can deviate and change from the protocol for any medically unavoidable reason 
(eg, to eliminate an immediate hazard to study patients) without a prior written agreement with 
the sponsor or a prior approval from the IRB. In the event of a deviation or change, the principal 
investigator should notify the sponsor and the head of the site of the deviation or change as well 
as its reason in a written form, and then retain a copy of the written form. When necessary, the 
principal investigator may consult and agree with the sponsor on a protocol amendment. If the 
protocol amendment is appropriate, the amendment proposal should be submitted to the head of 
the site as soon as possible and an approval from the IRB should be obtained.
14.3
Quality Assurance Audits and Regulatory Agency Inspections
The study site also may be subject to quality assurance audits by the sponsor or designees. In this 
circumstance, the sponsor-designated auditor will contact the site in advance to arrange an 
auditing visit. The auditor may ask to visit the facilities where laboratory samples are collected, 
where the medication is stored and prepared, and any other facility used during the study. In 
addition, there is the possibility that this study may be inspected by regulatory agencies, 
including those of foreign governments (eg, the FDA, the United Kingdom [UK] Medicines and 
Healthcare products Regulatory Agency [MHRA], the Pharmaceuticals and Medical Devices 
Agency of Japan [PMDA]). If the study site is contacted for an inspection by a regulatory body, 
the sponsor should be notified immediately. The investigator and institution guarantee access for 
quality assurance auditors and regulatory agency inspectors to all study documents as described 
in Section 14.1.
15.0
ETHICAL ASPECTS OF THE STUDY
This study will be conducted with the highest respect for the individual participants (ie, patients) 
according to the protocol, the ethical principles that have their origin in the Declaration of 
Helsinki, and the ICH E6 Guideline for GCP. Each investigator will conduct the study according 
to applicable local or regional regulatory requirements and align his or her conduct in accordance 
with the “Responsibilities of the Investigator” that are listed in Appendix B. The principles of 
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Helsinki are addressed through the protocol and through appendices containing requirements for 
informed consent and investigator responsibilities.
15.1
IRB and/or IEC Approval
IRBs and IECs must be constituted according to the applicable state and federal/local 
requirements of each participating region. The sponsor or designee will require documentation 
noting all names and titles of members who make up the respective IRB or IEC. If any member 
of the IRB or IEC has direct participation in this study, written notification regarding his or her 
abstinence from voting must also be obtained. Those American sites unwilling to provide names 
and titles of all members due to privacy and conflict of interest concerns should instead provide a 
Federal-wide Assurance number or comparable number assigned by the US Department of 
Health and Human Services.
The sponsor or designee will supply relevant documents for submission to the respective IRB or 
IEC for the protocol’s review and approval. This protocol, the investigator’s brochure, a copy of 
the ICF, and, if applicable, subject recruitment materials and/or advertisements and other 
documents required by all applicable laws and regulations, must be submitted to a central or 
local IRB or IEC for approval. The IRB’s or IEC’s written approval of the protocol and subject 
informed consent must be obtained and submitted to the sponsor or designee before 
commencement of the study (ie, before shipment of the sponsor-supplied drug or study specific 
screening activity). The IRB or IEC approval must refer to the study by exact protocol title, 
number, and version date; identify versions of other documents (eg, ICF) reviewed; and state the 
approval date. The sponsor will ship drug and notify the site once the sponsor has confirmed the 
adequacy of site regulatory documentation and, when applicable, the sponsor has received 
permission from a competent authority to begin the study. Until the site receives 
drug/notification, no protocol activities, including screening, may occur.
Sites must adhere to all requirements stipulated by their respective IRB or IEC. This may include 
notification to the IRB or IEC regarding protocol amendments, updates to the ICF, recruitment 
materials intended for viewing by subjects, local safety reporting requirements, reports and 
updates regarding the ongoing review of the study at intervals specified by the respective IRB or 
IEC, and submission of the investigator’s final status report to IRB or IEC. All IRB and IEC 
approvals and relevant documentation for these items must be provided to the sponsor or its 
designee.
Subject incentives should not exert undue influence for participation. Payments to subjects must 
be approved by the IRB or IEC and sponsor.
15.2
Subject Information, Informed Consent, and Subject Authorization
Written consent documents will embody the elements of informed consent as described in the 
Declaration of Helsinki and the ICH E6 Guideline for GCP and will be in accordance with all 
applicable laws and regulations. The ICF describes the planned and permitted uses, transfers, and 
disclosures of the subject’s personal and personal health information for purposes of conducting 
the study. The ICF further explains the nature of the study, its objectives, and potential risks and 
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benefits, as well as the date informed consent is given. The ICF will detail the requirements of 
the participant and the fact that he or she is free to withdraw at any time without giving a reason 
and without prejudice to his or her further medical care.
The investigator is responsible for the preparation, content, and IRB or IEC approval of the ICF. 
The ICF must be approved by both the IRB or IEC and the sponsor before use.
The ICF must be written in a language fully comprehensible to the prospective subject. It is the 
responsibility of the investigator to explain the detailed elements of the ICF to the subject. 
Information should be given in both oral and written form whenever possible and in the manner 
deemed appropriate by the IRB or IEC. In the event the subject is not capable of rendering 
adequate written informed consent, then the subject’s legally acceptable representative may 
provide such consent for the subject in accordance with applicable laws and regulations.
The subject, or the subject’s legally acceptable representative, must be given ample opportunity 
to: (1) inquire about details of the study and (2) decide whether or not to participate in the study. 
If the subject, or the subject’s legally acceptable representative, determines he or she will 
participate in the study, then the ICF must be signed and dated by the subject, or the subject’s 
legally acceptable representative, at the time of consent and before the subject entering into the 
study. The subject or the subject’s legally acceptable representative should be instructed to sign 
using their legal names, not nicknames, using blue or black ballpoint ink. The investigator must 
also sign and date the ICF at the time of consent and before the subject enters into the study; 
however, the sponsor may allow a designee of the investigator to sign to the extent permitted by 
applicable law.
Once signed, the original ICF will be stored in the investigator’s site file. The investigator must 
document the date the subject signs the informed consent in the subject’s medical record. A copy 
of the signed and dated ICF shall be given to the subject.
All revised ICFs must be reviewed, signed, and dated by relevant subjects or the relevant 
subject’s legally acceptable representative in the same manner as the original informed consent. 
The date the revised consent was obtained should be recorded in the subject’s medical record, 
and the subject should receive a copy of the revised ICF.
15.3
Subject Confidentiality
The sponsor and designees affirm and uphold the principle of the subject’s right to protection 
against invasion of privacy. Throughout this study, a subject’s source data will only be linked to 
the sponsor’s clinical study database or documentation via a unique identification number. As 
permitted by all applicable laws and regulations, limited subject attributes, such as sex, age, or 
date of birth, and subject initials may be used to verify the subject and accuracy of the subject’s 
unique identification number.
To comply with ICH Guidelines for GCP and to verify compliance with this protocol, the 
sponsor requires the investigator to permit its monitor or designee’s monitor, representatives 
from any regulatory authority (eg, US FDA, UK MHRA, EMA, Japan PMDA), the sponsor’s 
designated auditors, and the appropriate IRBs and IECs to review the subject’s original medical 
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records (source data or documents), including, but not limited to, laboratory test result reports, 
ECG reports, admission and discharge summaries for hospital admissions occurring during a 
subject’s study participation, and autopsy reports. Access to a subject’s original medical records 
requires the specific authorization of the subject as part of the informed consent process (see 
Section 15.2).
Copies of any subject source documents that are provided to the sponsor must have certain 
identifying personal information removed (eg, subject name, address, and other identifier fields 
not collected on the subject’s eCRF).
15.4
Publication, Disclosure, and Clinical Trial Registration Policy
15.4.1
Publication
The investigator is obliged to provide the sponsor with complete test results and all data derived 
by the investigator from the study. During and after the study, only the sponsor may make study 
information available to other study investigators or to regulatory agencies, except as required by 
law or regulation. Except as otherwise allowable in the clinical study site agreement, any public 
disclosure (including publicly accessible websites) related to the protocol or study results, other 
than study recruitment materials and/or advertisements, is the sole responsibility of the sponsor.
The sponsor may publish any data and information from the study (including data and 
information generated by the investigator) without the consent of the investigator. Manuscript 
authorship for any peer-reviewed publication will appropriately reflect contributions to the 
production and review of the document. All publications and presentations must be prepared in 
accordance with this section and the Clinical Study Site Agreement. In the event of any 
discrepancy between the protocol and the Clinical Study Site Agreement, the Clinical Study Site 
Agreement will prevail.
15.4.2
Clinical Trial Registration
To ensure that information on clinical trials reaches the public in a timely manner and to comply 
with applicable laws, regulations, and guidance, Takeda will, at a minimum, register 
interventional clinical trials it sponsors anywhere in the world on ClinicalTrials.gov or other 
publicly accessible websites on or before start of study, as defined in Takeda Policy/Standard. 
Takeda contact information, along with investigator’s city, state (for Americas investigators), 
country, and recruiting status will be registered and available for public viewing.
As needed, Takeda and investigator/site contact information may be made public to support 
participant access to trials via registries. In certain situations/registries, Takeda may assist 
participants or potential participants to find a clinical trial by helping them locate trial sites 
closest to their homes by providing the investigator name, address, and phone number via 
e-mail/phone or other methods preferred by callers requesting trial information. Once subjects 
receive investigator contact information, they may call the site requesting enrollment into the 
trial. The investigative sites are encouraged to handle the trial inquiries according to their 
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established subject screening process. If the caller asks additional questions beyond the topic of 
trial enrollment, they should be referred to the sponsor.
Any investigator who objects to Takeda providing this information to callers must provide 
Takeda with a written notice requesting that their information not be listed on the registry site.
15.4.3
Clinical Trial Results Disclosure
Takeda will post the results of clinical trials on ClinicalTrials.gov or other publicly accessible 
websites (including the Takeda corporate site) and registries, as required by Takeda 
policy/standards, applicable laws and/or regulations.
The sponsor is committed to responsible sharing of clinical data with the goal of advancing 
medical science and improving patient care. Qualified independent researchers will be permitted 
to use data collected from patients during the study to conduct additional scientific research, 
which may be unrelated to the study drug or the patient’s disease. The data provided to external 
researchers will not include information that identifies patients personally.
15.5
Insurance and Compensation for Injury
Each subject in the study must be insured in accordance with the regulations applicable to the 
site where the subject is participating. If a local underwriter is required, then the sponsor or 
sponsor’s designee will obtain clinical study insurance against the risk of injury to clinical study 
subjects. Refer to the Clinical Study Site Agreement regarding the sponsor’s policy on subject 
compensation and treatment for injury. If the investigator has questions regarding this policy, he 
or she should contact the sponsor or sponsor’s designee.
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16.0
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nitrosourea (ENU)-based mutagenesis screen: high efficacy of drug combinations. Blood 
2006;108(7):2332-8.
21. Zabriskie MS, Eide CA, Tantravahi SK, Vellore NA, Estrada J, Nicolini FE, et al. BCR-
ABL1 compound mutations combining key kinase domain positions confer clinical resistance 
to ponatinib in Ph chromosome-positive leukemia. Cancer Cell 2014;26(3):428-42.
22. Paquette R, Shah N, Sawyers C, Martinelli G, John N, Chalukya M, et al. PHA-739358, an 
Aurora kinase inhibitor, induces clinical responses in chronic myeloid leukemia harboring 
T3151 mutations of BCR-ABL[abstract]. Blood 2007;110:312a.
23. Cortes JE, Kim DW, Pinilla-Ibarz J, le Coutre P, Paquette R, Chuah C, et al. A phase 2 trial 
of ponatinib in Philadelphia chromosome-positive leukemias. N Engl J Med 
2013;369(19):1783-96.
24. Cortes JE, Kantarjian H, Shah NP, Bixby D, Mauro MJ, Flinn I, et al. Ponatinib in refractory 
Philadelphia chromosome-positive leukemias. N Engl J Med 2012;367(22):2075-88.
25. Pritchard J, Schmitt M, Hodgson J, Lustgarten S, Tang S, Loeb L, et al. Analysis of the sub-
clonal origins of compound mutations in patients with refractory ph+ malignancies treated 
with ponatinib. Blood 2016;128:1061.
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26. Berry DA, Zhou S, Higley H, Mukundan L, Fu S, Reaman GH, et al. Association of Minimal 
Residual Disease With Clinical Outcome in Pediatric and Adult Acute Lymphoblastic 
Leukemia: A Meta-analysis. JAMA Oncol 2017;3(7):e170580.
27. van Dongen JJ, van der Velden VH, Bruggemann M, Orfao A. Minimal residual disease 
diagnostics in acute lymphoblastic leukemia: need for sensitive, fast, and standardized 
technologies. Blood 2015;125(26):3996-4009.
28. Short NJ, Jabbour E, Sasaki K, Patel K, O'Brien SM, Cortes JE, et al. Impact of complete 
molecular response on survival in patients with Philadelphia chromosome-positive acute 
lymphoblastic leukemia. Blood 2016;128(4):504-7.
29. Nashed AL, Rao KW, Gulley ML. Clinical applications of BCR-ABL molecular testing in 
acute leukemia. J Mol Diagn 2003;5(2):63-72.
30. Common Terminology Criteria for Adverse Events (CTCAE), Version 5.0. U.S. Department 
of Health and Human Services National Cancer Institute. 27 Nov 2017.
31. ICLUSIG (ponatinib). Package Insert. Cambridge, MA: Takeda Pharmaceuticals Company 
Limited, 12/2017.
32. Janssen MF, Birnie E, Haagsma JA, Bonsel GJ. Comparing the standard EQ-5D three-level 
system with a five-level version. Value Health 2008;11(2):275-84.
33. Janssen MF, Pickard AS, Golicki D, Gudex C, Niewada M, Scalone L, et al. Measurement 
properties of the EQ-5D-5L compared to the EQ-5D-3L across eight patient groups: a multi-
country study. Qual Life Res 2013;22(7):1717-27.
34. Pickard AS, De Leon MC, Kohlmann T, Cella D, Rosenbloom S. Psychometric comparison 
of the standard EQ-5D to a 5 level version in cancer patients. Med Care 2007;45(3):259-63.
35. Pickard AS, Kohlmann T, Janssen MF, Bonsel G, Rosenbloom S, Cella D. Evaluating 
equivalency between response systems: application of the Rasch model to a 3-level and 5-
level EQ-5D. Med Care 2007;45(9):812-9.
36. Thygesen K, Alpert JS, Jaffe AS, Simoons ML, Chaitman BR, White HD, et al. Third 
universal definition of myocardial infarction. Glob Heart 2012;7(4):275-95.
37. Easton JD, Saver JL, Albers GW, Alberts MJ, Chaturvedi S, Feldmann E, et al. Definition 
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on Cardiovascular Surgery and Anesthesia; Council on Cardiovascular Radiology and 
Intervention; Council on Cardiovascular Nursing; and the Interdisciplinary Council on 
Peripheral Vascular Disease. The American Academy of Neurology affirms the value of this 
statement as an educational tool for neurologists. Stroke 2009;40(6):2276-93.
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39. Jennison C, Turnbull B. Group Sequential Methods with Application to Clinical Trials: 
Chapman & Hall; 2000.
40. Hwang IK, Shih WJ, De Cani JS. Group sequential designs using a family of type I error 
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41. Hung HM, Wang SJ, O'Neill R. Statistical considerations for testing multiple endpoints in 
group sequential or adaptive clinical trials. Journal of Biopharmaceutical Statistics 
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42. Coiffier B, Altman A, Pui CH, Younes A, Cairo MS. Guidelines for the management of 
pediatric and adult tumor lysis syndrome: an evidence-based review. J Clin Oncol 
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Lymphoma. Version 4.2014 National Comprehensive Cancer Network. 2014.
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Appendix A
Schedule of Events
Table 1 Schedule of Events: Screening, Induction Phase, and Consolidation Phases
Study Procedures
Screening / 
Baseline
Induction Phase
Consolidation Phase
28-Day Cycles
Cycle 1
Cycle 2
Cycle 3
Cycle 4
Cycle 5
Cycle 6
Cycle 7
Cycle 8
Cycle 9
Cycle Days
-28 to -
1
1
7, 14, 
21
1
7, 14, 
21
1
7, 14, 
21
1
7, 14,
21
1
7, 14,
21
1
7, 14,
21
1
7, 14, 21
1
7, 14,
21
1
7, 14,
21
Window (days) a
N/A
±3
±3
±3
±3
±3
±4
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
Informed consent b
X
Enrollment b
X
Med/Surg history and 
demographics c
X
Pregnancy test d
X
X
X
X
X
X
X
X
X
X
Leukemia diagnosis
X
Prior medications e
X
Vital signs f
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Physical exams g
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
ECOG g
X
X
X
X
ABI h
X
Additional Assessments as Clinically Indicated
Framingham score i
X
12-Lead ECG j
X
X
X
ECHO k
X
Additional Assessments as Clinically Indicated
Eye exams l 
X
Additional Assessments as Clinically Indicated
PROs m
X
X
X
X
MRU n
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Diary review
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
CNS prophylaxis o
X
X o
X
X o
X
X o
X
X o
X
X o
X
X o
AE monitoring
Recorded at every visit from the signing of ICF through 30 days after last dose of study drug (See Section 10.0)
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Table 1 Schedule of Events: Screening, Induction Phase, and Consolidation Phases
Study Procedures
Screening / 
Baseline
Induction Phase
Consolidation Phase
28-Day Cycles
Cycle 1
Cycle 2
Cycle 3
Cycle 4
Cycle 5
Cycle 6
Cycle 7
Cycle 8
Cycle 9
Cycle Days
-28 to -
1
1
7, 14, 
21
1
7, 14, 
21
1
7, 14, 
21
1
7, 14,
21
1
7, 14,
21
1
7, 14,
21
1
7, 14, 21
1
7, 14,
21
1
7, 14,
21
Window (days) a
N/A
±3
±3
±3
±3
±3
±4
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
Concomitant 
medications p
Recorded at every visit from Cycle 1 Day 1 through 30 days after last dose of study drug.
Alternative therapy 
and/or HSCT q
Documented Per Occurrence
Clinical Laboratory Sampling
Hep B serology r
X
Additional Assessments as Clinically Indicated
Plasma samples for PK 
(Cohort A)
X s
X t
X s
X t
X s
X s
X s
X s
CBC with diff u
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Chemistry v
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Fasting glucose, 
cholesterol, lipids, and 
HbA1c w
X
X
X
X
CRP, cTnI, and NT-
proBNP or BNP x
X
X
X x
X
X x
X
X x
X
X
X
X
X
X
Bone marrow aspirate
y,z,aa,
X y
X y
X y
X aa y
X y
X y
X y
Peripheral blood sample 
bb
X bb
X bb
X
X
X
X
X
Extramedullary 
assessments cc
X
X
X
X
X
X
X
X
X
X
X
X
X
Additional Assessments as Clinically Indicated
Abbreviations: β-HCG, beta-human chorionic gonadotropin; ABI, ankle-brachial index; AE, adverse event; ANC, absolute neutrophil count; ALP, alkaline phosphatase; ALT, 
alanine aminotransferase; AST, aspartate aminotransferase; BCR-ABL, breakpoint cluster region-Abelson; BP, blood pressure; BM, bone marrow; BNP, B-type natriuretic 
peptide; BSA, body surface area; BUN, blood urea nitrogen; CAD, coronary artery disease; CBC with Diff, complete blood count with differential; CNS, central nervous system; 
CR, complete remission; CRP, C-reactive protein; cTnI, cardiac troponin-I; CSF, cerebrospinal fluid; CV, cardiovascular; CVA, cerebrovascular accident; DIC, disseminated 
intravascular coagulation; DVT, deep venous thrombosis; ECG, electrocardiogram; ECHO, echocardiogram; ECOG, Eastern Cooperative Oncology Group; eCRF, electronic case 
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report form; ECG, electrocardiogram; ECHO, echocardiogram; EOT, end of treatment; EQ-5D-5L, EuroQOL-5 dimension-5 level (patient-reported outcome tool); FACT-Leu, 
Functional Assessment of Cancer Therapy – Leukemia; F/U, follow-up; HbA1c, glycosylated hemoglobin; Hep, hepatitis; HSCT, hematopoietic stem cell transplant; ICF, 
informed consent form; IEC, independent ethics committee; IRB, institutional review board; IRT, interactive response technology; IV, intravenous; LDH, lactic dehydrogenase; 
LVEF, left ventricular ejection fraction; Med/Surg, medical and surgical; MI, myocardial infarction; MR3, molecular response 3-log reduction (BCR-ABL1/ABL1 ≤0.1%); MRD, 
minimum residual disease; MRU, medical resource utilization; MUGA, multigated acquisition; N/A, not applicable; NT-proBNP, N-terminal pro-brain natriuretic peptide; PK, 
pharmacokinetic; PROs, patient-reported outcomes; QTcF, QT interval corrected per Fridericia method; SOC; standard of care; TIA, transient ischemic attack; TKI, tyrosine 
kinase inhibitor; Tx, therapy; WBC, white blood cell.
COVID-related safety and/or logistical issues: All attempts should be made to perform the assessments with the patient present at the site. However, in cases where patient’s visit 
to the site is not feasible (patient cannot travel to the site or in cases where the investigator believes that is best for patient’s and site staff’s safety not to visit to the site), alternative 
evaluation such as local laboratories and/or telehealth (the ability to connect a physician to a patient)/telemedicine (remote clinical assessments) or home healthcare (performing 
some assessments in a patient’s home by a qualified health care professional) will be allowed if permitted by local regulations. Sites will contact the sponsor’s medical 
monitor/designee to discuss individual cases. The data collected from home healthcare visits may be handled differently in the final data analysis, with this documentation included 
in the statistical analysis plan. Separate consent may be required. In the event that a patient cannot visit the site to obtain the study drug, sites should contact the sponsor’s medical 
monitor/designee to arrange for an alternate mechanism of drug dispensation (eg, dispensing additional study drug at clinic visits or direct-to-patient shipment). Additionally, it is 
expected that during the first 20 cycles of treatment (induction, consolidation, and maintenance phases), patient will visit the site at least once per cycle for chemotherapy 
administration (as they are administered intravenously) and/or bone marrow aspiration or any other procedures critical for patient management.
Subject safety will be monitored during the time between on-site visits. At minimum, there will be a phone call with a study site physician within specified-visit window time 
frame which will include AE assessments, documentation of concomitant medication, and an assessment of clinical symptoms. There will be no interval longer than 8 weeks 
without a clinical safety lab and vital signs collection.
a Visit windows: Tests and procedures should be performed on schedule, but occasional changes are allowable within a window (±3 days; a window of ±4 days is allowed only for 
Cycle 4/Day 1 visit or Cycle 10/Day 1 visit) for holidays, vacations, and other administrative reasons. See Table 2 for acceptable visit window at the 30-day follow-up visit and for 
survival follow-up. See footnote y and bb for additional guidance on the permitted windows for the bone marrow aspirate and peripheral blood sample, respectively.
b Enrollment: Screening and randomization procedures should be performed within the 28-day screening period. Central laboratory results will be used for determination of 
eligibility criteria, but local laboratory results may also be used. The ICF may be signed more than 28 days before Cycle 1 Day 1. An Eligibility Verification Form and required 
supporting documentation, as allowed by local regulations, should be sent to the sponsor’s medical monitor or designee as soon as the screening procedures are completed for 
confirmation of patient eligibility (specific instructions for randomization will be supplied in the site operations manual).Confirmation of patient eligibility by the sponsor’s 
medical monitor or designee is required before randomization and first dose administration. Cycle 1 Day 1 should be no later than 7 days after the date of enrollment call in IRT. 
Specific instructions for randomization will be supplied in the site operations manual.
c Medical and surgical history and demographic information will include all diagnoses, therapies, and medical and surgical treatments. 
Special attention should be paid to documenting risk factors for cardiovascular, cerebrovascular, peripheral vascular, and venous thromboembolic disease, including but not limited 
to any history of ischemic heart disease (eg, angina, MI, acute coronary syndrome); valvular heart disease; congestive heart failure; arrhythmias; myocarditis; peripheral arterial 
occlusive disease (eg, claudication, distal extremity amputation, angioplasty); or stroke (eg, TIAs, cerebral atherosclerosis). Any type of revascularization procedures (eg, stent, 
arterial bypass grafts) must also be recorded. 
In addition, diabetes mellitus; hypertension; hypercholesterolemia; hyperlipidemia; DVT; pulmonary embolism; any other coagulopathy (for example, protein S or protein C 
deficiency or anticardiolipin antibody); physical activity status; obesity; and history of and current smoking status. 
Family medical history will be collected, and should include any history of CAD, early death from MI or CVA, sudden death, or bleeding or clotting diatheses in first-degree 
relatives. 
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Demographic information will include the patient’s date of birth (outside European Economic Area) or age (European Economic Area), sex, race, and ethnicity (optional 
depending on country), to be recorded during screening (as allowed by local law and regulations).
d Pregnancy test must be performed for patients of childbearing potential during screening and again at Cycle 1 Day 1 before the first dose of study drug, if the screening test was 
performed >4 days before the visit. For screening, a serum β-HCG test must be performed. The results must be negative within 4 days before the first dose of study drug is 
administered (ie, within the 4 days before Cycle 1 Day 1), or as otherwise required by local regulations (patients with positive serum pregnancy test who have undergone a 
complete abortion in the last 60 days may be included in the study [See Section 7.2]). Monthly urine pregnancy testing will be performed during the study (through Cycle 20). 
Women who are not of childbearing potential (status posthysterectomy, status post-bilateral oophorectomy, or postmenopausal [defined as amenorrhea for at least 12 months]) do 
not need to have the test performed. Serum pregnancy testing (instead of urine) or additional pregnancy testing may be performed during the study at the discretion of the 
investigator, upon request of an IEC/IRB, or if required by local regulations.
e Prior medication data collection should include those listed in the exclusion criteria to determine the patient’s eligibility for the study, as well as all other medications/therapies 
received within 30 days before the first dose of study drug. Prior medications that are ongoing as of the first dose of study drug will then be recorded as concomitant medications.
f Vital signs will be performed at every visit before IV chemotherapy dosing and will include systolic and diastolic BP, heart rate, respiratory rate, and body temperature. On Cycle 
1 Day 1 only, vital signs should be performed before IV chemotherapy dosing, as well as at 1, 3, and 8 hours (±15 minutes) postdose. All BP measurements should be assessed in a 
seated position after the patient has been sitting quietly for 5 minutes, performed 3 times with 2-minute intervals between BP assessments. BP can be measured manually or with 
an automated device, but must be done using a consistent method for all patients at a given site. Monitor and manage BP elevations during the study and treat hypertension to 
normalize BP.
g Physical examinations will include a complete physical (including weight) performed at screening and at every visit before IV chemotherapy dosing during the induction and 
consolidation phases. The examination at Cycle 1 Day 1 should be performed before the first administration of study drug, but is not required if the screening physical examination 
was conducted and medical history obtained within 2 days before administration of the first dose of study drug. Sites should calculate BSA from the weight and height measured at 
baseline, and the additional weight assessments will be documented in the eCRF without the need to calculate the BSA. The extent of the physical examination should be 
consistent with the medical history and the patient’s underlying disease. All physical examinations should address the presence or absence of hepatomegaly and splenomegaly, and 
all findings should be recorded in the eCRF. ECOG performance status should be evaluated during physical examination at screening, Day 1 of Cycle 1, end of Cycle 3 (Day 1 of 
Cycle 4) and end of Cycle 6 (Day 1 of Cycle 7). Height measurement is required at screening only.
h ABI will be performed at screening and as clinically indicated to assess patients for the risk of peripheral arterial disease (see also Table 2). In a supine position, the patient’s BP 
will be assessed in both arms and again in both ankles with BP measured three times at each side. A hand-held Doppler ultrasound may be used to confirm the diastolic pressure in 
the arms and ankles. Instructions for scoring the ABI will be provided in the site operations manual, however, local standard of care process may be used.
i Framingham Score will be done at screening to assess patients who may be at risk for cardiovascular events (see also Table 2).
j ECGs must all be 12-lead ECGs, performed at screening and before IV chemotherapy dosing on Day 1 after every 3 cycles (ie, Cycles 4 and 7) (see also Table 2 for assessments 
continuing with the maintenance phase). ECGs may be performed at other times as clinically indicated. Ventricular rate (or heart rate in case ventricular rate is not available), PR 
interval, RR interval, QRS duration, QT interval, and QTcF interval must be documented in the eCRF. ECGs are to be interpreted by a local cardiologist in cases where there are 
significant findings or when the investigator cannot interpret the findings. If medications known to prolong the QTcF interval are used while a patient is on study, then additional 
ECG monitoring should be performed as clinically indicated. If the timing of a PK blood sample or other blood draw coincides with the timing of an ECG measurement, the ECG 
measurement should be taken first, followed by the blood draw.
k ECHO for assessment of LVEF must be performed at screening; additional ECHOs need only be performed if clinically indicated. As deemed appropriate by the investigator, 
ECHO could be substituted with multigated acquisition (MUGA) scan.
l Eye examinations must be performed at screening (including a detailed history) and as clinically indicated. If performing the screening eye examination is not feasible during the 
screening period (eg, in-patient, no ophthalmologist available, etc), the screening eye examination should be performed by the end of Cycle 1. It is recommended to use 
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Ophthalmoscopy to perform the eye examination (additional tests may be used as clinically indicated or as per physician discretion). The eye examinations should test the retinal 
vasculature and any clinically significant abnormalities should be noted in the CRF.
m PROs include both the EQ-5D-5L instrument from the EuroQOL group and the FACT-Leu instrument, used to collect patient-assessed quality-of-life and health outcomes 
measures, respectively. The instruments will be implemented at screening; at Cycle 1 Day 1, and at Day 1 of Cycles 4 and 7 (see Table 2 for assessments continuing with the 
maintenance phase). All instruments will be administered to patients when they arrive for their scheduled visits, before any clinical measurements, assessments, evaluations, or 
procedures. Patients are required to complete the instruments if there is a validated translation available in a language in which they are fluent.
n MRU: All medical care encounters will be collected each time an AE or unscheduled physician visit occurs. Examples of data to be collected are the number of medical care 
encounters, such as hospital admissions or major diagnostic procedures.
o CNS prophylaxis will be administered on Day 1 and Day 14 of the 3 induction phase Cycles 1, 2, and 3 and the first 3 consolidation phase Cycles 4, 5, and 6 (total: 6 cycles, 
12 intrathecal injections). CNS prophylaxis will comprise a triple intrathecal injection of methotrexate, cytarabine, and corticosteroids (recommended: dexamethasone) as per 
current practice in each center.
p Concomitant medications include all medications/therapies that are ongoing as of or started on Cycle 1 Day 1.
q Alternative therapy and/or proceeding to HSCT will be documented if applicable. Patients who proceed to alternative therapy and/or HSCT will be discontinued from study 
treatment and the date that the patient starts an alternative therapy and/or HSCT should be noted. These patients will, however, continue in the study to be followed additionally 
every 3 months until they withdraw from the study (Section 9.8). Every effort should be made to capture transplant-related procedures, investigator-reported disease status (eg, 
relapse from CR), survival, and the use of alternative therapy and/or post-transplant treatment (chemotherapy, TKI).
r Hepatitis B serology will be performed during screening and as clinically indicated for hepatitis B surface antigen, hepatitis B core antibody, and hepatitis B surface antibody, at 
minimum. Note: Patients who are chronic carriers of hepatitis B virus and receive a BCR-ABL1 TKI therapy may have a reactivation of hepatitis B. For patients with evidence of 
prior or current hepatitis B infection, please refer to Section 8.8 and the investigator’s brochure. If the patient was found to be HBsAg negative but HBcAb positive, a PCR HBV 
DNA needs to be conducted. The patient may be accepted if the PCR HBV DNA is not detectable.
s Pre- and postdose ponatinib plasma sample for PK: Patients should be instructed to not take their dose of ponatinib on the days of predose PK sampling, ie, at Day 1 of Cycles 1, 
2, 3, 4, 6, 9, and 12 (see also Table 2). Patients will be administered ponatinib at the site on those days no later than 1 hour after the predose sample is obtained. Additional plasma 
samples for PK will be obtained postdose during Cycle 2 Day 1 only, at 1 hour (±15 minutes), and at 4 and 6 hours (±30 minutes) postdose. Note: An unscheduled trough (predose) 
sample will be collected at the first scheduled visit following a dose reduction of at least 7 days duration before the visit. The date and exact time of dosing of the 2 preceding doses 
of ponatinib before all PK sample collections, and the date and exact time of collection of all the PK samples, should be recorded in the eCRF.
t Postdose ponatinib plasma sample for PK: Ponatinib should be taken early in the morning at home on the days of postdose PK sampling, ie, on Day 14 of Cycle 1 and Cycle 2, 
and sites should obtain the first postdose PK sample before initiating the vincristine infusion. An additional PK sample will be obtained on these days (Day 14 of Cycles 1 and 2) 
after the vincristine infusion is completed and immediately before leaving the clinic. Note: A distribution of visit times during the day is recommended for these visits to provide a 
range of PK blood sampling times relative to the timing of early morning at-home dosing of ponatinib. The date and exact time of dosing of the 2 preceding doses of ponatinib 
before all PK sample collections, and the date and exact time of collection of all the PK samples, should be recorded in the eCRF.
u CBC with differential testing will be performed centrally at screening and at every visit throughout the induction and consolidation phase, and additionally as clinically indicated. 
Testing should be completed within 24 hours before IV chemotherapy dosing in all cycles; however, every effort should be made to perform the test on the day of dosing. 
Eligibility verification during screening and dose modifications for hematologic adverse drug reactions (see Table 8.e for ponatinib and Section 8.4.2.2 for imatinib) and could be 
based on local laboratory results. CBC with differential is defined as peripheral blood total WBC count, hemoglobin, hematocrit, platelet count, ANC, and WBC differential, 
reported individually for each cell type. Cell types required for diagnosis and response assessment (including basophils, myelocytes, metamyelocytes, promyelocytes, and blasts, 
when present) must be quantified. Additionally, tests related to CR or relapse from CR assessments should be performed locally at these visits, and at other times when clinically 
indicated. Results from local laboratory hematology testing (including CR or relapse from CR assessments), whether scheduled or unscheduled, must be entered in the patient’s 
eCRF. 
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v Serum chemistry testing will be performed centrally at screening and at every visit throughout the induction and consolidation phase, and additionally as clinically indicated. 
Testing should be completed within 24 hours before IV chemotherapy dosing in all cycles; however, every effort should be made to perform the test on the day of dosing. 
Eligibility verification during screening and dose modifications for nonhematologic adverse drug reactions related to serum chemistry (see Table 8.d for ponatinib and 
Section 8.4.2.1 for imatinib) could be based on local laboratory results. Serum chemistry testing consists of a peripheral blood draw with the following assessments: sodium; 
potassium; chloride; bicarbonate (or CO2); BUN (urea); uric acid; albumin; creatinine; total, direct, and indirect bilirubin; AST; ALT; ALP; LDH; magnesium; phosphorous; 
calcium; amylase; and lipase. In case of a suspicion for disseminated intravascular coagulation (DIC), sites should perform tests at the local laboratory according to the applicable 
local guidelines. Results from any local laboratory chemistry testing, whether scheduled or unscheduled, must be entered in the patient’s eCRF (local laboratory results should only 
be entered if the local laboratory results and required supporting documentation are used for treatment-related decisions).
w Fasting glucose, cholesterol, lipids, and HbA1c must be performed at screening, at Cycle 1 Day 1, and on Day 1 of every third cycle thereafter (ie, Cycle 4, Cycle 7, Cycle 10, 
etc), or more frequently as clinically indicated. Tests performed within 3 days before Cycle 1 Day 1 need not be repeated at that visit.
x CRP, cTnI assessments, and NT-proBNP or BNP assessments will be performed at Days 1 and 14 of Cycles 1-3 (induction phase) and at Day 1 of Cycles 4-9 (consolidation 
phase), or more frequently as clinically indicated. For maintenance phase, CRP, cTnI assessments and NT-proBNP or BNP testing must be included with every blood draw (except 
Cycle 10, Day 7). In patients with persistent elevation of cTnI or NT-proBNP/BNP, performing an ECHO and/or consulting a cardiologist should be considered.
y BM aspirates will be obtained at screening and within ±7 days before Day 1 of Cycles 1, 2, 3, and 4, and also before Day 1 of Cycles 6 and 8 (if MRD- negativity has not been 
achieved by this time) (see Table 2 for assessment schedule during the remainder of the study). Cycle 1 Day 1 assessments need not be repeated if the screening assessment was 
within 14 days before Cycle 1 Day 1. BM aspirates may be performed at other times as per SOC or when clinically indicated. Tests related to CR and relapse from CR assessments 
should be performed locally. A portion of BM aspirate sample will be sent to a local laboratory for CR and relapse from CR assessments. At any point that a BM aspirate is 
collected for tests related to CR and relapse from CR assessments, a portion of BM aspirate sample should also be sent to central laboratory for molecular assessment. In instances 
where a BM aspirate is a dry tap, BM biopsy could be used (any BM biopsy sample, if collected, will be evaluated locally). Results from local laboratory testing of any BM 
aspirate (or biopsy, if performed), whether scheduled or unscheduled, must be recorded in the patient’s eCRF (local BCR-ABL1 results should only be entered if the local 
laboratory results and required supporting documentation are used for treatment-related decisions). Note: A screening/diagnostic dry tap will not make the patient ineligible for the 
study as peripheral blood specimen is also collected at the same time and will be used for transcript determination.
z Confirmation of loss of MRD negativity: For assessments beyond Cycle 4, if a patient had achieved MRD negativity at the previous assessment and subsequently no longer meets 
the criteria for achievement, MRD status should be assessed again within 4 weeks at the central laboratory, with either a BM aspirate (optional) or peripheral blood, unless 
associated with loss of MR3 or relapse from CR.
aa BM aspirate on Cycle 3 Day 1: This sample is only required in patients who have not achieved CR at Cycle 2 Day 1.
bb Peripheral blood sample collection for assessment of molecular response and exploratory biomarkers must occur at screening and within ±7 days before Day 1 of Cycles 1, 2, 3, 
4, 6, and 8 (see Table 2 for assessment schedule during the remainder of the study). Cycle 1 Day 1 molecular response assessments need not be repeated if the screening 
assessment was within 7 days before Cycle 1 Day 1. A portion of the sample collected for molecular response assessment may also be used for exploratory biomarker assessment; 
which will include analysis of molecular determinants of response or resistance to ponatinib or imatinib, including BCR-ABL1 mutation analysis and/or biomarkers affecting 
ponatinib efficacy or safety. Specific instructions for collection of peripheral blood for molecular response and exploratory assessments will be provided in the laboratory manual. 
For assessments beyond Cycle 4, in the event that a patient had achieved MRD negativity at the previous assessment and subsequently no longer meets the criteria for 
achievement, MRD status should be assessed again within 4 weeks, with either a BM aspirate (optional) or peripheral blood, unless associated with loss of MR3 or relapse from 
CR.
cc Extramedullary assessments will be performed locally and will include lumbar punctures to test CSF for CNS disease at screening (if clinically indicated), on Day 1 and Day 14 
of Cycles 1, 2, 3, 4, 5, and 6 and as clinically indicated thereafter. Additional assessments for other extramedullary involvement (ie, lymphadenopathy, splenomegaly, skin/gum 
infiltration, testicular mass) should be performed as clinically indicated throughout the study. When imaging studies have been used to assess extramedullary involvement, the 
same imaging methods should be used consistently throughout the study for individual patients. Results from local laboratory testing, whether scheduled or unscheduled, must be 
recorded in the patient’s eCRF.
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Table 2 Schedule of Events: Maintenance Phase, Single-Agent Therapy, End-of-Treatment, and Follow-up
Study Procedures
Maintenance Phase
Single Agent 
Tx a
EOT
30 Days After Last Dose 
or D/C b
Survival 
Follow-up
Q3 mo after 
D/C c,d,e
28-Day Cycles
Cycle 10
Cycle 
11
Cycle 
12
Cycle 
13
Cycle 
14
Cycle 
15
Cycle 
16
Cycle 
17
Cycle 
18
Cycle 
19
Cycle 
20
Cycle Days
1
7
1
1
1
1
1
1
1
1
1
1
1, Q3 mo
Window (days) f
±4
±3
±4
±4
±4
±4
±4
±4
±4
±4
±4
±4
±4
+7
±14
Vital signs g
X
X
X
X
X
X
X
X
X
X
X
X
X g
X
Physical exams h
X
X
X
X
X
X
X
X
X
X
X
X
X h
X
ECOG h
X
X
X
X
X h
X
12-lead ECGs i
X
X
X
X
X i
X
PROs j
X
X
X
X
X j
X
X j
MRU k
X
X
X
X
X
X
X
X
X
X
X
X k
X
Diary review l
X
X
X
X
X
X
X
X
X
X
X
X l
X
AEs
Recorded at every visit through the 30-day EOT visit or longer
Concomitant 
medications m
Recorded at every visit through the 30-day EOT visit or longer
Pregnancy test n
Performed monthly through Cycle 20; subsequently, pregnancy test to be performed quarterly (at every 
scheduled patient visit which occurs every 3 months).
X
ABI o
Additional Assessments as Clinically Indicated
X
Framingham score p
X
ECHOs q
Additional Assessments as Clinically Indicated
X
Eye exams r
Additional Assessments as Clinically Indicated
X
Clinical Laboratory Sampling
Plasma samples for PK 
s
X
CBC with diff t
X
X
X
X
X
X
X
X
X
X
X
X
X t
X
Chemistry u
X
X
X
X
X
X
X
X
X
X
X
X
X u
X
Fasting glucose, 
cholesterol, lipids, and 
HbA1c v
X
X
X
X
X v
X
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Table 2 Schedule of Events: Maintenance Phase, Single-Agent Therapy, End-of-Treatment, and Follow-up
Study Procedures
Maintenance Phase
Single Agent 
Tx a
EOT
30 Days After Last Dose 
or D/C b
Survival 
Follow-up
Q3 mo after 
D/C c,d,e
28-Day Cycles
Cycle 10
Cycle 
11
Cycle 
12
Cycle 
13
Cycle 
14
Cycle 
15
Cycle 
16
Cycle 
17
Cycle 
18
Cycle 
19
Cycle 
20
Cycle Days
1
7
1
1
1
1
1
1
1
1
1
1
1, Q3 mo
Window (days) f
±4
±3
±4
±4
±4
±4
±4
±4
±4
±4
±4
±4
±4
+7
±14
CRP, cTnI, and NT-
proBNP or BNP w
X
X
X
X
X
X
X
X
X
X
X
X w
X
BM aspirate x,y,z
X
X
X x,y
Xz
Peripheral blood 
sample aa
X
X
X
X
X aa
X
Hep B serology bb
Additional assessments as Clinically Indicated
Extramedullary 
assessments cc
Additional Assessments as Clinically Indicated
X cc
Abbreviations: β-HCG, beta-human chorionic gonadotropin; ABI, ankle-brachial index; AE, adverse event; ANC, absolute neutrophil count; ALP, alkaline phosphatase; ALT, 
alanine aminotransferase; AST, aspartate aminotransferase; AOE, arterial occlusive event; BCR-ABL, breakpoint cluster region-Abelson; BM, bone marrow; BNP, B-type 
natriuretic peptide; BP, blood pressure; BSA, body surface area; BUN, blood urea nitrogen; CBC with Diff, complete blood count with differential; chemo, chemotherapy; CNS, 
central nervous system; CR, complete remission; CRP, C-reactive protein; CSF, cerebrospinal fluid; cTnI, cardiac troponin-I; CV, cardiovascular; D/C, discontinuation; DIC, 
disseminated intravascular coagulation; ECG, electrocardiogram; ECHO, echocardiogram; ECOG, Eastern Cooperative Oncology Group; EOS, end of study; eCRF, electronic 
case report form; EOT, end of treatment; EQ-5D-5L, EuroQOL-5 dimension-5 level (patient-reported outcome tool); FACT-Leu, Functional Assessment of Cancer Therapy –
Leukemia; F/U, follow-up; HbA1c, glycosylated hemoglobin; Hep, hepatitis; HSCT, hematopoietic stem cell transplant; IEC, independent ethics committee; IRB, institutional 
review board; LDH, lactic dehydrogenase; LVEF, left ventricular ejection fraction; Med/Surg, medical and surgical; MR3, molecular response 3-log reduction (BCR-ABL1/ABL1 
≤0.1%); MRD, minimum residual disease; MRU, medical resource utilization; MUGA, multigated acquisition; NT-proBNP, N-terminal pro-brain natriuretic peptide; PD, 
progressive disease; PROs, patient-reported outcomes (EQ-5D-5L and FACT-Leu); Q3 mo, every 3 months; QTcF, QT interval corrected per Fridericia method; SAE, serious 
adverse event; SOC, standard of care; TKI, tyrosine kinase inhibitor; Tx, therapy; VTE, venous thrombotic/embolic event;; WBC, white blood cell.
COVID-related safety and/or logistical issues: All attempts should be made to perform the assessments with the patient present at the site. However, in cases where patient’s visit 
to the site is not feasible (patient cannot travel to the site or in cases where the investigator believes that is best for patient’s and site staff’s safety not to visit to the site), alternative 
evaluation such as local laboratories and/or telehealth (the ability to connect a physician to a patient)/telemedicine (remote clinical assessments) or home healthcare (performing 
some assessments in a patient’s home by a qualified health care professional) will be allowed if permitted by local regulations. Sites will contact the sponsor’s medical 
monitor/designee to discuss individual cases. The data collected from home healthcare visits may be handled differently in the final data analysis, with this documentation included 
in the statistical analysis plan. Separate consent may be required. In the event that a patient cannot visit the site to obtain the study drug, sites should contact the sponsor’s medical 
monitor/designee to arrange for an alternate mechanism of drug dispensation (eg, dispensing additional study drug at clinic visits or direct-to-patient shipment). Additionally, it is 
expected that during the first 20 cycles of treatment (induction, consolidation, and maintenance phases), patient will visit the site at least once per cycle for chemotherapy 
administration (as they are administered intravenously) and/or bone marrow aspiration or any other procedures critical for patient management.
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Subject safety will be monitored during the time between on-site visits. At minimum, there will be a phone call with a study site physician within specified-visit window time 
frame which will include AE assessments, documentation of concomitant medication, and an assessment of clinical symptoms. There will be no interval longer than 8 weeks 
without a clinical safety lab and vital signs collection.
a Single-Agent Therapy: After the end of Cycle 20, patients will receive single-agent TKIs (ponatinib or imatinib) continuously until they have experienced relapse from CR or PD, 
have an unacceptable toxicity, withdraw consent, proceed to HSCT or alternative therapy, have completed the study, or until the sponsor terminates the study, whichever occurs 
first. Note: Efficacy and safety data (as indicated on the table) will be collected Q3 months after the end of Cycle 20 (ie, Day 1 of Cycles 21, 24, 27, etc).
b EOT visit should occur 30 days after a patient has discontinued the study drug (last dose) (a window of + 7 days is acceptable), with the exception of less than 30 days because 
that the EOT visit must occur before HSCT or before initiation of any alternative treatment (if applicable). 
c Survival follow-up: Patients who have been discontinued from study drug for any reason will be contacted every 3 months (±14 days) and followed for investigator-reported 
disease status (eg, relapse from CR) with date of relapse reported and source documentation should be noted, and survival until they withdraw from the study or until the patient’s 
death has been reported. Delayed treatment-related SAEs, AOEs, and VTEs will be followed until resolution or the start of subsequent alternative anticancer therapy. The EOS 
eCRF page is to be completed at the time the patient discontinues from the survival follow-up period.
d Alternative therapy: The start date of alternative therapy should be noted. Patients proceeding to alternative therapy will be discontinued from study treatment but will be 
followed for investigator-reported disease status (eg, relapse from CR) and survival until the patient’s death or the patient withdraws from the study (Section 9.8).
e Transplant follow-up: Patients who proceed to HSCT will be discontinued from study treatment and the date that the patient receives HSCT should be noted. These patients will, 
however, continue in the study to be followed additionally every 3 months until the patient’s death or the patient withdraws from the study (Section 9.8). Every effort should be 
made to capture transplant-related procedures, investigator-reported disease status (eg, relapse from CR), survival, and the use of post-transplant treatment (chemotherapy, TKI).
f Visit windows: Tests and procedures should be performed on schedule, but occasional changes are allowable within a window (±3 days for Day 7 of Cycle 10; ±4 days for Day 1 
of Cycles 10-20, during single agent treatment) for holidays, vacations, and other administrative reasons. See footnote b for additional guidance on the permitted window for EOT 
visit; and, see x and z for additional guidance on the permitted windows for the bone marrow aspirate and peripheral blood sample, respectively.
g Vital signs will be performed at every visit before dosing, including during the single-agent therapy phase and EOT, and will include systolic and diastolic BP, heart rate, 
respiratory rate, and body temperature. All BP measurements should be assessed in a seated position after the patient has been sitting quietly for 5 minutes, performed 3 times with 
2-minute intervals between BP assessments. BP can be measured manually or with an automated device, but must be done using a consistent method for all patients at a given site. 
Monitor and manage BP elevations during the study and treat hypertension to normalize BP.
h Physical examinations will include a complete physical (including weight) performed before dosing on Day 1 and Day 7 of Cycle 10, Day 1 of every subsequent cycle, Day 1 of 
every third cycle in the single-agent therapy phase (eg, Day 1 of Cycles 21, 24, 27, and so on) to be consistent with the visit schedule, and at the EOT Visit. The weight 
assessments will be documented in the electronic case report form without the need to calculate the BSA. The extent of the physical examination should be consistent with the 
medical history and the patient’s underlying disease. All physical examinations should address the presence or absence of hepatomegaly and splenomegaly, and all findings should 
be recorded in the eCRF. ECOG performance status should be evaluated during physical examination at Day 1 every third cycle after Cycle 7 (ie, Day 1 of Cycles 10, 13, 16, 19), 
and then on Day 1 of Cycle 21 and then at least every 6 cycles (eg, Day 1 of Cycles 21, 27, and so on) to be consistent with the visit schedule, and EOT. Height measurement is not 
required.
i ECGs must all be 12-lead ECGs, performed before dosing on Day 1 of every third cycle after Cycle 7 (ie, Day 1 of Cycles 10, 13, 16, 19), and then on Day 1 of Cycle 21 and then 
at least every 6 cycles (eg, Day 1 of Cycles 21, 27, and so on) to be consistent with the visit schedule, and at the EOT visit; ECGs may be performed at other times as clinically 
indicated. Ventricular rate (or heart rate in case ventricular rate is not available), PR interval, RR interval, QRS duration, QT interval, and QTcF interval must be documented in 
the eCRF. ECGs are to be interpreted by a local cardiologist in cases where there are significant findings or when the investigator cannot interpret the findings. If medications 
known to prolong the QTcF interval are used while a patient is on study, then additional ECG monitoring should be performed as clinically indicated.
j PROs include both the EQ-5D-5L instrument from the EuroQOL group and the FACT-Leu instrument, used to collect patient-assessed quality-of-life and health outcomes 
measures, respectively. The instruments will be implemented at Day 1 every third cycle after Cycle 7 (ie, Day 1 of Cycles 10, 13, 16, 19), and then on Day 1 of Cycle 21 and then 
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at least every 6 cycles (eg, Day 1 of Cycles 21, 27, and so on) to be consistent with the visit schedule, and EOT. All instruments will be administered to patients when they arrive 
for their scheduled visits, before any clinical measurements, assessments, evaluations, or procedures. Patients are required to complete the instruments if there is a validated 
translation available in a language in which they are fluent. At the survival follow-up assessments, only the EQ-5D-5L should be administered (at least once in 6 months) if 
telephone contact with the patient or caregiver is feasible.
k MRU: All medical care encounters will be collected each time an AE or unscheduled physician visit occurs. Examples of data to be collected are the number of medical care 
encounters, such as hospital admissions or major diagnostic procedures.
l Diary review will continue at every visit, including during the single-agent therapy phase and at the EOT visit.
m Concomitant medications include all medications/therapies that are ongoing as of or started on Cycle 10 Day 1.
n Monthly urine pregnancy testing will be performed during the study (through Cycle 20); subsequently, urine pregnancy test to be performed quarterly (at every scheduled patient 
visit which occurs every 3 months) (serum pregnancy test may be performed instead at the discretion of the investigator, upon request of an IEC/IRB, or if required by local 
regulations). If the pregnancy test was deemed necessary at screening, it must be performed again at the EOT visit. For EOT visit, a serum β-HCG test must be performed. Women 
who are not of childbearing potential (status posthysterectomy, status post-bilateral oophorectomy, or postmenopausal [defined as amenorrhea for at least 12 months]) do not need 
to have the test performed. Additional pregnancy testing may be performed during the study at the discretion of the investigator, upon request of an IEC/IRB, or if required by local 
regulations.
o ABI will be repeated at the EOT visit and as clinically indicated to assess patients for the risk of peripheral arterial disease. In a supine position, the patient’s BP will be assessed 
in both arms and again in both ankles with BP measured three times at each side. A hand-held Doppler ultrasound may be used to confirm the diastolic pressure in the arms and 
ankles. Instructions for scoring the ABI will be provided in the site operations manual, however, local standard of care process may be used.
p Framingham Score will be done at the EOT visit to assess patients who may be at risk for cardiovascular events.
q ECHO for assessment of LVEF should be performed at the EOT and need only be repeated if clinically indicated. As deemed appropriate by the investigator, ECHO could be 
substituted with multigated acquisition (MUGA) scan.
r Eye examinations should be repeated at the EOT visit and as clinically indicated. It is recommended to use Ophthalmoscopy to perform the eye examination (additional tests may 
be used as clinically indicated or as per physician discretion). The eye examinations should test the retinal vasculature and clinically significant abnormalities should be noted in 
the CRF.
s Predose plasma sample for PK: Patients should be instructed to not take their dose of ponatinib on Cycle 12 Day 1. Patients will be administered ponatinib at the site that day 
within 1 hour after the predose sample is obtained. Note: An unscheduled trough (predose) sample will be collected at the first scheduled visit following a dose reduction of at least 
7 days duration before the visit. The date and exact time of dosing of the 2 preceding doses of ponatinib before all PK sample collections, and the date and exact time of collection 
of all the PK samples should be recorded in the eCRF.
t CBC with differential assessments will be performed centrally and will continue on Day 1 and Day 7 of Cycle 10, Day 1 of every subsequent cycle, Day 1 of every third cycle 
during single-agent therapy, and at the EOT visit. Testing should be completed within 24 hours before dosing in all cycles; however, every effort should be made to perform the 
test on the day of dosing. Dose modifications for hematologic adverse drug reactions (see Table 8.e for ponatinib and Section 8.4.2.2 for imatinib) could be based on local 
laboratory results. CBC with differential is defined as peripheral blood total WBC count, hemoglobin, hematocrit, platelet count, ANC, and WBC differential, reported individually 
for each cell type. Cell types required for diagnosis and response assessment (including basophils, myelocytes, metamyelocytes, promyelocytes, and blasts, when present) must be 
quantified. Additionally, tests related to CR or relapse from CR assessments should be performed locally at these visits, and at other times when clinically indicated. Results from 
local laboratory hematology testing (including CR or relapse from CR assessments), whether scheduled or unscheduled, must be entered in the patient’s eCRF.
u Serum chemistry assessments will be performed centrally and will continue on Day 1 and Day 7 of Cycle 10, Day 1 of every subsequent cycle, Day 1 of every third cycle during 
single-agent therapy, and at the EOT visit. Testing should be completed within 24 hours before dosing in all cycles; however, every effort should be made to perform the test on 
the day of dosing. Dose modifications for nonhematologic adverse drug reactions related to serum chemistry (see Table 8.d for ponatinib and Section 8.4.2.1 for imatinib) could be 
based on local laboratory results. Serum chemistry consists of a peripheral blood draw with the following assessments: sodium; potassium; chloride; bicarbonate (or total CO2); 
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BUN (or urea); uric acid; albumin; creatinine; total, direct, and indirect bilirubin; AST; ALT; ALP; LDH; magnesium; phosphorous; calcium; amylase; and lipase. In case of a 
suspicion for disseminated intravascular coagulation (DIC), sites should perform tests at a local laboratory according to the applicable local guidelines. Results from any local 
laboratory chemistry testing, whether scheduled or unscheduled, must be entered in the patient’s eCRF (local laboratory results should only be entered if the local laboratory results 
and required supporting documentation are used for treatment-related decisions).
v Fasting glucose, cholesterol, lipids, and HbA1c should be included on Day 1 of every third cycle starting with Cycle 10 (eg, Cycle 10, Cycle 13, Cycle 16), including during 
single-agent therapy and at the EOT visit, or more frequently as clinically indicated. 
w CRP, cTnI assessments, and NT-proBNP or BNP assessments must be included with every blood draw (except Cycle 10, Day 7) to assess CV risks or more frequently as 
clinically indicated. In patients with persistent elevation of cTnI or NT-proBNP/BNP, performing an ECHO and/or consulting a cardiologist should be considered.
x BM aspirate must occur within ±7 days of the scheduled assessments. BM aspirates will continue on Day 1 of every sixth cycle starting with Cycle 10 (ie, Day 1 of Cycles 10 and 
16). During the single-agent therapy phase, sampling will start on Day 1 of Cycle 21 and then at least annually (eg, Day 1 of Cycles 21, 33, and so on) to be consistent with the 
visit schedule. BM aspirates may be performed at other times as per SOC or when clinically indicated. Tests related to CR and relapse from CR assessments should be performed 
locally. A portion of BM aspirate sample will be sent to a local laboratory for CR and relapse from CR assessments. At any point that a BM aspirate is collected for tests related to 
CR and relapse from CR assessments, a portion of BM aspirate sample should also be sent to central laboratory for molecular assessment. In instances where a BM aspirate is a dry 
tap, BM biopsy could be used (any BM biopsy sample, if collected, will be evaluated locally). Results from local laboratory testing of any BM aspirate (or biopsy, if performed), 
whether scheduled or unscheduled, must be recorded in the patient’s eCRF (local BCR-ABL1 results should only be entered if the local laboratory results and required supporting 
documentation are used for treatment-related decisions). 
y Confirmation of loss of MRD negativity: In the event that a patient had achieved MRD negativity at the previous assessment and subsequently no longer meets the criteria for 
achievement, MRD status should be assessed again within 4 weeks at the central laboratory, with either a BM aspirate (optional) or peripheral blood, unless associated with loss of 
MR3 or relapse from CR.
z BM aspirate to be collected at EOT visit with the exception of not being required if BM was collected through C4D1 and the EOT visit date is less than 4 weeks from last BM 
collection.
aa Peripheral blood samples for molecular response assessment must occur within 7 days of the scheduled assessments. Samples will be obtained on Day 1 of every third cycle 
starting with Cycle 10 (eg, Cycles 10, 13, 16, 19). During the single-agent therapy phase, sampling will start on Day 1 of Cycle 21 (eg, Cycles 21, 24, 27) to be consistent with the 
visit schedule. A portion of the sample collected for molecular response assessment may also be used for exploratory biomarker assessment; which will include analysis of 
molecular determinants of response or resistance to ponatinib or imatinib, including BCR-ABL1 mutation analysis and/or biomarkers affecting ponatinib efficacy or safety. 
Specific instructions for collection of peripheral blood for molecular response and exploratory assessments will be provided in the laboratory manual. In the event that a patient had 
achieved MRD negativity at the previous assessment and subsequently no longer meets the criteria for achievement, MRD status should be assessed again within 4 weeks, with 
either a BM aspirate (optional) or peripheral blood.
bb Hepatitis B serology will be performed as clinically indicated for hepatitis B surface antigen, hepatitis B core antibody, and hepatitis B surface antibody, at minimum. Note: 
Patients who are chronic carriers of hepatitis B virus and receive a BCR-ABL1 TKI therapy may have a reactivation of hepatitis B. For patients with evidence of prior or current 
hepatitis B infection, please refer to Section 8.8 and the investigator’s brochure.
cc Extramedullary assessments will be performed locally as clinically indicated and will include lumbar punctures to test CSF for CNS disease at the EOT visit and as clinically 
indicated during the maintenance phase and the single-agent therapy phase. Additional assessments for other extramedullary involvement (ie, lymphadenopathy, splenomegaly, 
skin/gum infiltration, testicular mass) should be performed as clinically indicated throughout the study. When imaging studies have been used to assess extramedullary 
involvement, the same imaging methods should be used consistently throughout the study for individual patients. Results from local laboratory testing, whether scheduled or 
unscheduled, must be recorded in the patient’s eCRF.
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Appendix B
Responsibilities of the Investigator
Clinical research studies sponsored by the sponsor are subject to ICH GCP and all the applicable 
local laws and regulations. The responsibilities imposed on investigators by the FDA are 
summarized in the “Statement of Investigator” (Form FDA 1572), which must be completed and 
signed before the investigator may participate in this study.
The investigator agrees to assume the following responsibilities by signing a Form FDA 1572:
1. Conduct the study in accordance with the protocol.
2. Personally conduct or supervise the staff who will assist in the protocol.
3. If the investigator/institution retains the services of any individual or party to perform 
trial-related duties and functions, the investigator/institution should ensure that this 
individual or party is qualified to perform those trial-related duties and functions and should 
implement procedures to ensure the integrity of the trial-related duties and functions 
performed and any data generated.
4. Ensure that study-related procedures, including study specific (non-routine/non-standard 
panel) screening assessments are NOT performed on potential subjects, before the receipt of 
written approval from relevant governing bodies/authorities.
5. Ensure that all colleagues and employees assisting in the conduct of the study are informed 
of these obligations.
6. Secure prior approval of the study and any changes by an appropriate IRB/IEC that conform 
to 21 CFR Part 56, ICH, and local regulatory requirements.
7. Ensure that the IRB/IEC will be responsible for initial review, continuing review, and 
approval of the protocol. Promptly report to the IRB/IEC all changes in research activity and 
all anticipated risks to subjects. Make at least yearly reports on the progress of the study to 
the IRB/IEC, and issue a final report within 3 months of study completion.
8. Ensure that requirements for informed consent, as outlined in 21 CFR Part 50 ICH and local 
regulations, are met.
9. Obtain valid informed consent from each subject who participates in the study, and document 
the date of consent in the subject’s medical chart. Valid informed consent is the most current 
version approved by the IRB/IEC. Each ICF should contain a subject authorization section 
that describes the uses and disclosures of a subject’s personal information (including personal 
health information) that will take place in connection with the study. If an ICF does not 
include such a subject authorization, then the investigator must obtain a separate subject 
authorization form from each subject or the subject’s legally acceptable representative.
10. Prepare and maintain adequate case histories of all persons entered into the study, including 
eCRFs, hospital records, laboratory results, etc, and maintain these data for a minimum of 
2 years following notification by the sponsor that all investigations have been discontinued or 
that the regulatory authority has approved the marketing application. The investigator should 
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contact and receive written approval from the sponsor before disposing of any such 
documents.
11. Allow possible inspection and copying by the regulatory authority of GCP-specified essential 
documents.
12. Maintain current records of the receipt, administration, and disposition of sponsor-supplied 
drugs, and return all unused sponsor-supplied drugs to the sponsor. *This responsibility lies 
on the appropriate individual, designated by the site in Japan.
13. Report adverse reactions to the sponsor promptly. In the event of an SAE, notify the sponsor 
within 24 hours.
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Appendix C
Investigator Consent to Use of Personal Information
Takeda will collect and retain personal information of the investigator, including his or her name, 
address, and other identifying personal information. In addition, the investigator’s personal 
information may be transferred to other parties located in countries throughout the world (eg, the 
UK, US, and Japan), including the following:

Takeda, its affiliates, and licensing partners.

Business partners assisting Takeda, its affiliates, and licensing partners.

Regulatory agencies and other health authorities.

IRBs and IECs.
The investigator’s personal information may be retained, processed, and transferred by Takeda 
and these other parties for research purposes including the following:

Assessment of the suitability of the investigator for the study and/or other clinical studies.

Management, monitoring, inspection, and audit of the study.

Analysis, review, and verification of the study results.

Safety reporting and pharmacovigilance relating to the study.

Preparation and submission of regulatory filings, correspondence, and communications to 
regulatory agencies relating to the study.

Preparation and submission of regulatory filings, correspondence, and communications to 
regulatory agencies relating to other medications used in other clinical studies that may 
contain the same chemical compound present in the study medication.

Inspections and investigations by regulatory authorities relating to the study.

Self-inspection and internal audit within Takeda, its affiliates, and licensing partners.

Archiving and audit of study records.

Posting investigator site contact information, study details and results on publicly accessible 
clinical trial registries, databases, and websites.
The investigator’s personal information may be transferred to other countries that do not have 
data protection laws that offer the same level of protection as data protection laws in 
investigator’s own country.
The investigator acknowledges and consents to the use of his or her personal information by 
Takeda and other parties for the purposes described above.
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use

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Appendix D
ECOG Scale for Performance Status
Grade
Description
0
Normal activity. Fully active, able to carry on all predisease performance without restriction.
1
Symptoms but ambulatory. Restricted in physically strenuous activity, but ambulatory and able to 
carry out work of a light or sedentary nature (eg, light housework, office work).
2
In bed <50% of the time. Ambulatory and capable of all self-care, but unable to carry out any work 
activities. Up and about more than 50% of waking hours.
3
In bed >50% of the time. Capable of only limited self-care, confined to bed or chair more than 
50% of waking hours.
4
100% bedridden. Completely disabled. Cannot carry on any self-care. Totally confined to bed or 
chair.
5
Dead.
Source: Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, et al. Toxicity and response 
criteria of the Eastern Cooperative Oncology Group. Am Jf Clin Oncol. 1982; 5(6):649-55.
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Appendix E
Drugs With a Risk of TdP
Four categories of QT-prolonging drugs that may be used as a guide for this protocol can be 
accessed at crediblemeds.org. This website identifies drugs with known risk of TdP, drugs with 
possible risk of TdP, drugs with conditional risk of TdP (ie, can cause TdP under certain 
conditions), and drugs to be avoided by congenital long QT patients. The investigator site should 
register (under the “For Healthcare Providers” tab) to access these categories. If the investigator 
site does not wish to register, a composite list, including all categories, is available.
A subset of drugs categorized in crediblemeds.org as having a known risk, a possible risk, and a 
conditional risk of TdP that are often used to treat patients including those with hematologic 
cancer are listed in Table 1; drugs with a known risk are presented in bold font and should be 
avoided.
Note: The website and table are only to be used as a guideline and are not comprehensive. It is 
the investigator’s responsibility to ensure that any drugs under consideration have not been 
newly identified as causing TdP.
Table 1 Drugs Listed as Having a Known, Possible, or Conditional Risk of TdP
Generic Name
Brand Name
Class
Risk 
Category a
Aclarubicin
Aclacin, Aclacinomycine, Aclacinon, 
Aclaplastin, Jaclacin
Anti-cancer
KR
Alimemazine 
(Trimeprazine)
Nedeltran, Panectyl, Repeltin, Therafene, 
Theraligene, Theralen, Theralene, Vallergan, 
Vanectyl, Temaril
Antihistamine
PR
Amantadine
Symmetrel, Symadine
Antiviral
CR
Amiodarone
Cordarone, Pacerone, Nexterone
Antiarrhytmic
KR
Amisulpride
Barhemsys, Solian, Supitac, Soltus, Amitrex, 
Amazeo
Antiemetic, 
Antipsychotic
CR
Amitriptyline
Tryptomer, Tryptizol, Laroxyl, Saroten, 
Sarotex, Lentizol, Endep 
Antidepressant
CR
Amphotericin B
Fungilin, Fungizone, Abelcet, AmBisome, 
Fungisome, amphocil
Antifungal
CR
Amsacrine
Amsidine
Antineoplastic agent
CR
Anagrelide
Agrylin, Xagrid
Phospodiesterase 3 
inhibitor
KR
Aripiprazole
Ability, Aripiprex
Antipsychotic, 
atypical
PR
Arsenic trioxide
Trisenox
Anti-cancer
KR
Asenapine
Saphris, Sycrest
Antipsychotic, 
atypical
PR
Astemizole
Hismanal
Antihistamine
KR
Atomoxetine
Strattera
CNS stimulant
PR
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Table 1 Drugs Listed as Having a Known, Possible, or Conditional Risk of TdP
Generic Name
Brand Name
Class
Risk 
Category a
Azithromycin
Zithromax, Zmax
Antibiotic
KR
Bedaquiline
Sirturo
Antibiotic
PR
Bendamustine
Treanda, Treakisym, Ribomustin, Levact
Anti-cancer
PR
Bendroflumethiazide
Aprinox, Corzide
Diuretic thiazide
CR
Benperidol
Anquil, Glianimon
Antipsychotic
PR
Bepridil
Vascor
Antianginal
KR
Betrixaban
Bevyxxa
Anticoagulant
PR
Bortezomib
Velcade, Bortecad
Proteasome inhibitor
PR
Bosutinib
Bosulif
Anticancer
PR
Buprenorphine
Butrans, Belbuca, Bunavail, Buprenex, 
Subutex, Suboxone, Zubsolv
Opioid agonist
PR
Cabozantinib
Cometriq
Anticancer
PR
Capecitabine
Xeloda
Anticancer
PR
Carbetocin
Pabal, Lonactene, Duratocin
Uteotonic
PR
Ceritinib
Zykadia
Anticancer
PR
Cesium Chloride
Energy Catalyst
Toxin
KR
Chloral hydrate
Aquachloral, Novo-Chlorhydrate, Somnos, 
Noctec, Somnote
Sedative
CR
Chloroquine
Aralen
Antimalarial
KR
Chlorpromazine
Thorazine, Largactil, Megaphen
Antipsychotic/ 
Antiemetic
KR
Chlorprothixene
Truxal
Antipsychotic
KR
Cilostazol
Pletal
Phosphodiesterase 3 
inhibitor
KR
Cimetidine
Tagamet
Antacid
CR
Ciprofloxacin
Cipro, Cipro-XR, Neofloxin
Antibiotic
KR
Cisapride
Propulsid
GI stimulant
KR
Citalopram
Celexa, Cipramil
Antidepressant, SSRI
KR
Clarithromycin
Biaxin, Prevpac
Antibiotic
KR
Clofazimine
Lamprene
Antibiotic
PR
Clomipramine
Anafranil
Antidepressant, 
tricyclic
CR
Clotiapine
Entumine
Antipsychotic, 
atypical
PR
Clozapine
Clozaril, Fazaclo, Versacloz
Antipsychotic, 
atypical
PR
Cobimetinib
Cotellic
Anticancer
PR
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Table 1 Drugs Listed as Having a Known, Possible, or Conditional Risk of TdP
Generic Name
Brand Name
Class
Risk 
Category a
Cocaine
Cocaine
Local anesthetic
KR
Crizotinib
Xalkori
Anticancer
PR
Cyamemazine
(Cyamepromazine)
Tercian
Antipsychotic
PR
Dabrafenib
Tafinlar
Anticancer
PR
Dasatinib
Sprycel
Anticancer
PR
Degarelix
Firmagon, Ferring
Anti-androgen
PR
Delamanid
Deltyba
Antibiotic
PR
Desipramine
Pertofrane, Norpramin
Antidepressant, 
tricyclic
PR
Dexmedetomidine
Precedex, Dexdor, Dexdomitor
Sedative
PR
Dextromethorphan 
(Quinidine)
Neudexta
Unknown
PR
Diphenhydramine
Benadryl, Nytol, Unisom, Sominex, Dimedrol, 
Daedalon, Banophen
Antihistamine
CR
Disopyramide
Norpace
Antiarrhythmic
KR
Dofetilide
Tikosyn
Antiarrhythmic
KR
Dolasetron
Anzemet
Antiemetic
PR
Domperidone
Motilium, Motillium, motinorm Costi, 
Nomit
for complete list see: 
drugs.com/international/domperidone.html
Antiemetic
KR
Donepezil
Aricept
Cholinesterase 
inhibitor
KR
Doxepin
Silenor, Sinequa, Aponal, Adapine, Doxal, 
Deptran, Sinquan
Antidepressant
CR
Dronedarone
Multaq
Antiarrhythmic
KR
Droperidol
Droleptan, Dridol, Inapsine, Xomolix
Antipsychotic / 
Antiemetic
KR
Encorafenib
Braftovi
BRAF inhibitor
PR
Eperisone
Myonal Epry
Antispasmodic
CR
Epirubicin
Ellence, Pharmorubicin, Epirubicin Ebewe
Anticancer
PR
Eribulin mesylate
Halaven
Anticancer
PR
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Table 1 Drugs Listed as Having a Known, Possible, or Conditional Risk of TdP
Generic Name
Brand Name
Class
Risk 
Category a
Erythromycin
E.E.S., Robimycin, EMycin, Erymax, Ery-
Tab, Eryc Ranbaxy, Erypar, Eryped, 
Erythrocin Sterate Filmtab, Erythrocot, e-
Base, Erythroped, Elosone, MY-E, 
Pediamycin, Abboticin, Abboticin-ES, 
Erycin, PCE Dispertab, Stiemycine, 
Acnasol, Tiloryth
Antibiotic
KR
Escitalopram
Cipralex, Lexapro, Nexito, Anxiset-E, 
Exodus, Esto, Seroplex, Elicea, Lexamil, 
Lexam, Entact, Losita, Reposil, Animaxen, 
Esitalo, Lexamil
Antidepressant, SSRI
KR
Esomeprazole
Nexium, Nexum, Inexium
Proton Pump 
Inhibitor
CR
Ezogabine (Retigabine)
Potiga, Trobalt
Anticonvulsant
PR
Famotidine
Pepci, Fluxid, Quamatel
H2-receptor 
antagonist
CR
Felbamate
Felbatol
Anticonvulsant
PR
Flecainide
Tambocor, Almarytm, Apocard, Ecrinal, 
Flécaine
Antiarrhythmic
KR
Fluconazole
Diflucan, Trican
Antifungal
KR
Fluorouracil (5-FU)
Adrucil, Carac, Efudex, Efudix
Anticancer
CR
Fluoxetine
Prozac, Sarafem, Fontex
Antidepressant
CR
Fluvoxamine b
Luvox, Luvox CR
Antidepressant, SSRI
CR
Flupentixol
Depixol, Fluanxol
Antipsychotic
PR
Fluvoxamine
Faverin, Fevarin, Floxyfral, Dumyrox, Luvox
SSRI
CR
Furosemide
Lasix, Fusid, Frumex, Lasilix
Diuretic
CR
Garenoxacin
Geninax
Antibiotic
CR
Gatifloxacin
Tequin
Antibiotic
KR
Gemifloxacin
Factive
Antibiotic
PR
Gilteritinib
Xospata
Antineoplastic
PR
Glasdegib
Daurismo
Anticancer
PR
Granisetron
Granisol, Kytril, Sancuso
Antiemetic
PR
Grepafloxacin
Raxar
Antibiotic
KR
Haloperidol
Haldol, Aloperidin, Biperidolo, Brotopon, 
Dozic, Duraperidol, Einalon S, Eukystol, 
Halosten, Keselan, Linton, Peluces, 
Serenace, Serenase, Sigaperidol
Antipsychotic
KR
Hydrochlorothiazide
Apo-Hydro, Aquazide H, BP Zide, 
Dichlotride, Hydrodiuril, Hydrosaluric, 
Microzide, Esidrex, Oretic
Diuretic
CR
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Table 1 Drugs Listed as Having a Known, Possible, or Conditional Risk of TdP
Generic Name
Brand Name
Class
Risk 
Category a
Hydrocodone-ER
Hysingla™ ER, Zohydro ER
Analgesic
PR
Hydroquinidine
Serecor
Antiarrhythmic
KR
Hydoxychloroquine
Plaquenil, Quineprox
Anti-inflammatory, 
antimalarial
KR
Hydroxyzine
Atarax, Vistaril, Aterax, Alamon, Durrax, 
Equipose, Masmoran, Orgatrax, Paxistil 
Quiess, Tran-Q, tranquizine
Antihistamine
CR
Ibutilide
Corvert
Antiarrhytmic
KR
Iloperidone
Fanapt, Fanapta, zomaril
Antipsychotic, 
atypical
PR
Imipramine (melipramine)
Tofranil
Antidepressant
PR
Indapamide
Lozol, Natrilix, Insig
Diuretic
CR
Inotuzumab ozogamicin
Besponsa
Anti-cancer
PR
Isradipine
Dynacirc
Antihypertensive
PR
Itraconazole
Spranox, Onmel
Antifungal
CR
Iabradine
Procoralan, Coralan, Corlentor, Coraxan, 
Ivabid, Bradia
Antianginal
CR
Ivosidenib
Tibsovo
IDH1 inhibitor
PR
Ketanserin
Sufrexal
Antihypertensive
PR
Ketoconazole
Nizoral, Sebizole, Ketomed, Keton
Antifungal
CR
Lacidipine
Lacipil, Motens
Calcium channel 
blocker
PR
Lansoprazole
Prevacid, Ogast
Proton Pump 
Inhibitor
CR
Lapatinib
Tykerb, Tyverb
Anticancer
PR
Lefamulin
Xenleta
Antibiotic
PR
Lenvatinib
Lenvima
Anticancer
PR
Leuprolide
Eligard, Lupron, Viadur, Carcinil, Enanton, 
Leuplin, Lucrin, Procren, Prostap
Anticancer
PR
Levetiracetam
Keppra
Anti-seizure
PR
Levofloxacin
Levaquin, Tavanic
Antibiotic
KR
Levomepromazine 
(Methotrimeprazine)
Nosinan, Nozinan, Levoprome
Antipsychotic
KR
Levosulpiride
Lesuride, Levazeo, Enliva
Antipsychotic
KR
Linezolid
Zyvox, Zyvoxam, Zyvoxid
Antibiotic
PR
Lithium
Eskaith, Lithobid
Antimanic
PR
Loperamide
Imodium
Opioid agonist
CR
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Table 1 Drugs Listed as Having a Known, Possible, or Conditional Risk of TdP
Generic Name
Brand Name
Class
Risk 
Category a
Lumateperone
Caplyta
Antipsychotic, 
atypical
PR
Lurasidone
Latuda
Antipsychotic, 
atypical
PR
Maprotiline
Ludiomil
Anti-depressant, 
tetracyclic
PR
Melperone
Bunil, Buronil, Eunerpan
Antipsychotic, 
atypical
PR
Mesoridazine
Serentil
Antipsychotic
KR
Methadone
Dolohine, Symoron, Amidone, Methadose, 
Physeptone, Heptadon
Opioid agonist
KR
Metoclopramide
Gimoti, Afipran, Maxolon, Cerucal, 
Clopamon, Clopra, Maxeran, Metozolv, 
Reglan, Plasil, Pramin, Primperan, Perinorm
Antiemetic
CR
Metolazone
Zytanix, Zaroxolyn, Mykrox
Diuretic
CR
Metronidazole
Flagyl, Helidac
Antibiotic
CR
Mianserin
Tolvon
Antidepressant
PR
Midostaurin
Rydapt
Anticancer
PR
Mifepristone
Korlym, Mifeprex
Progesterone 
antagonist
PR
Mirabegron
Myrbetriq
Beta3 adrenergic 
antagonist
PR
Mirtazapine
Remeron
Antidepressant, 
tetracyclic
PR
Moxifloxacin
Avelox, Avalox, Avelon
Antibiotic
KR
Necitumumab
Portrazza
Anticancer
PR
Nicardipine
Cardene
Antihypertensive
PR
Nifekalant
Shinbit
Antiarrhythmic
KR
Nilotinib
Tasigna
Anticancer
PR
Norfloxacin
Noroxin, Ambigram
Antibiotic
PR
Nortriptyline
Aventyl, Pamelor, Sensova, Norpress, 
Allegron, Noritren, Nortilen
Antidepressant, 
tricyclic
PR
Nusinersen
Spinraza
Antisense 
oligonucleotide
PR
Ofloxacin
Floxin
Antibiotic
PR
Olanzapine
Zyprexa, Zydis, Relprevv
Antipsychotic, 
atypical
CR
Oliceridine
Olinvyk
Analgesia
PR
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Table 1 Drugs Listed as Having a Known, Possible, or Conditional Risk of TdP
Generic Name
Brand Name
Class
Risk 
Category a
Omeprazole
Losec, Prilosec, Zegerid, Mopral
Proton Pump 
Inhibitor
CR
Ondansetron
Zofran, Anset, Emeset, Emetron, Ondavell, 
Ondemet, Ondisolv, Setronax, Zuplenz
Antiemetic
KR
Osimertinib
Tagrisso
Anticancer
PR
Oxaliplatin
Eloxatin
Anticancer
KR
Paliperidone
Invega, Xepilon
Antipsychotic, 
atypical
PR
Palonosetron
Aloxi
Antiemetic
PR
Pantoprazole
Protonix, Inipomp, Eupantol
Proton Pump 
Inhibitor
CR
Papaverine HCl
Vasodilator, coronary
KR
Paroxetine
Aropax, Paxil, Pexeva, Seroxat, Sereupin, 
Deroxat
Antidepressant, SSRI
CR
Pazopanib
Votrient
Anticancer
PR
Pentamidine
Pentam
Antifungal
KR
Perphenazine
Trilafon, Etrafone/Triavil, Decentran
Antipsychotic
PR
Pilsicainide
Sunrythm
Antiarrhythmic
PR
Pimvanserin
Nuplazid
Antipsychotic, 
atypical
PR
Pimozide
Orap
Antipsychotic
KR
Pipamperone
Dipiperon, Propitan, Diperperal, Piperonil, 
Piperonyl
Antipsychotic
PR
Piperacillin/Tazobactam
Tazosyn, Zosyn
Antibiotic
CR
Pitolisant
Wakix
Histamine 3 
antagonist/ inverse 
agonist
PR
Posaconazole
Noxafil, Posamol
Antifungal
CR
Pretomanid
Antitubercular
PR
Probucol
Lorelco
Antilipemic
KR
Procainamide
Pronestyl, Procan
Antiarrhythmic
KR
Promethazine
Phenergan
Antiemetic
PR
Propafenone
Rythmol SR Rytmonorm
Sodium channel 
blocker
CR
Propofol
Diprivan, Propoven
Anesthetic
KR
Prothipendyl
Domminal, Largophren, Timoval, Timovan, 
Tumovan
Antipsychotic
PR
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Table 1 Drugs Listed as Having a Known, Possible, or Conditional Risk of TdP
Generic Name
Brand Name
Class
Risk 
Category a
Quetiapine
Seroquel
Antipsychotic, 
atypical
CR
Quinidine
Quinaglute, Duraquin, Quinact, Quinidex, 
Cin-Quin, Quinora
Antiarrhytmic
KR
Ranolazine
Ranexa, Ranozex
Antianginal
CR
Remimazolam
Byfavo
Sedative
PR
Ribociclib
Kisqali
Anticancer
PR
Risperidone
Risperdal
Antipsychotic, 
atypical
CR
Roxithromycin
Rulide, Xthrocin, Roxl-150, Roxo, Surlid, 
Rulide, Biaxsig, Roxar, Roximycinv, 
Roxomycin, Rulid, Tirabicin, Coroxin
Antibiotic
KR
Sertindole
Sedolect, Serlect
Antipsychotic, 
atypical
KR
Sertraline
Zoloft, Lustral
Antidepressant, SSRI
CR
Sevoflurane
Ulane, Sojourn
Anesthetic
KR
Solifenacin
Vesicare
Muscle relaxant
CR
Sorafenib
Nexavar
Anticancer
PR
Sotalol
Betapace, Sotalex, Sotacor, Sotalol-AF
Antiarrhythmic
KR
Sparfloxacin
Zagam
Antibiotic
KR
Sulpiride
Dogmatil, Dolmatil, Eglonyl, Espiride, 
Modal, Sulpor
Antipsychotic, 
atypical
KR
Sultopride
Barnetil, Barnotil, Topral
Antipsychotic, 
atypical
KR
Sunitinib
Sutent
Anticancer
PR
Tacrolimus
Prograf, Advagraf, Protopic
Immunosuppressant
PR
Tamoxifen
Nolvadex, Istubal
Anticancer
PR
Telaprevir
Incivo, Incivek
Antiviral
CR
Telavancin
Vibativ
Antibiotic
PR
Telithromycin
Ketek
Antibiotic
PR
Terfenadine
Seldane
Antihistamine
KR
Terlipressin
Teripress, Glypressin, Terlipin, Remestyp, 
Tresil, Teriss
Vasoconstrictor
KR
Terodiline
Micturin, Mictrol
Muscle relaxant
KR
Thioridazine
Mellaril, Novoridazine, Thioril
Antipsychotic
KR
Tipiracil / Trifluridine
Lonsurf
Anticancer
PR
Tizanidine
Zanaflex, Sirdalud
Muscle relaxant
PR
Tolterodine
Detrol, Detrusitol
Muscle relaxant
PR
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Table 1 Drugs Listed as Having a Known, Possible, or Conditional Risk of TdP
Generic Name
Brand Name
Class
Risk 
Category a
Toremifene
Fareston
Estrogen agonist/ 
antagonist
PR
Torsemide (Torasemide)
Demadex, Diuver, Examide
Diuretic
CR
Tramadol
Crispin, Ralivia ER, Ralivia, Flashtab, 
Tramadolum, Tramal, Tramodol, Tridural, 
Ultram, Ultram ER, Zydol, Ixprim, Zaldiar, 
Topalgic
Analgesic
PR
Trazodone
Desyrel, Desirel, Oleptro, Beneficat, Deprax, 
Molipaxin, Thombran, Trazorel, Trialodine, 
Trittico, Mesyrel
Antidepressant, SARI
CR
Trimipramine
Surmontil, Rhotrimine, Stangyl
Antidepressant, 
tricyclic
PR
Tropisetron
Navoban, Setrovel
Antiemetic
PR
Valbenazine
Ingrezza
Vesicluar monamine 
transporter 2 inhibitor
PR
Vandetanib
Caprelsa
Anticancer
KR
Vardenafil
Levitra
Phosphodiesterase 5 
inbibitor
PR
Vemurafenib
Zelboraf
Anticancer
PR
Venlafaxine
Effexor, Efexor
Antidepressant, SNRI
PR
Voclosporin
Lupkynis
Immunosupressant
PR
Voriconazole
VFend
Antifungal
CR
Vorinostat
Zolinza
Anticancer
PR
Ziprasidone
Geodon, Zeldox
Antipsychotic, 
atypical
CR
Zotepine
Losizopilon, Lodopin Setous, Zoleptil
Antipsychotic, 
atypical
PR
Zuclopenthixol 
(Zuclopentixol)
Cisordinol, Clopixol, Acuphase
Antipsychotic 
PR
Source: crediblemeds.org; QTDrugs List, revision date 03 May 2021. 
Abbreviation: CR, conditional risk; KR, known risk; PR, possible risk; TdP, torsades de pointes.
a KR of TdP: Substantial evidence supports the conclusion that these drugs prolong the QT interval and are clearly 
associated with a risk of TdP, even when taken as directed in official labeling.
b CR of TdP: Substantial evidence supports the conclusion that these drugs are associated with a risk of TdP but only 
under certain conditions (eg, excessive dose, hypokalemia, congenital long QT or by causing a drug-drug interaction 
that results in excessive QT interval prolongation).
c PR of TdP: Substantial evidence supports the conclusion that these drugs can cause QT prolongation but there is 
insufficient evidence at this time that these drugs, when used as directed in official labeling, are associated with a 
risk of causing TdP.
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Appendix F
Drugs That Inhibit or Induce CYP3A
The list of drugs that inhibit or induce CYP3A can be found online at 
fda.gov/drugs/developmentapprovalprocess/developmentresources/druginteractionslabeling/ucm
093664.htm [Accessed 07 February 2018]. Drugs listed as strong inhibitors and inducers of 
CYP3A should be avoided, if possible. See Section 8.5, for dose reduction recommendations if 
medications that are strong CYP3A inhibitors are required and a suitable alternative cannot be 
identified.
Note: The website should be used as a guideline and is not necessarily comprehensive. It is the 
investigator’s responsibility to ensure that any drugs under consideration have not been newly 
identified as strong CYP3A4/5 inhibitors or inducers.
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Appendix G
Copy of Framingham Score
The following is a sample screenshot of the Framingham score; the Framingham score tool will 
be supplied in the site operations manual.
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Appendix H
EQ-5D-5L
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Appendix I
FACT-Leu
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Appendix J
Leucovorin (Folinic Acid) Rescue Therapy for Methotrexate
Loading dose: 
Leucovorin 50 mg IV or PO (× 1 dose)
Starting 12 (±2) h after completion of methotrexate 
infusion
Additional: 
Leucovorin 15 mg IV or PO q6 h (× 8 doses) until 
serum methotrexate level is <0.1 µM/L (if the 
methotrexate level is <0.1 µM/L with fewer than 
8 doses of leucovorin, then leucovorin can be 
discontinued). 
Starting 6 h after completion of loading dose
Note: 
Increase leucovorin rescue to 50 mg IV or PO q6 h 
until serum methotrexate level is <0.1 µM/L
If methotrexate level is >20 µM/L at time “0” (first 
assessment)
OR
If methotrexate is >1 µM/L at 24 h
OR
If methotrexate is >0.1 µM/L at 48 h
Abbreviations: IV, intravenous; PO, by mouth; q, every.
Alternative dose modifications/schedules may be recommended after discussion with the investigator and 
sponsor’s medical monitor/designee to maximize exposure of study treatment while protecting patient safety. 
Sites can implement an alternative rescue therapy for methotrexate as per their standard of care.
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Appendix K
Cytarabine Dose Adjustments for Creatinine Clearance Values
Serum Creatinine Clearance (CrCl) Value
Cytarabine Dose Adjustment
89-60 mL/min
1000 mg/m2 q12 h on Days 1, 3, and 5
59-30 mL/min
500 mg/m2 q12 h on Days 1, 3, and 5
29-15 mL/min
500 mg/m2 q24 h on Days 1, 3, and 5
OR
Option to stop
<15 mL/min or hemodialysis
Stop cytarabine.
Abbreviations: CrCl, creatinine clearance; q, every.
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Appendix L
Management of Tumor Lysis Syndrome
Patients at risk for TLS should receive prophylaxis consistent with local guidelines. Prophylaxis 
may include hydration with diuresis, alkalinization of the urine, and treatment with allopurinol or 
other approved uric acid lowering agents.
If TLS occurs, patients should receive treatment and supportive care consistent with local 
guidelines. The management for TLS includes adequate hydration, management of 
hyperuricemia, management of electrolyte abnormalities, and additional supportive care 
including monitoring of renal function and fluid balance, as clinically indicated. General 
guidelines for management of electrolyte abnormalities with TLS are presented in the table 
below [42]. Management of hyperuricemia should be done per best local practice. Rasburicase is 
indicated in cases where uric acid remains elevated despite treatment with allopurinol or in 
patients with renal insufficiency [43].
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Table 1 Management of Electrolyte Abnormalities for TLS
Abnormality
Management Recommendation
Hyperphosphatemia
Moderate, ≥2.1 mmol/L
Avoid IV phosphate administration
Administration of phosphate binder
Severe
Dialysis, CAVH, CVVH, CAVHD, or CVVHD
Hypocalcemia, ≤1.75 mmol/L
Asymptomatic
No therapy
Symptomatic
Calcium gluconate 50-100 mg/kg IV administered slowly with 
ECG monitoring
Hyperkalemia
Moderate and asymptomatic, ≥6.0 mmol/L
Avoid IV and oral potassium
ECG and cardiac rhythm monitoring
Sodium polystyrene sulphonate
Severe (>7.0 mmol/L) and/or symptomatic
Same as above, plus:
Calcium gluconate 100-200 mg/kg by slow IV infusion for life-
threatening arrhythmias
Regular insulin (0.1 U/kg IV) + D25 (2 mL/kg) IV
Sodium bicarbonate (1-2 mEq/kg IV push) can be given to 
induce influx of potassium into cells. However, sodium 
bicarbonate and calcium should not be administered through 
the same line
Dialysis
Renal dysfunction (uremia)
Fluid and electrolyte management
Uric acid and phosphate management
Adjust renally excreted drug doses
Dialysis (hemo- or peritoneal)
Hemofiltration (CAVH, CVVH, CAVHD, or CVVHD)
Source: Coiffier B et al, 2008.
Abbreviations: CAVH, continuous arterial-venous hemodialysis; CAVHD, continuous arterial-venous hemodialysis; 
CVVH, continuous veno-venous hemofiltration; CVVHD, continuous veno-venous hemodialysis; 
ECG, electrocardiogram; IV, intravenous; TLS, tumor lysis syndrome.
Alterations per local guidelines are acceptable.
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Appendix M Enrollment Projections at Primary Endpoint Analyses
Table 1 Enrollment Projections at Primary Endpoint Analyses
Analyses
Time Point 
From FPI
Time Point From 
Last Patient In for 
This Analysis
Enrollment 
Percentage at 
the Time of 
Data Cutoff 
Date
Enrollment 
Percentage at 
the Time of 
Topline Data 
Report
Additional 
Comments
MRD-negative 
CR IA
FPI + 2 years
Approximately 
3.5 months after 
115 patients enrolled
57%-63%
66%-83%
MRD-negative 
CR FA if MRD-
negative CR IA is 
not statistically 
significant
FPI + 3 years
Approximately 
3.5 months after 
230 patients enrolled
100%
100%
120-day safety 
data will include a 
minimum of 
12 months of 
follow up for the 
final analysis on 
the primary 
endpoint
Abbreviations: CR, complete remission; FA, final analysis; FPI, first patient in; IA, interim analysis; MRD, minimal 
residual disease.
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Appendix N
Amendment History
Date
Amendment Number
Amendment Type 
Region
20 October 2021
10
Substantial
Global
07 May 2021
9
Substantial
Global
10 February 2021
8
Substantial
Global
13 August 2019
7
Substantial
Japan
29 July 2019
6
Substantial
Argentina
23 July 2019
5
Substantial
South Korea
09 May 2019
4
Substantial
Global
06 December 2018
3 
Substantial
South Korea
08 Nov 2018
2
Substantial
Global
22 May 2018
1
Nonsubstantial
Global
12 March 2018
Initial Protocol
Not applicable
Global
Rationale for Amendment 9
This section describes the changes to the protocol incorporating Amendment 9. The primary 
reason for this amendment is to: 

Clarify that the breakpoint cluster region-Abelson (BCR-ABL1)/ABL1 minimal residual 
disease (MRD) assessment will be conducted using the same methodology in more than 
1 central laboratory due to local regulations that prohibit shipping of biological samples.
Minor grammatical, editorial, formatting, and administrative changes not affecting the conduct of 
the study are included in this amendment for clarification and administrative purposes only and 
are not listed in the summary of changes below. 
Protocol Amendment 9
Summary of Changes Since the Last Version of the Approved Protocol
Change 
Number
Sections Affected by 
Change
Description of Each Change and Rationale
Location
Description
Rationale
21.
Section 2.0 Study 
Summary
Section 6.1 Overview 
of Study Design
Clarified that the BCR-ABL1/ABL1 MRD 
assessment will be conducted using the same 
methodology in more than 1 central 
laboratory.
Due to local regulations that 
prohibit shipping of biological 
samples, more than 1 central 
laboratory is required.
22.
Section 9.1 Study 
Personnel and 
Organizations
Updated “central laboratory” to “central 
laboratories” and deleted “any additional 
clinical laboratories” to reflect the use of 
more than 1 central laboratory.
More than 1 central laboratory 
is being used in the study.
23.
Appendix A Schedule 
of Events Table 1, 
Footnote y
Deleted from Footnote y: (which is required 
as per the study inclusion criteria 3)
Correction; inclusion criterion 
3 was deleted in 
Amendment 8.
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Rationale for Amendment 8
This section describes the changes to the protocol incorporating Amendment 8. The primary 
reasons for this amendment are to: 

Change the study design: 
–
From an adaptive design to a group sequential design for the primary endpoint of 
minimal residual disease (MRD)-negative complete remission/response (CR) at the end 
of induction (CR and breakpoint cluster region-Abelson [BCR ABL1]/ABL1 ≤0.01%). 
–
To add an interim analysis for event-free survival (EFS).

Update the definition for EFS. 

Provide guidance for collecting data, conducting study procedures, and managing 
investigational product(s) to maintain patient safety, confidentiality, and study integrity 
during unavoidable circumstances such as the coronavirus disease 2019 (COVID-19) 
pandemic.
Minor grammatical, editorial, formatting, and administrative changes not affecting the conduct of 
the study are included in this amendment for clarification and administrative purposes only and 
are not listed in the summary of changes below. 
Protocol Amendment 8
Summary of Changes Since the Last Version of the Approved Global Protocol
Sections Affected by Change
Description of Each Change and Rationale
Location
Description
Rationale
1.
Title Page
Section 2.0 Study 
Summary
Section 3.4 Corporate 
Identification
Replaced sponsor information for Millennium 
Pharmaceuticals with sponsor information for 
Takeda Development Center Americas.
Administrative change.
2.
Section 2.0 Study 
Summary
Clarified that study data will be evaluated for 
approximately 3-6 years rather than 5 years 
after enrollment of the last patient.
Clarification.
3.
Section 2.0 Study 
Summary
Section 5.1.2 
Secondary Objectives
Removed “the rate of” from the key secondary 
objective to clarify that the comparison of 
event-free survival (EFS) is the objective rather 
than rate of EFS.
Removed “To compare the rate of MR4.5 
(including best response) between the 2 cohorts, 
at multiple intervals including the end of 
induction, the end of consolidation, and prior to 
HSCT.” from Secondary Objectives.
Clarification.
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Protocol Amendment 8
Summary of Changes Since the Last Version of the Approved Global Protocol
Sections Affected by Change
Description of Each Change and Rationale
Location
Description
Rationale
4.
Section 5.2.2.1 Key 
Secondary Endpoints
Section 6.3.3 Time 
Frames for Primary and 
Secondary Endpoints 
to Support Disclosures 
(Table 6.a)
Section 13.1.3.2 Key 
Secondary Efficacy 
Endpoint Assessment
Section 13.1.3.4 
Definitions of 
Response Criteria
Removed “minimum residual disease (MRD)-
negative” from the definition of EFS.
Updated the definition for EFS 
so that one of the events for 
EFS is based on failure to 
achieve CR by the end of 
induction instead of failure to 
achieve MRD-negative CR by 
the end of induction.
5.
Section 2.0 Study 
Summary
Section 5.2.2.2 Other 
Secondary Endpoints
Section 6.1 Overview 
of Study Design
Section 13.1.3.3 Other 
Secondary Efficacy 
Endpoint Assessments
Removed “Rates of molecular response 
(MR)4.5 (including best response) at multiple 
intervals including the end of induction, the end 
of consolidation, and prior to hematopoietic 
stem cell transplantation (HSCT)” from the 
Other Secondary Endpoints.
Clarified that overall survival (OS) and rate of 
relapse from CR are the only analyses to be 
conducted specifically for on-study patients 
with and without HSCT.
Clarification.
6.
Section 2.0 Study 
Summary
Section 6.1 Overview 
of Study Design 
Clarified that for patients in the ponatinib cohort 
who achieve CR but do not achieve the primary 
endpoint at the end of induction and who 
continue in the study at the investigator’s 
discretion, the dose of ponatinib “will be” 
reduced at any time when the patient achieves 
MRD-negative CR and re-escalated upon loss 
of response. 
Clarification on ponatinib dose 
modification for patients who 
achieve MRD-negative CR 
anytime during the study.
7.
Section 2.0 Study 
Summary
Section 6.2 Number of 
Patients 
Section 13.3 
Determination of 
Sample Size
Clarified that the number of patients enrolled in 
the study is to be approximately 230 and 
increased the number of study sites from 110 to 
120.
Increased the number of study 
sites to meet accrual goals.
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Protocol Amendment 8
Summary of Changes Since the Last Version of the Approved Global Protocol
Sections Affected by Change
Description of Each Change and Rationale
Location
Description
Rationale
8.
Section 6.3.3 Time 
Frames for Primary and 
Secondary Endpoints 
to Support Disclosures
Section 13.1.3.4 
Definitions of 
Response Criteria
Replaced the definition of relapse from CR with 
a link to the definition in Table 13a.
Clarified that overall survival (OS) and rate of 
relapse from CR are the only analyses to be 
conducted specifically for on-study patients 
with and without HSCT.
Revised the interval for OS to begin at 
“randomization” rather than “the first dose date 
of study drug”.
Updated to reference the 
definition of relapse from CR 
through a link to Table 13a and 
to accurately reflect the interval 
for OS.
9.
Section 6.3.3 Time 
Frames for Primary and 
Secondary Endpoints 
to Support Disclosures
Updated the maximum time frame for the key 
secondary endpoint of EFS from approximately 
3 years to approximately 3-6 years.
Revised the maximum time frame for several 
key secondary endpoints from “up to 
approximately 3 years” or “updated annually 
after year 3” to “up to approximately 3-6 years”. 
Revised based on the change in 
study design and projected 
timing of EFS based on the 
interim analysis (IA) for EFS.
10.
Section 6.3.4 Total 
Study Duration
Clarified the duration of the study will be 
approximately 6 to 9 years, including 
approximately 36 months for enrollment and 
approximately 3-6 years of follow-up from the 
date that the last patient enrolled.
Revised based on the change in 
study design and projected 
timing of EFS based on the IA 
for EFS.
11.
Section 2.0 Study 
Summary
Section 7.1 Inclusion 
Criteria 
Deleted inclusion criterion 3.
Stratification based on 
transcript type was removed 
from the study.
12.
Section 2.0 Study 
Summary
Section 7.1 Inclusion 
Criteria 
Removed “and amylase” from inclusion 
criterion 4 d (formerly 5 d).
Serum lipase is more specific 
than amylase for pancreatic 
abnormalities.
13.
Section 2.0 Study 
Summary
Section 7.2 Exclusion 
Criteria 
Revised exclusion criterion 13 to allow the 
enrollment of patients with lymphadenopathy or 
hepatosplenomegaly. 
Most patients with acute 
lymphoblastic leukemia have 
lymphadenopathy or 
hepatosplenomegaly.
14.
Section 2.0 Study 
Summary
Section 7.2 Exclusion 
Criteria
Revised exclusion criterion 16 e to clarify that 
isolated elevation(s) of systolic and/or diastolic 
BP during screening are not exclusionary.
Clarification to ensure true 
cases of hypertension are 
excluded.
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Protocol Amendment 8
Summary of Changes Since the Last Version of the Approved Global Protocol
Sections Affected by Change
Description of Each Change and Rationale
Location
Description
Rationale
15.
Section 2.0 Study 
Summary
Section 7.2 Exclusion 
Criteria
Revised exclusion criterion 16 f to clarify that 
patients will be excluded due to any history of 
myocardial infarction (MI), unstable angina, 
coronary artery disease (CAD), cerebrovascular 
accident (CVA), ischemic stroke, or transient 
ischemic attack (TIA), whether considered 
clinically significant or not.
Clarification
16.
Section 2.0 Study 
Summary 
Section 7.2 Exclusion 
Criteria
Revised exclusion criterion 16.k to clarify that 
“patients with catheter-associated deep vein 
thrombosis (DVTs) which are considered to be 
resolved/controlled may be included after 
discussion with the sponsor’s medical 
monitor/designee.”
DVT is common in patients 
with Philadelphia 
chromosome–positive acute 
lymphoblastic leukemia; most 
events are catheter-related and 
easy to manage.
17.
Section 2.0 Study 
Summary 
Section 7.2 Exclusion 
Criteria
Removed definition for poorly controlled 
diabetes from exclusion criterion 17.
Revised to allow clinical 
judgment for guiding eligibility 
of patients with diabetes 
mellitus.
18.
Section 2.0 Study 
Summary 
Section 7.2 Exclusion 
Criteria
Deleted exclusion criteria 20 and 21.
These criteria are not relevant 
for this study.
19.
Section 2.0 Study 
Summary
Section 7.2 Exclusion 
Criteria
Appendix A Table 1, 
Footnote d
Revised exclusion criterion 22 (formerly 24) to 
allow enrollment of female patients with a 
positive serum pregnancy test who have 
undergone a complete abortion in the last 4-6 
weeks after discussion with the sponsor’s 
medical monitor/designee.
Clarification.
20.
Section 2.0 Study 
Summary 
Section 8.1.2 Induction 
Phase (Cycles 1 
Through 3)
Section 8.1.3 
Consolidation Phase 
(Cycles 4 Through 9)
Updated lumbar puncture assessment be 
performed to test CSF for CNS disease “as 
clinically indicated” in addition to Day 1 and 
Day 14 of the 3 induction phase cycles and the 
first 3 consolidation phase cycles (total: 6 
cycles, 12 samples).
Clarification.
21.
Section 2.0 Study 
Summary 
Section 8.1.3 
Consolidation Phase 
(Cycles 4 Through 9)
Updated methotrexate and cytarabine dosing 
information to revise age ranges from ≤ and > 
60 years to < and ≥ 60 years.
Removed an additional slash in the cytarabine 
dosing information to clarify that the dose is to 
be administered every 12 hours and not split 
into 2 doses.
Correction.
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Protocol Amendment 8
Summary of Changes Since the Last Version of the Approved Global Protocol
Sections Affected by Change
Description of Each Change and Rationale
Location
Description
Rationale
22.
Section 2.0 Study 
Summary
Section 8.1.3 
Consolidation Phase 
(Cycles 4 Through 9)
Moved reference to Appendix K (cytarabine 
dose adjustment by creatinine clearance) to the 
<60 age group.
Added that the cytarabine dose should be 
reduced or possibly discontinued for patients 
≥60 years with impaired renal function.
Correction.
23.
Section 8.4.1.1 Dose 
Reduction for Drug-
Related Adverse 
Events
Updated definitions for Grade 3 and Grade 4 
events of pancreatitis and elevation of lipase 
leading to dose modification.
Updated to expand list of drug-
related adverse events (AEs) of 
serum lipase and pancreatitis 
leading to dose modification.
24.
Section 8.4.1.2.2 VTEs
Removed the word “arterial” from “arterial 
venous thrombotic/embolic events (VTEs)”.
Correction.
25.
Section 8.5 Excluded 
Concomitant 
Medications and 
Procedures
Clarified wording around medication that 
should be avoided.
Corrected the following statement to read 
“Elective surgery requiring inpatient care that 
can be postponed until study completion.”
Clarification and correction.
26.
Section 8.10.2 Imatinib
Revised the description of imatinib tablets to 
include generic imatinib.
Imatinib is available as a 
generic tablet, and both brand-
name and generic forms could 
be used in the study.
27.
Section 8.13.2 
Handling and 
Accountability
Section 9.4.19 Changes 
to Study Procedures 
Due to COVID 19 
Pandemic
Section 13.1 Statistical 
and Analytical Plans
Section 14.1 Study Site 
Monitoring Visits
Section 14.2 Protocol 
Deviations
Appendix ASchedule 
of Events
Added information about study procedure 
flexibility permitted in extenuating 
circumstances such as the coronavirus disease 
2019 (COVID-19) pandemic.
In the Schedule of Events all 2-day visit 
windows were changed to 3 days.
Revised to ensure the safety of 
patients participating in the 
study and the integrity of data 
collected during the course of 
the study during COVID-19 
pandemic.
28.
Section 9.4.15.3
Appendix A Schedule 
of Events Table 2, 
footnote bb
Added that extramedullary assessments will be 
performed locally “as clinically indicated.”
Clarification.
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Protocol Amendment 8
Summary of Changes Since the Last Version of the Approved Global Protocol
Sections Affected by Change
Description of Each Change and Rationale
Location
Description
Rationale
29.
Section 10.2 
Procedures for 
Recording and 
Reporting AEs and 
SAEs
Updated procedures for recording and reporting 
AEs and serious adverse events (SAEs). 
Updated to incorporate the 
sponsor’s current procedures.
30.
Section 10.4 
Procedures for 
Reporting Drug 
Exposure During 
Pregnancy and Birth 
Events
Updated procedures for reporting drug exposure 
during pregnancy.
Added that study drug must be discontinued 
immediately for patients who become pregnant.
Updated to incorporate the 
sponsor’s current procedures 
and revised to ensure the safety 
of patients who may become 
pregnant during the study.
31.
Section 10.5 
Procedures for 
Reporting Product 
Complaints or 
Medication Errors 
(Including Overdose)
Updated procedures for reporting product 
complaints or medication errors (including 
overdose).
Updated to incorporate the 
sponsor’s current procedures.
32.
Section 11.2 
Independent Data 
Monitoring Committee
Added that “The independent data monitoring 
committee (IDMC) will review the outcomes at 
the interim and final analyses for MRD-
negative CR, EFS, and the futility analysis for 
OS.”
Updated to support the change 
in study design.
33.
Section 13.1.1.2 Per-
Protocol Population 
Section 13.1.3.1 
Primary Efficacy 
Endpoint Assessment
Added that a sensitivity analysis of the intent-
to-treat (ITT) population for the primary 
efficacy endpoint, MRD negative CR, may be 
performed in the per-protocol (PP) population, 
if needed.
Clarification.
34.
Section 2.0 Study 
Summary 
Section 13.1.3 Efficacy 
Analysis
Section 13.3 
Determination of 
Sample Size
Revised the efficacy analysis and determination 
of sample size to reflect the change in study 
design from an adaptive design to a group 
sequential design.
Updated to incorporate the 
change in study design.
35.
Section 2.0 Study 
Summary
Section 13.1.3 Efficacy 
Analysis
Section 13.2 IA and 
Criteria for Early 
Termination
Revised text regarding the IA and criteria for 
early termination to reflect the change in study 
design. 
Updated to incorporate the 
change in study design.
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Protocol Amendment 8
Summary of Changes Since the Last Version of the Approved Global Protocol
Sections Affected by Change
Description of Each Change and Rationale
Location
Description
Rationale
36.
Section 13.1.3.4 
Definitions of 
Response Criteria
Corrected the definition for loss of MR4.5 to 
state: “This result must be confirmed at the 
subsequent visit, unless it is associated with loss 
of MR3 or relapse from CR” rather than a loss 
of MR 4.5.
Correction.
37.
Section 13.1.7 Safety 
Analysis
Added that “a descriptive safety analyses of OS 
will be conducted at the IA (or FA, as 
applicable) for MRD-negative CR if there are a 
sufficient number of deaths to perform such an 
analysis.”
Update.
38.
Section 13.2 IA and 
Criteria for Early 
Termination
Added a reference to Appendix M: Enrollment 
Projections at Primary Endpoint Analyses
Updated to incorporate the 
change in study design.
39.
Section 13.4 Blinding 
of Trial Management 
Team for Data Review
Revised study team blinding requirements to 
state that: the study team “will be blinded to 
treatment assignment for aggregate efficacy-
related data, unless publicly released, as well as 
individual patient-level data (except a few 
members who are included in patient 
management and monitoring of the study; 
however, generation of any aggregate summary 
of efficacy data by treatment arm is not 
allowed).”
Update.
40.
Section 16.0 
REFERENCES
The following citations/references were 
removed in this amendment: 
Mehta 2011, Hung 2006, Fielding 2010, Pfeifer 
2010, Mizuta 2011, and Cui 1999.
Hwang et al 1990 and Lan K, DeMets DL 1983 
reference was added.
Adjusted to reflect text changes.
41.
Appendix A Schedule 
of Events Table 1, 
Footnote b
Clarified the use of local laboratory results 
during screening.
Added that an Eligibility Verification Form and 
required supporting documentation, as allowed 
by local regulations, should be sent to the 
sponsor’s medical monitor or designee as soon 
as the screening procedures are completed for 
confirmation of patient eligibility (specific 
instructions for randomization will be supplied 
in the site operations manual).
Updated to provide flexibility 
in obtaining laboratory results 
when screening patients for 
eligibility.
42.
Appendix A Schedule 
of Events Table 1, 
Footnotes f, g, j, u, and 
v
Updated “before dosing” to “before intravenous 
(IV) chemotherapy dosing”.
Clarification.
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CONFIDENTIAL
Protocol Amendment 8
Summary of Changes Since the Last Version of the Approved Global Protocol
Sections Affected by Change
Description of Each Change and Rationale
Location
Description
Rationale
43.
Appendix A Schedule 
of Events Table 1, 
Footnotes h and j
Appendix A Schedule 
of Events Table 2, 
Footnotes i and o
Clarified instructions for performing and 
recording blood pressure and electrocardiogram 
(ECG) assessments.
Added to Table 1, footnote j and Table 2, 
footnote i that ECGs are to be interpreted by a 
local cardiologist “in cases where there are 
significant findings or when the investigator 
cannot interpret the findings.”
Update and clarification.
Revised to reduce the burden of 
having the local cardiologist 
interpret all ECGs.
44.
Appendix A Schedule 
of Events Table 1, 
Footnote v; Table 2, 
Footnote u.
Added to Table 1, footnote v and Table 2, 
footnote u: “local laboratory results should only 
be entered if the local laboratory results and 
required supporting documentation are used for 
treatment-related decisions.”
Clarification.
45.
Appendix A Schedule 
of Events Table 1, 
Footnote x
Deleted from Table 1, Footnote x: “C-reactive 
protein (CRP), cardiac troponin-I (cTnI), and N-
terminal pro-brain natriuretic peptide (NT-
proBNP) or BNP assessments must also be 
included with blood draws Days 1, 7, 14, and 21 
of Cycles 1-3 and Day 1 of Cycles 4-9 to assess 
cardiovascular (CV) risks,”
Added to Table 1, Footnote x: “For 
maintenance phase, CRP, cTnI assessments and 
NT-proBNP or BNP testing must be included 
with every blood draw (except Cycle 10, Day 
7).”
Correction.
46.
Appendix A Schedule 
of Events Table 1, 
Footnote bb
Added to Table 1, Footnote bb: “Cycle 1 Day 1 
molecular response assessments need not be 
repeated if the screening assessment was within 
7 days before Cycle 1 Day 1.”
Clarification.
47.
Appendix A Schedule 
of Events Table 2, 
Footnote w
Added to Table 2, Footnote w: performing an 
ECHO “and/or consulting a cardiologist” should 
be considered
Update.
48.
Appendix A Schedule 
of Events Table 1, 
Footnote y and Table 2, 
Footnote x
Deleted from Table 1, Footnote y: BM aspirate 
must occur within 28 days before enrollment.
Added to Table 1, Footnote y and Table 2, 
Footnote x: “ (local BCR-ABL1 results should 
only be entered if the local laboratory results 
and required supporting documentation are used 
for treatment-related decisions).”
Clarification.
49.
Appendix A Schedule 
of Events Table 2, 
footnote b
Revised one of the end-of-treatment (EOT) visit 
specifications from “the decision to discontinue 
treatment” to “30 days after a patient has 
discontinued the study drug”.
Clarification.
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CONFIDENTIAL
Protocol Amendment 8
Summary of Changes Since the Last Version of the Approved Global Protocol
Sections Affected by Change
Description of Each Change and Rationale
Location
Description
Rationale
50.
Appendix J Leucovorin 
(Folinic Acid) Rescue 
Therapy for 
Methotrexate
Added the following for clarification: “if the 
methotrexate level is <0.1 µM/L with fewer 
than 8 doses of leucovorin, then leucovorin can 
be discontinued.”
Clarification.
51.
Appendix K 
Cytarabine Dose 
Adjustments for 
Creatinine Clearance
Updated the serum creatinine clearance values 
for cytarabine dose adjustments:
From
To
90-60 mL/min
89-60 mL/min
60-30 mL/min
59-30 mL/min
30-15 mL/min
29-15 mL/min
Correction of overlapping 
serum creatinine clearance 
values.
52.
Appendix M 
Enrollment Projections 
at Primary Endpoint 
Analyses
Added Appendix M to present the enrollment 
projections for the primary endpoint analyses.
Updated to incorporate the 
change in study design.
Rationale for Amendment 07
This section describes the changes to the protocol incorporating Amendment 07. The primary 
reason for this amendment is to allow Japanese sites to enroll patients into cohort A (ponatinib) 
without any randomization.
Minor grammatical, editorial, formatting, and administrative changes not affecting the conduct of 
the study are included for clarification and administrative purposes only. 
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CONFIDENTIAL
Protocol Amendment 07
Summary of Changes Since the Last Version of the Approved Protocol
Description of Each Change and Rationale
Location
Description
Rationale
Section 9.4.3
Section 2.0 Study Summary,
Section 6.1 Overview of Study 
Design,
Section 7.1 Inclusion Criteria,
Section 7.2 Exclusion Criteria,
Section 8.9 Blinding and Unblinding,
Section 9.3 Treatment Group 
Assignments,
Section 9.4.1 Screening Period 
Procedures,
Section 9.4.18 PK Measurements: 
Ponatinib,
Section 13.1.1.1 Intent-to-Treat 
Population,
Section 13.1.1.3 Safety Population,
Section 13.1.3.1 Primary Efficacy 
Endpoint Assessment
Section 13.1.3.4 Definitions of 
Response Criteria,
Section 13.1.5.1 Time-to-Next-
Treatment and Time-to-HSCT 
Analyses,
Appendix A, Table 1, Footnotes b 
and y.
Clarified that patients enrolled at 
Japanese sites will be assigned (not 
randomized) only to cohort A 
(ponatinib).
“Enrollment” used to include both 
assignment (Japan) and 
randomization (rest of world) to 
cohorts.
Section 13.3.1 Rationale for Sample 
Size Selection in Japan.
Section 2.0 Study Summary,
Section 6.1 Overview of Study 
Design,
Section 6.2 Number of Patients.
Added rationale for sample size 
selection for Japanese patients.
To provide rationale for the 
addition of 10 Japanese patients.
Section 13.1.3.1 Primary Efficacy 
Endpoint Assessment
Clarified that minimal residual 
disease-negative patients will be 
analyzed in the safety population
To include patients with MRD-
negative CR in the safety 
population.
Section 13.1.3.2 Key Secondary 
Efficacy Endpoint Assessment
Clarified that event-free survival will 
be analyzed in the safety population
To include EFS analysis in the 
safety population.
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CONFIDENTIAL
Rationale for Amendment 06
This section describes the changes to the protocol incorporating Amendment 06, this amendment 
applies only to Argentina. The primary reason for this amendment is to incorporate advice from 
the National Administration of Drugs, Food and Medical Technology. 
Minor grammatical, editorial, formatting, and administrative changes not affecting the conduct of 
the study are included for clarification and administrative purposes only.
Protocol Amendment 06
Summary of Changes Since the Last Version of the Approved Protocol
Sections Affected by the Change
Description of Each Change and Rationale
Location
Description
Rationale
Section 7.1 Inclusion Criteria
Section 2.0 STUDY SUMMARY,
Section 6.1 Overview of Study 
Design,
Section 7.0 STUDY 
POPULATION.
Raised the minimum age for 
participation in this study from 18 
years to 40 years
Raised the minimum age of study 
participants in order to comply 
with local laws.
Rationale for Amendment 05
This section describes the changes to the protocol incorporating Amendment 05; this amendment 
applies only to South Korea. The primary reasons for this amendment are to incorporate changes 
from global Amendment 04 including updating the stratification of randomization criteria to 
allow for patients to be randomized more proficiently, to revise exclusion criteria to be less 
restrictive, and to modify assessments on the schedule of events to be less of a burden on 
patients.
Minor grammatical, editorial, formatting, and administrative changes not affecting the conduct of 
the study are included for clarification and administrative purposes only. 
Protocol Amendment 05
Summary of Changes Since the Last Version of the Approved Protocol
Sections Affected by the 
Change
Description of Each Change and Rationale
Location
Description
Rationale
Section 2.0 Study Summary
Removed stratification factor 2 
(Transcript 190 versus 210) from 
stratification of randomization.
Decrease frequency of ECOG assessments 
beginning at Cycle 10 from once per cycle to 
once every 3 cycles.
Section 6.1 Overview of Study 
Design
Added text to use blood samples 
if bone marrow (BM) samples are 
not evaluable or not available.
Decrease frequency of ECOG assessments 
beginning at Cycle 10 from once per cycle to 
once every 3 cycles.
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20 October 2021
CONFIDENTIAL
Protocol Amendment 05
Summary of Changes Since the Last Version of the Approved Protocol
Sections Affected by the 
Change
Description of Each Change and Rationale
Location
Description
Rationale
Section 7.1 Inclusion Criteria
Section 2.0 STUDY 
SUMMARY.
Section 6.1 Overview of Study 
Design.
Section 7.0 STUDY 
POPULATION.
Appendix A, Table 1 Schedule 
of Events: Screening, 
Induction Phase, and 
Consolidation
Phases, footnote c.
Added upper limit to age for 
patients with comorbidities and/or 
poor functional status.
Added upper limit for clarification purposes.
Section 7.1 Inclusion Criteria
Section 2.0 Study Summary
Revised inclusion criterion 
number 5.
Updated to align with other clinical studies 
within the ponatinib clinical program.
Section 7.1 Inclusion Criteria
Section 2.0 Study Summary
Revised inclusion criterion 
number 7.
Text revised for clarification to allow for 
compliance with any local regulations.
Section 7.2 Exclusion Criteria
Section 2.0 Study Summary
Revised exclusion criterion 
number 2.
Updated to allow usage of some 
chemotherapy before randomization, based 
on feedback received from study sites.
Section 7.2 Exclusion Criteria
Section 2.0 Study Summary
Revised exclusion criterion 
number 6.
Revised exclusion criterion to be less 
restrictive.
Section 7.2 Exclusion Criteria
Section 2.0 Study Summary
Revised exclusion criterion 
number 8.
Revised exclusion criterion to be less 
restrictive.
Section 7.2 Exclusion Criteria
Revised exclusion criterion 
number 11.
Revised exclusion criterion for clarification.
Section 7.2 Exclusion Criteria
Revised exclusion criterion 
number 13.
Removed requirement for mandatory CSF 
analysis at screening
Section 8.4 Dose Modification 
Guidelines for Safety
Added text clarifying time frame 
for sites to communicate any 
variation of dose modification 
guidelines.
Text added to provide a time frame for sites 
to communicate to the sponsor any variation 
from dose reduction guidelines for safety.
Table 8.f Dose Modifications 
for AOEs: Ponatinib
Updated table detailing ponatinib 
dose modification strategy in 
response to Grade 2 arterial 
occlusion (cardiovascular [CV] 
and cerebrovascular events).
To align with the guidelines for other safety 
events.
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CONFIDENTIAL
Protocol Amendment 05
Summary of Changes Since the Last Version of the Approved Protocol
Sections Affected by the 
Change
Description of Each Change and Rationale
Location
Description
Rationale
Section 8.8 Management of 
Clinical Events
Appendix A Schedule of 
Events Table 1
Added text to provide additional 
guidance in managing persistent 
elevation of cardiac troponin-I 
(cTnI) or N-terminal pro-brain 
natriuretic peptide (NT 
proBNP)/B-type natriuretic 
peptide (BNP).
Guidance was added for 
monitoring/managing persistent elevation of 
CTnI or NT-proBNP/BNP.
Sections 9.4.6 Pregnancy Test
Appendix A Schedule of 
Events
Added text regarding country-
specific requirements for serum 
pregnancy test.
Updated text to address country-specific 
requirements.
Section 9.4.9 Vital Signs
Appendix A Schedule of 
Events
Removed requirement that body 
temperature must be measured 
orally.
Removed the word “oral” to generalize the 
way body temperature is measured.
Section 9.4.14.2 Serum 
Analysis
Appendix A Schedule of 
Events
Added NT-proBNP/BNP testing 
to required serum analyses.
Added guidance for monitoring/managing 
persistent elevation of CTnI or NT-
proBNP/BNP.
Section 9.7 Discontinuation of 
Treatment With Study Drug 
and Patient Replacement
Section 10.4 Procedures for 
Reporting Drug Exposure 
During Pregnancy and Birth 
Events
Revised text regarding 
discontinuation of a patient who 
becomes pregnant.
Revised wording to align with other clinical 
studies within the ponatinib clinical program.
Section 9.7 Discontinuation of 
Treatment With Study Drug 
and Patient Replacement.
Clarified wording for study 
discontinuation.
To clarify permanent discontinuation on 
study drug.
Section 9.10 Post-treatment 
Follow-Up Assessments.
Deleted incorrect text regarding 
study termination.
Deleted text was here by error as nothing 
more is collected once the study is 
terminated.
Section 11.3 Cardiovascular 
Endpoint Adjudication 
Committee.
Generalized documentation 
requirement for the cardiovascular 
endpoint adjudication 
committee’s assessment of each 
potential CV endpoint.
Removed clinical database language because 
the independent cardiovascular adjudication 
does not occur in the sponsor’s clinical 
database to ensure the independence of the 
committee’s decision-making.
Section 13.1.5.4 Biomarkers 
of Disease Sensitivity and 
Resistance to Ponatinib and 
Imatinib.
Added text to clarify that 
mutation analysis will be done as 
clinically needed.
Added text for clarification and consistency 
throughout protocol.
Section 13.2 IA and Criteria 
for Early Termination.
Added text regarding interim 
analysis to clarify timing.
Added text inserted for consistency and 
clarification.
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20 October 2021
CONFIDENTIAL
Protocol Amendment 05
Summary of Changes Since the Last Version of the Approved Protocol
Sections Affected by the 
Change
Description of Each Change and Rationale
Location
Description
Rationale
Appendix A Schedule of 
Events
Section 9.4.15.1 BM Aspirate
Added text to revise BM aspirate 
schedule, and clarify collection 
and assessment procedures.
Changes made to reduce sample collection 
burden on patients and clarify BM aspirate 
collections.
Appendix A Schedule of 
Events
Removed requirement that all 
electrocardiograms (ECGs) are to 
be signed by a local cardiologist.
Change made to reduce the burden of getting 
signature of a cardiologist.
Appendix A Schedule of 
Events
Added text for clarification of 
complete blood count with 
differential testing.
Added text for clarification of CBC and 
differential testing.
Appendix A Schedule of 
Events
Clarified text for serum chemistry 
testing and total, indirect, and 
direct bilirubin testing.
Change made to clarify serum chemistry 
testing and total, direct, and indirect bilirubin 
test needed.
Appendix A Schedule of 
Events
Revised Schedule of Events 
(SOE) footnote for single-agent 
therapy sample collection.
Revised footnotes to be consistent with the 
visit schedule.
Appendix A Schedule of 
Events Table 2.
Added text to SOE to clarify that 
end-of-treatment visit should 
occur within 30 days after last 
dose or discontinuation.
This change was made to clarify timing of 
the EOT visit.
Appendix A Schedule of 
Events Table 2 footnotes and
corresponding table row.
Appendix A Schedule of 
Events, Table 1, footnote cc
Updated maintenance phase SOE 
footnotes for vital signs, physical 
exams, ECGs, and patient-
reported outcomes for consistency
Revised footnotes to be consistent with the 
visit schedule.
Appendix J Leucovorin 
(Folinic Acid) Rescue Therapy 
for Methotrexate.
Updated Appendix J footnote for 
clarification of leucovorin (folinic 
acid) rescue therapy for 
methotrexate.
To clarify that sites may use alternative 
rescue therapy for methotrexate.
Appendix A, Table 2.
Decrease frequency of ECOG 
assessments beginning at Cycle 
10 from once per cycle to once 
every 3 cycles.
To align with ECOG assessment frequency in 
the induction and consolidation phases of the 
study.
Rationale for Amendment 04
This section describes the changes to the protocol incorporating Amendment 04. The primary 
reasons for this amendment are to update the stratification of randomization criteria to allow for 
patients to be randomized more proficiently, to revise exclusion criteria to be less restrictive, and 
to modify assessments on the schedule of events to be less of a burden on patients.
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20 October 2021
CONFIDENTIAL
Minor grammatical, editorial, formatting, and administrative changes not affecting the conduct of 
the study are included for clarification and administrative purposes only. 
Protocol Amendment 04
Summary of Changes Since the Last Version of the Approved Protocol
Sections Affected by the Change
Description of Each Change and Rationale
Location
Description
Rationale
Section 2.0 Study Summary
Removed stratification factor 2 
(Transcript 190 versus 210) from 
stratification of randomization
Update allows for patients to be 
randomized more proficiently. The 
SAP specifies that stratification based 
on transcript type will be used for 
post hoc analysis of efficacy and 
safety, and it will balance for any 
differences in the safety or efficacy 
outcomes between the 2 transcript 
types
Section 6.1 Overview of Study 
Design
Added text to use blood samples if 
bone marrow (BM) samples are not 
evaluable or not available
Added text to address instances where 
BM samples will not be evaluable or 
not available.
Section 7.1 Inclusion Criteria
Section 2.0 Study Summary
Revised inclusion criterion number 
5.
Updated to align with other clinical 
studies within the ponatinib clinical 
program.
Section 7.1 Inclusion Criteria
Section 2.0 Study Summary
Revised inclusion criterion number 
7.
Text revised for clarification to allow 
for compliance with any local 
regulations.
Section 7.2 Exclusion Criteria
Section 2.0 Study Summary
Revised exclusion criterion number 
2.
Updated to allow usage of some 
chemotherapy before randomization,
based on feedback received from 
study sites.
Section 7.2 Exclusion Criteria
Section 2.0 Study Summary
Revised exclusion criterion number 
6.
Revised exclusion criterion to be less 
restrictive
Section 7.2 Exclusion Criteria
Section 2.0 Study Summary
Revised exclusion criterion number 
8.
Revised exclusion criterion to be less 
restrictive
Section 8.4 Dose Modification 
Guidelines for Safety
Added text clarifying time frame 
for sites to communicate any 
variation of dose modification 
guidelines.
Text added to provide a time frame 
for sites to communicate to the 
sponsor any variation from dose 
reduction guidelines for safety.
Table 8.f Dose Modifications for 
AOEs: Ponatinib
Updated table detailing ponatinib 
dose modification strategy in 
response to Grade 2 arterial 
occlusion (cardiovascular [CV] and 
cerebrovascular events).
To align with the guidelines for other 
safety events.
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20 October 2021
CONFIDENTIAL
Protocol Amendment 04
Summary of Changes Since the Last Version of the Approved Protocol
Sections Affected by the Change
Description of Each Change and Rationale
Location
Description
Rationale
Section 8.8 Management of Clinical 
Events
Added text to provide additional 
guidance in managing persistent 
elevation of cardiac troponin-I 
(cTnI) or N-terminal pro-brain 
natriuretic peptide (NT-
proBNP)/B-type natriuretic peptide 
(BNP).
Guidance was added for 
monitoring/managing persistent 
elevation of CTnI or NT-
proBNP/BNP.
Section 9.4.6 Pregnancy Test
Appendix A Schedule of Events
Added text regarding country-
specific requirements for serum 
pregnancy test
Updated text to address country-
specific requirements
Section 9.4.9 Vital Signs
Removed requirement that body 
temperature must be measured 
orally
Removed the word “oral” to 
generalize the way body temperature 
is measured.
Section 9.4.14.2 Serum Analysis
Appendix A Schedule of Events
Added NT-proBNP/BNP testing to 
required serum analyses.
Added guidance for 
monitoring/managing persistent 
elevation of CTnI or NT-
proBNP/BNP
Section 9.7 Discontinuation of 
Treatment With Study Drug and 
Patient Replacement
Section 10.4 Procedures for 
Reporting Drug Exposure During 
Pregnancy and Birth Events
Revised text regarding 
discontinuation of a patient who 
becomes pregnant.
Revised wording to align with other 
clinical studies within the ponatinib 
clinical program
Section 9.7 Discontinuation of 
Treatment With Study Drug and 
Patient Replacement
Clarified wording for study 
discontinuation.
To clarify permanent discontinuation 
on study drug
Section 9.10 Post-treatment Follow-
Up Assessments
Deleted incorrect text regarding 
study termination.
Deleted text was here by error as 
nothing more is collected once the 
study is terminated
Section 11.3 Cardiovascular 
Endpoint Adjudication Committee
Generalized documentation 
requirement for the cardiovascular 
endpoint adjudication committee’s 
assessment of each potential CV 
endpoint.
Removed clinical database language 
because the independent 
cardiovascular adjudication does not 
occur in the sponsor’s clinical 
database to ensure the independence 
of the committee’s decision-making
Section 13.1.5.4 Biomarkers of 
Disease Sensitivity and Resistance 
to Ponatinib and Imatinib
Added text to clarify that mutation 
analysis will be done as clinically 
needed.
Added text for clarification and 
consistency throughout protocol
Section 13.2 IA and Criteria for 
Early Termination
Added text regarding interim 
analysis to clarify timing.
Added text inserted for consistency 
and clarification
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20 October 2021
CONFIDENTIAL
Protocol Amendment 04
Summary of Changes Since the Last Version of the Approved Protocol
Sections Affected by the Change
Description of Each Change and Rationale
Location
Description
Rationale
Appendix A Schedule of Events
Section 9.4.15.1 BM Aspirate
Added text to revise BM aspirate 
schedule, and clarify collection and 
assessment procedures.
Changes made to reduce sample 
collection burden on patients and 
clarify BM aspirate collections
Appendix A Schedule of Events
Removed requirement that all 
electrocardiograms (ECGs) are to 
be signed by a local cardiologist.
Change made to reduce the burden of 
getting signature of a cardiologist
Appendix A Schedule of Events.
Added text for clarification of 
complete blood count with 
differential testing.
Added text for clarification of CBC 
and differential testing
Appendix A Schedule of Events
Clarified text for serum chemistry 
testing and total, indirect, and direct 
bilirubin testing.
Change made to clarify serum 
chemistry testing and total, direct, and 
indirect bilirubin test needed
Appendix A Schedule of Events
Revised Schedule of Events (SOE) 
footnote for single-agent therapy 
sample collection.
Revised footnotes to be consistent 
with the visit schedule
Appendix A Schedule of Events
Added text to SOE to clarify end-
of-treatment visit should occur 
within 30 days after last dose or 
discontinuation.
This change was made to clarify 
timing of the EOT visit
Appendix A Schedule of Events 
Table 2 footnotes and corresponding 
table row
Updated maintenance phase SOE 
footnote for vital signs, physical 
exams, ECGs, and patient-reported 
outcomes for consistency.
Revised footnotes to be consistent 
with the visit schedule
Appendix J Leucovorin (Folinic 
Acid) Rescue Therapy for 
Methotrexate
Updated Appendix J footnote for 
clarification of leucovorin (folinic 
acid) rescue therapy for 
methotrexate.
To clarify that sites may use 
alternative rescue therapy for 
methotrexate
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20 October 2021
CONFIDENTIAL
Rationale for Amendment 03
This section describes the changes to the protocol incorporating Amendment 03; this amendment 
applies only to South Korea. The primary reason for this amendment is to incorporate advice 
from South Korea Ministry of Health. 
Protocol Amendment 03
Summary of Changes Since the Last Version of the Approved Protocol
Sections Affected by the Change
Description of Each Change and Rationale
Location
Description
Rationale
Section 7.0 Study Population
Section 2.0 Study Summary (Study 
Design, Patient Population, Main 
Criteria for Inclusion [1])
Section 6.1 Overview of Study 
Design
Appendix A, Table 1, Footnote c.
Revised age/health status inclusion 
criterion for patients in South Korea 
only to include patients aged ≥65 
years, or aged ≥18 years with 
comorbidities and/or poor functional 
status that, after 
discussion/agreement with the 
sponsor’s medical monitor/designee, 
are considered to make the patient 
unfit for any intensive therapy.
Incorporate advice from South 
Korea Ministry of Health
Rationale for Amendment 02
This section describes the changes to the protocol incorporating Amendment 02. The primary 
reasons for this amendment are to incorporate advice from regulatory agencies including United 
States (US) Food and Drug Administration (FDA) and Spain Ministry of Health (MoH), to revise 
text to reflect inclusion of Japan in the study, and to update text based on recent updates to the 
Takeda Oncology Protocol template. Changes made based on advice from FDA include the 
addition of an endpoint to assess minimal residual disease (MRD)-negative complete remission 
(CR) at multiple intervals after the end of induction and the addition of timepoints for some other 
secondary endpoints; corresponding objectives were revised accordingly. Based on 
recommendations from Spain MoH, guidance was added regarding monitoring patients with 
evidence of prior hepatitis B infections for clinical and laboratory signs of hepatitis B virus 
reactivation or hepatitis during study treatment as well as the addition of monthly pregnancy 
testing during study treatment. Given a recent decision to implement this study in Japan, 
operational text specific to Japan has been added from the Takeda oncology protocol template. In 
addition, a posttrial access section is now included based on an update to the Takeda oncology 
template. 
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20 October 2021
CONFIDENTIAL
Protocol Amendment 02
Summary of Changes Since the Last Version of the Approved Protocol
Sections Affected by the Change
Description of Each Change and Rationale
Location
Description
Rationale
Section 4.1.1.1 Ph+ ALL
Delete inaccurate statement 
regarding incidence of Philadelphia 
chromosome–positive acute 
lymphoblastic leukemia (Ph+ ALL)
This statement was incorrect as the 
reference describes incidence of ALL, 
not Ph+ ALL; thus, the statement is 
not needed
Section 5.1.2 Secondary Objectives
Section 2.0 Study Summary
Add new secondary efficacy 
objective and add additional 
timepoints to secondary efficacy 
endpoints that have specific 
timepoints
Revise exploratory objective 
regarding biomarkers
Section 5.1.4 Exploratory Objectives
Revise exploratory objective 
regarding biomarkers
To expand exploratory objective to
include biomarkers affecting 
ponatinib efficacy or safety
Section 5.2.2.2 Other Secondary 
Endpoints
Section 2.0 Study Summary.
Section 6.1 Overview of Study 
Design.
Section 13.1.3.3 Other Secondary 
Efficacy Endpoint Assessments
Add new secondary efficacy
endpoint and add timepoints to 
secondary efficacy endpoints that 
have specific timepoints
Changes to secondary endpoints were 
made based on advice from FDA
Section 5.2.5 Exploratory Endpoints
Section 2.0 Study Summary.
Section 6.1 Overview of Study 
Design.
Section 13.1.5 Exploratory 
Endpoints
Revise exploratory endpoint 
regarding biomarkers
To expand exploratory endpoint to 
include the exploration of biomarkers 
affecting ponatinib efficacy or safety
Section 6.3.1 Duration of an 
Individual Patient’s Study
Participation
Section 2.0 Study Summary.
Section 8.1.5 Postcycle 20 Therapy.
Section 9.5 Completion of Study 
Treatment (for Individual Patients)
Add clarification to description of 
duration of individual patient 
participation
Text added for clarification of 
duration of individual patient 
participation
Section 6.3.5 Posttrial Access
Add posttrial access section
This section was added to conform to 
updates to the Takeda Oncology 
Protocol Template in compliance with 
the posttrial access initiative
Section 7.2 Exclusion Criteria
Add exclusion criterion #11 
regarding previous malignancy 
diagnosis
Revision made for guidance regarding 
exclusion based on previous 
malignancy diagnosis.
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Ponatinib
Study No. Ponatinib-3001
Page 162 of 166
Protocol Incorporating Amendment No. 10
20 October 2021
CONFIDENTIAL
Protocol Amendment 02
Summary of Changes Since the Last Version of the Approved Protocol
Sections Affected by the Change
Description of Each Change and Rationale
Location
Description
Rationale
Section 7.2 Exclusion Criteria
Revise exclusion criterion #13 
regarding patients with central 
nervous system (CNS) or 
extramedullary involvement
Revision made for clarity
Section 7.2 Exclusion Criteria
Revise exclusion criterion #16.j. 
regarding patients with pleural or 
pericardial effusions
Revision made for clarity
Table 8.a Induction Phase Treatment 
footnotes
Section 2.0 Study Summary
Table 8.b Consolidation Phase 
Treatment
Table 8.c Maintenance Phase 
Treatment
Appendix J Leucovorin (Folinic 
Acid) Rescue Therapy for 
Methotrexate
Add guidance regarding alternative 
dose modifications/schedules 
during study
To provide guidance regarding 
procedure for potential use of 
alternative dose 
modifications/schedules
Section 8.0 Study Drug
Correct error regarding number of 
cycles in maintenance phase
Correction was made for consistency 
with other sections
Table 8.c Maintenance Phase 
Treatment
Section 2.0 Study Summary
Add guidance regarding use of 
prednisolone if prednisone is not 
available
Footnote added as clarification and 
additional guidance for sites
Section 8.3.1 Mandatory Dose 
Reduction for Response
Clarify guidance regarding timing 
of dose reduction for response
Text was added as guidance for sites 
based on FDA advice
Section 8.4.1.1 Dose Reduction for 
Drug-Related AEs
Clarify guidance regarding dose 
reduction for drug-related adverse 
events (AEs)
Text was added as guidance for sites 
based on FDA advice
Section 8.4.1.2 Dose Modifications 
for AOEs and VTEs
Revise text related to dose 
modifications for arterial occlusive 
events (AOEs) and venous 
thrombotic/embolic events (VTEs)
Text was added as guidance for sites 
based on FDA advice
Section 8.5 Excluded Concomitant 
Medications and Procedures
Clarify definition of “other 
anticancer therapies” that are 
considered excluded concomitant 
medications
Text was added to clarify which 
anticancer therapies are considered 
exclusionary
Section 8.8 Management of Clinical 
Events
Section 9.4.14.2 Serum Analysis
Appendix A Schedule of Events
Add guidance regarding monitoring 
of patients with evidence of prior 
hepatitis B infection
Text added per Spain MoH advice
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Study No. Ponatinib-3001
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Protocol Incorporating Amendment No. 10
20 October 2021
CONFIDENTIAL
Protocol Amendment 02
Summary of Changes Since the Last Version of the Approved Protocol
Sections Affected by the Change
Description of Each Change and Rationale
Location
Description
Rationale
Section 8.8 Management of Clinical 
Events
Appendix A Schedule of Events, 
Table 1, footnote f and Table 2, 
footnote g
Add guidance for 
monitoring/managing any blood 
pressure (BP) elevations during 
ponatinib use
Text was added to provide guidance 
for sites in monitoring and managing
any BP elevations during ponatinib 
treatment
Section 9.4.6 Pregnancy Test
Appendix A, Table 1 and Table 2
Increase frequency of pregnancy 
testing
Add monthly pregnancy testing per
Spain MoH advice
Section 9.4.7 Physical Examination 
and ECOG Performance Status
Appendix A Schedule of Events
Replace calculation of body mass 
index (BMI) with calculation of 
body surface area (BSA) at baseline
BSA is needed for dosing some of the 
study drugs and, therefore, BMI was 
changed to BSA
Section 9.4.15.1 BM Aspirate
Add guidance regarding shipment 
of bone marrow (BM) samples
Text added as guidance/clarification 
for sites and consistency with SOE
Section 9.4.15.2 Peripheral Blood 
Samples for Molecular Response, 
CR and Exploratory Biomarker 
Assessments
Add clarification regarding 
collection and analysis of 
peripheral blood samples
Text added as guidance/clarification 
for sites
Section 10.1.4 AEs of Special 
Interest Definitions
Clarify definition of adverse events 
of special interest (AESIs)
Revisions to this section clarify the 
definition of AESIs
Section 10.1.4 AEs of Special 
Interest Definitions
Correct definition of myocardial 
infarction (MI)
MI definition was incorrect; added 
text based on source for MI definition
Section 10.1.4. AEs of Special 
Interest Definitions
Add guidance regarding sponsor 
monitoring of AESIs
Text added as guidance for sites 
regarding sponsor monitoring of 
AESIs
Section 10.2 Procedures for 
Recording and Reporting AEs and 
SAEs
Clarify guidance for reporting 
SAEs to local health authorities
The amended wording provides 
guidance and clarifies sponsor 
responsibilities for reporting of SAEs 
to local health authorities
Section 12.2.1 Japan Record 
Retention
Add section for Japan record 
retention
Text added per decision to implement 
study in Japan
Table 13.a Definitions of Efficacy 
Response Criteria
Add footnote to Table 13.a. 
Definitions of Efficacy Response 
Criteria to clarify definition of 
CNS-3
Footnote added to clarify definition of 
CNS-3
Figure 13.a Statistical Design: Alpha 
Spending Plan
Revise Figure 13.a Statistical 
Design: Alpha Spending Plan
The revision to the figure is intended 
to provide a more accurate plan for 
regulatory strategy
Section 14.2.1 Japan Protocol 
Deviations
Add section for Japan protocol 
deviations
Section added per decision to 
implement study in Japan
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Study No. Ponatinib-3001
Page 164 of 166
Protocol Incorporating Amendment No. 10
20 October 2021
CONFIDENTIAL
Protocol Amendment 02
Summary of Changes Since the Last Version of the Approved Protocol
Sections Affected by the Change
Description of Each Change and Rationale
Location
Description
Rationale
Appendix A, Table 1 and Table 2
Revisions to Schedule of Events 
table include:
a) Change in duration of windows
for specific visits
b) Increase frequency of
pregnancy testing (also see Change
20)
c) Add guidance for
monitoring/managing BP
elevations during ponatinib use
(also see Change 19)
d) Reduce frequency of Eastern
Cooperative Oncology Group
(ECOG) assessments
e) Add guidance regarding
monitoring of patients with
evidence of prior hepatitis B
infection (also see Change 18)
f)Reduce frequency of C-reactive
protein (CRP) and cardiac
troponin-I (cTnI) assessments
Increasing the duration of windows 
for visits that include certain 
assessments (BM aspirate, peripheral 
blood sample, and extramedullary 
assessments) and reducing the 
frequency of other assessments 
(ECOG, chemistry, CRP and cTnI) 
eliminates unnecessary testing and 
reduces the burden on patients and 
their families
Appendix A, Table 1. Schedule of 
Events
Revise guidance regarding eye 
examinations in the Schedule of 
Events
The SOE footnote was revised to 
provide guidance regarding the timing 
and type of eye examination(s) to be 
performed
Appendix B Investigator 
Responsibilities
Add clarification specific to Japan 
to Appendix B, Investigator 
Responsibilities
Section added per decision to 
implement study in Japan
Rationale for Amendment 01
This document describes the changes in reference to the protocol incorporating Amendment 01.
The primary reason for this amendment is to provide guidance on imatinib dose modifications 
for adverse drug reactions, guidance on the prevention and management of tumor lysis 
syndrome, and to allow patients with complete remission (CR) who have not achieved minimal 
residual disease (MRD)-negative CR at the end of induction to remain on study treatment at the 
investigator’ discretion. Additional updates include increasing the planned number of sites 
because of updated recruitment forecasts, clarifying the follow-up of patients who discontinue 
study treatment, and clarifying the requirements for patient rescreening.
Minor grammatical, editorial, formatting, and administrative changes not affecting the conduct of 
the study are included for clarification and administrative purposes only. 
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Ponatinib
Study No. Ponatinib-3001
Page 165 of 166
Protocol Incorporating Amendment No. 10
20 October 2021
CONFIDENTIAL
Changes in Amendment 1
Protocol Amendment 01
Summary of Changes Since the Last Version of the Approved Protocol
Sections Affected by the Change
Description of Each Change and Rationale
Location
Description
Rationale
Section 8.4 Dose Modification 
Guidelines for Adverse Drug 
Reactions
Section 2.0 Study Summary
Add guidance on imatinib dose 
modifications for adverse drug 
reactions
Dose modification guidelines for 
imatinib are added to help 
investigators make dosing decisions 
on the basis of safety events
Section 8.8 Management of Clinical 
Events
Add discussion of tumor lysis 
syndrome (TLS) risk factors
This information was added as TLS is 
a risk factor in this patient population
Appendix L Management of Tumor 
Lysis Syndrome
Add guidance on the prophylaxis 
and management of TLS
This information was added as TLS is 
a risk factor in this patient population
Section 6.1 Overview of Study 
Design
Section 2.0 Study Summary
Section 6.3.1 Duration of an 
Individual Patient’s Study 
Participation
Section 8.3.1 Mandatory Dose 
Reduction for Response
Section 9.4.15.1 BM Aspirate
Section 9.5 Completion of Study 
Treatment (for Individual Patients)
Section 9.10 Post-treatment Follow-
Up Assessments
Allow patients who have achieved 
CR to remain on study treatment at 
the investigator’s discretion
To clarify the possibility of further 
continuation in the study for patients 
achieving CR at the end of induction
Section 6.3.1 Duration of an 
Individual Patient’s Study
Participation
Section 2.0 Study Summary
Section 8.1.5 Postcycle 20 Therapy
Section 9.10 Post-treatment Follow-
Up Assessments
Table 2 Schedule of Events: 
Maintenance Phase, Single-Agent 
Therapy, End-of-Treatment, and 
Follow-up, footnote e
Clarify how patients discontinuing 
study treatment, including patients 
proceeding to hematopoietic stem 
cell transplant (HSCT) or 
alternative therapy, will be 
followed in the study
To clarify post-treatment data 
collection
Section 2.0 Study Summary
Section 6.2 Number of Patients
Increase number of planned sites
Revised recruitment projections 
suggested that more sites may be 
necessary
Section 2.0 Study Summary
Add a range to the number of 
patients to be randomized in each 
arm
The protocol uses an adaptive design 
that provides variable numbers of 
patients, dependent on
conditional power. The study 
summary was modified to show the 
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Ponatinib
Study No. Ponatinib-3001
Page 166 of 166
Protocol Incorporating Amendment No. 10
20 October 2021
CONFIDENTIAL
Protocol Amendment 01
Summary of Changes Since the Last Version of the Approved Protocol
Sections Affected by the Change
Description of Each Change and Rationale
Location
Description
Rationale
expected range of numbers of 
patients, rather than the expected 
maximum number of patients. The 
power calculations and study design 
were not changed.
Section 8.7 Precautions and 
Restrictions
Add guidance regarding patient 
counseling on pre-study sperm and 
egg storage
Updated per protocol template 
changes
Section 9.4.15.1 BM Aspirate
Section 9.4.15.3 Extramedullary 
Disease
Clarify tests to be conducted at 
central and local laboratories
To provide clarification regarding 
location of tests related to the CR 
component of the study
Section 10.2 Procedures for 
Recording and Reporting AEs, 
SAEs, and AESIs
Update SAE reporting process per 
updated pharmacovigilance 
procedure
Updated per protocol template 
changes with respect to updated 
pharmacovigilance procedures
Section 10.3 Monitoring of AEs and 
Period of Observation
Update language on monitoring of 
adverse events (AEs) per updated 
pharmacovigilance procedure
Updated per protocol template 
changes with respect to updated 
pharmacovigilance procedures
Section 13.1.3.3 Other Secondary 
Efficacy Endpoint Assessments
Add details on post-transplantation 
competing risk analysis
To clarify that additional competing 
risk analysis will be carried out in 
patients’ post-transplantation as a part 
of study evaluation
Section 13.4 Blinding of Trial 
Management Team for Data Review
Section 8.9 Blinding and Unblinding
Section 9.4.3 Enrollment and 
Randomization
Add description of blinding of 
study management team to study 
data
To clarify steps taken to avoid bias 
during data review
Section 8.13.1 Storage
Clarify the storage conditions for 
ponatinib and imatinib
To clarify storage conditions for study 
drug for sites globally
Section 8.10.1 Ponatinib
Section 8.1.1 Investigational 
Therapy: Ponatinib
Update information on ponatinib 
tablets
To update information on how 
ponatinib will be supplied
Section 8.10.2 Imatinib
Update information on imatinib 
tablets
To update information on how 
imatinib will be supplied
Section 9.4.1 Screening Period 
Procedures
Clarify procedures for rescreening 
of patients
To define when procedures must be 
repeated in re-screening
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ELECTRONIC SIGNATURES 
Signed by 
Meaning of Signature 
Server Date 
(dd-MMM-yyyy HH:mm ‘UTC’) 
 
 
 
090101d6811fc818
Amendment 10 to A Phase 3, Randomized, Open-label, Multicenter Study Comparing Ponatinib Versus Imatinib,
Administered in Combination With Reduced-Intensity Chemotherapy, in
Clinical Approval
29-Oct-2021 20:07 UTC
Clinical Pharmacology Approval
29-Oct-2021 21:04 UTC
Biostatistics Approval
29-Oct-2021 22:11 UTC
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